Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 1 of 39 PageID# 272 IN THE UNITED STATES DISTRICT COURT FOR THE EASTERN DISTRICT OF VIRGINIA ALEXANDRIA DIVISION _________________________________ ) AMERICAN TRADITION INSTITUTE ) ENVIRONMENTAL LAW CENTER, ) ) Plaintiff, ) ) v. ) Civil Action No. 1:12-cv-1066-AJT-TCB ) UNITED STATES ENVIRONMENTAL ) PROTECTION AGENCY, et al., ) ) Defendants. ) _________________________________ ) UNITED STATES= MEMORANDUM IN OPPOSITION TO PLAINTIFF’S MOTION FOR TEMPORARY RESTRAINING ORDER IGNACIA S. MORENO Assistant Attorney General Environment & Natural Resources Division U.S. Department of Justice CYNTHIA J. MORRIS ELIZABETH DAWSON Environmental Defense Section P.O. Box 7611 Washington, D.C. 20044 (202) 616-7554 (Morris) (202) 514-8293 (Dawson) OF COUNSEL: JOHN HANNON STEVEN SILVERMAN Office of General Counsel U.S. Environmental Protection Agency 1200 Pennsylvania Ave. NW Washington, D.C. 20460 BERNARD KIM Assistant United States Attorney Justin W. Williams U.S. Attorney's Building 2100 Jamieson Avenue Alexandria, Virginia 22314 (703) 299-3911 (direct) (703) 299-3983 (fax) bernard.kim@usdoj.gov Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 2 of 39 PageID# 273 TABLE OF CONTENTS INTRODUCTION .....................................................................................................................1 STANDARD OF REVIEW .......................................................................................................2 STATUTORY AND REGULATORY BACKGROUND .........................................................4 STATEMENT OF FACTS ........................................................................................................4 ARGUMENT ...........................................................................................................................10 I. PLAINTIFFS CANNOT ESTABLISH A LIKELIHOOD OF SUCCESS ON THE MERITS .......................................................................................................................11 A. This Court Lacks Subject Matter Jurisdiction over Plaintiff’s Claim..............11 B. EPA’s Research Complies with EPA’s Regulations and the Common Rule. .................................................................................................15 1. The participants in EPA studies were, and continue to be, fully informed of the risks posed by PM2.5. .................................................15 2. Any risks to CAPTAIN study participants are minimal. .....................19 3. The CAPTAIN study does not impose unreasonable risks in relation to the importance of the knowledge to be gained from the research..................................................................................22 4. Participants were not, and are not, exposed to risk of substantial injury. .................................................................................24 II. ATI HAS NOT ESTABLISHED THAT ITS MEMBERS WILL FACE IRREPARABLE INJURY ABSENT EXTRAORDINARY INJUNCTIVE RELIEF ............................25 III. THE BALANCE OF EQUITIES WEIGHS IN FAVOR OF EPA ..............................28 IV. DENIAL OF THE PRELIMINARY INJUNCTION IS IN THE PUBLIC INTEREST ...................................................................................................30 CONCLUSION ........................................................................................................................30 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 3 of 39 PageID# 274 TABLE OF AUTHORITIES CASES: Allen v. Wright, 468 U.S. 737 (1984) .................................................................................................................11 Batterton v. Marshall, 648 F.2d 694 (D.C. Cir. 1980) .................................................................................................14 Bd. of Gov., Fed. Reserve Sys. V. MCorp Fin., Inc., 502 U.S. 32 (1991) ...................................................................................................................15 Bender v. Williamsport Area School Dist., 475 U.S. 534 (1984) .................................................................................................................11 Bennett v. Spear, 520 U.S. 154 (1997) .............................................................................................................3, 13 Blackwelder Furniture Co. of Statesville v. Seilig Mfg. Co., Inc., 550 F.2d 189(550 F.2d 189 (4th Cir. 1977) ...........................................................................2, 3 Chalk v. U.S. Dist. Court Cent. Dist. of Cal., et al., 840 F.2d 701 (9th Cir. 1988) .............................................................................................27–28 Chaplaincy of Full Gospel Churches v. England, 454 F.3d 290 (D.C. Cir. 2006) .................................................................................................26 Citizens United v. Federal Election Comm’n, 558 U.S. 310 (2010) ...................................................................................................................2 Doran v. Salem Inn, Inc. 422 U.S. 922 (1975) .............................................................................................................2, 26 Flue-Cured Tobacco Coop. Stabilization Corp. v. EPA, 313 F.3d 852 (4th Cir 2002) ........................................................................................11, 12, 14 Hearst Radio, Inc. v. FCC, 167 F.2d 225 (D.C. Cir. 1948) .................................................................................................12 Hi-Tech Pharmacal Co., Inc. v. FDA, 587 F. Supp. 2d 1(D.D.C. 2008) ..............................................................................................26 INS v. Nat’l Ctr. For Immigrants’ Rights, Inc., 502 U.S. 183 (1991) ...................................................................................................................4 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 4 of 39 PageID# 275 Invention Submission Corp. v. Rogan, 357 F.3d 452 (4th Cir. 2004) ...................................................................................................12 Kennedy v. Sec. of Army, 191 F.3d 460 (9th Cir. 1999) ...................................................................................................27 Leedom v. Kyne, 358 U.S. 184 (1958) .................................................................................................................14 Long Term Care Partners, LLC v. United States, 516 F.3d 225 (4th Cir. 2008) .............................................................................................11, 15 Mazurek v. Armstrong, 520 U.S. 390 (1997) .............................................................................................................2, 26 Motor Vehicle Mfrs. Ass’n v. State Farm Mut. Auto. Ins. Co., 463 U.S. 29 (1983) .....................................................................................................................4 Mylan Pharms., Inc. v. Shalala, 81 F. Supp. 2d 30 (D.D.C. 2000) .............................................................................................28 National Ass’n of Homebuilders v. Norton, 298 F. Supp. 2d 68 (D.D.C. 2003) ...........................................................................................14 Power Mobility Coal. v. Leavitt, 404 F. Supp. 2d 190 (D.D.C. 2005) .........................................................................................26 Power Mobility Coal. v. Leavitt, 2005 WL 3312962 (D.D.C. Dec. 7, 2005) .................................................................................2 Real Truth About Obama, Inc. v. Federal Election Comm’n, 575 F.3d 342 (4th Cir. 2009) ...........................................................................................2, 3, 25 Real Truth About Obama, Inc. v. Federal Election Comm’n, 607 F.3d 355 (4th Cir. 2010) .....................................................................................................2 Reno v. Flores, 507 U.S. 292 (1993) ...................................................................................................................4 Sherley v. Sebelius, 644 F.3d 388 (D.C. Cir. 2011) ...................................................................................................4 University of Texas v. Camenisch, 451 U.S. 390 (1981) ...................................................................................................................2 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 5 of 39 PageID# 276 Winter v. Natural Resource Defense Council, Inc., 555 U.S. 7 (2008) ...................................................................................................................2, 3 Wisconsin Gas Co. v. FERC, 758 F.2d 669 (D.C. Cir. 1985) .................................................................................................26 Wollman v. Geren, 603 F. Supp. 2d. 879 (E.D. Va. 2009) .....................................................................................12 STATUTES: 5 U.S.C. § 301 ................................................................................................................................13 5 U.S.C. §§ 551–559, 701–706, 1305, 3105, 3344, 4301, 5335, 5362, 7521 ..................................3 5 U.S.C. § 551(13) .........................................................................................................................13 5 U.S.C. § 702 ................................................................................................................................12 5 U.S.C. § 704 ................................................................................................................................12 5 U.S.C. § 706(2)(A)........................................................................................................................4 7 U.S.C. § 136w(a)(1) ....................................................................................................................13 21 U.S.C. § 346a(e)(1)(c) ..............................................................................................................13 26 U.S.C. § 501(c)(3) .......................................................................................................................1 28 U.S.C. § 1391(b) .......................................................................................................................11 42 U.S.C. § 300v-1(b) ....................................................................................................................13 42 U.S.C. § 7403(a) .........................................................................................................................4 42 U.S.C. § 7403(a)(1) ...............................................................................................................4, 22 42 U.S.C. § 7409(b)(1) ....................................................................................................................6 REGULATIONS: 40 C.F.R. Part 26..........................................................................................................................5, 7 40 C.F.R. § 26.101 .........................................................................................................................13 40 C.F.R. § 26.102(i) .....................................................................................................................19 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 6 of 39 PageID# 277 40 C.F.R. § 26.110(b)(1) ................................................................................................................19 40 C.F.R. § 26.111 .........................................................................................................................22 40 C.F.R. § 26.111(a).......................................................................................................................7 40 C.F.R. § 26.111(a)(1) ................................................................................................................20 40 C.F.R. § 26.111(a)(2) ................................................................................................................23 40 C.F.R. § 26.116 .............................................................................................................15, 17, 19 40 C.F.R. § 26.116(a)(1) ................................................................................................................19 40 C.F.R. § 26.116(a)(2) ..........................................................................................................16, 17 40 C.F.R. § 26.116(a)(3) ................................................................................................................17 40 C.F.R. § 26.116(a)(7) ................................................................................................................19 40 C.F.R. § 26.120(a)...............................................................................................................22, 23 40 C.F.R. § 26.123 .........................................................................................................................13 40 C.F.R. § 26.1501 .......................................................................................................................13 40 C.F.R. § 26.1502 .......................................................................................................................13 40 C.F.R. § 26.1503 .......................................................................................................................13 40 C.F.R. § 26.1504 .......................................................................................................................13 40 C.F.R. § 26.1506 .......................................................................................................................13 40 C.F.R. § 26.1507 .......................................................................................................................13 40 C.F.R. § 50.13(a).........................................................................................................................1 40 C.F.R. § 50.13(c).........................................................................................................................8 FEDERAL REGISTER: 56 Fed. Reg. 28003 (June 18, 1991) ................................................................................................5 77 Fed. Reg. 38890 (June 29, 2012) ..........................................................................................6, 25 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 7 of 39 PageID# 278 LEGISLATIVE MATERIALS: Pub. L. No. 109-54 .........................................................................................................................13 MISCELLANEOUS: EPA Nat’l Exposure Research Lab., Office of Research and Dev., Scientific and Ethical Approaches for Observational Exposure Studies, EPA 600/R-08/062 (May 2008), available at http://www.epa.gov/nerl/sots/SEAOES_doc20080707.pdf. ......................................17 EPA Order 1000.17 A1 § 4(d), available at http://www.epa.gov/nerl/sots/SEAOES_doc20080707.pdf. ..........................................................24 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 8 of 39 PageID# 279 UNITED STATES= MEMORANDUM IN OPPOSITION TO PLAINTIFF’S MOTION FOR TEMPORARY RESTRAINING ORDER INTRODUCTION In its Complaint, American Tradition Institute Environmental Law Center (“ATI”) challenges the legality of the Environmental Protection Agency (“EPA”)’s controlled human exposure studies relating to fine particulate matter, or PM2.5. In its Motion for Temporary Restraining Order (“Motion”), ATI seeks to halt the continuation of the CAPTAIN study and any other EPA-conducted study involving controlled human exposure to fine particulate matter. 1 The CAPTAIN study is investigating the effects of exposure to concentrated air particles (“CAPS”), in particular, PM2.5, on healthy individuals between 50 and 75 years of age who have a genetic trait related to protection from oxidants. Declaration of Dr. James Samet (“Samet Decl.”) ¶¶ 8–9. At this time the CAPTAIN study is the only ongoing controlled human exposure study EPA is conducting that involves PM2.5. Therefore, this Opposition focuses on the facts surrounding CAPTAIN. ATI’s Motion must be denied because ATI has established no likelihood of success on the merits of the Complaint, it will suffer no irreparable harm in the absence of the injunctive relief requested, the balance of equities strongly favors continuation of the CAPTAIN study, and the public interest will not be served by delaying the CAPTAIN study. STANDARD OF REVIEW Because a “preliminary injunction is an extraordinary and drastic remedy,” Mazurek v. Armstrong, 520 U.S. 968, 972 (1997) (per curiam), whose “purpose . . . is merely to preserve the 1 Under the guise of protecting human health by halting EPA’s research, Plaintiffs seek as their ultimate relief to stay the implementation of any rules promulgated under the CAA to control PM2.5 -- the very regulations that protect human health and welfare. Complaint ¶ 116. 1 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 9 of 39 PageID# 280 relative positions of the parties until a trial on the merits can be held,” Univ. of Texas v. Camenisch, 451 U.S. 390, 395 (1981), the party seeking such an injunction must make a “clear showing” that temporary equitable relief is necessary. Mazurek, 520 U.S. at 972; see Doran v. Salem Inn, Inc., 422 U.S. 922, 931 (1975) (“stringent” showing required). The standard for granting injunctive relief was set forth by the Supreme Court in Winter v. Natural Resource Defense Council, Inc., 555 U.S. 7 (2008) and embraced by the Fourth Circuit in Real Truth About Obama, Inc. v. Federal Election Comm’n, 575 F.3d 342, 346 (4th Cir. 2009) (vacated on other grounds, in Citizens United v. Federal Election Commission, 558 U.S. 310 (2010), standard reaffirmed in Real Truth About Obama, Inc. v. Federal Election Com’n, 607 F.3d 355 (4th Cir. 2010)). A plaintiff must establish: (1) that it is likely to succeed on the merits; (2) that it is likely to suffer irreparable harm in the absence of injunctive relief; (3) that the balance of equities tips in its favor and (4) that an injunction is in the public interest. Winter, 555 U.S. at 20 (citations omitted); Real Truth About Obama, 575 F.3d at 346. The Fourth Circuit has abandoned the “balance of hardship” test of Blackwelder Furniture Co. of Statesville v. Seilig Manufacturing Co., Inc., 550 F.2d 189 (4th Cir. 1977), which is relied upon by Plaintiff. Motion at 6. Blackwelder held that “the likelihood of success requirement [need] be considered, if at all, only after a balancing of hardships is conducted, and then only under the relaxed standard of showing that ‘grave or serious questions are presented’ for litigation.” Real Truth About Obama, 575 F.3d at 346, quoting Blackwelder, 550 F.2d at 195-96 (emphasis in original). The Winter standard is much stricter. Plaintiffs must now establish each element independently and, regardless of the balance of hardships, it is no longer sufficient to demonstrate a “grave or serious question” regarding the merits. A plaintiff must 2 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 10 of 39 PageID# 281 now make a “clear showing that it will likely succeed on the merits.” Real Truth About Obama, 575 F.3d at 346, citing Winter, 555 U.S. at 22. In assessing whether Plaintiff has established a likelihood of success on the merits, this Court must determine whether it has jurisdiction to consider the claims asserted in the Complaint. 2 Because the claims are asserted under the Administrative Procedure Act (“APA”), 5 U.S.C. § 551, et. seq. Plaintiff must identify a final agency action that is subject to judicial review. Bennett v. Spear 520 U.S. 154 (1997). If this Court finds that there is a final agency action subject to judicial review, it must apply the applicable standard of review for administrative action, and EPA’s action must be upheld unless it is found to be “arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with law.” 5 U.S.C. § 706(2)(A). The court may not substitute its judgment for that of the agency, but must instead affirm the agency’s action so long as the agency has considered the relevant factors and articulated a “‘rational connection between the facts found and the choice made.’” Motor Vehicle Mfrs. Ass’n v. State Farm Mut. Auto. Ins. Co., 463 U.S. 29, 43 (1983) (citation omitted). In the case of a facial challenge to a final agency action, it is not enough to show that the agency action may be invalid in some cases. See INS v. Nat’l Ctr. for Immigrants’ Rights, Inc., 502 U.S. 183, 188 (1991). Rather, Plaintiff has the burden of establishing that “no set of 2 In addition to determining jurisdiction, the court must also determine whether venue is proper in this Court. Venue would rest more appropriately in the District of Columbia, where EPA resides, or in North Carolina, where the challenged activity is taking place. 28 U.S.C. § 1391(b). The Court must also determine whether Plaintiff has standing to assert the claims. If this Court concludes that this is an improper venue or that Plaintiff lacks standing, then Plaintiff cannot succeed on the merits and the motion must be denied. The United States is not briefing those issues in opposition to the Motion for Temporary Restraining Order, but reserves the right to raise and fully brief these issues in a subsequent motion. 3 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 11 of 39 PageID# 282 circumstances exists under which the agency action would be valid.” Reno v. Flores, 507 U.S. 292, 301 (1993) (citation omitted); accord Sherley v. Sebelius, 644 F.3d 388, 397 (D.C. Cir. 2011). STATUTORY AND REGULATORY BACKGROUND The Clean Air Act (“CAA”) requires EPA to “establish a national research and development program for the prevention and control of air pollution” including “experiments, demonstrations . . . and studies relating to the causes, effects (including health and welfare effects), extent, prevention, and control of air pollution.” 42 U.S.C. §§ 7403(a), 7403(a)(1). 3 To implement this statutory mandate, EPA conducts controlled human exposure testing to evaluate important and legitimate research objectives. EPA conducts its controlled human exposure studies in accordance with the requirements of the “Common Rule.” The Common Rule is a set of regulations promulgated by EPA, along with fourteen other federal departments and agencies, to govern the ethical and scientific conduct of research with human subjects conducted or supported by those federal departments or agencies. See Federal Policy for the Protection of Human Subjects, 56 Fed. Reg. 28003 (June 18, 1991). EPA has codified the Common Rule in its regulations at 40 C.F.R. Part 26. STATEMENT OF FACTS EPA, along with 14 other federal departments and agencies as well as numerous research institutions both domestic and foreign (including the University of Michigan, University of Washington, University of Rochester, the University of Southern California, and Rutgers), conduct or support research involving human participants. Controlled human exposures studies 3 It is this statutory authority that governs EPA’s research, not descriptions of such research in budgetary line-items, as ATI erroneously suggests. Motion at 11. 4 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 12 of 39 PageID# 283 have been conducted for decades on important air pollutants such as ozone, particulate matter (PM) 4, nitrogen dioxide (NO2), sulfur dioxide (SO2), and carbon monoxide (CO). Devlin Decl ¶¶ 8,9,10. The National Research Council of the National Academy of Science has recognized that controlled human exposure studies provide an opportunity to gain valuable scientific insights in the health effects of particulate matter. Devlin Decl. ¶ 8. Most of the controlled human exposure studies involving exposure to PM are in fact conducted by research institutions other than EPA. Declaration of Wayne Cascio (“Cascio Decl.”) ¶ 11. This research has provided valuable information to help characterize and control risks to public health. See id. Exh. 1. These studies help to determine whether the mathematical associations between ambient (outdoor) levels of air pollutants and health effects seen in large-scale epidemiological studies are biologically plausible (or are not). They help to determine the mechanisms by which air pollutants cause adverse effects, whether certain people are more or less susceptible to exposure to air pollutants, and (for PM2.5) whether certain chemical types are responsible (or not) for adverse effects. Controlled human exposures studies have been conducted for decades on important air pollutants such as ozone, particulate matter, nitrogen dioxide (NO2), sulfur dioxide (SO2), and carbon monoxide (CO). Devlin Decl. ¶¶ 8–10. 4 The term “particulate matter” (PM) covers a broad class of discrete, but chemically and physically diverse, particles in the ambient air. There are two generally different modes of PM – fine and coarse. Fine particles derive from combustion by-products or from gases (such as sulfur oxides and nitrogen oxides) that react and transform in the atmosphere after being emitted. PM2.5 is roughly synonymous with fine PM, and generally includes all particulate matter with an aerodynamic diameter of 2.5 micrometers or less. 40 C.F.R. § 50.13(a). Principal sources of PM2.5 are fossil fuel combustion, including motor vehicle and power plant emissions, natural and anthropogenic biomass burning, as well as other industrial processes such as smelting. Declaration of Robert Devlin (“Devlin Decl.”) ¶ 4. 5 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 13 of 39 PageID# 284 This controlled exposure research provides information that cannot be obtained from large-scale epidemiological studies. Epidemiological studies, the primary tool in the discovery of risks to public health presented by ambient PM2.5, typically use data from large populations of people with varying susceptibility to PM2.5. They evaluate the relationship between changes in ambient levels of PM2.5 and changes in health effects. However epidemiological studies do not generally provide direct evidence of causation; instead they indicate the existence or absence of a statistical relationship. Large population studies cannot assess the biological mechanisms that could explain how inhaling ambient air pollution particles can cause illness or death in susceptible individuals. Devlin Decl. ¶¶ 6,7,8. For PM2.5, the epidemiological studies indicate that when very large numbers of people are exposed, as occurs in major population centers, the overall risk to the public is large enough to present a serious public health problem in the form of increased mortality and morbidity. The studies also indicate that the risk of serious health effects from exposure to typical levels of PM2.5 is largely focused on people with preexisting illnesses, such as people with cardiovascular diseases or respiratory illnesses. See 77 Fed. Reg. 38890, 38906-911 (June 29, 2012). It is this serious risk to the overall public health that leads EPA to describe PM as a serious public health problem. Devlin Decl. ¶¶ 12–14. Controlled human exposure studies are used to help answer the questions these epidemiological studies do not answer: Why does PM2.5 have this effect? What are the biological mechanisms that lead to this result? Answers to these questions assist in finding causes and treatments for PM-related health effects, and inform EPA’s judgment in carrying out its statutory responsibility to establish national ambient air quality standards (NAAQS), which protect the public. 42 U.S.C. § 7409(b)(1). 6 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 14 of 39 PageID# 285 EPA’s National Health and Environmental Research Laboratory (NHEERL), which conducts CAPTAIN and other controlled human exposure studies, only conducts a human exposure study if there is prior data from one or more of the following types of research: testing in laboratory animals, observational research involving only naturally-occurring human exposures, or human studies involving a closely related air pollutant, and only if the biological effects to study participants will be mild, temporary, and reversible. Devlin Decl. ¶ 11. EPA’s regulations implementing the Common Rule require, among other elements, informed consent of study participants, approval of the proposed research by a special review body, minimization of risk to study participants, and a reasonable relationship between risks (if any), benefits, and the importance of the knowledge that may reasonably be expected to result. 40 C.F.R. § 26.111(a). In addition to the required approval by an Institutional Review Board (“IRB”), EPA has a rigorous internal approval process that further ensures the integrity of the proposed research. See Samet Decl. Section II. The CAPTAIN study seeks to obtain information regarding the effects of exposure to PM2.5 on 50-75 year-old healthy individuals who have a genetic trait that precludes them from making a specific protein involved in protection from oxidants (GSTM1).5 This genetic trait is present in approximately 40% of the population. Samet Decl. ¶ 5. Under the CAPTAIN study protocol, study volunteers are exposed to concentrated PM2.5 from the ambient air in Chapel Hill, North Carolina. Samet Decl. ¶ 26. Hence, this type of study is often referred to as a Concentrated Air Particle Study, or “CAPS.” The level of 5 While this trait results in a different biological response to PM2.5, there is no evidence that it increases the risk of an adverse cardiovascular effect. Prior studies involving exposure of people with this trait to concentrated PM2.5 demonstrate no adverse effects. Samet Decl. ¶ 9. 7 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 15 of 39 PageID# 286 exposure experienced thus far by the 6 volunteers who have participated in CAPTAIN is well within expected exposure levels in their normal day-to-day life. The average dose of PM received by these subjects is equivalent to experiencing a concentration of 19.85 ug/m3 (micrograms per cubic meter of air) over a 24 hour period. Samet Decl. ¶ 11. This is well below the level of the 24-hour average National Ambient Air Quality Standard for PM2.5 of 35 ug/m3 (micrograms per cubic meter of air). 40 C.F.R. § 50.13(c). 6 In evaluating the risk to research volunteers, it must be recognized that the risk to an individual is very different from the overall public health risk associated with exposures of large populations of people to typical ambient air levels of PM2.5. This is especially the case if the individual does not have the health conditions most at risk, such as a preexisting cardiovascular or respiratory illness. While small risks to individuals may evidence themselves as much larger overall public health risks when large populations are exposed to ambient levels of PM2.5, this does not change the fact that the risk for individuals that do not exhibit these health conditions will be small. Devlin Decl. ¶ 15. Given the expected levels of exposure in the study, the generally low annual and 24-hour levels experienced on a day-to-day basis in Chapel Hill, the good health of the participants and their absence of evidence of cardiovascular or respiratory disease, the expert judgment of the EPA was that the risk to an individual participant in the CAPTAIN study is very small. Samet Decl. ¶ 12. The IRB and the internal EPA review process reached the same conclusions. Samet 6 The NAAQS for PM2.5 includes both an annual average standard and a 24-hour average standard. The 24-hour standard is for the 98th percentile of days, meaning that approximately 7 or 8 days a year could be above 35 ug/m3. The air quality in Chapel Hill, NC, the location of the CAPTAIN study, is well within levels that attain the annual and 24-hour NAAQS for PM2.5. Devlin Decl. ¶ 16, n.2. 8 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 16 of 39 PageID# 287 Decl. Exhs. 4, 5. This is fully consistent with EPA’s view that the risks to society as a whole are much larger and more serious when large populations of people, including those with preexisting illnesses, are exposed to high ambient levels of PM. Devlin Decl. ¶ 14. Nevertheless, studies involving human exposure entail some risk, even if it is small. Because exposure to PM2.5 is not free of risk, EPA carefully screens the people who apply for the CAPTAIN study to assure that they are healthy and not the type of susceptible individual who could be at greater risk from short-term exposure to PM2.5.7 EPA thoroughly informs participants of the risks associated with their participation. EPA does so both with a written consent form and during extensive oral interviews with each potential study participant. See, e.g., Samet Decl. ¶ 26. Researchers inform potential participants that they will be exposed to fine particulate matter, how that will occur, and what tests will be performed to gauge their biological reactions. They are also made aware that there is a possibility of airway irritation, cough, shortness of breath, wheezing, and other potential temporary irritations. They are told that everyone is exposed to PM in daily life and that exposure has been associated with increased illness and death. Samet Decl. ¶¶ 20–30; Declaration of Haiyan Tong (“Tong Decl.”) ¶¶ 5–11; Declaration of Martin Case (“Case Decl.”) ¶¶ 5–15. Researchers also explain to participants the rationale for the CAPTAIN study, and it is made clear that the benefit of the study is not to the individual participant, but rather to society as a whole. Each participant receives monetary compensation and a medical examination. Participants are given ample opportunity to ask 7 People with a history of angina, cardiac arrhythmias, ischemic myocardial infarction, or coronary bypass surgery are excluded. Also excluded are people using pacemakers, suffering from uncontrolled hypertension, or with a history of bleeding diathesis. Likewise, people with illnesses such as diabetes and cancer may not participate. Samet Decl. ¶ 8. 9 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 17 of 39 PageID# 288 questions about all of this during the interview process, and they can end their participation in the study at any time. Samet Decl. ¶¶ 20–22, 27–29. During the exposure, participants are continuously monitored by electrocardiography (ECG) and pulse oximetry (measuring the amount of oxygen in the blood). Blood pressure is also monitored at intervals throughout the exposure. If at any time a rapid change in symptoms or other cause for concern to the participant or researcher were to occur, the exposure would cease. The participant’s ECG is also monitored for 20 hours following the exposure, and there is a follow-up appointment with a nurse the next day. Samet Decl. ¶¶ 14–16. EPA takes its responsibility for the safety of participants very seriously. EPA has conducted 297 controlled human exposures to PM with only one clinically significant event, in which the study participant experienced no harm or injury. 8 These studies are an integral part of EPA’s effort to understand the effects of particulate air pollution on human health, and support its statutory mandate to protect human health and the environment. ARGUMENT Plaintiff is not entitled to the injunctive relief requested because it cannot establish a likelihood of success on the merits. As explained below, Plaintiff has no likelihood of success on the merits because (1) the court lacks jurisdiction over the Complaint because Plaintiff has not 8 In one case a research volunteer was exposed to concentrated ambient particulate matter and during the exposure the normal heart rhythm converted to atrial fibrillation. The subject was not aware of the change in the rhythm, and was completely free of any symptoms. However, because atrial fibrillation persisting for more than 24 hours can be associated with an increased risk for stroke, she was transferred to the University of North Carolina Hospital for monitoring, assessment of the rhythm, and further evaluation and medical management. Even though the rhythm returned to normal prior to transfer, and persisted for much shorter than 24 hours, it was judged prudent to transfer her for further monitoring as a precautionary matter. At no time was the research volunteer's health in danger. Samet Decl. ¶ 19. 10 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 18 of 39 PageID# 289 identified any final agency action subject to judicial review under the APA; and (2) even if Plaintiff could identify a final agency action subject to judicial review, Plaintiff’s claims are demonstrably false, as EPA’s human testing is conducted safely and in full compliance with all applicable requirements. Because Plaintiffs cannot establish a likelihood of success on the merits, the Court need not consider the remaining elements for injunctive relief. To the extent the Court examines the remaining elements required for the grant of injunctive relief, Plaintiff’s request must fail because Plaintiff has identified no irreparable harm. Plaintiff’s request must also fail because an injunction is not in the public interest. The public interest is served by the significant societal benefits provided by these studies and no legitimate interest would be served by unnecessarily delaying the studies. These elements of Plaintiff’s claim for injunctive relief are discussed more fully below. I. PLAINTIFF CANNOT ESTABLISH A LIKELIHOOD OF SUCCESS ON THE MERITS. ATI is not likely to succeed on the merits of its claim because ATI has identified no agency action which is subject to judicial review under the APA. For that reason alone, this Court should deny the relief requested. However, should the Court decide to consider the merits of the claim, ATI cannot prevail because EPA is conducting its research in full compliance with all regulatory requirements. A. This Court Lacks Subject Matter Jurisdiction over Plaintiff’s Claim. 9 9 It also appears that Plaintiff lacks standing. While this is also a defect in subject matter jurisdiction, Bender v. Williamsport Area School Dist., 475 U.S. 534, 541 (1986) (standing defect is defect in court’s subject matter jurisdiction); Allen v. Wright, 468 U.S. 737, 750 (1984) (standing is a jurisdictional argument for which courts have courts have independent obligation to ensure compliance), we are limiting our argument here to final agency action because, in the (continued on the next page . . . ) 11 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 19 of 39 PageID# 290 This Court lacks subject matter jurisdiction because ATI has failed to identify a final agency action that is subject to judicial review under the APA. Flue-Cured Tobacco Coop. Stabilization Corp. v. EPA, 313 F.3d 852, 857 (4th Cir. 2002) (lack of final agency action is a lack of subject matter jurisdiction). The APA “does not provide judicial review for everything done by an administrative agency.” Invention Submission Corp. v. Rogan, 357 F.3d 452, 459 (4th Cir. 2004) (quoting Hearst Radio, Inc. v. FCC, 167 F.2d 225, 227 (D.C. Cir. 1948) (ruling that an advertising campaign undertaken by an agency was not reviewable under the APA)). The party asserting jurisdiction under the APA has the burden to demonstrate such jurisdiction. Wollman v. Geren, 603 F. Supp. 2d 879, 883 (E.D. Va. 2009). For a litigant to bring suit under the APA, it must identify either an “agency action” “made reviewable by statute” or a “final agency action for which there is no other adequate remedy in a court.” 5 U.S.C. §§ 702, 704. The APA defines “agency action” as “the whole or part of an agency rule, order, license, sanction, relief, or the equivalent or denial thereof, or failure to act.” 5 U.S.C. § 551(13). Plaintiff has identified no agency action—much less an agency action made reviewable by statute or a final agency action otherwise without remedy—that is reviewable under the APA. Plaintiff alleges that EPA is improperly conducting research using human participants. However, Plaintiff does not allege that these studies constitute a rule, an order, a license, a sanction, a form of relief, or a failure to act. The studies challenged by Plaintiff essentially constitute the collection of data — there is no agency action, as defined by the APA, associated Fourth Circuit, “analysis of whether a case presents ‘final agency action’ should precede a standing inquiry.” Long Term Care Partners, LLC v. United States, 516 F.3d 225, 231 (4th Cir. 2008) (citing Flue-Cured Tobacco, 313 F.3d at 857). However, we reserve the right to challenge standing in a later motion if the Court should find that there is a final agency action subject to judicial review. 12 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 20 of 39 PageID# 291 with them. While the studies may at some point be relied upon for support of an agency rulemaking, Plaintiff has identified no such rule or other agency action. Until the challenged data is used pursuant to EPA’s rulemaking authority, there is no final agency action that is subject to judicial review. Even if this Court were to find that EPA’s decision to conduct controlled human exposure studies constituted an “agency action” within the meaning of the APA, neither the statute nor the regulations governing the research provide a right to judicial review of EPA’s decision to undertake such studies, as 5 U.S.C. § 704 requires. The regulations were promulgated pursuant to 5 U.S.C. § 301, 7 U.S.C. § 136w(a)(1), 21 U.S.C. § 346a(e)(1)(C), Pub. L. No. 109-54 § 201, or 42 U.S.C. § 300v-1(b). See, e.g., 40 C.F.R. § 26.101. These statutes provide no right of judicial review. The regulations ATI alleges EPA is violating do not create rights for private entities to challenge any research involving human subjects. The only enforcement provisions contained within the relevant regulations exist at 40 C.F.R. § 26.123 and §§ 26.1501–07; they do not allow for private litigants to enforce the regulations. ATI identifies no provision of the regulations it cites that would allow it as a private party to challenge a particular study. While the challenged regulations would have been subject to judicial review when promulgated, the time for that challenge has long passed. Without a statute providing a right of review, Plaintiff must show that there is a “final agency action for which there is no other adequate remedy in a court.” 10 To be “final,” an 10 ATI has not established that there is no adequate remedy in court for participants in a study who allege that they have suffered injury as a result of participating in EPA’s research. In fact, the Consent form for the CAPTAIN study provides that participants may have a claim under the Federal Tort Claims Act. Samet Decl. Exh. 6 at 8. 13 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 21 of 39 PageID# 292 agency action must mark the “consummation of the agency’s decisionmaking process,” and it must be an action that determines rights or obligations or from which legal consequences flow. Bennett, 520 U.S. at 156 (citations omitted). There is no consummation of a decisionmaking process here—EPA is merely undertaking studies which may later inform final agency actions, e.g., rulemakings. In National Association of Homebuilders v. Norton the court found that the U.S. Fish and Wildlife Service’s formulation of survey protocols relating to an endangered species marked the consummation of its decisionmaking process (notably, not the implementation of the protocol, but the adoption of the final protocol itself), yet the action was nonetheless not a “final agency action” because no legal rights or duties flowed from that determination. 11 298 F. Supp. 2d 68, 78–79 (D.D.C. 2003). Similarly here, even if the Court were to find that the decision to undertake a particular study represented the consummation of EPA’s decisionmaking process, no legal rights or duties flow from the decision. Agency action which carries no “direct and appreciable legal consequences” is not reviewable under the APA. Flue-Cured Tobacco, 313 F.3d at 859 (citing Bennett, 520 U.S. at 178). In Flue-Cured Tobacco, plaintiffs challenged EPA’s publication of a report concerning the health hazards of secondhand tobacco smoke. Id. at 854. In finding that there was no final agency action, the Fourth Circuit pointed out that the report had no “legally binding authority” on the plaintiffs. Id. at 859. Significantly, the court found that “even when agency action significantly impacts the choices available to the final decisionmaker, this distinction does not transform the challenged action into reviewable agency action under the APA.” Id. at 860. 11 This is not a case similar to Batterton v. Marshall, where the court found a scientific methodology to be a “rule” because a statute made it the “critical factor in an otherwise inflexible” formula for allocating funds. 648 F.2d 694, 705 (D.C. Cir. 1980). 14 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 22 of 39 PageID# 293 Similarly here, EPA’s studies may one day be used to inform its rulemakings, which are final agency actions reviewable under the APA. The studies themselves, however, are not. In sum, Plaintiff has not identified any final agency action reviewable under the APA. Because this Court therefore does not have jurisdiction to consider the merits of the claim asserted, ATI has no likelihood of success on the merits of its APA claim. B. EPA’s Research Complies with EPA’s Regulations and the Common Rule. Should the Court find jurisdiction and proceed to consider the merits, ATI is not likely to succeed on its claim that EPA’s PM2.5 studies do not conform to the Common Rule. 12 EPA’s regulations implementing the Common Rule provide a detailed structure governing controlled human exposure research, with multiple levels of oversight, and EPA is fully compliant with these regulations. Furthermore, with respect to the present Motion, ATI has presented no evidence to support its factual assertions regarding the CAPTAIN study. As established in the Declarations submitted herewith, those factual assertions are demonstrably false, and EPA’s CAPTAIN study is in full compliance with the Common Rule and EPA’s regulations. 1. The participants in EPA studies were, and continue to be, fully informed of the risks posed by PM2.5. EPA’s regulations implementing the Common Rule require that all human participants of research studies provide their informed consent. 40 C.F.R. § 26.116. The informed consent regulations require that participants be informed of “any reasonably foreseeable risks or discomforts to the subject” that may result from participation in the study, 40 C.F.R. § 12 Although Plaintiff challenges several prior studies conducted by EPA as violating the Common Rule, the Motion for Temporary Restraining Order is limited to the CAPTAIN study, as that is the only study currently ongoing. 15 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 23 of 39 PageID# 294 26.116(a)(2) (emphasis added). The regulations do not require a description of the more generalized risks to the public at large posed by the subject matter of the study. Indeed, as explained above with respect to PM2.5, the risks to a healthy individual from a time-limited, though concentrated, exposure are wholly distinct from the larger societal risks, which include especially vulnerable populations. ATI asserts in its motion that EPA is violating the consent requirements of the Common Rule with respect to the CAPTAIN study. Motion at 5–6. However, ATI relies entirely on consent forms that do not relate to that study. 13 ATI Complaint Exhs. 1 (ECF 1-5), 2, (ECF 1-6) and 3 (ECF 1-7). Furthermore, ATI Complaint Exhibits 9–12 (ECF 1-13–1-16) are labeled as the “CAPTAIN IRB Application,” but are not the application for the CAPTAIN study and make no reference to the CAPTAIN study that even suggests it is related. The actual CAPTAIN IRB application and consent form are submitted as Exhibits 1 and 6 to the Declaration of Dr. Samet, respectively. While the utter lack of evidence presented regarding the CAPTAIN study alone should cause the Court to disregard ATI’s claim, EPA can unequivocally demonstrate that the CAPTAIN study is proceeding in accordance with its regulations. EPA obtained approval to conduct the CAPTAIN study from the IRB, Samet Decl. Exh. 4, and obtained valid informed consent from each participant. 13 In addition to the fact that the consent forms relied upon by ATI are not relevant to its Motion seeking to enjoin the CAPTAIN study, its assertion that those consent forms do not describe the risk of “cancer or the toxic effects of typical engine exhausts such as nitrogen oxides, sulfur dioxide, carbon monoxide, and heavy metals” is irrelevant. None of the studies to which those consent forms apply involve exposure of participants to “engine exhausts,” but rather to concentrated particulate matter from the ambient air in Chapel Hill. ATI Complaint Exhs. 1 (ECF 1-5) at 6, 2 (ECF 1-6) at 5, 3 (ECF 1-7) at 1. The CAPTAIN study similarly only involves concentrated particles from the ambient air in Chapel Hill, Samet Decl. Exh. 6 at 5, so this reference is completely unrelated to the subject of the Motion. 16 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 24 of 39 PageID# 295 40 C.F.R. § 26.116 sets out the requirements for informed consent for participants involved in human research studies. Basic requirements relevant here are that investigators provide an explanation of the purposes of the research, a description of any reasonably foreseeable risks or discomforts to a study participant, and a description of any benefits to the subject or to others reasonably to be expected from the research. 40 C.F.R. § 26.116(a)(1)-(3). EPA’s procedures for CAPTAIN (and its other studies) more than satisfy these requirements. CAPTAIN study prospective participants are given a written consent form and, in addition, participate in an oral interview with a researcher. This oral interview is important because “[p]articipants often find discussions with research staff more useful than written consent forms.” EPA Nat’l Exposure Research Lab., Office of Research and Dev., Scientific and Ethical Approaches for Observational Exposure Studies, EPA 600/R-08/062 at 53 (May 2008), available at http://www.epa.gov/nerl/sots/SEAOES_doc20080707.pdf (last visited October 2, 2012). Researchers inform participants about what they will be exposed to -- ambient air from Chapel Hill in which PM2.5 is concentrated for a period of two hours -- and what they may feel during the exposure. Samet Decl. ¶ 26. Specifically, the consent form states: During the exposure to the concentrated air pollution particles, you may experience some minor degree of airway irritation, cough, and shortness of breath or wheezing. These symptoms typically disappear 2 to 4 hours after exposure, but may last longer for particularly sensitive people…Air pollution particles may induce an inflammatory reaction that can last for 24 hours after exposure and may increase the chance of you catching a cold. Samet Decl. Exh. 6 at 7-8. Participants are informed that “the amount of particles [they] will [be] exposed to is less than what [they] would likely encounter over 24 hours on a smoggy day in an urban area.” Id. at 5. The consent form also explains the potential risks and discomforts which may result from performing breathing tests, having blood drawn, and experiencing heart 17 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 25 of 39 PageID# 296 monitoring, blood pressure monitoring, and brachial artery ultrasound. Id. at 7. Participants are also told how the study will be conducted, and what biological monitoring will be done before, during and after the test. Samet Decl. ¶¶ 23–26. Although the regulations do not require an explanation of the larger societal risks associated with PM2.5, participants are told that everyone is exposed to PM continuously in daily life and that such exposure has been associated with increased illness and death. Samet Decl. ¶ 26; Tong Decl. ¶ 6; Case Decl. ¶ 4. Researchers also explain to participants the rationale for the study. Specifically, the informed consent form states that “[t]he purpose of this research study is to determine if a component of ambient air pollution to which we are all exposed, particulate matter (PM), elevates the risks of cardiac changes and to investigate the role of a common genetic polymorphism (GSTM1) in these effects.” Samet Decl. Exh. 6 at 1. The consent form further explains: Results from this study may increase the understanding of how gaseous and particulate air pollutants (which cause the haze seen in some polluted cities) may adversely affect the functioning of the human cardiovascular (heart and blood vessels) and respiratory (lung) systems. This understanding may be especially important for patients with cardiopulmonary diseases. Id. The consent form makes clear that the benefit of the study is not to the individual participant, but rather to society as a whole. Participants are given ample opportunity to ask questions about all of this during the interview process, and they can end their participation at any time. Samet Decl. ¶¶ 27–29. This process fully and fairly satisfies the requirements for informed consent in 40 C.F.R. § 26.116. ATI has not and cannot demonstrate that EPA’s informed consent procedures are deficient. 18 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 26 of 39 PageID# 297 2. Any risks to CAPTAIN study participants are minimal. The participants in the CAPTAIN study are not exposed to more than minimal risk. 14 “Minimal risk” is defined as “the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.” 40 C.F.R. § 26.102(i). As explained above, CAPTAIN study participants are exposed to PM2.5 (air particles) drawn from the air surrounding the test building in Chapel Hill, North Carolina. On a mass dose basis, particle concentrations “will not exceed an exposure an individual receives over a 24 hour period while visiting a typical urban center in America on a smoggy day.” Samet Decl. Exh. 1 at 13, 16. Under the study protocol, the concentration of inhaled particle mass to which participants are exposed cannot exceed 600 ug/m3 for more than a few minutes during a two hour period. Id. at 13. Exposure will be terminated within 6 minutes if concentrations exceed 600 ug/m3. Id. In fact, study participants are exposed to far lower concentrations than authorized by the study protocol, which calls for dilution of air entering the study chamber when the concentration of particles is measured at 500 ug/m3 in any two minute average. Samet Decl. 14 While EPA’s studies do not expose participants to more than minimal risk, ATI is wrong in stating that the Common Rule and EPA regulations prohibit such exposure. Motion at 8. In fact, the regulations expressly contemplate that some controlled human exposure studies may subject participants to more than minimal risk. “For research involving more than minimal risk” participants must receive “an explanation as to whether any compensation” or “medical treatments are available if injury occurs,” along with the other requirements of informed consent. 40 C.F.R. § 26.116(a)(7). While the IRB must ensure, when reviewing a research proposal, that “[r]isks to subjects are minimized,” id. § 26.111(a)(1), it is only when a study seeks expedited review that the IRB must insure that the proposed research must “involve no more than minimal risk.” 40 C.F.R. § 26.110(b)(1). ATI’s characterization of EPA’s regulations is thus inaccurate, as are the conclusions ATI draws from this mischaracterization. In any even, the risks to participants in the CAPTAIN study are minimal. 19 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 27 of 39 PageID# 298 ¶ 11, Exh. 2. As a result, the PM2.5 concentrations to which the CAPTAIN participants have been exposed are well within expected exposure levels in their normal day-to-day life. The average dose of PM received by these subjects is 238.25 ug/m3. This concentration is equivalent to experiencing a concentration of 19.85 ug/m3 over a 24 hour period, far less than the level of the 24-hour PM2.5 NAAQS (35 ug/m3). Samet Decl. ¶, Exh. 3. 15 Although the possibility of adverse effects can never be completely ruled out, the risk posed to participants from exposure to PM2.5 in the CAPTAIN study “is very small.” While there is a risk of a serious impact on public health when a large population (tens of millions) containing people with significant risk factors such as cardiovascular disease is exposed to elevated ambient levels of PM2.5, the risk of a serious effect to any one person exposed to PM2.5 concentrations for a period of two hours under the controlled conditions of the CAPTAIN study is very small, especially since EPA excludes participants from the CAPTAIN study – or any controlled human exposure study of PM2.5 -- who have significant risk factors for experiencing adverse effects to PM2.5. Samet Decl. ¶ 12. Prospective participants in the CAPTAIN study are given a physical examination prior to being approved for participation, and are not accepted if they have a history of cardiac abnormalities or diseases or illnesses such as diabetes and cancer. Id. ¶ 8. To further assure participant safety, participants are monitored continuously by closedcircuit camera by trained EPA personnel stationed immediately outside the exposure facility while undergoing exposure to concentrated PM2.5, and a licensed physician is available at all 15 The dose of PM 2.5 to participant in the other EPA PM2.5 controlled human exposure studies low, averaging 120 ug/m3 over 2 hours. Samet Decl. ¶ 18. Over a 24-hour period this is equivalent to experiencing a concentration of 10 ug/m3, again far less than the 24-hour NAAQS. 20 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 28 of 39 PageID# 299 times to respond to any emergency. “Biomarkers” such as heart rate, bold oxygen, and blood pressure, are monitored either continuously or at regular intervals. In the event of “any rapid change in symptoms, tachycardia and/or arrthythmia, decline in arterial oxygen saturation, or any distress of concern to the volunteer or the console operator” exposure is terminated. Samet Decl. ¶ 14. Study researchers carefully monitor the symptoms, if any, that participants may experience either during or immediately after exposure to concentrated PM2.5. Possible symptoms, if any, from these two hour exposures include “chest pain, mild dyspnea [shortness of breath], headache, cough, and wheeze.” Id. ¶ 15. None of the CAPTAIN study participants, nor any participant enrolled in previous concentrated PM2.5 studies -- consisting of 297 exposures over a 15 year period -- has reported any of these symptoms. Id. 16 EPA’s National Health and Environmental Research Laboratory (NHEERL), which conducts CAPTAIN and other controlled human exposure studies, only conducts a human exposure study if biological effects will be mild, temporary and reversible, and if data already exists from animal testing, observational research, or studies of a related pollutant. Devlin Decl. ¶ 11. Potential risks to study participants are considered in the review process along with an array of sensitive health indicators. Given the expected levels of exposures in the study, the generally low annual and 24hour levels experienced on a day-to-day basis in Chapel Hill, NC, the good health of the participants, and the expert monitoring of biological functions, the risk to an individual participant is very small. 16 In the sole clinically significant event in these 297 controlled human exposures, at no time was the research volunteer's health in danger. The research volunteer experienced no harm or injury. Samet Decl. ¶ 19. 21 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 29 of 39 PageID# 300 EPA submitted all of this information to the IRB as part of the application required by the Common Rule. 40 C.F.R. § 26.111. Based on the information presented in the application, the UNC Chapel Hill School of Medicine IRB approved the CAPTAIN study. The IRB specifically found that “[t]his research involves no more than minimal risk.” Samet Decl. Exh. 4. Although not required by the Common Rule, EPA conducted a further multi-level intraagency review, culminating in the expert finding by EPA’s Human Subjects Research Review Official that the CAPTAIN study met all requirements of EPA’s Common Rule regulations. Samet Decl. Exh. 5. Plaintiffs have provided no reason whatsoever for this Court to question or doubt the expert judgment of EPA investigators, the University of North Carolina IRB, and EPA’s Human Subject Research Review official that the CAPTAIN study poses minimal risk to study participants, and otherwise satisfies the Common Rule. 3. The CAPTAIN study does not impose unreasonable risks in relation to the importance of the knowledge to be gained from the research. When conducting investigations pursuant to its statutory mandate, see 42 U.S.C. § 7403(a)(1), EPA is required to take into consideration “the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained.” 40 C.F.R. § 26.120(a) (emphasis added). 17 As discussed above, the risk to the participants in the CAPTAIN study is minimal, but the potential importance of the knowledge to be gained is not. Studies such as CAPTAIN provide 17 ATI asserts that EPA cannot conduct studies regarding the “fundamental causes and mechanisms of disease” by contrasting budgetary line-item descriptions of EPA and the Department of Health and Human Services. Motion at 11. This attempted distinction falls flat, because the statute is clear that Congress directs EPA to study the effects of air pollution, which causes disease. See 42 U.S.C. § 7403(a)(1). 22 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 30 of 39 PageID# 301 EPA with knowledge about how PM2.5 and its components affect human physiology, and how particular genetic traits can impact this effect. Epidemiological studies simply cannot perform this function. Devlin Decl. ¶ 7. Therefore, the minimal risk to participants in the study is not unreasonable on an individual level, and is clearly justified by the importance of the knowledge that can be gained. ATI’s claims, therefore, must fail. ATI argues that EPA may not consider this important knowledge as a benefit, and suggests that human research may only be approved if it provides some anticipated benefit to the participant. Motion at 10-13. But the regulatory language is directly to the contrary. 40 C.F.R. § 26.111(a)(2) requires that the IRB determine that “[r]isks to the subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result” (emphasis added). This regulation refutes ATI’s claim in two ways. First, the phrase “if any” modifies the phrase “anticipated benefits,” and thus specifically contemplates that a study may not have a direct benefit to the participant. EPA consent forms clearly explain when a study has no benefit to the participant (with the exception of monetary benefit and a medical examination). Samet Decl. ¶ 27. Second, and more critically, the regulation also directs that the reasonableness of the risk be evaluated in light of “the importance of the knowledge that may reasonably be expected to result.” 18 This plainly allows approval of studies that present risks even when there are no direct benefits to the participant. ATI attempts to read this requirement out of the regulation by referencing the third sentence of 40 C.F.R. § 26.111(a)(2) which directs the IRB not to consider “possible long-range 18 This is consistent with EPA’s obligation to take into consideration “the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained.” 40 C.F.R. § 26.120(a). 23 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 31 of 39 PageID# 302 effects of applying knowledge gained in the research . . . as among those research risks that fall within the purview of its responsibility.” Motion at 10. The two sentences, however, are not in conflict. The distinction being made in the first and third sentences is between the “importance of the knowledge” gained from the study, which may be considered, and a projection about the future risks from applying the knowledge that might be gained, which may not. The first sentence charges the IRB with valuing the research question being addressed; it asks the IRB to determine if that question has scientific merit. Consistent with this directive, the third sentence prevents the IRB from wandering too far afield in evaluating risk by barring speculation concerning how any knowledge gained, whatever it may be, might be applied, and what longrange effects such application might cause. Thus, ATI’s claim that the third sentence cancels out the first is untenable. In sum, EPA imposes no more than minimal risk when conducting studies such as the CAPTAIN study, and this minimal level of risk is reasonable in comparison with the importance of the knowledge EPA can gain as a result. 4. Participants were not, and are not, exposed to risk of substantial injury. As described above, participants in the CAPTAIN study are not exposed to more than minimal risk. If there is no more than minimal risk, there is certainly no risk of substantial injury. 19 There are serious public health risks from exposure of large populations of people, including those with pre-existing illnesses, to ambient levels of PM2.5. But these are not the 19 ATI again mischaracterizes the Common Rule and regulations as prohibiting any controlled human exposure study that involves risk of substantial injury. Motion at 13. While EPA’s stated presumption is that it will not approve studies involving a risk of substantial injury, EPA Order 1000.17 A1 does not prohibit them. EPA Order 1000.17 A1 § 4(d), available at http://www.epa.gov/phre/pdf/epa-order-1000_17-a1.pdf (last visited October 2, 2012). In any event, with regard to the CAPTAIN study, no such risk exists. 24 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 32 of 39 PageID# 303 same as the very small risks that individuals who do not have such conditions face when volunteering to participate in a controlled study. While ATI asserts that “EPA believes there is no safe level of PM2.5” (Motion at 4), that is not an accurate representation of EPA’s position. Current standards for PM2.5 are based primarily on epidemiological studies. 77 Fed. Reg. 38890, 38901 (June 29, 2012). EPA has explained setting such standards is “complicated by the recognition that no population threshold, below which it can be concluded with confidence that PM2.5-related effects do not occur, can be discerned from the available evidence.” Id. (emphasis added). Again, these statements are made in the context of “population” level risks, and do not reflect individual risks. If anything, this uncertainty emphasizes the need for controlled human exposure studies to increase the body of knowledge. Because the state of the science regarding PM2.5 is not complete, it is important that EPA conduct research to better understand how PM2.5 affects people and what particular human characteristics might impact the likelihood of an adverse reaction to it. EPA conducts all of its studies, including CAPTAIN, in full compliance with the Common Rule and its regulations, and ATI has not shown otherwise. Accordingly, ATI has not “made a clear showing that it will likely succeed on the merits.” Real Truth About Obama, 575 F.3d at 346, and its motion for emergency relief must be denied. II. ATI HAS NOT ESTABLISHED THAT ITS MEMBERS WILL FACE IRREPARABLE INJURY ABSENT EXTRAORDINARY INJUNCTIVE RELIEF Because a “preliminary injunction is an extraordinary and drastic remedy,” the party seeking such an injunction must make a “clear showing” that temporary equitable relief is necessary. Mazurek, 520 U.S. at 972. The movant therefore carries a heavy burden not only of demonstrating that “he is likely to prevail on the merits” but also that “he will suffer irreparable 25 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 33 of 39 PageID# 304 injury” without injunctive relief. Doran, 422 U.S. at 931 (emphasis added). The failure to demonstrate harm is “grounds for refusing to issue a preliminary injunction, even if the other three factors entering the calculus merit such relief.” Chaplaincy of Full Gospel Churches v. England, 454 F.3d 290, 297 (D.C. Cir. 2006); accord Power Mobility Coal. v. Leavitt, 404 F. Supp. 2d 190, 204 (D.D.C. 2005), supplemented by No. 05cv2027 (RBW), 2005 WL 3312962 (D.D.C. Dec. 7, 2005). The burden of establishing irreparable harm is “considerable” and “require[s] proof that the movant’s injury is ‘certain, great and actual--not theoretical--and imminent, creating a clear and present need for extraordinary equitable relief to prevent harm.’” Power Mobility Coal., 404 F. Supp. 2d at 204 (quoting Wisconsin Gas Co. v. FERC, 758 F.2d 669, 674 (D.C. Cir. 1985)); accord Hi-Tech Pharmacal Co., Inc. v. FDA, 587 F. Supp. 2d 1, 11 (D.D.C. 2008) (“the alleged injury must be certain, great, actual, and imminent”). “Bare allegations of what is likely to occur are of no value since the court must decide whether the harm will in fact occur.” Wisconsin Gas Co., 758 F.2d at 674 (emphasis in original). Accordingly, “[t]he movant must provide proof . . . indicating that the harm is certain to occur in the near future . . . [and] that the alleged harm will directly result from the action which the movant seeks to enjoin.” Id. In contrast to this demanding standard, ATI alleges only that the challenged actions “threaten[] to result in irreparable harm.” Motion at 3. A mere “threatened” harm clearly falls short of the requirement in Wisconsin Gas Co. that harm will “in fact occur,” and that the harm “is certain to occur in the near future.” 758 F.2d at 674 (emphasis in original). Moreover, the threatened harm Plaintiff alleges is only potential harm to “prospective and current subjects of the PM 2.5 human experimentation.” Motion at 3. Again, such potential harm to prospective 26 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 34 of 39 PageID# 305 subjects is not a harm that will “in fact occur,” or one that “is certain to occur in the near future.” Id. Not only is the alleged harm not certain and imminent, but Plaintiff does even identify any of the “prospective or current subjects” of the studies and does not assert that any of them are members of ATI on whose behalf Plaintiff is seeking injunctive relief. There is simply no basis presented in the ATI Motion or in its supporting Declarations that would support a finding of irreparable harm. 20 Perhaps in recognition of this fatal flaw in Plaintiff’s motion for emergency relief, Dr. Schnare filed a Supplemental Declaration (ECF No. 6) asserting that his knowledge of the studies authorized by EPA has caused him emotional distress. Such alleged emotional distress of someone who did not even participate in any of the challenged studies does not amount to irreparable harm. The only support offered by ATI for its assertion that emotional injury can be cognizable as irreparable harm was made in a dissent to an unpublished opinion in the Ninth Circuit. Moreover, that case involved an action by a government agency that directly affected the person claiming emotional injury. Kennedy v. Sec. of Army, 191 F.3d 460, at *4 (9th Cir. 1999) (unpublished) (Reinhardt, J., dissenting). Similarly, Chalk v. U.S. District Court Central District of California, et al., cited in the Kennedy dissent, also involved a situation where the plaintiff was directly affected by the defendant’s conduct (emotional injury when plaintiff was transferred to different employment). 840 F.2d 701, 709 (9th Cir. 1988). ATI cites no case finding that an irreparable emotional injury can flow from the knowledge that someone else has been subjected to an alleged harm. 20 Not only is the alleged harm merely threatened and potential, but it is extremely unlikely to occur. As demonstrated in Argument I.B., above, there is no more than minimal risk to any of the participants in the CAPTAIN study, or any prior controlled human exposure study involving PM2.5. In the absence of any risk of injury there is no irreparable harm to the participants. 27 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 35 of 39 PageID# 306 Even if generalized allegation of distress caused by the awareness of the alleged experimentation on others could be considered irreparable harm, Dr. Schnare does not declare that he has planned or would plan a visit to either of the places that cause him distress at any time in the foreseeable future. Nor is the distress alleged in the Declaration of such a magnitude that it could be considered “great,” as required to constitute irreparable harm. Because the alleged harm is not “certain, great, actual, and imminent,” Hi-Tech Pharmacal, 587 F. Supp. 2d at 11, it does not justify the request for emergency relief. In any event, as demonstrated in Argument I.B., above, there is no more than minimal risk to any of the participants in the CAPTAIN study, or any prior controlled human exposure study involving PM2.5. Given the minimal risk of injury to any of the actual participants, there can be no irreparable harm to third parties who are not directly affected. The alleged harm, if any, is not only speculative, but seemingly imaginary. Finally, ATI’s assertion that immediate injunctive relief is necessary to avoid irreparable harm is belied by its delay in seeking any relief at all. The Complaint alleges violations that occurred as early as 2004, and one of its members participated in a controlled human exposure study in 2006 and 2007. This apparent lack of urgency further undermines ATI’s assertion that immediate injunctive relief is necessary here. A delay in seeking injunctive relief, though not dispositive, can “militate[] against a finding of irreparable harm.” Mylan Pharms., Inc. v. Shalala, 81 F. Supp. 2d 30, 44 (D.D.C. 2000). The Court should therefore deny ATI’s motion. III. THE BALANCE OF EQUITIES WEIGHS IN FAVOR OF EPA The balance of equities tips decidedly in favor of EPA. As indicated above, there is very little weight on the ATI side of the scales because ATI has no likelihood of success on the merits 28 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 36 of 39 PageID# 307 and it has demonstrated no irreparable harm that will occur in the short term while this case is pending. 21 Accordingly, the burden on EPA to shift the balance is very modest indeed. In contrast to the utter lack of irreparable harm demonstrated by ATI, significant administrative interests are at stake here. It is important -- not just for this case, but for all regulatory actions -- that non-final and non-binding agency activities are not subject to judicial review. To hold otherwise would encourage premature judicial challenges before the administrative process has been completed, would interfere with the administrative process, and unnecessarily waste judicial resources. The orderly functioning of legitimate government activity weighs heavily in favor of the United States and compels denial of the emergency relief requested. Moreover, any delay in the CAPTAIN study will cause harm to EPA’s legitimate research objectives. The CAPTAIN study is part of the body of research designed to provide important insights into the potential biological mechanisms or pathways for effects already observed in epidemiological studies. The CAPTAIN study also supports forthcoming clinical studies, many of which are already scheduled. These studies relate not only to PM2.5 but to exposure to other air pollutants as well, and examine the effects (if any) on persons with the genotype studied in CAPTAIN. Delaying the progress of CAPTAIN could thus upset the scheduling of later studies as well. Harm would occur not only to EPA, but also to the past and future participants. CAPTAIN participants have already been screened for testing, have changed their diets pursuant to the study protocol, and otherwise rearranged their schedules to be available on the days of the study. Their lives will be disrupted if the study is delayed. 21 Because this is a claim brought pursuant to the APA, it should to be resolved on cross-motions for summary judgment without discovery and trial, if not decided earlier on a motion to dismiss. 29 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 37 of 39 PageID# 308 Furthermore, should the CAPTAIN study be delayed to the point where it is not feasible, financially or otherwise, to resume, past participants’ participation will have been in vain. Any satisfaction they may have from knowing they contributed to this important body of research will be erased. Consequently, the equities weigh in favor of allowing EPA to continue the CAPTAIN study for the purposes authorized by the CAA in an orderly and coordinated manner, and subject to the scrutiny of the IRB. For these reasons, the balance of the equities compels denial of the preliminary injunction. IV. DENIAL OF THE PRELIMINARY INJUNCTION IS IN THE PUBLIC INTEREST Absent any likelihood that ATI will succeed on the merits of its claims, and absent any irreparable harm, there is simply no public interest that would be served by an injunction here. By contrast, the studies being performed by EPA will benefit society generally by providing important information regarding the biological effects of PM2.5 and will support further research to determine the causes of certain health effects. The entire public benefits from the advancement of science as facilitated by these studies. Therefore, the public interest is served by allowing EPA to continue its work and the public interest would not be served by enjoining this legitimate governmental activity. CONCLUSION For the foregoing reasons, the United States respectfully requests that the Court deny Plaintiff’s motion for temporary injunction. Respectfully submitted, 30 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 38 of 39 PageID# 309 IGNACIA S. MORENO Assistant Attorney General Environment & Natural Resources Division U.S. Department of Justice CYNTHIA J. MORRIS ELIZABETH DAWSON Environmental Defense Section P.O. Box 7611 Washington, D.C. 20044 (202) 616-7554 (Morris) (202) 514-8293 (Dawson) /s/ Bernard Kim Bernard G. Kim Assistant United States Attorney Justin W. Williams U.S. Attorney's Building 2100 Jamieson Avenue Alexandria, Virginia 22314 (703) 299-3911 (direct) (703) 299-3983 (fax) bernard.kim@usdoj.gov OF COUNSEL: JOHN HANNON STEVEN SILVERMAN Office of General Counsel U.S. Environmental Protection Agency 1200 Pennsylvania Ave. NW Washington, D.C. 20460 31 Case 1:12-cv-01066-AJT-TCB Document 14 Filed 10/04/12 Page 39 of 39 PageID# 310 IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF VIRGINIA ALEXANDRIA DIVISION AMERICAN TRADITION INSTITUTE ENVIRONMENTAL LAW CENTER, Plaintiff, v. UNITED STATES ENVIRONMENTAL PROTECTION AGENCY, et al., Defendants. _________________________________ ) ) ) ) ) ) ) ) ) ) ) ) Civil Action No. 1:12-cv-1066-AJT-TCB I hereby certify that on this 4th day of October, 2012, I electronically filed the foregoing AUnited States= Memorandum in Opposition to Plaintiff=s Motion for Temporary Restraining Order,@ with the Clerk of the Court using the CM/EMF system which will send notification of such filing to the following: /s/ Bernard Kim Assistant U.S. Attorney Attorney for the Defendants Case Document 14-1 Filed 10/04/12 Page 1 of 135 Page D# 311 IN THE UNITED STATES DISTRICT COURT FOR THE EASTERN DISTRICT OF VIRGINIA ALEXANDRIA DIVISION I AMERICAN TRADITION INSTITUTE I ENVIRONMENTAL LAW CENTER, I Plaintiff, I I v. I Civil Action No. I UNITED STATES ENVIRONMENTAL I PROTECTION AGENCY, gt at, Defendants. I I DECLARATION OF WAYNE CASCIO. MD 1, Wayne Cascio, pursuant to 28 U.S.C. 1746, declare, under penalty of perjury, that the following statements are true and correct based upon my personal knowledge, experience or upon information provided to me by persons under my supervision: 1. I am the Director of the Environmental Public Health Division for the National Health and Environmental Effects Research Laboratory (NHEERL), Of?ce of Research and Development (0RD), US. Environmental Protection Agency (EPA). I have been employed by Case Document 14-1 Filed 10/04/12 Page 2 of 135 Page D# 312 the EPA since January 16, 2011. I am a physician/scientist board certi?ed in Internal Medicine and Cardiovascular Diseases. 2. As the Director of the Environmental Public Health Division I have supervisory responsibilities for the management and administration of scienti?c activities conducted by the Division?s scientists, and support staff. 3. I have an MD degree from the University of Maryland at Baltimore 1980), and a BA degree from The Johns Hoypkins University (1977). I completed a residency in Internal Medicine and fellowship in Cardiovascular Diseases at the University of North Carolina Hospitals between 1980 and 1986. I joined the Department of Medicine faculty at the University of North Carolina in 1986. Between 1987 and 1989 I was a visiting Scientist at the University of Bern, Switzerland where I did basic science work on the electrical properties of the heart, in rabbit models. I returned to the University of North Carolina in 1989 and over the years performed clinical service, academic departmental adminstration, education and research. I have authored or co-authored 1 10 peer-reviewed papers, 33 are in the ?eld of environmental health primarily related to the effects of PM or its constituents on cardiovascular physiology or cardiovascular health. 4. I have reviewed the Complaint and exhibits ?led in the captioned case. 5. EPA and 14 other federal departments and agencies conduct or support research with human participants. Over the years, scienti?c research with human subjects has provided much valuable information to help characterize and control risks to public health. 6. EPA and all other federal departments and agencies that conduct or support research with human subjects abide by the governance of the Common Rule, which establishes a Case Document 14-1 Filed 10/04/12 Page 3 of 135 Page D# 313 comprehensive framework for the review and conduct of proposed human research to ensure that it will be performed ethically. EPA has codi?ed the Common Rule at 40 CFR part 26. The central requirements of the Common Rule are: a. That people who participate as subjects in covered research are selected equitably and give their fully informed, fully voluntary written consent; and b. That proposed research be reviewed by an oversight group referred to as an Institutional Review Board (IRB), and approved only if risks to Subjects have been minimized and are reasonable in relation to anticipated bene?ts, if any, to the subjects, and the importance of the knowledge that may reasonably be expected to result. 7. In developing and conducting research involving controlled exposure of humans to substances, EPA has established an institutional culture stressing the safety of study participants. One of the main outcomes of EPA screening of volunteers is the risk- strati?cation of potential participants and exclusion of those that would be put at undue risk by participating in research. In addition, each study has eligibility requirements, many of which are for participant safety. 8. In all phases of the process from initial screening to study participation, EPA provides a detailed written description of what the screening, physical exam, or study involves. This document is the informed consent form. All participants are asked to read it, ask as many questions about the study as they wish, and sign it to con?rm that they understand before beginning the study. As part of the informed consent process in research involving controlled exposure of humans to substances, EPA tells all participants what they will be exposed to (in the case of the CAPTAIN study, to ?ne particulate matter In addition, EPA researchers conduct extensive oral interviews with each potential study participant and Case Document 14-1 Filed 10/04/12 Page 4 of 135 Page D# 314 10. ll. discuss with them the public health risks of exposure to PMM, potential risks to which study participants would be exposed, effects and discomforts which they may experience as a result of testing, and that their individual risk of adverse health effects as a result of exposure to PMH in the test would be extremely small. Before enrolling any participants, all research studies are reviewed by an Institutional Review Board (IRB), the University of North Carolina School of Medicine Of?ce of Human Research Ethics. This review, which is required by the Common Rule, ensures compliance with all Federal and State regulations for safe, ethical, and fair treatment of research participants. Following IRB approval of research involving controlled exposure of humans, EPA then undertakes a further multi-level internal review. Between 2000 and 2012 environmental research scientists in the US and abroad published 61 controlled human exposure studies in peer?reviewed scienti?c journals related to PM exposures. These controlled human exposure studies encompassed a variety of common air pollutants including: concentrated air particles, dilute diesel exhaust, wood smoke, and ultra?ne carbon and zinc particles. Only 8, or 13% of these studies were conducted and published by the US EPA. The balance of studies, or 87% of all controlled human exposure studies to PM were approved, conducted and published by non-EPA scientists. Other institutions who have or are conducting such studies include: the University of Rochester School of Medicine and Dentistry, Rochester, University of Michigan, Ann Arbor, University of Washington, Seattle, WA, University of Southern California, Los Angeles, Rutgers The State University and University of Medicine and Dentistry of New ersey- Robert Wood Johnson Medical School,Piscataway, NJ. All of these studies have been Case Document 14-1 Filed 10/04/12 Page 5 of 135 Page D# 315 approved by Institutional Review Boards as conforming to the provisions of the Common Rule. In addition, similar studies involving controlled human exposure to PM are conducted by non-domestic institutions including the University of Toronto, Toronto, Ontario, Canada; University of Edinburgh, Edinburgh, UK, Goteborg University, Goteborg, Sweden; Umea University, Umea, Sweden; University of Copenhagen, Denmark, and the University of Southainpton, Southampton, UK. Attached as Exhibit 1 to this af?davit are excerpts from 2009 Integrated Science Assessment for Particulate Matter (Devlin Declaration para. 5) summarizing the results of controlled human exposure studies involving exposure to PM2.5- 12. The EPA supports extramural research through the National Center for Environmental Research (N CER). NCER is currently providing research funding for human controlled exposure studies to two US academic centers; namely, the University of Michigan, Aim Arbor, Michigan, and University of Washington, Seattle, Washington. These studies also involve research collaborators and their laboratories at Michigan State University, East Lansing, Ohio State University, Columbus, University California at Los Angeles, Los Angeles, and the Lovelace Respiratory Research Institute, Albuquerque, NM. Dated: October 4, 2012 ?Ma/iCn n0 WAYNE E. CASCIO, MD Case Document 14-1 Filed 10/04/12 Page 6 of 135 Page D# 316 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 7 of 135 PageID# 317 IN THE UNITED STATES DISTRICT COURT FOR THE EASTERN DISTRICT OF VIRGINIA ALEXANDRIA DIVISION AMERICAN TRADITION INSTITUTE ENVIRONMENTAL LAW CENTER, Plaintiff, v. UNITED STATES ENVIRONMENTAL PROTECTION AGENCY, et al., Defendants. ) ) ) ) ) ) ) ) ) ) ) ) ) CivilActionNo. 1:12-cv-1066-AJT-TCB DECLARATION OF MARTIN W. CASE I, Martin Wendell Case, pursuant to 28 U.S.C. § 1746, declare, under penalty of perjury, that the following statements are true and correct based upon my personal knowledge and experience: 1. I am the Clinical Research Studies Coordinator for the CAPTAIN controlled human exposure study 2. As a Clinical Research Studies Coordinator, my duties include training, testing, monitoring, and coordinating human clinical research studies for the Environmental Public Health Division of the US EPA. 3. I received a BA in Chemistry from the University ofNorth Carolina at Chapel Hill, Chapel Hill, NC in 1980. I also hold a Bachelor of Science degree in Public Health from the same university (1983). My clinical research experience consist of 28 years of performing and carrying out human subject testing for the Environmental Protection Agency and 21 years Medical Technology Clinical Laboratory testing in the area of Hematology/Coagulation for the University ofNorth Carolina Healthcare System. 4. I have reviewed the Complaint and exhibits filed in the captioned case and the Motion for a Temporary Restraining Order. Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 8 of 135 PageID# 318 5. My first approach after being introduced to the subject by the medical station staff is to ask the subject if they have read the consent form. The subjects for CAPTAIN have been given the informed study consent form on a previous visit, and, they are also given the same consent to read again if they have not read the consent the day of the training. 6. My next approach is to ask the question: "Do you have any questions about what you have read, and do you understand what you have read?" Based on their response, this gives me the opportunity for me to judge whether I may need the principal investigator for the scientific aspect of the study, or, one of the medical doctors to answer anything that I think I may not be able to explain to the satisfaction of myself and to the subject. 7. Then based on my comfort level from that point, I go to what I consider the main assurance to the subject that he or she is not committed or obligated in anyway to what they have read or will sign about their participation for being in this study. I state very clearly that "their participation in this study and any study here at EPA is strictly and completely volunteer, and that they may stop their participation at anytime for any reason without any coercion whatsoever." 8. Next I go into the details of the study (purpose). I always have a copy of the identical consent form in front of me as guidance. I explain what they will be receiving in the way of air pollution, how they will receive the air pollution, and describe how the air pollution is delivered in the chamber. I will explain to them that they will be receiving clean air on one day of the study, concentrated particles from the air outside the test building on the second day of the study, and the third day is a follow-up day. I will state in lay terms how they will be exposed to the particles for 2 hours, and explain what this is similar to (comparable to) as compared to going about their everyday activities based on where they live. 9. Next I go over the CAPTAIN medical screening questions about any reasons they should not participate in this study, and their requirements and compliance restrictions for being in this study. 10. Then I explain a very detailed time line for all the things they will have to do each day in the study, stepping them through what will be happening or being performed on or to them in each phase. As always, I pause, and ask for questions as I step them through the different Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 9 of 135 PageID# 319 events/procedures. Next I discuss discomforts, risks, and symptoms they may incur from doing procedures we will do on them. Again, this is the time I always add: "if you do like doing or feel uncomfortable with any procedure, then don 't hesitate to say ' I don't want to do this', the subject always has the avenue to say no." 11. At this point I do a more scripted presentation of the consent where I may read or follow closely the sections of the consent dealing with: " possible benefits from being in the study, how their privacy is protected, what will happen ifthey are injured by or while in the study, and their rights as a research subject. " I inform that EPA will reimburse them up to $5,000.00 if is it determined by our on-call duty doctor that we have injured them in any way or caused illness by participating in thi s study. I always assure them that by signing this consent they are not signing away their right to sue if they feel they have been injured or wrongfully damaged by lack of reasonable care or neglect on our part. 12. Then, I go over thoroughly their payment for being in the study, their different types of reimbursement, and the our method of determining reimbursement that can be affected by scheduling conflicts, the weather, their level of or lack of performance, their cancellation, our cancellation, and our ability to notify them when scheduling problems arise due to equipment failures or facility type issues. 13. Finally, I assure them of our concern for their safety first and foremost. Specifically, I tell them of the safe guards we have in place for monitoring their vitals signs, (e.g. EKG telemetry, blood pressure, and oxygen saturation; 'especially while in the chamber' ). I show the subject that they are always on camera, that they can just speak up to be heard, and that I am always just several feet away at the console watching them. As I am performing the training, I physically show them the controlled testing chambers and point out all of these features and safe guards that we have in place. In addition, I informed them of our emergency medical equipment, our overhead paging capability, immediate emergency response by our nurses, and that a dedicated on-call physician is always in the facility at all times when any study is taking place. I state again, "any questions." 14. I provide participants with information about fine particles (PM2.s). I say that PM2.s are particles so small that they are able past through your airways and go deep into your lungs, these Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 10 of 135 PageID# 320 particles are so small that your usual lining and cilia of your airways are not able to prevent these particles from passing into your lungs, Therefore, if you are a person that for example lives in a large city like Los Angeles or New York, and it's been a very hot day, and you can see the haze in the air, and you happen to be someone that works outside, and if you have an underlying unknown health condition, or, you may be older in age; the chances are that you could end up in the emergency room later on that night, wondering what's wrong, possibly having cardiac changes that could lead to a heart attack; there is the possibility you may die from this. 15. I make sure they have initialed and dated every page of the consent form, printed and signed their name in the proper place, and correctly dated the consent. I in tum do the same as the person obtaining their consent. I file this copy in their study chart, and I also make sure they have a signed identical copy to take with them as reference, with contact telephone numbers of the PI, study personnel, our EPA approval medical officer (who oversees our research protocols), and the telephone number with contact information for the Internal Review Board of the University of North Carolina at Chapel Hill who oversees and approves this and all of our studies. Dated: October 3, 2012 r1oi::; IJ. Martin W. Case ~~ Case Document 14-1 Filed 10/04/12 Page 11 of 135 PagelD# 321 IN THE UNITED STATES DISTRICT COURT FOR THE EASTERN DISTRICT OF VIRGINIA ALEXANDRIA DIVISION - AMERICAN TRADITION INSTITUTE ENVIRONMENTAL LAW CENTER, Plaintiff, v. Civil Action No. UNITED STATES ENVIRONMENTAL PROTECTION AGENCY, e_t Defendants. DECLARATION OF ROBERT DEVLIN I, Robert B. Devlin, pursuant to 28 U.S.C. 1746, declare, under penalty of perjury, that the following statements are true and correct based upon my personal knowledge, experience or upon information provided to me by persons under my supervision: 1. I am a Senior Scientist (ST) for the Environmental Public Health Division (EPHD), National Health and Environmental Research Laboratory (NHEERL), Of?ce of Research and Development (0RD), US. Environmental Protection Agency. As one of three STs in NHEERL I am expected to be a scienti?c leader in the area of air pollution research, to de?ne important areas of research, assemble teams to carry out that research and ensure it is completed in a timely manner and published in peer-reviewed journals. I am currently on detail as Acting Associated Director for Health for NHEERL. PriOr to my current position, I was Chief of the Clinical Research Branch (CRB) of the EPHD from 1994 2003. The CRB is responsible for doing nearly all controlled human exposure studies within NHEERL. I as also acting Director of EPHD (then call Human Studies Division) in 200?; the Director oversees all research in the Division including epidemiology, clinical and in vitro studies. I was acting National Program Case Document 14-1 Filed 10/04/12 Page 12 of 135 PagelD# 322 Director for Air Research Program in 2000. This position is the lead for developing research plans related to air pollution for all of ORD and representing the program to grOups outside the EPA. I hold adjunct faculty appointments at the University of North Carolina (Chapel Hill) and North Carolina State University. I have been engaged in performing controlled human exposure studies as an EPA investigator since 1986. I have authored or co- authored more than 190 scienti?c articles, 53 of which involved controlled exposure of human volunteers to air pollutants. The quality of my work at EPA has been recognized by several awards, including one gold and 9 bronze medals, and 8 EPA Scienti?c and Technological Achievement Awards. I have been invited to present my research at more than 100 Universities, Workshops, and International Meetings. 2. I have a B.S. Degree from the University of Texas (El Paso) that was granted in 1969 and a degree from the University of Virginia that was granted in 1976. I was a member of the faculty at Emory University (Atlanta) from 1979 1986. 3. I have reviewed the Complaint and exhibits ?led in the above?captioned case 4. The term particulate matter (PM) covers a broad class of discrete, butichemically and physically diverse, particles that are ubiquitously present in the ambient air and are emitted from different sources such as power plants, mobile sources, biomass burning, and dust generated by mechanical processes. There are three generally recognized modes of PM de?ned by particle diameter: very small so-called ultra?ne particles that result from the primary emissions related to engine combustion and which are usually in close proximity to those sources; large (coarse) particles primarily generated by abrasive processes and from wind-blown dust; and so-called ?ne particles which derive from combustion lay-products that volatilize and quickly condense or from gases (such as sulfur oxides and nitrogen oxides) that react and transferm in the atmosphere after Case Document 14-1 Filed 10/04/12 Page 13 of 135 PagelD# 323 being emitted. PM2.S is roughly synonymous with ?ne PM, and generally includes all particulate matter with an aerodynamic diameter of 2.5 micrometers or less. 40 CFR Principal sources of PM2.S are fossil fuel combustion, including motor vehicle and power plant emissions, natural and anthropogenic biomass burning, as well as other industrial processes such smelting The EPA has Speci?c regulations to control levels of both ?ne and coarse particles. 5. In December 2009 EPA issued the Integrated Science Assessment (ISA) for Particulate Matter, pursuant to section 108 of the Clean Air Act (CAA), 42 U.S.C. 7408. The ISA is an update of prior science assessments of PM, and re?ects the state of the science at that time. The ISA was developed after review by the Clean Air Scienti?c Advisory Committee, a federally mandated body charged with advising EPA about scienti?c matters relating to particulate matter and other forms of air pollution. CAA 109(d)(2), 42 U.S.C. 7409(d)(2). Development of an ISA typically involves the consideration of thousands of scienti?c studies conducted in the U.S. and around the world as part of assessing the relationship between air pollutant exposures and health effects. In the ISA, the entire body of scienti?c evidence, including epidemiological, controlled human exposure, animal toxicological studies, studies with cultured cells, as well as other sources of information, is assessed and an overall judgment is made on the causal relationship between exposure to ambient PM2.5 and health effects. The ISA provides the scienti?c basis for development of the National Ambient Air Quality Standards (NAAQS) for an air pollutant. CAA 6. Epidemiological studies typically use data from large populations of people with varying susceptibility to PM2.5 and evaluate the relationship between short or long-term changes in ambient levels of PM2.5, e. g. changes in the 24-hour average level of PM2.S measured at Ambient air refers to outdoor air in places that members of the public have access to. 40 C.F.R. 50. l. 3 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 14 of 135 PageID# 324 monitors in a metropolitan area, with changes in mortality and morbidity such as the numbers of emergency department visits and hospital admissions. This generally involves the use of complex statistical methods to evaluate the mathematical relationship between variations in measured ambient air pollution levels and health data. 7. Epidemiological observations are the primary tool in the discovery of risks to public health such as that presented by ambient PM2.5. However, epidemiological studies do not generally provide direct evidence of causation. They indicate the existence or lack of a statistical relationship between ambient levels of PM2.5 and adverse health outcomes. Large population studies cannot assess the biological mechanisms (called biological plausibility) that could explain how inhaling ambient air pollution particles can cause illness or death in susceptible individuals. This sometimes leaves open the question of whether the observed association in the epidemiological study is causal or whether PM2.5 is merely a marker for some other unknown substance. 8. Controlled human exposure studies conducted by EPA scientists and EPA funded scientists at multiple universities in the United States fill an information gap that cannot be filled by large population studies. In 1998 the Committee on Research Priorities for Airborne Particulate Matter was established by the National Research Council in response to a request from Congress. The committee was charged with producing four reports over a five-year period which describe a conceptual framework for an integrated national program of particulate-matter research and identified the most critical research needs linked to key policy-related scientific uncertainties. Excerpts from their most recent report (published in 2004) are attached as Exhibit 1 to this Declaration. On page 36 the Committee says: Controlled human exposure studies offer the opportunity to study small numbers of human subjects under carefully controlled exposure conditions and gain valuable insights 4 Case Document 14-1 Filed 10/04/12 Page 15 of 135 PagelD# 325 into both the relative deposition of inhaled particles and the resulting health effects. Individuals studied can range from healthy people to individuals with cardiac or respiratory diseases of varying degrees of severity. In all cases, the speci?c protocols de?ning the subjects, the exposure conditions, and the evaluation procedures must be reviewed and approved by institutional review boards providing oversight for human experimentation. The exposure atmoSpheres studied vary, ranging from well-de?ned, single-component aerosols (such as black carbon or sulfuric acid) to atmospheres produced by recently developed particle concentrators, which concentrate the particles present in ambient air. The concentrations of particles studied are limited by ethical considerations and by concern for the range of concentrations, from the experimental setting to typical ambient concentration, over which ?ndings need to be extrapolated. Exhibit 1 at 36. Controlled human exposures studies have been conducted for decades on important pollutants such as ozone, particulate matter, nitrogen dioxide (N02), sulfur dioxide VOCS emitted in from new homes, and carbon monoxide (CO). 9. Controlled human exposure studies assess the biological plausibility of the associations observed in the large-population epidemiological studies. Controlled human exposure studies usually compare the response of an individual following exposure to clean air with their response following exposure to a pollutant that was generated or prepared under carefully controlled conditions, thus providing direct causal evidence that observed effects are related to the pollutant of interest. These studies are done under conditions that are controlled to ensure safety, with measurable, reversible physiological responses. They are not meant to cause clinically signi?cant adverse health effects, but rather reversible physiological responses can be indicators of the potential for more serious outcomes in susceptible populations identi?ed in epidemiology studies. As such, controlled human exposure studies do not study individuals felt to be at signi?cant risk; they almost always study healthy individuals or people with conditions such as mild asthma. Controlled human exposure studies, together with toxicological studies, provide important insights which can improve our understanding of the potential biological mechanisms or pathways for effects observed in epidemiological studies (cg, respiratory or 5 Case Document 14-1 Filed 10/04/12 Page 16 of 135 PagelD# 326 cardiovascular events, hospital admissions or emergency department visits, or premature death). 10. Obtaining information on the biological impacts of exposure to PM2.5 from controlled human exposure studies such as the CAPTAIN study is a very important element in developing an integrated body of scienti?c knowledge to evaluate the impact on health from exposure to PM 2.5 air pollution. The CAPTAIN study is particularly important in that it addresses an area of PM research where there are still important questions related to fully understanding the role of speci?c components included in the mixtures of fine particles represented by that may be more closely related to the cardiovascular health effects observed in epidemiological studies. PM2.5 is a complex mixture derived from several different sources. There is still uncertainty as to which components or sources of PM2.5 are most responsible for causing effects people and if different components or sources cause effects by different biological mechanisms. This type of research can help address existing uncertainties in the PM scienti?c literature, providing important evidence for informing future PM NAAQS reviews and, in particular, consideration of possible alternative particle indicators andi?or standard levels. In some cases, research in these areas can go beyond aiding standard setting to informing the development of more efficient and effective control strategies. ll. For ethical and safety reasons, controlled human exposure studies to air pollution conducted by NHEERL are initiated only if there is evidence that any effects to the subjects resulting from exposure will be mild, transient, and reversible, and if there is prior data from one or more of the following types of research: a. Testing in laboratory animals. 13. Observational research involving only naturally occurring human exposures. Case Document 14-1 Filed 10/04/12 Page 17 of 135 PagelD# 327 c. Human studies involving a closely related air pollutant. 12. Based on the entire body of scienti?c evidence, including epidemiological, controlled human exposure, and toxicological studies, the ISA for PM drew several important conclusions about the relationship between exposure to PM2.5 and health effects. For short-term exposures to PM2.5, the ISA concluded there was a causal relationship between ambient PM and cardiovascular effects. The epidemiologic evidence showed that increases in 24-hour levels of ambient PM2.5 was mathematically associated with an increase in hospital admission or emergency room visits, predominantly for ischemic heart disease and congestive heart failure See ISA p. 2-9, attached as Exhibit 2 to this Declaration. There was also evidence from a small number of toxicological and controlled human exposure studies that supported the biological plausibility of this conclusion, although these studies needed to be duplicated and expanded to identify specific PM components and sources which are of most concern. The ISA also concluded there was a causal relationship between ambient PM and mortality. An evaluation of the epidemiological literature indicates consistent positive associations between short-term exposure to PM2.5 and all-cause, cardiovascular-, and respiratory-related mortality. ISA p. 2-10, Exhibit 2 to this Declaration. Finally, the ISA concluded that there was a likely casual relationship between ambient PM and respiratory effects. The recent epidemiological studies that have been evaluated report consistent positive associations between short-term exposure to PM2.5 and respiratory emergency department visits and hospital admissions for chronic obstructive pulmonary disease (COPD) and respiratory infections. ISA p.22-10, Exhibit 2 to this Declaration. The evidence of serious health effects such as hospital admissions, emergency department visits, and death, all derived from a large body of epidemiological studies. Case Document 14-1 Filed 10/04/12 Page 18 of 135 PagelD# 328 13. The risk of serious health effects from exposure to typical levels of PM2.5 is largely . focused on people with preexisting illnesses, such as elderly people with cardiovascular diseases or COPD. Even for people with preexisting diseases, there is no evidence that all persons are affected the same way or have the same degree of risk. 14. The body of scienti?c evidence also informs us on what risks there are to an individual that is exposed to PM2.S. For example, it is clear that PM2.5 is not lethal or toxic to all people. The risk of serious health effects is clearly focused on people such as those with pro?existing cardio or respiratory illness. When very large numbers of people are exposed, as occurs in major population centers, the overall risk to the public is large enough to present a serious public health problem in the form of increased mortality and morbidity. It is this serious risk to the overall public health that leads EPA to describe PM as a serious public health problem. 15. However, the risk to an individual is very different from the overall public health risk associated with exposures of large populations of people to ambient air levels of PM2.5. This is especially true if the individual does not have pre?existing health conditions such as preexisting cardiovascular disease. While it is impossible to say there is no risk to a healthy individual, epidemiology studies provide evidence that the risk to healthy individuals is considered to be very small. Institutional review boards are charged with overseeing the safe and ethical conduct of human studies. IRBs from the University of North Carolina Medical School (which oversee EPA studies done on the campus of the University of North Carolina) as well as those which oversee human studies at several universities throughout the US, in Canada, England, and Sweden have all examined the risk posed to individuals exposed to particulate air pollution and concluded that these studies are safe and ethical to perfOrm. 16. EPA relies on the entire body of scientific evidence to draw judgments about the risk to the Case Document 14-1 Filed 10/04/12 Page 19 of 135 PagelD# 329 public health from exposure to ambient PM. In settings the NAAQS, EPA exercise it scienti?c and public health judgment and determines levels that will protect the public health, including groups of people that are more at risk to the air pollutant under consideration, with an adequate margin of safety. In the case of PM2.5, the people most at risk from exposure to ambient PM2.5 include those with pre-existing cardiovascular illness or respiratory illness. The current NAAQS is 15.0 ug/In3 annual average, and a 35 ug/m3 24-hour average. The 24 hour average is met if the 3 year average of the 98th percentile is 35 ug/m3 or below. The 98?? percentile means that approximately 6 or 7 days in the year can have higher concentrations than the day used to cempare to the 35 ug/m3. 2 Dated: October 3, 2012 Robert B. Devlin 2 The air quality in Chapel Hill, NC, where the subjects are tested, is well within the levels that attain the current NAAQs Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 20 of 135 PageID# 330 Devlin Declaration Exhibit 1 Research Filed 10/04/12 Page 21 Of 135 Page D# 331 Research Priorities for Airborne Particulate Matter -IV- Continuing Research Progress Committee on Research Priorities for Airborne Particulate Matter Board on Environmental Studies and Toxicology Division on Earth and Life Studies NATIONAL RESEARCH COUNCIL OF THE NATFONAI. THE NAHONAL ACADEMIES PRESS Washington, D.C. Copyright National Academy of Sciences. All rights reserved. Research Filed 10/04/12 Page 22 Of 135 Page D# 332 THE NATIONALACADEMIES PRESS 500 Fifth Street, NW Washington, DC NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This project was supported by Contract No. 63-(3-93-003 between the National Academyr of Sciences and the LLB. Environmental Protection Agency. Any opinions, ?ndings, conclusions, or recommendations expressed in this publication are those of the authorfs) and do not necessarin re?ect the view ofthc organizations or agencies that provided support for this project. Library.r of Congress Control Number 2004] 12036 International Standard Book Number $309?$9199?3 {Book} 0-309-53ITU-5 Additional copies of this report are available ?ow The National Academies Press 500 Fifth Street, NW Box 235 Washington, DC 20055 202?334?3313 [in the Washington metropolitan area) Copyright 2004 by the National Academy of Sciences. All rights reserved. Printed in the United States of America Copyright National Academy of Sciences. All rights reserved, Research Filed 10/04/12 Page 23 Of 135 PagelD# 333 .ed ulcatalog? 095?.html 3 6 Research Priorities for Airborne Particulate Matter but some of the groups considered most susceptible?persons with ad- vanced chronic heart and lung diseases?are not yet well studied. Addition- ally, the extent to which ?ndings from any particular location can be gener- alized is uncertain, and many studies to date have focused primarily on total particle mass, rather than more detailed particle characteristics, such as their chemical composition. Epidemiological studies take advantage of naturally occurring varia- tion in exposure, across groups or over time, to estimate the effect of PM on one or more health outcome indicators. In an effort to provide evidence relevant to the NAAQS for PM, epidemiologists design studies that have the potential to estimate the effect of PM without contamination (confound- ing) by the effects of other pollutants. This approach implicitly assumes that inhaled particles have effects on health that are independent of other pollut- ants, an underlying assumption in having a NAAQS for PM. Alternatively, the effect assigned to PM may re?ect the total effect of the air pollution mixture or some other factor that varies with PM, and PM is serving as a surrogate index. Even with careful design and analysis, there is the possi- bility of some residual confounding of the effect of PM by other pollutants or other factors. Some epidemiological studies take advantage of historical data on air quality and community health. Other studies use air quality and health data collected prospectively to address specific hypotheses. Controlled human exposure studies offer the opportunity to study small numbers of human subjects under carefully controlled exposure conditions and gain valuable insights into both the relative deposition of inhaled particles and the resulting health effects. Individuals studied can range from healthy people to individuals with cardiac or respiratory dis- eases of varying degrees of severity. In all cases, the specific protocols de?ning the subjects, the exposure conditions, and the evaluation proce- dures must be reviewed and approved by institutional review boards provid- ing oversight for human experimentation. The exposure atmospheres studied vary, ranging from well-de?ned, single-component aerosols (such as black carbon5 or sulfuric acid) to atmospheres produced by recently developed particle concentrators, which concentrate the particles present in ambient air. The concentrations of particles studied are limited by ethical considerations and by concern for the range of concentrations, from the experimental setting to typical ambient concentration, over which ?ndings need to be extrapolated. Toxicological studies with laboratory animals provide the opportunity S?Black carbon? is a general tertn that is often used interchangeably with ?elemental carbon? or ?soot.? Copyright National Academy of Sciences. All rights reserved. Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 24 of 135 PageID# 334 Devlin Declaration Exhibit 2 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 25 of 135 PageID# 335 Chapter 2. Integrative Health and Welfare Effects Overview The subsequent chapters of this ISA will present the most policy-relevant information related to this review of the NAAQS for PM. This chapter integrates the key findings from the disciplines evaluated in this current assessment of the PM scientific literature, which includes the atmospheric sciences, ambient air data analyses, exposure assessment, dosimetry, health studies (e.g., toxicological, controlled human exposure, and epidemiologic), and welfare effects. The EPA framework for causal determinations described in Chapter 1 has been applied to the body of scientific evidence in order to collectively examine the health or welfare effects attributed to PM exposure in a two-step process. As described in Chapter 1, EPA assesses the results of recent relevant publications, building upon evidence available during the previous NAAQS reviews, to draw conclusions on the causal relationships between relevant pollutant exposures and health or environmental effects. This ISA uses a five-level hierarchy that classifies the weight of evidence for causation: ƒ Causal relationship ƒ Likely to be a causal relationship ƒ Suggestive of a causal relationship ƒ Inadequate to infer a causal relationship ƒ Not likely to be a causal relationship Beyond judgments regarding causality are questions relevant to quantifying health or environmental risks based on our understanding of the quantitative relationships between pollutant exposures and health or welfare effects. Once a determination is made regarding the causal relationship between the pollutant and outcome category, important questions regarding quantitative relationships include: ƒ What is the concentration-response or dose-response relationship? ƒ Under what exposure conditions (amount deposited, dose or concentration, duration and pattern) are effects observed? ƒ What populations appear to be differentially affected (i.e., more susceptible) to effects? ƒ What elements of the ecosystem (e.g., types, regions, taxonomic groups, populations, functions, etc.) appear to be affected, or are more sensitive to effects? To address these questions, in the second step of the EPA framework, the entirety of quantitative evidence is evaluated to identify and characterize potential concentration-response relationships. This requires evaluation of levels of pollutant and exposure durations at which effects were observed for exposed populations including potentially susceptible populations. This chapter summarizes and integrates the newly available scientific evidence that best informs consideration of the policy-relevant questions that frame this assessment, presented in Chapter 1. Section 2.1 discusses the trends in ambient concentrations and sources of PM and provides a brief summary of ambient air quality. Section 2.2 presents the evidence regarding personal exposure to ambient PM in outdoor and indoor microenvironments, and it discusses the ƒ Note: Hyperlinks to the reference citations throughout this document will take you to the NCEA HERO database (Health and Environmental Research Online) at http://epa.gov/hero. HERO is a database of scientific literature used by U.S. EPA in the process of developing science assessments such as the Integrated Science Assessments (ISA) and the Integrated Risk Information System (IRIS). December 2009 2-1 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 26 of 135 PageID# 336 relationship between ambient PM concentrations and exposure to PM from ambient sources. Section 2.3 integrates the evidence for studies that examine the health effects associated with shortand long-term exposure to PM and discusses important uncertainties identified in the interpretation of the scientific evidence. Section 2.4 provides a discussion of policy-relevant considerations, such as potentially susceptible populations, lag structure, and the PM concentration-response relationship, and PM sources and constituents linked to health effects. Section 2.5 summarizes the evidence for welfare effects related to PM exposure. Finally, Section 2.6 provides all of the causal determinations reached for each of the health outcomes and PM exposure durations evaluated in this ISA. 2.1. Concentrations and Sources of Atmospheric PM 2.1.1. Ambient PM Variability and Correlations Recently, advances in understanding the spatiotemporal distribution of PM mass and its constituents have been made, particularly with regard to PM 2.5 and its components as well as ultrafine particles (UFPs). Emphasis in this ISA is placed on the period from 2005-2007, incorporating the most recent validated EPA Air Quality System (AQS) data. The AQS is EPA’s repository for ambient monitoring data reported by the national, and state and local air monitoring networks. Measurements of PM 2.5 and PM 10 are reported into AQS, while PM 10-2.5 concentrations are obtained as the difference between PM 10 and PM 2.5 (after converting PM 10 concentrations from STP to local conditions; Section 3.5). Note, however, that a majority of U.S. counties were not represented in AQS because their population fell below the regulatory monitoring threshold. Moreover, monitors reporting to AQS were not uniformly distributed across the U.S. or within counties, and conclusions drawn from AQS data may not apply equally to all parts of a geographic region. Furthermore, biases can exist for some PM constituents (and hence total mass) owing to volatilization losses of nitrates and other semi-volatile compounds, and, conversely, to retention of particle-bound water by hygroscopic species. The degree of spatial variability in PM was likely to be region-specific and strongly influenced by local sources and meteorological and topographic conditions. 2.1.1.1. Spatial Variability across the U.S. AQS data for daily average concentrations of PM 2.5 for 2005-2007 showed considerable variability across the U.S. (Section 3.5.1.1). Counties with the highest average concentrations of PM 2.5 (>18 µg/m3) were reported for several counties in the San Joaquin Valley and inland southern California as well as Jefferson County, AL (containing Birmingham) and Allegheny County, PA (containing Pittsburgh). Relatively few regulatory monitoring sites have the appropriate co-located monitors for computing PM 10-2.5 , resulting in poor geographic coverage on a national scale (Figure 3-10). Although the general understanding of PM differential settling leads to an expectation of greater spatial heterogeneity in the PM 10-2.5 fraction, deposition of particles as a function of size depends strongly on local meteorological conditions. Better geographic coverage is available for PM 10 , where the highest reported annual average concentrations (>50 µg/m3) occurred in southern California, southern Arizona and central New Mexico. The size distribution of PM varied substantially by location, with a generally larger fraction of PM 10 mass in the PM 10-2.5 size range in western cities (e.g., Phoenix and Denver) and a larger fraction of PM 10 in the PM 2.5 size range in eastern U.S. cities (e.g., Pittsburgh and Philadelphia). UFPs are not measured as part of AQS or any other routine regulatory network in the U.S. Therefore, limited information is available regarding regional variability in the spatiotemporal distribution of UFPs. Spatial variability in PM 2.5 components obtained from the Chemical Speciation Network (CSN) varied considerably by species from 2005-2007 (Figures 3-12 through 3-18). The highest annual average organic carbon (OC) concentrations were observed in the western and southeastern U.S. OC concentrations in the western U.S. peaked in the fall and winter, while OC concentrations in the Southeast peaked anytime between spring and fall. Elemental carbon (EC) exhibited less seasonality than OC and showed lowest seasonal variability in the eastern half of the U.S. The December 2009 2-2 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 27 of 135 PageID# 337 highest annual average EC concentrations were present in Los Angeles, Pittsburgh, New York, and El Paso. Concentrations of sulfate (SO 4 2–) were higher in the eastern U.S. as a result of higher SO 2 emissions in the East compared with the West. There is also considerable seasonal variability with higher SO 4 2– concentrations in the summer months when the oxidation of SO 2 proceeds at a faster rate than during the winter. Nitrate (NO 3 –) concentrations were highest in California and during the winter in the Upper Midwest. In general, NO 3 – was higher in the winter across the country, in part as a result of temperature-driven partitioning and volatilization. Exceptions existed in Los Angeles and Riverside, CA, where high NO 3 – concentrations appeared year-round. There is variation in both PM 2.5 mass and composition among cities, some of which might be due to regional differences in meteorology, sources, and topography. 2.1.1.2. Spatial Variability on the Urban and Neighborhood Scales In general, PM 2.5 has a longer atmospheric lifetime than PM 10-2.5 . As a result, PM 2.5 is more homogeneously distributed than PM 10-2.5 , whose concentrations more closely reflect proximity to local sources (Section 3.5.1.2). Because PM 10 encompasses PM 10-2.5 in addition to PM 2.5 , it also exhibits more spatial heterogeneity than PM 2.5 . Urban- and neighborhood-scale variability in PM mass and composition was examined by focusing on 15 metropolitan areas, which were chosen based on their geographic distribution and coverage in recent health effects studies. The urban areas selected were Atlanta, Birmingham, Boston, Chicago, Denver, Detroit, Houston, Los Angeles, New York, Philadelphia, Phoenix, Pittsburgh, Riverside, Seattle and St. Louis. Inter-monitor correlation remained higher over long distances for PM 2.5 as compared with PM 10 in these 15 urban areas. To a large extent, greater variation in PM 2.5 and PM 10 concentrations within cities was observed in areas with lower ratios of PM 2.5 to PM 10 . When the data was limited to only sampler pairs with less than 4 km separation (i.e., on a neighborhood scale), inter-sampler correlations remained higher for PM 2.5 than for PM 10 . The average inter-sampler correlation was 0.93 for PM 2.5 , while it dropped to 0.70 for PM 10 (Section 3.5.1.3). Insufficient data were available in the 15 metropolitan areas to perform similar analyses for PM 10-2.5 using co-located, low volume FRM monitors. As previously mentioned, UFPs are not measured as part of AQS or any other routine regulatory network in the U.S. Therefore, information about the spatial variability of UFPs is sparse; however, their number concentrations are expected to be highly spatially and temporally variable. This has been shown on the urban scale in studies in which UFP number concentrations drop off quickly with distance from roads compared to accumulation mode particle numbers. 2.1.2. Trends and Temporal Variability Overall, PM 2.5 concentrations decreased from 1999 (the beginning of nationwide monitoring for PM 2.5 ) to 2007 in all ten EPA Regions, with the 3-yr avg of the 98th percentile of 24-h PM 2.5 concentrations dropping 10% over this time period. However from 2002-2007, concentrations of PM 2.5 were nearly constant with decreases observed in only some EPA Regions (Section 3.5.2.1). Concentrations of PM 2.5 components were only available for 2002-2007 using CSN data and showed little decline over this time period. This trend in PM 2.5 components is consistent with trends in PM 2.5 mass concentration observed after 2002 (shown in Figures 3-44 through 3-47). Concentrations of PM 10 also declined from 1988 to 2007 in all ten EPA Regions. Using hourly PM observations in the 15 metropolitan areas, diel variation showed average hourly peaks that differ by size fraction and region (Section 3.5.2.3). For both PM 2.5 and PM 10 , a morning peak was typically observed starting at approximately 6:00 a.m., corresponding with the start of morning rush hour. There was also an evening concentration peak that was broader than the morning peak and extended into the overnight period, reflecting the concentration increase caused by the usual collapse of the mixing layer after sundown. The magnitude and duration of these peaks varied considerably by metropolitan area investigated. UFPs were found to exhibit similar two-peaked diel patterns in Los Angeles and the San Joaquin Valley of CA and Rochester, NY as well as in Kawasaki City, Japan, and Copenhagen, Denmark. The morning peak in UFPs likely represents primary source emissions, such as rush-hour traffic, while the afternoon peak likely represents the combination of primary source emissions and nucleation of new particles. December 2009 2-3 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 28 of 135 PageID# 338 2.1.3. Correlations between Copollutants Correlations between PM and gaseous copollutants, including SO 2 , NO 2 , carbon monoxide (CO) and O 3 , varied both seasonally and spatially between and within metropolitan areas (Section 3.5.3). On average, PM 2.5 and PM 10 were correlated with each other better than with the gaseous copollutants. Although data are limited for PM 10-2.5 , the available data suggest a stronger correlation between PM 10 and PM 10-2.5 than between PM 2.5 and PM 10-2.5 on a national basis.There was relatively little seasonal variability in the mean correlation between PM in both size fractions and SO 2 and NO 2 . CO, however, showed higher correlations with PM 2.5 and PM 10 on average in the winter compared with the other seasons. This seasonality results in part because a larger fraction of PM is primary in origin during the winter. To the extent that this primary component of PM is associated with common combustion sources of NO 2 and CO, then higher correlations with these gaseous copollutants are to be expected. Increased atmospheric stability in colder months also results in higher correlations between primary pollutants (Section 3.5). The correlation between daily maximum 8-h avg O 3 and 24-h avg PM 2.5 showed the highest degree of seasonal variability with positive correlations on average in summer (avg = 0.56) and negative correlations on average in the winter (avg = -0.30). During the transition seasons, spring and fall, correlations were mixed but on average were still positive. PM 2.5 is both primary and secondary in origin, whereas O 3 is only secondary. Photochemical production of O 3 and secondary PM in the planetary boundary layer (PBL) is much slower during the winter than during other seasons. Primary pollutant concentrations (e.g., primary PM 2.5 components, NO and NO 2 ) in many urban areas are elevated in winter as the result of heating emissions, cold starts and low mixing heights. O 3 in the PBL during winter is mainly associated with air subsiding from above the boundary layer following the passage of cold fronts, and this subsiding air has much lower PM concentrations than are present in the PBL. Therefore, a negative association between O 3 and PM 2.5 is frequently observed in the winter. During summer, both O 3 and secondary PM 2.5 are produced in the PBL and in the lower free troposphere at faster rates compared to winter, and so they tend to be positively correlated. 2.1.4. Measurement Techniques The federal reference methods (FRMs) for PM 2.5 and PM 10 are based on criteria outlined in the Code of Federal Regulations. They are, however, subject to several limitations that should be kept in mind when using compliance monitoring data for health studies. For example, FRM techniques are subject to the loss of semi-volatile species such as organic compounds and ammonium nitrate (especially in the West). Since FRMs based on gravimetry use 24-h integrated filter samples to collect PM mass, no information is available for variations over shorter averaging times from these instruments. However, methods have been developed to measure real-time PM mass concentrations. Real-time (or continuous and semi-continuous) measurement techniques are also available for PM species, such as particle into liquid sampler (PILS) for multiple ions analysis and aerosol mass spectrometer (AMS) for multiple components analysis (Section 3.4.1). Advances have also been achieved in PM organic speciation. New 24-h FRMs and Federal Equivalent Methods (FEMs) based on gravimetry and continuous FEMs for PM 10-2.5 are available. FRMs for PM 10-2.5 rely on calculating the difference between co-located PM 10 and PM 2.5 measurements while a dichotomous sampler is designated as an FEM. 2.1.5. PM Formation in the Atmosphere and Removal PM in the atmosphere contains both primary (i.e., emitted directly by sources) and secondary components, which can be anthropogenic or natural in origin. Secondary PM components can be produced by the oxidation of precursor gases such as SO 2 and NO X to acids followed by neutralization with ammonia (NH 3 ) and the partial oxidation of organic compounds. In addition to being emitted as primary particles, UFPs are produced by the nucleation of H 2 SO 4 vapor, H 2 O vapor, and perhaps NH 3 and certain organic compounds. Over most of the earth’s surface, nucleation is probably the major mechanism forming new UFPs. New UFP formation has been observed in environments ranging from relatively unpolluted marine and continental environments to polluted December 2009 2-4 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 29 of 135 PageID# 339 urban areas as an ongoing background process and during nucleation events. However, as noted above, a large percentage of UFPs come from combustion-related sources such as motor vehicles. Developments in the chemistry of formation of secondary organic aerosol (SOA) indicate that oligomers are likely a major component of OC in aerosol samples. Recent observations also suggest that small but significant quantities of SOA are formed from the oxidation of isoprene in addition to the oxidation of terpenes and organic hydrocarbons with six or more carbon atoms. Gasoline engines have been found to emit a mix of nucleation-mode heavy and large polycyclic aromatic hydrocarbons on which unspent fuel and trace metals can condense, while diesel particles are composed of a soot nucleus on which sulfates and hydrocarbons can condense. To the extent that the primary component of organic aerosol is overestimated in emissions from combustion sources, the semi-volatile components are underestimated. This situation results from the lack of capture of evaporated semi-volatile components upon dilution in common emissions tests. As a result, neartraffic sources of precursors to SOA would be underestimated. The oxidation of these precursors results in more oxidized forms of SOA than previously considered, in both near source urban environments and further downwind. Primary organic aerosol can also be further oxidized to forms that have many characteristics in common with oxidized SOA formed from gaseous precursors. Organic peroxides constitute a significant fraction of SOA and represent an important class of reactive oxygen species (ROS) that have high oxidizing potential. More information on sources, emissions and deposition of PM are included in Section 3.3. Wet and dry deposition are important processes for removing PM and other pollutants from the atmosphere on urban, regional, and global scales. Wet deposition includes incorporation of particles into cloud droplets that fall as rain (rainout) and collisions with falling rain (washout). Other hydrometeors (snow, ice) can also serve the same purpose. Dry deposition involves transfer of particles through gravitational settling and/or by impaction on surfaces by turbulent motions. The effects of deposition of PM on ecosystems and materials are discussed in Section 2.5 and in Chapter 9. 2.1.6. Source Contributions to PM Results of receptor modeling calculations indicate that PM 2.5 is produced mainly by combustion of fossil fuel, either by stationary sources or by transportation. A relatively small number of broadly defined source categories, compared to the total number of chemical species that typically are measured in ambient monitoring source receptor studies, account for the majority of the observed PM mass. Some ambiguity is inherent in identifying source categories. For example, quite different mobile sources such as trucks, farm equipment, and locomotives rely on diesel engines and ancillary data is often required to resolve these sources. A compilation of study results shows that secondary SO 4 2– (derived mainly from SO 2 emitted by Electricity Generating Units [EGUs]), NO 3 – (from the oxidation of NO x emitted mainly from transportation sources and EGUs), and primary mobile source categories, constitute most of PM 2.5 (and PM 10 ) in the East. PM 10-2.5 is mainly primary in origin, having been emitted as fully formed particles derived from abrasion and crushing processes, soil disturbances, plant and insect fragments, pollens and other microorganisms, desiccation of marine aerosol emitted from bursting bubbles, and hygroscopic fine PM expanding with humidity to coarse mode. Gases such as HNO 3 can also condense directly onto preexisting coarse particles. Suspended primary coarse PM can contain Fe, Si, Al, and base cations from soil, plant and insect fragments, pollen, fungal spores, bacteria, and viruses, as well as fly ash, brake lining particles, debris, and automobile tire fragments. Quoted uncertainties in the source apportionment of constituents in ambient aerosol samples typically range from 10 to 50%. An intercomparison of source apportionment techniques indicated that the same major source categories of PM 2.5 were consistently identified by several independent groups working with the same data sets. Soil-, sulfate-, residual oil-, and salt-associated mass were most clearly identified by the groups. Other sources with more ambiguous signatures, such as vegetative burning and traffic-related emissions were less consistently identified. Spatial variability in source contributions across urban areas is an important consideration in assessing the likelihood of exposure error in epidemiologic studies relating health outcomes to sources. Concepts similar to those for using ambient concentrations as surrogates for personal exposures apply here. Some source attribution studies for PM 2.5 indicate that intra-urban variability increases in the following order: regional sources (e.g., secondary SO 4 2– originating from EGUs) < area sources (e.g., on-road mobile sources) < point sources (e.g., metals from stacks of smelters). December 2009 2-5 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 30 of 135 PageID# 340 Although limited information was available for PM 10-2.5 , it does indicate a similar ordering, but without a regional component (resulting from the short lifetime of PM 10-2.5 compared to transport times on the regional scale). More discussion on source contributions to PM is available in Section 3.6. 2.1.7. Policy-Relevant Background The background concentrations of PM that are useful for risk and policy assessments, which inform decisions about the NAAQS are referred to as policy-relevant background (PRB) concentrations. PRB concentrations have historically been defined by EPA as those concentrations that would occur in the U.S. in the absence of anthropogenic emissions in continental North America defined here as the U.S., Canada, and Mexico. For this document, PRB concentrations include contributions from natural sources everywhere in the world and from anthropogenic sources outside continental North America. Background concentrations so defined facilitated separation of pollution that can be controlled by U.S. regulations or through international agreements with neighboring countries from those that were judged to be generally uncontrollable by the U.S. Over time, consideration of potential broader ranging international agreements may lead to alternative determinations of which PM source contributions should be considered by EPA as part of PRB. Contributions to PRB concentrations of PM include both primary and secondary natural and anthropogenic components. For this document, PRB concentrations of PM 2.5 for the continental U.S. were estimated using EPA’s Community Multi-scale Air Quality (CMAQ) modeling system, a deterministic, chemical-transport model (CTM), using output from GEOS-Chem a global-scale model for CMAQ boundary conditions. PRB concentrations of PM 2.5 were estimated to be less than 1 µg/m3 on an annual basis, with maximum daily average values in a range from 3.1 to 20 µg/m3 and having a peak of 63 µg/m3 at the nine national park sites across the U.S. used to evaluate model performance for this analysis. A description of the models and evaluation of their performance is given in Section 3.6 and further details about the calculations of PRB concentrations are given in Section 3.7. 2.2. Human Exposure This section summarizes the findings from the recent exposure assessment literature. This summary is intended to support the interpretation of the findings from epidemiologic studies and reflects the material presented in Section 3.8. Attention is given to how concentration metrics can be used in exposure assessment and what errors and uncertainties are incurred for different approaches. Understanding of exposure errors is important because exposure error can potentially bias an estimate of a health effect or increase the size of confidence intervals around a health effect estimate. 2.2.1. Spatial Scales of PM Exposure Assessment Assessing population-level exposure at the urban scale is particularly relevant for time-series epidemiologic studies, which provide information on the relationship between health effects and community-average exposure, rather than an individual’s exposure. PM concentrations measured at a central-site ambient monitor are used as surrogates for personal PM exposure. However, the correlation between the PM concentration measured at central-site ambient monitor(s) and the unknown true community average concentration depends on the spatial distribution of PM, the location of the monitoring site(s) chosen to represent the community average, and division of the community by terrain features or local sources into several sub-communities that differ in the temporal pattern of pollution. Concentrations of SO 4 2– and some components of SOA measured at central-site monitors are expected to be uniform in urban areas because of the regional nature of their sources. However, this is not true for primary components like EC whose sources are strongly spatially variable in urban areas. At micro-to-neighborhood scales, heterogeneity of sources and topography contribute to variability in exposure. This is particularly true for PM 10-2.5 and for UFPs, which have spatially December 2009 2-6 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 31 of 135 PageID# 341 variable urban sources and loss processes (mainly gravitational settling for PM 10-2.5 and coagulation for UFPs) that also limit their transport from sources more readily than for PM 2.5 . Personal activity patterns also vary across urban areas and across regions. Some studies, conducted mainly in Europe, have found personal PM 2.5 and PM 10 exposures for pedestrians in street canyons to be higher than ambient concentrations measured by urban central site ambient monitors. Likewise, microenvironmental UFP concentrations were observed to be substantially higher in near-road environments, street canyons, and tunnels when compared with urban background concentrations. In-vehicle UFP and PM 2.5 exposures can also be important. As a result, concentrations measured by ambient monitors likely do not reflect the contributions of UFP or PM 2.5 exposures to individuals while commuting. There is significant variability within and across regions of the country with respect to indoor exposures to ambient PM. Infiltrated ambient PM concentrations depend in part on the ventilation properties of the building or vehicle in which the person is exposed. PM infiltration factors depend on particle size, chemical composition, season, and region of the country. Infiltration can best be modeled dynamically rather than being represented by a single value. Season is important to PM infiltration because it affects the ventilation practices (e.g., open windows) used. In addition, ambient temperature and humidity conditions affect the transport, dispersion, and size distribution of PM. Residential air exchange rates have been observed to be higher in the summer for regions with low air conditioning usage. Regional differences in air exchange rates (Southwest < Southeast < Northeast < Northwest) also reflect ventilation practices. Differential infiltration occurs as a function of PM size and composition (the latter of which is described below). PM infiltration is larger for accumulation mode particles than for UFPs and PM 10-2.5 . Differential infiltration by size fraction can affect exposure estimates if not accurately characterized. 2.2.2. Exposure to PM Components and Copollutants Emission inventories and source apportionment studies suggest that sources of PM exposure vary by region. Comparison of studies performed in the eastern U.S. with studies performed in the western U.S. suggest that the contribution of SO 4 2– to exposure is higher for the East (16-46%) compared with the West (~4%) and that motor vehicle emissions and secondary NO 3 – are larger sources of exposure for the West (~9%) as compared with the East (~4%). Results of source apportionment studies of exposure to SO 4 2– indicate that SO 4 2– exposures are mainly attributable to ambient sources. Source apportionment for OC and EC is difficult because they originate from both indoor and outdoor sources. Exposure to OC of indoor and outdoor origin can be distinguished by the presence of aliphatic C-H groups generated indoors, since outdoor concentrations of aliphatic C-H are low. Studies of personal exposure to ambient trace metal have shown significant variation among cities and over seasons. This is in response to geographic and seasonal variability in sources including incinerator operation, fossil fuel combustion, biomass combustion (wildfires), and the resuspension of crustal materials in the built environment. Differential infiltration is also affected by variations in particle composition and volatility. For example, EC infiltrates more readily than OC. This can lead to outdoor-indoor differentials in PM composition. Some studies have explored the relationship between PM and copollutant gases and suggested that certain gases can serve as surrogates for describing exposure to other air pollutants. The findings indicate that ambient concentrations of gaseous copollutants can act as surrogates for personal exposure to ambient PM. Several studies have concluded that ambient concentrations of O 3 , NO 2 , and SO 2 are associated with the ambient component of personal exposure to total PM 2.5 . If associations between ambient gases and personal exposure to PM 2.5 of ambient origin exist, such associations are complex and vary by season and location. 2.2.3. Implications for Epidemiologic Studies In epidemiologic studies, exposure may be estimated using various approaches, most of which rely on measurements obtained using central site monitors. The magnitude and direction of the biases introduced through error in exposure measurement depend on the extent to which the error is associated with the measured PM concentration. In general, when exposure error is not strongly correlated with the measured PM concentration, bias is toward the null and effect estimates are December 2009 2-7 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 32 of 135 PageID# 342 underestimated. Moreover, lack of information regarding exposure measurement error can also add uncertainty to the health effects estimate. One important factor to be considered is the spatial variation in PM concentrations. The degree of urban-scale spatial variability in PM concentrations varies across the country and by size fraction. PM 2.5 concentrations are relatively well-correlated across monitors in the urban areas examined for this assessment. The limited available evidence indicates that there is greater spatial variability in PM 10-2.5 concentrations than PM 2.5 concentrations, resulting in increased exposure error for the larger size fraction. Likewise, studies have shown UFPs to be more spatially variable across urban areas compared to PM 2.5 . Even if PM 2.5 , PM 10-2.5 , or UFP concentrations measured at sites within an urban area are generally highly correlated, significant spatial variation in their concentrations can occur on any given day. In addition, there can be differential exposure errors for PM components (e.g., SO 4 2–, OC, EC). Current information suggests that UFPs, PM 10-2.5, and some PM components are more spatially variable than PM 2.5 . Spatial variability of these PM indicators adds uncertainty to exposure estimates. Overall, recent studies generally confirm and build upon the key conclusions of the 2004 PM AQCD: separation of total PM exposures into ambient and nonambient components reduces potential uncertainties in the analysis and interpretation of PM health effects data; and ambient PM concentration can be used as a surrogate for ambient PM exposure in community time-series epidemiologic studies because the change in ambient PM concentration should be reflected in the change in the health risk coefficient. The use of the community average ambient PM 2.5 concentration as a surrogate for the community average personal exposure to ambient PM 2.5 is not expected to change the principal conclusions from time-series and most panel epidemiologic studies that use community average health and pollution data. Several recent studies support this by showing how the ambient component of personal exposure to PM 2.5 could be estimated using various tracer and source apportionment techniques and by showing that the ambient component is highly correlated with ambient concentrations of PM 2.5 . These studies show that the non-ambient component of personal exposure to PM 2.5 is largely uncorrelated with ambient PM 2.5 concentrations. A few panel epidemiologic studies have included personal as well as ambient monitoring data, and generally reported associations with all types of PM measurements. Epidemiologic studies of long-term exposure typically exploit the differences in PM concentration across space, as well as time, to estimate the effect of PM on the health outcome of interest. Long-term exposure estimates are most accurate for pollutants that do not vary substantially within the geographic area studied. 2.3. Health Effects This section evaluates the evidence from toxicological, controlled human exposure, and epidemiologic studies that examined the health effects associated with short- and long-term exposure to PM (i.e., PM 2.5 , PM 10-2.5 and UFPs). The results from the health studies evaluated in combination with the evidence from atmospheric chemistry and exposure assessment studies contribute to the causal determinations made for the health outcomes discussed in this assessment (a description of the causal framework can be found in Section 1.5.4). In the following sections a discussion of the causal determinations will be presented by PM size fraction and exposure duration (i.e., short- or long-term exposure) for the health effects for which sufficient evidence was available to conclude a causal, likely to be causal or suggestive relationship. Although not presented in depth in this chapter, a detailed discussion of the underlying evidence used to formulate each causal determination can be found in Chapters 6 and 7. December 2009 2-8 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 33 of 135 PageID# 343 2.3.1. Exposure to PM2.5 2.3.1.1. Effects of Short-Term Exposure to PM 2.5 Table 2-1. Summary of causal determinations for short-term exposure to PM 2.5 . Size Fraction PM 2.5 Outcome Causality Determination Cardiovascular Effects Causal Respiratory Effects Likely to be causal Mortality Causal Cardiovascular Effects Epidemiologic studies that examined the effect of PM 2.5 on cardiovascular emergency department (ED) visits and hospital admissions reported consistent positive associations (predominantly for ischemic heart disease [IHD] and congestive heart failure [CHF]), with the majority of studies reporting increases ranging from 0.5 to 3.4% per 10 μg/m3 increase in PM 2.5 . These effects were observed in study locations with mean 1 24-h avg PM 2.5 concentrations ranging from 7-18 μg/m3 (Section 6.2.10). The largest U.S.-based multicity study evaluated, Medicare Air Pollution Study (MCAPS), provided evidence of regional heterogeneity (e.g., the largest excess risks occurred in the Northeast [1.08%]) and seasonal variation (e.g., the largest excess risks occurred during the winter season [1.49%]) in PM 2.5 cardiovascular disease (CVD) risk estimates, which is consistent with the null findings of several single-city studies conducted in the western U.S. These associations are supported by multicity epidemiologic studies that observed consistent positive associations between short-term exposure to PM 2.5 and cardiovascular mortality and also reported regional and seasonal variability in risk estimates. The multicity studies evaluated reported consistent increases in cardiovascular mortality ranging from 0.47 to 0.85% in study locations with mean 24-h avg PM 2.5 concentrations above 12.8 μg/m3 (Table 6-15). Controlled human exposure studies have demonstrated PM 2.5 -induced changes in various measures of cardiovascular function among healthy and health-compromised adults. The most consistent evidence is for altered vasomotor function following exposure to diesel exhaust (DE) or CAPs with O 3 (Section 6.2.4.2). Although these findings provide biological plausibility for the observations from epidemiologic studies, the fresh DE used in the controlled human exposure studies evaluated contains gaseous components (e.g., CO, NO x ), and therefore, the possibility that some of the changes in vasomotor function might be due to gaseous components cannot be ruled out. Furthermore, the prevalence of UFPs in fresh DE limits the ability to conclusively attribute the observed effects to either the UF fraction or PM 2.5 as a whole. An evaluation of toxicological studies found evidence for altered vessel tone and microvascular reactivity, which provide coherence and biological plausibility for the vasomotor effects that have been observed in both the controlled human exposure and epidemiologic studies (Section 6.2.4.3). However, most of these toxicological studies exposed animals via intratracheal (IT) instillation or using relatively high inhalation concentrations. In addition to the effects observed on vasomotor function, myocardial ischemia has been observed across disciplines through PM 2.5 effects on ST-segment depression, with toxicological studies providing biological plausibility by demonstrating reduced blood flow during ischemia (Section 6.2.3). There is also a growing body of evidence from controlled human exposure and toxicological studies demonstrating PM 2.5 -induced changes on heart rate variability (HRV) and ƒ 1 In this context mean represents the arithmetic mean of 24-h avg PM concentrations. December 2009 2-9 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 34 of 135 PageID# 344 markers of systemic oxidative stress (Sections 6.2.1 and 6.2.9, respectively). Additional but inconsistent effects of PM 2.5 on blood pressure (BP), blood coagulation markers, and markers of systemic inflammation have also been reported across disciplines. Toxicological studies have provided biologically plausible mechanisms (e.g., increased right ventricular pressure and diminished cardiac contractility) for the associations observed between PM 2.5 and CHF in epidemiologic studies. Together, the collective evidence from epidemiologic, controlled human exposure, and toxicological studies is sufficient to conclude that a causal relationship exists between short- term exposures to PM 2.5 and cardiovascular effects. Respiratory Effects The recent epidemiologic studies evaluated report consistent positive associations between short-term exposure to PM 2.5 and respiratory ED visits and hospital admissions for chronic obstructive pulmonary disease (COPD) and respiratory infections (Section 6.3). Positive associations were also observed for asthma ED visits and hospital admissions for adults and children combined, but effect estimates are imprecise and not consistently positive for children alone. Most studies reported effects in the range of ~1% to 4% increase in respiratory hospital admissions and ED visits and were observed in study locations with mean 24-h avg PM 2.5 concentrations ranging from 6.1-22 µg/m3. Additionally, multicity epidemiologic studies reported consistent positive associations between short-term exposure to PM 2.5 and respiratory mortality as well as regional and seasonal variability in risk estimates. The multicity studies evaluated reported consistent, precise increases in respiratory mortality ranging from 1.67 to 2.20% in study locations with mean 24-h avg PM 2.5 concentrations above 12.8 µg/m3 (Table 6-15). Evidence for PM 2.5 -related respiratory effects was also observed in panel studies, which indicate associations with respiratory symptoms, pulmonary function, and pulmonary inflammation among asthmatic children. Although not consistently observed, some controlled human exposure studies have reported small decrements in various measures of pulmonary function following controlled exposures to PM 2.5 (Section 6.3.2.2). Controlled human exposure studies using adult volunteers have demonstrated increased markers of pulmonary inflammation following exposure to a variety of different particle types; oxidative responses to DE and wood smoke; and exacerbations of allergic responses and allergic sensitization following exposure to DE particles (Section 6.3). Toxicological studies have provided additional support for PM 2.5 -related respiratory effects through inhalation exposures of animals to CAPs, DE, other traffic-related PM and wood smoke. These studies reported an array of respiratory effects including altered pulmonary function, mild pulmonary inflammation and injury, oxidative responses, airway hyperresponsiveness (AHR) in allergic and non-allergic animals, exacerbations of allergic responses, and increased susceptibility to infections (Section 6.3). Overall, the evidence for an effect of PM 2.5 on respiratory outcomes is somewhat restricted by limited coherence between some of the findings from epidemiologic and controlled human exposure studies for the specific health outcomes reported and the sub-populations in which those health outcomes occur. Epidemiologic studies have reported variable results among specific respiratory outcomes, specifically in asthmatics (e.g., increased respiratory symptoms in asthmatic children, but not increased asthma hospital admissions and ED visits) (Section 6.3.8). Additionally, respiratory effects have not been consistently demonstrated following controlled exposures to PM 2.5 among asthmatics or individuals with COPD. Collectively, the epidemiologic, controlled human exposure, and toxicological studies evaluated demonstrate a wide range of respiratory responses, and although results are not fully consistent and coherent across studies the evidence is sufficient to conclude that a causal relationship is likely to exist between short-term exposures to PM 2.5 and respiratory effects. Mortality An evaluation of the epidemiologic literature indicates consistent positive associations between short-term exposure to PM 2.5 and all-cause, cardiovascular-, and respiratory-related mortality (Section 6.5.2.2.). The evaluation of multicity studies found that consistent and precise risk estimates for all-cause (nonaccidental) mortality that ranged from 0.29 to 1.21% per 10 µg/m3 December 2009 2-10 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 35 of 135 PageID# 345 increase in PM 2.5 at lags of 1 and 0-1 days. In these study locations, mean 24-h avg PM 2.5 concentrations were 12.8 µg/m3 and above (Table 6-15). Cardiovascular-related mortality risk estimates were found to be similar to those for all-cause mortality; whereas, the risk estimates for respiratory-related mortality were consistently larger (i.e., 1.01-2.2%) using the same lag periods and averaging indices. The studies evaluated that examined the relationship between short-term exposure to PM 2.5 and cardiovascular effects (Section 6.2) provide coherence and biological plausibility for PM 2.5 -induced cardiovascular mortality, which represents the largest component of total (nonaccidental) mortality (~ 35%) (American Heart Association, 2009, 198920). However, as noted in Section 6.3, there is limited coherence between some of the respiratory morbidity findings from epidemiologic and controlled human exposure studies for the specific health outcomes reported and the subpopultions in which those health outcomes occur, complicating the interpretation of the PM 2.5 respiratory mortality effects observed. Regional and seasonal patterns in PM 2.5 risk estimates were observed with the greatest effect estimates occurring in the eastern U.S. and during the spring. Of the studies evaluated only Burnett et al. (2004, 086247), a Canadian multicity study, analyzed gaseous pollutants and found mixed results, with possible confounding of PM 2.5 risk estimates by NO 2 . Although the recently evaluated U.S.-based multicity studies did not analyze potential confounding of PM 2.5 risk estimates by gaseous pollutants, evidence from the limited number of single-city studies evaluated in the 2004 PM AQCD (U.S. EPA, 2004, 056905) suggest that gaseous copollutants do not confound the PM 2.5 -mortality association. This is further supported by studies that examined the PM 10 -mortality relationship. An examination of effect modifiers (e.g., demographic and socioeconomic factors), specifically air conditioning use as an indicator for decreased pollutant penetration indoors, has suggested that PM 2.5 risk estimates increase as the percent of the population with access to air conditioning decreases. Collectively, the epidemiologic literature provides evidence that a causal relationship exists between short-term exposures to PM 2.5 and mortality. 2.3.1.2. Effects of Long-Term Exposure to PM 2.5 Table 2-2. Summary of causal determinations for long-term exposure to PM 2.5 . Size Fraction PM 2.5 Outcome Causality Determination Cardiovascular Effects Causal Respiratory Effects Likely to be causal Mortality Causal Reproductive and Developmental Suggestive Cancer, Mutagenicity, and Genotoxicity Suggestive Cardiovascular Effects The strongest evidence for cardiovascular health effects related to long-term exposure to PM 2.5 comes from large, multicity U.S.-based studies, which provide consistent evidence of an association between long-term exposure to PM 2.5 and cardiovascular mortality (Section 7.2.10). These associations are supported by a large U.S.-based epidemiologic study (i.e., Women’s Health Initiative [WHI] study) that reports associations between PM 2.5 and CVDs among post-menopausal women using a 1-yr avg PM 2.5 concentration (mean = 13.5 µg/m3) (Section 7.2). However, epidemiologic studies that examined subclinical markers of CVD report inconsistent findings. Epidemiologic studies have also provided some evidence for potential modification of the PM 2.5 -CVD association when examining individual-level data, specifically smoking status and the use of anti- December 2009 2-11 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 36 of 135 PageID# 346 hyperlipidemics. Although epidemiologic studies have not consistently detected effects on markers of atherosclerosis due to long-term exposure to PM 2.5 , toxicological studies have provided strong evidence for accelerated development of atherosclerosis in ApoE-/- mice exposed to CAPs and have shown effects on coagulation, experimentally-induced hypertension, and vascular reactivity (Section 7.2.1.2). Evidence from toxicological studies provides biological plausibility and coherence with studies of short-term exposure and cardiovascular morbidity and mortality, as well as with studies that examined long-term exposure to PM 2.5 and cardiovascular mortality. Taken together, the evidence from epidemiologic and toxicological studies is sufficient to conclude that a causal relationship exists between long-term exposures to PM 2.5 and cardiovascular effects. Respiratory Effects Recent epidemiologic studies conducted in the U.S. and abroad provide evidence of associations between long-term exposure to PM 2.5 and decrements in lung function growth, increased respiratory symptoms, and asthma development in study locations with mean PM 2.5 concentrations ranging from 13.8 to 30 µg/m3 during the study periods (Section 7.3.1.1 and Section 7.3.2.1). These results are supported by studies that observed associations between long-term exposure to PM 10 and an increase in respiratory symptoms and reductions in lung function growth in areas where PM 10 is dominated by PM 2.5 . However, the evidence to support an association with long-term exposure to PM 2.5 and respiratory mortality is limited (Figure 7-7). Subchronic and chronic toxicological studies of CAPs, DE, roadway air and woodsmoke provide coherence and biological plausibility for the effects observed in the epidemiologic studies. These toxicological studies have presented some evidence for altered pulmonary function, mild inflammation, oxidative responses, immune suppression, and histopathological changes including mucus cell hyperplasia (Section 7.3). Exacerbated allergic responses have been demonstrated in animals exposed to DE and wood smoke. In addition, pre- and postnatal exposure to ambient levels of urban particles was found to affect lung development in an animal model. This finding is important because impaired lung development is one mechanism by which PM exposure may decrease lung function growth in children. Collectively, the evidence from epidemiologic and toxicological studies is sufficient to conclude that a causal relationship is likely to exist between long-term exposures to PM 2.5 and respiratory effects. Mortality The recent epidemiologic literature reports associations between long-term PM 2.5 exposure and increased risk of mortality. Mean PM 2.5 concentrations ranged from 13.2 to 29 µg/m3 during the study period in these areas (Section 7.6). When evaluating cause-specific mortality, the strongest evidence can be found when examining associations between PM 2.5 and cardiovascular mortality, and positive associations were also reported between PM 2.5 and lung cancer mortality (Figure 7-7). The cardiovascular mortality association has been confirmed further by the extended Harvard Six Cities and American Cancer Society studies, which both report strong associations between longterm exposure to PM 2.5 and cardiopulmonary and IHD mortality (Figure 7-7). Additional new evidence from a study that used the WHI cohort found a particularly strong association between long-term exposure to PM 2.5 and CVD mortality in post-menopausal women. Fewer studies have evaluated the respiratory component of cardiopulmonary mortality, and, as a result, the evidence to support an association with long-term exposure to PM 2.5 and respiratory mortality is limited (Figure 7-7). The evidence for cardiovascular and respiratory morbidity due to short- and long-term exposure to PM 2.5 provides biological plausibility for cardiovascular- and respiratory-related mortality. Collectively, the evidence is sufficient to conclude that a causal relationship exists between long-term exposures to PM 2.5 and mortality. December 2009 2-12 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 37 of 135 PageID# 347 Reproductive and Developmental Effects Evidence is accumulating for PM 2.5 effects on low birth weight and infant mortality, especially due to respiratory causes during the post-neonatal period. The mean PM 2.5 concentrations during the study periods ranged from 5.3-27.4 µg/m3 (Section 7.4), with effects becoming more precise and consistently positive in locations with mean PM 2.5 concentrations of 15 μg/m3 and above (Section 7.4). Exposure to PM 2.5 was usually associated with greater reductions in birth weight than exposure to PM 10 . The evidence from a few U.S. studies that investigated PM 10 effects on fetal growth, which reported similar decrements in birth weight, provide consistency for the PM 2.5 associations observed and strengthen the interpretation that particle exposure may be causally related to reductions in birth weight. The epidemiologic literature does not consistently report associations between long-term exposure to PM and preterm birth, growth restriction, birth defects or decreased sperm quality. Toxicological evidence supports an association between PM 2.5 and PM 10 exposure and adverse reproductive and developmental outcomes, but provide little mechanistic information or biological plausibility for an association between long-term PM exposure and adverse birth outcomes (e.g., low birth weight or infant mortality). New evidence from animal toxicological studies on heritable mutations is of great interest, and warrants further investigation. Overall, the epidemiologic and toxicological evidence is suggestive of a causal relationship between long- term exposures to PM 2.5 and reproductive and developmental outcomes. Cancer, Mutagenicity, and Genotoxicity Multiple epidemiologic studies have shown a consistent positive association between PM 2.5 and lung cancer mortality, but studies have generally not reported associations between PM 2.5 and lung cancer incidence (Section 7.5). Animal toxicological studies have examined the potential relationship between PM and cancer, but have not focused on specific size fractions of PM. Instead they have examined ambient PM, wood smoke, and DEP. A number of studies indicate that ambient urban PM, emissions from wood/biomass burning, emissions from coal combustion, and gasoline and DE are mutagenic, and that PAHs are genotoxic. These findings are consistent with earlier studies that concluded that ambient PM and PM from specific combustion sources are mutagenic and genotoxic and provide biological plausibility for the results observed in the epidemiologic studies. A limited number of epidemiologic and toxicological studies examined epigenetic effects, and demonstrate that PM induces some changes in methylation. However, it has yet to be determined how these alterations in the genome could influence the initiation and promotion of cancer. Additionally, inflammation and immune suppression induced by exposure to PM may confer susceptibility to cancer. Collectively, the evidence from epidemiologic studies, primarily those of lung cancer mortality, along with the toxicological studies that show some evidence of the mutagenic and genotoxic effects of PM is suggestive of a causal relationship between long-term exposures to PM 2.5 and cancer. 2.3.2. Integration of PM 2.5 Health Effects In epidemiologic studies, short-term exposure to PM 2.5 is associated with a broad range of respiratory and cardiovascular effects, as well as mortality. For cardiovascular effects and mortality, the evidence supports the existence of a causal relationship with short-term PM 2.5 exposure; while the evidence indicates that a causal relationship is likely to exist between short-term PM 2.5 exposure and respiratory effects. The effect estimates from recent and older U.S. and Canadian-based epidemiologic studies that examined the relationship between short-term exposure to PM 2.5 and health outcomes with mean 24-h avg PM 2.5 concentrations <17 μg/m3 are shown in Figure 2-1. A number of different health effects are included in Figure 2-1 to provide an integration of the range of effects by mean concentration, with a focus on cardiovascular and respiratory effects and all-cause (nonaccidental) mortality (i.e., health effects categories with at least a suggestive causal determination). A pattern of consistent positive associations with mortality and morbidity effects can be seen in this figure. Mean PM 2.5 concentrations ranged from 6.1 to 16.8 µg/m3.in these study locations. December 2009 2-13 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 38 of 135 PageID# 348 Study Outcome Chimonas & Gessner (2007, 093261) Asthma HA LRI HA Lisabeth et al. (2008, 155939) Ischemic Stroke/TIA HA Slaughter et al. (2005, 073854) Asthma Exacerbation Rabinovitch et al. (2006, 088031) Asthma Medication Use Chen et al. (2004, 087262) COPD HA Chen et al. (2005, 087555) Respiratory HA Fung et al. (2006, 089789) Respiratory HA Villeneuve et al. (2003, 055051) Nonaccidental Mortality Stieb et al. (2000, 011675) CVD ED Visits Respiratory ED Visits Villeneuve et al. (2006, 090191) Hemhrgc Stroke HA Ischemic Stroke HA TIA HA Lin et al. (2005, 087828) RTI HA Mar et al. (2004, 057309) Respiratory Symptoms (any) Respiratory Symptoms (any) Rich et al. (2005, 079620) Ventricular Arrhythmia Dockery et al. (2005, 078995) Ventricular Arrhythmia Rabinovitch et al. (2004, 096753) Asthma Exacerbation Pope et al. (2006, 091246) IHD HA Slaughter et al. (2005, 073854) CVD HA Respiratory ED Visits Pope et al. (2008, 191969) CHF HA Zanobetti and Schwartz (2006, 090195) MI HA Pneumonia HA Peters et al. (2001, 016546) MI Delfino et al. (1997, 082687) Respiratory HA (summer) Sullivan et al. (2005, 050854) MI Burnett et al. (2004, 086247) Nonaccidental Mortality Bell et al. (2008, 156266) Respiratory HA CVD HA m Wilson et al. (2007, 157149) CVD Mortality Zanobetti & Schwartz (2009, 188462) Nonaccidental Mortality Burnett and Goldberg (2003, 042798) Nonaccidental Mortality Dominici et al. (2006, 088398) CBVD HA PVD HA IHD HA Dysrhythmia HA CHF HA COPD HA RTI HA Fairley (2003, 042850) Nonaccidental Mortality Zhang et al. (2009, 191970) ST Segment Depression O’Connor et al. (2008, 156818) Wheeze/Cough Klemm and Mason (2003, 042801) Nonaccidental Mortality Franklin et al. (2008, 097426) Nonaccidental mortality NYDOH (2006, 090132) Asthma ED Visits Ito et al. (2007, 156594) Asthma HA Franklin et al. (2007, 091257) Non-accidental Mortality Rich et al. (2006, 089814) Ventricular Arrhythmia Symons et al. (2006, 091258) CHF HA Sheppard (2003, 042826) Asthma HA NYDOH (2006, 090132) Asthma ED Visits Burnett et al. (1997, 084194) Respiratory HA (summer) CVD HA (summer) a µg/m3 Study did not present mean; median presented. c Mean estimated from data in study. d Mean value slightly different from those reported in the published study or not reported in the published study; mean was either provided by study authors or calculated from data provided by study authors. e Mean value not reported in study; median presented. f 98th percentile of PM 2.5 distribution was either provided by study authors or calculated from data provided by study authors. g 98th estimated from data in study. b Figure 2-1. December 2009 Meana 98tha 6.1 6.1 e 7.0 e 7.3 7.4 7.7 7.7 7.7 7.9 8.5 8.5 8.5 8.5 8.5 9.6 c 9.8 c 9.8 e 9.8 e 10.3 d 10.6 c 10.7 10.8 10.8 10.8 e 11.1 e 11.1 12.1 12.1 12.8 12.8 d 12.9 d 12.9 13.0 d 13.2 13.3 13.3 13.3 13.3 13.3 13.3 13.3 13.3 13.6 j 13.9 c 14.0 e,i 14.7 14.8 k 15.0 15.1 15.6 e 16.2 d 16.5 16.7 l 16.7 16.8 16.8 Effect Estimate (95% CI) ----f 23.6 --f 17.2 --------f 27.3 f 27.3 f 24.0 f 24.0 f 24.0 --f 25.8 f 25.8 ----f 29.3 --f 29.6 f 29.6 d 44.5 ----f 28.2 f 31.2 --f 38.0 f 34.2 f 34.2 f 31.6 f 34.3 f 38.9 f 34.8 f 34.8 f 34.8 f 34.8 f 34.8 f 34.8 f 34.8 f 59.0 f 37.6 g 39.0 --f 43.0 --f 39.0 f 45.8 --f 50.1 f 46.6 --f 47.4 f 47.4 h Averaged annual values for years in study from data provided by study author. i Air quality data obtained from original study by Schwartz et al. (1996, 077325) j Mean PM 2.5 concentration reported is for lag 0-2. k Bronx; TEOM data. l Manhattan; TEOM data. m Study does not present an overall effect estimate; the vertical lines represent the effect estimate for each of the areas of Phoenix examined. Relative Risk / Odds Ratio Summary of effect estimates (per 10 µg/m3) by increasing concentration from U.S. studies examining the association between short-term exposure to PM 2.5 and cardiovascular and respiratory effects, and mortality, conducted in locations where the reported mean 24-h avg PM 2.5 concentrations were <17 µg/m3. 2-14 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 39 of 135 PageID# 349 Long-term exposure to PM 2.5 has been associated with health outcomes similar to those found in the short-term exposure studies, specifically for respiratory and cardiovascular effects and mortality. As found for short-term PM 2.5 exposure, the evidence indicates that a causal relationship exists between long-term PM 2.5 exposure and cardiovascular effects and mortality, and that a causal relationship is likely to exist between long-term PM 2.5 exposure and effects on the respiratory system. Figure 2-2 highlights the findings of epidemiologic studies where the long-term mean PM 2.5 concentrations were ≤ 29 µg/m3. A range of health outcomes are displayed (including cardiovascular mortality, all-cause mortality, infant mortaltiy, and bronchitis) ordered by mean concentration. The range of mean PM 2.5 concentrations in these studies was 10.7-29 µg/m3 during the study periods. Additional studies not included in this figure that focus on subclinical outcomes, such as changes in lung function or atherosclerotic markers also report effects in areas with similar concentrations (Sections 7.2 and 7.3). Although not highlighted in the summary figure, long-term PM 2.5 exposure studies also provide evidence for reproductive and developmental effects (i.e., low birth weight) and cancer (i.e., lung cancer mortality) in response to to exposure to PM 2.5 . Study Outcome Mean+ Zeger et al. (2008, 191951) Kim et al. (2004, 087383) Zeger et al. (2008, 191951) Miller et al. (2007, 090130) Eftim et al. (2008, 099104) Goss et al. (2004, 055624) McConnell et al. (2003, 049490) Zeger et al. (2008, 191951) Krewski et al. (2009, 191193) Eftim et al. (2008, 099104) Lipfert et al. (2006, 088756) Dockery et al. (1996, 046219) Woodruff et al. (2008, 098386) Laden et al. (2006, 087605) Woodruff et al. (2008, 098386) Enstrom (2005, 087356) Chen et al. (2005, 087942) All-Cause Mortality, Central U.S. Bronchitis (Children) All-Cause Mortality, Western U.S. CVD Morbidity or Mortality All-Cause Mortality, ACS Sites All-Cause Mortality Bronchitis (Children) All-Cause Mortality, Eastern U.S. All-Cause Mortality All-Cause Mortality, Harv 6-Cities All-Cause Mortality Bronchitis (Children) Infant Mortality (Respiratory) All-Cause Mortality Infant Mortality (Respiratory) All-Cause Mortality CHD Mortality, Females CHD Mortality, Males 10.7 12.0 13.1 13.5 13.6 13.7 13.8 14.0 14.0 14.1 14.3 14.5 14.8 16.4* 19.2 23.4 29.0 29.0 Effect Estimate (95% CI) * Mean estimated from data in study + µg/m3 Relative Risk Figure 2-2. Summary of effect estimates (per 10 µg/m3) by increasing concentration from U.S. studies examining the association between long-term exposure to PM 2.5 and cardiovascular and respiratory effects, and mortality. The observations from both the short- and long-term exposure studies are supported by experimental findings of PM 2.5 -induced subclinical and clinical cardiovascular effects. Epidemiologic studies have shown an increase in ED visits and hospital admissions for IHD upon exposure to PM 2.5 . These effects are coherent with the changes in vasomotor function and STsegment depression observed in both toxicological and controlled human exposure studies. It has been postulated that exposure to PM 2.5 can lead to myocardial ischemia through an effect on the autonomic nervous system or by altering vasomotor function. PM-induced systemic inflammation, oxidative stress and/or endothelial dysfunction may contribute to altered vasomotor function. These effects have been demonstrated in recent animal toxicological studies, along with altered microvascular reactivity, altered vessel tone, and reduced blood flow during ischemia. Toxicological studies demonstrating increased right ventricular pressure and diminished cardiac contractility also provide biological plausibility for the associations observed between PM 2.5 and CHF in epidemiologic studies. Thus, the overall evidence from the short-term epidemiologic, controlled human exposure, and toxicological studies evaluated provide coherence and biological plausibility for cardiovascular effects related to myocardial ischemia and CHF. Coherence in the cardiovascular effects observed December 2009 2-15 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 40 of 135 PageID# 350 can be found in long-term exposure studies, especially for CVDs among post-menopausal women. Additional studies provide limited evidence for subclinical measures of atherosclerosis in epidemiologic studies with stronger evidence from toxicological studies that have demonstrated accelerated development of atherosclerosis in ApoE-/- mice exposed to PM 2.5 CAPs along with effects on coagulation, experimentally-induced hypertension, and vascular reactivity. Repeated acute responses to PM may lead to cumulative effects that manifest as chronic disease, such as atherosclerosis. Contributing factors to atherosclerosis development include systemic inflammation, endothelial dysfunction, and oxidative stress all of which are associated with PM 2.5 exposure. However, it has not yet been determined whether PM initiates or promotes atherosclerosis. The evidence from both short- and long-term exposure studies on cardiovascular morbidity provide coherence and biological plausibility for the cardiovascular mortality effects observed when examining both exposure durations. In addition, cardiovascular hospital admission and mortality studies that examined the PM 10 concentration-response relationship found evidence of a log-linear no-threshold relationship between PM exposure and cardiovascular-related morbidity (Section 6.2) and mortality (Section 6.5). Epidemiologic studies have also reported respiratory effects related to short-term exposure to PM 2.5 , which include increased ED visits and hospital admissions, as well as alterations in lung function and respiratory symptoms in asthmatic children. These respiratory effects were found to be generally robust to the inclusion of gaseous pollutants in copollutant models with the strongest evidence from the higher powered studies (Figure 6-9 and Figure 6-15). Consistent positive associations were also reported between short-term exposure to PM 2.5 and respiratory mortality in epidemiologic studies. However, uncertainties exist in the PM 2.5 -respiratory mortality associations reported due to the limited number of studies that examined potential confounders of the PM 2.5 respiratory mortality relationship, and the limited information regarding the biological plausibility of the clinical and subclinical respiratory outcomes observed in the epidemiologic and controlled human exposure studies (Section 6.3) resulting in the progression to PM 2.5 -induced respiratory mortality. Important new findings, which support the PM 2.5 -induced respiratory effects mentioned above, include associations with post-neonatal (between 1 mo and 1 yr of age) respiratory mortality. Controlled human exposure studies provide some support for the respiratory findings from epidemiologic studies, with demonstrated increases in pulmonary inflammation following short-term exposure. However, there is limited and inconsistent evidence of effects in response to controlled exposures to PM 2.5 on respiratory symptoms or pulmonary function among healthy adults or adults with respiratory disease. Long-term exposure epidemiologic studies provide additional evidence for PM 2.5 -induced respiratory morbidity, but little evidence for an association with respiratory mortality. These epidemiologic morbidity studies have found decrements in lung function growth, as well as increased respiratory symptoms, and asthma. Toxicological studies provide coherence and biological plausibility for the respiratory effects observed in response to short and long-term exposures to PM by demonstrating a wide array of biological responses including: altered pulmonary function, mild pulmonary inflammation and injury, oxidative responses, and histopathological changes in animals exposed by inhalation to PM 2.5 derived from a wide variety of sources. In some cases, prolonged exposures led to adaptive responses. Important evidence was also found in an animal model for altered lung development following pre- and post-natal exposure to urban air, which may provide a mechanism to explain the reduction in lung function growth observed in children in response to long-term exposure to PM. Additional respiratory-related effects have been tied to allergic responses. Epidemiologic studies have provided evidence for increased hospital admissions for allergic symptoms (e.g., allergic rhinitis) in response to short- and long-term exposure to PM 2.5 . Panel studies also positively associate long-term exposure to PM 2.5 and PM 10 with indicators of allergic sensitization. Controlled human exposure and toxicological studies provide coherence for the exacerbation of allergic symptoms, by showing that PM 2.5 can promote allergic responses and intensify existing allergies. Allergic responses require repeated exposures to antigen over time and co-exposure to an adjuvant (possibly DE particles or UF CAPs) can enhance this response. Allergic sensitization often underlies allergic asthma, characterized by inflammation and AHR. In this way, repeated or chronic exposures involving multifactorial responses (immune system activation, oxidative stress, inflammation) can lead to irreversible outcomes. Epidemiologic studies have also reported evidence for increased hospital admissions for respiratory infections in response to both short- and long-term exposures to PM 2.5 . Toxicological studies suggest that PM impairs innate immunity, which is the first line of December 2009 2-16 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 41 of 135 PageID# 351 defense against infection, providing coherence for the respiratory infection effects observed in epidemiologic studies. The difference in effects observed across studies and between cities may be attributed, at least in part, to the differences in PM composition across the U.S. Differences in PM toxicity may result from regionally varying PM composition and size distribution, which in turn reflects differences in sources and PM volatility. A person’s exposure to ambient PM will also vary due to regional differences in personal activity patterns, microenvironmental characteristics and the spatial variability of PM concentrations in urban areas. Regional differences in PM 2.5 composition are outlined briefly in Section 2.1 above and in more detail in Section 3.5. An examination of data from the CSN indicates that East-West gradients exist for a number of PM components. Specifically, SO 4 2concentrations are higher in the East, OC constitutes a larger fraction of PM in the West, and NO 3 concentrations are highest in the valleys of central California and during the winter in the Midwest. However, the available evidence and the limited amount of city-specific speciated PM 2.5 data does not allow conclusions to be drawn that specifically differentiate effects of PM in different locations. It remains a challenge to determine relationships between specific constituents, combinations of constituents, or sources of PM 2.5 and the various health effects observed. Source apportionment studies of PM 2.5 have attempted to decipher some of these relationships and in the process have identified associations between multiple sources and various respiratory and cardiovascular health effects, as well as mortality. Although different source apportionment methods have been used across these studies, the methods used have been evaluated and found generally to identify the same sources and associations between sources and health effects (Section 6.6). While uncertainty remains, it has been recognized that many sources and components of PM 2.5 contribute to health effects. Overall, the results displayed in Table 6-18 indicate that many constituents of PM 2.5 can be linked with multiple health effects, and the evidence is not yet sufficient to allow differentiation of those constituents or sources that are more closely related to specific health outcomes. Variability in the associations observed across PM 2.5 epidemiologic studies may be due in part to exposure error related to the use of county-level air quality data. Because western U.S. counties tend to be much larger and more topographically diverse than eastern U.S. counties, the day-to-day variations in concentration at one site, or even for the average of several sites, may not correlate well with the day-to-day variations in all parts of the county. For example, site-to-site correlations as a function of distance between sites (Section 3.5.1.2) fall off rapidly with distance in Los Angeles, but high correlations extend to larger distances in eastern cities such as Boston and Pittsburgh. These differences may be attributed to a number of factors including topography, the built environment, climate, source characteristics, ventilation usage, and personal activity patterns. For instance, regional differences in climate and infrastructure can affect time spent outdoors or indoors, air conditioning usage, and personal activity patterns. Characteristics of housing stock may also cause regional differences in effect estimates because new homes tend to have lower infiltration factors than older homes. Biases and uncertainties in exposure estimates resulting from these aspects can, in turn, cause bias and uncertainty in associated health effects estimates. The new evidence reviewed in this ISA greatly expands upon the evidence available in the 2004 PM AQCD particularly in providing greater understanding of the underlying mechanisms for PM 2.5 induced cardiovascular and respiratory effects for both short- and long-term exposures. Recent studies have provided new evidence linking long-term exposure to PM 2.5 with cardiovascular outcomes that has expanded upon the continuum of effects ranging from the more subtle subclinical measures to cardiopulmonary mortality. December 2009 2-17 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 42 of 135 PageID# 352 2.3.3. Exposure to PM10-2.5 2.3.3.1. Effects of Short-Term Exposure to PM 10-2.5 Table 2-3. Summary of causal determinations for short-term exposure to PM 10-2.5 . Size Fraction PM 10-2.5 Outcome Causality Determination Cardiovascular Effects Suggestive Respiratory Effects Suggestive Mortality Suggestive Cardiovascular Effects Generally positive associations were reported between short-term exposure to PM 10-2.5 and hospital admissions or ED visits for cardiovascular causes. These results are supported by a large U.S. multicity study of older adults that reported PM 10-2.5 associations with CVD hospital admissions, and only a slight reduction in the PM 10-2.5 risk estimate when included in a copollutant model with PM 2.5 (Section 6.2.10). The PM 10-2.5 associations with cardiovascular hospital admissions and ED visits were observed in study locations with mean 24-h avg PM 10-2.5 concentrations ranging from 7.4 to 13 µg/m3. These results are supported by the associations observed between PM 10-2.5 and cardiovascular mortality in areas with 24-h avg PM 10-2.5 concentrations ranging from 6.1-16.4 µg/m3 (Section 6.2.11). The results of the epidemiologic studies were further confirmed by studies that examined dust storm events, which contain high concentrations of crustal material, and found an increase in cardiovascular-related ED visits and hospital admissions. Additional epidemiologic studies have reported PM 10-2.5 associations with other cardiovascular health effects including supraventricular ectopy and changes in HRV (Section 6.2.1.1). Although limited in number, studies of controlled human exposures provide some evidence to support the alterations in HRV observed in the epidemiologic studies (Section 6.2.1.2). The few toxicological studies that examined the effect of PM 10-2.5 on cardiovascular health effects used IT instillation due to the technical challenges in exposing rodents via inhalation to PM 10-2.5 , and, as a result, provide only limited evidence on the biological plausibility of PM 10-2.5 induced cardiovascular effects. The potential for PM 10-2.5 to elicit an effect is supported by dosimetry studies, which show that a large proportion of inhaled particles in the 3-6 micron (d ae ) range can reach and deposit in the lower respiratory tract, particularly the tracheobronchial (TB) airways (Figures 4-3 and 4-4). Collectively, the evidence from epidemiologic studies, along with the more limited evidence from controlled human exposure and toxicological studies is suggestive of a causal relationship between short-term exposures to PM 10-2.5 and cardiovascular effects. Respiratory Effects A number of recent epidemiologic studies conducted in Canada and France found consistent, positive associations between respiratory ED visits and hospital admissions and short-term exposure to PM 10-2.5 in studies with mean 24-h avg concentrations ranging from 5.6-16.2 μg/m3 (Section 6.3.8) . In these studies, the strongest relationships were observed among children, with less consistent evidence for adults and older adults (i.e., ≥ 65). In a large multicity study of older adults, PM 10-2.5 was positively associated with respiratory hospital admissions in both single and copollutant models with PM 2.5 . In addition, a U.S.-based multicity study found evidence for an increase in respiratory mortality upon short-term exposure to PM 10-2.5 , but these associations have not been consistently December 2009 2-18 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 43 of 135 PageID# 353 observed in single-city studies (Section 6.3.9). A limited number of epidemiologic studies have focused on specific respiratory morbidity outcomes, and found no evidence of an association with lower respiratory symptoms, wheeze, and medication use (Section 6.3.1.1). While controlled human exposure studies have not observed an effect on lung function or respiratory symptoms in healthy or asthmatic adults in response to short-term exposure to PM 10-2.5 , healthy volunteers have exhibited an increase in markers of pulmonary inflammation. Toxicological studies using inhalation exposures are still lacking, but pulmonary injury has been observed in animals after IT instillation exposure (Section 6.3.5.3). In some cases, PM 10-2.5 was found to be more potent than PM 2.5 and effects were not attributable to endotoxin. Both rural and urban PM 10-2.5 have induced inflammation and injury responses in rats or mice exposed via IT instillation, making it difficult to distinguish the health effects of PM 10-2.5 from different environments. Overall, epidemiologic studies, along with the limited number of controlled human exposure and toxicological studies that examined PM 10-2.5 respiratory effects provide evidence that is suggestive of a causal relationship between short- term exposures to PM 10-2.5 and respiratory effects. Mortality The majority of studies evaluated in this review provide some evidence for mortality associations with PM 10-2.5 in areas with mean 24-h avg concentrations ranging from 6.1-16.4 μg/m3. However, uncertainty surrounds the PM 10-2.5 associations reported in the studies evaluated due to the different methods used to estimate PM 10-2.5 concentrations across studies (e.g., direct measurement of PM 10-2.5 using dichotomous samplers, calculating the difference between PM 10 and PM 2.5 concentrations). In addition, only a limited number of PM 10-2.5 studies have investigated potential confounding by gaseous copollutants or the influence of model specification on PM 10-2.5 risk estimates. A new U.S.-based multicity study, which estimated PM 10-2.5 concentrations by calculating the difference between the county-average PM 10 and PM 2.5 , found associations between PM 10-2.5 and mortality across the U.S., including evidence for regional variability in PM 10-2.5 risk estimates (Section 6.5.2.3). Additionally, the U.S.-based multicity study provides preliminary evidence for greater effects occurring during the warmer months (i.e., spring and summer). A multicity Canadian study provides additional evidence for an association between short-term exposure to PM 10-2.5 and mortality (Section 6.5.2.3). Although consistent positive associations have been observed across both multi- and single-city studies, more data are needed to adequately characterize the chemical and biological components that may modify the potential toxicity of PM 10-2.5 and compare the different methods used to estimate exposure. Overall, the evidence evaluated is suggestive of a causal relationship between short-term exposures to PM 10-2.5 and mortality. 2.3.4. Integration of PM 10-2.5 Effects Epidemiologic, controlled human exposure, and toxicological studies have provided evidence that is suggestive for relationships between short-term exposure to PM 10-2.5 and cardiovascular effects, respiratory effects, and mortality. Conclusions regarding causation for the various health effects and outcomes were made for PM 10-2.5 as a whole regardless of origin, since PM 10-2.5 -related effects have been demonstrated for a number of different environments (e.g., cities reflecting a wide range of environmental conditions). Associations between short-term exposure to PM 10-2.5 and cardiovascular and respiratory effects, and mortality have been observed in locations with mean PM 10-2.5 concentrations ranging from 5.6 to 33.2 µg/m3, and maximum PM 10-2.5 concentrations ranging from 24.6 to 418.0 µg/m3) (Figure 2-3). A number of different health effects are included in Figure 2-3 to provide an integration of the range of effects by mean concentration, with a focus on cardiovascular and respiratory effects, and mortality (i.e., health effects categories with at least a suggestive causal determination). To date, a sufficient amount of evidence does not exist in order to draw conclusions regarding the health effects and outcomes associated with long-term exposure to PM 10-2.5 . In epidemiologic studies, associations between short-term exposure to PM 10-2.5 and cardiovascular outcomes (i.e., IHD hospital admissions, supraventricular ectopy, and changes in HRV) have been found that are similar in magnitude to those observed in PM 2.5 studies. Controlled human exposure studies have also observed alterations in HRV, providing consistency and coherence December 2009 2-19 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 44 of 135 PageID# 354 for the effects observed in the epidemiologic studies. To date, only a limited number of toxicological studies have been conducted to examine the effects of PM 10-2.5 on cardiovascular effects. All of these studies involved IT instillation due to the technical challenges of using PM 10-2.5 for rodent inhalation studies. As a result, the toxicological studies evaluated provide limited biological plausibility for the PM 10-2.5 effects observed in the epidemiologic and controlled human exposure studies. Study Outcome Chen et al. (2004, 087262) Fung et al. (2006, 089789) Chen et al. (2005, 087942) Villeneuve et al. (2003, 055051) Lipfert et al. (2000, 004088) Peters et al. (2001, 016546) Tolbert et al. (2007, 090316) COPD HA RD HA RD HA Nonaccidental Mortality CVD Mortality MI CVD ED Visits RD ED Visits Klemm et al. (2003, 042801) Nonaccidental Mortality Metzger et al. (2007, 092856) Ventricular Arrhythmia Peel et al. (2005, 056305) Asthma ED Visits COPD ED Visits RD ED Visits Pneumonia ED Visits URI ED Visits Metzger et al. (2004, 044222) CHF ED Visits IHD ED Visits Klemm et al. (2004, 056585) Nonaccidental Mortality Mar et al. (2004, 057309) Symptoms (any) Asthma Symptoms Lin et al. (2005, 087828) RTI HA Burnett et al. (2004, 086247) Non-accidental Mortality Burnett et al. (1997, 084194) CVD HA Respiratory HA Fairley (2003, 042850) Nonaccidental Mortality Zanobetti & Schwartz (2009, 188462) Nonaccidental Mortality Lin et al. (2002, 026067) Asthma HA (boys) Lin et al. (2002, 026067; 2004, 056067) Asthma HA (girls) Peng et al. (2008, 156850) RD HA CVD HA Burnett and Goldberg (2003, 042798) Nonaccidental Mortality Ito (2003, 042856) Nonaccidental Mortality CHF HA IHD HA COPD HA Pneumonia HA Thurston et al. (1994, 043921) Respiratory HA Sheppard (2003, 042826) Asthma HA Ostro et al. (2003, 042824) CVD Mortality Mar et al. (2003, 042841) CVD Mortality a Meana 5.6 5.6 5.6 6.1 d 6.9 7.4 9.0 9.0 b 9.0 9.6 9.7 9.7 9.7 9.7 9.7 d 9.7 d 9.7 9.9 c 10.8 c 10.8 10.9 11.4 d 11.5 d 11.5 d 11.7 11.8 12.2 12.2 d 12.3 d 12.3 12.6 d 13.3 d 13.3 d 13.3 d 13.3 d 13.3 c 14.4 16.2 30.5 33.2 Maxa Effect Estimate (95% CI) 24.6 27.1 24.6 72.0 28.3 --50.3 50.3 30.0 50.3 e 34.2 e 34.2 e 34.2 e 34.2 e 34.2 e 34.2 e 34.2 25.2 e 50.9 e 50.9 45.0 151.0 56.1 56.1 55.2 e 88.3 68.0 68.0 e 81.3 e 81.3 99.0 50.0 50.0 50.0 50.0 50.0 33.0 88.0 418.0 158.6 µg/m3 Study did not present mean; median presented. c Mean estimated from data in study. d Mean value slightly different from those reported in the published study; mean was either provided by study authors or calculated from data provided by study authors. e Maximum PM 10-2.5 concentration provided by study authors or calculated from data provided by study authors. b Figure 2-3. Relative Risk / Odds Ratio Summary of U.S. studies examining the association between short-term exposure to PM 10-2.5 and cardiovascular morbidity/mortality and respiratory morbidity/mortality. All effect estimates have been standardized to reflect a 10 µg/m3 increase in mean 24-h avg PM 10-2.5 concentration and ordered by increasing concentration. Limited evidence is available from epidemiologic studies for respiratory health effects and outcomes in response to short-term exposure to PM 10-2.5 . An increase in respiratory hospital admissions and ED visits has been observed, but primarily in studies conducted in Canada and Europe. In addition, associations are not reported for lower respiratory symptoms, wheeze, or medication use. Controlled human exposure studies have not observed an effect on lung function or respiratory symptoms in healthy or asthmatic adults, but healthy volunteers have exhibited pulmonary inflammation. The toxicological studies (all IT instillation) provide evidence of December 2009 2-20 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 45 of 135 PageID# 355 pulmonary injury and inflammation. In some cases, PM 10-2.5 was found to be more potent than PM 2.5 and effects were not solely attributable to endotoxin. Currently, a national network is not in place to monitor PM 10-2.5 concentrations. As a result, uncertainties surround the concentration at which the observed associations occur. Ambient concentrations of PM 10-2.5 are generally determined by the subtraction of PM 10 and PM 2.5 measurements, using various methods. For example, some epidemiologic studies estimate PM 10-2.5 by taking the difference between collocated PM 10 and PM 2.5 monitors while other studies have taken the difference between county average PM 10 and PM 2.5 concentrations. Moreover, there are potential differences among operational flow rates and temperatures for PM 10 and PM 2.5 monitors used to calculate PM 10-2.5 . Therefore, there is greater error in ambient exposure to PM 10-2.5 compared to PM 2.5 . This would tend to increase uncertainty and make it more difficult to detect effects of PM 10-2.5 in epidemiologic studies. In addition, the various differences between eastern and western U.S. counties can lead to exposure misclassification, and the potential underestimation of effects in western counties (as discussed for PM 2.5 in Section 2.3.2). It is also important to note that the chemical composition of PM 10-2.5 can vary considerably by location, but city-specific speciated PM 10-2.5 data are limited. PM 10-2.5 may contain Fe, Si, Al, and base cations from soil, plant and insect fragments, pollen, fungal spores, bacteria, and viruses, as well as fly ash, brake lining particles, debris, and automobile tire fragments. The 2004 PM AQCD presented the limited amount of evidence available that examined the potential association between exposure to PM 10-2.5 and health effects and outcomes. The current evidence, primarily from epidemiologic studies, builds upon the results from the 2004 PM AQCD and indicates that short-term exposure to PM 10-2.5 is associated with effects on both the cardiovascular and respiratory systems. However, variability in the chemical and biological composition of PM 10-2.5 , limited evidence regarding effects of the various components of PM 10-2.5 , and lack of clearly defined biological mechanisms for PM 10-2.5 -related effects are important sources of uncertainty. 2.3.5. Exposure to UFPs 2.3.5.1. Effects of Short-Term Exposure to UFPs Table 2-4. Summary of causal determinations for short-term exposure to UFPs. Size Fraction UFPs Outcome Causality Determination Cardiovascular Effects Suggestive Respiratory Effects Suggestive Cardiovascular Effects Controlled human exposure studies provide the majority of the evidence for cardiovascular health effects in response to short-term exposure to UFPs. While there are a limited number of studies that have examined the association between UFPs and cardiovascular morbidity, there is a larger body of evidence from studies that exposed subjects to fresh DE, which is typically dominated by UFPs. These studies have consistently demonstrated changes in vasomotor function following exposure to atmospheres containing relatively high concentrations of particles (Section 6.2.4.2). Markers of systemic oxidative stress have also been observed to increase after exposure to various particle types that are predominantly in the UFP size range. In addition, alterations in HRV parameters have been observed in response to controlled human exposure to UF CAPs, with inconsistent evidence for changes in markers of blood coagulation following exposure to UF CAPs December 2009 2-21 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 46 of 135 PageID# 356 and DE (Sections 6.2.1.2 and 6.2.8.2). A few toxicological studies have also found consistent changes in vasomotor function, which provides coherence with the effects demonstrated in the controlled human exposure studies (Section 6.2.4.3). Additional UFP-induced effects observed in toxicological studies include alterations in HRV, with less consistent effects observed for systemic inflammation and blood coagulation. Only a few epidemiologic studies have examined the effect of UFPs on cardiovascular morbidity and collectively they found inconsistent evidence for an association between UFPs and CVD hospital admissions, but some positive associations for subclinical cardiovascular measures (i.e., arrhythmias and supraventricular beats) (Section 6.2.2.1). These studies were conducted in the U.S. and Europe in areas with mean particle number concentration ranging from ~8,500 to 36,000 particles/cm3. However, UFP number concentrations are highly variable (i.e., concentrations drop off quickly from the road compared to accumulation mode particles), and therefore, more subject to exposure error than accumulation mode particles. In conclusion, the evidence from the studies evaluated is suggestive of a causal relationship between short-term exposures to UFPs and cardiovascular effects. Respiratory Effects A limited number of epidemiologic studies have examined the potential association between short-term exposure to UFPs and respiratory morbidity. Of the studies evaluated, there is limited, and inconsistent evidence for an association between short-term exposure to UFPs and respiratory symptoms, as well as asthma hospital admissions in locations a median particle number concentration of ~6,200 to a mean of 38,000 particles/cm3 (Section 6.3.10). The spatial and temporal variability of UFPs also affects these associations. Toxicological studies have reported respiratory effects including oxidative, inflammatory, and allergic responses using a number of different UFP types (Section 6.3). Although controlled human exposure studies have not extensively examined the effect of UFPs on respiratory outcomes, a few studies have observed small UFP-induced asymptomatic decreases in pulmonary function. Markers of pulmonary inflammation have been observed to increase in healthy adults following controlled exposures to UFPs, particularly in studies using fresh DE. However, it is important to note that for both controlled human exposure and animal toxicological studies of exposures to fresh DE, the relative contributions of gaseous copollutants to the respiratory effects observed remain unresolved. Thus, the current collective evidence is suggestive of a causal relationship between short-term exposures to UFPs and respiratory effects. 2.3.6. Integration of UFP Effects The controlled human exposure studies evaluated have consistently demonstrated effects on vasomotor function and systemic oxidative stress with additional evidence for alterations in HRV parameters in response to exposure to UF CAPs. The toxicological studies provide coherence for the changes in vasomotor function observed in the controlled human exposure studies. Epidemiologic studies are limited because a national network is not in place to measure UFP in the U.S. UFP concentrations are spatially and temporally variable, which would increase uncertainty and make it difficult to detect associations between health effects and UFPs in epidemiologic studies. In addition, data on the composition of UFPs, the spatial and temporal evolution of UFP size distribution and chemical composition, and potential effects of UFP constituents are sparse. More limited evidence is available regarding the effect of UFPs on respiratory effects. Controlled human exposure studies have not extensively examined the effect of UFPs on respiratory measurements, but a few studies have observed small decrements in pulmonary function and increases in pulmonary inflammation. Additional effects including oxidative, inflammatory, and proallergic outcomes have been demonstrated in toxicological studies. Epidemiologic studies have found limited and inconsistent evidence for associations between UFPs and respiratory effects. Overall, a limited number of studies have examined the association between exposure to UFPs and morbidity and mortality. Of the studies evaluated, controlled human exposure and toxicological studies provide the most evidence for UFP-induced cardiovascular and respiratory effects; however, many studies focus on exposure to DE. As a result, it is unclear if the effects observed are due to UFP, larger particles (i.e., PM 2.5 ), or the gaseous components of DE. Additionally, UF CAPs systems December 2009 2-22 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 47 of 135 PageID# 357 are limited as the atmospheric UFP composition is modified when concentrated, which adds uncertainty to the health effects observed in controlled human exposure studies (Section 1.5.3). 2.4. Policy Relevant Considerations 2.4.1. Potentially Susceptible Populations Upon evaluating the association between short- and long-term exposure to PM and various health outcomes, studies also attempted to identify populations that are more susceptible to PM (i.e., populations that have a greater likelihood of experiencing health effects related to exposure to an air pollutant (e.g., PM) due to a variety of factors including, but not limited to: genetic or developmental factors, race, gender, life stage, lifestyle (e.g., smoking status and nutrition) or preexisting disease; as well as, population-level factors that can increase an individual's exposure to an air pollutant (e.g., PM) such as socioeconomic status [SES], which encompasses reduced access to health care, low educational attainment, residential location, and other factors). These studies did so by conducting stratified analyses; by examining effects in individuals with an underlying health condition; or by developing animal models that mimic the pathophysiologic conditions associated with an adverse health effect. In addition, numerous studies that focus on only one potentially susceptible population provide supporting evidence on whether a population is susceptible to PM exposure. These studies identified a multitude of factors that could potentially contribute to whether an individual is susceptible to PM (Table 8-2). Although studies have primarily used exposures to PM 2.5 or PM 10 , the available evidence suggests that the identified factors may also enhance susceptibility to PM 10-2.5 . The examination of susceptible populations to PM exposure allows for the NAAQS to provide an adequate margin of safety for both the general population and for susceptible populations. During specific periods of life (i.e., childhood and advanced age), individuals may be more susceptible to environmental exposures, which in turn can render them more susceptible to PMrelated health effects. An evaluation of age-related health effects suggests that older adults have heightened responses for cardiovascular morbidity with PM exposure. In addition, epidemiologic and toxicological studies provide evidence that indicates children are at an increased risk of PMrelated respiratory effects. It should be noted that the health effects observed in children could be initiated by exposures to PM that occurred during key windows of development, such as in utero. Epidemiologic studies that focus on exposures during development have reported inconsistent findings (Section 7.4), but a recent toxicological study suggests that inflammatory responses in pregnant women due to exposure to PM could result in health effects in the developing fetus. Epidemiologic studies have also examined whether additional factors, such as gender, race, or ethnicity modify the association between PM and morbidity and mortality outcomes. Although gender and race do not seem to modify PM risk estimates, limited evidence from two studies conducted in California suggest that Hispanic ethnicity may modify the association between PM and mortality. Recent epidemiologic and toxicological studies provided evidence that individuals with null alleles or polymorphisms in genes that mediate the antioxidant response to oxidative stress (i.e., GSTM1), regulate enzyme activity (i.e., MTHFR and cSHMT), or regulate levels of procoagulants (i.e., fibrinogen) are more susceptible to PM exposure. However, some studies have shown that polymorphisms in genes (e.g., HFE) can have a protective effect against effects of PM exposure. Additionally, preliminary evidence suggests that PM exposure can impart epigenetic effects (i.e., DNA methylation); however, this requires further investigation. Collectively, the evidence from epidemiologic and toxicological, and to a lesser extent, controlled human exposure studies, indicate increased susceptibility of individuals with underlying CVDs and respiratory illnesses (i.e., asthma) to PM exposure. Controlled human exposure and toxicological studies provide additional evidence for increased PM-related cardiovascular effects in individuals with underlying respiratory health conditions. Recently studies have begun to examine the influence of preexisting chronic inflammatory conditions, such as diabetes and obesity, on PM-related health effects. These studies have found some evidence for increased associations for cardiovascular outcomes along with pathophysiologic alterations in markers of inflammation, oxidative stress, and acute phase response. However, more December 2009 2-23 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 48 of 135 PageID# 358 research is needed to thoroughly examine the affect of PM exposure on obese individuals and to identify the biological pathway(s) that could increase the susceptibility of diabetic and obese individuals to PM. There is also evidence that SES, measured using surrogates such as educational attainment or residential location, modifies the association between PM and morbidity and mortality outcomes. In addition, nutritional status, another surrogate measure of SES, has been shown to have protective effects against PM exposure in individuals that have a higher intake of some vitamins and nutrients. Overall, the epidemiologic, controlled human exposure, and toxicological studies evaluated in this review provide evidence for increased susceptibility for various populations, including children and older adults, people with pre-existing cardiopulmonary diseases, and people with lower SES. 2.4.2. Lag Structure of PM-Morbidity and PM-Mortality Associations Epidemiologic studies have evaluated the time-frame in which exposure to PM can impart a health effect. PM exposure-response relationships can potentially be influenced by a multitude of factors, such as the underlying susceptibility of an individual (e.g., age, pre-existing diseases), which could increase or decrease the lag times observed. An attempt has been made to identify whether certain lag periods are more strongly associated with specific health outcomes. The epidemiologic evidence evaluated in the 2004 PM AQCD supported the use of lags of 0-1 days for cardiovascular effects and longer moving averages or distributed lags for respiratory diseases (U.S. EPA, 2004, 056905). However, currently, little consensus exists as to the most appropriate a priori lag times to use when examining morbidity and mortality outcomes. As a result, many investigators have chosen to examine the lag structure of associations between PM concentration and health outcome instead of focusing on a priori lag times. This approach is informative because if effects are cumulative, higher overall risks may exist than would be observed for any given single-day lag. 2.4.2.1. PM-Cardiovascular Morbidity Associations Most of the studies evaluated that examined the association between cardiovascular hospital admissions and ED visits report associations with short-term PM exposure at lags 0- to 2-days, with more limited evidence for shorter durations (i.e., hours) between exposure and response for some health effects (e.g., onset of MI) (Section 6.2.10). However, these studies have rarely examined alternative lag structures. Controlled human exposure and toxicological studies provide biological plausibility for the health effects observed in the epidemiologic studies at immediate or concurrent day lags. Although the majority of the evidence supports shorter lag times for cardiovascular health effects, a recent study has provided preliminary evidence suggesting that longer lag times (i.e., 14day distributed lag model) may be plausible for non-ischemic cardiovascular conditions (Section 6.2.10). Panel studies of short-term exposure to PM and cardiovascular endpoints have also examined the time frame from exposure to health effect using a wide range of lag times. Studies of ECG changes indicating ischemia show effects at lags from several hours to 2 days, while lag times ranging from hours to several week moving averages have been observed in studies of arrhythmias, vasomotor function and blood markers of inflammation, coagulation and oxidative stress (Section 6.2). The longer lags observed in these panel studies may be explained if the effects of PM are cumulative. Although few studies of cumulative effects have been conducted, toxicological studies have demonstrated PM-dependent progression of atherosclerosis. It should be noted that PM exposure could also lead to an acute event (e.g., infarction or stroke) in individuals with atherosclerosis that may have progressed in response to cumulative PM exposure. Therefore, effects have been observed at a range of lag periods from a few hours to several days with no clear evidence for any lag period having stronger associations then another. 2.4.2.2. PM-Respiratory Morbidity Associations Generally, recent studies of respiratory hospital admissions that evaluate multiple lags, have found effect sizes to be larger when using longer moving averages or distributed lag models. For example, when examining hospital admissions for all respiratory diseases among older adults, the strongest associations were observed when using PM concentrations 2 days prior to the hospital December 2009 2-24 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 49 of 135 PageID# 359 admission (Section 6.3.8). Longer lag periods were also found to be most strongly associated with asthma hospital admissions and ED visits in children (3-5 days) with some evidence for more immediate effects in older adults (lags of 0 and 1 day), but these observations were not consistent across studies (Section 6.3.8). These variable results could be due to the biological complexity of asthma, which inhibits the identification of a specific lag period. The longer lag times identified in the epidemiologic studies evaluated are biologically plausible considering that PM effects on allergic sensitization and lung immune defenses have been observed in controlled human exposure and toxicological studies. These effects could lead to respiratory illnesses over a longer time course (e.g., within several days respiratory infection may become evident, resulting in respiratory symptoms or a hospital admission). However, inflammatory responses, which contribute to some forms of asthma, may result in symptoms requiring medical care within a shorter time frame (e.g., 0-1 days). 2.4.2.3. PM-Mortality Associations Epidemiologic studies that focused on the association between short-term PM exposure and mortality (i.e., all-cause, cardiovascular, and respiratory) mostly examined a priori lag structures of either 1 or 0-1 days. Although mortality studies do not often examine alternative lag structures, the selection of the aforementioned a priori lag days has been confirmed in additional studies, with the strongest PM-mortality associations consistently being observed at lag 1 and 0-1-days (Section 6.5). However, of note is recent evidence for larger effect estimates when using a distributed lag model. Epidemiologic studies that examined the association between long-term exposure to PM and mortality have also attempted to identify the latency period from PM exposure to death (Section 7.6.4). Results of the lag comparisons from several cohort studies indicate that the effects of changes in exposure on mortality are seen within five years, with the strongest evidence for effects observed within the first two years. Additionally, there is evidence, albeit from one study, that the mortality effect had larger cumulative effects spread over the follow-up year and three preceding years. 2.4.3. PM Concentration-Response Relationship An important consideration in characterizing the PM-morbidity and mortality association is whether the concentration-response relationship is linear across the full concentration range that is encountered or if there are concentration ranges where there are departures from linearity (i.e., nonlinearity). In this ISA studies have been identified that attempt to characterize the shape of the concentration-response curve along with possible PM “thresholds” (i.e., levels which PM concentrations must exceed in order to elicit a health response). The epidemiologic studies evaluated that examined the shape of the concentration-response curve and the potential presence of a threshold have focused on cardiovascular hospital admissions and ED visits and mortality associated with short-term exposure to PM 10 and mortality associated with long-term exposure to PM 2.5 . A limited number of studies have been identified that examined the shape of the PMcardiovascular hospital admission and ED visit concentration-response relationship. Of these studies, some conducted an exploratory analysis during model selection to determine if a linear curve most adequately represented the concentration-response relationship; whereas, only one study conducted an extensive analysis to examine the shape of the concentration-response curve at different concentrations (Section 6.2.10.10). Overall, the limited evidence from the studies evaluated supports the use of a no-threshold, log-linear model, which is consistent with the observations made in studies that examined the PM-mortality relationship. Although multiple studies have previously examined the PM-mortality concentration-response relationship and whether a threshold exists, more complex statistical analyses continue to be developed to analyze this association. Using a variety of methods and models, most of the studies evaluated support the use of a no-threshold, log-linear model; however, one study did observe heterogeneity in the shape of the concentration-response curve across cities (Section 6.5). Overall, the studies evaluated further support the use of a no-threshold log-linear model, but additional issues such as the influence of heterogeneity in estimates between cities, and the effect of seasonal and regional differences in PM on the concentration-response relationship still require further investigation. December 2009 2-25 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 50 of 135 PageID# 360 In addition to examining the concentration-response relationship between short-term exposure to PM and mortality, Schwartz et al. (2008, 156963) conducted an analysis of the shape of the concentration-response relationship associated with long-term exposure to PM. Using a variety of statistical methods, the concentration-response curve was found to be indistinguishable from linear, and, therefore, little evidence was observed to suggest that a threshold exists in the association between long-term exposure to PM 2.5 and the risk of death (Section 7.6). 2.4.4. PM Sources and Constituents Linked to Health Effects Recent epidemiologic, toxicological, and controlled human exposure studies have evaluated the health effects associated with ambient PM constituents and sources, using a variety of quantitative methods applied to a broad set of PM constituents, rather than selecting a few constituents a priori (Section 6.6). There is some evidence for trends and patterns that link particular ambient PM constituents or sources with specific health outcomes, but there is insufficient evidence to determine whether these patterns are consistent or robust. For cardiovascular effects, multiple outcomes have been linked to a PM 2.5 crustal/soil/road dust source, including cardiovascular mortality and ST-segment changes. Additional studies have reported associations between other sources (i.e., traffic and wood smoke/vegetative burning) and cardiovascular outcomes (i.e., mortality and ED visits). Studies that only examined the effects of individual PM 2.5 constituents found evidence for an association between EC and cardiovascular hospital admissions and cardiovascular mortality. Many studies have also observed associations between other sources (i.e., salt, secondary SO 4 2–/long-range transport, other metals) and cardiovascular effects, but at this time, there does not appear to be a consistent trend or pattern of effects for those factors. There is less consistent evidence for associations between PM sources and respiratory health effects, which may be partially due to the fact that fewer source apportionment studies have been conducted that examined respiratory-related outcomes (e.g., hospital admissions) and measures (e.g., lung function). However, there is some evidence for associations between respiratory ED visits and decrements in lung function with secondary SO 4 2– PM 2.5 . In addition, crustal/soil/road dust and traffic sources of PM have been found to be associated with increased respiratory symptoms in asthmatic children and decreased PEF in asthmatic adults. Inconsistent results were observed in those PM 2.5 studies that used individual constituents to examine associations with respiratory morbidity and mortality, although Cu, Pb, OC, and Zn were related to respiratory health effects in two or more studies. A few studies have identified PM 2.5 sources associated with total mortality. These studies found an association between mortality and the PM 2.5 sources: secondary SO 4 2–/long-range transport, traffic, and salt. In addition, studies have evaluated whether the variation in associations between PM 2.5 and mortality or PM 10 and mortality reflects differences in PM 2.5 constituents. PM 10 mortality effect estimates were greater in areas with a higher proportion of Ni in PM 2.5 , but the overall PM 10 -mortality association was diminished when New York City was excluded in sensitivity analyses in two of the studies. V was also found to modify PM 10 -mortality effect estimates. When examining the effect of species-to-PM 2.5 mass proportion on PM 2.5 -mortality effect estimates, Ni, but not V, was also found to modify the association. Overall, the results indicate that many constituents of PM can be linked with differing health effects and the evidence is not yet sufficient to allow differentiation of those constituents or sources that are more closely related to specific health outcomes. These findings are consistent with the conclusions of the 2004 PM AQCD (U.S. EPA, 2004, 056905) (i.e., that a number of source types, including motor vehicle emissions, coal combustion, oil burning, and vegetative burning, are associated with health effects). Although the crustal factor of fine particles was not associated with mortality in the 2004 PM AQCD (U.S. EPA, 2004, 056905), recent studies have suggested that PM (both PM 2.5 and PM 10-2.5 ) from crustal, soil or road dust sources or PM tracers linked to these sources are associated with cardiovascular effects. In addition, PM 2.5 secondary SO 4 2– has been associated with both cardiovascular and respiratory effects. December 2009 2-26 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 51 of 135 PageID# 361 2.5. Welfare Effects This section presents key conclusions and scientific judgments regarding causality for welfare effects of PM as discussed in Chapter 9. The effects of particulate NO X and SO X have recently been evaluated in the ISA for Oxides of Nitrogen and Sulfur – Ecological Criteria (U.S. EPA, 2008, 157074). That ISA focused on the effects from deposition of gas- and particle-phase pollutants related to ambient NO X and SO X concentrations that can lead to acidification and nutrient enrichment. Thus, emphasis in Chapter 9 is placed on the effects of airborne PM, including NO X and SO X , on visibility and climate, and on the effects of deposition of PM constituents other than NO X and SO X , primarily metals and carbonaceous compounds. EPA’s framework for causality, described in Chapter 1, was applied and the causal determinations are highlighted. Table 2-5. Summary of causality determination for welfare effects. Welfare Effects Causality Determination Effects on Visibility Causal Effects on Climate Causal Ecological Effects Likely to be causal Effects on Materials Causal 2.5.1. Summary of Effects on Visibility Visibility impairment is caused by light scattering and absorption by suspended particles and gases. There is strong and consistent evidence that PM is the overwhelming source of visibility impairment in both urban and remote areas. EC and some crustal minerals are the only commonly occurring airborne particle components that absorb light. All particles scatter light, and generally light scattering by particles is the largest of the four light extinction components (i.e., absorption and scattering by gases and particles). Although a larger particle scatters more light than a similarly shaped smaller particle of the same composition, the light scattered per unit of mass is greatest for particles with diameters from ~0.3-1.0 μm. For studies where detailed data on particle composition by size are available, accurate calculations of light extinction can be made. However, routinely available PM speciation data can be used to make reasonable estimates of light extinction using relatively simple algorithms that multiply the concentrations of each of the major PM species by its dry extinction efficiency and by a water growth term that accounts for particle size change as a function of relative humidity for hygroscopic species (e.g., sulfate, nitrate, and sea salt). This permits the visibility impairment associated with each of the major PM components to be separately approximated from PM speciation monitoring data. Direct optical measurement of light extinction measured by transmissometer, or by combining the PM light scattering measured by integrating nephelometers with the PM light absorption measured by an aethalometer, offer a number of advantages compared to algorithm estimates of light extinction based on PM composition and relative humidity data. The direct measurements are not subject to the uncertainties associated with assumed scattering and absorption efficiencies used in the PM algorithm approach. The direct measurements have higher time resolution (i.e., minutes to hours), which is more commensurate with visibility effects compared with calculated light extinction using routinely available PM speciation data (i.e., 24-h duration). Particulate sulfate and nitrate have comparable light extinction efficiencies (haze impacts per unit mass concentration) at any relative humidity value. Their light scattering per unit mass concentration increases with increasing relative humidity, and at sufficiently high humidity values (RH>85%) they are the most efficient particulate species contributing to haze. Particulate sulfate is December 2009 2-27 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 52 of 135 PageID# 362 the dominant source of regional haze in the eastern U.S. (>50% of the particulate light extinction) and an important contributor to haze elsewhere in the country (>20% of particulate light extinction). Particulate nitrate is a minor component of remote-area regional haze in the non-California western and eastern U.S., but an important contributor in much of California and in the upper Midwestern U.S., especially during winter when it is the dominant contributor to particulate light extinction. EC and OC have the highest dry extinction efficiencies of the major PM species and are responsible for a large fraction of the haze, especially in the northwestern U.S., though absolute concentrations are as high in the eastern U.S. Smoke plume impacts from large wildfires dominate many of the worst haze periods in the western U.S. Carbonaceous PM is generally the largest component of urban excess PM 2.5 (i.e., the difference between urban and regional background concentration). Western urban areas have more than twice the average concentrations of carbonaceous PM than remote areas sites in the same region. In eastern urban areas PM 2.5 is dominated by about equal concentrations of carbonaceous and sulfate components, though the usually high relative humidity in the East causes the hydrated sulfate particles to be responsible for about twice as much of the urban haze as that caused by the carbonaceous PM. PM 2.5 crustal material (referred to as fine soil) and PM 10-2.5 are significant contributors to haze for remote areas sites in the arid southwestern U.S. where they contribute a quarter to a third of the haze, with PM 10-2.5 usually contributing twice that of fine soil. Coarse mass concentrations are as high in the Central Great Plains as in the deserts though there are no corresponding high concentrations of fine soil as in the Southwest. Also the relative contribution to haze by the high coarse mass in the Great Plains is much smaller because of the generally higher haze values caused by the high concentrations of sulfate and nitrate PM in that region. Visibility has direct significance to people’s enjoyment of daily activities and their overall sense of wellbeing. For example, psychological research has demonstrated that people are emotionally affected by poor VAQ such that their overall sense of wellbeing is diminished. Urban visibility has been examined in two types of studies directly relevant to the NAAQS review process: urban visibility preference studies and urban visibility valuation studies. Both types of studies are designed to evaluate individuals’ desire for good VAQ where they live, using different metrics. Urban visibility preference studies examine individuals’ preferences by investigating the amount of visibility degradation considered unacceptable, while economic studies examine the value an individual places on improving VAQ by eliciting how much the individual would be willing to pay for different amounts of VAQ improvement. There are three urban visibility preference studies and two additional pilot studies that have been conducted to date that provide useful information on individuals’ preferences for good VAQ in the urban setting. The completed studies were conducted in Denver, Colorado, two cities in British Columbia, Canada, and Phoenix, AZ. The additional studies were conducted in Washington, DC. The range of median preference values for an acceptable amount of visibility degradation from the 4 urban areas was approximately 19-33 dv. Measured in terms of visual range (VR), these median acceptable values were between approximately 59 and 20 km. The economic importance of urban visibility has been examined by a number of studies designed to quantify the benefits (or willingness to pay) associated with potential improvements in urban visibility. Urban visibility valuation research was described in the 2004 PM AQCD (U.S. EPA, 2004, 056905) and the 2005 PM Staff Paper (U.S. EPA, 2005, 090209). Since the mid-1990s, little new information has become available regarding urban visibility valuation (Section 9.2.4). Collectively, the evidence is sufficient to conclude that a causal relationship exists between PM and visibility impairment. 2.5.2. Summary of Effects on Climate Aerosols affect climate through direct and indirect effects. The direct effect is primarily realized as planet brightening when seen from space because most aerosols scatter most of the visible spectrum light that reaches them. The Intergovernmental Panel on Climate Change (IPCC) Fourth Assessment Report (AR4) (IPCC, 2007, 092765), hereafter IPCC AR4, reported that the radiative forcing from this direct effect was -0.5 (±0.4) W/m2 and identified the level of scientific understanding of this effect as 'Medium-low'. The global mean direct radiative forcing effect from individual components of aerosols was estimated for the first time in the IPCC AR4 where they were reported to be (all in W/m2 units): -0.4 (±0.2) for sulfate, -0.05 (±0.05) for fossil fuel-derived organic December 2009 2-28 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 53 of 135 PageID# 363 carbon, +0.2 (±0.15) for fossil fuel-derived black carbon (BC), +0.03 (±0.12) for biomass burning, -0.1 (±0.1) for nitrates, and -0.1 (±0.2) for mineral dust. Global loadings of anthropogenic dust and nitrates remain very troublesome to estimate, making the radiative forcing estimates for these constituents particularly uncertain. Numerical modeling of aerosol effects on climate has sustained remarkable progress since the time of the 2004 PM AQCD (U.S. EPA, 2004, 056905), PM AQCD, though model solutions still display large heterogeneity in their estimates of the direct radiative forcing effect from anthropogenic aerosols. The clear-sky direct radiative forcing over ocean due to anthropogenic aerosols is estimated from satellite instruments to be on the order of -1.1 (±0.37) W/m2 while model estimates are -0.6 W/m2. The models' low bias over ocean is carried through for the global average: global average direct radiative forcing from anthropogenic aerosols is estimated from measurements to range from -0.9 to -1.9 W/m2, larger than the estimate of -0.8 W/m2 from the models. Aerosol indirect effects on climate are primarily realized as an increase in cloud brightness (termed the 'first indirect' or Twomey effect), changes in precipitation, and possible changes in cloud lifetime. The IPCC AR4 reported that the radiative forcing from the Twomey effect was -0.7 (range: -1.1 to +4) and identified the level of scientific understanding of this effect as “Low” in part owing to the very large unknowns concerning aerosol size distributions and important interactions with clouds. Other indirect effects from aerosols are not considered to be radiative forcing. Taken together, direct and indirect effects from aerosols increase Earth's shortwave albedo or reflectance thereby reducing the radiative flux reaching the surface from the Sun. This produces net climate cooling from aerosols. The current scientific consensus reported by IPCC AR4 is that the direct and indirect radiative forcing from anthropogenic aerosols computed at the top of the atmosphere, on a global average, is about -1.3 (range: -2.2 to -0.5) W/m2. While the overall global average effect of aerosols at the top of the atmosphere and at the surface is negative, absorption and scattering by aerosols within the atmospheric column warms the atmosphere between the Earth's surface and top of the atmosphere. In part, this is owing to differences in the distribution of aerosol type and size within the vertical atmospheric column since aerosol type and size distributions strongly affect the aerosol scattering and reradiation efficiencies at different altitudes and atmospheric temperatures. And, although the magnitude of the overall negative radiative forcing at the top of the atmosphere appears large in comparison to the analogous IPCC AR4 estimate of positive radiative forcing from anthropogenic GHG of about +2.9 (± 0.3) W/m 2, the horizontal, vertical, and temporal distributions and the physical lifetimes of these two very different radiative forcing agents are not similar; therefore, the effects do not simply off-set one another. Overall, the evidence is sufficient to conclude that a causal relationship exists between PM and effects on climate, including both direct effects on radiative forcing and indirect effects that involve cloud feedbacks that influence precipitation formation and cloud lifetimes. 2.5.3. Summary of Ecological Effects of PM Ecological effects of PM include direct effects to metabolic processes of plant foliage; contribution to total metal loading resulting in alteration of soil biogeochemistry and microbiology, plant growth and animal growth and reproduction; and contribution to total organics loading resulting in bioaccumulation and biomagnification across trophic levels. These effects were wellcharacterized in the 2004 PM AQCD (U.S. EPA, 2004, 056905). Thus, the summary below builds upon the conclusions provided in that review. PM deposition comprises a heterogeneous mixture of particles differing in origin, size, and chemical composition. Exposure to a given concentration of PM may, depending on the mix of deposited particles, lead to a variety of phytotoxic responses and ecosystem effects. Moreover, many of the ecological effects of PM are due to the chemical constituents (e.g., metals, organics, and ions) and their contribution to total loading within an ecosystem. Investigations of the direct effects of PM deposition on foliage have suggested little or no effects on foliar processes, unless deposition levels were higher than is typically found in the ambient environment. However, consistent and coherent evidence of direct effects of PM has been found in heavily polluted areas adjacent to industrial point sources such as limestone quarries, cement kilns, and metal smelters (Sections 9.4.3 and 9.4.5.7). Where toxic responses have been December 2009 2-29 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 54 of 135 PageID# 364 documented, they generally have been associated with the acidity, trace metal content, surfactant properties, or salinity of the deposited materials. An important characteristic of fine particles is their ability to affect the flux of solar radiation passing through the atmosphere, which can be considered in both its direct and diffuse components. Foliar interception by canopy elements occurs for both up- and down-welling radiation. Therefore, the effect of atmospheric PM on atmospheric turbidity influences canopy processes both by radiation attenuation and by changing the efficiency of radiation interception in the canopy through conversion of direct to diffuse radiation. Crop yields can be sensitive to the amount of radiation received, and crop losses have been attributed to increased regional haze in some areas of the world such as China (Section 9.4.4). On the other hand, diffuse radiation is more uniformly distributed throughout the canopy and may increase canopy photosynthetic productivity by distributing radiation to lower leaves. The enrichment in photosynthetically active radiation (PAR) present in diffuse radiation may offset a portion of the effect of an increased atmospheric albedo due to atmospheric particles. Further research is needed to determine the effects of PM alteration of radiative flux on the growth of vegetation in the U.S. The deposition of PM onto vegetation and soil, depending on its chemical composition, can produce responses within an ecosystem. The ecosystem response to pollutant deposition is a direct function of the level of sensitivity of the ecosystem and its ability to ameliorate resulting change. Many of the most important ecosystem effects of PM deposition occur in the soil. Upon entering the soil environment, PM pollutants can alter ecological processes of energy flow and nutrient cycling, inhibit nutrient uptake, change ecosystem structure, and affect ecosystem biodiversity. The soil environment is one of the most dynamic sites of biological interaction in nature. It is inhabited by microbial communities of bacteria, fungi, and actinomycetes, in addition to plant roots and soil macro-fauna. These organisms are essential participants in the nutrient cycles that make elements available for plant uptake. Changes in the soil environment can be important in determining plant and ultimately ecosystem response to PM inputs. There is strong and consistent evidence from field and laboratory experiments that metal components of PM alter numerous aspects of ecosystem structure and function. Changes in the soil chemistry, microbial communities and nutrient cycling, can result from the deposition of trace metals. Exposures to trace metals are highly variable, depending on whether deposition is by wet or dry processes. Although metals can cause phytotoxicity at high concentrations, few heavy metals (e.g., Cu, Ni, Zn) have been documented to cause direct phytotoxicity under field conditions. Exposure to coarse particles and elements such as Fe and Mg are more likely to occur via dry deposition, while fine particles, which are more often deposited by wet deposition, are more likely to contain elements such as Ca, Cr, Pb, Ni, and V. Ecosystems immediately downwind of major emissions sources can receive locally heavy deposition inputs. Phytochelatins produced by plants as a response to sublethal concentrations of heavy metals are indicators of metal stress to plants. Increased concentrations of phytochelatins across regions and at greater elevation have been associated with increased amounts of forest injury in the northeastern U.S. Overall, the ecological evidence is sufficient to conclude that a causal relationship is likely to exist between deposition of PM and a variety of effects on individual organisms and ecosystems, based on information from the previous review and limited new findings in this review. However, in many cases, it is difficult to characterize the nature and magnitude of effects and to quantify relationships between ambient concentrations of PM and ecosystem response due to significant data gaps and uncertainties as well as considerable variability that exists in the components of PM and their various ecological effects. 2.5.4. Summary of Effects on Materials Building materials (metals, stones, cements, and paints) undergo natural weathering processes from exposure to environmental elements (wind, moisture, temperature fluctuations, sunlight, etc.). Metals form a protective film of oxidized metal (e.g., rust) that slows environmentally induced corrosion. However, the natural process of metal corrosion is enhanced by exposure to anthropogenic pollutants. For example, formation of hygroscopic salts increases the duration of surface wetness and enhances corrosion. A significant detrimental effect of particle pollution is the soiling of painted surfaces and other building materials. Soiling changes the reflectance of opaque materials and reduces the transmission December 2009 2-30 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 55 of 135 PageID# 365 of light through transparent materials. Soiling is a degradation process that requires remediation by cleaning or washing, and, depending on the soiled surface, repainting. Particulate deposition can result in increased cleaning frequency of the exposed surface and may reduce the usefulness of the soiled material. Attempts have been made to quantify the pollutant exposure levels at which materials damage and soiling have been perceived. However, to date, insufficient data are available to advance the knowledge regarding perception thresholds with respect to pollutant concentration, particle size, and chemical composition. Nevertheless, the evidence is sufficient to conclude that a causal relationship exists between PM and effects on materials. 2.6. Summary of Health Effects and Welfare Effects Causal Determinations This chapter has provided an overview of the underlying evidence used in making the causal determinations for the health and welfare effects and PM size fractions evaluated. This review builds upon the main conclusions of the last PM AQCD (U.S. EPA, 2004, 056905): ƒ “A growing body of evidence both from epidemiological and toxicological studies… supports the general conclusion that PM 2.5 (or one or more PM 2.5 components), acting alone and/or in combination with gaseous copollutants, are likely causally related to cardiovascular and respiratory mortality and morbidity.” (pg 9-79) ƒ “A much more limited body of evidence is suggestive of associations between short-term (but not long-term) exposures to ambient coarse-fraction thoracic particles… and various mortality and morbidity effects observed at times in some locations. This suggests that PM 10-2.5 , or some constituent component(s) of PM 10-2.5 , may contribute under some circumstances to increased human health risks… with somewhat stronger evidence for… associations with morbidity (especially respiratory) endpoints than for mortality.” (pg 9-79 and 9-80) ƒ “Impairment of visibility in rural and urban areas is directly related to ambient concentrations of fine particles, as modulated by particle composition, size, and hygroscopic characteristics, and by relative humidity.” (pg 9-99) ƒ “Available evidence, ranging from satellite to in situ measurements of aerosol effects on incoming solar radiation and cloud properties, is strongly indicative of an important role in climate for aerosols, but this role is still poorly quantified.” (pg 9-111) The evaluation of the epidemiologic, toxicological, and controlled human exposure studies published since the completion of the 2004 PM AQCD have provided additional evidence for PM-related health effects. Table 2-6 provides an overview of the causal determinations for all PM size fractions and health effects. Causal determinations for PM and welfare effects, including visibility, climate, ecological effects, and materials are included in Table 2-7. Detailed discussions of the scientific evidence and rationale for these causal determinations are provided in the subsequent chapters of this ISA. December 2009 2-31 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 56 of 135 PageID# 366 Table 2-6. Summary of PM causal determinations by exposure duration and health outcome. Size Fraction Exposure Short-term PM 2.5 Long-term Outcome Causality Determination Cardiovascular Effects Causal Respiratory Effects Likely to be causal Central Nervous System Inadequate Mortality Causal Cardiovascular Effects Causal Respiratory Effects Likely to be Causal Mortality Causal Reproductive and Developmental Suggestive Cancer, Mutagenicity, Genotoxicity Suggestive Short-term PM 10-2.5 Long-term Cardiovascular Effects Suggestive Respiratory Effects Suggestive Central Nervous System Inadequate Mortality Suggestive Cardiovascular Effects Inadequate Respiratory Effects Inadequate Mortality Inadequate Reproductive and Developmental Inadequate Cancer, Mutagenicity, Genotoxicity Inadequate Short-term UFPs Long-term Cardiovascular Effects Suggestive Respiratory Effects Suggestive Central Nervous System Inadequate Mortality Inadequate Cardiovascular Effects Inadequate Respiratory Effects Inadequate Mortality Inadequate Reproductive and Developmental Inadequate Cancer, Mutagenicity, Genotoxicity Inadequate December 2009 2-32 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 57 of 135 PageID# 367 Table 2-7. Summary of PM causal determinations for welfare effects Welfare Effects Causality Determination Effects on Visibility Causal Effects on Climate Causal Ecological Effects Likely to be causal Effects on Materials Causal December 2009 2-33 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 58 of 135 PageID# 368 Chapter 2 References American Heart Association (2009). Cardiovascular disease statistics. Retrieved 17-NOV-09, from http://www.americanheart.org/presenter.jhtml?identifier=4478. 198920 ATSDR (2006). A study of ambient air contaminants and asthma in New York City: Part A and B. Agency for Toxic Substances and Disease Registry; Public Health Service; U.S. Department of Health and Human Services. Atlanta, GA.http://permanent.access.gpo.gov/lps88357/ASTHMA_BRONX_FINAL_REPORT.pdf. 090132 Bell ML; Ebisu K; Peng RD; Walker J; Samet JM; Zeger SL; Dominic F (2008). Seasonal and regional short-term effects of fine particles on hospital admissions in 202 U.S. counties, 1999-2005. 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Epidemiology, 19: 209-216. 099104 Enstrom JE (2005). Fine particulate air pollution and total mortality among elderly Californians, 1973-2002. Inhal Toxicol, 17: 803-816. 087356 ƒ Note: Hyperlinks to the reference citations throughout this document will take you to the NCEA HERO database (Health and Environmental Research Online) at http://epa.gov/hero. HERO is a database of scientific literature used by U.S. EPA in the process of developing science assessments such as the Integrated Science Assessments (ISA) and the Integrated Risk Information System (IRIS). December 2009 2-34 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 59 of 135 PageID# 369 Fairley D (2003). Mortality and air pollution for Santa Clara County, California, 1989-1996, In: Revised analyses of timeseries studies of air pollution and health. Special report. Health Effects Institute. Boston, MA.http://www.healtheffects.org/Pubs/TimeSeries.pdf . 042850 Franklin M; Koutrakis P; Schwartz J (2008). 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The influence of ambient coarse particulate matter on asthma hospitalization in children: case-crossover and time-series analyses. Environ Health Perspect, 110: 575-581. 026067 Lin M; Stieb DM; Chen Y (2005). Coarse particulate matter and hospitalization for respiratory infections in children younger than 15 years in Toronto: a case-crossover analysis. Pediatrics, 116: 235-240. 087828 Lipfert FW; Baty JD; Miller JP; Wyzga RE (2006). PM2.5 constituents and related air quality variables as predictors of survival in a cohort of U.S. military veterans. Inhal Toxicol, 18: 645-657. 088756 Lipfert FW; Morris SC; Wyzga RE (2000). Daily mortality in the Philadelphia metropolitan area and size-classified particulate matter. J Air Waste Manag Assoc, 50: 1501-1513. 004088 Lisabeth LD; Escobar JD; Dvonch JT; Sanchez BN; Majersik JJ; Brown DL; Smith MA; Morgenstern LB (2008). Ambient air pollution and risk for ischemic stroke and transient ischemic attack. Ann Neurol, 64: 53-59. 155939 Mar TF; Larson TV; Stier RA; Claiborn C; Koenig JQ (2004). An analysis of the association between respiratory symptoms in subjects with asthma and daily air pollution in Spokane, Washington. Inhal Toxicol, 16: 809-815. 057309 Mar TF; Norris GA; Larson TV; Wilson WE; Koenig JQ (2003). Air pollution and cardiovascular mortality in Phoenix, 1995-1997. Health Effects Institute. Cambridge, MA. 042841 December 2009 2-35 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 60 of 135 PageID# 370 McConnell R; Berhane K; Gilliland F; Molitor J; Thomas D; Lurmann F; Avol E; Gauderman WJ; Peters JM (2003). Prospective study of air pollution and bronchitic symptoms in children with asthma. Am J Respir Crit Care Med, 168: 790-797. 049490 Metzger KB; Klein M; Flanders WD; Peel JL; Mulholland JA; Langberg JJ; Tolbert PE (2007). Ambient air pollution and cardiac arrhythmias in patients with implantable defibrillators. Epidemiology, 18: 585-592. 092856 Metzger KB; Tolbert PE; Klein M; Peel JL; Flanders WD; Todd KH; Mulholland JA; Ryan PB; Frumkin H (2004). Ambient air pollution and cardiovascular emergency department visits. Epidemiology, 15: 46-56. 044222 Miller KA; Siscovick DS; Sheppard L; Shepherd K; Sullivan JH; Anderson GL; Kaufman JD (2007). Long-term exposure to air pollution and incidence of cardiovascular events in women. N Engl J Med, 356: 447-458. 090130 O'Connor GT; Neas L; Vaughn B; Kattan M; Mitchell H; Crain EF; Evans R 3rd; Gruchalla R; Morgan W; Stout J; Adams GK; Lippmann M (2008). Acute respiratory health effects of air pollution on children with asthma in US inner cities. J Allergy Clin Immunol, 121: 1133-1139. 156818 Ostro BD; Broadwin R; Lipsett MJ (2003). Coarse particles and daily mortality in Coachella Valley, California. Health Effects Institute. Boston, MA. 042824 Peel JL; Tolbert PE; Klein M; Metzger KB; Flanders WD; Knox T; Mulholland JA; Ryan PB; Frumkin H (2005). Ambient air pollution and respiratory emergency department visits. Epidemiology, 16: 164-174. 056305 Peng RD; Chang HH; Bell ML; McDermott A; Zeger SL; Samet JM; Dominici F (2008). Coarse particulate matter air pollution and hospital admissions for cardiovascular and respiratory diseases among Medicare patients. JAMA, 299: 2172-2179. 156850 Peters A; Dockery DW; Muller JE; Mittleman MA (2001). Increased particulate air pollution and the triggering of myocardial infarction. Circulation, 103: 2810-2815. 016546 Pope C; Renlund D; Kfoury A; May H; Horne B (2008). Relation of heart failure hospitalization to exposure to fine particulate air pollution. Am J Cardiol, 102: 1230-1234. 191969 Pope CA III; Muhlestein JB; May HT; Renlund DG; Anderson JL; Horne BD (2006). Ischemic heart disease events triggered by short-term exposure to fine particulate air pollution. Circulation, 114: 2443-2448. 091246 Rabinovitch N; Strand M; Gelfand EW (2006). Particulate levels are associated with early asthma worsening in children with persistent disease. Am J Respir Crit Care Med, 173: 1098-1105. 088031 Rabinovitch N; Zhang LN; Murphy JR; Vedal S; Dutton SJ; Gelfand EW (2004). Effects of wintertime ambient air pollutants on asthma exacerbations in urban minority children with moderate to severe disease. J Allergy Clin Immunol, 114: 1131-1137. 096753 Renwick LC; Brown D; Clouter A; Donaldson K (2004). Increased inflammation and altered macrophage chemotactic responses caused by two ultrafine particle types. Occup Environ Med, 61: 442-447. 056067 Rich DQ; Kim MH; Turner JR; Mittleman MA; Schwartz J; Catalano PJ; Dockery DW (2006). Association of ventricular arrhythmias detected by implantable cardioverter defibrillator and ambient air pollutants in the St Louis, Missouri metropolitan area. Occup Environ Med, 63: 591-596. 089814 Rich DQ; Schwartz J; Mittleman MA; Link M; Luttmann-Gibson H; Catalano PJ; Speizer FE; Dockery DW (2005). 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J Expo Sci Environ Epidemiol, 15: 153-159. 073854 December 2009 2-36 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 61 of 135 PageID# 371 Stieb DM; Beveridge RC; Brook JR; Smith-Doiron M; Burnett RT; Dales RE; Beaulieu S; Judek S; Mamedov A (2000). Air pollution, aeroallergens and cardiorespiratory emergency department visits in Saint John, Canada. J Expo Sci Environ Epidemiol, 10: 461-477. 011675 Sullivan J; Sheppard L; Schreuder A; Ishikawa N; Siscovick D; Kaufman J (2005). Relation between short-term fineparticulate matter exposure and onset of myocardial infarction. Epidemiology, 16: 41-48. 050854 Symons JM; Wang L; Guallar E; Howell E; Dominici F; Schwab M; Ange BA; Samet J; Ondov J; Harrison D; Geyh A (2006). A case-crossover study of fine particulate matter air pollution and onset of congestive heart failure symptom exacerbation leading to hospitalization. Am J Epidemiol, 164: 421-433. 091258 Thurston GD; Ito K; Hayes CG; Bates DV; Lippmann M (1994). 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Environ Health Perspect, 117: 751-756. 191970 December 2009 2-37 Case Document 14-1 Filed 10/04/12 Page 62 of 135 PagelD# 372 IN THE UNITED STATES DISTRICT COURT FOR THE EASTERN DISTRICT OF VIRGINIA ALEXANDRIA DIVISION AMERICAN TRADITION INSTITUTE ENVIRONMENTAL LAW CENTER, Plaintiff, v. Civil Action No. UNITED STATES ENVIRONMENTAL PROTECTION AGENCY, e_t Defendants. DECLARATION OF JAMES SAMET I, James Martin Samet, pursuant to 28 U.S.C. I746, declare, under penalty of perjury, that the following statements are true and correct based upon my personal knowledge, experience or upon information provided to me by persons under my Supervision: 1. I am a research biologist with the Clinical Research Branch, Environmental Public Health Division, National Health and Effects Research Laboratory, Of?ce of Research and Development, U. S. Environmental Protection Agency. I have been employed in this capacity by the Agency for 15 years. I have been the Principal Investigator in three previous clinical studies conducted at the Human Studies Facility, which have produced four peer reviewed publications to date. 2. As a PI in the Clinical Research Branch, my duties include designing, administering and conducting clinical studies involving controlled exposure of human volunteers to atmospheres containing air pollutants. I am responsible for coordinating the study team, which includes co- Case Document 14-1 Filed 10/04/12 Page 63 of 135 PagelD# 373 investigators, recruitment contractors, EPA nurses and physicians, study coordinators, engineering contractors, EPA laboratory staff, and other personnel such as statisticians. As Pl, I am also responsible for interacting directly and complying with requirements from the Institutional Review Board at the University of North Carolina, which has oversight over clinical studies conducted at the EPA Human Studies Facility. In addition to preparing documents required for IRB approval, including consent forms, I obtain intramural (EPA) approvals for the study, which includes the preparation of Quality Assurance documents, external peer reviews, and other required study materials such as fact sheets. Upon completion of the study, 1 am responsible for coordinating the collection and analyses of the data and preparing the ?ndings for publication. I am also responsible for the preparation of the research manuscripts, either as a lead author or co-author, and seeking the dissemination of the study findings at national and international scienti?c meetings and ultimately in peer reviewed scienti?c journals. 3. I received a in toxicology from the University of North Carolina at Chapel Hill in 1990, and a Master of Public Health degree from the School of Public Health at UNC Chapel Hill in 1992. I have been a diplomate of the American Board of Toxicology since 1996. I hold an appointment as Adjunct Professor in the Department of Environmental Sciences and Engineering at the University of North Carolina at Chapel Hill. Overall, I have authored or co?authored over 86 scienti?c publications including peer-reviewed articles, book chapters and reviews. 4. I have reviewed the Complaint and exhibits ?led in the captioned case and the Motion for a Temporary Restraining Order. 1. Institutional Review Board Approval Process CAPTAIN Study Case Document 14-1 Filed 10/04/12 Page 64 of 135 PagelD# 374 5. The application for the CAPTAIN study (attached as Exhibit 1 to this Declaration) discusses the purpose of the study and its potential bene?ts to society. The purpose of the study is to test the hypothesis that ambient particulate matter with a mean aerodynamic diameter less than 2.5 microns (PM 2.5) concentrated from ambient air in Chapel Hill, NC, (CAPS) causes reversible biological changes in participants that, while not placing them individually at risk, provides information about the potential mechanisms by which PM can cause adverse cardiovascular (CV) effects in susceptible populations such as elderly people with CV disease. The study speci?cally seeks to obtain information regarding the effects of exposure to PM2.5 on 50-75 year~old healthy individuals, some of whom have a genetic trait that precludes them from making a speci?c protein involved in protection from oxidants (GSTMI). Application for IRB Approval of Human Subjects Research (November 9, 2011) (Exhibit 1), at 8. This genetic trait is present in approximately 40% of the population. E. In addition, the study will provide information as to which sources of ambient air pollution contribute most to causing these effects. at 15. Findings from this study will also have ?the potential to contribute to devising effective strategies aimed at the protection of the public from the untoward effects of these pollutants.? 6. The application includes a full description of the study design, methods and procedures. These include the regimen by which each test participant will undergo exposures to clean air and to CAPS, the CAPs concentration and duration of exposure, and the biological endpoints to be studied. These exposures and end points were chosen based on information obtained from 12 previous studies conducted at the EPA facility over the previous 15 years, as well as similar studies performed at several U.S. Universities and research institutions in Canada and England. Case Document 14-1 Filed 10/04/12 Page 65 of 135 PagelD# 375 7. application for approval showed that risks to participants are minimized by using procedures which are consistent with sound research design and are in accordance with the Common Rule and rules regarding the ethical conduct of human studies (40 CPR. Part 26). 8. Participants of the study are ?healthy 50-75 year-old male and female volunteers?, with normal resting electrocardiograms, and oxygen saturation greater than 94% at the time of the screening physical examination. Before enrolling a volunteer in the study, a physical examination is performed by licensed EPA nurses and physicians to minimize the chance that an underlying medical condition would place a volunteer at increased risk if they were to participate in the study. Exhibit 1 at 8-11. Persons with a history of angina, cardiac, and ischemic myocardial infarction or coronary bypass surgery are excluded, as are persons using pacemakers, those suffering from uncontrolled hypertension, or anyone with a history of bleeding diathesis. Persons with enumerated non-degenerative diseases and chronic illnesses (including diabetes and cancer) are likewise excluded from being study participants. Li. at 9. 9. The CAPTAIN study enrolls participants who have a genetic trait that precludes them from making a speci?c protein involved in protection from certain oxidants (these individuals are therefore described as being null for the GSTM1 gene). Approximately 40% of the population has this trait. I_d. at 3. Although individuals with this genotype appear to have a enhanced biological response to concentrated PM2.5 in CAPS studies, there is no evidence that this genotype makes an individual more at risk for an adverse cardiovascular effect. In addition, people with this genotype have been exposed previously to PM2.5 at the EPA and in controlled exposure studies conducted at other locations and none of these earlier studies reported adverse effects on their well being. Case Document 14-1 Filed 10/04/12 Page 66 of 135 PagelD# 376 10. Participants are exposed to PM2.5 drawn from the air surrounding the test building in Chapel Hill, North Carolina. These particles are concentrated and introduced into the test chamber without concentrating gases and vapors that are also present in the air. On a mass dose basis, particle concentrations ?will not exceed an exposure an individual receives over a 24 hour period while visiting a typical urban center in America on a smoggy day.? at 13; see also i at 16. The concentration of inhaled particle mass to which participants are exposed to over a two hour period is limited. at 13. Exposure will be terminated within 6 minutes if concentrations exceed 600 ug/m3. 1 1. Because the study will be terminated if concentrations of particulate matter exceed 600 ug/m3 for more than a few minutes, the study engineers monitor concentrations continuously. They seek to keep concentrations within an appreciable margin from the predetermined maximum level. Speci?cally, engineers will use clean air to dilute the stream of air containing CAPS going into the exposure facility, and thereby reduce the concentration of particulate matter to which the participant is exposed, if PM2.5 concentrations measured in any two minute average exceed 500 ugi?rn3. Protocol Operating Procedure for CAPTAIN at 2 (attached as Exhibit 2 to this Declaration). As a result, the particulate matter concentrations to which participants are exposed are considerably less than 600 ug/m3 over the two hour period. The level of exposme experienced thus far by the 6 volunteers who have participated in CAPTAIN is well within exposure levels that they are expected to encounter in their normal day to day life. The average dose of PM received by these subjects is 238.25 uglm3. See Spreadsheet of CAPTAIN concentrations (attached as Exhibit 3 to this Declaration). This concentration is equivalent to experiencing a concentration of 19.35 ugfm3 over a 24 hour period, far less than the level of the 24-hour PM2.5 NAAQS (35 ug/m3). The exposure in the test is not the only exposure they Case Document 14-1 Filed 10/04/12 Page 67 of 135 PagelD# 377 receive during a day, but the average daily ambient PM levels in Chapel Hill North Carolina are relatively low. 12. Although the possibility of adverse effects from exposure to PM2.5 can never be completely ruled out since participants are exposed ?to a particulate exposure burden they would likely encounter if visiting a large city,? the risk posed to participants frOm exposure to PM2.5 in the CAPTAIN study ?is very small.? Exhibit 1 at 16. While there is the risk of a serious impact on public health when a large population (containing people with signi?cant risk factors such cardiovascular disease is exposed to elevated levels of ambient PM2.5, the risk of a serious effect to any one person exposed to PM2.S concentrations for 2 heurs under the controlled conditions of the CAPTAIN study is very small, especially since EPA scientists do not enroll participants in PM2.5 CAPs studies who have signi?cant risk factors for experiencing adverse effects to PM2.5. Given the expected levels of exposures in the study, the generally low annual and 24-hour PM2.S levels experienced on a day to day basis in Chapel Hill, NC, the good health of the subjects and the absence of evidence of cardiovascular or respiratory disease, expert judgment is that the risk to an individual subject in the CAPTAIN study is very small. 13. Similarly, the risks to study participants from conducting pulmonary function tests, electrocardiogram and heart rate variability testing, brachial artery ultrasound, blood pressure monitoring, and drawing of blood, although not non-existent, are very small. Exhibit 1 at 15-16. 14. While undergoing exposure to concentrated PM2.5 participants are monitored continuously by closed?circuit camera by trained EPA personnel stationed immediately outside the exposure facility, and a licensed physician is available at all times to respond to any emergency. Exhibit 1 at 15. During the exposure, heart rate and is monitored continuously by electrocardiography (ECG) and the amount of oxygen present in blood is Case Document 14-1 Filed 10/04/12 Page 68 of 135 PagelD# 378 monitored continuously by pulse oximetry. Blood pressure is monitored at intervals throughout the exposure. at 16. Exposure would be terminated ?for any rapid change in tachycardia andfor decline in arterial oxygen saturation, or any distress of concern to the volunteer, the console operator or the medical staff at 15. 15. Study researchers carefully monitor the if any, that participants may experience either during or immediately after exposure to CAPs. Possible if any, from these two hour exposures include ?chest pain, mild [shortness of breath], headache, cough, and wheeze.? at 16. None of the CAPTAIN participants, nor any participant enrolled in previous concentrated PM2.5 (CAPS) studies, which total 297 exposures over a 15-year period, has reported any of these 16. Before CAPTAIN participants leave the EPA facility they are given the number of an EPA physician to call if they experience any or other medical problems. Their electrocardiogram ECG is also monitored continuously for 20 hours following concentrated PM2.5 exposure. Participants retum to the EPA facility the morning after a PM2.S exposure where they are seen by a nurse, and a series of questions are asked to assess whether the participant experienced any or other medical issues from the previous day. In addition, the participant?s ECG is again brie?y monitored, blood pressure recOrded, and blood oxygen saturation is measured. 17. Based on the information presented in the application, the UNC Chapel Hill School of Medicine IRB approved the CAPTAIN study. The IRB speci?cally found that ?This research involves no more than minimal risk.? Approval letter of November 11, 201] (attached as Exhibit 1 to this Declaration). Case Document 14-1 Filed 10/04/12 Page 69 of 135 PagelD# 379 18. EPA has conducted 297 controlled human exposures to concentrated PM2.5 over a 15- year period. The average PM2.5 concentration for those exposures was 120 ug/m3. However, that is an exposure just for 2 hours. That level of exposure for 2 hours is the same as a 24 hour average exposure to PM2.5 of 10 ug/m3, well within the level of the 24-hour NAAQs for PM2.5 of35 ug/m3. 40 CPR. Of the 297 exposures, ?ve have been the same as a 24 hour average exposure that is somewhat higher than the level of the 24-hour however the standard allows 2-3 days a year above the 24-hour level NAAQS. 40 CFR section 19. In the 297 controlled human exposures to concentrated PM2.5 conducted by EPA, there has been only one clinically signi?cant event. In one case a research volunteer was exposed to concentrated ambient particulate matter and during the exposure their normal heart converted to atrial ?brillation. The subject was not aware of the change in the and was completely free of any However, because atrial fibrillation that persists for more than 24 hours can be associated with an increased risk for stroke, this research volunteer was transferred to the University ofNorth Carolina Hospitals for monitoring, assessment of cardiac and further evaluation and medical management. Even though the cardiac returned to normal prior to transfer, it was judged prudent to transfer the research volunteer for further monitoring. At no time was the research volunteer's health in danger. The research volunteer experienced no harm or injury. The research volunteer reported no history of heart disturbance during the screening phase or during the review of systems interview during the physical examination prior to exposure. An electrocardiogram did not did not identify any markers of an increased risk of atrial ?brillation. Atrial premature beats present on telemetry and on a previous ambulatory electrocardiogram are often increased in individuals at risk for atrial ?brillation, but are too non-speci?c to be used to exclude research volunteers from study. Case Document 14-1 Filed 10/04/12 Page 70 of 135 PagelD# 380 ll. Post IRB approval process within EPA Following approval by the UNC IRB of a study, internal procedures required that investigators also obtain EPA approval before a study can begin. The investigator must prepare a Study Justi?cation Document, which describes the relevance of the research to the Agencyis mission, the value added by human studies, the value to society, and any issues regarding subject safety. The IRB approved protocol and consent form, Study Justi?cation document, copies ensuring the all personnel associated with the study have had ethics training, copies of outside peer reviews, and other relevant documents are then reviewed by an EPA Quality Assurance Of?cer. If approved, the package is then reviewed by the Division Director, the Human Research Protection Of?ce, the Associate Director for Health, and the EPA Human Subjects Research Review Of?cial. Only after signed approval is given by each of these individuals may a study begin. The CAPTAIN protocol received written approval from all of these individuals culminating in ?nal approval by the EPA Human Subjects Research Review Official (attached as Exhibit 5 to this Declaration). Informed Consent CAPTAIN Study 20. Study investigators take all necessary steps to ensure that prospective volunteers for the CAPTAIN study are provided all information needed to reach an informed consent prior to participation, including the rationale for the study, bene?ts to society, and the risks associated with their participation. This is done in the following manner. 21. The informed consent form (attached as Exhibit 6 to this Declaration) states that CAPTAIN is a research study, explains the purposes of the research and the expected duration of the participant?s participation, and describes all study procedures. Case Document 14-1 Filed 10/04/12 Page 71 of 135 PagelD# 381 22. Specifically, the informed consent form states that ?[t]he purpose of this research study is to determine if a component of ambient air pollution to which we are all exposed, particulate matter (PM), elevates the risks of cardiac changes and to investigate the role of a common genetic polymorphism (GSTMI) in these effects.? Exhibit 6 at 1. The consent form further explains that Results from this study may increase the understanding of how gaseous and particulate air pollutants (which causes the haze seen in some polluted cities) may adversely affect the functioning of the human cardiovascular (heart and blood vessels) and respiratory (lung) systems. This understanding may be especially important for patients with cardiopulmonary diseases. 1; 23. Study procedures including types of breathing instruments used, duration of testing and test conditions, and post-exposure testing?are explained in detail in the consent form. 24. Speci?cally, potential participants are told that they will wear a face mask in an exposure facility during which they will be exposed for 2 hours to clean air and to CAPS on successive days. at 5. Potential participants are also informed of the medical procedures to be performed immediately before and after exposure (including having vital signs checked, performing a breathing test, heart monitoring, blood drawn, and brachial artery ultrasound measurement), and that theses test will be performed again the following morning. at 5-6. 25. The consent form explains the reasonably foreseeable risks or discomforts that the test participant may experience. Specifically, the form states that During the exposure to the concentrated air pollution particles, you may experience some minor degree of airway irritation, cough, and shortness of breath or wheezing. These typically disappear 2 to 4 hours after exposure, but may last longer for particularly sensitive people. . . .Air pollution particles may induce an in?ammatory reaction that can last for 24 hours after exposure and may increase the chance of you catching a cold. 10 Case Document 14-1 Filed 10/04/12 Page 72 of 135 PagelD# 382 It; at 6?7. Overall, ?the amount of particles you will exposed to is less than what you would likely encounter over 24 hours on a smoggy day in an urban area.? Li at 5. The consent form also explains the potential risks and discomforts which may result from performing breathing tests, having blood drawn, and experiencing heart monitoring, blood pressure monitoring, and brachial artery ultrasound testing. at 7. 26. This written description is not the only information presented to potential test participants regarding potential risks. All potential participants have an initial interview, ranging from 30 minutes up to three hours where EPA investigators explain the protocol and associated risks to them. Participants are encouraged to ask questions about anything that they do not understand about the study or any concerns they might have. Li. at 3. During the interview, I tell participants thatj as a regulatory agency, the EPA has an interest in understanding the mechanistic basis for the morbidity and mortality associated with human exposure to ambient PM. PM is de?ned and explained in terms that subjects of varying educational backgrounds can understand. I tell them that everyone is exposed to PM continuously and inform them that exposure to PM has been associated in epidemiological studies with increased illness and premature death. I tell participants that the people most susceptible to experiencing illness and death or other adverse effects are those with pre-existing cardiac (heart) or respiratory (lung) disease, and that no such individuals will be admitted to CAPTAIN. I further inform participants that what they will be exposed to is outside air from Chapel Hill in which particles are concentrated to about 10 to 20 times what they are in Chapel Hill air on the day of their exposure. I tell them that the dose of particles they receive during the two hour exposure is equivalent to what they might receive during a 24 hour period in many major US. cities and that this exposure presents a very low risk to healthy individuals. I tell them that that they have been 11 Case Document 14-1 Filed 10/04/12 Page 73 of 135 PagelD# 383 examined by EPA medical staff for conditions and medication use that might put them at increased risk, and I go over this list of exclusion criteria to make sure the participant does not meet any of the exclusion criteria. I tell them that the EPA Medical Staff is satis?ed that they are healthy enough to participate in CAPTAIN. I go through the entire consent form in order, section by section, explaining the procedures involved, the risks, the bene?ts (stating clearly that society is the bene?ciary, not the participant), their rights as a participant and what is done to protect them. 27. The informed consent form informs study participants that ?[y]ou will not bene?t directly from being in this research study?. Li. at 6. The consent from further notes that there is an ancillary benefit of participating in the study in the form of a medical examination including blood work, respiratory testing, and an ECG. at 6. 28. The consent form further explains the bene?ts to others that may result from the participant?s participation in the study: ?[t]he research is designed to bene?t society by gaining new knowledge that may be used to devise effective regulatory strategies aimed at protecting the population from the untoward effects of air pollutants.? 29. The consent form informs potential participants that their participation is voluntary and that they may terminate participation in the study at any time without penalty. E. at 9. 30. I ?rmly believe that the consent form, as well as the face-to-face interview with potential participants, fully provides participants with the opportunity to provide informed consent to their participation. IV. Harm in Delaying CAPTAIN Study 31. Delay in the CAPTAIN study will cause harm to legitimate research objectives, and also inconvenience to study participants. CAPTAIN participants have already been screened 12 Case Document 14-1 Filed 10/04/12 Page 74 of 135 PagelD# 384 for testing, have changed their diets pursuant to the study protocol, and otherwise rearranged their schedules to be available on the days of the study. At the least, they will be signi?cantly inconvenienced if the study is delayed. Furthermore, the CAPTAIN study supports on-going EPA research into, and study of, health effects of PM2.5 and the biological mechanisms for those effects. As noted above, controlled human exposure studies provide important insights which can improve our understanding of the potential biological mechanisms or pathways for effects observed in epidemiological studies and the CAPTAIN study promotes these objectives. The CAPTAIN study also supports forthcoming clinical studies, many of which are already scheduled. As resources at the Human Studies Facility are limited delay of CAPTAIN would upset the scheduling of later studies as well as disrupting the CAPTAIN study itself. x'r Viz/{M7 JAMES SAMET Dated: October 3, 2012 13 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 75 of 135 PageID# 385 Samet Declaration Exhibit 1 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 76 of 135 PageID# 386 OFFICE OF HUMAN RESEARCH ETHICS Institutional Review Board APPLICATION FOR IRB APPROVAL OF HUMAN SUBJECTS RESEARCH Version 19-Feb-2008 Part A.1. Contact Information, Agreements, and Signatures Date: November 9, 2011 Title of Study: Cardiopulmonary Effects of Exposure of Healthy Older GSTM1 Null and Sufficient Individuals to Concentrated Ambient Air Particles (CAPTAIN) Name and degrees of Principal Investigator: James M Samet, PhD, MPH Co- Principal Investigator: Haiyan Tong, MD, PhD Department: Clinical Research Branch, US EPA Mailing address/CB #: 104 Mason Farm Rd. Chapel Hill, NC 27599-7315 UNC-CH PID: Phone #: (919) 966-0665 Pager: Fax #: (919) 966-6271 Email Address: samet.james@epa.gov For trainee-led projects: __ undergraduate __ graduate _ postdoc __ resident __ other X NA Name of faculty advisor: James M Samet, PhD, MPH Department: US EPA Mailing address/CB #: 104 Mason Farm Rd. Chapel Hill, NC 275997315 Phone #: (919) 966-0665 Fax #: (919) 966-6271 Email Address: samet.james@epa.gov Center, institute, or department in which research is based if other than department(s) listed above: Name of Project Manager or Study Coordinator (if any): Department: Mailing address/CB #: Phone #: Fax #: Email Address: List all other project personnel including co-investigators, and anyone else who has contact with subjects or identifiable data from subjects. Include email address for each person who should receive electronic copies of IRB correspondence to PI: Martha Almond RRT; Maryann Bassett, RN; Philip Bromberg, MD; Martha Sue Carraway, MD; Martin Case, BS; Wayne Cascio, MD; Melissa Caughey, BS, RVT; David DeMarini, PhD; Andrew Ghio MD; Milan Hazucha, MD, PhD; Alan Hinderliter, MD; Fernando Holguin, MD; Margaret Herbst, RN, MSN; Sally Ivins, BA; Howard Kehrl, MD; Tracey Montilla, RN; Lynne Newlin-Clapp, BA; Dave Peden, MD, MS; Carole Robinette, MS; Michael Schmitt, MS; Ana Rappold, PhD, Susan Steck, PhD, RD; Haibo Zhou, PhD, Heidi Hiers, RN, Michael (Billy) Ray, BS. Application for IRB Approval of Human Subjects Research page 1 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 77 of 135 PageID# 387 Name of funding source or sponsor (please do not abbreviate): __ not funded _X_ Federal __ State __ industry __ foundation __ UNC-CH __ other (specify): EPA Intramural Federal Research For industry sponsored research (if applicable): Sponsor’s master protocol version #: Version date: Investigator Brochure version #: Version date: Any other details you need documented on IRB approval: RAMSeS proposal number (from Office of Sponsored Research): Application for IRB Approval of Human Subjects Research page 2 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 78 of 135 PageID# 388 Checklist of Items to Include with Your Submission Include the following items with your submission, where applicable. • Check the relevant items below and include one copy of all checked items 1-11 in the order listed. • Also include two additional collated sets of copies (sorted in the order listed) for items 1-7. → Applications will be returned if these instructions are not followed. Check X X □ X X □ □ □ □ □ □ Total No. of Copies 1. This application. One copy must have original PI signatures. 3 2. Consent and assent forms, fact or information sheets; include phone and 3 verbal consent scripts. 3. HIPAA authorization addendum to consent form. 3 4. All recruitment materials including scripts, flyers and advertising, letters, 3 emails. 5. Questionnaires, focus group guides, scripts used to guide phone or in3 person interviews, etc. 6. Documentation of reviews from any other committees (e.g., GCRC, Oncology Protocol Review Committee, or local review committees in 3 Academic Affairs). 7. Protocol, grant application or proposal supporting this submission, if any (e.g., extramural grant application to NIH or foundation, industry 1 protocol, student proposal). This must be submitted if an external funding source or sponsor is checked on the previous page. 8. Addendum for Multi-Site Studies where UNC-CH is the Lead 1 Coordinating Center. 9. Data use agreements (may be required for use of existing data from third 1 parties). 10. Only for those study personnel not in the online UNC-CH human research ethics training database 1 (http://cfx3.research.unc.edu/training_comp/): Documentation of required training in human research ethics. 11. Investigator Brochure if a drug study. 1 Item Application for IRB Approval of Human Subjects Research page 3 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 79 of 135 PageID# 389 Principal Investigator: I will personally conduct or supervise this research study. I will ensure that this study is performed in compliance with all applicable laws, regulations and University policies regarding human subjects research. I will obtain IRB approval before making any changes or additions to the project. I will notify the IRB of any other changes in the information provided in this application. I will provide progress reports to the IRB at least annually, or as requested. I will report promptly to the IRB all unanticipated problems or serious adverse events involving risk to human subjects. I will follow the IRB approved consent process for all subjects. I will ensure that all collaborators, students and employees assisting in this research study are informed about these obligations. All information given in this form is accurate and complete. Signature of Principal Investigator Date Faculty Advisor if PI is a Student or Trainee Investigator: I accept ultimate responsibility for ensuring that this study complies with all the obligations listed above for the PI. Signature of Faculty Advisor Date Note: The following signature is not required for applications with a student PI. Department or Division Chair, Center Director (or counterpart) of PI: (or Vice-Chair or Chair’s designee if Chair is investigator or otherwise unable to review): I certify that this research is appropriate for this Principal Investigator, that the investigators are qualified to conduct the research, and that there are adequate resources (including financial, support and facilities) available. If my unit has a local review committee for pre-IRB review, this requirement has been satisfied. I support this application, and hereby submit it for further review. Signature of Department Chair or designee Date Print Name of Department Chair or designee Department Application for IRB Approval of Human Subjects Research page 4 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 80 of 135 PageID# 390 Part A.2. Summary Checklist Are the following involved? Yes No A.2.1. Existing data, research records, patient records, and/or human biological specimens? X __ A.2.2. Surveys, questionnaires, interviews, or focus groups with subjects? _X_ __ A.2.3. Videotaping, audiotaping, filming of subjects, or analysis of existing tapes? __ _X_ A.2.4. a. b. c. d. e. f. g. A.2.5. b. _X_ __ __ _ __ __ __ __ __ __ _X_ X__ _X _X_ _X_ _X_ _X_ _X_ __ __ __ __ __ __ __ __ _X_ __ __ __ __ __ __ __ _X_ _X_ _X_ _X_ __ _X_ __ _X_ A.2.11. Fetal tissue? A.2.12. Genetic studies on subjects’ specimens? __ _X_ _X_ __ A.2.13. Storage of subjects’ specimens for future research? If yes, see instructions for Consent for Stored Samples. _X_ __ __ _X_ A.2.15. Recombinant DNA or gene transfer to human subjects? If yes, approval by the UNC-CH Institutional Biosafety Committee is required. __ _X_ A.2.16. Does this study involve UNC-CH cancer patients? If yes, submit this application directly to the Oncology Protocol Review Committee. __ _X_ A.2.17. Will subjects be studied in the General Clinical Research Center (GCRC)? If yes, obtain the GCRC Addendum from the GCRC and submit complete application (IRB application and Addendum) to the GCRC. __ X Do you plan to enroll subjects from these vulnerable or select populations: UNC-CH students or UNC-CH employees? Non-English-speaking? Decisionally impaired? Patients? Prisoners, others involuntarily detained or incarcerated, or parolees? Pregnant women? Minors (less than 18 years)? If yes, give age range: to years a. Are sites outside UNC-CH engaged in the research? Is UNC-CH the sponsor or lead coordinating center for a multi-site study? If yes, include the Addendum for Multi-site Studies. If yes, will any of these sites be outside the United States? If yes, is there a local ethics review committee agency with jurisdiction? (provide contact information) A.2.6. Will this study use a data and safety monitoring board or committee? If yes: UNC-CH School of Medicine DSMB? (must apply separately) Lineberger Cancer Center DSMC? Other? Specify: A.2.7. a. Are you collecting sensitive information such as sexual behavior, HIV status, recreational drug use, illegal behaviors, child/physical abuse, immigration status, etc? b. Do you plan to obtain a federal Certificate of Confidentiality for this study? A.2.8. a. Investigational drugs? (provide IND # ) b. Approved drugs for “non-FDA-approved” conditions? All studies testing substances in humans must provide a letter of acknowledgement from the UNC Health Care Investigational Drug Service (IDS). A.2.9. Placebo(s)? A.2.10. Investigational devices, instruments, machines, software? (provide IDE # ) A.2.14. Diagnostic or therapeutic ionizing radiation, or radioactive isotopes, which subjects would not receive otherwise? If yes, approval by the UNC-CH Radiation Safety Committee is required. A.2.18. Will gadolinium be administered as a contrast agent? Application for IRB Approval of Human Subjects Research ..__ .._X_ page 5 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 81 of 135 PageID# 391 Part A.3. Conflict of Interest Questions and Certification The following questions apply to all investigators and study staff engaged in the design, conduct, or reporting results of this project and/or their immediate family members. For these purposes, "family" includes the individual’s spouse and dependent children. “Spouse” includes a person with whom one lives together in the same residence and with whom one shares responsibility for each other’s welfare and shares financial obligations. A.3.1. Currently or during the term of this research study, does any member of the research team or his/her family member have or expect to have: (a) A personal financial interest in or personal financial relationship (including gifts of cash or in-kind) with the sponsor of this study? __ yes _X no (b) A personal financial interest in or personal financial relationship (including gifts of cash or in-kind) with an entity that owns or has the right to commercialize a product, process or technology studied in this project? __ yes _X no (c) A board membership of any kind or an executive position (paid or unpaid) with the sponsor of this study or with an entity that owns or has the right to commercialize a product, process or technology studied in this project? __ yes _X no A.3.2. Has the University or has a University-related foundation received a cash or inkind gift from the sponsor of this study for the use or benefit of any member of the research team? __ yes _X no A.3.3. Has the University or has a University-related foundation received a cash or inkind gift for the use or benefit of any member of the research team from an entity that owns or has the right to commercialize a product, process or technology studied in this project? __ yes _X no If the answer to ANY of the questions above is yes, the affected research team member(s) must complete and submit to the Office of the University Counsel the form accessible at http://coi.unc.edu. List name(s) of all research team members for whom any answer to the questions above is yes: Certification by Principal Investigator: By submitting this IRB application, I (the PI) certify that the information provided above is true and accurate regarding my own circumstances, that I have inquired of every UNC-Chapel Hill employee or trainee who will be engaged in the design, conduct or reporting of results of this project as to the questions set out above, and that I have instructed any such person who has answered “yes” to any of these questions to complete and submit for approval a Conflict of Interest Evaluation Form. I understand that as Principal Investigator I am obligated to ensure that any potential conflicts of interest that exist in relation to my study are reported as required by University policy. Signature of Principal Investigator Date Faculty Advisor if PI is a Student or Trainee Investigator: I accept ultimate responsibility for ensuring that the PI complies with the University’s conflict of interest policies and procedures. Signature of Faculty Advisor Application for IRB Approval of Human Subjects Research Date page 6 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 82 of 135 PageID# 392 Part A.4. Questions Common to All Studies For all questions, if the study involves only secondary data analysis, focus on your proposed design, methods and procedures, and not those of the original study that produced the data you plan to use. A.4.1. Brief Summary. Provide a brief non-technical description of the study, which will be used in IRB documentation as a description of the study. Typical summaries are 50-100 words. Please reply to each item below, retaining the subheading labels already in place, so that reviewers can readily identify the content. Purpose: Advanced age and common genetic polymorphism of the antioxidant enzyme glutathione-s-transferase M1 (GSTM1) appear to confer susceptibility to ambient particulate matter (PM). This study will compare responses to PM exposure in older volunteers with GSTM1 null and sufficient genotypes. Participants: 30 healthy 50-75 yo subjects. Procedures (methods): Subjects will be placed on a diet restricted of omega and oleic fatty acids for approximately 42 days prior to undergoing sequential exposures to air (control) and concentrated ambient PM (CAP) for 2 hr. Pulmonary, vascular and cardiac function will be evaluated pre, immediately post and 18 hr post exposure. A.4.2. Purpose and Rationale. Provide a summary of the background information, state the research question(s), and tell why the study is needed. If a complete rationale and literature review are in an accompanying grant application or other type of proposal, only provide a brief summary here. If there is no proposal, provide a more extensive rationale and literature review, including references. Numerous epidemiological studies have demonstrated an association between acute and chronic exposure to ambient levels of particulate matter (PM) and various adverse cardiopulmonary effects including mortality, respiratory tract infection, exacerbation of asthma, chronic bronchitis, ischemic heart disease, and stroke (see review, (1)). A recent national scale epidemiological study has shown that short-term exposure to particulate matter (PM) is associated with increased rates of hospital admission for cardiovascular and respiratory symptoms. The cardiovascular risk tended to be higher in the Eastern United States. This study also indicated a disproportionate risk among the elderly who are exposed to PM (2). Dietary factors such as intake of omega-3 fatty acids have been linked to human susceptibility to the adverse effects of ambient PM (14).Although air pollution exposure has long been known to be a risk factor for respiratory disease, over the last decade, a growing body of epidemiological studies has heightened concern over elevated rates of cardiovascular events related to both short-term and long-term exposure to PM (3). The risk of death from cardiovascular disease (myocardial infarction, heart failure, and fatal arrhythmias) in response to chronically high levels of air pollution was much greater than that from lung disease (4-6). Short-term elevations in ambient PM levels are capable of evoking cardiac arrhythmias, worsening heart failure, and triggering acute atherosclerotic/ischemic cardiovascular complications, particularly in certain at-risk subsets of population (3). PM exposure can result in increases in heart rate, and decreases in heart rate variability (HRV; defined as changes in mean heart rate during 24 hrs, which is a reflection of autonomic tone on the heart (7). PM has been associated with transient increases in plasma viscosity (8), endothelial dysfunction (9) and acute-phase reactants (10, 11) such as C-reactive protein (12). Animal Application for IRB Approval of Human Subjects Research page 7 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 83 of 135 PageID# 393 studies have suggested that long-term exposure to low concentration of PM altered vasomotor tone, induces vascular inflammation and potentiates atherosclerosis (13). Despite a decade of intensive studies, much about the PM health effects problem, especially the cardiovascular effect, is still not well understood. The present study is designed to test the hypothesis that genetic expression of the Phase II metabolizing enzyme GSTM1 alters the outcome of adverse responses to PM exposure. 1. Sydbom, A., Blomberg, A., Parnia, S., Stenfors, N., Sandstrom, T. and Dahlen, S.E. (2001). Health effects of diesel exhaust emissions. Eur Respir J 17:733-746. 2. Dominici, F., Peng, R.D., Bell, M.L., Pham, L., McDermott, A., Zeger, S.L. and Samet, J.M. (2006). Fine particulate air pollution and hospital admission for cardiovascular and respiratory diseases. JAMA 295:1127-1134. 3. Brook, R.D., Franklin, B., Cascio, W., Hong, Y., Howard, G., Lipsett, M., Luepker, R., Mittleman, M., Samet, J., Smith, S.C., Jr. and Tager, I. (2004). Air pollution and cardiovascular disease: a statement for healthcare professionals from the Expert Panel on Population and Prevention Science of the American Heart Association. Circulation 109:2655-2671. 4. Hoek, G., Brunekreef, B., Fischer, P. and van Wijnen, J. (2001). The association between air pollution and heart failure, arrhythmia, embolism, thrombosis, and other cardiovascular causes of death in a time series study. Epidemiology 12:355-357. 5. Peters, A., Dockery, D.W., Muller, J.E. and Mittleman, M.A. (2001). Increased particulate air pollution and the triggering of myocardial infarction. Circulation 103:2810-2815. 6. Johnson, R.L., Jr. (2004). Relative effects of air pollution on lungs and heart. Circulation 109:5-7. 7. Pope, C.A., 3rd, Verrier, R.L., Lovett, E.G., Larson, A.C., Raizenne, M.E., Kanner, R.E., Schwartz, J., Villegas, G.M., Gold, D.R. and Dockery, D.W. (1999). Heart rate variability associated with particulate air pollution. Am Heart J 138:890-899. 8. Peters, A., Doring, A., Wichmann, H.E. and Koenig, W. (1997). Increased plasma viscosity during an air pollution episode: a link to mortality? Lancet 349:1582-1587. 9. Brook, R.D., Brook, J.R., Urch, B., Vincent, R., Rajagopalan, S. and Silverman, F. (2002). Inhalation of fine particulate air pollution and ozone causes acute arterial vasoconstriction in healthy adults. Circulation 105:15341536. 10. Peters, A., Frohlich, M., Doring, A., Immervoll, T., Wichmann, H.E., Hutchinson, W.L., Pepys, M.B. and Koenig, W. (2001). Particulate air pollution is associated with an acute phase response in men; results from the MONICA-Augsburg Study. Eur Heart J 22:1198-1204. 11. Schwartz, J. (2001). Air pollution and blood markers of cardiovascular risk. Environ Health Perspect 109 Suppl 3:405-409. 12. Sandhu, R.S., Petroni, D.H. and George, W.J. (2005). Ambient particulate matter, C-reactive protein, and coronary artery disease. Inhal Toxicol 17:409-413. 13. Sun, Q., Wang, A., Jin, X., Natanzon, A., Duquaine, D., Brook, R.D., Aguinaldo, J.G., Fayad, Z.A., Fuster, V., Lippmann, M., Chen, L.C. and Rajagopalan, S. (2005). Long-term air pollution exposure and acceleration of atherosclerosis and vascular inflammation in an animal model. JAMA 294:3003-3010. 14. Holguin F, Tellez-Rojo MM, Lazo M, et al. Cardiac autonomic changes associated with fish oil vs soy oil supplementation in the elderly. Chest. Apr 2005;127(4):1102-1107. A.4.3. Subjects. You should describe the subject population even if your study does not involve direct interaction (e.g., existing records). Specify number, gender, ethnicity, race, and age. Specify whether subjects are healthy volunteers or patients. If patients, specify any relevant disease or condition and indicate how potential subjects will be identified. Subjects for this study will be healthy 50-75 year-old male and female volunteers of any ethnicity and race. The study will enroll both GSTM1 null and sufficient subjects. The fraction of subjects who are GSTM1 null will be targeted to be approximately 40 %, reflecting the prevalence of this polymorphism in the general US population. Application for IRB Approval of Human Subjects Research page 8 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 84 of 135 PageID# 394 Based on recently completed studies for subjects with the characteristics sought in this study, the expected screening attrition rate is up to 70 %, with a heavy effect of genotype requirement. Postscreening completion rate is up to 50 %. Extrapolating from these rates, we can expect a 15% overall completion yield. Therefore, to obtain 30 subjects, we will enroll up to 200 subjects. Subjects will be recruited through an-on site contract with the Westat Corporation (see section B1 below). A.4.4. Inclusion/exclusion criteria. List required characteristics of potential subjects, and those that preclude enrollment or involvement of subjects or their data. Justify exclusion of any group, especially by criteria based on gender, ethnicity, race, or age. If pregnant women are excluded, or if women who become pregnant are withdrawn, specific justification must be provided. Inclusion criteria: • Age 50-75 years old generally healthy male and female. • Normal resting ECG. • Oxygen saturation greater than 94% at the time of physical exam. Exclusion criteria: • A history of angina, cardiac arrhythmias, and ischemic myocardial infarction or coronary bypass surgery. • Cardiac pacemaker. • Uncontrolled hypertension (> 150 systolic, > 90 diastolic). • Neurodegenerative diseases such as Parkinson’s and Alzheimer disease. • History of bleeding diathesis. • Currently taking β-blockers to control hypertension and/or arrhythmias. • Use of oral anticoagulants. • Participants must refrain from all over-the-counter NSAIDs for a period of two weeks prior to exposure. Low-dose aspirin will be acceptable. Medications not specifically mentioned here may be reviewed by the investigators prior to a participant’s inclusion in the study. • Subjects will be required to avoid taking antioxidants (e.g., beta-carotene, selenium, vitamin C, vitamin E, zinc) for approximately 6 weeks before the exposures. Calcium supplements and statins are permitted. • Subject is pregnant, attempting to become pregnant or breastfeeding. • No exposure will be conducted within 4 weeks of a respiratory tract infection. • Eye or abdominal surgery (e.g., hernia surgery) within 6 weeks will be exclusionary. • Active allergies. Seasonal allergies are not exclusive if out of season throughout participation in study. • A history of chronic illnesses such as diabetes, cancer (non-melanoma skin cancer may be acceptable), rheumatologic diseases, immunodeficiency state, known cardiovascular disease, chronic respiratory diseases such as chronic obstructive pulmonary disease or asthma. Hypothyroid is acceptable. • Subjects will be required to avoid taking omega-3 fatty acids for 6 weeks before the exposure day. Subjects who are on prescriptions taking omega-3 fish oil as therapy will be excluded. • Subjects will be instructed to avoid more than one 4-6 oz/serving of all types of fish and shellfish, as well as all types of nuts, flaxseeds and flaxseed oil, rapeseed oil, canola oil, Application for IRB Approval of Human Subjects Research page 9 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 85 of 135 PageID# 395 • • • • • soybeans and soy products, omega-3 fortified eggs, and cod liver oil for 6 weeks before their first exposure. Individuals who are unable to comply with these restrictions will be excluded. Subjects will be required to limit their use of all cooking oils, dressings, and sauces during the study and to avoid olive oil and other vegetable oils because of their oleic and omega-3 contents. Use of a cooking spray such as PAM will be allowed. Male subjects will be asked to refrain from using erectile dysfunction drugs 72 hrs before exposure. Because of reported cardioprotective effects of red wine, subjects will be prohibited from drinking red for 6 weeks prior to their first exposure. Subjects who are currently smoking or have smoking history within 1 year of study (defined as more than one pack of cigarettes in the past year) or smoked more than 5 pack-years in lifetime. Because the exposures use a facemask that could trigger headaches in sensitive individuals, subjects who suffer from migraines will be excluded from participation. Use of other medications will be evaluated on a case-by-case basis. There is the potential that an individual’s current medication use will preclude them from participating in the study at the current time, but they may be reassessed and potentially rescheduled for participation at a later time. A.4.5. Full description of the study design, methods and procedures. Describe the research study. Discuss the study design; study procedures; sequential description of what subjects will be asked to do; assignment of subjects to various arms of the study if applicable; doses; frequency and route of administration of medication and other medical treatment if applicable; how data are to be collected (questionnaire, interview, focus group or specific procedure such as physical examination, venipuncture, etc.). Include information on who will collect data, who will conduct procedures or measurements. Indicate the number and duration of contacts with each subject; outcome measurements; and follow-up procedures. If the study involves medical treatment, distinguish standard care procedures from those that are research. If the study is a clinical trial involving patients as subjects and use of placebo control is involved, provide justification for the use of placebo controls. Approximately 30 subjects will complete a regimen in which each subject will undergo exposures to clean air and to CAP sequentially on successive days. Each exposure will be 2 hours in duration with the subject at rest in a specialized exposure chamber. The primary endpoints include HRV, pulmonary function, and biomarkers that include neutrophils, platelets, fibrinogen, C-reactive protein, lactate and plasminogen activator inhibitor. We will also assess endothelial cell function by brachial artery ultrasound. We will carefully monitor the symptoms that subjects may develop during the exposure and over a 24 hour period following exposure. The symptoms include chest pain, dyspnea, pallor, ataxia, and significant heart rhythm anomalies like rapid heartbeat or skipped beats, or arrhythmias noted on EKG. In addition, analyses of blood samples taken after exposure will be scrutinized for abnormalities, including neutrophil counts. Symptoms and/or changes detected in the genotyping blood samples that are considered clinically significant could prompt the study physicians to stop the study. To the extent possible, subjects who fall ill during their participation in the study will be rescheduled. Subject Qualification Application for IRB Approval of Human Subjects Research page 10 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 86 of 135 PageID# 396 Screening: Subjects will be recruited by the Westat Corporation (see section B1 below). During an initial telephone interview, the subjects will receive information regarding the study and their eligibility status will be assessed. Subjects whose responses indicate that they are likely to meet the criteria will be scheduled for a genetic screening appointment in the medical station in the US EPA Human Studies Facility (HSF). Depending on the need to maintain a representative population of subjects over time, GSTM1 null or sufficient subjects may be enrolled exclusively at various points in the study. At that time a genotype screening informed consent form and a consent form for storing blood with identifying information will also be signed. The subjects identified from a previous study (see page 26, methods of recruiting) will not need genotype screening. Subjects will then undergo a brief medical history screening and blood pressure measurement. Subjects will then have approximately 20 ml of blood collected. A portion of the blood will be used for genetic screening for GSTM1 sufficiency and another portion of the blood will be used for the cholesterol levels, fatty acid analysis, and biochemistry analysis. Information obtained from the blood analyses at this point could be used by the study physicians to stop a subject’s participation or end the study. Subjects will be given a copy of the Medical History Form to be filled out and mailed back after they are selected on the genotype. GSTM1/GSTP1 genotype screening: A portion of the blood sample (about 5 ml) will be used for genotyping of GSTM1 and other non-selective genotypic markers such as GSTP1. Total DNA will be isolated from the blood sample and polymeric chain reaction (PCR) will be run to determine if the subject carries a GSTM1 positive or null gene polymorphism. Physical exam: Subjects who are not excluded during the genetic screening will be scheduled for a physical examination in the HSF. During this visit, subjects will sign an informed consent to undergo the screening procedures and physical examination as per the previously UNC IRBapproved protocol, Recruitment and Screening of Potential Participants for U.S. EPA Studies (95-EPA-66). Subjects will then undergo a physical exam, pulse oximetry, and screening/baseline 12-lead electrocardiogram (ECG). A menstrual history will be collected on all female subjects. Training session: Those subjects who are not excluded on the basis of the physical exam and genetic screening will undergo a training session to familiarize them with the study protocol. At that time the study protocol will be outlined and informed consent obtained to initiate the study. Subjects will ask any questions they might have regarding their participation in the study. Subjects will then undergo spirometry for pulmonary function assessment. Subjects will also undergo a min ventilation measurement recorded while sitting at rest. Pregnancy tests will be administrated to any female subjects who may have child-bearing potential on the training day and on the exposure day if more than 7 days since the last pregnancy test have elapsed. Dietary Restriction and Recording: As specified above under Subject Exclusions, subjects will be required to restrict their dietary consumption of fish, seafood, oils, nuts, omega-3 fatty acid fortified foods and dietary supplements and vitamins for approximately 42 days. During their training day subjects will receive instruction on foods to avoid and on estimating dietary portions. Subjects will be asked to record their diet for two 24 hr periods, one during the week and one during the weekend, approximately midway during their dietary restriction period. Exposure Day In order to participate in this study, subjects will be required to: Application for IRB Approval of Human Subjects Research page 11 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 87 of 135 PageID# 397 • • • • • • • Avoid smoke and fumes for 24 hours before all visits. Avoid drinking alcohol 24 hours before all visits. Avoid strenuous exercise for 24 hours prior to and after all visits. Refrain from eating pan fried and/or grilled foods after midnight prior to the exposure day. Refrain from ingesting caffeine for 12 hours prior to all study visits. Eat a light breakfast on the exposure day. Bring a lunch to each exposure day. The lunch composition will be specified to minimize potential variations that could affect the arterial diameter measurements. Subjects will be compensated for the cost of the lunch. Pre-exposure: On the day of the study, the subject will report to the medical station in the HSF at which time the general health of the subject will be evaluated and the appropriate pre-exposure measurements (blood pressure, HRV, endothelial cell function by brachial artery ultrasound (BAU), pulmonary function by spirometry and diffusion limited uptake of CO (DLCO), and blood sampling) will be completed. • HRV measurement will be done with the use of a Holter monitor. Electrodes for HRV measurement will be placed. The skin in the areas of electrode placement will be cleaned and shaved (if necessary) to ensure that the electrodes will remain securely attached. These leads will be connected to a Holter monitor and will remain in place for approximately 48 hours. Standard telemetry leads will also be placed, and removed when the patient leaves for the day. The subject will then be allowed to relax for 20-30 minutes in a reclined position. • Brachial artery ultrasound. Brachial artery ultrasound (BAU) to evaluate flow-mediated dilatation will be performed using a 14 MHz imaging probe interfaced with an Ultrasonix SP or Touch Pharma ultrasound machine. The diameter of the brachial artery will be measured at baseline, during reactive hyperemia and after administration of sublingual nitroglycerin. The subject will lie supine, and a pneumatic tourniquet will be placed around the right upper arm proximal to the target artery. Gated baseline images of the brachial artery will be acquired after 15 minutes of supine rest. The pneumatic cuff will then be inflated to a pressure of 200 mm Hg for 5 minutes, and increased flow will be induced by sudden cuff deflation. A second scan will be performed following deflation. The subject will rest another 10 minutes and a third ultrasound scan will be performed. Sublingual nitroglycerin (~0.4 mg) will be administered, followed in three to four minutes by the final ultrasound study. Subjects will then rest quietly for 5 minutes. Images of the brachial artery will be acquired and stored on a personal computer, and subsequently analyzed using a semi-automated offline quantification system. • Pulmonary function: will be measured by spirometry, including measurement of single breath CO diffusing capacity (DLCO). Cardiac output (Qc or pulmonary capillary flow) will be simultaneously measured from the uptake of inhaled acetylene gas during the same single breath procedure. • Blood sampling: approximately 46.2 ml of blood will be collected pre-exposure in the study. Application for IRB Approval of Human Subjects Research page 12 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 88 of 135 PageID# 398 • Symptom questionnaire before and after exposure may be collected. • Blood Pressure Monitor: An ambulatory blood pressure monitoring device will be placed on the subject’s arm and begin collecting readings. Subjects will wear the blood pressure monitor and cuff for the rest of the day after leaving the facility but will be instructed to remove it before going to bed. . Exposure: All exposures will be carried out at the EPA Human Studies Facility on the UNC campus. Subjects will enter an exposure chamber for the 2-hour exposure to clean air. The next day they will undergo exposure to fine/ultrafine CAP for 2 hours. The CAP exposure day may be rescheduled if the particulate concentrations are too low on the scheduled day. The actual concentration of CAP will be determined retrospectively by filter gravimetry, with exposures monitored in real time with a tapered element oscillating microbalance (TEOM). Subjects will be monitored continuously by the EPA personnel by closed-circuit camera, blood pressure measurements, pulse oximetry and ECG telemetry. A duty physician will be available at all times. The subjects will be able to end their exposure and exit the chamber at any time if they choose to end their participation in the study. Blood pressure, heart rate, and oxygen saturation will be measured continuously during the exposure period. A confirmed blood O2 saturation levels less than 89 % will result in a cessation of exposure. Heart rate alarm limits will be set up for each subject and monitored continuously by the console operator and the nursing staff. CAP Exposures-Concentrated particles will be generated by drawing ambient air from above the roof of the Human Studies Facility and passing the air through a 2 stage aerosol concentrator which produces up to a 20-fold increase in particle number and mass. Particles larger than about 2.5 microns will be excluded by a size-selective inlet from entering the concentrator at the rooftop intake. During the particle concentrating process, ambient air pollution gases will be diluted by a factor of four. Air temperature and humidity will be monitored and maintained to ensure proper operation of the concentrator. An air conditioner in the chamber can be utilized to both heat or cool chamber air for subject comfort. The flow of air into the chamber will be 65 liters per minute, with approximately 15 liters per minute diverted for analytical instrumentation and filter devices attached upstream from the chamber. The remaining approximately 50 L/min will be provided to the subject through a face mask. Since the air will be pulled into the chamber by a suction blower connected downstream of the chamber, the chamber will be slightly below atmospheric pressure. The concentration of particles delivered to the chamber will vary depending on the levels of naturally occurring particles in the Chapel Hill air. Although 24 hr averages seldom exceed 15-20 ug/m3, peak values in the summer can be as high as 50-60 ug/m3 with lower values during the rest of the year. A face mask is used to reduce the daily and seasonal variability of PM concentration. Our past experience provides a basis to expect the particle mass delivered to the mask will be up to 600 ug/m3. The particle burden, on a mass basis presented to the volunteer will not exceed an exposure an individual receives over a 24 hour period while visiting a typical urban center in America on a smoggy day. The particle mass of the outdoor air entering and exiting the aerosol concentrator will be monitored continuously. Filter samples will be obtained from the devices located upstream from the chamber and analyzed for both mass and chemical composition of particles. If it is confirmed that particulate mass levels exceed 600 ug/m3 for greater than 6 minutes, exposure will be terminated. The process for confirmation may take up to Application for IRB Approval of Human Subjects Research page 13 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 89 of 135 PageID# 399 additional 10 minutes. The shutdown procedure involves venting a valve on the exposure chamber, which markedly reduces the particle exposure, and alerting the investigator with both auditory and visual signals leading to removal of the subject from the chamber. Blood pressure, telemetry, and oxygen saturation will be measured during the exposure period. Immediate Post-exposure: Subjects will be released while wearing the Holter and blood pressure monitors. Symptoms questionnaire after exposure will be collected. Blood pressure, lung function, endothelial cell function, and heart rate variability will be measured and approximately 46.2 ml of blood samples will be collected. Eighteen Hours Post-PM exposure: Eighteen hours after the exposure, the subjects will return to the HSF to undergo a brief medical evaluation, including blood pressure, spirometry (pulmonary function testing) and endothelial cell function (BAU) measurements. The subject will then be allowed to relax for 20-30 minutes in a reclined position, after which a 10-minute resting HRV measurement will be obtained, and approximately 46.2 ml of blood will be taken. Holter monitor will be removed. OUTCOMES: Pulmonary Function will be measured before and after exposure. Subjects who have recent abdominal and/or eye surgery or any type of hernia will not be tested for pulmonary function. Subjects will perform spirometry and single breath diffusing capacity (DLCO) on a Sensor Medic Vmax pulmonary function system according to the standard procedure published by the American Thoracic Society. In addition, regional DLCO and pulmonary capillary blood flow (Qc) will be obtained by the intrabreath technique using the same system. Heart Rate Variability (HRV) data will be gathered for 24 hours using a Holter monitor. Specific 10 minute epochs to be analyzed for frequency domain variables include times immediately prior to exposure, immediately following exposure, and approximately 24 hours after exposure. Both time and frequency domain variables will be analyzed, as will abnormal responses (e.g. premature atrial complex, premature ventricular contractions, bradycardia, and tachycardia). Flow-Mediated Dilatation (brachial artery ultrasound). Changes in diameter of arteries caused by reactive hyperemia (endothelium-dependent vasodilatation) and by administration of sublingual nitroglycerin, typically 0.4 mg, (endothelium-independent vasodilatation) will be expressed as a percent change in diameter relative to resting baseline values. Peripheral Venous Blood Sample. Approximately 50 ml of venous blood will be drawn before, immediately after (within 1 hr after exposure ends), and approximately 18 hrs after exposure (Please refer to Table 1 in this section). The site will be prepared with isopropyl alcohol and a tourniquet is applied. Blood is drawn from an antecubital or other appropriate vein. Endpoint measurements will include, but are not limited to the following: blood lipid omega-3 fatty acid levels, biomarkers for specific and non-specific immune responses, coagulation factors, vasoactive factors, and soluble components of PM (e.g. transition metals). Genotype Screen 20 Air Exposure 46.2/46.2 Ozone-Exposure 46.2/46.2 Follow-up 46.2 TOTAL 251 ml Table 1. Blood Draws Application for IRB Approval of Human Subjects Research page 14 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 90 of 135 PageID# 400 Our primary endpoints will be HRV measurement, pulmonary function and peripheral venous blood markers. Our secondary endpoints will be arterial wall function and pulmonary function measurements. A.4.6. Benefits to subjects and/or society. Describe any potential for direct benefit to individual subjects, as well as the benefit to society based on scientific knowledge to be gained; these should be clearly distinguished. Consider the nature, magnitude, and likelihood of any direct benefit to subjects. If there is no direct benefit to the individual subject, say so here and in the consent form (if there is a consent form). Do not list monetary payment or other compensation as a benefit. Subjects will receive no direct benefit from participating in this study other than receiving a medical examination, including blood work, brachial artery ultrasound, spirometry, and an ECG. Subjects will have full access to these records. They will also gain knowledge about their responsiveness to ambient particulate matter. For society, this study will provide new information on the effects of ambient particulate matter on lung function, inflammation, and the cardiovascular system. Data from this study will help the US EPA better understand the components of air pollution that are responsible for increasing morbidity and mortality of cardiopulmonary fatality so that National Ambient Air Quality Standards and motor vehicle emission standards can be properly set. Findings from this study will also become the potential to contribute to devising effective strategies aimed at the protection of the public from the untoward effects of these pollutants. A.4.7. Full description of risks and measures to minimize risks. Include risk of psychosocial harm (e.g., emotional distress, embarrassment, breach of confidentiality), economic harm (e.g., loss of employment or insurability, loss of professional standing or reputation, loss of standing within the community) and legal jeopardy (e.g., disclosure of illegal activity or negligence), as well as known side effects of study medication, if applicable, and risk of pain and physical injury. Describe what will be done to minimize these risks. Describe procedures for follow-up, when necessary, such as when subjects are found to be in need of medical or psychological referral. If there is no direct interaction with subjects, and risk is limited to breach of confidentiality (e.g., for existing data), state this. General measures to minimize the risks: Medical screening of the potential subjects is designed to exclude those that may be at risk from the study procedures. A qualified physician is available in the building whenever a subject is undergoing any procedure. The exposure will be terminated for any rapid change in symptoms, tachycardia and/or arrhythmia, decline in arterial oxygen saturation, or for any distress of concern to the volunteer or the console operator. Medical staff and medication are immediately available (within the building) should it be necessary. HSF has a fully stocked medical station and the University of North Carolina Hospital is a short distance from the HSF. On days after exposure subjects will be urged to contact the medical station should they experience any of the following symptoms: epistaxis, persistent cough, chest pain, dyspnea, wheezing, hoarseness, or sore throat. Risks associated with specific study procedures are as follows: • Pulmonary function tests (spirometry) are standard non-invasive techniques that are commonly used in studies of pulmonary function on populations of all ages and entail little or no risk to the subject. The intrabreath technique uses a single breath of 0.3 % acetylene uptake for measurement of pulmonary blood flow (cardiac output). Although large doses of acetylene can cause nausea, vomiting, and headache our subjects will be exposed to a single inhalation of a low Application for IRB Approval of Human Subjects Research page 15 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 91 of 135 PageID# 401 concentration of acetylene for a brief period of time. Thus the risks of these complications to our subjects are extremely low. • ECG and heart rate variability are standard non-invasive techniques commonly used for heart rate and rhythm analysis and entail little or no risk to the subject. There is the possibility that preparation of the skin for electrode placement and removal may cause skin irritation, itching, or soreness in some subjects. • Brachial artery ultrasound: There are no known risks associated with imaging of the brachial artery. However, intermittent brief occlusion of blood flow to the forearm may cause mild discomfort and temporary sensations such as tingling and numbness until the blood pressure cuff is released. Approximately 0.5 % of participants develop painless petechiae in the arm which is examined and these resolve within a few days. Sublingual nitroglycerin used in the brachial artery ultrasound measurement is a potent vasodilator, and may cause headache, flushing, and transient hypotension. These effects are short-lived because the peak plasma concentration occurs within 4 minutes of administration and the plasma half-life is approximately 5 minutes. To minimize the risk of hypotension, the subject will remain lying down for 10 minutes after receiving nitroglycerin. In addition, individuals who may be at risk of excessive blood pressure lowering (i.e. individuals who have baseline systolic blood pressure < 90 mm Hg, or who have obstruction of the left ventricular outflow tract due to aortic stenosis or a dynamic outflow gradient) will be excluded from this study during screening. Allergic reactions to nitroglycerin have been reported, but are rare. • Blood Pressure Monitoring. There is a small chance of bruising as a result of wearing the blood pressure monitoring cuff. • Venipuncture will be done by insertion of the needle and may cause minor discomfort at the site of injection and there is a possibility that a bruise will form which may be painful for 2-3 days. It is possible that the subject may feel lightheaded or even faint due to anxiety about the blood draw. Rarely, a skin infection may occur. To minimize these risks, blood is drawn by trained medical professionals. Subjects are in a semirecumbent position and closely monitored for any signs of faintness, given liquids and food to eat if requested, and only allowed to leave the facility after a 15-minute waiting period to make sure they are stable when in the erect position. • CAP Exposure . The subjects in this study will be exposed to an inhaled particle mass that does not exceed what they would encounter over 24 hours in a typical urban environment on a smoggy day. It is expected that particulate exposure levels will be up to 600 ug/m3 and the exposure will be terminated if the level exceeds 600 ug/m3 for greater than 6 minutes. Thus while we cannot completely rule out the possibility of an adverse effect, since we are exposing the volunteers to a particulate exposure burden they would likely encounter if visiting a large city, we feel the risk posed to volunteers is very small. Possible health effects of acute exposures to air pollution particles include chest pain, mild dyspnea, headache, cough, and, wheeze. All of these effects would be expected to resolve spontaneously within hours of exposure cessation. The particulate exposure may possibly cause increased airways inflammation. It is also possible that exposure could uncover a previously unidentified pre-existing cardiac condition that could present a health risk to a subject. During the exposures, subjects will be continuously monitored during the entire exposure by direct observation. A physician on duty in the facility will be available when exposures are occurring. Heart rate, continuous electrocardiogram via telemetry, and SaO2 by pulse oximetry will also be monitored continuously, and blood pressure will be monitored every 15 minutes. Indications for terminating the exposure include significant respiratory distress or dyspnea, chest or angina-like pain, significant cardiac arrhythmias, pallor, or ataxia. Subjects will be aware that they can terminate their exposure for any reason and still Application for IRB Approval of Human Subjects Research page 16 Field Cod Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 92 of 135 PageID# 402 receive compensation for the entire session. The investigators or duty physician will end the exposure if the subject is found to be suffering from any adverse effect. Full resuscitation equipment will be available at all times during exposures and in the event of an emergency, after initial medical assessment, patients will be transported to UNC Hospitals Emergency Department for continued treatment. • Confidentiality Risk of breach of confidentiality is minimal. All subjects will be assigned a study number which will be used for data recording – not the subject’s name. The study number is all that will be entered into computer databases. All paper files that may contain the subject’s name or screening number are secure in the EPA building that has limited access 24 hours/day. Any abnormal medical findings (CBC, ECG, brachial artery ultrasound image, spirometry) will be discussed with the volunteer and the volunteer will be counseled to seek treatment from his/her personal physician if indicated. Samples will be stored at the U.S. EPA HSF. A numeric coding system will be used to ensure that subjects cannot be directly identified from the samples alone. A.4.8. Data analysis. Tell how the qualitative and/or quantitative data will be analyzed. Explain how the sample size is sufficient to achieve the study aims. This might include a formal power calculation or explanation of why a small sample is sufficient (e.g., qualitative research, pilot studies). To test our hypothesis that CAP causes adverse cardiovascular effects in GSTM1 null older human volunteers, we will measure a number of relevant endpoints , including blood pressure, HRV, brachial arterial blood flow rate, change in blood coagulation factors, platelets, fibrinogen, c-reactive protein, lactate, plasminogen activator inhibitor, ferretin, and α1-antitrypsin. In this study, our primary endpoints will be HRV measurement and peripheral venous blood markers. Our secondary endpoints will be endothelial cell function and pulmonary function measurements. Statistical data analyses will consist of ANOVA for continuous variables and rank sum tests for non-continuous variables pre- and post-exposure. A p value of 0.05 or less will be considered significant. The sample size was calculated to detect a difference of 10% change in HRV assuming a standard deviation of 9 %. Using GraphPad software, an N of 15 was derived using a power of 0.8 and an α of 0.05. This study will enroll approximately 30 subjects in order to provide sufficient power to all for the examination of differences between GSTM1 null and positive subjects. The study cohort will be monitored through genetic screening to ensure that individuals with GSTM1 null genotype are represented in a proportion approximately equal to the prevalence in the US population, about 40%. Based on recently completed studies for subjects with the characteristics sought in this study, the expected screening attrition rate is up to 70 %, with a heavy effect of genotype requirement. Postscreening completion rate is up to 50 %. Extrapolating from these rates, we can expect a 15% overall completion yield. Therefore, to obtain 30 subjects, we will enroll approximately 200 subjects. A.4.9. Will you collect or receive any of the following identifiers? Does not apply to consent forms. __ No X Yes If yes, check all that apply: Application for IRB Approval of Human Subjects Research page 17 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 93 of 135 PageID# 403 a. _X_ Names b. _X_ Telephone numbers c. _X_ Any elements of dates (other than year) for dates directly related to an individual, including birth date, admission date, discharge date, date of death. For ages over 89: all elements of dates (including year) indicative of such age, except that such ages and elements may be aggregated into a single category of age 90 and older d. _X_ Any geographic subdivisions smaller than a State, including street address, city, county, precinct, zip code and their equivalent geocodes, except for the initial three digits of a zip code e. __ Fax numbers f. _X_ Electronic mail addresses g. __ Social security numbers h. __ Medical record numbers i. j. k. l. m. n. o. p. q. r. __ Health plan beneficiary numbers __ Account numbers __ Certificate/license numbers __ Vehicle identifiers and serial numbers (VIN), including license plate numbers __ Device identifiers and serial numbers (e.g., implanted medical device) __ Web universal resource locators (URLs) __ Internet protocol (IP) address numbers __ Biometric identifiers, including finger and voice prints __ Full face photographic images and any comparable images __ Any other unique identifying number, code, or characteristic, other than dummy identifiers that are not derived from actual identifiers and for which the reidentification key is maintained by the health care provider and not disclosed to the researcher A.4.10. Identifiers in research data. Are the identifiers in A.4.9 above linked or maintained with the research data? X yes - no A.4.11. Confidentiality of the data. Describe procedures for maintaining confidentiality of the data you will collect or will receive. Describe how you will protect the data from access by those not authorized. How will data be transmitted among research personnel? Where relevant, discuss the potential for deductive disclosure (i.e., directly identifying subjects from a combination of indirect IDs). No personal identifying information will be attached to the samples. No subjects will be identified in any report or publication about this study. Study samples will be stored in a secure room with restricted access. The sample will be prepared and stored indefinitely in a freezer for future testing. Portions of the sample may be shared with researchers at other scientific institutions or sent to outside clinical laboratories for analysis, however, only coded samples will be sent. All medical records generated during this study will be kept in the medical records office at the U.S. EPA Human Studies Facility. Application for IRB Approval of Human Subjects Research page 18 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 94 of 135 PageID# 404 A.4.12. Data sharing. With whom will identifiable (contains any of the 18 identifiers listed in question A.4.9 above) data be shared outside the immediate research team? For each, explain confidentiality measures. Include data use agreements, if any. _X_ No one __ Coordinating Center: __ Statisticians: __ Consultants: __ Other researchers: __ Registries: __ Sponsors: __ External labs for additional testing: __ Journals: __ Publicly available dataset: __ Other: A.4.13. Data security for storage and transmission. Please check all that apply. For electronic data: _X_ Secure network _X_ Password access __ Encryption __ Other (describe): __ Portable storage (e.g., laptop computer, flash drive) Describe how data will be protected for any portable device: For hardcopy data (including human biological specimens, CDs, tapes, etc.): __ Data de-identified by research team (stripped of the 18 identifiers listed in question A.4.9 above) __ Locked suite or office _X_ Locked cabinet __ Data coded by research team with a master list secured and kept separately __ Other (describe): A.4.14. Post-study disposition of identifiable data or human biological materials. Describe your plans for disposition of data or human biological specimens that are identifiable in any way (directly or via indirect codes) once the study has ended. Describe your plan to destroy identifiers, if you will do so. Samples will be stored in a repository where only project members of the study will have access to the samples. Application for IRB Approval of Human Subjects Research page 19 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 95 of 135 PageID# 405 Part A.5. The Consent Process and Consent Documentation (including Waivers) The standard consent process is for all subjects to sign a document containing all the elements of informed consent, as specified in the federal regulations. Some or all of the elements of consent, including signatures, may be altered or waived under certain circumstances. • • • • If you will obtain consent in any manner, complete section A.5.1. If you are obtaining consent, but requesting a waiver of the requirement for a signed consent document, complete section A.5.2. If you are requesting a waiver of any or all of the elements of consent, complete section A.5.3. If you need to access Protected Health Information (PHI) to identify potential subjects who will then be contacted, you will need a limited waiver of HIPAA authorization. This is addressed in section B.2. You may need to complete more than one section. For example, if you are conducting a phone survey with verbal consent, complete sections A.5.1, A.5.2, and possibly A.5.3. A.5.1. Describe the process of obtaining informed consent from subjects. If children will be enrolled as subjects, describe the provisions for obtaining parental permission and assent of the child. If decisionally impaired adults are to be enrolled, describe the provision for obtaining surrogate consent from a legally authorized representative (LAR). If non-English speaking people will be enrolled, explain how consent in the native language will be obtained. Address both written translation of the consent and the availability of oral interpretation. After you have completed this part A.5.1, if you are not requesting a waiver of any type, you are done with Part A.5.; proceed to Part B. The subject will be given an opportunity to read the consent. At that time a member of the study team (usually the PI) will verbally describe the study and the subject will have an opportunity to ask questions or address concerns about any aspect of the study. The subject will be given a copy of the signed consent form for his/her records. Genotyping and consent forms will be administered by nursing staff and/or study team members. The Main Consent Form will be provided to the subject at the time of the Genotypinc Screen visit. A.5.2. Justification for a waiver of written (i.e., signed) consent. The default is for subjects to sign a written document that contains all the elements of informed consent. Under limited circumstances, the requirement for a signed consent form may be waived by the IRB if either of the following is true. Chose only one: a. The only record linking the subject and the research would be the consent document and the principal risk would be potential harm resulting from a breach of confidentiality (e.g., study topic is sensitive so that public knowledge of participation could be damaging). Explain. __ yes __ no b. The research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context (e.g., phone survey). Explain. __ yes __ no If you checked “yes” to either (and you are not requesting a waiver in section Application for IRB Approval of Human Subjects Research page 20 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 96 of 135 PageID# 406 A.5.3) consent must be obtained orally, by delivering a fact sheet, through an online consent form, or be incorporated into the survey itself. Include a copy of the consent script, fact sheet, online consent form, or incorporated document. → If you have justified a waiver of written (signed) consent (A.5.2), you should complete A.5.3 only if your consent process will not include all the other elements of consent. Application for IRB Approval of Human Subjects Research page 21 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 97 of 135 PageID# 407 A.5.3. Justification for a full or partial waiver of consent. The default is for subjects to give informed consent. A waiver might be requested for research involving only existing data or human biological specimens (see also Part C). More rarely, it might be requested when the research design requires withholding some study details at the outset (e.g., behavioral research involving deception). In limited circumstances, parental permission may be waived. This section should also be completed for a waiver of HIPAA authorization if research involves Protected Health Information (PHI) subject to HIPAA regulation, such as patient records. __ Requesting waiver of some elements (specify; see SOP 28 on the IRB web site): __ Requesting waiver of consent entirely If you check either of the boxes above, answer items a-f.. To justify a full waiver of the requirement for informed consent, you must be able to answer “yes” (or “not applicable” for question c) to items a-f. Insert brief explanations that support your answers. a. Will the research involve no greater than minimal risk to subjects or to their privacy? Explain. __ yes __ no b. Is it true that the waiver will not adversely affect the rights and welfare of subjects? (Consider the right of privacy and possible risk of breach of confidentiality in light of the information you wish to gather.) Explain. __ yes __ no c. When applicable to your study, do you have plans to provide subjects with pertinent information after their participation is over? (e.g., Will you provide details withheld during consent, or tell subjects if you found information with direct clinical relevance? This may be an uncommon scenario.) Explain. __ yes __ not applicable d. Would the research be impracticable without the waiver? (If you checked “yes,” explain how the requirement to obtain consent would make the research impracticable, e.g., are most of the subjects lost to follow-up or deceased?). Explain. __ yes __ no e. Is the risk to privacy reasonable in relation to benefits to be gained or the importance of the knowledge to be gained? Explain. __ yes __ no If you are accessing patient records for this research, you must also be able to answer “yes” to item f to justify a waiver of HIPAA authorization from the subjects. f. Would the research be impracticable if you could not record (or use) Protected Health Information (PHI)? (If you checked “yes,” explain how not recording or using PHI would make the research impracticable). Explain. Application for IRB Approval of Human Subjects Research __ yes __ no page 22 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 98 of 135 PageID# 408 Part B. Questions for Studies that Involve Direct Interaction with Human Subjects → If this does not apply to your study, do not submit this section. B.1. Methods of recruiting. Describe how and where subjects will be identified and recruited. Indicate who will do the recruiting, and tell how subjects will be contacted. Describe efforts to ensure equal access to participation among women and minorities. Describe how you will protect the privacy of potential subjects during recruitment. For prospective subjects whose status (e.g., as patient or client), condition, or contact information is not publicly available (e.g., from a phone book or public web site), the initial contact should be made with legitimate knowledge of the subjects’ circumstances. Ideally, the individual with such knowledge should seek prospective subjects’ permission to release names to the PI for recruitment. Alternatively, the knowledgeable individual could provide information about the study, including contact information for the investigator, so that interested prospective subjects can contact the investigator. Provide the IRB with a copy of any document or script that will be used to obtain the patients’ permission for release of names or to introduce the study. Check with the IRB for further guidance. Subjects will be recruited for this study by the Westat Corporation, which has recruited for studies at the U.S EPA HSF since 1998. The manner in which this will be done is similar that that of past U.S. EPA studies and specific recruitment procedures as per the previously UNC IRB-approved protocol, Recruitment and Screening of Potential Participants for U.S. EPA Studies (95-EPA-66). Every effort will be made to recruit women and members of racial minority groups into this study. Since this study will recruit older healthy subjects and one human study conducted at HSF (“Cardioprotective Effects of Omega-3 Fatty Acids Supplementation in Healthy Older Subjects Exposed to Air Pollution Particles”, Haiyan Tong) also involved the same age groups, therefore we are likely to re-contact with these subjects to check if they are interested in participation in this study. Subjects will be asked to call the recruitment office. During the telephone interview, the subjects will receive information regarding the study and their eligibility for the study will be assessed. Subjects who provide responses which indicate that they are likely to meet the criteria will be scheduled for an appointment in the Medical Station in the U.S. Human Studies Facility. B.2. Protected Health Information (PHI). If you need to access Protected Health Information (PHI) to identify potential subjects who will then be contacted, you will need a limited waiver of HIPAA authorization. If this applies to your study, please provide the following information. a. Under this limited waiver, you are allowed to access and use only the minimum amount of PHI necessary to review eligibility criteria and contact potential subjects. What information are you planning to collect for this purpose? b. How will confidentiality/privacy be protected prior to ascertaining desire to participate? c. When and how will you destroy the contact information if an individual declines participation? Application for IRB Approval of Human Subjects Research page 23 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 99 of 135 PageID# 409 B.3. Duration of entire study and duration of an individual subject’s participation, including follow-up evaluation if applicable. Include the number of required contacts and approximate duration of each contact. It is anticipated that the duration of the study will be approximately 18 months. Participant recruitment and screening is expected to be continuous throughout the study until the intended number of participants is reached. Genotype Screen 1 hr Physical Examination 2 hrs Training Day 3 hr Air Exposure Day 8 hrs Ozone Exposure Day 8 hrs Follow-up Day 3 hrs Table 2. Study Visit Schedule If the subject is eligible for the study he/she will make up to 6 visits to the HSF over approximately 5-6 weeks. The number of visits will be determined in part by each subject’s previous participation in EPHD studies, as repeating genotyping or baseline ECG measurements may not be necessary. The pre-enrollment genotyping visit will take approximately 1 hour. It may also be determined that the individual is not eligible for continuation in the study after genotyping of the blood sample. The physical exam will take approximately 2 hours. The training day will require approximately 3 hours.. Exposure days will last approximately 8 hours. Eighteen hours after the exposure, the subject will return for a follow-up visit which will last approximately 3 hours. Application for IRB Approval of Human Subjects Research page 24 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 100 of 135 PageID# 410 B.4. Where will the subjects be studied? Describe locations where subjects will be studied, both on and off the UNC-CH campus. Subjects will be seen in the U.S. EPA Human Studies Facility on Mason Farm Road in Chapel Hill, NC. B.5. Privacy. Describe procedures that will ensure privacy of the subjects in this study. Examples include the setting for interviews, phone conversations, or physical examinations; communication methods or mailed materials (e.g., mailings should not indicate disease status or focus of study on the envelope). All interviews, phone conversations, and physical examinations will be conducted in private rooms in the U.S. EPA Human Studies Facility. This facility is guarded and only individuals working in the building have access beyond the guard’s desk without an escort. Additionally, subjects will need to initial the consent form indicating whether or not they would be willing to participate in the study with another volunteer present. B.6. Inducements for participation. Describe all inducements to participate, monetary or nonmonetary. If monetary, specify the amount and schedule for payments and if/how this will be prorated if the subject withdraws (or is withdrawn) from the study prior to completing it. For compensation in foreign currency, provide a US$ equivalent. Provide evidence that the amount is not coercive (e.g., describe purchasing power for foreign countries). Be aware that payment over a certain amount may require the collection of the subjects’ Social Security Numbers. If a subject is paid more than $40.00 at one time or cumulatively more than $200.00 per year, collection of subjects’ Social Security Number is required (University policy) using the Social Security Number collection consent addendum found under forms on the IRB website (look for Study Subject Reimbursement Form). Subjects will receive monetary compensation for their time (approximately $12 per hour) and for procedures in the study. In addition, subjects traveling from areas beyond Chapel Hill/Carrboro will be reimbursed for travel expenses commensurate with the US Government mileage rate in effect at the time. Parking will be provided or costs will be paid. Payments will be made after each segment of the study, unless the subject requests otherwise. A subject who is unable to complete the study for voluntary reasons or is dismissed for failure to comply with eligibility requirements will receive compensation for his/her participation up to that point. Subjects who are dismissed by the investigators for involuntary reasons after enrollment in the study but prior to completion will be paid for the entire study, excluding completion bonus. In the event a scheduled study activity must be cancelled by the investigators with less than 72 hours prior notice, subjects will be paid $12 per hour for the time scheduled and canceled. Subjects will be paid in full for any procedures that may have been started during the current visit. Cancellations could occur due to adverse weather conditions, equipment failure, and other unforeseen events. When feasible, canceled visits will be rescheduled. The following table details the expected compensation for completion of the entire study: Application for IRB Approval of Human Subjects Research page 25 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 101 of 135 PageID# 411 Subjects will be paid approximately $12 per hour for participation in this study. 1. If following genotyping of the blood samples on screening day, it is determined that the individual’s genotype is not needed for completion of the study, then that subject may be informed that his/her participation in this study is no longer necessary. The subject will be notified by phone and the total compensation for this study will be approximately $30. 2. If the subject is qualified and finishes the entire study, the total compensation for completion of this study will be approximately $1857. Pre-study qualifications (screening+blood+physical) $60 Training day (3 hours) + Dietary recording $200 Exposure Day Time and Procedures (includes $5 for lunch) Total: Follow- up Day Time and Procedures Total: On-Time Bonus Dietary Compliance Study Completion Bonus ($603/day) $1206 $141 $50 $100 $100 Approximate TOTAL for completion of study = $1857 If a subject is terminated from the study or chooses to withdraw he/she will be reimbursed for time and procedures completed up to that time point. B.7. Costs to be borne by subjects. Include child care, travel, parking, clinic fees, diagnostic and laboratory studies, drugs, devices, all professional fees, etc. If there are no costs to subjects other than their time to participate, indicate this. There will be no cost to the subject. Subjects traveling from areas beyond Chapel Hill/Carrboro will be reimbursed for travel expenses commensurate with the U.S. Government mileage rate in effect at the time. Parking will be provided or costs will be paid. Payments will be made after each segment of the study, unless the subject requests otherwise. Application for IRB Approval of Human Subjects Research page 26 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 102 of 135 PageID# 412 Part C. Questions for Studies using Data, Records or Human Biological Specimens without Direct Contact with Subjects → If this does not apply to your study, do not submit this section. C.1. What records, data or human biological specimens will you be using? (check all that apply): __ __ __ __ __ __ Data already collected for another research study Data already collected for administrative purposes (e.g., Medicare data, hospital discharge data) Medical records (custodian may also require form, e.g., HD-974 if UNC-Health Care System) Electronic information from clinical database (custodian may also require form) Patient specimens (tissues, blood, serum, surgical discards, etc.) Other (specify): C.2. For each of the boxes checked in 1, how were the original data, records, or human biological specimens collected? Describe the process of data collection including consent, if applicable. C.3. For each of the boxes checked in 1, where do these data, records or human biological specimens currently reside? C.4. For each of the boxes checked in 1, from whom do you have permission to use the data, records or human biological specimens? Include data use agreements, if required by the custodian of data that are not publicly available. C.5. If the research involves human biological specimens, has the purpose for which they were collected been met before removal of any excess? For example, has the pathologist in charge or the clinical laboratory director certified that the original clinical purpose has been satisfied? Explain if necessary. __ yes __ no __ not applicable (explain) C.6. Do all of these data records or specimens exist at the time of this application? If not, explain how prospective data collection will occur. __ yes __ no If no, explain Application for IRB Approval of Human Subjects Research page 27 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 103 of 135 PageID# 413 SUBJ #_________ DATE__________ SYMPTOM QUESTIONNAIRE FOR CHAMBER EXPOSURE STUDIES Pre-Exposure / End Exposure / 4 hrs post end Exposure (Circle one) INSTRUCTIONS: Please indicate if you are experiencing any of the symptoms or restrictions listed below, using the following scale to indicate the severity. Circle the number. 0 = NONE (not present) 1 = TRACE/NOTICED (barely detectable) 2 = MILD/LIGHT (present, but not annoying) 3 = MODERATE (present, but somewhat annoying) 4 = SEVERE/HEAVY (present and very annoying and painful) ______________________________________________________________________________ NONE TRACE MILD MODERATE SEVERE SYMPTOMS ______________________________________________________________________________ 1. HEADACHE 0 1 2 3 4 2. IRRITATION OF THE NOSE 0 1 2 3 4 3. STUFFY NOSE/SINUS CONGESTION 0 1 2 3 4 4. RUNNY NOSE 0 1 2 3 4 5. DRY/SORE THROAT 0 1 2 3 4 6. PAIN on DEEP INSPIRATION 0 1 2 3 4 7. UNUSUAL FATIGUE OR TIREDNESS 0 1 2 3 4 8. EYE IRRITATION 0 1 2 3 4 9. SHORTNESS OF BREATH 0 1 2 3 4 10. SNEEZING 0 1 2 3 4 11. COUGH 0 1 2 3 4 12. WHEEZING/WHISTLING in CHEST 0 1 2 3 4 13. CHEST TIGHTNESS 0 1 2 3 4 14. SWEATING 0 1 2 3 4 15. Other___________________________ 0 1 2 3 4 Application for IRB Approval of Human Subjects Research page 28 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 104 of 135 PageID# 414 Application for IRB Approval of Human Subjects Research page 29 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 105 of 135 PageID# 415 Samet Declaration Exhibit 2 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 106 of 135 PageID# 416 OPERATION, MAINTENANCE, AND MODIFICATION OF THE HUMAN STUDIES FACILITY PROTOCOL OPERATIONS PLAN for Cardiopulmonary Effects of Exposure of Healthy Older GSTM1 Null and Sufficient Individuals to Concentrated Ambient Air Particles (CAPTAIN) 11-1807 Prepared for The Environmental Protection Agency Research Triangle Park, NC 27711 In Response To Contract EP-D-10-095, EPA Work Order #1202 Prepared by TRC Environmental Corporation 5540 Centerview Drive, Suite 100 Raleigh, NC 27606 September 27, 2012 Document Number EPD10095-0030POP-R2 Case Document 14-1 Filed 10/04/12 Page 107 of 135 Page D# 417 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 108 of 135 PageID# 418 Protocol Operations Plan for CAPTAIN TRC Environmental Corporation EPD10095-0030POP-R2 1.0 INTRODUCTION The U.S. Environmental Protection Agency has contracted with TRC Environmental Corporation to operate, maintain, and modify specific components of the EPA's Human Studies Facility located in Chapel Hill, North Carolina. Included are systems associated with human exposure chambers, subject test rooms, and the Medical Station; small scale human exposure systems; and the in vitro exposure system. Other tasks include computer operations, data management, safety assurance, quality assurance, and system documentation and preparation of technical reports. Specific TRC responsibilities are described in the work plan and contract statement of work. This Protocol Operations Plan details the support provided by TRC for the study entitled Cardiopulmonary Effects of Exposure of Healthy Older GSTM1 Null and Sufficient Individuals to Concentrated Ambient Air Particles (CAPTAIN), study number 11-1807. Routine activities performed by TRC to support research conducted at the NHEERL are described in the contract Work Plan and are not reiterated here. This document is a supplement to the Work Plan identifying exceptions to the Work Plan and describing additional effort resulting from this specific protocol. Appendix A contains a summary Subject Activity Schedule for general reference. Appendix B contains a summary of equipment and configuration parameters that will be utilized for this study. The EPA Principal Investigator (PI) responsible for this study is Dr. James Samet. This protocol received approval from the UNC Committee on the Protection of Human Subjects on November 21, 2011. 2.0 TASK 1 - SYSTEM MAINTENANCE AND OPERATION The following paragraphs describe the operational requirements of equipment and systems maintained by TRC and utilized in support of this research study. Up to 200 test subjects aged 50 – 75 will be recruited to participate in this study, with the goal of completing 30. TRC will monitor the schedule maintained by the subject recruitment contractor (Westat) to determine when to prepare study areas for CAPTAIN activities. Screening and training periods will precede the exposures. At the training period, subjects will be instructed in dayof-exposure activities, and baseline spirometry, diffusion limited uptake of CO (DLCO), and resting minute ventilation measurements will be obtained. In addition, during the training session, the PI will be responsible for determining the size of face mask required for the subject, and measuring the subject’s nose/mouth position while seated in the chamber. A measuring system is available inside and outside Chamber AC89 to enable the PI to determine this vertical position, and forms will be available in a notebook at the console to record the measurement. TRC must make all necessary adjustments prior to starting the aerosol concentrator, which is approximately three hours prior to the scheduled exposure. Exposures will be conducted in the aerosol exposure chambers located in Room 89, with subjects seated during the entire exposure. Each subject will undergo two two-hour exposures. The first exposure (Tuesday) will be clean air in Chamber PC89. The clean air presented to the subject will be medical grade air that has been humidified to 50 ±10% RH. The second exposure (Wednesday) will be concentrated fine and ultrafine particles in Chamber AC89. Both Page 1 September 27, 2012 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 109 of 135 PageID# 419 Protocol Operations Plan for CAPTAIN TRC Environmental Corporation EPD10095-0030POP-R2 clean air and concentrated particles will be presented to the subject through a face mask. Particle exposure sessions can begin no earlier than 10:00 a.m. On particle exposure days, the TRC Pollutant Control System (PCS) operators will monitor chamber particulate measurements prior to the exposure. If chamber particulate measurements are estimated to be less than 50µg/m3, TRC will inform the PI, who will determine whether to run or reschedule the exposure. Training, as well as pre- and post-exposure spirometry and DLCO measurements will be performed in non-exposure Test Room TB87 utilizing a SensorMedics digital plethysmography system. Minute ventilation measurements will be taken utilizing a custom Minute Ventilation System developed in-house. Telemetry ECG will be used to monitor test subjects during all testing. A Holter ECG monitor will be used to monitor subjects during, and for 18 hours after, the exposures. Blood pressure will be monitored periodically throughout the exposure day activities. An oxygen saturation monitor will be available in the chamber during exposure sessions. TRC staff will be responsible for calibrating and maintaining the SensorMedics equipment, telemetry system, ambulatory blood pressure monitor, pulse oximeter, and Holter recorders used during the testing. TRC has no responsibility for the brachial artery ultrasound (BAU) system. TRC staff will be responsible for maintaining and operating the aerosol concentrator, aerosol chambers, and particulate measurement devices (i.e., filter sampler, Condensation Particle Counter (CPC), Scanning Mobile Particle Sizers (SMPSs), DataRAMs™, Tapered Element Oscillating Microbalance (TEOM) Particulate Mass Monitor, and a total filter monitoring the chamber environment. Specifically, the following describes TRC activities for all subject particle exposures conducted in Chamber AC89: The concentrator will be configured with the size selective inlet but without the size selective outlet. In this configuration, the concentrator is configured to remove particles larger than 2.5µm. However, because the size selective inlet does not have an infinitely sharp cutoff point, some coarse particles (larger than 2.5µm) will enter the chamber. The concentrator will be configured to utilize the air stream dryers (Harvard dryers) that were part of the original system. The Harvard dryers will be used with the maximum flow of chilled water, and the exit air temperature will not be controlled. A single total Teflo filter will be configured to sample delivery air to the chamber. One CPC, one DataRAM™, one SMPS, and one TEOM® will be configured to sample delivery air to the chamber. The chamber exhaust flow will be adjusted to keep the total flow through the system at approximately 65 l/min, which will provide approximately 50 l/min to the subject. The remainder of the air flow is required by the sampling equipment. The chamber inlet will be configured such that the face mask, when attached, will accommodate the seated subject’s nose/mouth area as determined by the PI during training. This position measurement must be communicated to TRC at least three hours prior to the exposure. The temperature of the conditioning air will be adjusted as necessary to maximize the performance of the concentrator. A standalone air conditioner in the chamber will be available for use in establishing and maintaining a comfortable environment for the subject. The concentrator system will be started two to three hours before the subject is scheduled to enter the chamber to establish exposure conditions. PCS will be configured to dilute the particle concentration presented to the subject such that measurements do not exceed 600µg/m3. Specifically, the PCS operator will monitor the real-time TEOM® and DataRAM™ measurements once the aerosol concentrator system has stabilized. Historically, the average of TEOM® measurements over an entire exposure session has matched the final filter concentration fairly closely, but the Page 2 September 27, 2012 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 110 of 135 PageID# 420 Protocol Operations Plan for CAPTAIN TRC Environmental Corporation EPD10095-0030POP-R2 instrument reacts rather slowly to changes in the environment. The relative accuracy of the DataRAM™, on the other hand, has been fairly inconsistent from one exposure to another but the instrument is much faster to react to changes in the environment. Therefore, once the concentrator system has stabilized, the PCS operator will observe the approximate relative accuracy of DataRAM™ to TEOM® measurements and will configure the dilution system, which is based upon DataRAM™ measurements, appropriately. Note that the dilution system will be configured such that dilution begins when the concentration as measured by the TEOM® is approximately 500µg/m3. If for any reason the dilution system fails to perform properly, the PCS operator will use the particle concentration as measured by the DataRAM™ and TEOM® to determine if the exposure should be terminated due to excessively high concentrations. Specifically, the PCS software will issue an audible alarm if the twominute average concentration measured by the DataRAM™ exceeds 20% of the dilution point. At that time, the PCS operator will initiate continuous monitoring of the two instruments’ readings. The PCS operator will carefully monitor the concentration as reported by the TEOM® if the two-minute average DataRAM™ concentrations remain higher than the alarm limit for more than three consecutive average periods. If the TEOM® concentration shows a reasonably steep increase in concentration over the last several minutes or if the TEOM® concentration exceeds 600µg/m3, the PCS operator will initiate removal of the subject from the chamber. TRC will make a decision within 14 minutes of the first alarm and the PI will be notified if the decision is to abort the exposure. Exposure chamber temperature and relative humidity data, as well as the temperature and relative humidity at the inlet to the face mask, will be collected by the PCS. Filter media from the sampler will be removed and placed in cold storage at the conclusion of each subject exposure. When sufficient samples are available, TRC will weigh the filters. For clean air exposures in Chamber PC89, TRC will configure one DataRAM™ to sample delivery air to the chamber. The chamber inlet will be configured such that the face mask, when attached, will accommodate the seated subject’s nose/mouth area as determined by the PI during training. In addition, the incoming medical-grade air (approximately 50 l/min) will be humidified to approximately 50% RH. The temperature and relative humidity at the inlet to the face mask will be collected by the PCS. TRC will maintain Subject Entry/Exit Logs for Chambers AC89 and PC89. The study console operator will be required to enter the date and time that the subject entered and exited the chamber for each exposure session. The study operator will also be required to communicate with the PCS operator to verify that the chamber is ready for subject exposure, and to coordinate with the PCS operator when the subject enters the chamber. At that time, the PCS operator will begin filter sampling. At the end of the exposure period, the study console operator will be required to inform the PCS operator when the subject is leaving the chamber. The telephone number of the PCS control room is posted on the study console. 3.0 TASK 2 - COMPUTER OPERATION AND DATA PROCESSING An automated symptom questionnaire will be available on the spirometry computers in the Medical Station and in Room TB87. TRC will ensure that the questionnaire data, which will be stored in an Excel spreadsheet, will be saved in a study-specific file on a network drive for convenient access. No modification of the existing OMEGACON questionnaire is planned, and TRC will have no other responsibility for the collection or maintenance of questionnaire data. Page 3 September 27, 2012 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 111 of 135 PageID# 421 Protocol Operations Plan for CAPTAIN TRC Environmental Corporation EPD10095-0030POP-R2 Because there are no exposure activities other than blood pressure measurements that will be pre-programmed for the ambulatory blood pressure monitor, there will be no automated study timer established for the CAPTAIN study at the Chamber AC89 or PC89 consoles. The following data processing activities will be conducted for this study: Subject chamber entry and exit times will be manually recorded by the investigator(s)/operator(s). TRC personnel will enter the data into the database and perform a verification of the input. Roof weather station data for approximately the 24-hour period preceding the exposure will be printed and saved with other operational data. TRC staff will analyze filter weight data from Chamber AC89 to determine exposure conditions (e.g., mass concentration). A spreadsheet with these calculations will be available on the EPA network. Data will be obtained from Internet sources and used in a trajectory model to show the geographical origins of Chapel Hill particulates. Model reports will be printed and saved with other operational data. All raw data and analysis spreadsheets will be archived. Data obtained in hard copy format will be delivered periodically to the Agency. Computer systems involved in the collection of medical data will be connected to the Agency network such that data collected using those systems can be stored on a network drive for more convenient access. TRC has no other responsibility for medical data. 4.0 TASK 3 - QUALITY CONTROL Standard TRC QA/QC procedures will be implemented for this protocol. A Protocol Performance Report and other protocol-specific QA/QC reports will be prepared unless otherwise directed by the Project Officer. Periodically, TRC staff will verify the calculations used to determine summary exposure conditions from filter data, which are provided as part of routine filter analysis. Any discrepancies will be reported immediately to the PI. 5.0 TASK 4 - SAFETY No special safety measures are required for this study. 6.0 TASK 5 - UPGRADING OF SYSTEMS No system upgrades are required for this study. 7.0 TASK 6 - SYSTEM DOCUMENTATION AND TECHNICAL REPORTS No special system documentation or technical reports are anticipated as a result of this study. Page 4 September 27, 2012 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 112 of 135 PageID# 422 Protocol Operations Plan for CAPTAIN TRC Environmental Corporation EPD10095-0030POP-R2 APPENDIX A CAPTAIN SUBJECT ACTIVITY SCHEDULE1 TRAINING (Medical Station, Test Room TB87, Chamber AC89) Medical screening Explain study and obtain informed consent Training – PFT, minute ventilation EXPOSURE Time2 Procedure -2:15 Check-in Review exclusion criteria Venipuncture; collect blood sample Apply electrodes and begin ECG monitoring Brachial artery ultrasound (BAU) Complete symptom questionnaire 00:00 Begin chamber exposure 02:00 Leave chamber Complete symptom questionnaire Measurements Location Vital signs Medical Station HRV Spirometry DLCO SPO2 BP Spirometry DLCO HRV Collect blood BAU Room 7 Test Room TB87 Chamber AC89 or Chamber PC89 Test Room TB87 Medical Station Room 7 EIGHTEEN HOURS POST PARTICULATE EXPOSURE (Test Room TB87, Medical Station, Room 7) Medical screening Blood sample; HRV; spirometry; DLCO; BAU; symptom questionnaire 1 Schedule provided for general reference. Activities identified are not performed by TRC staff. 2 Times listed are relative to start of exposure. Page 5 September 27, 2012 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 113 of 135 PageID# 423 Protocol Operations Plan for CAPTAIN TRC Environmental Corporation EPD10095-0030POP-R2 APPENDIX B CAPTAIN EQUIPMENT AND CONFIGURATION Study Summary Number of subjects: Locations: Exposures per subject: 200 recruited/30 complete Chamber AC89, Chamber PC89, Test Room TB87, Medical Station Two 2-hour exposures using face mask – first to clean air; second to concentrated fine/ultrafine particles (preferably >50 µg/m3) N/A Study blind status: Parameter Mass concentration Mass concentration Particle size distribution Particle count Temperature Relative humidity Real-Time Controlled and Monitored Parameters Status Device Target Warning Concentration Limit Controlled4 DataRAM >50 µg/m3 20%5 Monitored6 TEOM® N/A N/A Monitored6 SMPS N/A N/A Monitored6 Monitored CPC Rotronics temperature/RH sensor Rotronics temperature/RH sensor Controlled7 Shutdown Limit3 4 600 µg/m3 N/A N/A N/A N/A N/A N/A N/A 50% RH N/A N/A TRC-Maintained Biomedical Equipment Requirements Equipment Plethysmograph Minute ventilation Telemetry ECG Holter monitor Pulse oximeter Ambulatory BP monitor Symptom questionnaire Room TB87 Chamber AC89 Chamber PC89 Medical Station 3 Shutdown concentration reflects instrument readings, not actual subject exposure conditions. Manual shutdown occurs after confirming that concentrations exceed limits for six consecutive minutes. See text for details. 4 Controlled during particle exposures only; monitored during clean air exposures. Note that dilution point is determined immediately prior to exposure based on relative accuracy of DataRAM™ to TEOM® measurements. See text for details. 5 Percentage above dilution point 6 Not monitored during clean air exposures. 7 Controlled during clean air exposures only; monitored during particle exposures. Page 6 September 27, 2012 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 114 of 135 PageID# 424 Samet Declaration Exhibit 3 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 115 of 135 PageID# 425 TOTAL FILTER DATA Note (see below) Date Protocol Subject Number Filter location VAPS - Start time VAPS - Stop time VAPS - Total time (min) External - Start time External - Stop time External - Total time (min) Chamber Pressure (mm Hg) Chamber Temperature (C) Barometric Pressure (mm Hg) Teflon Filter Holder ID Media ID Mass Flow Controller Channel External Average Flow (lpm) Total volume (m^3) Corrected volume (m^3) Total Volume (m^3) Mass on filter (ug) Mass Concentration (ug/m^3) Summary Data - CAPTAIN Date Outlet TEOM Data (ug/m3) 07/25/2012 08/08/2012 09/05/2012 CAPTAIN CAPTAIN CAPTAIN 1 2 4 AC89 AC89 AC89 10:10 10:04 10:09 12:10 12:04 12:09 120 120 120 10:10 10:04 10:09 12:10 12:04 12:09 120 120 120 743.7 744.6 743.2 22.2 22.5 22.4 748.1 749.0 747.6 VAPS - Fine VAPS - Fine VAPS - Fine 449 449 449 4146 4148 4150 AC89FC4 AC89FC4 AC89FC4 14.949 15.907 14.909 1.794 1.909 1.789 1.817 1.933 1.814 1.817 1.933 1.814 759 324 424.5 417.75 167.62 233.95 07/25/2012 08/08/2012 421.1 162.2 09/05/2012 229.1 09/12/2012 CAPTAIN 5 AC89 10:07 12:07 120 10:07 12:07 120 753.6 22.4 757.9 VAPS - Fine 449 4152 AC89FC4 14.966 1.796 1.796 1.796 425.5 236.88 09/19/2012 CAPTAIN 6 AC89 10:13 12:13 120 10:13 12:13 120 745.7 22.3 750.4 VAPS - Fine 449 4154 AC89FC4 14.986 1.798 1.817 1.817 284 156.29 09/26/2012 CAPTAIN 7 AC89 10:06 12:06 120 10:06 12:06 120 749.9 22.8 754.2 VAPS - Fine 449 4156 AC89FC4 14.974 1.797 1.809 1.809 392.5 217.02 09/12/2012 251.1 09/19/2012 178.7 09/26/2012 221.2 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 116 of 135 PageID# 426 Samet Declaration Exhibit 4 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 117 of 135 PageID# 427 OFFICE OF HUMAN RESEARCH ETHICS Medical School Building 52 Mason Farm Road CB #7097 Chapel Hill, NC 27599-7097 (919) 966-3113 Web site: ohre.unc.edu Federalwide Assurance (FWA) #4801   To: James Samet  Environmental Protection Agency  CB: 7315      From: Biomedical IRB  Approval Date: 11/21/2011  Expiration Date of Approval: 10/08/2012  RE: Notice of IRB Approval by Full Board Review  Submission Type: Initial  Study #: 11-1807  Study Title: Cardiopulmonary Effects of Exposure of Healthy Older GSTM1 Null and Sufficient Individuals to Concentrated Ambient Air Particles (CAPTAIN) Sponsors: US Environmental Protection Agency - GRANTS This submission has been approved by the above IRB for the period indicated.  Study Description:  Purpose: Advanced age and common genetic polymorphism of the antioxidant enzyme glutathione-s-transferase (GSTM1) appear to confer susceptibility to ambient particulate matter (PM). This study will compare responses to PM exposure in older volunteers with GSTM1 null and sufficient genotypes. Participants: 30 healthy 50-75 yo subjects. Procedures (methods): Subjects will be placed on a diet restricted of omega and oleic fatty acids for approximately 42 days prior to undergoing sequential exposures to air (control) and concentrated ambient PM (CAP) for 2 hr. Pulmonary, vascular and cardiac function will be evaluated pre, immediately post and 18 hr post exposure.  Regulatory and other findings: The Board agreed that this research involves no more than minimal risk and future reviews may be done on an expedited basis, under Expedited Review, Category 9.  Based on the information provided, the IRB has determined that HIPAA does not apply to this study. Investigator’s Responsibilities: Federal regulations require that all research be reviewed at least annually. It is the Principal Investigator’s responsibility to submit for renewal and obtain approval before the expiration date. You may not continue any research activity beyond the expiration date without IRB approval. Failure to receive approval for continuation before the expiration date will result in automatic page 1 of 2 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 118 of 135 PageID# 428 termination of the approval for this study on the expiration date.  IF YOU SUBMITTED ON PAPER, enclosed are stamped copies of approved consent documents and other recruitment materials (when applicable). You must copy the stamped consent forms for use with subjects unless you have approval to do otherwise. IF YOU SUBMITTED ONLINE (Behavioral and Public Health-Nursing IRBs Only), your approved consent forms and other documents are available online at http://apps.research.unc.edu. You are required to obtain IRB approval for any changes to any aspect of this study before they can be implemented (use the modification form at ohre.unc.edu/forms). Any unanticipated problem involving risks to subjects or others (including adverse events reportable under UNC-Chapel Hill policy) should be reported to the IRB using the web portal at https://irbis.unc.edu/irb.   Researchers are reminded that additional approvals may be needed from relevant "gatekeepers" to access subjects (e.g., principals, facility directors, healthcare system).  This study was reviewed in accordance with federal regulations governing human subjects research, including those found at 45 CFR 46 (Common Rule), 45 CFR 164 (HIPAA), 21 CFR 50 & 56 (FDA), and 40 CFR 26 (EPA), where applicable. CC: Deepika Polineni, (EPA), Non-IRB Review Contact page 2 of 2 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 119 of 135 PageID# 429 Samet Declaration Exhibit 5 Case Document 14-1 Filed 10/04/12 Page 120 of 135 Page MEMORANDUM FROM: Warren Lux EPA Human Subjects Research Review Of?cial T0: R. Julian Preston Associate Director for Health. NI SUBJECT: Approval of Research involving Human Subjects DATE: March 6. 2012 have reviewed the study cited below according to the requirements of Order 1000.]? Change (Policy and Procedures on Protection of Human Research Subjects in EPA Conducted or Supported Research} and have determined that it qualities as intentional exposure research involving human subjects that complies with EPA Regulation 40 CFR 26 (Protection of Human Subjects). The ?nding of compliance includes the determination that the research is non-exempt under 40 26. 0] that it has been approved by the of record. and that the institution engaged in the research has a valid Federalwide Assurance on ?le with the HHS Of?ce for Human Research Protections. Accordingly. approval is granted for recruitment and enrollment of human research subjects into the study. Study Title: ('urdioprdmononv Efforts of'firposure of?cnl'thy ()fdcr (ESTMI and Sufficient Individuals hereon-med Ambient Air Particles (I: PTA IN) Engaged Institution: US. [Environmental Protection Agency. National Health Environmental Effects Research Laboratory FWA it: Protocol l1-1807 Principal Investigator: James Samct HSRRO Study CC: Deepika Polineni. Director. Human Research Protocol Of?ce Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 121 of 135 PageID# 431 Samet Declaration Exhibit 6 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 122 of 135 PageID# 432 University of North Carolina at Chapel Hill Consent to Participate in a Research Study Adult Participants Consent Form Version Date: September 12, 2012 IRB Study # 11-1807 Title of Study: Cardiopulmonary Effects of Exposure of Healthy Older GSTM1 Null and Sufficient Individuals to Concentrated Ambient Air Particles (CAPTAIN) Principal Investigator: James Samet Principal Investigator Department: Environmental Protection Agency Principal Investigator Phone number: 919-966-0665 Principal Investigator Email Address: samet.james@epa.gov Funding Source and/or Sponsor: US Environmental Protection Agency - GRANTS _________________________________________________________________ What are some general things you should know about research studies? You are being asked to take part in a research study. To join the study is voluntary. You may refuse to join, or you may withdraw your consent to be in the study, for any reason, without penalty. Research studies are designed to obtain new knowledge. This new information may help people in the future. You may not receive any direct benefit from being in the research study. There also may be risks to being in research studies. Deciding not to be in the study or leaving the study before it is done will not affect your relationship with the researcher, your health care provider, or the University of North Carolina-Chapel Hill. If you are a patient with an illness, you do not have to be in the research study in order to receive health care. Details about this study are discussed below. It is important that you understand this information so that you can make an informed choice about being in this research study. You will be given a copy of this consent form. You should ask the researchers named above, or staff members who may assist them, any questions you have about this study at any time. What is the purpose of this study? The purpose of this research study is to determine if a component of ambient air pollution to which we are all exposed, particulate matter (PM), elevates the risks of cardiac changes and to investigate the role of a common genetic polymorphism (GSTM1) in these effects. Results from this study may increase the understanding of how gaseous and particulate air pollutants (which causes the haze seen in some polluted cities) may adversely affect the functioning of the human cardiovascular (heart and blood vessels) and respiratory (lungs) systems. This understanding may be especially important for patients with cardiopulmonary diseases. Some of your blood will also be used to determine the type of a particular gene you carry. This gene, glutathione-S-transferase (GSTM1) is one of several genes responsible for protecting your body against oxidants such as air pollutants, and some recent studies have shown that people carrying a mutation in this specific gene, which renders this gene inactive maybe more susceptible to the effects of air pollutants. 11-1807 CAPTAIN MAIN CONSENT FORM 090912 Page 1 of 11 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 123 of 135 PageID# 433 You are being asked to be in this study because: You are 50-75 years old, generally healthy. You have a normal resting electrocardiogram (ECG). Your oxygen saturation is greater than 94% at the time of physical exam. Are there any reasons you should not be in this study? You should not participate in this study if… You have a history of chest pain, irregular heart beats, heart failure, and heart attack or coronary bypass surgery. You have a heart pacemaker. You have untreated high blood pressure (> 150 systolic, > 90 diastolic). You have a history of chronic lung diseases such as chronic obstructive pulmonary disease or asthma. You have a history of migraine headache. A history of rheumatologic diseases or immunodeficiency state, You have allergies to fish or omega-3 fatty acids. You are on doctor's orders to take fish oil, which could interfere with this study. We do not want to interfere with your therapy. You are currently taking b-blockers (such as atenolol, metoprolol, propanolol, and acebutolol). You have a history of bleeding or coagulation disorders and are taking blood thinner medication. You are currently smoking or have a smoking history within 1 year of the study (defined as more than one pack of cigarettes in the past year) or have a greater than/equal to a 5 pack year smoking history. You are a diabetic. You have cancer (exception for history of nonmelanoma skin cancer). You are pregnant, attempting to become pregnant or breastfeeding. You have an allergy to latex. History of skin allergy to tape or electrodes. You should NOT participate if you are unable to comply with the following requirements: No over-the-counter pain medications such as aspirin, Advil, Aleve or other non-steroidal anti-inflammatory medications for 2 weeks prior to exposure. Low-dose aspirin and Tylenol (acetaminophen) are permitted. No omega-3 fatty acids or more than one 4-6 oz/serving of all types of fish and shellfish, as well as all types of nuts, flaxseeds and flaxseed oil, rapeseed oil, canola oil, soybeans and soy products, Eggland’s Best eggs, and cod liver oil for 6 weeks before exposures. No olives, avocados or nuts of any type. Use a cooking spray (such as PAM) for cooking. No antioxidants (e.g., beta-carotene, selenium, vitamin C, vitamin E, zinc) for 6 weeks before exposure. Use only sparing quantities olive oil for cooking, dressings, and sauces during this study. Avoid drinking red wine during this study. Avoid smoke and fumes for 24 hours before all visits. 11-1807 CAPTAIN MAIN CONSENT FORM 090912 Page 2 of 11 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 124 of 135 PageID# 434 Avoid drinking alcohol 24 hours before all visits. Avoid strenuous exercise for 24 hours prior to and after all visits. Eat a light breakfast on the exposure days. No pan fried and/or grilled foods after midnight prior to the exposure day. No caffeine for 12 hours prior to all study visits. How many people will take part in this study? There will be approximately 30 people in this research study. How long will your part in this study last? You will have up to 6 visits to the research facility over approximately 6-7 weeks if you are eligible for the study (see attached study design flow chart). Your participation in this study will include two parts: 1) A 6-week period of dietary restriction, and 2) Exposures to air and concentrated ambient PM (CAP). The exposure part includes one Training Day (today) for about 3 hours and two Exposure Days which last approximately 8 hours each, and one 3 hour Follow-up Day 18 hours after the second exposure. Storage of some of your blood samples in this study may be indefinite. What will happen if you take part in the study? Before you agree to participate in this study, you must read the consent form in its entirety. The research and medical staff will then answer all of your questions and explain all of the risks involved in this study to your satisfaction. You should have already undergone an initial screening visit and a general physical examination to ensure that you are a candidate for this study. If you are a female participating in this study, you should have been asked about your menstrual history. You will have a pregnancy test today and you will have another pregnancy test on exposure day if it is more than 7 days since today’s pregnancy test. Today’s visit is expected to last about 3 hours. We will review the inclusion and exclusion criteria and any medical conditions that you have or medications that you are currently taking. We will go over the study in detail so that you will know what we will expect from you as a participant and what you should expect from us as investigators. If you agree to participate in the study you will sign 2 copies of the study consent form and we will give one copy to you. We will then train you on a breathing instrument to prepare you for your exposure session. This is known as spirometry, and you will breathe through a filter into the instrument. We will coach you, and you will be asked to take a full breath in and then blow it out as hard and fast as you can. We will ask you to do this several times. Then we will check your resting breathing rate. You will tour the exposure chamber to acquaint you with the equipment. Measurements will be taken of your face and neck while seated in the exposure chamber in order to fit you for the exposure face mask. After these tests have been successfully performed, and if you are deemed to be a suitable candidate 11-1807 CAPTAIN MAIN CONSENT FORM 090912 Page 3 of 11 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 125 of 135 PageID# 435 and you decide to participate in this study, you will be given a list of medications, environmental exposures, and foods to avoid in the next four weeks. In order to protect the interpretation of the data obtained from your participation in this study, you will be asked to restrict your dietary intake of fish, seafood, nuts, oils, omega-3 fortified foods, dietary supplements and vitamins for a period of approximately 42 days. You will receive instruction on estimating dietary portions. You will be asked to record your diet for two 24 hr periods, once during the week and once during the weekend, approximately midway during the dietary restriction period. Exposure days We will call you a few days before the exposure session to remind you of your scheduled visit. We will also remind you to refrain from alcohol, excessive amounts of caffeine, and from any activities where you could be exposed to high levels of pollutants (e.g., cigarette smoke, paint fumes) for a couple of days before your visit. You should not eat pan fried or grilled meat after midnight of the exposure day. You will be asked to eat a light breakfast and arrive at the EPA medical station at approximately 8 am. Please bring a lunch with you on each exposure day. The lunch composition will be specified to minimize potential variations that could affect the arterial diameter measurements. You will be compensated $5 for the cost of the lunch each day. Prior to exposure, you will: Have your vital signs checked (heart rate, respiratory rate, blood pressure, oxygen saturation level, and a symptom questionnaire). Have your heart rate viability (HRV) measured by a Holter monitor. You will have several ECG leads attached to your chest. It may be necessary to clean and shave the areas of your chest where these leads will be placed. Excessive deodorant, skin lotions, and body sprays may interfere with the function of some of these leads so we will ask you to not apply these to your chest area on the day you report to the Human Studies Facility. The leads will be connected to 2 monitors (small recording devices about the size and weight of a portable tape player) to obtain readings of your heart rate and rhythm. You will be asked to recline quietly and breathe at a constant rate for 20 minutes, after which the ECG monitor will take a 10-minute measurement of your heart rhythm. It is important that you do not fall asleep during this 30-minute period. During your next visit to the facility, there will be another 30 minute measurement of your heart rate. These monitors will allow us to determine if PM causes small changes in the ability of your nervous system to regulate how your heart beats. You will return to the HSF about 48 hr later to get the monitor removed. Please avoid any strenuous activities while you are wearing this monitor. Because the leads are not waterproof, you will not be able to take a shower or bathe until you are discharged on the follow up day after your second exposure. Have your blood pressure and heart rate measured intermittently by a blood pressure monitor. You will wear a pressure cuff and a monitor which is about the size of the Holter monitor. Please keep your arm relaxed and still when the pressure cuff is inflated. You will wear the blood pressure cuff for the rest of the day and remove it just prior to going to sleep. You will receive instructions on how to remove the cuff. Please bring it with you to the facility the next day. 11-1807 CAPTAIN MAIN CONSENT FORM 090912 Page 4 of 11 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 126 of 135 PageID# 436 the next day. Have about 50 ml of blood drawn (about 4 tablespoons). We will test this blood to see if PM affects the ability of your blood to clot correctly, changes proteins on the surface of blood cells, and other parameters that could indicate a response to the exposure. With your permission, we may also store some of your blood we obtained during the study for yet-to-be-determined tests in the future. We will conduct an ultrasound of an artery in your arm. The ultrasound operator will scan your arm with probe and then place a tourniquet on your arm, much like a cuff used to measure blood pressure. Measurement of the size of the artery will be made four times. First, you will be asked to rest quietly for 15 minutes, and then the first 90 second scan will be performed. Then the blood pressure cuff on your arm will be inflated for 5 minutes in order to stop the flow of blood. You may feel sensations similar to those when your foot “goes to sleep”, such as “pins and needles” and tingling. After the pressure is released, a second scan will be taken of the artery. You will rest quietly for another 10 minutes, and a third ultrasound scan will be taken at the end of this rest period. Have a breathing test (spirometry). You will breathe through a filter into the machine. We will coach you, and you will be asked to take a full breath in and then blow it out as hard and fast as you can. We will ask you to do this several times. You will then enter the exposure chamber and be exposed to Air or CAP. During the exposure, you will: You will wear a face mask in a chamber under exposures of 2 hours duration to clean air on the first day then to concentrated Chapel Hill air particles on the second day; the amount of particles you will be exposed to is less than what you would likely encounter over 24 hours on a smoggy day in an urban area. Chamber conditions will be at a comfortable temperature and relative humidity. A trained person will be seated outside the chamber observing you at all times. During the exposure, your heart will be monitored and the amount of oxygen present in your blood will be monitored by placing a device (pulse oximeter) on your finger. Your blood pressure will be measured intermittently. If it appears you are experiencing significant discomfort, breathing or heart problems, the exposure will be terminated immediately. In addition, you may elect to terminate the exposure at any time for any reason. If you do so, you will be paid in full for that day’s session, but will be ineligible for further participation in the study and any payments you would have received for future participation. Immediately following the exposure, you will: Have your vital signs checked. Have a breathing test (spirometry). You will breathe through a filter into the machine. We will coach you, and you will be asked to take a full breath in and then blow it out as hard and fast as you can. We will ask you to do this several times. You will recline quietly for 20 minutes, after which the Holter monitor will take a 10-minute recording of your heart rhythm. Have blood drawn (about 80 ml or about 5 1/3 tablespoons). Fill out a symptom score questionnaire. Have another brachial artery ultrasound (BAU) measurement. Be assessed and discharged by the nursing staff. 11-1807 CAPTAIN MAIN CONSENT FORM 090912 Page 5 of 11 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 127 of 135 PageID# 437 You will be asked to wear the portable ECG monitor attached to your chest throughout the night, for your safety you should not shower or bathe until after the monitor is removed. Eighteen hours after PM exposure follow up visit (about 3 hours) You will return to the HSF the next morning (approximately 18 hours after PM exposure) and you will: Have your vital signs checked. Have a breathing test (spirometry). You will breathe through a filter into the machine. We will coach you, and you will be asked to take a full breath in and then blow it out as hard and fast as you can. We will ask you to do this several times. You will recline quietly for 20 minutes, after which the Holter monitor will take a 10-minute measurement of your heart rhythm. Have your blood pressure and heart rate measured intermittently by a blood pressure monitor and removed when you leave. You will have another BAU measurement. Have blood drawn (about 80 ml or about 5 1/3 tablespoons). Fill out a symptom score questionnaire. Have the Holter monitor removed. If there are any samples left over after all study information is collected, we will continue to store the samples for as yet undesignated studies. This allows us to make the best use of the samples we collect from subjects. You will be given a separate consent form for this storage, and you do not have to allow your samples to be stored indefinitely in order to participate in this study. What are the possible benefits from being in this study? You will not benefit directly from being in this research study, though by participating in this study you will receive a medical examination that includes blood work, respiratory testing, and ECG monitoring of heart at no charge. However, this is not a substitute for a routine doctor visit. The medical staff will explain to you any remarkable findings regarding your overall health status. In addition, if we observe changes in your health status as a consequence of exposure to air pollutants, we will discuss this with you. This research is designed to benefit society by gaining new knowledge that may be used to. deviseeffective regulatory strategies aimed at protecting in the population from the untoward effects of air pollutants. What are the possible risks or discomforts involved from being in this study? This study might involve the following risks and/or discomforts to you: If you have any tendency to become uncomfortable in small closed spaces, it is possible that you may become uncomfortable during this study. You will be taken to the exposure chamber when you are first evaluated for suitability for the study to allow you an opportunity to see where you will sit and what the chamber looks like. PM exposure: During the exposure to the concentrated air pollution particles, you may experience some minor degree of airway irritation, cough, and shortness of breath or wheezing. These 11-1807 CAPTAIN MAIN CONSENT FORM 090912 Page 6 of 11 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 128 of 135 PageID# 438 symptoms typically disappear 2 to 4 hours after exposure, but may last longer for particularly sensitive people. You will be monitored continuously during the exposure session through a window in the chamber or by closed-circuit television, and can communicate with a staff member via an intercom. Your heart rate and rhythm will also be constantly monitored for any adverse changes brought about by the exposure. In the unlikely event that you develop medically significant symptoms, the exposure will be terminated and the appropriate medical intervention will be provided if required. A physician is always available on the premises to respond to an emergency and full resuscitation equipment is available for use in the event of a cardiac or pulmonary emergency. Air pollution particles may induce an inflammatory reaction that can last for 24 hours after exposure and may increase the chance of you catching a cold. You should not engage in heavy levels of exercise for 24 hours before and after the exposure period. If you have any tendency to become uncomfortable in small closed spaces, it is possible that you may become uncomfortable during the chamber exposure. Although the chamber is somewhat small, it has multiple windows and you will be in constant visual contact with the investigator who will be monitoring you during the exposure. You also will be able to verbally communicate with the investigator via a microphone headset. Heart rhythm monitoring: There is little risk associated with monitoring your heart by ECG or blood oxygen by pulse oximetry. However, preparing your skin for placement of adhesive ECG electrodes and removing the electrodes the next day may cause some irritation or skin discoloration, itching, or burning in some people. If this occurs you should call the nursing staff. Venous blood sampling: The risks associated with taking blood samples are considered minimal. A well?trained member of the staff will draw the blood. Drawing blood could cause some bruising or minor pain, which usually resolves quickly. Also, a rare complication is skin infection or an infection of the vein in which the blood has been drawn. The risk of getting an infection is minimized by the use of sterile technique. If you do have signs of infection at the site (redness, warmth, painful skin, and swelling) after completion of the procedure, you will need to contact the EPA medical station. Brachial artery ultrasound: There are no significant risks associated with ultrasound imaging of the brachial artery, or with brief episodes of forearm ischemia (reduced blood flow). Occlusion of blood flow to the arm may result in mild discomfort or temporary sensations of tingling or numbness until the blood pressure cuff is released. A small number of patients (about 1 in 200) develop a painless rash on the arm where the blood pressure cuff is placed; this disappears over several days. Some risks and discomforts may be unforeseeable. Breathing tests (spirometry): You may cough or become dizzy during these tests. You will be seated in a chair, and if these symptoms occur, they are usually only temporary. You will be exposed to low dose of acetylene for a brief period of time (single breath in and breath out), thus the risk will be very low. Blood pressure monitor: Similar to the regular blood pressure measurement, the risk associated with blood pressure monitor is considered minimal. In addition, there may be uncommon or previously unrecognized risks that might occur. If you do notice any unusual symptoms occurring during the study you should call the EPA medical station or the on-call physician to report them. There may be uncommon or previously unknown risks. You should report any problems to the researcher. 11-1807 CAPTAIN MAIN CONSENT FORM 090912 Page 7 of 11 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 129 of 135 PageID# 439 Pregnancy tests will be done on all females who might be able to get pregnant at the start of the study. These tests will be done at no cost to you. What if we learn about new findings or information during the study? You will be given any new information gained during the course of the study that might affect your willingness to continue your participation. How will your privacy be protected? You will be given a study code number. All electronic documents will only have that number. The paper records that the coordinators and medical doctors use may have your name. Your information can be linked to your personal information by the study number, however only study personnel have access to your personal information. Paper records that use your name are kept in a locked file cabinet in the EPA Medical Station of the Human Studies Facility. The Medical Station is locked when not attended by study staff, and the EPA Human Studies Facility has limited access to authorized individuals only, 24 hours/day for 7 days/week. Blood samples will be stored at the EPA Human Studies Facility. Research studies may be done at many places at the same time. Your personal identifying information will not be sent to outside researchers. No subjects will be identified in any report or publication about this study. Although every effort will be made to keep research records private, there may be times when federal or state law requires the disclosure of such records, including personal information. This is very unlikely, but if disclosure is ever required, the U.S. Environmental Protection Agency will take steps allowable by law to protect the privacy of personal information. In some cases, your information in this research study could be reviewed by representatives of the University, research sponsors, or government agencies for purposes such as quality control or safety. What will happen if you are injured by this research? All forms of medical research, diagnosis, and treatment involve some risk of injury or illness. Despite our high level of precaution, you may develop an injury or illness due to participating in this study. If you develop an injury or illness determined by the on duty physician to be due to your participation in this research, the EPA will reimburse your medical expenses to treat the injury or illness up to $5000. If you believe your injury or illness was due to a lack of reasonable care or other negligent action, you have the right to pursue legal remedy. The Federal Tort Claims Act, 28 U.S.C. 2671 et. seq., provides for money damages against the United Sates when personal injury or property loss results from the negligent or wrongful act or omission of any employee of the EPA while acting within the scope of his or her employment. Signing this consent form does not waive any of your legal rights or release the investigator, the sponsor, the institution, or its agents from liability for negligence. If a research related injury or illness occurs, you should contact the Director of the EPA NHEERL Human Research Protocol Office at 919-966-6217. What if you want to stop before your part in the study is complete? You can withdraw from this study at any time, without penalty. The investigators also have the right to stop your participation at any time. This could be because you have had an unexpected reaction, or have failed to follow instructions, or because the entire study has been stopped. Will you receive anything for being in this study? You will be paid approximately $12 per hour for your participation in this study and the total 11-1807 CAPTAIN MAIN CONSENT FORM 090912 Page 8 of 11 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 130 of 135 PageID# 440 compensation for completion of this study will be approximately $1757. If you are unable to complete the study for voluntary reasons or failure to comply with eligibility requirements you will receive full compensation for your participation up to that point. We anticipate performing several tests on you during the course of this study. However, circumstances beyond our control may arise (i.e. equipment failure) which may prevent us from performing a specific test on you. If we are unable to perform a specific test on you which is a primary endpoint for us, you will be compensated for all tests and time completed on that day and rescheduled. If this test is a secondary endpoint for us and is also a source of compensation, you will be paid for that test, but not rescheduled to make up the procedure. In addition, you will be reimbursed for reasonable travel expenses and for parking costs while at the research facility. Money received by participants in research studies is normally treated as ordinary income by taxing authorities and we will report payments made to you to the Internal Revenue Service as required by law. Payments totaling more than $600 in a year from a single or multiple EPA studies will be reported to the IRS. This summary is to emphasize the importance of all the visits, and to signify the importance of your time and commitment to the research study. The following table details the expected compensation for completion of the entire study: Pre-study qualifications (screening+blood+physical) $60 Training day (3 hours) + Dietary records $100 Exposure Day Time and Procedures (includes $5 for lunch) Total: Follow- up Day Time and Procedures Total: On-Time Bonus Dietary Compliance Study Completion Bonus $100 = ($603/day) $1206 $141 $50 $100 Approximate TOTAL for completion of study $1757 Subjects will be provided $5 to cover the cost of their lunch on exposure days. If a subject is terminated from the study or chooses to withdraw he/she will be reimbursed for time and procedures completed up to that time point. You should understand that your participation is voluntary. You may terminate your participation in the study at any time without penalty. If you voluntarily elect to withdraw from the study at any time or you fail to maintain compliance with eligibility requirements, you will be paid for that portion of the study that has been completed. In the event a scheduled study activity must be cancelled by the investigators with less than 72 hours prior notice, you will be paid $12 per hour for the time scheduled and canceled. You will be paid in full for any procedures that may have been started during the current visit. Cancellations could occur due to adverse weather conditions, equipment failure, and other unforeseen events. When feasible, canceled visits will be rescheduled. The investigators also have the right to stop your participation in the study at any time. This could be because you have had an unexpected reaction, or because the entire study has been stopped, or for some other reason. If you are dismissed by the investigators prior to completion for a reason that is 11-1807 CAPTAIN MAIN CONSENT FORM 090912 Page 9 of 11 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 131 of 135 PageID# 441 not your fault, you will be paid for the entire day in which the dismissal occurs. Will it cost you anything to be in this study? There will be no cost to you for participating in the study. However, if you are deemed not eligible to participate in the study for medical reasons, we may suggest that you seek follow-up care from your own health care provider for abnormalities discovered during the screening history, physical examination, or the study. Such care is entirely at your own expense. EPA will not provide reimbursement for any follow-up care. All study procedures will be paid for by the study. We will give you parking coupons to cover the cost of parking. If you live beyond Chapel Hill/Carrboro you will be reimbursed for mileage at the US Government mileage rate in effect at the time. What if you are a UNC student? You may choose not to be in the study or to stop being in the study before it is over at any time. This will not affect your class standing or grades at UNC-Chapel Hill. You will not be offered or receive any special consideration if you take part in this research. What if you are a UNC employee? Taking part in this research is not a part of your University duties, and refusing will not affect your job. You will not be offered or receive any special job-related consideration if you take part in this research. Who is sponsoring this study? This research is funded by The U.S. Environmental Protection Agency. This means that the research team is being paid by the sponsor for doing the study. The researchers do not, however, have a direct financial interest with the sponsor or in the final results of the study. What if you have questions about this study? You have the right to ask, and have answered, any questions you may have about this research. If you have further questions regarding this study, you should call one of the listed investigators on the first page of this form. If you feel a research-related injury has occurred, please contact the HSF medical station or one of the investigators listed above. In addition, you should contact the Human Studies Division Human Research Officer and Director of the National Health Effects and Environmental Research Laboratory Human Research Protocol Office at 919-966-6217. What if you have questions about your rights as a research subject? All research on human subjects is reviewed by a committee that works to protect your rights and welfare. If you have questions or concerns about your rights as a research subject you may contact, anonymously, if you wish, the Institutional Review Board at 919-966-3113 or by email to IRB_ subjects@unc.edu and/or the EPA Director of the National Health and Environmental Effects Human Research Laboratory Protocol Office at 919-966-6217. Title of Study: Cardiopulmonary Effects of Exposure of Healthy Older GSTM1 and Sufficient Individuals to Concentrated Ambient Air Particles (CAPTAIN) Principal Investigator: James M. Samet, PhD, MPH Subject’s Agreement: 11-1807 CAPTAIN MAIN CONSENT FORM 090912 Page 10 of 11 Case 1:12-cv-01066-AJT-TCB Document 14-1 Filed 10/04/12 Page 132 of 135 PageID# 442 I have read the information provided above. I have asked all the questions I have at this time. I voluntarily agree to participate in this research study. _________________________________________ Signature of Research Subject _________________ Date _________________________________________ Printed Name of Research Subject _________________________________________ Signature of Person Obtaining Consent _________________ Date _________________________________________ Printed Name of Person Obtaining Consent Genotype Screen Air Exposure PM Exposure Follow-up TOTAL 20 46.2/46.2 46.2/46.2 46.2 251 ml Table 1. Blood Draws Genotype Physical Training Air Exposure Screen Examination Day Day 1 hr 2 hrs 3 hr 8 hrs Table 2. Study Visit Schedule 11-1807 PM Exposure Day 8 hrs CAPTAIN MAIN CONSENT FORM 090912 Follow-up Day 3 hrs Page 11 of 11 Case Document 14-1 Filed 10/04/12 Page 133 of 135 Page D# 443 IN THE UNITED STATES DISTRICT COURT FOR THE EASTERN DISTRICT OF VIRGINIA ALEXANDRIA DIVISION I AMERICAN TRADITION INSTITUTE I ENVIRONMENTAL LAW CENTER, I I plaintiff, I I v. I Civil Action No. I UNITED STATES ENVIRONMENTAL I PROTECTION AGENCY, e_t I I Defendants. I DECLARATION OF HAIYAN TONG I, Haiyan Tong, pursuant to 28 U.S.C. 1746, declare, under penalty of perjury, that the following statements are true and correct based upon my personal knowledge, experience or upon information provided to me by persons under my supervision: 1. I am the Research Biologist for the Office of Environmental Programs (OEPI, Environmental Assessment and Innovation Division (EAIDI, U.S. Environmental Protection Agency (EPA) Region I have been conducting air pollution research at the EPA Human Studies Facility for six years. Case Document 14-1 Filed 10/04/12 Page 134 of 135 PagelD# 444 2. My research focuses on the cardiovascular effects of air pollution exposure and the interventional strategy to mitigate the adverse health effects of air pollution exposure in humans. I am co-Investigator in the CAPTAIN study. 3. I received my MD from China Medical University in 1938 and my MD. degree was certi?ed by the US Educational Commission for Foreign Medical Graduates (ECFMG). After five years of residency training at Beijing Friendship Hospital I came to the US and received my in Physiology from the University of Florida College of Medicine in 1998. After eight years of cardiovascular research at the National Institute of Environmental Health Sciences, National Institute of Health, and Duke University I moved to EPA to do clinical research in 2006. 4. I have reviewed the Complaint and exhibits ?led in the captioned case. 5. As part of the process of obtaining informed consent from study participants, I give subjects time to read the consent form first either at home or at the medical station, which usually takes about 30 minutes. Then I start the consent by going through the consent form page by page with each potential participant. 6. First I talk about the rationale of the study, stating that we at EPA are doing air pollution particulate matter research. I tell study participants that air pollution particulate matter exposure in general is associated with sickness and death and has a risk to the cardiovascular and respiratory system. talk about the purpose of doing this CAPTAIN study by focusing on the cardiovascular effects of concentrated Chapel Hill particulate matter exposure and to determine the different responses in subjects carrying GSTM1 gene (GSTMI suf?cient} vs. carrying no such gene null]. Case Document 14-1 Filed 10/04/12 Page 135 of 135 Page D# 445 8. I then tell the subjects that they have passed the screening process with medical conditions and that they are otherwise healthy to meet the study volunteers? selection criteria. I check the subject again for each listed exclusion criteria and medication and supplements use during the study. 9. I then explain the study procedures, the risks and benefits, and reimbursement. I read word-to- word of the legal verbiage to the subjects. During the consent process state several times that ?You are volunteering to participate in this study and you are also volunteering to stop at any time. There is no obligation to participate and complete the study". 10. When explaining the subjects? risk from PMLS exposure, I state that the exposure to concentrated Chapel Hill for 2 is equivalent to what they would experience over a longer period by visiting a polluted city in the world. 11. 1 then ask the subjects if they have any questions and concerns about the study and repeat again that if they are volunteering to participate then please sign the consent form. I then train the subjects on the lung function test, tour the exposure chamber, and measure the face mask size. I send them back to the nurses to provide the information on dietary instruction and recordings. Dated: October 3, 2012 ?77 Haiyan Tong