rue YORK TIMES THE ENVIRONMENT TUESDAY, MAY :5 2990 Scientists Are Unlocking Secrets Of Dioxin?s Devastating Power Tests show how the chemicals mimic steroid hormones. 3 *7 By JON R. LUOMA Few pollutants have generated as much alarm over their potentially damaging health effects on humans as dioxins Research now appears to have es- tablished that they can affect animals and humans by steroid hormones, which are themselves ex- tremely potent chemicals. The same may be true of a host of chemically related toitic agents, including poly- chlorinaled biphenyls and some chlorinated pesticides like DDT. Hot monal disruption appears to eit- plain the puzzling array of symp- toms, Some of them fatal. found in laboratory animals exposed to DI), one of 75 forms of dioxin, which has been characterized as ?the most tox- lt' known" based on its ex- toxicity to some laboratory 'lliose range from sup. piesSion of the immune system to striking disruptions in cell growth and differentiation. particularly le- ial development. Although research- ers now believe that alone does not cause cells to mutate and become cancerous. as do most chemical car- cinogens. the hormonal disruption nevertheless appears to play a role. along With other substances. in pro- moting some kinds of tumors. notably liver tumors some animal species. The hormonal theory also appears to explain why rodents exposed to TCDD showed reductions in rates of other kinds of cancers. notably cuti- ters of the breast and uterus, which are believed to be promoted by the female sex hormone estrogen. tlor- inonally. TCDD appears to function as an "anti-estrogen." The findings have led at least one pharmacological research team to begin a search for chemicals that are structurally Simtlar to dioxin but that are not as toxic so that they might serve as anti-estrogenic treatments for breast and uterine cancers. No Reason for Complacency Dioxins are environmental con- taminants formed in minute amounts as byproducts of various industrial and combustion processes. including garbage incineration. some kinds of paper manufacturing and autumn- biles. Virtually everyone carries traces of dioxin in their fatty tissues. at a level of about three parts per trillion Fitvn'onmentalists are con- cerned that the chemical is exceed- ingly persistent, breaking down slow- ly in the. environment. if at all. Researchers now generalltr agree that exposing cells to TCDI) does not, as once feared. immediately cause them to become cancerous, although it does accelerate the development of cancers that are lnllialt?tl in animals by other causes. Nor have dioxins been shown to cause severe health effects in humans comparable to those found in animals. Bill scientists say that is no reason for Complacen- cv. Dr. Michael A. Gallo, professor of tomcology at the Robert Wood John- son Medical School of Rutgers Uni- versity. said. "From a toxicological point of view. nothing we've learned has caused us to back away from the idea that these are very, very potent chemicals." TCDD "is as potent as any hor- mone," Dr. Gallo said. "And it doesn't take much hormone, or dioxin. to have a tremendous effect." Probably no pollutant chemical has generated as much fear and contro- versy as dioxin. especially among Vietnam veterans exposed to Agent Orange. a dioxm-contaminat ed jungle defoliant. 1n Marclithe Department of Veterans Affairs agreed to com- pensate about 1.600 Vietnam veterans with non-Hodgkins a can- cer of the glands that studies had shown occurred at much higher Michal-l for 11w ?t'nil. 'l'iim'x Dr. Donald Barnes at E.P.A. says dioxin molecules can set off a cas- cade of pl'iysiological changes. rates among the veterans, although the studies did not link the disease to Agent Orange exposure. . Paper Mill Discharges EnVironmentalists have pressed Government regulators to eliminate dioxin discharges from pulp mills and have vigorously opposed the con- struction of some. municipal garbage incinerators because of known dis- charges ol traces of dioxin. Last month, the Environmental Protection Agency and the Food and Drug Ad? ministration announced that they would take steps to curb discharges lrom paper mills and to eliminate traces of dioxin found in some paper food containers. including milk car- tons. Scientists have long known that hormones are extraordinarily power- ful in minute. doses. Because of their role as chemical messengers, single molecules of hormones react bio~ chemically with genes in target cells to catalyze dramatic changes in the body. ranging from regulation of the sugar-insulin balance to intricate con- trol of the reproductive cycle to con- trol of the growth, development and maturation of the body and its or- gans At the molecular level, steroids like testosterone. a male sex hormone, and estrogen function by entering cells and bonding to receptor mole- cules present in the cell. The receptor molecules then bond to a specific site on DNA within the cell nucleus. There, the hormone-receptor com- plex can turn on or off a series of biochemical switches that control bodily functions. Dr. Donald Barnes. a senior re- search scientist at the Enwronmen- tal Protection Agency, said the dioxin molecules were structurally similar to natural hormones. They fit into receptor molecules and then onto the DNA ?docking sites" much like pre- cisely machined keys into precisely machined keyholes. Once docked on the DNA, the dioxin-receptor com- plex apparently sets off the cascade of physiological changes researchers have seen in laboratory animals. A Severe Form of Acne In animal studies. TCDD (2.3.7.8- tetrachtorodibenzo?p-dioxin) has demoastrated a breathtaking toxic- ity. killing hamsters at a concentra- tion of only one Ell-thousandth of the fatal dose of sodium cyanide. But researchers have long been puzzled by the wide ranges in responses to dioxin from species to species. The hamsters die of a wastin dyn? drome that appears to destroy mus- cle and fat tissue. Yet it ta es 40 times that dose to kill mice. R??ts and mice develop liver tumors wlen ex- The Wrong Key: How Dioxln Acts Dioxin molecules appear to mimic structurally similar natural steroid hormones. these hormones react with genes in cells to catalyze complex changes in the body. Like a steroid, a dioxin molecule enters a cell and bonds to a receptor molecule, ?tting like a key in a lock. The mulling complex in turn attaches to a specific site on . the cell's DNA. 3 Dioxin con? plex turns blocnemscai switches 2 Dioxin- receptor complex anaches to cell DNA Because the dioxin molecule replaces the natural hormone. it creates an altered form of the hormone-receptor complex. The complex apparently turns genetic switches on and oil _an inappropriate way, producing the Structurally similar natural 'honnone Sauce: American Journal or industrial moraine The damage is strikingly different from species to species. posed to dioxin. but guinea pigs do not. Humans, monkeys and rabbits develop a severe form of acne, chlor~ acne, but most other species do not. ?With laboratory animals, it seemed as if dioxin caused just about any effect you can think of," said Steven Safe. a professor of toxicology at Texas A University. "You name it, it did it, and at extraordinari- ly low doses. But one of the mysteries has been that unlike most toxic chem- icals, it didn't cause all the effects on all species, or even on all strains." Dr. Safe said the mystery has been largely solved by confirmation that TCDD and other toxic agents interact with DNA, since genetic makeup var- ies among species, strains and indi- Viduais. The dioxin-hormonal connection with cancers that are promoted or suppressed by sex hormones is obvi- ous. ess obvious is the relationship of xin to such as high rates of cleft palate found in the off- cascades of sometimes fatal spring in mice. But Dr. Ellen Silbergeld, a visiting professor in toxicology at the Univer- sity of Maryland Medical School, said one of dioxin?s major effects appears to be disruption of a growth hormone. responsible for cell growth and differ- entiation of skin and membrane tis- sue. She suggests that such disrup~ lions lead to the misformed palate tissue in mice, chloracne on human skin, and improperly formed tissue enclosing various glands in other ani- mats. intrigued by the apparent protec- tive effect of TCDD against breast and uterine cancers in tests with lab animals, Dr. Safe and colleagues are trying to develop chemical analogues of the dioxin. ?Dioxin itself is far too toxic to use as a drug," he said. ?But an analogue could be a potential treatment for certain cancers." Examining Courtship Behavior in addition to the 75 forms of diuxrn, there are a host of similar sub- stances, including dozens of forms of dlbenzofurans, PCB's and chlorinat. ed pesticides. Some appear to have no toxrc effects. But researchers exam- tning others have discovered differ- ent sorts of hormone-like effects, in- cluding estrogenic, rather than anti- estrogenic, responses. In the 1970's, Michael Fry, a biolo- gist at the University of California at Davis, examined male birds that had physiological changes that researchers have seen in laboratory animals. Megan .l.u~geimnn lhr- a ?t wrl. i .- becn exposed to high doses of Hill and PCB's. The birds had failed Lu exhibit male courtship behaviors. Dr. Fry found that some of tin- males had partially developed [Olihtli' sex organs. In follow-up studies, in- exposed embryonic male sea guilt to the pollutants. The birds were born with malformed testes and had begun to develop oviducts. "Essentially thin,- were chemically castrated." he said. Other studies have shown that estro- gen exposure creates a similar effect in birds. Thr- researchers caution that, be yond a propensity for chioracne, most effects of dioxins have not material- ized among humans. Dr. Barnes of the E.P.A. said the existing 20 to 25 percent rate of human cancers would tend to obscure all but a very dro- manc statistical jump in response to a specific toxicant. Because of the potential risks to human subjects, almost all concerns about dioxin?s effects on people have been inferred from animal studn-s. However, studies of humans exposed accidentally to TCDD have shown unusually high levels of enzymes that are typically induced by steroid hor- mones, a strong clue that a hormone like response is triggered in hurtx-in. exposed to dioxin as well. 40% .. Appendix Review of Dioxin Contamination Dioxin Contaminant Table 8-32 presents a summary of results obtained by EPA for in eight technical herbicides; these data were extracted from program ?les in OPP. Because some of these ?les contained CBI, the data in this table were reviewed by OPP staff to ensure that no CBI was being disclosed (memorandum dated May 28, 1996, from S. Funk, U.S. EPA, to W. Hazel, US. EPA). Figure 8?5 presents a congener pro?le for based on the average congener concentrations reported in Table 8-32. An estimated 28,100 metric tons of were used in the United States in 2000, making it one of the top 10 pesticides in terms of quantity used (EPA proprietary data). The pesticide is the only product judged to have the potential for environmental release through its agricultural use. However, no estimate of environmental release can be made for 2000. Since 1995, the chemical manufacturers of have been undertaking voluntary actions to signi?cantly reduce the dioxin content of the product. No information is available on the level of dioxin contamination, if any, that may have been present in in 2000. An estimated 26,300 and 30,400 metric tons were used during 1995 and 1987, respectively (U.S. EPA, 1997e, 1988d). 0n the basis of the average congener concentrations in presented in Table 8-33 (not including OCDD and 0CDF), the corresponding TEQDF-WHO98 concentration is 1.1 ug/kg (0.7 pg Combining this TEQ concentration with the activity level estimates for 1995 and 1987 indicates that 28.9g (18.4 were released in 1995 and 33.4 TEQDF-WHOQ8 (21.3 ITEQDF) in 1987. The release estimates for 1987 and 1995 are assigned a high con?dence rating, indicating high con?dence in both the production and the emission factor estimates. Because no estimate can be made for 2000, it is rated as Category (no estimate of environmental release of can be made because of the poor quality of existing information). E-2 Table 8-32. Summary of results for in technical and ester herbicides Number of Observed EPA technicals maximum Average Total no. of greater than cone. cones Congener (uglkg) technicals LOQ (pg/kg) (pg/kg) 0.1 8 2 0.13 0.06 0.5 8 3 2.6 0.78 2.5 8 0 0.81 0.31 2.5 8 0 0.77 0.39 2.5 8 0 0.68 0.24 100.0 8 0 1 .5 0.21 OCDD - - - - - 1 8 0 0.27 0.07 5 8 0 0.62 0.38 5 7 0 0.73 0.07 25 8 0 1.6 0.1.4 0.16 25 8 0 1.1 0.14 1,000 8 0 8.3 2.17 1,000 8 0 1.2 0.18 OCDF - - - - 5.6 0.7 l. a required by EPA in the data call-in. Average of the mean results for multiple analyses of four technical andfor ester products for which detectable CDDICDF congener concentrations less than the LOQs were quanti?ed; nondetect values were assumed to be zero. Total equals the sum of the individual congener averages. LOQ Limit ofquantitation -- Analyses not performed Source: US. EPA Of?ce of Pesticide Programs ?le. UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON. D.C. 20460 This Membrandum May Contain Confidential Business Information OFFICE OF PESTICIDES AND TOXIC SUBSTANCES MEMORANDUM DATE: MAY 7 1932 TO: John Melone, Acting Director Hazard Evaluation Division (TS-769) FROM: M. Adrian Gross Hazard Evaluation Division (TS-769) SUBJECT: Summary of Chronic and Oncogenic Effects bf Permethrin I I have your memorandum under reference of April the 16th, 1982, and I must say that I was puzzled by the reaction my comments of April the 10th seem to have engendered in you. You refer to that communication of mine as being "totally unsatisfactory and unprofessional". This kind of evaluation on your part is a source of disappointment to me, particularly since you must know that one of my main objectives has always been to make myself useful and helpful to you. You also complain there that my memorandum of April the 10th, does not offer "a shred of supporting evidence", presumably for such conclusions as I had reached. That is true enough but the reason for this situation, clearly not of my own choice, must be sought in the nature of this assignment as given by you:- a) On March the 31st you informed me that the Paynter- Budd "document" (hereinafter referred to simply as the Assessment) is to be "peer reviewed" and you ask me "to serve as a peer reviewer"; you also requested my comments by the close of business on April the 10th, 1982. b) Much of the time that I devoted to this task was wasted since on April 6th I was presented with a new version of the "document" dated the previous day and which was said to supersede the one enclosed with your request made six days earlier; thus I had only less than four days to complete this task April the 10th was a Saturday, according to my calendar, a day when we ordinarily do not conduct business. c) During this abbreviated period of time at my disposal, I could form and report on only a general impression of the Assessment. d) I note that the letter drafted by you and signed by Mr. Johnson which was addressed to the other two peer reviewers, one in California and one in Kansas, states that 2 page written response would be sufficient." That letter also refers to the "urgent need" for the response arising out of having to resolve "some tolerance issues before this growing An "early response" is emphasized again in the next sentence there which also mentions that ?the situation as regards permethrin is really quite urgent". Also worth noting is that the other two peer reviewers were given until April the 12th to respond, which is somewhat different than the deadline given to me; in fact one of them responded on that day and the other one did so on the following day. From all this I concluded, perhaps wrongly, that the main emphasis in this request for peer review was speed rather than taking the time to ponder at length and in detail on all the scientific aspects involved with the health hazard posed by this pesticide product. Since I also knew that my ?peer review" colleagues were not given at least some, if not all, of the toxicology reviews which served as the basis for the so?called "facts" presented in the Assessment, I could easily predict the nature of their reaction to it in advance. Their actual responses turned out to be fully and precisely in accord with what I had expected of them under the peculiar circumstances in which they were placed. I thought, therefore, that inasmuch as I would be the only one of the three "peers" who would be in a position to question those "facts" through my having access to all the underlying reviews, the value of my comments would not fail to be appreciated by you. Apparently I was wrong in having entertained such hopes. This sort of thing brings me naturally to observe that your actions in the last few months as pertaining to this particular product have had the unfortunate and potentially dangerous effect of preventing a rather full consideration or airing of the health and safety aspects associated with its use; you probably feel that any such in-depth enquiry undertaken with full information for all those concerned with it might conflict or collide with the interests of the regulated industry and of the users of this particular pesticide. The "urgent needs" for each growing season in the past few years is the kind of familiar refrain that I associate with those particular circles. I have reached this impression after considering several events in which you have had a hand in the past, all such instances having, like Ariadne's thread, a common theme:- For example, I am informed that on January the 15th of this year, during a conference telephone conversation with representatives of the major manufacturers of permethrin (ICI, Burroughs?Wellcome and FMC), in reply to a question of theirs on whether a peer review and risk assessment were necessary for the conclusion reached by the EPA which was communicated to them at that time, your own answer to them was that neither a peer review nor a risk analysis would be ?useful". Note that this was some three months before the Toxicology Branch presented its final Assessment on the health aspects of permethrin. A few days later, on January the let, a meeting was held here again with the representatives of the same firms and the minutes of that meeting (written by you, as your signature indicates) reveal inter alia:- As of that date presented its final toxicological conclusions regarding potential oncogenicity of permethrin and other effects observed in the seven oncogenicity studies submitted by the three registrants. Data showed that permethrin was tumorigenic in mice at high doses, but not tumorigenic in two of three rat studies. The third rat study (the FMC study) was not considered a valid total weight of evidence indicates that permethrin has demonstrated virtually no potential as a human oncogen. EPA therefore decided it would not regulate permethrin as an oncogen. This finding is consistent with the opinion expressed by the FIFRA Science Advisory Gene Paynter will provide a final written toxicological opinion within a month.? 4? N. ?3?4 I wonder just how you allowed the EPA to reach an institutional decision such as described when you must have known in January 1982 that:- 1. The final toxicological review for two of those seven studies (the CFLP mouse study and the Charles River SPF Wistar strain rat study) were not complete at that time in fact, they were not completed until March of this year. Even then, since Marchascertain that those reviews were of an acceptable quality; as we shall see later here, that particular rat study was reviewed in a manner that has remained unacceptable to this very day. 2. At another meeting held here again with representatives from the three major registrants on November the 18th, 1981 which you yourself convened and chaired, data were shown for the only other rat study which was considered to be "valid? (the other Wistar rat study) which indicated significant increases in the incidence of adrenal cortical adenomas amongst exposed female animals, a significant increase in the incidence of a variety of brain (glial) tumors amongst exposed male animals, a significant increase in the incidence of meningiomas (tumors of the covering of the brain) amongst exposed male and female animals, all of which are "rare or unusual" types of tumors, to say nothing of a borderline significant increase in the incidence of mammary tumors amongst exposed female rats. All of this is hardly consistent with permethrin being "not tumorigenic in two of three rat studies". 3. One of the consultants which also attended that November 1981 meeting, Dr. Bates from Clement Associates, who was hired for the express purpose to provide scientific advice on this problem, was not given for his consideration all the toxicologic reviews pertaining to permethrin's tumor induction potential. 4. The remaining consultants, also hired for the same purpose, were apparently given for evaluation only the review and statistical analysis pertaining to but one of the seven studies:? the CFLP mouse study, as their report clearly indicates. 5. The FIFRA Scientific Advisory Panel's meeting held here in March 1981, issued their report on the 20th of that month. Although you refer to that Panel in the minutes you wrote in January 1982, you must have known that the Hazard Evaluation Division's representatives who made presentations at that March 1981 SAP meeting were allowed to present in detail only the results of the Second FMC/Biodynamics mouse study. The regulated industry representatives were placed under no such restriction and their own highly biased evaluation of the data arising from the other six studies went largely unchallenged. Thus, by no stretch of the imagination can one entertain the notion that the Science Advisory Panel had received a "balanced" presentation of the conflicting evaluations of all the data. Furthermore, as remarked near the top of the previous page here, the toxicologic reviews of two of the seven studies was not available until nearly a year following that SAP meeting in 1981. The common thread that I see in all these situations was that although advice from experts outside the Agency has been sought on a number of occasions (the SAP, last Fall's consultants, the recent "peer reviews", etc.) for no such instance can it be said that any of these experts were given a full and reliable set of summaries of the data prepared by our own reviewers. It is abundantly clear that none of these scientists can undertake their own reviews of the original voluminous reports on the studies submitted by the registrants and thus they are forced to rely on the integrity of summaries provided by our own reviewers. This problem likely is not limited merely to those experts from outside the Agency; you have informed me recently that the Paynter-Budd Assessment was sent for review to still other scientists within our own Office of Toxic Substances such as Dr. Barnes and Dr. Hill. Were these gentlemen provided with an opportunity to verify the "facts" alleged in that Assessment? I would be surprised to learn that they were. I would also be surprised to learn that in any of the countless briefings held by you or other members of this Division for Mr. Campt, Mr. Johnson, Mr. Gray or others on the subject of permethrin, you had ensured that the full and relevant set of facts on the tumor-induction potential of this agent had in fact been communicated to each of these people. Earlier last month, on April the lst, I informed you that for me to carry out my task of "peer review? in an adequate manner, it would be necessary that I have available more than merely the Paynter-Budd Assessment since some of the ?facts? contained in it need verification. Your written response on this addressed to me that very same day states that you are ?somewhat disturbed" by my need to examine some of the data themselves. In the very same communication of yours you emphasize that I was not asked to "second guess the reviewers". In case you are not aware of this by now, I wish to inform you that I have been in the scientific review game for some time; I have worked under the direction of a number of outstanding scientists and others for the last couple of decades and scientific reviews in the field of cancer or toxicology are constantly sought from me by sundry editors of prominent professional and science publications, by various attorneys, etc. Throughout this time none of these people have ever displayed your lack of manners, your impudence and nerve to tell me just how I ought to do my own job. They have been invariably grateful for such reviews as I have provided to them and I believe that the real value they see in such work of mine is precisely that it is as thorough and critical as possible and that every statement placed before me is in fact weighed or ?second guessed". Without this essential element of second?guessing, no review of any kind, peer or otherwise, is worth making. Accordingly, and since I believe that your instruction to me on ?second guessing" the reviewers was an improper one for you to give, I have elected to ignore it. I should think that had I not done so, a number of serious problems with the Assessment might not have surfaced to the attention of the decision?makers in this Agency, and this in itself could have represented a measure of threat to the public health. Perhaps this is the real reason for my having incurred your displeasure as amply evident in your April the 16th memorandum to me. I wonder if you have communicated similar sentiments to the other peer-reviewers whose response does not seem to me to contain any substantive "evidence" for whatever views they had advanced on the merits of the Assessment. I also note in the same memorandum of yours that despite the fact that you were the one who had solicited my views in the first place, you intend to treat them as "innuendo" (a seemingly favorite term of yours) or ?calculated malice". You accuse me of impugning the competence of the Chief of the Toxicology Branch, Dr. Paynter, when in fact I did not mention him at all in my April the 10th response to you. All these groundless accusations of yours seem to me to be little more than your thrashing around and attempting to strike out in all directions simultaneously. To correct such misconception as you apparently have on this score, let me assure you that I have formed no judgment on the professional competence of Dr. Paynter with whom I have had very little contact during the few months he has been here. I would assume, however, that he must be competent or else he would not have been both hired and rehired by this Agency. I bear no malice whatsoever towards him since I have no reason ?innuendo? goes, this quite capable, thank you, of expressing my views directly and explicitly and thus there would be no reason whatsoever for my having to resort to allusions or innuendo. In reality I have a great deal of sympathy for Dr. Paynter; as far as this entire business with permethrin goes, he seems to me to have been placed in a highly unenviable predicament:- as indicated in your own writing of last January, the Agency had evidently reached its "final toxicological conclusions regarding potential oncogenicity of it) decided it would not regulate permethrin as an oncogen' and clearly, Dr. Paynter must have been instructed to ratify a fait accompli through his being told to provide the scientific justification or underpinnings for a decision already made. This is hardly the kind of situation that any scientist with any measure of professional integrity would enjoy. Therefore my understanding and sympathy for his plight. Although Dr. Paynter turned out to be almost two months late in completing his task (perhaps one reason for this is that he had all kinds of help in this from the people in Toxicology Branch) and although both he and his lieutenant there, Mr. Budd, could have done a better job at supervising the work of Dr. Doherty in the latter's review of the Burroughs- Wellcome rat study, these are not matters for me to criticize. The unprecedented fiasco associated with the management of this entire safety evaluation of this pesticide in this Division cannot be charged to Dr. Paynter since, as far as I know, at no time did he attempt to restrict the quantity and quality of information relayed to other "inside" or "outside" experts, panel members, consultants, administrators, lawyers, peer reviewers, etc. If there has been here a seemingly total failure to obtain balanced and reliable views from scientists not associated with the manufacturers of permethrin (through their not having been provided full information relevant in this matter), if there has been here another kind of lack of balance in the sense that the views of professional consumer organizations have not been sought and no access was given to them to the actual safety facts on permethrin, these would not be failures ascribable to Dr. Paynter. Rather, and lest I be accused again of using mere innuendo, I shall make it fully explicit here as to whom I see as bearing the chief burden of responsibility for this entire sorry messz? you and you alone. with these introductory remarks out of the way, I shall now proceed with the next section which details some of the problems in the Paynter-Budd Assessment. DETAILS OF THE INDIVIDUAL STUDIES a) The First Charles River strain (FMC/Biodynamics) Mouse Study. This study was submitted by the registrants and it has been reviewed in the Toxicology Branch more than four years ago (3/30/78). None of the observations contained in the eight pages of that review are mentioned in the Assessment which dismisses that study for being ?of no in a single paragraph on its first page. Although there appear to have been serious problems with the execution of that study, it is interesting to note that the Toxicoldgy Branch made no attempt whatsoever to investigate those problems through an intensive audit of the results. We recall that in the case with the Second FMC/Biodynamics Mouse Study (which was also seriously flawed but for which I insisted that an in-depth investigation be carried out) it was concluded (Chitlik to Campt, 10/16/80) that although l'This study is not useful for assessment of chronic toxicity for a variety of oncogenic findings are confirmed and strengthened;". It appears that the top exposure level tried in that study (4,000 ppm) caused some 38/56 68% of the females to die after the 16th month in the study and, therefore, that level cannot be thought to be very informative. But at the (u other exposure levels tried there (0, 20 and 500 ppm) even if we set aside the reviewer's observation that "there appears to be a dose-dependent excess mortality in the later part of the (page 10) and focus merely on the initial number of animals (75/sex/1evel) we note (page 12 of the review) only 10/75 13.33% of control females manifesting mali nant conditions versus as many as 44/150 29.33% among E?e ?emaIes at the low and mid levels of exposure; this leads to an adjusted chi square of 6.167,76 whose one-sided probability is only less than 0.006,506. Most of these conditions were due to reticulo-endothelial neoplasia (a mali nant, usually multicentric expression) for which a similar contrast as made above (8/75 or 10.67% versus 37/150 or 24.67%) yields an adjusted chi square value of 5.281.25 whose one-sided probability is only less than 0.010.779. For sarcomas of an undifferentiated cell type, another kind of mali nant neoplasm, we find (page 11 of the review) 1/150 controls of both sexes exhibiting this type of tumor versus as many as 12/300 of the animals at the first two exposure levels; this is significant at the less than 0.036,54 one-sided probability level. Based on these findings alone, I would conclude that this study, for all its faults, has yielded highly significant indications of carcinogenicity (as distinct from mere tumorigenicity). Yet the Assessment is silent on these results and it appears to be content in merely forgetting such conclusions. Additionally, I was interested to note that the reviewer of that study signalled on her page 18 a spectacular increase in amyloidosis amongst both male and female animals for a large array of different tissues:? stomach, heart, pancreas, salivary gland, thyroid gland, uterus and liver. We recall that this is the identical change to which I had reference beginning near the bottom of page 8 of my own review dated 1/19/81 for the Second FMC/Biodynamics Mouse Study; as also pointed out there, amyloidosis was glossed over in the Toxicology Branch review of that study even though the differences in incidence for the various experimental groups were very highly significant for a number of different tissues. The Assessment before us chooses to be silent also on this issue as it is also for cardiac thrombosis featured on page 15 of the Toxicology Branch review and which appears to be associated with amyloidosis of the heart. ?t 10 Another problem here is that the dosages tried in this study which are listed on page 1 of the Assessment are inconsistent with what is in the Toxicology Branch review of this work (page 9 there); thus, for Group II 3 mgm/kgm/day is listed in the Assessment even though for more than 80% of the duration of this study no animal in that group received more than 2.4 mgm/kgm/day; for Group the Assessment lists 75 mgm/kgm/day even though for most of the study these animals received 235-520 mgm/kgm/day; for Group IV the Assessment lists 600 mgm/kgm/day even though no animal in that group received more than 560 mgm/kgm/day at any time and, for most of the time, the dosage for that group could have been only a small fraction of this. It is also a source of wonder to me just why the Assessment elected to report the dosages used in this study in terms of mgm/kgm/day when it appears that in actuality such dosages were presented to the animals in terms of parts per million in the diet. b) The Alderly Park strain (ICI) Mouse Study. As with the previously discussed study, the dosages reported in the Assessment are listed on a basis of mgm/kgm/day, even though the Toxicology Branch review of this study, dated 7/18/78, lists such dosages in terms of parts per million in the diet. This study is considered in the middle two paragraphs of page 2 of the Assessment. I was dismayed to note there a glossing-over with respect to the lung tumors noted amongst the males:- increased incidence of lung adenomas was 6/70, 12/70 and 17/70 for control, low, mid and high dosage levels respectively. Statistical analysis of this finding revealed a positive trend for this lesion in Permethrin treated males (Armitage test); but after correction for departure from linearity, this trend was not significant." My own calculations indicate for the data cited there an estimated slope of 0.000,346,5 with a standard error of only 0.000,l49,3, less than l/2.3 times as large, which indicates rather high statistical significance:- chi square value of 5.322 with one degree of freedom which is associated with a one-sided probability value of less than 0.010.53. The chi square for departure from linearity for the same data was only l.324,095 which, with two degrees of freedom, yields a two-sided probability as large as 0.516. I would conclude, therefore, that:- a) the increased incidence of lung adenomas noted in the male mice in this study was not merely I'slight" (as the Assessment has it) but highly significant at least in a probability sense; a ?u 11 b) no correction for departure from linearity is indicated here since the data are not inconsistent with a linear dose-response relationship. The Assessment makes no mention whatsoever of the distribution of lung adenomas amongst the female mice in this study which is given in the same table of ESE-feview carried out in Toxicology Branch for this study, page 28 there, (11/70, 8/70, 10/70 and 15/70) for the same sequence of exposure levels as cited in the Assessment for the male animals. If we combine the data for the two sexes, we obtain for the same sequence of exposure levels as cited earlier, 21/140, 14/140, 22/140 and 32/140 respectively. This yields a trend or slope of 0.000,276,70 (standard error of 0.000,105,26) which is significant at the 0.004,43 one-sided probability level (adjusted chi square with one degree of freedom of 6.850,5) and a non?significant (p 0.376,6) departure from linearity for the two degrees of freedom chi square of l.953,2. The 7/18/78 Toxicology Branch Review on this study does not make it clear whether the three male mice with malignant lung tumors noted in this study were animals that did not exhibit benign such tumors; if these are in fact tumor-bearing animals additional to those with benign lung tumors, the trend or slope becomes 0.000,288,46 (standard error of the slope of 0.000,106,64) which is even more highly significant:- one-sided probability level less than 0.003,549 (chi square with one degree of freedom as high as 7.248,4) and, again, an insignificant (p 0.474,3) departure from linearity chi square with two degrees of freedom of only l.491,8. Further, in the same paragraph of the Assessment as cited earlier we read:- ?Toxicology Branch considers the biological significance of this finding (the lung adenomas amongst male mice) to be of only marginal I must confess that I do not know what "biological significance" is, nor how exactly it might differ from statistical significance. Not knowing what it is or just how Toxicology Branch might choose to define it, I cannot assess just how it was characterized as being of only ?marginal concern". As far as the health significance of tumors of the lung goes, I have up to now held the view that to any subject sufficiently unfortunate to harbor one of these, such an event would be somewhat more than merely of "marginal concern". 12 Another point to note here is that 10 animals in each group were supposed to have been killed for detailed examination at both the 6 and the 12 months marks of exposure. Thus, for the total number of such killings (2 occasions, each for 10 animals/group/sex, 160 animals) only 141 such animals are listed as having actually been examined in this manner. What happened to the balance of 19 and on what basis were the findings on them, if any, excluded? Surely, post-mortem autolytic changes in their tissues could not have accounted for this shortcoming; but then, what precisely did so? It is worth noting that, as with the previously listed study here, no attempt at examination by the Toxicology Branch of the original laboratory records for this work was ever carried out. As far as I know, no tissues were examined histopathologically by any of our own pathologists or by any of our selection and I, for one, know nothing whatsoever on the identity or competence of the pathologist(s) who were responsible for this particular work carried out in the U.K. It seems to me that before we can conclude that this study is fully useful in the safety assessment for this pesticide or that the adverse findings reported are of only ?marginal concern", we ought to provide for the American public some assurance that our confidence or sanguine attitude on our part with respect to this study are not misplaced. This is particularly important if we keep in mind that for those experimental studies on permethrin which were audited by us and for which pathologists of our own choice have examined the available material, it was determined that either such studies had major flaws in their execution or that the circumstances under which they were carried out were not truthfully reported to us, or the number of tumor-bearing animals in such studies was significantly under-reported. Finally, I would note that the Hazard Evaluation Division had reached an understanding with the Health Protection Branch, Canada Health and Welfare, that this particular study (and its companion rat study carried out by ICI) be reviewed in detail in Canada. I remember that last November the 18th, the Canadian reviewers presented at a meeting here a number of significant findings concerning the tumor?induction potential of permethrin as determined by them to have been elicited in this particular study. I do not see those findings being reflected in the Assessment. Aside from this, I have been personally assured by the Canadians that they also have made no effort whatsoever during the course of their review to examine any part of the original laboratory records or any tissue sections associated with any of these two ICI studies. t6. 13 c) The Second Charles River strain (FMC/Biodynamics) Mouse Study. The Assessment discusses this at the bottom of its page 2 and continues through the middle of its page 4. Again, the fiction is being perpetrated that the dosages given to the experimental animals were on a body?weight basis when in fact the experimental agent was presented as a fixed part of the animals' diet. I note a reference to amyloidosis which, as mentioned in section here, was glossed over in the Toxicology Branch review of this study but discussed in some detail in my own review of it, being "dismissed as having no significant influence on the interpretation of results". As indicated previously here, its distribution in many organs and tissues of both sexes of both FMC/Biodynamics mouse studies was so spectacularly increased in incidence amongst exposed animals by reference to their equivalent controls, that I cannot conceive on what possible grounds this could be judged as not being significant. This Assessment is entitled "Chronic and Oncogenic Effects" and I should think that amyloidosis of the particular distribution as noted here ought to be thought of less for its influence on the interpretation of results than as constituting itself such a result, and a very important one at that. The reference to the ?focal areas of alveolar cell proliferation"' noted in the EPL report is interpreted somewhat misleadingly in the Assessment as constituting an "indicator of increased numbers of lung cells", a characterization not supplied by the EPL pathologist who refers to this particular pathologic change by its appropriate terminology "adenomatosis"; needless to add, this term is not used in the Assessment. Adenomatosis represents a histologic alteration of the cells lining the pulmonary alveoli and is characterized by metaplastic transformation, hypertrophy and hyperplasia of the normally flat alveolar lining cells into cuboidal or columnar cells which often contain mucus. Thus, adenomatosis represents not merely "an increased number of lung cells?, as misleadingly presented in the Assessment, but a uniform transformation of the alveolar lining cells into cords of cuboidal or columnar non-ciliated cells where the basic alveolar architecture of the lung may be distorted. It can have a number of varied types of etiologic agents including sundry chemicals, toxins, irritants, etc. In some animals, such as sheep, various forms of adenomatosis have been observed to have metastasized to regional nodes. At its worst, pulmonary adenomatosis can be considered at least as a preneoplastic change. 14 The Assessment mentions that this particular lesion has merely a ?dose-related incidence in the female animals". For the observations cited there, I obtain a positive trend (slope) of 0.000,169,2 with standard error of 0.000,056,68 which is highly significant:- chi square value of 8.713,86 which, with one degree of freedom, yields a one-sided probability of only 0.001,58 and a non-significant departure from linearity (chi square of only 0.902,2 with two degrees of freedom for a probability value as high as 0.637). The same problem is evident also for the last part of the first paragraph on page 3 of the Assessment which has reference to multifocal hepatocytomegaly. The Assessment mentions the fact that "The nature of these lesions as precursors of neoplasms is disputed" but it fails to give the significance of the trend of incidences cited amongst the females; rather it appears to be content with observing merely that for the sequence 0/74 (the denominator given in the Assessment for this ratio may be incorrect) 3/76, 6/76, and 9/75 there is an ?increased frequency" which any schoolchild can tell quite readily by mere inspection. The slope that I obtained for this distribution is 0.000,l36,l with standard error 0.000,043,59 which is very highly significant:- chi square of 9.503,4 with one degree of freedom which has a one- sided probability of only 0.001,03 and only a relatively small (p 0.579) departure from linearity for the chi square with two degrees of freedom of l.09l,47. Apparently this attempt at "playing down" the significance of this particular finding was not sufficient for the authors of this Assessment. They neglected to call attention to the distribution of multifocal hepatocytomegaly amongst the male mice in this study. The distribution of this change is given in the same EPL report as 1/74, 6/75, 7/75 and 14/74 for the sequence of exposure levels 0, 4, 75 and 300 mgm/kgm/day. This trend is even more highly significant:- slope of 0.000,475,6 and standard error of the slope of 0.000,l36,3 which yields a one degree of freedom chi square as high as 11.768 with a one- sided probability of only 0.000,301,294; the departure from linearity chi square was only 1.912 which, for two degrees of freedom, has a probability as large as 0.384. Putting these results for the male and female animals together, we obtain the following:- (see next page) 15 Paired comparison to control rate mgm/kgm/day observed result (one?sided probability) 0 1/148 0.68% - 4 9/151 5.96% 0.010,59 75 7/ 75 9.33% 0.002.326 300 14/ 74 18.92% 0.000,000,938 375 6/ 76 7.90% 0.006,764 750 9/ 75 12.00% 0.000,285 All exp. lev. 45/451 10.02% 0.000,020,9 This is the kind of thing which the authors of the Assessment apparently elected to ignore and perhaps the reason for this is that it would have placed in jeopardy the statement made at the bottom of paragraph 2 on page 9 of the Assessment:- "Based on a consideration of the totality of evidence in all 3 mouse studies (including the Second Charles River strain mouse study discussed here), the NOEL (no observable effect level) for non-oncogenic effects in mice has been determined to be 50 mg/kg/day." In this connection, and speaking strictly for multifocal hepatocytomegaly, we note that:? a) a non-zero NOEL for this particular lesion has not been established at all in this study; b) the estimate given in the Assessment (50 mgm/kgm/day) is quite close to 75 mgm/kgm/day for which we have seen significance to obtain at the 0.002.326 probability level; c) the table on the page immediately preceding the remarkable conclusion in the Assessment that was cited above, attempts to create the impression that:- l) multifocal hepatocytomegaly in the FMC Mouse II study was noted only amongst the female animals: 2) it was noted only at the 375 and 750 mgm/kgm/day levels not at the 4, 75, and 300 mgm/kgm/day levels where not only was it present, but where it was present to a remarkably highly significant extent) when we have conclusively demonstrated here that neither of these statements are even remotely true. 16 As far as frank tumor-induction is concerned, this is discussed in the rest of page 3 of the Assessment where we note the same disturbing tendency to improperly minimize the level of statistical significance of the results. I have complained (in writing) about this problem with respect to this particular study more than one year ago, but seemingly of no avail; saying merely that a certain trend is "statistically significant" without indicating the actual level of significance is misleading since a reader might be tempted to equate or give the same weight to results significant at, say, the 0.000,000,5 probability level as he does to those significant at the, say, 0.05 probability level. For the values cited in paragraph 2 on page 3 of the Assessment I obtain the following estimates:- a) bronchogenic adenoma (results of 2/7/80:- 12/72, 14/75, 28/74 and 28/73 for the sequence of exposure levels of 0, 4, 375, and 750 mgm/kgm/day - estimates given in column below; b) all alveolar cell neoplasms (results of 15/75, 24/76, 35/75 and 44/75 for the same sequence of exposure levels as cited above - estimates given in column below; c) pulmonary carcinoma amongst female animals:? 6/75, 7/76, 11/75 and 15/75 for the same sequence of exposure levels as cited above estimates given in column below:? (C) slope (trend) 0.000,300,6 0.000,450,5 0.000,153,3 standard error of slope 0.000,082,97 0.000,087,29 0.000,062,03 chi square with one degree of freedom for slope 12.648 24.617 6.022 one-sided probability for the chi square with one 0.000,189 0.000,000,351 0.007,065 degree of freedom for slope chi square with two degrees of freedom for departure 2.651 2.514 0.051 from linearity two-sided probability for the chi square with two 0.266 0.285 0.975 degrees of freedom for departure from linearity 17 The contrast cited at the end of the second paragraph on page 3 of the Assessment and about which it is said that it merely "revealed statistical significance" yields an adjusted chi square with one degree of freedom of 3.543,? whose one- sided probability is only 0.029,89. I would also note that the actual ratios quoted there (15/75 and 6/75) are not in strict accord with the equivalent ones presented in Mr. Litt's analysis of 2/10/82. Far more important, however, is the fact that the Assessment completely ignores the principal conclusions reached by Mr. Litt in that communication of his:- namely that the increase in incidence of lung tumors amongst exposed animals is of extreme statistical significance, of very many orders of magnitude higher than the customary "critical? value of 0.05; one value for this probability that Mr. Litt quotes there is 0.000,000,084,9 which is not exactly equivalent to 0.05. My own analysis for this study which was presented before the Science Advisory Panel last year initially indicated that kind of extreme statistical significance and thus I find Mr. Litt's recent computations as confirmatory of this sort of situation. The Assessment before us at this time elected to ignore also the estimates that I made at that time, just as it chose to set aside any consideration of the risk analyses independently made by both Mr. Litt and me without giving any reason for this. Perhaps, however, the real reason for this is, as noted in the introduction here, your view that a risk analysis in connection with permethrin would not be "useful". I note at the end of the first paragraph on page 4 of the Assessment that ?Biologically, Toxicology Branch considers these tumors to be related to the ingestion of Permethrin". We recall that for exactly the same type of tumor noted in the ICI mouse study, the same Toxicology Branch considered its biological significance ?to be of only marginal concern." Question:- in what "biological" way is a lung adenoma in a male Alderly Park mouse "different" from a lung adenoma in a female Charles River mouse? And, if in fact Toxicology Branch insists that there is such a "biological? difference for exactly the identical tumor type between these two separate studies, would this 295 be a function of the actual level of statistical significance? If we also recall that in the ICI mouse study the increased incidence of lung adenomas amongst exposed animals over comparable unexposed controls was likely the result of permethrin (p 0.010,53) we may also ask:- at precisely what particular value would Toxicology Branch begin to be impressed that "biological significance" had been achieved? 18 Very much the same comments as were made above for the lung tumors that were noted in this study apply also to the liver tumors which are discussed in the second paragraph of page 4 of the Assessment; I discern there the same propensity to refer to certain differences as being merely "statistically significant" without indicating the actual level of such significance; the same failure to refer to the detailed analyses for significance provided independently by Mr. Litt and I and to the risk analyses also carried out by each of us. In actuality, however, things are much worse here by comparison with the situation pertaining to the lung tumors. The EPL Report (what is referred to in the Assessment as "the second report") clearly indicates in the second paragraph of its summary (page 2) that "There was an increase in (the incidence of) the benign proliferative lesions in the livers of male mice in all the treated groups." The EPL summary incidence list indicates for the sequence of exposure levels cited (0, 4, 75 and 300 mgm/kgm/day) respectively 8/74, 19/75. 17/75 and 18/74 males positive for hepatocellular adenoma: this would yield a contrast of 8/74 10.81% positive controls versus 54/224 24.11% positive animals from amongst those having been exposed to any level of the agent on test. Such difference leads to a continuity- adjusted chi square value with one degree of freedom of 5.189 whose one-sided probability value is only 0.011.366. of rather high statistical significance. This entire matter of liver tumors noted amongst the male animals in this study is not mentioned or indicated in any fashion in the Assessment, we have here yet another reflection of the thoroughness with which its authors carried out their task. If we combine the response of the two sexes for benign liver tumors we obtain the following distribution:- Paired comparison to control rate mgm/kgm/day observed result (one?sided probability) 0 11/148 7.43% - 4 23/151 15.23% 0.026.08 75 17/ 75 22.67% 0.001.224 300 18/ 74 24.32% 0.000.468 375 23/ 76 30.26% 0.000.008.09 750 29/ 75 38.67% 0.000,000,013,7 l9 slope (trend) 0.000,370,2 standard error of the slope 0.000.062.96 chi square with one degree of freedom for slope 32.792 probability of chi square for slope (one?sided) 0.000.000.005,15 chi square for departure from linearity 6.192 degrees of freedom for chi square 4 just above probab. for chi square just above 0.185 (two-sided) Note the monotone increasing incidence for the six exposure levels (including the controls), the high significance pertain- ing to the response for the lowest level tried (4 mgm/kgm/day), the increasing significance for all other levels of exposure and the extremely high significance (barely more than five per billion) for the slope. If, as the Assessment has it, these results indicate merely "weak" tumor-induction potential for this particular pesticide product and if such characterization has reference to the fact that it takes only very high levels of exposure to induce tumors in experimental animals (see the reference to the minutes of last January's meeting with the registrants written by you) then I must say that I cannot think of many other registered products whose potential in this respect can be regarded as being "stronger". In addition to this, I also cannot think of many such products for which the evidence for such tumor-induction potential was more clearly or more persuasively demonstrated. Still another failure in its discussion on the tumor results of this study is the Assessment's silence on the entire topic of the female animals? likelihood to exhibit either lung or liver tumors as well as their likelihood to manifest jointly?Both lung and liver tumors. Analyses of these aspects as well as the risk arising from such considerations were presented before the Science Advisory Panel at their meeting here of March the 10th, 1981. when the tumor?induction potential for this specific product was discussed. Some of the probabilities listed there were as low as 0.000,000,000.47l and none were greater than 0.000.322, indicating additional extreme significance. 20 With respect to the last paragraph in this section of the Assessment, I would disagree at least partially with the statement on the audit of the results of this study not having revealed "any inadequacies in the conduct or reporting of (the results of) this study serious enough to compromise the usefulness or validity of these study results." If the thrust of this statement has reference to the regulatory utility of this study insofar as establishing that the agent on test is qualitatively a remarkably clear tumor- inducer, I would agree that such view had not been substantially compromised by the conduct of this study or by the reporting of its results. If, on the other hand, the statement is meant to have reference to the reliabilit of the individual results themselves as estimators of the quantitative strength of tumor-induction, then our confidence must Be discounted by several aspects of the audit:- a) Evidence that the control animals' diet having been contaminated with the agent on test; the net impact of this finding can be in only one direction:- to blur the distinction (and thus the significance) of any reported differences in the incidence of tumors of various kinds between animals exposed and those allegedly I?not exposed" to the agent on test. It is also evident that potentially serious problems with the amount of the test agent having been mixed into the diet of the experimental animals were present also in the case of the other two trials on permethrin undertaken for FMC at Biodynamics:- the first mouse study as well as the rat study, as the audit had established. b) The fact that a number of tumor-bearing animals were detected following examination of the tissues by the EPA pathologist who took part in the audit, such animals having been missed as being tumor~bearers by the pathologist retained by the registrants; this search by the auditing EPA pathologist was no more than a rather limited or superficial one. o) The same EPA pathologist having noted that "the high incidence of pneumonia, amyloidosis and marked nephritis in all groups reflect (sic) the poor general condition of the animals in this experiment." and that "these shortcomings make the reliability of the experiment questionable". While I would not challenge this general assertion, I would recall again that amyloidosis was reported to have been considerably more prevalent amongst exposed animals than it was amongst those not exposed in two separate such mouse studies which would indicate its cause as residing perhaps elsewhere than the ?poor general condition of the animals in this experiment." 21 d) "The unusually high (46-66%) spontaneous death rate, which indicates an unsatisfactory observation of animal colonies and allowing the moribund animals to die. These animals, because of the rapidly developing autolysis, have limited value for histopathology (approximately 50% fall in this category). All of these animals are listed on each pathology sheet as (having had) organs not suitable for histopathologic observation, or they were Kasza (the EPA pathologist) points out that this, and other mentioned factors raise the question of reliability in the investigation of the effects of permethrin in this experiment." (The foregoing is a quote from the official inspection report). e) The fact that apparently no professional pathologist was in attendance at the time the experimental animals were dissected after death in order to record grossly observable pathologic alterations in their carcasses and tissues. It may be worth noting here that we are now some 18 months down the road since that investigation was carried out and, to my knowledge, this Division has yet to inform officially either the registrants or the contract laboratory which executed that study of the view this Agency takes of such practices and what corrections in this respect are expected by us. On the other hand, and as stated in the Assessment, this Division may be of a view that none of these problems represent questionable practices that are ?serious enough". Even with that extensive on-site investigation in which a number of members from the Toxicology Branch participated, not all the problems with reference to this study were addressed. For example, no attempt was made to verify the correlation between ante-mortem observations, those made following the gross post-mortem examination and those following the histopathologic evaluation of the lesions for tissues other than the lung and liver; this limitation took place despite the many such problems that I signalled in this respect as having been present with a variety of such tissues. Also apparently not addressed was the thoroughness of the ante?mortem examinations of the experimental animals, another feature highlighted in my own review of this study. Finally here, although a number of requests for additional information on this study were made of the registrants by the investigative team, I have not been able to find in the files any of this additional information: I wonder whether the registrants ever complied with these requests and, if they did not, whether this constitutes a concern on our part. 22 d) The CFLP strain (Burroughs-Wellcome) mouse study. This study is discussed beginning near the bottom of page 4 of the Assessment. As was the case with the mouse study considered in the previous section here, we see reference to a lesion that, from its description, appears to me to be likely pulmonary adenomatosis, though this term is not being used in the Assessment anymore than it was used in the previously discussed study. The lesion is termed to be "controversial" in the Assessment and I wonder just how its authors arrived at such judgment since, to my knowledge, neither they nor anyone else in the Toxicology Branch made any effort to examine first-hand the changes manifested by these animals. However, perhaps what they meant to say there is that its constituting a pre-neoplastic change may be a controversial matter, but this would be quite a different thought. It also seems rather odd (but hardly surprising) that the Assessment mentions only the females as exhibiting this change when the lungs of the exposed male mice exhibited almost as high an incidence of the same lesion as did the female animals; just as we have seen here repeatedly so far, the statistical significance of this particular pathologic alteration is being glossed over in the Assessment. For the exposure levels 0, 10, 50, and 250 mgm/kgm/day, the sequence of observed incidences in the females which were cited in the Assessment presents a trend or slope of 0.000,274,1 with standard error of 0.000,075,68 which is highly significant:- chi square with one degree of freedom of 12.669 which has a one-sided probability of only less than 0.000,186. For the males, the incidences corresponding to the same exposure levels yield a slope of 0.000,l42,5 with standard error of 0.000,069,18 which is also highly significant:? chi square with one degree of freedom of 4.212 which has a one- sided probability of only 0.020,066. For the data for both sexes combined (0/195, 1/146, 2/147 and 8/148 respectively for the same sequence of exposure levels as cited) the slope or trend is 0.000,208,l (intermediate between those for each sex), the standard error is only 0.000,051,23 (smaller than that for either sex, as expected, due to the larger number of subjects observed) and here the significance is extremely high:- chi square with one degree of freedom as high as 16.123 whose one-sided probability is as small as less than 0.000,029,56. 23 For the data on females, on males, and on both sexes jointly, the departure from linearity chi square with two degrees of freedom is respectively 0.019, 0.121 and 0.403 indicating in each case an insignificant such departure:- probabilities as high as 0.991, 0.941 and 0.818 respectively. Furthermore, the observed incidence for both sexes noted at the top exposure level is highly significantly greater than that of the control animals:? less than 0.001,076,2. The Assessment mentions (page 5) that for the lung tumors in the female mice Peto's Prevalence Method indicates a trend significant at the level less than 0.01 and that Armitage's method yields a probability level for the trend of less than 0.02. My own calculations for the same data yield a trend or slope of 0.000,624,6 with standard error of the slope of 0.000,l62,l which is much more highly significant:? chi square with one degree of freedom of 14.267 whose one-sided probability is only less than 0.000,079,36, more than two orders of magnitude greater than what is being cited in the Assessment. The departure from linearity chi square with two degrees of freedom of 0.721 was insignificant (p 0.697). The Assessment also mentions the comparison between the incidence noted at the top exposure level and that for the control animals while noting that this yields merely l'high statistical significance by Fisher's Exact Test". What I get as a result of applying that very same test is less than 0.000.339.61 which, to me, indicates very high significance. Interestingly, what the Assessment fails to mention in this connection is that even the incidence at the mid exposure level (which was less than one-half that noted at the top level) when compared to that of control animals is of "borderline signfiicance" (p less than With reference to the malignant tumors discussed in the Assessment, I should think that a lung tumor which extends into the respiratory airways or into the surrounding lung tissue, one that manifests invasive properties, can be classified as being in fact malignant. Thus, the contrast between 8/74 female animals at the top level which exhibited these kinds of tumor and the equivalent 3/96 controls is significant at the 0.044,26 probability level. If we form the contrast between the same 8/74 positive females at the top exposure level and the 7/241 such females at all other exposure levels, we obtain significance at the less than 0.013,09 probability level, which is the one associated (one-side) with the continuity adjusted chi square value of 6.157,5 with one degree of freedom. 24 If we focus merely on the metastasizing or widely destructive adenocarcinomas of the lung, the contrast between 3/148 positive females at the top two exposure levels versus 0/167 such animals at the other two levels is of borderline significance:- less than 0.102.61. It is interesting to observe that, despite everything noted for this study, the Assessment considers all this as being merely I'highly suggestive of a possible oncogenic effect in lungs". It is also worth noting (from the statement at the bottom of page 11 of the Assessment) that this particular study did not, in the View of its authors, provide any "evidence of Permethrin oncogenicity? since they presumably reserve such attribute to "only one sex of one strain of mouse" (likely the females in the Caesarean-derived Charles River Second FMC/Biodynamics mouse study). Also worth mentioning here is that, as was the case with the two studies carried out by ICI, no attempt whatsoever was made to examine the conduct of this study in ways other than merely reading the report on it issued by the registrants:- examination of at least part of the pathologic material and of at least part of the original laboratory records which were at the basis of that report. Looking merely at the Toxicology Branch review for this study written in early March of this year by Mr. Budd (one of the two co-authors of the Assessment) I have some questions which apparently did not occur to him:- 1) why were the lungs of 14 of the experimental animals not reported as having been examined? 2) why were the lungs of 6 of the animals which were killed at the end of the observation period (and thus could not possibly exhibit post-mortem autolytic changes) not reported as having been examined? 3) why was the liver of 10 of the experimental animals not reported as having been examined? 4) why was the liver of 5 males at the high level of exposure which were killed at the end of the observation period (and thus could not possibly exhibit post-mortem autolytic changes) not reported as having been examined? 5) why was the pituitary gland of 131 of the experimental animals not reported as having been examined? 6) why was the pituitary gland of 35 of the animals which were killed at the end of the observation period (and thus could not possibly exhibit post?mortem autolytic changes) not reported as having been examined? 25 7) are there any other tissues or organs where not all animals (particularly those terminally killed) had all such tissues or organs examined and, if so, how extensive?Were such shortages? 8) in the light of all these problems as well as those to be discussed subsequently here for the companion rat study carried out at the same institution, would Mr. Budd still stand on the conclusion reached in his review that this ?study was 9) would he not agree with me that such confidence as he seems to have displayed there would have been better justified had a detailed audit of that study been carried out with the caveat that no serious problems would have been uncovered during such audit? 10) would he care to revise the statement in the summary of his review that "Complete gross necropsies and histopathological examinations of all major tissues and organs were conducted on all animals that died or were sacrificed in extremis during the study and on all animals sacrificed at the end of the study"? Incidentally, what precisely is a "major" organ or tissue? Is it the "largest" organ or tissue, such as the skin perhaps? Are the lung, liver and pituitary gland not major organs? What would be the minor organs and tissues? 11) what would be the reason for his review as well as for the Assessment that he co?authored having referred to the statistical analyses for significance carried out by Mr. Litt on October the 7th, 1981 yet having totally ignored the risk analysis presented in the very same communication by Mr. Litt? Was this due to some technical problem with that risk analysis, or was Mr. Budd "instructed" to do so as a matter of policy? 12) with reference to that analysis carried out by Mr. Litt, how would the latter explain the fact that the ratio that he has on his page 6 there (6000 gm/25 gm)l/3 is neither 126 as he stated six times on that page nor 12.6 as he stated another six times on the same page but, rather, 6.214,5? If the correct answer is the latter one, as I suspect it is, would not all the estimates for the virtually safe dose for humans that are stated there be wrong by an appreciable factor? Would the same estimates reached for the one?hit model (bottom half of his table on page 6 there) not be wrong even if (6000/25)l/3 were in reality 12.6 as stated there? 26 e) The Specific Pathogen-Free Wistar derived (ICI) rat study This is discussed near the bottom of page 5 and the top of page 6 of the Assessment, and the conclusion reached there is that "No tumors considered by the Toxicology Branch to be related to or attributable to the ingestion of Permethrin were observed in this study". The review and evaluation of this work, carried out in the Toxicology Branch and reported on as long ago as July, 1978, refers to the following:- 1) The exposed males dying with tumors did so earlier than those in the unexposed group which suggests an acceleration or reduction in the latent period of neoplasia, assuming that the course of such conditions is essentially similar. For the contrast cited in the review with reference to the males at the mid-level of exposure, a probability of 0.002 is indicated there which is approximately one-half as small as what I get:? 0.004,193, but even the latter figure is impressive and it indicates very high statistical significance. This observation was omitted from the discussion in the Assessment on pages 5 and 6 as well as from that on page 13 where the subject of acceleration is addressed specifically. 2) The third paragraph on page 12 of the Assessment states:? "Rare or unusual tumors were not observed in any of the mouse or rat long-term studies." Yet in the 1978 Toxicology Branch review for this study I find that:- "Among the types of malignancies which occurred among treated but not controls, 3 mammary adenoacanthomata and a keratoacanthoma, all at 2,500 (the top exposure level) are of interest because of their relation to squamous cell carcinomas." Although I would not necessarily endorse the view that either mammary adenoacanthoma or keratoacanthoma is invariably a malignant type of neoplasm, the fact is that each of these can certainly be regarded as being a rare or unusual type of tumor in the rat as well as in other species including the human. The review continues:- "The squamous cell carcinomas which did occur in both treated and control animals, developed in unusual sites among treat(ed) animals. Two were found in the corpus of the uterus in females fed 1,000 ppm. The thymus was the site in one female from each treatment group, and in one male fed 2,500 ppm. The tooth-socket was the origin of one in another male fed 2,500 ppm. The other was in the skin. The totals including acanthomas, suggest a dose-dependency. There was one in a control male, one in a 500 female, five at 1,000 (2 in males and 3 in females) and 8 at 2,500 (4 in each sex)." 27 "Of the benign neoplasms which occurred only in treated animals, the most common were skin papillomas. There were 3 affected animals in each group of treated males. It is interesting that there are both benign and malignant neoplasms increased (in frequency) in treated groups which may involve proliferation of squamous cells with varying degrees of keratinization.? I have discussed this problem with my fellow pathologists who reviewed this study in Canada. Since they are of a sort which can best be described as "purist", they informed me that they did not group all of these keratinizing tumors together since they are of a view that some may be ontogenically unrelated, they may arise from different embryologic germ layers. I would certainly not dispute this kind of assertion and, in fact, I even see some merit in it. However, for those who may be less inclined to take seriously such scientific refinements or rather esoteric considerations, it may be informative to look at the situation while overlooking such objections as were raised by the Canadians in this respect:- If we were to combine all of these ?rare or unusual" keratinizing tumors of the benign and malignant varieties together for both sexes, we obtain for the sequence of exposure levels 0, 500, 1,000 and 2,500 ppm, 1/120, 4/120, 8/120 and 11/120 positive animals respectively. This yields a trend or slope of 0.000,032,l43 with standard error of the slope of 0.000,010,555 which is very highly significant:? chi square with one degree of freedom of whose one-sided probability is only 0.001,253,7, and the chi square with two degrees of freedom for departure from linearity of l.040,l is insignificant (p 0.594). The contrast between the incidences at the top level of exposure and that in the control group is significant at the 0.002,599 probability level and for that at the middle level, the probability is If, in deference to the way the Canadians feel about combining the incidence of these keratinizing tumors, we would have refrained from doing so, the incidence of each distinct type of such tumors amongst each of the two sexes of exposed animals is likely of very high or perhaps even extreme significance, given the rarity with which such tumors occur in control animals. If we had reliable estimates of their "control" incidence in a large series of such unexposed animals, and we used those estimates as a basis for comparison, I have no doubt whatsoever that such extreme significance would have revealed itself. 28 3) Mammary neoplasms among the females at the same exposure levels as cited above were observed with respective rates of 10/60, 10/60, 11/60, and 17/60; this yields a slope of 0.000,050,00 with standard error of the slope of 0.000,027,528 which is also quite significant:? chi square with one degree of freedom of 3.281,25 whose one-sided probability is only 0.035,04; the chi square with two degrees of freedom for departure from linearity is only 0.260,4 which is of practically no significance whatsoever (p 0.878). I might add in this connection that the Canadian reviewers arrived at somewhat different summary incidences for these particular tumors, but I shall not give any details on this here; such details were presented by the Canadians themselves at the meeting which you convened and chaired here last November the 18th. The same details are also presented in the written material the Canadian Government recently made available to Mr. Johnson on a confidential basis; Mr. Johnson allowed me to see those details again but, given the Canadians' reluctance to have their evaluation quoted, I shall refrain from doing so. Suffice it to note that the two authors of this Assessment also attended the November the 18th meeting and they must have been aware of the discrepancy in the data regarding the mammary tumors noted in this study between the Toxicology Branch's version of this and the Canadians' such version, yet apparently no attempt whatsoever was made by them to resolve this difference in the sense of establishing precisely which particular set of figures, if any, is the correct one. Another kind of "rare or unusual" tumors noted in this study (also not mentioned in the Assessment) are the meningiomas noted amongst both male and female animals:? in the control group of 57 females and 54 males there was one such animal observed for each sex; none of 58 females and one out of the 59 males exposed to the low level manifested such tumors; at the mid level of exposure, 1,000 ppm, none of the 59 females and two of the 57 males exhibited this tumor, and at the top exposure level, 2,500 ppm, three of the 60 females and three of the 56 males also had this kind of tumor. Putting these results for the two sexes together, we obtain for the sequence of exposure levels 0, 500, 1,000, and 2,500 respectively 2/111, 1/117, 2/116, and 6/116 animals positive for meningioma. Even if we were not to refer to any long series of "historical control incidences" of meningiomas in rats but consider merely the I'local" or "contemporaneous" control incidence, this would yield a slope or trend of 0.000,015,95 with standard error of the slope of 0.000,007,608 which is highly significant:- chi square with one degree of freedom of 4.364 whose one-sided probability is only 0.018,359; the departure from linearity chi square with two degrees of freedom was only 1.050,4 and its probability is as high as 0.591. 29 Still another kind of ?rare or unusual" tumor noted in this study (also not mentioned in the Assessment) is the glioma of different types (astrocytic. mixed, undifferentiated, and not otherwise specified) which was noted amongst the males in this study. For this particular kind of brain tumor there were 1/54 positive controls, 0/59 rats exposed to 500 ppm. 1/57 of those exposed to 1,000 and 3/56 positive rats at the top exposure level of 2.500 ppm. The slope or trend for this distribution was 0.000.017.92 with standard error of 0.000.010.52, which lead to a chi square with one degree of freedom of 2.889 whose one-sided probability is only 0.044.59; the two degree of freedom chi square for departure from linearity was only 1.093.288 whose two-sided probability is as high as 0.579. Yet another similar such "rare or unusual tumor" observed in the female rats in this study (also not mentioned in the Assessment) was the adrenal cortical adenoma. There was one of the 58 controls exhibiting this tumor, none of the 59 females at each of the two exposure levels 500 and 1.000 ppm, and as many as three of the 59 females at the top exposure level manifesting it. The slope for this distribution was 0.000.016.95 with standard error 0.000.008.994 which yield a chi square value with one degree of freedom of 3.528 whose one-sided probability is only 0.030,2. The departure from linearity chi square with two degrees of freedom was 2.550 and its probability was 0.279. In view of all this we can establish that both statements in the Assessment made near the bottom of page 5 ("No tumors considered by the Toxicology Branch to be related to or attributable to the ingestion of Permethrin were observed in this study?) and the one in the third paragraph on page 12 of the Assessment ("Rare or unusual tumors were not observed in any of the mouse or rat long-term studies") are false and misleading. f) The Long-Evans strain (FMC/Biodynamics) rat study. This study cannot be classified as having been fully informative or relevant as a carcinogenesis study:? the maximal level of exposure was only 25 mgm/kgm/day (at least according to the Assessment) which is not only one-fifth the maximal level for the study considered in the prev1ous section here (and one-half the middle level of exposure in the same study) but as little as one-tenth of the top exposure level in the study to be next section here. As one could have expected. the Assessment did not see fit to discuss or draw attention to this not insignificant problem. 30 The other major difficulty with this study as far as quality of execution goes (also not alluded to in the Assessment) has to do with the lack of adequate follow-up of the ante?mortem findings suspected of representing neoplastic proliferation at the necropsy examination and the further follow-up of post-mortem observations in the same category during the histopathologic evaluation. This sort of thing was signalled prominently in the Toxicology Branch review of this study which was dated more than four years ago and which prompted an audit of this study to have been carried out. As a consequence of that audit, the registrants submitted a report of their own which was represented as being the result of their own audit on the conduct of the study. That report from the registrants, dated July the 2nd, 1979, fell considerably short from allaying our fears that this particular study was woefully inadequate at least as far as the pathology operations were concerned. The following are some of the items of interest in that report:- 1) Gross lesions suggestive of neoplasia are not limited merely to what the rather inexperienced prosectors at Biodynamics chose to define as distinct or circumscribed l'tissue masses"; a diffuse enlargement of part of (or the entire) such tissue or organ might also represent neoplastic transformation, yet this would not have been termed as a "mass" by those prosectors. These kinds of lesions were not addressed in the registrants' report. 2) The fact that a certain tissue with a "mass? described in it was merely examined microscopically provides little if any assurance that such "mass" was in fact itself sectioned, examined and accounted for during the histopathologic evaluation. It seems to me as if the registrants have a misconception here, whether real or merely pretended. 3) Although not directly related to neoplastic lesions but, nevertheless, indicative of the general quality of pathology operations at Biodynamics (and thus indirectly referable to the reliability of that laboratory to present an adequate report of any long-term toxicology study) is the fact, signalled in the Toxicology Branch's review of 1978, that "of 82 animals reported to have some degree of cataract within one week of sacrifice, only 3 were found to have any ocular pathology (findings reported after histopathological observation)." This feature was not addressed in the FMC "audit". 31 4) I find the explanation given by FMC (bottom of page 4 of their submission) is not unreasonable to assume that some masses may have simply been missed by the prosector due to their small size, unusual location. or the condition of the animal at the time of necropsy. Many of the palpable masses which were noted at the last in-life physical examination and which were not confirmed during the gross necropsy examination were less than 0.5 cm in diameter and/or were located in areas tail) which might not be examined for palpable masses as thoroughly as others abdomen).? as being no explanation at all:- while all this may not be "unreasonable". it certainly can be viewed as little more than arrant nonsense and as being completely unacceptable for a carcinogenesis study. I cannot see how anyone in complete control of his senses could place any kind of reliability in any study conducted according to such practices. As mentioned above. the Assessment before us makes no reference whatsoever to such problems. I would further question the propriety of the Assessment's (line 12, last paragraph on its page 6) speculating on the reason for the registrants having decided to collect many sections from the lung tissue blocks of the male animals. If we are to speculate on the likely reason for such decision of theirs, I might as well be free to advance my own "theory" on this:- the most likely such reason, I believe, was not (as the Assessment has it) an "effort to perform a more critical and detailed evaluation of lung since, if this were so. the registrants would have done so initially or subsequently for the lungs of both male and female rats or, indeed, for any other of their tissues. Rather, I suspect. what really prompted and propelled them in such action was the ?bad news" they had received following the initial analysis of the lung tumor data for the males. They probably reasoned that the collecting of additional lung sections from the male animals (especially a larger number of sections from the control than from the exposed rats) could not but enhance the likelihood of one's finding additional tumors in the lungs of control animals but less so in the lungs of those exposed to the agent on test. This kind of intention seems to have been "rewarded? as it were by what actually happened:? the rate of tumor incidence increased from the initial estimate of 1/60 1.67% to as much as 8/60 13.33% for an ei ht-fold increase in the case of control animals. as a result of this curious "step- sectioning" procedure, but only from 17/177 9.60% to 26/177 14.69%. a mere one and one-half fold increase for the animals exposed to permethrin. 32 The Assessment discusses the "bias" in each of these examinations but it fails to mention that following an investigation on our part into this strange episode, it turned out that the registrants had made likely false and misleading representations to the EPA concerning this matter of the "step?sections". As far as tumors elicited in this study are concerned, the Assessment does not mention the following aspects of the 1978 Toxicology Branch review of this study:- Among the 60 control males (45 or 75.00% of which bore neoplasms of any kind) there were only 5 or 8.33% with malignancies; among the 180 exposed males (where only 116 or 64.44% had neoplasms of any kind) as many as 27 or 15.00% had malignancies. Thus the ratio of animals bearing mali nant tumors out of all tumor-bearers was only 5/45 for unexposed males versus as many as 27/116 23.28% for the exposed males, a more than a two-fold increase. This is of borderline significance (p less than 0.064,8) and suggests an increase in the malignancy status of tumors as a result of exposure to permethrin at relatively low levels. The other comment to be made here is that any study where 45/60 75.00% of the control males and 46/60 76.67% of the control females turn out to be tumor-bearers cannot be thought to be very informative on the cancer-induction potential of any agent on test; perhaps a more suitable experimental host than the Long-Evans strain of rat could have been used by the registrants. Also not mentioned in the Assessment are the malignant keratoacanthomas noted in the Toxicology Branch review of 1978. There were 3/120 animals of either sex at the top exposure level versus none of the 360 animals in the rest of the trial; the significance of this particular contrast is quite high (p less than We recall that we have discussed keratinizing tumors, all of which are "rare or unusual? neoplasms in any species, in the previous section here devoted to the ICI rat study. Other "rare or unusual" types of tumors observed in this study, yet not signalled in the Assessment, were the ganglioneuromas noted amongst exposed male and female animals as well as the mali nant mixed tumors of the kidney of similar distribution. The statistical significance that attaches to these latter two types is identical with that mentioned above for the malignant keratoacanthomas. We see therefore that inasmuch as the Assessment focussed its comments for this study entirely on the subject of the lung tumors noted amongst only the male rats, this can also be considered as being false and misleading. 33 g) The Charles River Specific Pathogen-Free (Burroughs-wellcome) rat study. As noted with other studies discussed in these pages, the reliability of the conduct and reporting of this particular work is not touched upon in the Assessment which devotes to it a grand total of two paragraphs at the end of its page 7. Yet we find that in July 1981, the original Toxicology Branch reviewer of this study drew attention to the fact that the registrants originally reported virtually all tissues from virtually all animals in the experiment to have been examined histopathologically. The same information was given again to the EPA following a specific request for clarification on this on June the 29th, 1981. Yet, when we insisted on a signed statement to this effect from the pathologist who actually carried out such examinations, a very different story was presented by the registrants in September of that same year. According to that submission and considering merely the top exposure level animals killed at the end of the observation period, the bone marrow was not examined for any of the 12 males and for 37 of the 40 females. For the control animals also killed terminally, the bone marrow is said to be "missing" for 24/25 males and for 35/38 females. Among the other tissues "missing" with somewhat lesser frequency but still in substantial proportions are the thymus, the skin, the parathyroid gland, the thyroid gland, the nodes, etc., all of which were originally signalled by the registrants to have been examined for absolutely or virtually every animal in the study. Despite this problem as well as the one with tissue examination discussed in the section pertaining to the mouse study carried out at the same institution as the rat study dealt with here, no audit of the original laboratory records was carried out of either study and, as far as I know, there are at present no plans for this in the future. As far as observed "non-oncogenic effects" go, the Assessment lists as merely "relevant" hepatocyte hypertrophy and a focal disturbance in the growth pattern of the thyroid gland's follicular cells. The mere wording of this latter change, would make me highly suspicious that perhaps a neoplastic process in the thyroid gland is being disguised or camouflaged here. Accordingly, I would recommend that sections of these tissues from all animals in this study be reviewed by our own pathologists on a first-hand basis. 99-1- 10 34 The Assessment gives no details on the incidences or significance of the trends in the case of these two changes. For both sexes, I obtain the following:? For periacinar hepatic hypertrophy mgm/kgm/day observed result_ trend or slope 0.001.771 0 6/120 5.00% standard error of Slope 0.000.158,l 10 6/120 5.00% chi square for slope 99.800 50 - 21/120 17.50% prob. of chi square above 250 59/120 49.17% chi square for lin. dep. 1.213 (two deg. of freedom) prob. of chi square above 0.545 For the thyroid gland lesion mgm/kgm/day observed result trend or slope 0 3/120 2.50% standard error of slope 0.000,106,3 10 3/120 2.50% chi square for slope 10.727 50 9/120 7.50% prob. of chi square above 0.000.528 250 14/120 11.67% chi square for lin. dep. 1.7138 (two deg. of freedom) prob. of chi square above 0.424 As far as the results on frank tumor-induction potential of the agent on test as revealed in this particular study are concerned I find the Toxicology Branch review of March the 3rd 1982 as being utterly unsatisfactory:? the tables on its (un- numbered) pages 8 and 9 have reference only to the total number of neoplasms found in each group and not at all to the number of tumor?bearing animals. Not only is the author of that review the very same individual who seriously bungled the review of another carcinogenesis study on this -agent two years ago (see my oWn review of 1/19/81) but it is worth noting that this serious blunder was not detected by either author of the Assessment (the first and second? level r? supervisors of that reviewer) who had approved and forwarded that review for action to the Registration Division. . . .4 . . '19 - 35 The Assessment mentions that "none of the tumor types observed in this study were considered by.Toxicology Branch to be related to or attributable to the ingestion of Permethrin". This despite the fact that even the inadequate review that was carried out in the Toxicology Branch mentions seven males with malignant noted amongst the 120 animals at the two top exposure levels versus none in the remaining 120 males in this experiment. This contrast is significant at the 0.007.141 probability level. Yet, strangely, the reviewer concludes:? "The development of malignant in males is not considered to be related to ingestion of the test chemical." I wonder by just what kind of mental process (if one can call it that) he had arrived at this particular judgment. - 36 SUMMARY OF THE REMARKS ON THE INDIVIDUAL STUDIES The foregoing comments can be conveniently summarized at this point in the following outline fashion:? (in the table below some of the probabilities given in the foregoing test appear in parentheses) Inadequate Review and Evaluation by Toxicology Branch: Problems with the Conduct of Study 1. Audits carried out and serious problems demonstrated:? 2. Audits not carried out, but problems likely exist:- 3. Insufficient levels of exposure 4. Excessive control incidence of tumors Possible pre?neoplastic lesions l. adenomatosis of the lung females (0.001,58) females (0.000,186) males (0.020,07) both Sexes (0.000,029,56) 2. multifocal hepatocytomegaly females (0.001,03) (0.000,302) males both sexes (0.010.59 - 0.000.001) Experimental animal and section where 1. CR SPF Wistar rat Charles River mouse Charles River mouse Long?Evans rat Alderly Park mouse CFLP mouse CR SPF Wistar rat Long-Evans rat Long?Evans rat Charles River mouse CFLP mouse CFLP mouse CFLP mouse Charles River mouse Charles River mouse Charles River mouse (9). (Of 37 Benign tumors 1. primary pulmonary females (0.000.189) males (0.010.53) females (0.000,079,36) both sexes (0.004,43) 2. primary hepatic males (0.0ll,37) females Charles River mouse both sexes (0.000,000,005,15) Rare or Unusual Benign Tumors l. ganglioneuroma both sexes (0.015.34) 2. adrenal cortical adenoma females (0.030,2) 3. glial tumors males (0.044,59) 4. meningiomas both sexes (0.018,36) Lesions which on further examination by our own pathologists may turn out to represent rare or unusual benign tumors. Focal disturbance in growth of follicular cells of the thyroid gland both sexes (0.000,528) Charles River mouse Alderly Park mouse CFLP mouse Alderly Park mouse Charles River mouse Charles River mouse Long?Evans SPF Wistar SPF Wistar SPF Wistar CR SPF Wistar rat rat rat rat rat (C) (C) (C) 38 Experimental animal and section where discussed G. Benign and malignant tumors primary pulmonary females (0.000.000.351- Charles River mouse both sexes (0.003.55) (clarification needed - see text) Alderly Park mouse H. Rare or unusual benign and malignant tumors keratinizing tumors (see text for discussion) both sexes (0.001.26) SPF Wistar rat I. Malignant tumors 1. Malignancies in general females (03006.51) Charles Riuer mouse 2. Reticulo-endothelial malignancies females (0.010.78) Charles River mouse males (0.007.141) CR SPF Wistar rat 3. primary pulmonary females (0.007,07) Charles River mouse females (0.044,26 0.013,09) CFLP mouse J. Rare or unusual malignant tumors 1. sarcomas of undifferentiated cell type both sexes (0.036.54) Charles River mouse 2. malignant keratoacanthoma both sexes (0.015.34) Long?Evans rat 3. malignant mixed kidney tumor both sexes (0.015.34) Long-Evans rat .. (C) 39 PoSsible acCeleration of latent period {reduced time to death of tumor-bearing animals) males (0.004,20) SPF Wistar rat Increase in malignancy status of tumors for tumor-bearing animals males (0.064,8) boderline signific. Long-Evans rat The summary above readily reveals that, from amongst the seven studies discussed here, one has not been satisfactorily reviewed, and each of the three that were carried out in this country and were audited at least to some extent has revealed . serious problems with its execution. No audits of any kind were - carried out for any of the four studies conducted in the U.K., even though problems in execution or reporting of the findings are likely to be present in at least three of those four studies. Moreover, problems in the design and choice of experimental animals are evident for at least one of the seven studies. Possible pre-neoplastic lesions in the lung were noted in two separate strains of mouse (both sexes for one of them) and in the liver for both sexes of one strain of mouse. Benign tumors were observed for each of the three species of mouse tested as well as for each of the twO?studies of rats which were satisfactorily reviewed; these included lung, liver and mammary gland tumors as well as certain "rare or unusual" types of the central nervous system, of the meninges, of the adrenal cortex and of the ganglia. Keratinizing tumors of various types including malignant varieties were observed in both separate strains of rats. Each of the two sexes of both mice and rats exhibited some of these tumor types. Malignant tumors were manifested either by males or by females exposed mice and rats and, as in the case of the merely benign tumors, they also included certain "rare or unusual" types such as undifferentiated sarcomas, mixed tumors of the kidney, and keratoacanthomas. Most of the increased incidences in tumors amongst exposed animals by comparison with control incidences were shown to be associated with highly significant dose-response trends, in some cases such significance being extremely high. In view of all this, I would conclude that none of these seven studies can be regarded as having established that permethrin is "safe" from a carcinogenesis point of view in a reliable fashion; moreover, it can be said that for all the faults noted merely so far with these studies, the evidence is overwhelming that permethrin has a marked tumor?inducing or carcinogenic activity which is expressed in many different forms. 40 OTHER FALSE AND MISLEADING STATEMENTS MADE IN THE ASSESSMENT So far we have examined a number of false or misleading assertions made merely through page 7 of the Assessment; given the summary of the tumor findings presented in the previous section here, we are now in a position to identify a number of other such false or misleading state- ments in the Assessment:- a) page 11, paragraph 2, line "In the ICI study, a slight - (nonsignificant) increased incidence of lung adenomas was observed in male mice." I b) line "Only females of the Charles River strain (FMC II study) showed evidence of lung and liver oncogenicity apparently due to Permethrin exposure.? c) paragraph 3, line "0f the three long?term rat studies, the ICI (Wistar strain) and the (Wistar strain) studies revealed no tumors, in either sex, which were considered to be related to or attributable to the ingestion of Permethrin.? d) line "The FMC (Long?Evans strain) study produced evidence suggestive of an oncogenic effect in the lungs of males only." e) paragraph 4, line ?Among the six long?term studies, evidence of Permethrin oncogenicity was observed in the lungs and liver of only one sex of one strain of mouse." f) page 12, paragraph 1, line "With the exception of a marginal effect in males in the ICI study, increased incidences of lung tumors were observed only in females (mice)." a 9) line "An increase in the number of . hepatomas was confined to females in the FMC Mouse II study." page 12, page 13, page 18, paragraph paragraph paragraph paragraph paragraph paragraph paragraph paragraph paragraph paragraph line line line line line line line line line line 41 14:? "Other types of tumors observed in either sex in the three mouse studies were not attributed to ingestion of Permethrin." "No tumors considered to be related to the ingestion of Permethrin were observed in the ICI or B-W Rat Studies." ?Rare or unusual tumors were not observed in any of the mouse or rat long?term studies." "Only the 750 mg/kg/day level females (in the FMC Mouse II study) exhibited a significantly increased lung carcinoma incidence relatively to the control females." 'Histopathological evidence for increased (incidence of) malignant lung tumors was observed in only one sex in one of six mouse and rat studies.? "In the ICI mouse study, no substantive evidence was developed which could be interpreted as a dose-response relationship for lung adenomas in either sex." "No dose?response relationships for tumors were observed in either sex in any of the long- term rat studies.? dose-related response for tumors was established only for female mice in the FMC Mouse II Study." "In the 3 long-term mouse studies, evidence of oncogenicity was observed in the lungs and liver of only one sex (female) of one strain (Charles River of mice." "There was no increased incidence of rare or unusual tumors in the mouse or the rat studies.? 3-1 page 18, paragraph 6, page 19, paragraph 1, paragraph 4: page 14, paragraph 2, page 20, paragraph 1, page 21, paragraph 2, line line line line line line line 42 "An increase in (the incidence of) malignant lung tumors was evident in only one of six long?term mouse and rat studies." ?Dose-related responses for tumors was (sic) established only for female mice in the FMC Mouse II Study." dose levels above 250 mg/kg/day for a lifetime, Permethrin exhibits a low oncogenicity potential in female mice." ?This potential is not supported by the other two long-term rat studies at dosage levels as high as 125 and 250 mg/kg/day." observed only in female mice in the FMC Mouse II "Among six long-term mouse and rat studies, an increase in (incidence of) malignant lung tumors was not evident except in one sex (female) in the Charles River mouse strain used in the FMC Mouse II Study." evidence only at high dose levels for one sex in one mouse study among three 43 THE RATHER ODD INTERPRETATION AND EVALUATION MADE IN THE ASSESSMENT. Note the highly peculiar form of expressing most of the false and misleading conclusions which nearly exhaust the alphabet in the previous section:? their clear implication is that either a particular observation was not made at all items made, what the Assessment seems to stress is that such observation was not replicated for the other sex, strains, species, or studies, as denoted in most other items on that list. Not only are the stated "facts? in the Assessment false in themselves, but this entire manner of thinking by its authors strikes me as denoting some kind of abberation in judgment. It implies that a carcinogen must necessarily induce the same kind of tumor of the same malignancy status in each sex for a variety of studies carried out with highly variable circumstance:- different species, different strains of animals, different susceptbilities, different levelsfof exposure, different environmental factors, different examining pathologists and different qualities in the execution of such studies. It follows therefore, according to this stran thought process, that unless a certain statistically significant observation (whose probability is seldom, if ever, specified in the Assessment) is seen with a measure of generality in widely different kinds of situations, it can be dismissed in importance since it can be regarded as being little more than a quirk or a "random event?. This kind of distorted analysis is predicated on the "averaging out" theory of observations; under this rather odd philosophy, if one contrasts such observation with a sufficiently large number of alternate observations, the net effect of the latter is to "cancel out" or "neutralize" the former. What the authors of this Assessment apparently fail to realize is that the only way a certain observation (such as an increased incidence of a particular tumor in exposed animals of one sex of a given strain of a given species, which has a certain statistical significance, say, 0.01) can be "neutralized", as it were, is for a totally comparable alternate experiment of equal quality and equal circumstance to demonstrate precisely the opposite:- that the identical tumor type in exposed animals of the same sex, strains, species, etc., is being inhibited by comparison with the control incidence and that the significance of the latter observation is at least 0.01. If one cannot demonstrate such ?inhibition? in alternate identical studies, these must be taken as having failed to confirm the original observation and thus they are to be regarded as being merely "inconclusive" or ?less conclusive" in that particular respect. 44 The next question is:- how many perfectly inconclusive studies would be necessary to ?cancel out" the highly significant findings arising from a single such study? To answer this kind of question, the following hypothetical exercise may be illuminating:? If a certain finding in some experiment of a given size was found to have a one-sided probability of 0.000,001 it is of very high or extreme significance) and we wish to be no more than 90% certain that such significance would decrease merely to the 0.05 one-sided probability level, how many perfectly inconclusive experiments of identical circumstance and size would be necessary in order to achieve such aim? Six such experiments? Sixty, perhaps? No; the answer which can be given by strict calculation is:- no less than 167 such experiments. It follows, therefore, that the apparent effort by the authors of this Assessment to downgrade or minimize the impact of whatever was observed to occur with high, very high, or extreme significance in any given study through their emphasizing ad nauseam that such observation was not replicated in any (or, at most, in a few) of the other studies, is probably calculated to impress the uninitiated and the gullible. If they actually believe in this kind of fallacy themselves, it seems to me that they have to travel a long road ahead of them before they can be thought of as being truly responsible in an area of science. If, on the other hand, they do not in fact believe this kind of nonsense themselves, but they merely attempt to peddle it to others as a matter of their own personal convenience, words would fail me to properly describe this kind of attitude. Aside from all this, the Assessment also contains in its "discussion" part several irrelevances:? a) The matter of mutagenicity (discussed on page 14 there) is out of place in this "document" entitled "Chronic and Oncogenic Effects" since mutagenicity does not represent either one of these. Furthermore, it is totally unclear whether the various tests comprising the "battery'I referred to in the Assessment can be considered as being mutually independent or uncorrelated with each other. If they are not, what precisely is the strength of such correlation? b) The so-called "historical control incidence data" discussed in the bottom half of page 14 of the Assessment followed by extensive tables on pages, 15 and 16 there, has reference largely to inbred strains of mice. Since no such mice were used in any of the studies referred to herewhich such estimates can be put by reference to our specific problem. Much the same goes for the table on page 17 of the Assessment which refers to Osborne-Mendel rats, again, not a strain used in any of the studies that concern us here. d9" 45 I regret to see that "Toxicology Branch recognizes some merit in this point of view" (page 18, paragraph 1 of the Assessment) such point of View having been made in the preceding sentence there:? possibility that these tumors may not be directly related to the ingestion of Permethrin, but, rather, may simply be an expression of the variability of the spontaneous and naturally occurring incidence of this lesion in mice." This particular "point of view" is another one of those with a familiar ring to it, its having been expressed repeatedly by those not altogether disinterested parties here, the registrants for permethrin. What such argument totally fails to consider is that any situation where a highly significant increased incidence of some tumor in exposed animals by comparison with unexposed ones, cannot be viewed as being due to some agent other than the one on test, and it cannot be viewed as merely an expression of the variability of the naturally occurring incidence of that tumor, or else the entire edifice of the theory of experimentation collapses into a shambles and we experience a return to the days of the jungle. This is to say nothing of such important aspects in the "historical" series in the'Assessment on which details are not given:? the duration of the observation period, the conditio?s of experimentation such as housing of the animals, their diet, state of health, their handling,?the competence of the ?observers", the uniformity of pathology criteria in the classification of tumors, etc., etc. 0) Section VI beginning on the second half of page 19 of the Assessment deals with three systems of ranking carcinogens:- the World Health Organization's International Agency for Research on Cancer's (IARC's), that of Weissburger and Williams' and that of Dr. Robert Squire's. I find each of these as being irrelevant with reference to our basic question here:? should permethrin, a specific chemical, be registered for use as a pesticide product for a variety of crops and should tolerances be established on raw agricultural commodities and on food or feed additives? What each of those three systems seem to have in common is a desire to rank carcinogens in a relative or mutual manner. Thus, if the regulatory action confronting us were, say, to remove from the environment a number of carcinogens now established in it, it would make sense to give priority to those agents for which evidence for carcinogenicity is "sufficient" before tackling those for which such evidence is merely "limited" (the IARC system), or give priority to the "genotoxic" over the "epigenetic" ones (the Weissburger and Williams system), or to those in Class I or II over those in lower classes (the.Squire system). As far as I know, permethrin is not now on any RPAR list and, therefore, it need not "compete" for resources in its being "removed from the environment". To my knowledge, it-is not registered for a great variety of crops and the real action before us seems to me to be not so much its "removal from the environment" as its widespread "introduction into the environment". Q. . 46 Even if all the three schemes for classification or ordering the evidence for carcinogenicity which were mentioned in the Assessment were relevant to the problem before us at this time, the actual classification of the evidence for permethrin arrived at by the authors of the Assessment would still be improper. For example, evidence which the IARC considers as "sufficient" (as distinct from ?limited") is quoted in the last paragraph of page 19 of the Assessment (the word "precocity" is misspelled there). If one were to address all the relevant facts arising out of the seven studies discussEd_here, it is clear that an increased incidence of malignant tumors in more than one species and strain of experimental animals was observed to an unusual degree with regard to incidence, site, and type, (possibly even with precocity of onset). What all this spells to me is that the evidence for permethrin being a potential carcinogen for humans is at least "sufficient" in IARC's terms. If the same facts, rather than those "filtered" by the Assessment, were to be cranked into Squire's scheme, would permethrin still emerge as a member of Class V, as indicated at the bottom of page 21 of the Assessment? With reference to Weissburger and Williams' system, which depends on evidence of the direct interaction of the carcinogen with the genetic material there is reference to the results of mutagenicity or to the so-called "short-term" tests) the IARC reference cited in the Assessment states on its page 19, paragraph "Negative results from short-term tests cannot be considered sufficient evidence to rule out carcinogenicity. Whether short-term tests will eventually be as reliable as long- term tests in predicting carcinogenicity in humans will depend on further demonstrations of consistency with long-term experiments and with data from humans." This statement was not deemed to be quotable in the Assessment. Finally, we have on the last page of the Assessment the ultimate fast shuffle by its authors:- ?The weight of scientific biological evidence produced by six long-term mouse and rat studies plus the use of three oncogenicity ranking and classification systems lead the Toxicology Branch to conclude that Permethrin's potential for induction of oncogenicity in experimental animals is Note that none of the "three oncogenicity ranking and classification systems" mentioned here have anything to do with the "potential" of any given agent to induce cancer in humans; furthermore, none of these systems is'concerned with classifying such potential as "weak", "strong', l'middling", or by any other such qualification. The IARC system makes an explicit point of this (paragraph 2 on page 19 of the reference cited):- tol' 47 "Some chemicals for which there is limited evidence of carcinOgenicity in animals have also been studied in humans with, in general, inconclusive results. While such chemicals may indeed be carcinogenic to humans, more experimental and epidemiological investigation is required." l?Hence sufficient evidence of carcinogenicity and limited evidence of carcinogenicity do not indicate categories of chemical the inherent definitions of these terms indicate varying degrees of experimental evidence, which may change if and when new data on the chemicals become available. The main drawback to any rigid classification of chemicals with regard to their carcinogenic capacity is the as yet incomplete knowledge on the mechanism(s) of carcinogenesis.? Similarly, Squire's system does not refer at all to "weak" or "strong" potentials and neither does the Weissburger and Williams cla351f1catio . At the risk of sounding redundant here, I would stress again that what all of these systems seem to be classifying is the evidence for carcinogenic activity rather than the potential for it. What then precisely would "lead the Toxicology Branch to conclude that the potential for induction of oncogenicity in experiemtnal animals is weak"? And, furthermore, "weak" by reference to what? To aflatoxin? Vinyl chloride, perhaps? Are any of these ?strong? carcinogens registered pesticide products? Or is the carcinogenic potential of permethrin "weak" by comparison with that of aldrin, dieldrin, mirex, chlordane, heptachlor, etc., all of which had been cancelled or suspended by this Agency some time ago? Do the laws that we are supposed to enforce have any reference to "weak'I carcinogens and, if so, do they specify how these ought to be handled? Lastly, even if we were to concede that the potential for tumor-induction by permethrin in experimental animals were "weak" (and, I hope it is clear that I am not inclined to grant such concession) from what precisely does it follow, as the Assessment has it in line 6 of its page 22, that risk of human oncogenic effects resulting from exposure to low levels of Permethrin is non existent or extremely low"? How low, precisely? 1" 48 RECOMMENDATIONS 1) By reference to the many false and misleading statements of facts made in it and by virtue of the faulty logic involved in interpreting such facts, I would recommend that the Paynter- Budd Assessment be set aside; it does not seem to have been carried out with acceptable scientific objectivity and integrity and it represents work of a standard far below what the American public has every right to expect from its civil servants. 2) By reference to the facts and summary made in the preceding text here, I would recommend that permethrin be regarded as a remarkably clear tumor?inducer or carcinogen, since the evidence for this is not only "sufficient" (in the IARC sense) but overwhelming; in view of this. I would also recommend that this agent be placed on the RPAR list for eventual cancellation or suspension. 3) I would recommend that pending the outcome of such RPAR proceedings, no further exemptions under Section 18 be granted unless adequate risk analyses are made and such exemptions are justified in the usual manner. 4) If such action is contemplated for the future. in order to carry out meaningful risk analyses, it is necessary that intensive data audits of the results accruing from these studies be commenced. 5) I would also recommend that Toxicology Branch carry out acceptable reviews and evaluations of all reports submitted by the regulated industry in support of sEfEty for this particular pesticide product. - to Kevin Keaney, Office of Pesticide Programs, cogv Jay Ellenberger, isrration Division Reg . MAR 2 1% ?rm M. Adrian cross, BUD, OPP: subj.:- Cxamvl (EI duPont de Nemours) Reg. No. 352-372 PP No. 1F2448 Accessionxo. 070136-143 Bac ground . (31 April the; 24th last year I wrote vou cm the difficulty with the "cut-and-paSte? reviews in the Hazard Evaluation Divi sion: the specific problem discussed at that time was malathion which had ?oeen signalled by Battelle as having been a case where copies veroatim registrant's Simmer-y (pp lC-ll fiche). There is no evidence of an independent analysis of the document. whi ch contains highly suggestive evidence of a dose- related carcinogenic This matter was referred to a "Ravi ew Group" oontai ping amongst its manners two former chiefs of the Branch: this strikes me as being rather odd:- after all, Battelle was actually retained by OPP at a considerable cost to conduct an investigation into this matter wi th rm "cut-and-paszze" reviews originating in the Toxi oology Branch: to have the final report of that organization "evaluated", as it were. for its merits by the very people who constituted the target of such investigation does not seem to me to indicative of any serious concern here that potential- ly toxic pesticide products may not have been regulated in the optimal manner as a result of those "cut-and-paste" reviews. If indeed there were such concern in the Office of Pesticide Programs, I should thi nk that at least the followirg should have happened:- a) The results of the Battelle investigation their final and detailed report) should have been referred for an assessment of its merits to a group which would not have a bui lt?in conflict of interests in this area: the actual "Peview Group" which was appointed for this purpose could have been expecred to weigh in with merits which were self?serving and whose main purpose was to cover-up the initial failure in that ciranczh to do the job that one mould expect to have been carried out there:- review and evaluate the road ci ty reports emanating ?rm the regulated industry in an independent, adecuate, ogjective, and critical fashion, rather than quote vet-satin an; thout attri outicn or "cut-and-paste" those registrants' own evaluations; o) Inasmuch as Battelle had investigated merely a sample of the reviews emanating from the Hazard Evaluation Division and inasmuch as that very sanpie itself provided ample evidence that this pracri ce of shoddy reviewing was extrenely' pervasive there, I mnpletelv fail to understand (?rm-new 9338540 just why that initial effort was not followed up by a more in?depth or a full account of all pesticide products for which ?cut-and-paste" reviews were carried out: this would have enabled One to determine what precisely had been "missed" as a consequence of such reviews and how would this alter whatever regulatory action was undertaken as a consequence of this kind of failure. The other day I asked Dr. Farber, the new chief of the Toxicology Branch in the Hazard Evaluation Dimsion, what had been done in the way of a follcw-up on this proolem: he replied that, as far as he knew, nothing had been done in this respect and, moreover, he had no plans at all to undertake any kind of follow-up in the future since he believes that this would create too much work for him and for his people there. In that meridian to you of last year that I cited at the beginning here had that the so?called "Regulatory Opinion" reached by the "Itaview Group" that had been appointed to pass on the Battelle findings was not only self-serving bot also totally improper:- rpalathipn in fact manifested highly significant carcinogenic activity in each of three separate bioassays conducted by the National Cancer Insti tute; in other words, the initial review had "missed" this feature, we have here a situation in all respects identi-cal to that which I had initially . brought to light in October, 1982, for harvade, another product altogether. In a memorandun that I wrote to Ed Gray less than a week later, April the 30th, 1984, I had also demonstrated (as illustrated by an entirely di f- ferent pesticide product, metalaxyl, which wasnot part of the initial Battelle "sanple") that when the Hazard Evaluation Division had been expressly and explicitly directed to carry out a full review of the toxicity for that product (following an initial "cut-and-paste" and otherwi se unacceptable review) even then the reviewers there elected to have reference oily to the surmarv prepared by theregistrants rather than address the detailed data contained in the entire report. Pecause of this, a number of important aspecrs tn the safety of metalaxyl were again glossed over. With reference to yet another "cut-and-paste" review for that same product, metalaxyl, - the one-year dog study carried out at International Research and Developnent Corporation - I have no knowledge that this had been re-reviewed by anyone even though I had demonstrated that this too had caused important safety aspects to be similarly 'inissed" by the EPA. Also in that memorandum addressed to Mr. Gray I indicated how a nunber of persons both within the EPA, including the Adninistrator himself, as well as others outside the Agency had been misled on the impact of the unacceptable manner in which health effecua of pesticide products _._are being evaluated in the Hazard Evaluation mvision. We are now almost a year down the road since I wrote those two memoranda in the Spring of last year and yet, unfortunately, we continue to be plagued by this apparently total failure to rectify what had gone wrong here. page three New Information. .Last month I was assigned to a team whose task was to audit a long- term toxicity study of oxemyl in mice. . - The review generated by the Hazard Eyeluadm D1v151cn for that study is reproduced in full tn the right side of the five pages to follow?' immediately here: opposite each such page on the right side I have "cut- and-pasted" on He page facirg it on the _l_eft side excerpts from the registrants' smmary to convey the actual_ source of the reviewer' .ccrm'entsr - . 0% page four -d;l?l AGENCY some eerie: 5F AND from: mm zslea MEMORANDUM DATE: June 13, 1981 SUBJECT: EPA Reg.#3524372; Long Tenn Feeding Study In Mice with Oxamvl CASHEL 5352,! :4 Accession#070136-l43 William Toxicologist Mag ?0 G, Toxicology Branch, HED (TS-759) TU: Jay ELlenberger (12) Registration Division (TS-T67) and Residue Chemistry Branch J?f Hazard Evaluation Divsion (TS-269) Recommendations: 1. Oxamyl was not oncogenic up to 75 in the diet of mice for two years. The study is acceptable as Core-Minimum Data. In- Review: l. Long Tenn Feeding Study in Mice with Oxamyl 77033; 5/29/81) Test Material: Technical grade Oxamyl, H#l0963, 97.l% purity, white powder . 1 Three hundred and twenty Charles River CD-1 mice of each sex were selected for study on the basis of body weight gain and findings observed during the quarantine period. The animals were randomized into four treatment groups according to body weight. The randomization process was done separately for males and Females. The mice were housed individually. Fresh water and Purina Laboratory meal were provided ad libitim throughout the study. .page five The dose levels in the groups were set based upon findings in an eight week range finding study run at report dated 9/27/77. Four groups consi_sting of 88 males and 80 females were established and were as follows: No. of Animals Treatment Group. Dose Level (ppml Hale - Female 100/75* - 80 80 *Uue to the unexpected high mortality rates in the mid- and high- dose groups during the first few_weeks, the 100 group was decreased to 75 on week 6. Also 22 extra mice, not previously selected for the study but from the same shipment were added 11/28-12/9/77 to provide additional mice for long term evaluation: 721 added to group 2 female 11/28/77; 722 added to group 3 male 11/28/77; 723, 724, 725, 726 added to group 3 female 11/28/77; 727, 728, 729 added to group 4 male 11/28/77; 730, 731, .732 added to group 4 female '11/28/77; 733, 734, 735, 736, 737 added to group 4 male 12/6/77; 738, 739, 740 added to group 4 female 12/6/77; 741 added to group 4 female 12/8/77; 742 added to group 4 female'12/9/77. These animal additions were made at the request of the sponsor after consultation with the study director. During the study, all mice were observed twice daily for signs of mortality, toxicity and behavioral changes. All mice were palpated once weekly for the presence of masses. . Any positive findings were recorded as to size, location and appearance. A record was kept on all mice that died or were killed in extremis during the study. Mice which became moribund or had a sudden large weight loss were sacrificed by 602 and necropsied according to- the original protocol. Tissues from animals dying before the end of the study or sacrificed in extremis were preserved for histopathologic examination. gross pathological examination was perfonned and the tissues saved in 10% buffered neutral formalin on all animals that died within the first weeks of dosing. Most of these latter tissues were not evaluated histopathologically as per instruction from the sponsor, since no alterations of a carcinogenic nature were anticipated from such a short exposure to the test diet. A weekly cumulative record of mortality was maintained. - page six -3- Body weights were measured for all mice once weekly during the first six months (weeks 1 through 29), once every week during the second half of the first year (weeks-31 through 53), and then once a month until study termination (weeks 37 through 105). Each time the mice were weighed, the amount of diet consumed by each sex of each group was measured. From these data, food efficiency and average intake of Oxamyl per group was calculated. Ten male and ten female mice randomly selected from each group were bled from the orbital sinus after 1, 3, 6, 12, and l8 months of dosing and prior to tennination of the study. Parameters evaluated were: HBC, RBC, hemoglobin, hematocnit, HCV, MCH, MCHC, complete differential NBC. . . All surviving mice were weighed, sacrificed with ?02 and necropsied on November l4, 15, 15 and 17I 1979 under the supervision of Dr. Fred H. Sigler. The following organs were weighed: liver, kidneys, tests, brain and stem, and heart. The following tissue specimens were taken and fixed in l0 to 20 volumes of 10% buffered neutral-formalin: Brain . - Prostate (Forebrain, midbrain and hindbrainl . -0varies Eyes with contiguous Harderian glands Corpus and cervix uteri Pituitary Spleen salivary glands. nodes Heart Skin Thymus - Sciatic nerve Thyroid (Parathyroid) Mammary gland - Lungs Bone, bone marrow, (2 coronal section with mainstem or tibio-femoral joint bronchi} Muscle Trachea Aorta Esophagus Uterus Stomach *Nasal cavity and paranasal . Intestine, smal and large sinuses Adrenals glands *Spinal cord (2 levels) Pancreas - *Head (3 coronal sections) Liver, 2 lobes . nasopharynx, middle ear, Gall bladder tongue and oral cavity Kidneys *Seminal vesicle Urinary bladder . . Gross lesions (with nonnal Testes, epididymides tissue} Prior to the issuance of the prOposed regulations tissue specimens were collected from animals found dead and sacrificed moribund throughout the study according to the above list expect for the tissues marked with Some animals died early in the first few weeks of the study and only a gross necrOpsy was perfonned, no tissues were histologically examined (see Mortality section). These mice were 2l0, group 2 male; 346, group 3 male; 489, 556, 495, 514, 503, 510, 500, 481, 547, 492 group 4 male; 269, 308, group 2 female; 438, 409, 436, 410, 443 group 3 female; 570, 606, 624, 626, 616, 600, 738, 592 group 4 female. Also, several mice were judged to be in such an advanced state of autolysis as to preclude histopathologic evaluation. These mice Tere 540, group 4 male; group female: 308, group 2 female; and 564, 583 group 4 female. Many other mice were found to have advanced postmortem autolysis, but it was not extensive enough to preclude a histopathological evaluation. I One mouse (71, group male) was cannibalized (cages used in the study had center dividers and one mouse penetrated the divider and was canninbalized) and one {600, group 4 female) was not necropsied (technician oversight). All other mice placed on the study were examined histologically.l Statistical analyses of the data were perfonned: Results: There was no apparent test material-related.effect on any clinical observations. Tissue masses observed and palpated throughout the study and at tenninati.on were evaluated histopathologically. No apparent - contistent test material-related effect was opted. Group 4 males mean food consumption was significantly less than that of the control, group 1, males for weeks ll through 84 with the exception of weeks l2 and 19. From week 88 through the end of the study there was no significant difference. No pattern was shown throughout the study for the other test groups 2 and 3 males and 2, 3, and 4 females. page eight The mean body weights for group 3 males were significantly less than those of the control from weeks l-al. The mean body weights for group 4 males were-significantly less than those of the controls from weeks 2-43 and were variable thereafter to the end of the studys There was no significant difference throughout the remainder of the study. The mean body weights for group 3 or 4 females were variably significantly-different during the first 21 weeks of study, but were only sporadically,significantly different after week 21. No other consistent pattern was noted.in any of the treated groups compared to the controls throughout the remainder of the study. - No consistent test material related effects were noted in the body weight of the treatment groups compared to that of the controls after the first 81 weeks of the study. The cumulative life graph data reflected the early mortalities. These deaths appeared to be related to the acute toxic effect of the test material in the diet mixture. Subsequently, life table analysis indicated no further increased mortality due to Oxamyl occurred during the remainder of the study. Sporadic significant differences in hematology parameters were noted throughout the study. These changes are suggestive of a compound related effect upon red cell mass in group 4 males early in the study week 4 but this did not persist, There was a slight decrease in absolute weight of the liver in group 3 males and a slight increase of the'hrgan to body weight ratios of the kidney for group 4 males. Based on the absence of histological findings, these effects are not considered significant. No significant histopathological changes were noted for the test groups when compared to those of the controls except that the chronic interstitial nephritis of the kidney was significantly less for the test groups (group 2, 3 and 4), males, compared to that of the Controls. Oxamyl was not oncogenic at any level tested. Conclusion: Oxamyl was not oncogenic at dietary levels up to 75 ppm. Classification} Core-Minimum Data page nine There is a surprising similarity between what is stated (tn the left side of the five foregoing pages) by the registrants in the surmary of their report with what are allegedly the ''independent" assessments of the Hazard Evaluation Division reviewer (given :11 the right side pages). Quite apart fron this feature, one may also note the following:- a) The registrants' report is of a total of 2,347 pages: yet the entire review originating in the Hazard Evaluation Divisicn has reference to what is gesented merely in the first pages of that report and to nothing else: it appears to me that the balance of 2,333 pages were not even cracked for a mere cursory examination by that reviewer. b) The initial page of that review (page 4 in this communication) reveals that its author in the Hazard Evaluatim Division saw ?t to initial for the signature of his own SectionSupervisor, perhaps in an attempt to circumvent the latter's possible finding that this was merely a "cut-and-paste" job. Also, although that review is dated June the 18th, 1981, (a date also found on its very last line) it was not until the next day when the reviewer apparently had decided to append his own initials for those of his supervisor. Four additional days seemingly elapsed before the entire docunent was stamped with the d_ate June the 23rd, 1981, perhaps to indicate that it took as long for this review to have 'ripened" in the Hazard Evaluation Division or to have been "approved"' by the Toxicology Branch Chief or theDirector of that Division, even though ?there is no evidence that any of these actually'saw it and agreed with its contents. It may also be pertinent to add here that the reviewer of record here is by no means some kind of neophyte or a recently recruited employee who may not be familiar with the way things ought be done. I am informed that he is a Toxi oologist, that he had recently been promoted to a grade level (a category denoting an "expert") and that he had recently been recognized as having performed in an "outstanding" fashicn for having a demonstrated unusual efficiency in Carrying out reviews of this sort. It is small wonder that by having reference to less than 1/100-th of the material in a toxicity report and, additionally, by helping himself to or appropriating the registrant's views and representing these as his own, he can be very efficient indeed, in that he took but a few minutes to do what it may take others hours, days, weeks, etc. This is to say nothing of the time that he had ?saved" his supervisors at three different levels to oversee the quality of this work. c) That particular mouse study with oxamyl had been signalled by Battelle to have been subjected to a "cut-and?paste" review. I an appen- -ding here= as Attachment 1 a otmmunication addressed to Douglas D. Campt, Director of the Registration Divisim of February the 3rd, 1984, which carries the signature of William L. Burnam of the Toxicology Branch, Hazard Evaluation Division and that of John W. Malone, me Director of that same Division which presents the Battelle cmments (allegedly, verbatim). In that same oommnicatim we also read under "Review Group's contents" that there was "an independent evaluation" by "the initial TOX page ten Branch review? (presumably ?ndependent' of that of the registrants) and that the 'evidence' for this was the fact that the review in question "included an analysis of the lung tunor data and noted no pesticide-related effects?. I have reproduced that review 'in toto' here cn pages 4 through 8 in this cormmicaticn. If anyone can denonstrate to me exactly where in that review there is any reference whatsoever to lung tutors. I would be willing not to characterize that assertion as a fabri cation out of whole cloth. as E?Erazen and total falsehood. Its mly purpose cannot be bit to save enbarassment for the Hazard Evaluation Divisim, even at the risk of misleading Mr. Canpt of the Registration Division. the person who would have the ultimate responsibility for serting a tolerance for this pesticide product. The risks to the consumers of this country apparently can be disregarded in this entirely wanttn and reckless manner, so long that no one in the Hazard Evaluation Division can be thought of as having acted in an improper way, and it seeningly does not matter even if it takes out-- right lies to achieve that end. Was Mr. Canpt in fact misled in this respect Appended here as Attachment 2 is the official document puoli shed in the Federal Regisrer which bears his signature and the date December the 4th. 1984. In the last paragraph of its semnd page we read:- l'I?he data submitted in the peti ticn and all other relevant material have been evaluated. The toxicological data considered in support of the tolerance included a mouse cncogenicity study which was negative up to 75 for 2 years.? This is reminiscent of what there is in the review originating from the Hazard Evaluation Division:-- "Oxamyl was not cncogenic at dietary levels up to 75 pm" under ?Rememdations? (first line of the review} . "Oxamyl was not cncogenic at any level tested (last line mfore 'tmclusims"), "Ora- was not cncogenic at dietary levels up to 75 ppn", the sun total of the "Conclusions" themselves. . This is by no means the first time Mr. Campt had been misled in; Mr. Melons, the Director of that Divisicn on the safety of a pesticide. Ch August 151:. 1983, I more to Mr. Campt a detailed memorandum indicating a similar such situation for the insecticide permethrin; unfortunately, he had not seen fit to even receipt of that oormunication of mine. I do not know to what extent the other studies mentioned in the - Federal Register statement of December, 1984, are justified in the sense of their having been based on reviews other than of the "cut-and-paste? type or, even if they were not of this variety, they were in fact reliable such reviews: I have not examined those reviews and, therefore, I shall have no further reference to them here. Rather, for the balance of the present communication. I shall limit my remarks merely to the 2-year mouse study with oxamyl, and, more: speci fically, I shall discuss only two aspects of it: did the reviewer indeed have reference to more than the initial 14 pages of the regi strants' report on that study, did he in fact make here a review wni ch was truly "i ndependent" of the evaluations reached by up page eleven the registrants and what are some of the examples on. what was "missed? in that evaluation. . . -. If, indeed, as the Burnam-Melcne communication to Campt given here in Attachment 1 states, the reviewer had in fact addressed the lung tuncrs noted in the mice in this study, he cpuild not have failed to notice that three of the females at the high level of exposure, Nos. 585, 612, and 587, presented grossly visible "nodules? in the lung which'could have turned out to be in Eacr pulmonary tumors, either benign or malignant and either ark 2 primary or netaStatic to the lung; in fact, however, those grossly-obser- ?mired lesions were not confirmed as being either tumors or any other kind of abnonnali ty during the microscopic examination of those particular lung sections. This is not sonathirg that was discovered by me as a consequence of exanining any "internal regards" maintained by the laboratory that executed the study: rather, it is present in the final report submitted by the registrants to the EPA which, presu'nahly, was available for the examination of the Hazard Evaluation Divisicn reviewer, had he in fact elected to merely glance at what is beyond the ?rst 14 pages of that report. . gr 3, Furthermore, and of far greater had the reviewer in fact examined the individual pathology reports of the. test animals beyond those initial 14 pages of the report, particularly with reference to the lung tunor data, he could not have concluded that, in the words of Burma- Melone, there are "no pesticide-related effects attaching to those lung tumor data: 'rather, he could have found what I did, in that same final report available for his revie The fanale animals with pt?monary adencma were Nos.:- 640, 724, 315, 155, 310, 448 (dead on 8/31/79), 634, 428, 307 (dead on 6/17/79), 302 (dead on 10/12/79), 423, 632, 628, 422, 297, 82, 637, 295, 413, 619 (dead on - 9/25/79), 288, 283, 605, 577 (dead C11 10/24/79), 572,267, 266,? 568, 566, 263, 639, 259', 116, and 561. In addition to those animals, Nos. 419 (dead on 8/3/79), 599 (dead on 3/16/79) and 586 (dead on 5/6/79) manifested malignant tuners primary in the lung, pulmonary adenocarci names. I The distribution of those animals amongst the various experimental groups (even if one were to ignore the three animals at the high level of exposure wi th grossly visible lesions suggestive of pulmonary tumors tut which here unconfirmed histopathologically) is such as to yield the fella-ling:- a) For merely the malignant primary pulmonary tunors and taking as the data base all females with lung sections examined microscopically, there is a dose-response lep-e of 0.000,365 with standard error 0.000.,197, yielding a chi square with one degree of freedcm of 3.407 whose one-sided probability is only 0.032 and which is consistent with linearity (chi square with two degrees of freedom of 0.442 whose two-sided probability is as high as 0.802): . page twelve b) For all pulmonary tunors primary in the lung regardless of their malignancy status and taking as the data base the same as in above. we have a dose-response slope of 0.001.65 with standard error of only 0.000.698. yielding a chi square with the degree of: freedom as high as 5.601. whose one-sided probability is only 0.008,97 and which is also consistent with linearity (chi square with two degrees of Ereedon of 4.074 whose tin-sided probability is as high as 0.130). For merely the low level of exposure the probability for the increased incidence of such tumors over the control rate is 0.011.01 4- 0.002.21 a 0.013,5 and fo: the high level it is 0.00151 0.000.22 0.000.02 0.000.00 0.001.753 c) As in above but taking as the data?beseuoilyghose Eenales whim coupleted the full exposure period. there is a dose-response slope of 0.002.300 with standard error of only 0.001.500, yielding a chi square with one degree of freedcm as high as 3.483 whose one-sided probability is as low as 0.031 and which is ccnsistent with linearity (cni square with on degrees of freedom of only 3.307, whose mas-sided probability is as high as 0.l91. For merely the low level of exposure the probability for the increased incidence of such tunors over the control rate is 0.025,0l 0.005.12 0.00059 0.000.03 0.030.75 and for the high level it is 0.006.83 0.001.01 0.000.09 0.000.00 0.007.93. This indicates that no matter how one analyzes the data on pulmonary tumors as a whole, or merely those 01 the malignant such tumors, we have here a highly signi?cant dose-related increase in incidence amongst exposed animals by conparism with the unexposed control animals. I should think this mnclusively and beyond any doubt whatsoever that not only was it not true. as Burnett-mime stated. that the initial review made in the Hazard Evaluation Division "included an analysis of the lung tuna- data" but it was also net true for than to imply that there are "no pesticide?related effects" related to those data. Conse- quently, their "evidence" such as this is in reality no evidence whatsoever for what they attempt to wnvey to Mr. Campt that there was an "independent evaluation" made here by the reviewer in their Division. Actually, if the is concerned with "evidence" in this respect, as Messrs. Burnt-m and Malone appear to be, there is additional evidence that in fact there was here no evaluation whatsoever which can be thought of as having been ?independent" of that made by the registrants. For example:- Note in the last paragraph before the ?Conclusion" on the last page of the review emanating the Hazard Evaluation Division (page 8 here) that "No significant histopathological changes were noted for the test groups when compared to those of the controls except that the chronic interstitial nephritis of the Kidney was significantly less for the test groups (group 2, 3, and 4) males. conpared to that of the controls." Had the reviewer ash less eager to call attention merely to what lesions were significantly less for the test groups, regurgitate page thirteen merely the resi strants' om evaluation, but instead made an effort to find out what lesicns in that very same organ. the kidney, were significantly increased in incidence amongst the exposed animals over their unexposed fellows (which would denote at least scme degree of concern on his part with the public health of those hunans exposed to this particular pesticide product) he mild have made at least a gesture towards examining this toxicity report bayond page 14. Had he in fact dme so. he have discovered that the distribution of male animals with glanerulosclerosis in the kidneys is associated with a dose-reapcnse slope of 0.001.458 with standard error of mly 0.000.642, yielding a chi square with one degree of freedom as high as 5.108 whose one-sided probability is as low as 0.012 and which was not inconsistent with linearity (chi square with two degrees of freedcm of only 1.876 whose two-sided probability is as high as? 0.391). As in the case of the pulmonary tumors amongst the fenale animals discussed above, this also indicates that a NOEL was not established in this study. Another example In the paragraph of the review made in the Hazard azaluaticn Division just prior to the one cited above. as find yet anotl?er untruth referable to the fact that the reviewer did not see fit to evaluate by himself the actual data submitted by the registrants in this report but. instead. chose to copy their own misleading evaluations. We ?nd there that there was "a slight increase of the organ to body weight ratics of the kidney for group 4 males. Based on the absence of histological ?ndings (in the lddneys of group 4 males. presumably), these effects are not considered signi ficant." What is clearly not true here is multifaceted:- a) "Histological findings" in the kidneys were not only present in those of group 4 males but also in the kidneys of all other male mice in this study; moreover, the increase in incidence of glonerulosclerosis in a dose-related manner was not only highly significant in: it also resulted in a NOEL not having been established in this study, as I demonstrated just above: b) For merely the group 4 males, the incidence of renal glcmerulc? sclerosis was increased from 3.80% in the control males to 14.29%. an almost 4-fold increase, which was significant at the 0.016.618 0.003.561 0.000.457 0.000.025 0.020.663 probability level: c) Even had there been no "histological ?ndings" such as glonerulosclerosis in the kidneys of those male mice, this would not make the increase in the relative weight of the kidney to be "not misidered significant". An increase in relative weight of any organ is a lesim or a manifestation of toxicity in its own right and in no way dependent tn or linked to the presence of other findings. For a toxi to have swallowed without blinking this kind of argument advanced the regis- trants and, moreover. to adopt it as his own, is in itself an eloquent page four teen mani festaticn of the Kind of "expertise" and independent cz- critical judg- ment that we seem to have here. As a matter of fact. the weight of the kidney relative to the body- weight in the male animals of this study manifested a dose-response slope of 0.003.016 with standard error of oily 0.001.117. yielding a value with 132 degrees of freedon as high as 2.701 whose one-sided probability is only 0.003.915 and which was oonsisrent with linearity (F value with 2 and 130 degrees of freedoa as low as 0.981 whose probability is as high as 0.38) and the chi square with two degrees of freedom for the goodness-of-Eit was as low as 0.003 whose two-sided probability is as high as 0.998. In sun. this represents the third aspect listed here which indicates the absence of a demonsrra'ole DUEL in this particular work. mother example The "absolute" (as disrinct tom the 'telative') weight of the Kidney- for the male mice in this study was even more spectacularly and signifi- cantly increased in a dose-related manner. yet this is being glossed over in the review originating fron the Hazard Evaluation Division: this is because the registrants elected not to_highlight this in the ?rst 14 pages of their report and. the EPA reviewer, in turn. chose to ignore everything else in that report. Had he not elected to do so. he could have detemined what I did:- a dose-response slaps of 0.000.752 with standard error of only 0.000.109. yielding a value with 132 degrees of freedcm as extranely high as 6.891 whose one-sided probabi lity is as extremely low as 0.000.000.000.5 and where the goodness-of-fit chi square with two degrees of freedom is as low asa 0.002.8 with a two-sided probability as high as 0.999. This would oonsti tute the fourth aspect listed here which indicates the absence of a demonstrable ROI-3L in this particular study. Still another example:? Yet another feature not addressed in the review originating from the Hazard Evaluation Division (again, probably because it was not addressed by the registrants in the initial pages of their report) is the highly significant slope of the dose-response function pertaining to the relative weight of the liver of the male animals. I found this to be as steep as - 0.015.441 with standard error of only 0.007.776 yielding a value with 132 degrees of freedom of - 1.986 whose one-sided probability is as low as 0.024.6 (0.049.2 two-sided) with insignificant departure from linearity value with 2 and 130 degrees of freedon of only 0.735 whose probability is as high as 0.481) and very good goodness-of?-fit (chi square with two degrees of freedom of 0.054 whose two-sided probability is as high as 0.973). This would be the fifth aspect listed here which indicates the absence of a demonstrable NOEL in this particular work. page E. fteen Although the few hours at my dig-osal to audit the data presented in this particular Study did not allow me to make an exhaustive evaluation of all aspects of toxicity for cucamyl manifested here, nevertheless, what is presented above is sufficient to that the Hazard Evaluation Division had in fact misled Mr. Canpt into stating in the Federal mgister proposal appended here as Attach-rent 2 that the (lowest) NOEL to be established for oxamyl can be derived from the rat study and estimated to be as high as 50 parts per million ?Do appreciate the worth of other estimates given in that same docu- ment, I am presenting below the results of a formal risk assessment made tn the basis of the data presented in iten or second paragraph :11 page 12 here. .. For additional details on this, I have used two separate extrapola- ting procedures:- the Mantel-Bryan approach (also know as the log-probit method) and the "one-hit"I procedure. In each case the maximal estimates of the "virtually safe? dosage or concentratim of oxamyl were provided by the results obtained at the middle level of exposure, and these are the ones tabulated below; for oonversicn of parts per million in the diet to per kgm, body-weight per day, I have used the factors given by the Association - of Food and Rug Of?cials of the United States, as well as the body- surface correction necessary for extrapolating small laboratory . rodents to hunans?; also used here was the Abbott Correction as well as a two-sided confidence interval of 90%. The estimates are given for a wide variety of choices for the upper limiw on the risk in the table following immediately here on the next page:- U'ooer limi on risk: 1/100,000,000 3/100,000,000 1/ 10,000,000 5/ 10,000,000 1/ 1,000,000 5/ 1,000,000 1/ 100,000 5/ 100,000 1/ 10,000 5/ 10,000 1/ 1,000 5/ 1,000 l/ 100 5/ 100 l/ 10 page sixteen OF THE FORMAL RISK ANALYSIS. ?Virtually safe? levels of exam}; expressed in Don MI. 0.000,501 0.000,966 0.001,29 0.002.53 0.003,61 0.007,84 0.0ll,l 0.026,3 0.039,l 0.105 0.166 0.543 0.965 4.63 10.7 one-hi 0.000,001,59 0.000,007,94 0.000,015,9 0.000,079,4 0.000,159 0.001,59- 0.007,94 0.015,9 0.079,4 0.159 0.796 1.60 16.7 I expressed in ugn/kgm/day lg?orobi .0.000,005,2 0.000,010,0 0.000,027,3 0.000,037,6 0.000,081,5 0.000,116 0.000,274 0.000,406 0.001.09 5 0.001,73 0.005,65 i 0.010,0 0.048,2 one-hit 0.000,000,016,5 0.000,000,082,6 0.000,000,165 0.000,000,326 0,000,001,65 0.000,008,26 0.000,082,6 0.000,165 0.000,826 0.001.65 0.008,28 0.016,6 0.084,? Couparing in the table above the estimates expressed in with those expressed im we may note that the latter are smaller than the former by a factor less than 100: bili ty of the estimates dures, as to the compara- generated by each of the two extrapolating proce- we may note that the Che-hit estimates are stellar parable ones generated by the log than the compa? -probit approach for the lower upper limits cm the risk:- thus for an upper limit can the risk of l/100,000,000, they are smaller by a factor in excess of 300; at the very high upper li- mits, the converse situation is true:- the estimates deriving from the one-hit method are larger than those originating from the log-probit method; the two kinds 0 of an upper limi estimates are virtually iden on the risk of circa l/l,000. tics]. in the neigh- page aventeen If we now focus on the new tolerance of oxamyl that had been increased bananas Costa Rica ?rst: 0.1 to 0.3 ppn, (see the proposal published in the Federal Register: and signed by Mr. Campt as given in Attachment 2 here) and assisting further that the pesticide could permeate the entire edible part of the fruit arr! thuscould be found there at a cmcentraticn of 0.3 pgn. we have the following:- Assuming. that merely one middle-size banana heighirg approximately 150 grams is included in the daily diet of an adult hman, such diet having an average weight of approximately 1.500 grams, this would represent the ingestion of l/lO-th of 0.3 ppm. 0.03 ppn. If we look up this value in the table presented on the previous page here, ,we note that it is asso? ciable with an upper limit tn the risk between 5/100,000 and 1/10,000 (log-probit) and between 1/10,000 and 5/10,000 (one-hit). Exact interpola- tion would yield estimates of the upper limit tn the risk ranging Eran ., 6.3/100.000 (log-probit) to (one-hit). as this would not represent an unreascnably high daily consumption rate of bananas. I should think that this kind of risk is perhaps. unacceptably high,- for those whose proportion of the daily diet cut-prised of bananas is higher. and perhaps for some infants. the risks would be correspondingly larger. If we now address Mr. Campt's statemnt that the ADI ft: tunans is calculated to be 0.025 rrg/Pg of body weight (bud/day? and look up this value in the table tn the. preceding page here. we note that this relates to upper limits on the risk between 1/100 and 5/100 both. the lcg-probit and the one-hit extrapolating procedures. More exact interpolation yields a value between 1.5/100 (one-hit) and 2.6/100 (log-probit). Overview and General Discussion. r?t Although it is amply evident Eon the foregoing text that in the first 14 pages of their report the registrants did not properly evaluate - the significance of the findings in this two-year mouse study with cranyl, I hasten to add that the Law. as I understand it. does not require them to .y do so. What the Federal statutes do require of registrants for "pesticide or other products is that the circumstances of the conduct of each study and the actual observational findings energing from it, "the facts", be fully and adequately presented to the Government. As a result of our audi of this work at the site where its original records are stored, I can state that we found no evidence whatsoever that this was not the case here. As to the process of the evaluation of such facts tr observational findings. the people of this country depend on their Federal Government. in this particular case, on the Environmental Protection Agency. It is, I believe. the functicn of this Agency to determine fron reports admitted to it by the regulated industry what. is the safety of such products and to regulate than in view of their potential benefits and risks. This is page eighteen basically the job that is entrusted to us and we are all being paid very well to do it. It is also ev1dent that in this partiallar case, as in other annular ones cited earlier here, such reliance and trust conferred tn this Agency may have been in fact misplaced. To 'wt-and-paste' parts of the evalua- ticn attanpted by the registrants and to represent this as consti tutirg an _independent and searchirg assessment of the technical facts simply so as to avoid-doing the work one gets paid to do and. additionally, to circuit- vent secondary review by siperviscxs who could have discovered such practices, strikes me as representing not only a font of serious negligence on the part of both his reviewer and cm the part of his expat-visors, but 1 j? I v. also an abuse of that trust and a total disregard a: perhaps downright contenpt for the health of the Merican people exposed to potentially toxic products. Disconcerting or disappointing as this might be, it is also clear that the si tuaticn in the particular caa discussed here was much further in actuality, what happened rare with this specific study 'had been to light sane time ago through the investigatim carried out by the Battelle Corporation. Their ?ndings, I'm-ever, as with their findings on many other similar reviews _in the Hazard Evaluation Division, were referred to a "Review Group?I numbering anongst its members scme the very unit which was implicated in such shoddy conduct. The supervisor of that unit, Mr. Burnam, in a view concurred with by his own immediate supervisor, Mr. Melons, the Director of that Division, apparently chose not cnly to ignore those revelations of Battelle's but to actually deceive others in this Pgency on what had happened here and this was done with the aid of bold and utter lies. I would assume that such "cover-up" effort was made by them out of a desire to deflect than- selves any possible criticisns tn their own responsibilities and. their own negligence in' this entire sordid matter. The net effect of such actions was that the Agency published in the Federal Register only a few months ago a proposal that, contrary to the explicit statement contained in it, is in fact not "protective of the public health" of the citizens of this country. It has been shown here in some detail that the risk of cancer associated with the new tolerance established for bananas imported fron Costa Rica may be unacceptably high (up to - and that the sane of risk emanating from what the Agency states is an "acceptable" consu'npticn rate for this pesticide product (0.025 trgm/kgm/day) is as high as 1.5 - 2. 6/100, clearly a rate that can be easily perceived to be nothing short of catastrophic. as? Perhaps as a result of such "calculations as listed in that Federal Register proposal of last December, the EPA Report from OPP dated as late as March the 8th, 1985, indicates that a Section 18 exemption from tole- rance had been approved for- oxa'nyl for another food modity only last month and that the preposed tolerance cn bananas published last December 4? had in the meantime becone "final". 3. page nineteen Entirely apart fro'n such regulatory considerations as discussed above, there is here yet an additional dimension, another indication on the philo- sophy or overall policy apparently in effect in the Hazard Evalua?m Division on the assessnent of risks posed by potentially to:. .-.10.000, 993..- 0. 000, 07a, 0 . 0.001.00 1/ 100 000? .- 001, 41 0. 000,112 a 5/ 100, 000 5,0. 003, 34 A: 0. 000 1/ 10~,000 0.004.95 2. 0.000.3931?. .0.021.6~ 3 0.001.71 5/ 10 000? 0.015.5 .90.109 1/ 1,000 0.021.1 901061.67 ?'90.255u wi _ff0.017.1 5/ 1'00519?7 1:0.06559 0.005.47 1.08 0.085,? 1/ 100 $0.122? 0.009.63 2.17 0.172 5/ 100 0.507 0.046,6 11.1 301 1/ 10 1.35 0.100 22.7 1.00 Comparison of equivalent estimates in the table above reveals that for very low upper limits on the risk, the, one-hit estimates for the "virtually safe doses- are generally lower than the corresponding Mantel- -Bryan estimates:- for an upper limit on the risk of 1/100, 000, 000 this difference is almost 30-fold. 9 This differenCe becomes progressively smaller for higher upper limits on the risk:- at approximately 5/l,000r000 the two types of estimates are virtually identical and, at still higher upper limits on the risk, it is the one-hit estimates which are the higher of the two:- at 1/10 they are higher by almost 17- fold. 0f more immediate regulatory concern, however it is also evident from the table that what the EPA vie as a 'safe' level of permethrin in the human diet, the Allowable Daily Intake of 0.05 mg/kg body?weight/day, is associated with an upper limit on the risk for cancer as high as between 1 and 5 per 1,000 human consumers for the one-hit method, and an even higher rate for the Mantel-Bryan extrapolation,, I (A?%7pro bet en 5/100 and 1/10 i.e. between 5 and 10% of) ulation, in fact the Allowable Daily Intake 0 [(376 0.05 mg/kg body-weight/day is only approximately one-half as 5? large as the dose of 0.108 mg/kg/day whose corresponding upper limit on the risk is as high as 10%. 12 I should think that risks of cancer of this order for a relatively new insecticide are unacceptable to any rational person. It follows, therefore, that the statements in the Melone communication of last September (Attachment here) where such risks were estimated to be in the range of 1/l,000,000 to l/10,000 are vastly misleading in the sense that they understate such risks by many orders of magnitude. I am taking the liberty of addressing copies of this communication to Chris Dively and Herb Harrison of your Division and to Ed Gray of the General Counsel's Office, all of whom had been concerned with the safety of this pesticide product in the past. Enclosures Attachments A through Copies:- Dively (TS-767-C) Harrison (TS-767-C) Gray (A-132) Touhey (TS-768-C) Li): .- ?0 Permethrin Assessment of Chronic and Oncogenic Effects A Summarx April 5' 1982 . a, "(Will/62' Toxicology Hazard Evaluat-on Division Office of Pesticide Programs Environmental Protection Agency II. IV. VI. Table of Contents Availability and usefulness of studies Synopses of individual longeterm studies Non-oncogenic NOEL for mouse studies Non-oncogenic for rat studies Overall assessment of the oncogenic potential in experimental animals Assessment of the oncogenic potential in humans ll 19 I. PERMETHRIN--ASSESSMENT OF CHRONIC AND ONCOGENIC EFFECTS Availability and Usefulness of Studies: Seven long?term chronic feeding/oncogenicity studies have been submitted to EPA in support of requests to register food -=and other uses of Permethrin. These studies are listed -below. Study Duration of Dosage Levels of Permethrin Identification Study (weeks) (mg/kg/day) ICI Mouse 93 o, 37.5, 150, 375 awe/m FHC Mouse 30?"14?" Mouse II 104 0, 4, 75. 300 (males) I 0, 4, 375, 750 (females) B-W Mouse 9210, 50, 250 The test material for all studies, with the exception of the B-W studies, was a 40:60 cisztrans isomer ratio of Permethrin. For the studies, the cis:trans isomer ratio was 25:75. Although the cis isomer is known to be more toxic than the trans isomer (based on the results of acute oral and other toxicity studies). the difference in isomer ratios used in? the chronic studies was not considered substantial enough to warrant separate consideration of the B-W studies. One study. the PMC House I study, has been judged to be of no usefulness due to a serious animal identification problem which arose during the study. This left an insufficient number of positively identified animals available at the end of the study to adequately evaluate the results. One other study, the FHC Rat study. has been judged to be of only limited usefulness with regard to evaluation of lung tissues for tumors. This resulted from a failure to treat lungs from control and test animals in a comparable manner - during preparation of these tissues for microscopic examination. The remaining five chronic studies have been determined to be useful and valid for the purpose of evaluating the chronic and oncogenic effects of Permethrin. II. The results of additional studies. particularly mutagenic, reproduction, teratology and metabolism studies, have also been considered in the overall assessment of the long-term effects of Permethrin. Synopses of Individual Long-Term Studies: Mouse Study - Central Toxicology Laboratory, ICI Report No. and January 27, 1978 Doses of 0 (control), 37.5, 150 and 375 mg/kg/day of Permethrin were administered in the diet to 70 male and 70 female Alderly Park strain mice/group for 98 weeks. Ten male and 10 female mice per group were sacrificed at 26 and 52 weeks and the remainder at 98 weeks. Relevant non-oncogenic effects observed during the study were increased mortality, increased liver enzyme (aminopyrine?N-demethylase) activity, increased liver weights, and eosinophilia of hepatocytes in both males and females at 375 mg/kg/day. Liver changes observed in this study were considered to be related in large measure to the induction of liver microsomal enzyme activity. Minimal liver changes were also observed at 150 mg/kg/day, but not at 37.5 mg/kg/day- A increased incidence of lung adenomas was observed in male mice in this study--lO/70, 6/70, 12/70, and 17/70 for control, low, mid, and high dosage levels respectively. Statistical analysis of this finding revealed a positive trend for this lesion in Permethrin treated males (Armitage test); but after correction for departure from linearity, this trend was non-significant. Fisher's Exact test showed significance (p .01) for increased risk among high dose' vs. low dose mice: but when any single Permethrin treated male group was directly compared to the concurrent control group statistical significance was not observed (9.1 0.10). Toxicology Branch considers the biological significance of this finding to be of only marginal concern when considered in isolation as an individual study, but notes that this finding does tend to support similar findings in the other 2 mouse studies. FHC House II Study - Bio/Dynamics Inc. Project No. 76-1695 October 9, 1979 Doses of 0 (control), 4, 75 and 300 mg/kg/day of Permethrin were administered in the diet to groups of 75 male Charles River strain mice and doses of 0 (control), 4, 375 and 750 mg/kg/day to groups of 75 female mice for 104 weeks. Initial concerns regarding yellow staining of the and-genital region, abdominal distention and amyloidosis of animals in this study have been dismissed as having no significant influence on the interpretation of results. Relevant non-oncogenic effects observed during the study were increased mortality in males at 300 mg/kg/day, increased liver weights in females at 375 and 750 mg/kg/day and increased lung weights in females at 750 mg/kg/day. Histopathologically, ?focal areas of alveolar cell proliferation? (an indicator of increased numbers of lung cells) was observed with a dose-related incidence in Permethrin treated females--3/75, 5/76, 11/75 and 13/75 for the control, low, mid and high dosage level females respectively. The proportion of female mice with ?focal areas of alveolar cell proliferation" as their most serious lung diagnosis was significantly higher (P I 0.001) among the high dose animals free of adenoma and/or carcinoma then among the comparable controls. Also, multifocal hepatocytomegaly (an indicator of increased liver cell volume) was observed with increased frequency in Permethrin treated 3/76, 6/76 and 9/75 for the control, lbw, mid and high dosage levels respectively. The nature of these lesions as precursors of neoplasms is disputed. With regard to oncogenic effects, the initial pathology report (submitted with the study and dated February 7, 1980) indicated an increased incidence of bronchioalveolar adenomas in female 14/75, 28/74 and 28/73 for control, low, mid . and high dosage levels respectively. A second reading of . the same lung slides (performed under contract to EPA: report dated February 23, 1981) also reported an increased incidence of alveolar cell neoplasms (adenomas and/or carcinomas) in female mice--15/75, 24/76, 35/75 and 44/75 for low, mid and high dosage level females respectively. The increased incidence reported in both readings was statistically significant. In addition, for the second reading, when this latter finding is ad?usted for time to tumor diagnosis, Peto's Prevalence method (2 shows statistical significance. The incidence of carcinoma, alone, when considered separately 'in the second report, was observed to increase in a dosage related manner (6/75, 7/76, 11/75 and 15/75) for control, low, mid and high dosage level females respectively. This trend is statistically significant (P 0.01). In addition, direct comparison of the incidence of lung carcinoma in the high dose females (15/75) to the control females (6/75) revealed statistical significance. The incidence of lung adenomas in female mice dying or sacrificed before the terminal sacrifice was 7/53, 6/42, 12/51 and 19/53 and of lung carcinomas, 4/53, 4/42, 7/51 and 11/53 for the control, low, mid and high dosage levels respectively. (1) pathology report, dated February 23, 1981. (2) Annex to Supplement II of I.A.R.C., 1981. -4- Toxicology Branch has determined the increased incidence of alveolar cell adenomas and carcinomas in the lungs of female mice in this study to be statistically significant at both the mid and high dosage levels (375 and 750 mg/kg/day). Biologically. Toxicology Branch considers these tumors to be related to the ingestion of Permethrin. A statistically significant increase in the incidence of hepatocellular neoplasms was also observed in female mice in this study at the mid and high dosage levels. The initial pathology report indicated 3/69, 2/68, 15/74 and 17/73 for hepatomas. 0/69, 2/68, 3/74 and 0/73 for hepatocellular carcinomas and the-second report 25/76 and 30/75 for total hepatocellular neoplasms (adenomas and carcinomas) for control. low, mid and-high dosage level females respectively. In the second report. hepatocellular adenomas were reported in 3/74, 4/76, 23/76 and 29/75 females and hepatocellular carcinomas in 4/74, 3/76, 3/76 and 2/75 females for the control, low, mid and high dosage level animals respectively. The incidence of hepatocellular adenomas was observed to increase in a dosage related manner. The number of carcinomas, however. did not increase with increasing dosage. Toxicology Branch has determined the increased incidence of hepatocellular adenomas in female.mice at the mid and high dosage levels (375 and 750 mg/kg/day) to be statistically significant. A joint FDA-EPA audit of this study coniucted in late 1980 at Bio/Dynamics and FHC facilities did not reveal any inadequacies in the conduct or reporting of this stuly serious enough to compromise the usefulness or validity of these study results. B-W Mouse Study 4 The Wellcome Foundation Lab. No. HEFG 80-29 Received by EPA on December 17, 1980 Permethrin was administered in the diet to male and female .CFLP strain mice for 92 weeks at dosage levels of 0 (control), 10. 50 and 250 mg/kg/day. One hundred mice/sex were used for the control group and 75 mice/sex for each of the test groups. Relevant non?oncogenic effects observed during the study were decreased mortality in females at 50 and 250 mg/kg/day, increased liver weights in males and increased kidney weights in females at 250 mg/kg/day. Histopathologically, an increased incidence of cuboidal/columnar metaplasia of the alveolar epithelium was observed in the lungs of female mice at the high dosage level (250 mg/kg/day). The incidence for this lesion was 0/96, 0/71. 1/74 and 5/74 f0r the control. low, mid and high dosage levels respectively. Although controversial. this lesion is considered by some pathologists to be a precursor of lung neopl in mice. f/ FYL 4-46/1 ?9 ?VII/?lly . If? (7- . For females in this study, but not for males, a dose-related trend in primary adenomatous tumors in the lungs was observed. 'The incidence of this neoplastic lesion in females was 3/96, 5/71. 7/74 and 15/74 for control, low, mid and high dosage level females respectively. The registrant (B-W) has submitted statistical data with the report of this study showing that by adjusting for time of diagnosis. Peto?s Prevalence method indicates a statistically significant (p .01) relationship between dose of Permethrin and primary lung tumors in females. When these data are evaluated by Armitage's method for linear trend. the level of statistical significance for the dose -response trend is .02. In addition, comparison of the number of tumors in the high dose group (15/74) to-the number in the controls (3/96) shows high statistical significance by Fisher's Exact test. For females dying or sacrificed prior to terminal sacrifice, the incidence of this lesion was 0/53. 0/41, 2/36 and 8/31 for the control. low, mid and high dosage level females respectively. Further, with respect to malignant lung tumors in these females. 1/74 animals in the mid dosage level group and 2/74 animals in the high dosage level group were diagnosed as having adencarcinomas whereas this diagnosis was not made for any tumors in the control or low dosage level animals. Toxicology Branch considers the increased incidence of lung tumors in female mice observed in this study. together with the other supportive evidence observed in this study. to be highly suggestive of a possible oncogenic effect in lungs -- particularly when considered in relation to the results of the other 2 oncogenic studies in mice. ICI Rat Study - Central Toxicology Laboratory. ICI Report No. Received by EPA on January 29, 1978 Doses of 0 (control), 25, 50 and 125 mg/kg/day of Permethrin were administered in the-diet to 60 male and 60 female Wistar strain rats/group for 104 weeks. Eleven or twelve rats of each sex in each dosage group were sacrificed at 52 weeks and the remainder at 104 weeks. Relevant non-oncogenic effects observed during the study were increased mortality in males and decreased mortality in females at 125 mg/kg/day, increased 7 liver weights in males and females at 125 and 50 mg/kg/day and in males only at 25 mg/kg/day. increased liver enzyme (aminopyrine-N-demethylase) activity in males-and females at 125 mg/kg/day, and hepatocyte vacuolization or hypertrophy in males and females at 125 and 50 mg/kg/day. Additional effects observed were increased kidney weights in males at 125, 50 and 25 mg/kg/day, and increased pituitary weights in males at 125 and 50 mg/kg/day. Body tremors were also observed in males and females during the first 3 weeks of the study at 125 mg/kg/day. No tumors considered by Toxicology Branch to be related to or attributable to the ingestion of Permethrin were observed in this study. - FMC Rat Study - Bio/Dynamics Inc. 'Project No. 74R-1022 November, 1977 Permethrin was administered in the diet.to 60 male and 60 female Long-Evans strain rats for 104 weeks at dosage levels of 0 (control), 1, 5 and 25 mg/kg/day. Ten males and 8 females from the 5 mg/kg/day group were sacrificed at 52 weeks to follow the hepatocyte hypertrophy observed in a previous 3 month study. The remaining animals were sacrificed at 104 weeks. Relevant non-oncogenic effects included increased . liver weights for males at 25 and 5 mg/kg/day. An increased incidence of adenomas and adenocarcinomas was initially reported in the lungs of male rats in this study. The reading of the original set of lung slides reported 1/59, 3/57, 6/57 and 5/56 lung neoplasms for control, low, mid and . high dosage level males respectively. This increased incidence was not statistically significant (p .05). These same lung slides were later reread by a second pathologist who reported sl/60, 3/57. 8/60 and 6/60 lung neoplasms for the respective groups. Based on the readings of the second pathologist, the increase in lung neoplasms was statistically significant (p .05) for the mid and high dosage level males relative to the male control group. In a subsequent effort to perform a more critical and detailed evaluation of lung tumors in male rats, all available lung tissues from the male animals were step-sectioned at 250 micron intervals to exhaustion of tissue and read by the original pathologist who then reported revised figures of 8/60, 6/57, 10/60 and 10/60 for the respective groups (based on original and step-sectioned slides). This finding was not statistically significant (p .20). Based?on information supplied by PMC and on a joint FDA-EPA audit of the laboratories and personnel involved in the histological processing of the lung slides, Toxicology Branch has determined that inconsistencies in the technical methodologies used in the original sectioning and processing and also later in the step-sectioning and processing of these lung tissues introduced serious bias into all these results-? largely due to inconsistent embedding techniques which resulted in unequal amounts of lung tissue being examined in the control and test groups. Readings of the original lung slides were biased in favor of finding relatively more tumors in the lungs of test animals whereas readings of the step?sectioned 'slides were biased in favor of finding relatively more tumors in the lungs of control animals. In an effort to resolve the dilemma of which figures to use. Toxicology Branch has made additional theoretical calculations of lung tumor incidence based on equal amounts of lung tissue (adjusted) from all control and test groups. These 'area adjusted" tumor incidences were calculated to be 1/60, 2/57, 5/60 and 4/60 for the original (non-step-sectioned slides) and 8/60, 8/57, 15/60 and 14/60 for all slides (original and step-sectioned slides). The statistical significance of these "area adjusted? findings was borderline (p approximately 0.10). Evidence suggests the possibility of an oncogenic effect occurring in the lungs of treated male rats in this study. Sufficient uncertainty regarding the validity of the incidence figures. however, precludes making a scientifically supportable evaluation of the results. B-W Rat Study - The Wellcome Foundation Lab. No. HEFG 80-33- July 2, 1980 Permethrin was administered in the_diet to 60 male and 60 female Wistar strain rats for 104 weeks at dosage levels of 0 (control). 10, 50 and 250 mg/kg/day. Relevant non-oncogenic effects observed during the study were increased mortality in males at 250 mg/kg/day, occasional body tremors in males and females at 250 mg/kg/day, increased liver weights in males at 250 mg/kg/day. hepatocyte hypertrophy in males and females at 250 mg/kg/day and focal disturbances in the growth pattern of thyroid follicular cells in males and females at 250 mg/kg/day. The microscopic liver and thyroid changes were also observed in males and females at 50 mg/kg/day. With respect to tumors, none of the tumor types observed in this study were considered by Toxicology Branch to be related to or attributable to the ingestion of Permethrin. -3- Non?Oncogenic NOEL for House Studies: Relevant non-oncogenic effects observed in the 3 long-term mouse studies are tabulated below. Dosage Level of 300 (M only) 375 (F only) Increased mortality (M) Increased liver weights (F) ?Focal areas of alveolar ce proliferation" (F), Hultifocal hepatocytomegaly Hepatocyte pigmentation (F) - Permethrin Study (mg/kg/day) Non?Oncogenic Effects ICI House 0 - None 150 - Minimal chahges in liver enzyme activity, liver weights and liver histo- pathology (eosinophilia of hepatocytes) 375 - Increased mortality Increased liver enzyme activity (HEP): Increased liver weights (Ma Eosinophilia of hepatocytes ENC House II 0 (HEP) - None 4 - None 75 (M only) - None 750 (F only) - Increased liver weights (F) Increased lung weights (P), ?Focal areas of alveolar ce proliferation? (F), Multifocal hepatocytomegaly Hepatocyte pigmentation (F) B-W House 0 - None 10 - None '50 - None 250 - increased liver weights (N), increased kidney weights (F), Cuboidal/columnar metaplasi of alveolar epithelium in lungs (F) (H) - male (F) - female IV. A consistent finding in all 3 mouse studies at high dosage levels was liver changes known to be associated with induction of the liver microsomal enzyme system. These changes included increased liver weights and increased enzyme This induction phenomenon is a well-known and frequently occurring response to the administration of many exogenous compounds.to experimental animals and man. It is widely accepted among knowledgeable scientists as being a normal and natural adaptive response of the organism to the presence of foreign chemicals and is not considered to be an adverse or toxicological effect of concern. Therefore. Toxicology Branch notes the presence of this phenomenon in mice treated with Permethrin, but will not use it to determine a NOEL. Of potentially more concern are other histopathological effects observed in liver cells that are not ordinarily associated with microsomal induction and could possibly be related to an adverse effect of Permethrin on the liver. These effects include excessive liver weight increases, multifocal hepatocytomegaly, hepatocyte pigmentation and possibly eoSinophilia of hepatocytes. These and other toxicological manifestations were used to determine a non -oncogenic NOEL for the mouse studies. Due to the considerably different dosage levels and spacing between levels employed in each of the 3 studies, Toxicology Branch believes the assignment of a specific NOEL to each mouse study would serve no useful purpose and might, in fact, be quite misleading. Based on a consideration of the totality of evidence in all 3 mouse studies, the NOEL for non-oncogenic effects in mice has been determined to be 50 mg/kg/day. Non-Oncogenic NOEL for Rat Studies: Relevant non-oncogenic effects observed in the 3 long-term rat studies are tabulated below. ?osage Level of Permethrin Study (mg/kg/day) Non-Oncogenic Effects ICI Rat 0 - None 25 - Increased liver weights (H), Increased kidney weights (M) 50 - Increased liver weights Hepatocyte vacuolation (HEP), Hepatocyte hypertrophy Increased kidney weights (H). Increased pituitary weights (b -10- cont . 125 - increased mortality (N), Increased liver enzyme activity Increased liver weights Hepatocyte vacuolation Hepatocyte hypertrophy Increased kidney weights (M), Increased pituitary weights (M), Body tremors (lst 3 weeks) FMC Rat 0 - None 1 - None 5 - increased liver weights (N 25 - Increased liver weights (N) B-W Rat - None 10 - None 50 - Hepatocyte hypertrophy Changes in thyroid cells 250 - Increased mortality (M), Increased liver weights (M), Hepatocyte hypertrophy (HEP), Changes in thyroid cells Occasional body tremors (N) - male (F) - female As with mice. a consistent finding in all 3 rat studies was liver changes known to be associated with induction of the microsomal enzyme system. This induction phenomenon, for reasons already presented, was again not considered by Toxicology Branch to be an adverse or toxicological effect of concern. The other toxic effects listed above were used to determine a non-oncogenic NOEL for the rat studies. For the PMC Rat Study, a NOEL of 5 mg/kg/day was determined. For the ICI Rat Study. a NOEL of 25 mg/kg/day was determined. For the B-W Rat Study, a NOEL of 10 mg/kg/day was determined. Based on a consideration of the totality of evidence in all 3 rat studies, the NOEL for non-oncogenic effects in rats has been determined to be 5 mg/kg/day. -11.. V. :Overall Assessment of the Oncogenic Potential in Experimental Animals. According to the International Agency for Research on Cancer (IARC), "the widely accepted meaning of the term 'chemical carcinogenesis' is the induction by chemicals of neoplasms that are not usually observed. the earlier induction by chemicals of neoplasms that are usually observed, and/or the induction by chemicals of more neoplasms than are usually found'' (3). The Toxicology Branch considers this definition and the following seven criteria to evaluate oncogenicity in experimental animals when multiple oncogenic studies are available on a single chemical: l. Oncogenicity in different a) species, b) strains. c) sexes and d) organs Three strains of mice were used in the long-term mouse studies: a) ICI, Alderly Park, (SPF Swiss); b) FMC II, Charles River and c) CFLP. In the ICI study, a slight (nonsignificant) increased incidence of lung adenomas was observed in male mice.? Females in the FMC II study exhibited an increased incidence of lung and liver tumors. In the B-W study, female mice exhibited a trend in adenomatous tumors in the lungs. Only females of the Charles River strain (FMC II study) showed evidence of lung and liver oncogenicity apparently due to Permethrin exposure. 4 6f the three long-term rat studies: the ICI (WiStar strain)~ and the?B-W tar strain) studies revealed no tumors. in either sex. which re con51 ere lated to or ttributable to the estion of Permethrin. Evan rain) study produced eVi oncogenic effect in the lungs of males only. Among the six long term studies. evidence of Permethrin oncogenicity was observed in the lungs and liver of only one jsex of one strain of mouse. 13) IARC Monographs on the Evaluation of the Carcinogenic ?isk of Chemicals to Humans, volume 22. p. 14. March 1980. 2. Presence of rare neoplasms and number of different types of neoplasms in one or more species ?Lung and liver tumors were the predominant neoplasms of potential concern in the long-term mouse studies. In mice, lung and liver tumors are not rare neoplasms. Both tumor types occur spontaneously in control mice and have highly variable incidence rates (occasionally quite high) from study to study. With the exception of a marginal effect in males in the ICI study. increased incidences of lung tumors were observed only in females. An increase in the number of hepatomas was confined to females in the PMC House II study. An increased incidence for this tumor type did not occur in either sex of the ICI or B-W studies. Other types of tumors observed in either sex in the three mouse studies were not attributed to ingestion of Permethrin. No tumors considered to be related to ingestion of Permethr awe a tu suggests ty of an oncogenic ?effect in the lungs of male rats: Lung adenomas are not a common tumor type in this species. The uncertainty of incidence figures precludes making a scientifically supportable evaluation og?this observation (see pp 6-7 for detailed discussion). Rare or unusual tumors were not observed in any of the mouse - or rat long-term studies. ?1ncreased incidence of malignant neoplasms. The number of malignant lung tumors at termination of the ICI Mouse Study was small. For males. the incidence was 0/70 for all groups. For females, the incidence was 0/70, and 1/70 for the control and the three treated groups. This was also true at termination of the B-w Mouse Study. The .hr incidence for males was 3/99. 1/75. 2/73, 1/74 and for females ,.bv 0/96, 0/71, 1/74, 2/74 for the control group and each of the JLJ treated groups respectively. At termination of the FMC Mouse 11 Study, an increased incidence of alveolar cell neoplasms was observed in females only. The {?ng number of adenomas alone was 10/75. 18/76, 26/75, and 37/75 for the female control and treated groups respectively. The number of lung carcinomas in these same groups was 6/75, 7/76. 11/75. 15/75 respectively. Only the 750 mg/kg/day level females exhibited a significantly increased lung carcinoma incidence relative to the control females. For males, the incidence of lung carcinoma was 7/75, 5/75. 13/74 and 4/75.. In this same study. the incidence, at termination, of hepatocellular carcinoma among females was 4/74, 3/76. 3/76. 2/75 for the control and each of the treated groups and among males 16/75. 12/75. 19/75 and 8/75 respectively. 1 . - .. .Av' k?~??750 15:25:51 I Z/f7 r' 25" - 13 The incidence of lung carcinoma in the FMC Rat Study was 1/60, 2/57, 5/60. 2/60 for the male control and treated groups respectively and zero for all female groups. Histopathological evidence for increased malignant lung tumors;) was observed in only one sex i se and rat studies. vidence for increased malignant liver tumors was not 0 served. 4. Decrease in latency (time to tumor) '7 Because these studiestdid include serial sacrifice_and the tumors did not appear to produce d?at??wtt?t?'?'s?orf time, the qS?studies do not permit conclusions regarding effects of permethrin go on tumor latency. There is, however an observed incidence in treated groups before terminal sacrifice among females in the 0F, B-W mouse study. The incidence in this study among females iAJ?yf acrificed or dying prior to termination of the study was 0/53. (Opes-own, 2/36 and 8/31 vs an overall termination incidence of I .. control and treated groups respectively. adenomas in females was 10/75, 18/76. 26/75 and 37/75 and for V?r? )73/96. 5/71, 7/74 and 15/74 for the female control and treated groups respectively. In the PMC House II Study, the incidence for lung adenomas in females prior to termination of the study I was 7/53. 6/42, 12/51 and 19/53 and for lung carcinomas, . 4/53, 4/42, 7/51 and 11/53. The overall incidence for lung af?uk lung carcinomas 6/75. 7/76. 11/75 and 15/75 for the female 9 7 5. Dose-response relationships . .J In the ICI House Study, no substantive evidence was developed which could be interpreted as a dose-response relationshi ung adenomas in either . in lung adenomas was observed for females only in the B-W House Study. The FMC 11 Mouse Study indicated a dose?related .response for both lung and liver neoplasms for females only. dose-response relationships for tumors were observed in either sex in any of the long-term rat studies. Ardose-related response for tumors was established only for (\female mice in the FHC House II Study. . . a? -14.. 6. Mutagenicity in appropriate tests -A battery of mutagenicity tests has been performed on Permethrin to detect gene mutations, chromosomal aberrations and primary DNA damage. These tests included studies on S. himurium and E. coli (with and without activation), mo?se Eymphoma, dominant lethal, rat cytogenetics, mitotic recombination in yeast, DNA repair in E. coli and g. subtilis and unscheduled DNA in human fibroblasts. In none of these studies has Permethrin shown a mutagenic potential. The mechanism of induction of oncogenicity observed only in female mice in the PMC Mouse II Study apparently does not operate by biological mechanisms which directly involve the genetic integrity of the cell. .7. Spontaneous tumor incidence in control groups Historical control incidence data for the particular strains of mice and rats used in the six long term studies with Permethrin is limited. Data submitted by one registrant presented the historical control incidence of lung tumors in female mice of the CFLP strain used in the B-W study. The data for 807 female control mice from nine studies was abstracted from proprietory data unrelated to Permethrin. This fact precluded proper validation and analysis. Nevertheless, the female control incidence for lung tumors ranged from 7.5 to 30.0% with a mean of 165/807 I 20.4%. The incidence in the B-W Permethrin study, at termination, was 3, 7, 9 and 20% for the female control, low, mid and high level treated groups respectively. 15 - _The following table gives pulmonary tumor incidences for _yarious strains of inbred mice. (4) Average 5train Incidence Age (Hos.) Comments A 90 >18 AB - 36-54 Breeding female 15-25 Virgin female A/Jax 40 Ma1e? 30 - Female 29 - . Male 26 Female BL . I 26 25 CC57W 24.5 High Both sexes High PBA 77 12 as >13 (4) K.. Garner, F.M.. and Jones, T.C., Ed. Patholo of Laboratory Animals. Springer-Verlag, NY. I TI. Table 12.1. p. 1055. 1978. The incidence of lung adenomas in the ICI study males was 14. 9. 17 and 24% for the control and treated male groups respectively. In the FMC House II Study, the incidence of combined lung neoplasms was 20, 32. 47 and 59% for the female control and treated groups respectively. - 15 - The female incidence of lung tumors observed in the s-w Permethrin study clearly falls within the range and is at or below the mean incidence observed in the historical female control data from various laboratories during the past 10-12 years. The incidence of lung adenomas in the ICI study males also falls below the range for this type of tumor in various strains of inbred mice (see table p. 15). In the FMC Mouse 11 Study, the combined lung neoplasm incidence for all female groups, except for the high level (750 mg/kg/day) group, is also near or within the range reported for various inbred strains. The following table presents data for hepatocellular carcinoma in various strains of inbred mice (4). Average Strain Incidence (3) Age (Mos.) Comments CBA 40.7 28.6 Male 26.6 13.45 Female High Older Hale 91 21.4 Breeding female 58 24.1 Virgin female 99 12 Hale C3H-Avny 96 16 Foster-bred females Common Older Hale C3H 85 14 Male 78 14 Male 72 14 Male In the FMC House II Study females, the only study and sex with an increased incidence of liver neoplasms, the incidence in the second pathology report was 8, 9, 33 and 40% for the combined tumors (adenoma/carcinoma) while the incidence of hepatocellular carcinomas alone was 5, 4, 4 and 3% for the :female controls and the female treated groups respectively. The incidence of combined liver neoplasms observed in the FMC House II Study females falls within or below the incidence for various inbred strains of female mice and the incidence of hepatocellular carcinoma is well below the range. 17 - "The following table presents data from two sources on the incidence of spontaneous lung tumors in Osborne-Mendel and Fischer -344 rats. Number of rats of 975 of 976 Strain Site Tumor type males females Osborne-Mendel (5) Respiratory tract Trachea Undifferentiated sarcoma 1(O.l) 0 Lung Alveolar/bronchiolar adenoma 4(0.4) 2(0.2) Alveolar/bronchiolar 2 carcinoma 3(0.3) Mucoepidermoid carcinoma l(0.l) 0 Adenosquamous carcinoma l(0.l) 0 Fischer-344 (6) Of 846 o: 840 Lung/Trachea 2.3% (5) Goodman. 575.. et. al. Neoplastic and Monneoplastic lesions in aging Osborne-Handel rats. Tax. and Appl. Pharma. 55, 433-447, Table I (1980) (6) Cueto, C.J., Env. Sc. and Health, BIS, 6. Table l. p. 954 (1980) The male incidence of lung neoplasms in the PMC Ra: Study, from the second pathology report (step-sectioned slides), -was 13, 10. 17 and 17% for the male control and each treated group respectively. The incidence of lung carcinomas, in the same reportfor the male control and treated groups. No carcinomas were observed among any of the female groups. The flaws in the preparation of lung tissues in this study render the incidence figures questionable. however. The incidence of lung neoplasms in males in this study is much higher. even in the control group, than the incidence reported for two other strains of rats. -13- ,If the mouse historical control data are valid, they raise the possibility that these tumors may not be directly related to the ingestion of Permethrin but, rather, may simply be an expression of the variability of the spontaneous and naturally ,occurring incidence of this lesion in mice. Toxicology Branch recognizes some merit in this point of view. In the absence of historical incidence data for the specific strains used in the ICI and FMC House II Studies.'it is Toxicology Branch's opinion that relatively more weight should be placed on the observed incidence of lung tumors in concurrent control groups than on that in the other strain historical controls since concurrent controls more accurately reflect the particular conditions of any given study and reduce the number of unknown and uncontrolled variables to a minimum. In addition, Toxicology Branch considers the lung tumors observed in the three mice studies to be highly supportive of one another. The incidence of lung neoplasms in the flawed FMC Rat Study, in the absence of such observations in the ICI and B-W rat studies and specific historical control incidence data for the Long-Evans rat strain, is very difficult to interpret. Their presence, however, is noted. Absence of strain specific historical control data for the mice and rat strains used in the long-term studies severely limits the use of such data in the evaluation of the oncogenicity potential of Permethrin. 'Summary and evaluation of criteria data In the 3 long-term mouse studies. evidence of oncogenicity was observed in the lungs and liver of only one sex (female) of one strain (Charles River of mice. . ere was no increased insidence of rare or unusua tumors in the mouse or the rat studies. Suggestive evidence of increased incidence of lung adenomas was observed in male rats in a flawed long-term study. 3. An increase in malignant lung tumors was evident in 2: I only one of six long-term mouse and rat studies. No increase in malignant liver tumors was observed. 4. These studies were not designed to detect latency differences between groups. Although two mouse studies indicated an increase in tumor rates before terminal sacrifice, they do not provide clear of decreased latency nor any indication of very early, treatment related tumors. VI. - 19 - Dose-related responses for tumors was established only for female mice in the FMC Mouse II Study. 6. In a battery of mutagenicity tests performed to detect gene mutatations, chromosomal aberrations and primary DNA damage. no mutagenic potential was evident. 7.- Historical control incidence data in the rodent strains tested is too limited to be of significance in evaluation of the oncogenic potential of Permethrin. The evaluation of the weight of toxicological evidence leads e.roxicology Branch to_conclude_that, at dose lgx?ls_abovex 250 mg/kg/day for a lifetime, Permethrin exhibits a low onco potential in female mice. 1 ence in FMC Rat ent that it precludes making a scientifically supportable evaluation, it is marginally suggestive that Permethri - ve a very low oncogenic .. -- in male rats. This potential is no suppor -- the other two ong- erm rat studies at dosage levels as high as 125 and 250 mg/kg/dayoncogeni - - rodents apparently does not operate by biological mechanisms which directly involve the genetic integrity of the cell. Assessment of the Oncogenic Potential in Humans Recently. several systems for ranking and classifying evidence from animal oncogenic studies have been developed or proposed. At present. only the International Agency for Research on Cancer (IARC) method has general acceptance. However, in evaluating the human ic' tial for Permethrin, two additional systems were useful. method classifies the evidence as either 'sufficient' or 'limited'. Evidence which is sufficient requires the animal experiments to demonstrate 'an increased incidence of malignant tumors: in multiple species or strains, and/or 1b) in multiple experiments (routes and/or doses); and/or -to an unusual degree (with regard to incidence. site, type, and/or precosity of onset).' (7) Data concerning dose-response, mutagenicity, and structure may provide additional evidence. Limited evidence, while not precisely defined by IARC, includes induction of ?certain neoplasms, including lung tumors and hepatomas in mice, which have been considered of lesser significance than neoplasms occurring at other sites for the purpose of evaluating the carcinogenicity of chemicals" (7) (7) f??c Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Volume 22, pp 18-19, March 1980. - 20 - Using the IARC criteria, Permethrin animal data does not meet the requirements for the I'sufficient" evidence category. Among six long-term mouse and rat studies, an increase in _malignant lung tumors was not evident except in one sex . 1female) in the Charles River mouse strain used in the FMC Mouse II Study. This tumor type and site is not rare or unusua . No evidence of mutagenic potential was observed in a battery of tests which included tests for DNA damage. Using the IARC criteria and considering all available biological data, Toxicology Branch concludes that the evidence for Permethrin carcinogenicity must fall into the ?limited" classification. The limited evidence strongly suggests that Permethrin is not a stron carcinogen in experimental animals but may possibly exE1bit a weak oncogenic potential for female mice. Weisburger and Williams (8) have proposed a mechanistic classification of carcinogens which is divided into two general categories: a) genotoxic and b) epigenetic. The genotoxic category contains those chemicals which function as electrophilic reactants or otherwise affect DNA. The epigenetic category contains carcinogenic substances for which no evidence of direct interaction with genetic material exists.? IThis classification, if ultimately validated, has major implications for risk extrapolation to humans of data on experimental carcinogenesis. Genotoxic carcinogens, because of their effects on genetic material, pose a clear qualitative hazard to humans. These carcinogens are occasionally effective after a single exposure, act in a cumulative manner, and act together with other genotoxic carcinogens having the same organotropism. Thus, the level of human exposure acceptable for 'no risk? to ensue needs to be evaluated most stringently in the light of existing data and relevant mechanisms. Often. with powerful carinogens. zero exposure is the goal. On the other hand, with some classes of epigenetic carcinogens, it is known that their carcinogenic effects occur only with high and sustained levels of exposure that lead to prolonged physiologic abnormalities, hormonal imbalances, or-tissue injury. Consequently. the risk from exposure may be of a quantitative nature. (8) Weisburger, J.H. and Williams. G.M., Chemical Cardinogens, In Doull. J. Toxicology: The Basic Science of Poisons, 2nd ed., Hacmillian Pub. Co., N.Y., 1980. 0 I -21- This is almost certainly the case with estrogens, which are carcinogenic at high, chronic exposure levels in animal studies. or otherwise every individual would develop cancer. Thus, with epigenetic carcinogens. it - may be possible to establish a 'safe' threshold of exposure, once their mechanism of action is elucidated." . Because of the lack of knowledge concerning Permethrin's mechanism of action. the entire Weisburger and Williams classification system can not be fully utilized. However. the lack of positive evidence for mutagenic potential from a_ battery of tests. including DNA repair and unscheduled DNA coupled with oncogenic evidence only at high dose levels for one sex in one mouse Study among three studies. indicates that Permethrin falls into the epigenetic category. According to this system of classification. Permethrin falls into the group where the risk from exposure may be of a quantitative nature. 7 Squire (9) has also proposed a system for ranking animal carcinogens based on available data and the current state of knowledge. The system's 'emphasis is on test animal data, since without further knowledge of mechanisms. this information is the most relevant to human risk. Whatever experimental data are to be included. however. the weight of scientific evidence should be considered in an appropriate system of carcinogen classification.? The system includes the following factors: a) number of different species affected: b) number of histogenetically different types of neoplasms in one or more species; c) spontaneous incidence in appropriate control groups of neoplasms induced in treated groups: d) dose- response relationships; e) malignancy of induced and f) genotoxicity, measured in an appropriate battery of tests. weighted numerical values were assigned to subparts of these factors by the author. Using these values the author ranks carcinogens into five classes. Classes I and II contain substances presenting the greatest potential hazard and have the highest priority for regulation. According to the author, chemicals in Classes to may permit many regulatory options including no action. approvals for limited uses. appropriate labeling. or public education programs. Using this system of ranking potential carcinogens. Toxicology Branch determined that Permethrin clearly falls into Class indicating the lowest potential risk of carcinogenicity. T5) ?quire. Animal Carcinogens: A_?roposed 'RegulatoEE Approach. Science, vol. 214, pp. 877-880. ov. . -22.. The weight of scientific biological evidence produced by six long-term mouse and rat studies plus the use of three qncogenicity ranking and classification systems lead the Texicology Branch to conclude that Permethrin's potential ?or induction of oncogenicity in experimental animals is weak and that the risk of human oncogenic effects resulting from exposure to low levels of Permethrin is non existent or extremely low. 1 v- 4%va') [333? 35/ RANDUNI or HEALTH. EDUCATION. AND WELFARE HEALTH SERVICE FOOD nan: onto .xnsuxrvl?nn'rnm t?p- Mr. Carl Sharp . . DETE: ?1 RON1 M. Adrian Gross . . i Draft Agreement for Validationaof Searle Aspartame Studies The following are some comments which you requested on the document under reference as well as on the cover memorandum Wylie/Gardner dated November l, 1976. I must confess that I became deeply disturbed on reading this effort - last July lAth in a telephone conversation I had with Commissioner Schmidt during which I stated my reservations about this entire plan, he assured me that whatever is being contemplated in this area will be undertaken in full knowledge of and consultation with some of us who were intimately involved with the Searle investigation and that whatever is finally accepted will be of such nature as not to jeopardize or undermine all of our previous work. Given this kind of background I suffered a rude shock by the proposed plan in front of us at this time. Let us put this matter in some perspective by establishing the basic facts here. .The Searle investigation which started in the Fall of l975 can be viewed as an investigation."for cause? following the discovery of certain improprieties in the conduct of animal studies during preliminary I inspections in l974 and in the first half of l975. The report of the - Task Force submitted in March l976 in essence constituted a stinging indictment of Searle and it contained various recommendations for regulatory action including referral-to the Justice Department for review of possible criminal violations of the law. The Aspartame studies to which we have'reference here are nothing but an extension of the studies which were reviewed by the Task Force. 1 see no essential difference between them and any of the studies already investigated. In the meantime this Agency has received a substantial amount of additional funding for the express purpose of monitoring the quality of research carried out by regulated industry in a much expanded fashion. As part of this program. there has been a marked degree of effort, time and money expended on setting up sundry task forces, steering committees. training courses for investigators. ?surveillance" inspections. regulations for good laboratory practices, compliance programs. etc. -dnan. Page Two . 'Yet, notwithstanding any of this, now that the Agency is confronted with the need of completing what it started out to do in this Searle matter, we seem to be turning to an outside group of questionable capability in this area:- the UAREP. I know absolutely nothing of the past experience of this outfit to carry out investigations of this sort - perhaps, whoever it was that selected this group to carry out our responsibilities for us might be as kind as to enlighten us on this point. I noted'the name of Dr. Stowell associated with this organization - I have known Dr. Stowell for many years now from the time he was Scientific Director of the Armed Forces Institute of Pathology and I can readily agree that he has impeccable credentials and a remarkable achievement in his own field of pathology; as far as investigations of the sort that we are concerned with here, however, I would judge him to be a complete neophyte in this particular area. I.also know nothing of the qualifications of the investigators which will be selected by Dr.'Stowell or others at UAREP to do the actual "hands-on" part of the investigation - we need additional details here but I would doubt very much that UAREP could come up with a number of workers who are both experienced and competent in matters of this sort. Speaking as a pathologist, I seriously question the wisdom of selecting a group of pathologists to oversee the kind of investigations that are called for here; pathology problems do not constitute but a small part of the difficulties involved in situations such as these. My own experience is that, as a rule, controversial technical aspects in pathology proper (such as whether any particular characterization of any given lesion is a proper one or not) are seldom an important factor in a determination whether any study contains serious flaws. This has been amply demonstrated in the extensive Searle investigation as well as in other investigations currently under way in the Bureau of Drugs. I have great difficulties in visualizing pathologists conducting a searching examination of a variety of records which have nothing to do with pathology or closely question a number of administrators, laboratory technicians or aids, animal caretakers, etc., on their practices, on . details of their tasks, adequacy of their observations and so on. I would not like to generate the impression here that scientific expertise in pathology or in any other scientific field asso?iated with studies like these could or should be totally ignored. far from it. However, the concept under which we have operated ever since I can remember is that investigations are best handled by trained and experienced investigators. Hhere there is a need to address certain scientific problems which transcend the capabilities of the investigators, the practice has always been for appropriately qualified specialists from the various Bureaus of the FDA to assist the investigators; in those few cases where outstanding technical difficulties beyond the capabilities of Agency scientists are required, we have not refrained in the past from using help from outside and I should hope we shall continue to do so in the future. But this help provided by scientists on an ad-hoc basis and only where it is required is an entirely different matter than having scientists direct the actual course of the . investigation. While I believe it is entirely proper (in fact preferable] to have scientists evaluate the scientific impact of a set of findings, I cannot see professional scientiSts do the ion of pnofessional'investigators any more than I could see members of a legal society doing the work of detectives or policemen in investigating various aspects of a specific crime. It disturbs me to see from the draft we have here that the r31e of what is non-4:. -. Page Three termed the Monitor? will be reduced to little more than having this person be present during communications between and Searle; I find this kind of prospect ludicrous and i do not understand the need for it. what I understand even less is why Searle should offer or be asked to pay the cost of this entire operation to the investigative agent in a direct manner; why is there a necessity for this body kind of fonnal contract with Searle and why are UAREP, to enter into any we expected to co?sign such a contract The fact that Searle will pay for this cannot but give them some kind of decision-making role as is eVident from merely reading the terms of this proposed contract. It seems to me that no-one except the FDA can have the responsibility for undertaking this kind of work - this is our mission and w?_are being paid from out. public funds to carry it Although, as expressed above, there is much I do not understand about this entire plan, particularly its basic raison d'?tre, there is something here that I appreciate fullyz- this is the statement at the top of page two of Hylie's memorandumz? "Searle understandably continues to press for the expediting of this agreement.? 1 would suggest that implementation of this contract can have only one of two predictable outcomes which are mutually exclusive:? a) There are serious improprieties in the If this is the case, i would submit that inexperienced outside conduct of these studies. scientists selected by an outside agency under contract to the firm which is the object of the invest markedly reduced probability of detect b) There are no serious improprieties in the con low that any report igation, will have a ing such imprOprieties; duct of these studies Ti?this is the case, it would necessarily fol written by the "investigators" would any such improprieties. as listed above, such a report may wel ot signal the presence of But, if so, for exactly the same reasons 1 be interpreted as being nothing short of an improper whitewash. My recommendation is simply that this entire pl an be aborted forthwith, and that we proceed with this matter in the way we are supposed to; this is the way we have handied things like this in anticipate to operate in the future. the pastgand the way we We Adrian Gross i i yet )rk asi- the at? ter not- I a a oke be- tres ?ChemiCal cOmpany accused of hiding presence of dioxins BY JOCK FERGUSON The Globe and Mali Monsanto Co.. the giant U.S. chemical maker, knowingly hid'the presence of dioxins in some of its products from the Canadian and U.S. governments, testimony in a suit against the company says. The company found small amounts of the most toxic form of dioxin 2.3.7.8-tetrachlorodibenzo- p-dioxin (TODD) in'its chlorinated phenol products including San- tophen, a germiCide. and 2.4-dich- lorophenol, which was made into a weed killer - when it started test- ing its products after an accidental spill in 1979. - Santophen was widely used as a disinfectant by hospitals and was the active ingredient in the widely sold household-disinfectant, Lysol. The maker of Lysol was not told by Monsanto of the presence of as much as three parts per billion of toxic dioxin in Santophen. accord- ing to evidence from company executives in a suit against Mon- santo filed in East St. Louis, 111. using Santophen in 1983. Documents from the trial given Harvey, NDP MP from Edmonton The maker of Lysol, stopped to The Globe and Mail by Ross; East, show Monsanto misled the Canadian government about the, . presence of TCDD contamination in Santophen, which it exported to Canada. in a Sept.3, 1991, letter to a Health and Welfare Canada task force studying- chemical safety, Monsanto said Santophen made betweien 1979 and 1930 showed no ?evidence of the presence of ?However, the company had evi- dence of 2.3.7.8-dioxin contami- nation in Santophen when the letter to Canada was written. James Wilson, the company's' manager of research and devel- opment, admitted in 1985 his letter to the Canadian government "was not correct . . . i was mistaken obviously in writingthat sentence. Mr. Harvey is investigating how much of the contaminated germi- cide was imported into Canada from Mons anto's Krumrnrich plant jury trial in U.S. history inEastSt. Louis. The aha-year trial. the longest ended in October, 1937, with the jury award- ing punitive damages against Mon- santo of $16.25-million. The compa- ny isnow appealing the verdict and questions about its behavior have surfaced again. Rex Carr is a laWyer for the plaintiffs; who claimed they were injured by the accidental spill of a dioxin-contaminated Monsanto chemical. In a brief to the illinois .Appeal Court, he says the trial transcript ?contains literally hun- dreds of admissions that Monsanto was selling dioxin-contaminated chlorophenol products . . . for 30 years. and that it did so with the knowledge that these products con- tained a contaminant that was highly toxic to both the environ- ment and tohuman beings. David Snively, a lawyer for Mon- santo in St. Louis, said what Mr. Carr alleges is a very selectiVe in- terpretation of company records and the testimony of its executives "during the trial. . Dan Bishop. a spokesman for Monsanto in St. Louis, said the company is moving to strike parts of Mr. Carr?s brief as ?grossly mis- leading and inaccurate.? The evidence of Monsanto exec- utives at the trial portrayed a cor- porate culture where sales and. prefits were given a higher priority than the safety of products and its -workers. ln the late 19703 and early 19805 company executives decided not to ?tell customers .about' the dioxin- contamination problems for fear of losing sales. Company records show the pres- ence of dioxins as high as 20,000 parts per billion in its chlorinated phenol products, yet it never noti- iied the U.S. Environmental Pro- tection Agency of possible hazards tousers, Mr. Carr said. Monsanto says that .the jury in the trial found that none of the plaintiffs had been injured in the .-- Spill. Damages were awarded against the company only because of Mr. Carr?s allegations, Mr. Sni- vely said in an interview. THE wan. S'l'ltl-Zii'l? 3001mm. Monday. October 17. 19333:. . zl Dow Chemical to Quit Selling 2 I?lerbieides, Ending EPA Battle fly WMJ. :12 .lnulm u. Staff ?Charter MIDLAND. Chemical Co. said ?it plans to stop controversial herbicides in the ending a four-year battle with the Environmental Protection {tgeuey over use of the chemicals. itul in announcing it wohld quit selling 2.- 4.5-1? and Slivex. a related substance, Dow continued to insist that "the great Weight of scientific evidence' stones that the weed- . killers can he USttl without nosing undue risks to human 0' animal safety. Dow no longer has any significant coin- ntercialstake in the chemicals in the us. it quit making in 1979. in the wake of an EPA order halting its use in forests, in pas- tures and along;r [timer-line rights of'way. The EPA had based its ban on animal test results-?andad?gh level of miscarriages .. .1: .. among women in an Oregon basin shortly. . after the chemical was applied to forests .- thcre. The agency continued to allow use of . . the chemical in rangelands and rice :2 hut Dow didn't bother to produce. any of it in the 0.8. for just those uses. . ?Dow spent Sill million trying..to get th? . EPA to change its stance on the chemicals: Jitrt Cfliilp??)? officials recently came to he; have tluw?h?i?lt?n lately under rev newed scrutiny. the a re- .. - Eersal of the ban were stun. 2 . ..*.Sitortiy after-?vows .. *ntentFI-?riday. in fact. the Eanxteudc-d its}; nation the use of to rangelands and;= rice fields as well. The EPA said the with-fl (irawal (it"Do'w. "the major registrant laud}; most rigorous proponent"- of the: use" ol?theg re 'L'fo'J chemicals." cleared the tray ?ifor ?the wider?rye". :1 .i II I A new spokesman said that the-company- now; would end (LS. sale of its old. domesti-._ catty produced inventories of the chemicals? aud resale in this country of foreign-made supplies of: the chemicals. But lietsaid Dow would continue to make its Now i? Zealaud- plant for sale in-- New?ealand.? ustraiia and other countries. The'conipany . lsosaid it. would cancel all of its remaining registrations for product's containingr . the. chemicals. - The i-li-?A said the pesticide'lnciudes di- oxin as :1 byproduct. liioxin has been linked to skin irritation and possibly to cancers. i 4 .1 ii 4' far. .. 12"" . 1-.- 'reaa Envi- will ught ed at day. it the iidn't con- i for "it is dule em- 2 to hat my id- EPA, Dow near-deal on dioxin-laced poison By an PETYKIEWICZ . N-whouae News Service . WASHINGTON Lawyers for the Environmental Protection Agency and Dow Chemical Co. have reached agree- ment on key parts of a proposal that would permit increased use of a herbi- cide containing traces of the deadly waste product dioxin. Described by sources as a ?draft document," the preliminary agreement would reduce the acceptable limit of dioxin within the herbicide 2.4.5-T in exchange for easing restrictions on its use. The EPA curbed use of in 1979 when an agency study linked it to miscarriages in seven women shortly after the weedkiller was used near their homes in Oregon. While that study has been widely criticized as scientifically weak. others concluded that the herbi- cide caused cancer in laboratory ani-. mals. Dioxin has been found in several sites across the country. including Times Beach. Mo., where the federal government has announced it will buy dioxin-contaminated land from home- owners. Recently published studies indi- cate dioxin also is present in small quantities in numerous rivers and streams in Michigan. . Dioxin is an unwanted but unavoid- able byproduct of several chemical manufacturing processes. including that for and is considered by numer- ous researchers and scientists to cause cancer in humans. Negotiations between Dow and EPA started after Dow sued the'agency over the 1979 restrictions ordered during the Carter administration. Shortly after the Reagan administration took office. EPA was instructed to reach an out-of-court settlement with Dow. once the chief maker of 2.4.5-T in the United States. ?It is fair to say that we have made progress." an EPA attorney said Wednesday. ?but i have.to emphasize that this is not completed. There are issues to be resolved.? Spokesman for Dow also stressed that a final settlement has not been reached. Several other chemical compa- nies besides Dow have participated in the negotiations. but the Michigan- based company has taken the industry lead. Both EPA and the chemical compa- nies are reviewing the areas of prelimi- nary agreement, according to-sources who say the. adverse publicity surround- ing allegations, of mismanagement with- in EPA as well as the dioxin contamina- tion of Times Beach have slowed the rush to reach a final settlement. don?t see how EPA. in today's ?environment, could announce a settle- ment on this; the politics are just not right,? a_ source said. Industry guidelines established sev- eral years ago recommend that dioxin levels in should not exceed 0.1 part per million. Most chemical compa- nies kept the level at 0.01 part per mil- lion, 10 times lower than the industry standard. menta Staffo. ronme. I any said Se Sen organiz its func Sen. son. Mi: of inevi: Crar the Den ?Itlr signed. (Secret: signed.? Sen 'content won't I dent's policie: Sta agency might' "Win?. .9725: - fiwrgr?. 1131?? ., . . #315 if" *v?ii? . I I Jet-13333Wm; 1.9: 1.3.133?? - 1 Ir 15-11? 11711131?? 1?11:. w! i . .I .3 3F: .g-Jlg? 653.I:.:1v4f2.II lax-.I'm? - . it. *Hfm-II-gwwe n: - remove-w rte-e err-unmet- "twentieth-neeunen-.any neg-3el'" .- Foresters call herbicide? ban political move. or tome truce Cantrell?wt. the cup?I- HIDLAND. hitch. Forertry ederttlele end cheer lcei industry [root the redee- e.l hen on the tree oi two here been ee- geged In lour-dey. eroond-the-eloch oi the report upon which the Endmornentei Protectbn in decision. The eonseneue Sunder wee thet the EPA manipu- leted dete in "e glertng oi eecrlilc- log ecleore lor politicel eepediency." eccordlog to one member at the group. Michael Newton. o! loreetry et Oregon State Unleereity. "Ale don't underetend It.? eeid Gery Jonee. when- men [or Dow Chemical Co? the principal menufectur- or or ltd-T. one oi two herbicidee hearted by the EPA ieet week. "We thought we were getting eion well with the he eeld. ?We?ve been working very timely with them. Thle hit tee like I belch.? Although eerlier reports etld there eppeered to be en cenee end between epreying oi 2.1.5-1' end rhlecerriegee in Aim. Dre. the EPA tut week mpeoded tree ol the! herbicide end Siluee hr cenee ?studies thow high miscarriage rete len- following the epreylng oi 2.1.5-T in the loreete eroded Sllree eleo eonteine rnlnute teecu oi chernieel oonumlnent. TCDD. one of dioelne the EPA In the pen hee linked with birth doinctelnd m. odd that elthough Dow. with heedquertere in Midlend. heen?t oillcieliy been noti?ed by the EPA oi the moonstone: order. the oom- my will ruin the decision through the lederel need- t'y'e epneliete chenneie. An EPA epohceroen eeid the: noti?able-n wee cent by regletered mail to ell chemi- tei leer. Thunder. - Oti'irtele of Dow celled the meeting to work out etreteg: to tight whet It end other herbicide end erucpute It the meeting included oil end Oregon Stete Univereity lore-my who here lent their upentee to the "line- the oi the ?Ne etndy. The egeney etudied ele yeere oi bon?re] records In the Attee em. where the treaty emu-ted won-ten hed been ?honed to herbicides in Mellie end In hlei- heltr County. wee chooen ee en other: ?con- trol" one end htelheur County wee chosen ee the run! ?mount" ee Iocetiooe where the herbicidal were ootueed. - The egeocy ctelcned It loonde delinlte reietlonehlp between "heevy herbicide entering end mleoer- The epreylng wee during Mereh. April end Hey. the EPA report rules. In June. en incensed ember ol wee reported. end Induetry It the meeting believe the etndy eteiree number or unreported without documentetlon thet woolen In the when control one oi Coreeilie were not eepoeed to 14.5-T or Silver. ellhough. to record: euppiled to The Oregonlen learn three retell outlet: in et $00 geilone or en herbicide used for controlling iewn weeds in urben end containing Sileel were sold during the int yeer. ?'lhe roret control eree ln Helheor County is In the middle ol the Veie project on lower Melheer River. Although the EPA we: told by the Benn or bed thet 11.5-1' hes not been and on our tend eince [912. the rurel control era is peaked" on need no common exrlcuiterel tools. enumed that the June peek in mixer- rtegu wee ectueiiy deleyed effect of herbicide wee-ring. The EPA did not check tor June peeks to other ervee ernund the country. Hnepirele in Mid tend eel Mien-u ehow June peeks in orient-rune for which obetetrteiene here no eeplenettnn. --The EPA relied to piece elenrilcenee In there-ct the! It the ectuel tlnre ol securing. the rete ol rniecer- rtege wen et in lowret. l?ubere Blunt. deputy dino- It! the EPA. hed end when the wee met the hen wee heceuee EPA etu- hreh lnridence ol ertlecerrtege lltr-l'eehwreg the noreetng oi nonete to the rem to term . the notion thee the mar-en In the Alan em end tn. morn ere-:1 were "Inner re ee- enee rune-e he tore. HM and the ell-nee helrttew-el dill-revere 'h Hun?me . In to [mutton lettering dinner where eeriety or . - - t-tcR?22?1993 ltZizj-l E.F.F. TD PW 'ilil'iTl?lEF- r? ?1 New View Calls Environmental Policy Misguided ll What Cleanup? . were ased on ttle if any sound re threaL Since 1980. for instance, thou- sponded to poisoned streams and ?lthy restrict commends that had caused. ment. many scientists. economists and cancer. in rats or mice, even though these animal studies often fail to pro? sands or regulations were written to . air with the world's lirSt comprehen- sive strategy to protent the environ- dict how the compounds might affect. humans. And with rare exceptions, Congress approved new laws without subjecting - I them to even rudimentary cost-benefit - analyses. One reason was that during .. the 1980's. when the economy seemed . healthier, there was far?loss pressure: on Congress to'tonsidcr the cost of - envirOnmental policyMisguided? it . a result, low scientistsand pub- I or ?a m. Tm New s-new Administration intent on no health spewrlists?say. billions 'of: Times Beach? environments} policy_is dollars arewarted each year in bat-n settling 'into office when competition problems that are-no longer confor same financial resources is keen. sidered especially dangerous. leaving go?ng' that the Eng?imr?m?nm 1:15:90 At the same time. sI_weolth of new little money for others that cause for Lion Agency estimates cost more than research shows that some of the na- Govom'rnent officials have reached the dismaying conclusion that much of America's environmental program has gone seriously awry. - 1- These experts say that in the last 15. it years environmental policy has too -..-. often evolvedulargely tn reaction to popular panics. not in response to sound scientific analyses of which envi- ronrnentol hazards present the great- By KEITH SCHNEIDER - Smllumli" ?m Search about the true nature of the WASHINGTON. 2? A 8811' First snide nt?a series. eration alter the United States re- 94 moreharm. - . $140 billion a year. roughly $100 billion 'tlon-s environmental protection efforts At Fit-st. Clear Bene?ts spent by industry and $40 when? ltire ?c?gswelyc?oosfu?f ?13:31-20 no ?Wm! 13 1 3. ?In the first wave of the modern envi~ Gwemme?L ron'rnental movement. starting about 30 years ago. the focus was on broad But what is now becoming apparent, some scientists and public health spe- spent and devoted to- the wrong problems. . . . This view is the van uard of new, efforts to eliminate the most visible .c1alists say. as matsome of these laws 8 . . it v. vi pollution pouring Afrom smokestadts written ?389110? ?3 130er com ?vegpiggigioe; magmiitsbmegha: 11: and sewer pipes programs with terns about waste dumps Ol? 83-, I . c138? 80315 that had bena?m hams the $4309?. examples - - Continued on Page?. Column 1 Slant 3 second wave began in the late - 1370's. with a new strategy intended to - - - limit visible pollution further and to begin attacking invisible threats from toxic substances. . To that end. state and Federal'gov- ?rnments began writing sweeping envi- - ronmental laws; some of which includ- ed strict regulations to insure that cer- tain toxic compounds were not present in air. water or the grout-lost levels that did exceed a few parts per billion. concentrations that could be measured with only the most sophisti- cated equipment. . result was" a tangle of regula- mom: '5?.th ?rc GWEN. @311" Careful Path to New Justice President Clinton met with top advis? er: on choosing a replacement {or Justice Byron White. focusing nat- . on names or qualifiutions but best timing and mechanics for the - - m1 53 nomination. Page 26. Post-It? brand fax transmittal memo 7571 ?feasts 5 Grouting UD With Hui-V. ?g From pm .3 A growing number of children born Co. Co. 5' 3 i with H.l.v. are surviving longer. even t: r_a_ g. into their teens, raising new medical Dept. an 51- issues and a host of difficult a 3- logical questions. Page 33. E6, 8. . . . to: rm Continued From Page i the late 1980?s among farmers. home- owners and others who were upset largely by the growing cost of regula- tions that didn't appear to bring any measurable benefits. Corporate execu- tives had long been making similar arguments but had gone ?even during 12 years of. Republican role, because often they were seen as interested only in saving money. Richard J. Mahoney, chairman and chief executive n'i Monsanto, the chem- ical company, said the nation may start li5tening to industry now. "People want to know, even with the envi- ronment. what we are getting for our mon? ey," he said. "The most positive thing since the elecuon is that we are beginning to recog-' nice that we do have finite resources. and one must make choices." . But leaders of the nation?s conservation organizations believe the new view is mis- guided. "We don't need a new paradigm,"4 said David D. Doniger. a senior lawyer with the Natural Resources Defense Council. ?For 35 years, the policy of the Governmenthas been that when there is uncertainty about a threat .it is better to be safe than sorry. When you are operating at the limits of what science knows; the big mistake would be to underesti- mate the real danger and leave pcopleunpro- tamed." . - Still. in the last few years the wave has moved into universities. city halls. State capi- tols and even to the highest levels of the EPA, whose Science Advisory Board in'lm cancluded that environmental laws ?are more re?ective of public perceptions of risk than or scientific understanding of risk." - tsw'roitows Paolo 2? William K. Reilly, the E.P.A. Administra- stor at' the time. agreed. And in a recent interview in his office at the World Wild?re ?fEund. he argued: ?People haves right to choices for the right reasons. Weneed "?lo develop a new system for taking action on the environment that isn't based on respond- r'mg to the news. What we have had in the United States is environmental agenda- tting by episodic panic." - I Richard D. Morgenstern. the acting admin- {Strator for policyplanning and evaluation at ?the E.P.A., explains the problem this way: I 1 "Our society is very reactive, and when Inconocrns are raised people want action. The problem in a democracy is you can't easily =sit idly heel: and tell people it would be better learn more." The result. he added. is that "we're now in the position of saying in quite a few of our programs, ?Oops. We made a mistake.? President Clinton is clearly aware of this view. As Governor of Arkansas. he continual- 1y complained as a Federal toxic waste - cleanup prOjBCt in Jacksonville devoured $25 million in state. Federal and private money. State officials said nearly a decade of work has produced little more than piles of techni- 'expect that public officials are making the .- I one NEW YORK TIMES NATIONAL SUNDAY, M. ew Debate Over the Environment: 1: ,l-vuv': A principal author of the Superfund law of 1980. Gov. Jim Florio of New jersey now so: clean up a rail yard in downtown Newark so it can be a drinking Water reservoir," in i '3'33 titlUllt UlL-l tJ 'i'o lur surc. hiil'llt' of Sl-ttl billion liltr nation is spending this year pays lorenvn?on- mental programs that are indisputably use- . ful. As an eitarnpler few experts question the I value of spending roughly 53 billion each year on new sewage treatment plants. Many eit- perts. however, question the wisdom of spending billions of dollars to protect people from trans of toxic compounds. . The new school of thought has blossomed - as policy makers confront planetary threats like global warming, ozone depletion and deforestation ?in which the consequences of wrong action are much greater. Unless the nation rethinks its approach to environmen- tal protection. some experts say, the United States could repeat its mistakes: . ?The President is aware of this dilemma. and there is leadership in this Administration for trying to change the way we do business in every aspect of governing. including envi- ronmental protectioan said Carol M.. Browner, the Administrator of the Environ- mental Protection Agency. ?We have to al- 5 low for change to occur as new information becomes available. This isnot an area where a solution will fit forever." till: 3:4 Pulley Now Costly Solutions Seeking Problems . Almost everyone involved, including com- munity and local envtronmentai groups. agrees that the toxic waste program stands as the most wastefulcffort of all. It began 15 years ago when the nation. rose in revulsion over the discovery of seeping chemicals at Love Canal in New York. Hundreds of people went: evacuated'from their homes. in response. Congress passed two-laws: the Superfund law of 1980 and amendments to the Resource Conservation and Recovery Act in 1984. A decade later, those laws have driven the Government to spend almost $2 billion a year for the Superfund, which cleans up toxic waste sites. and more than $8 billion more a year on similar programs in other agencies. even though many of the sites pose- little if any danger. . - - ?Does it make sense to spend millions of dollars cleaning up a site that only has a' tenth of an ounce of contamination?" asked Dr. Richareroodwln. a'private environmen- tal engineer in Upper Saddle River. who has overseen more than 20 toxic waste clean-. ups. ?i say no. All we're doing in most cases is throwing money at a problem without improving public health or .the environ. LII . Rush 13. Kaufman. a hazardous waste spe- cialist at the EPA. who helped uncover the problem at Lave Canal. said that in the few cases in which a site is near populated areas, ?the best thing we can do is evacuate people if they want. then put up a fence and a flag that says stay away." Mr. Kaufman said he?ltnows that his idea represents a marked change in the tradition- at ?ew of how the nation should care for its land. But he and other experts says it does "not make sense to clean up these wastes at cons that frequently exceed $10 million an acre. Even a principal author of the Superfund 'law. Gov. Jim Florin of New Jersey, who was chairm an of a House environmental subcom- mlttec in the 1970's. noyv argues that the A worker wearing protective clothing as he removed soil contaminated with toxic waste in - Mickey Oiiemld'lt'l' for The New vol-ll 7mm Some is years after hundreds of people left the Love Canal area of Niagara Falls, N.Y., after the discovery of seeping chemicals. some homes remain boarded up. I sources are too often devoted to making sites pristine. ?It doesn't make any sense to clean up a rail yard in downtown Newark so it can be a drinking water reservoir." he said, Speaking rhetorically'. . Toxic waste cleanups are one example of a program gone awry. Here are others; tiEarly in the 1930's, Government scien- tists argued that exposure to asbeStos could cause thousands of cancer deaths. Since a5- besios was used as insulation in schools and public buildings. parents reacted with alarm. 50 in 1985 Congress approved a sweeping law that led cities and states to Spend between $15 billion and $20 billion to remove asbeStos 1mm public buildings. But three'ycars ago, the E.P.A. completed research that ed officials to admit that ripping out the asbestos had been on expensive mistake; the removal otten sent tiny asbestos fibers into thelair. Now, except in cases when the ashes.- tos is damaged or crumbling. the Govern- ment's official advice is: Don't touch it. ?lIn 1982. high concentrations of dioxin were discovered in the dirt roads of Time-3 Beach. Mo, near St. Louis. Residents were alarmed; the Government had designated dioxin as one of the most toxic substances. known. The furor came in the middle of a scandal at the the agency's chief, Anne Gor5uch Burford, was accused of not enforcing environmental law and being too close to industry. And as that-scandal domi- nated the news. the Reagan Administration decided to evacuate all 2,240 residents of Times Beach, a project that cost the Govern- men1537 million. But new research indicates None of the former residents of Times Beach have been found to be harmed by. dioxin. and two years ago, Dr. Vernon N. Honk, the Federal official who urged the evacuation. declared that ho had made a mistake. Yet even as enormous sums of money were being spent on these problems, Washington was doing little about others. Here are two: tllillercury. a highly toxic metal. has con laminated thousands of lakes aeross the na- tion, poisoning Wildlife and threatening 'hu- man health, state environmental officials say. Twenty states. including New York, have ported warnings at lakes urging people not to eat the fish because they are tainted by mercury. which can cause nervous system disorders. But during debate on the Clean Air Act, in 1990, Congress considered limiting mercury emissions from coal-homing elec- tric plants. The lawmakers decided not to not because they believed utilities had already been asked to spend enough to control. acid rain, Senate'and House leaders said. ?lIn the last two years. several Federal agencies have Called exposure to lead the largest environmental threat to the nation?s children. Although some scientists dispute that. several Studies have shown that lead poisoning in children leads to reduced intelli- gence. learning disabilities and hyperactivi- ty. The problem is that most houses built. but ore the 1970?s could have some leadsbased point, and the fear is that children are eating point chips or inhaling lead'laden dust. Some experts have said removing the lead paint will cost at leaSI $200 billion. This year, the Govemmenl will spend $234 million on the problem. far less than it spends on cleaning Superfund cleanup project. Once completed a child could eat half a teaspoon of dirt every .mc Es. W1 Mi: Eve edge Chang: posed the let . pass." Alto inaccu in?ue?r ment presen Dun SUCCES ronmc River examp Act. Al Act, tli landm: that or By i Congre strictc: Reasal reduce and QC enviml news public paigns reguisi live at bills th In th tyrant bills on The re manda Admin? them. said hi Gaverr. opinion wrong pretty .- At th membc envipor ?It's Daniel Warml Club. an eco: ronmer But sues s: becomi tary lo' and pr devisin. ?we thus lo: the nth: health: or ?nix?con?ne: .Lu-qr lU l-?Hl YORK TIMES NATIONAL SUNDAY, MARCH 21, 15593 CnVironment: Is US. POlicy Misg?ided? \v I . I. - mg!? l' I?lhgzu non-3.319: Ali??New Times} of 1980, Gov. Jun Flono of New Jersey now says that resources are often devoted to making sites pristine. "It doesn't make any sense drinking water reservoir,? he said. speaking rhetlorically. referring to a site like the one. above. Notional Research Councll .or the National Academy of Sciences. Making Dirt Safe to-Eait Perhaps no onvlronmental program has come under more criticism than the Super- fund and its progeny. The Federal?progroms to clear toxic or radioactive wastes will con- sume mare than one-quarter of the roughly $38 billion that the Federal Government spends for environmental protection this year. Experts In and out of the Government assert. though. that the justification for these expenditures is often questionable. Consider the case of Columbia. Miss. The EPA. is Overseeing the last phases of a 520 million Superfund cleanup. project therei: Like many others around the country, this-1 one was guided by the'Govemment's as- sumptlon that children will eat dirt. Lots of it. And from that dirt. the (invernment theo- rized that they could develop cancer. Some evidence suggested that this was an exaggerated concern. In 1981.21 Study for the Congressional Office of Technology Assess- meat: which has been endorsed by the No- i i l. ACaseStudy I is he removed soil contaminated with toxic waste in Columbia. Miss. part of a $20 million letod a child could eat half a teaspoon of dirt every_month for 70 years and not get cancer. A II Gm Campbell tor The .nl?rfnf' . 0 . nail slimy Osterr?cm for 1110 New will; Times 2 left the Love Canal area of Niagara Falls. micals, some homes remain boarded up. 3 None of the former residents of Times Beach have been found to be harmed by dioxin. and two years ago, Dr. Vernon N. Hook, the Federal official who urged the evacuation, declared that he had made a mistake. Yet even as enormous sums of money were . I .. being spent on these problems. Washington ?was doing little about others. Here are two: - ?Mercury. a highly toxic metal. has con- taminated thousands of lakes across the na- tion. poisoning wildlife and threatening hu- man health. state environmental officials say. Twenty states, including New York. have posted warnings at lakes urging people i not toeat the ?sh because they are tainted by mercury. which can cause nervous system disorders. But during debate on the Clean Air Act. in 1990. Congress considered limiting memory emissions from coal?burning elec- tric plants. The lawmakers decided not to not because they believed utilities had already been asked to spend enough to control acid rain. Senate and House leaders said. illn the last two years. several Federal agencies have called exposure to lead the largest environmental threat to the nation's children. Although some scientists dispute that, several studies have shown that lead poisoning in children leads to reduced intelli- gence. teaming disabilities and hyperactivi?_ o?II?-l I?o' before the 1970?s could have some lead-based paint. and the fear is that children are eating paint chips or inhaling lead-laden dust. Some I experts have Said removing the lead paint i will cost at leaSt $200 billion. This year. the - Government will spend $234 million on the 3 problem. for less than it spends on cleaning ty. The problem is that most houses built 3. Path to Policy When Politics Mixes With Fear Even the advocates -of change acknowl- edge-that as science evolves. experts may - change their views again on the dangers posed by these and other substances. But at the least. ?sound science should be our com- . pass." as Mr. Reilly put it two years ago. After all, it was politics. misinterpreted or inaccurate scientific findings and a newly influential national environmental move ment that combined to set America down its present path. .- During the 1970's, the United States had successfully dealt with'many obvious envi- ronmental problems. When the Cuyahoga River in Cleveland caught fire in 1969, as an example, Congress passed the Clean Water Act About the same time came the Clean Air Act. the Endangered Species Act and other landmark environmental statutes laws that are now widely acclaimed. By the late 1970's. many Democrats in Congress believed the public wanted even stricter environmental law. But when Ronald Reagan was elected in 1980; he promised to- reduce regulation. While the White House and Congress battled over this. the national envxronmental movement, with help from the news media. took on the lob of warning the public about new threats and creating cam- paigns toenlist p0pular suppon for new regulations. They were spectacularly effeo tive at this. and Congress passed two dozen? bills that laid down a welter of mandates. in the 1970's. environmental statutes rare- 1y "ran more than 50 pages In the 1980's, these bills seldom numbered fewer than 500 pages. The reason was that Congress wanted to mandate safety limits so specific that the Administration could not ignore or evade them. Mr. Reilly, the former E.P.A. chief.? said he was largely unable to change the Government?s thinking. despite his strong opinion that environmental policy was en the wrong course, because "this represented a pretty significant change of direction." Legitimizing Pollution? At the leading environmental gmups, staff members dispute the developing view that envtl?onmental policy is off track. - - "it's an effort to legitimize pollution." said Daniel F- Becker, director of the Global Warming and Energy Program at the Sierra Club. "There are powerful forces who have. an economic stake in devemphaslzing envi- ronmental damage." But others who analyze environmental is- sues said thcse groups are in danger of becoming the green equivalent of the mili- tary lobby. more interested in sowing fear and protecting wasteful programs than in devising a new course. "We are in danger of lostng?credibility and thus losing public support if we don't modify the whole way we go about protecting public health and the environment." said Dr. Devra NW York . the agency set a limit low enough that a chil l; DSTI U5 :ll ill illi- merit. 'Ihls finding. however. has had little tnllucncc on Federal policy. The problem in Columbia was an Ell-acre site that over ils long life had been home to a lumber mill. a naval turpentine and pine tar plant and a chemical manufacturer. Soil tests taken in 1986 showed traces of compounds the Government defines as haz- ardous. The concentrations rarely exceeded 50 parts per million. or about two ounces of chemicals mixed in a ton of soil. But that level exceeded the Federal limit. and the Eli-?foil. placed the land on its lISt of dangerous toxic waste sites. - Some experts told the E.P.A. that such tiny amounts of contamination were harmless. ?They said the safest and most economical way to solve the problem would be to spread a layer of cleaner soil and call it day. The - cost: about $1 million. But two years ago. the E.P.A. settled on the most expensive possible solution. The Gov- ernment ordered Reichhold Chemical, th plant?s former owner. to dig up more the. 12.590 tons of soil and haul most oipit to commercial dump in Louisiana 450 dum' .truclt loads. each one costing $7.500. E.P.A. oificials said they wanted to mak' - the site safe enough to be used foran purpose. including houses though no on was proposing to build anything there. Wit? that as the goal, thesgency wanted to malt sure children could play in the dirt, even ea it, without risk. And since a chemi'cdi in th dirt had been shown to cause cancer in rats could eat half a teaspoon of dirt every mont for 70 years and not get cancer. . .. Last month. the EPA-officials acknow edged that at least half of the $14 billion in" nation has spent on Superfund cleanups was_ used to comply with similar ?dirt-eating: rules.? as they call them. ?i don?t think any way you look at this I could be seen as a practical solution." said Scott Phillips. an engineer with Malcolm Plrnie. an environmental planning company. that manages the cleanup. "it's a lot oi? money to spend moving dirt.? . I . . Next: The debate over ocean dumping. The New York Times. . 3 First thing in the morning. For home delivery call - Zu- 4" Ne w: Re lease For immediate Release Subject: PESTICIDE REGISTRATION REVIEW DRAFT REPORT RELEASED OTTAWA, Ju'ly 11. 1990 -- The federal Pesticide Registration Review Team today released its preliminary report outlining a proposal for a revised federal pest management regulatory system. This report is designed to solicit the views of Canadians prior to the Review Team submitting recommendations to the Minister of Agriculture in December 1990. The Review Team, which is independent of the federal government, began its work in June 1989. It consists of 12 individuals representing agricultural users, consumers, environmental groups, forestry users, labour, the pesticides industry, and public health groups. Or "Extensive negotiations and discussions have taken place during the past year. Despite their diverse interests. the Team members have developed a high degree of cooperation and dedication in dealing with this complex task. The Team believes that it has developed a proposed new system that is a significant improvement over the current one? said Leblond, Review Team chairman. All of the Review Team members. except the representative from the Canadian Labour Congress. have signed the preliminary report. The Team insisted on the need to ensure public input throughout the entire exercise. The public is now invited to participate through written submissions and/or attendance at public meetings in the fall of 1990. "We are looking toward to hearing the views of Canadians at public meetings scheduled in each province and territory this fall," said Mr. Leblond. Communique? Me rm l257/30 mwt?c? .NEJINVX. Vanguard Building Room 70] 1"1 Slater Street Ottawa. Ontario KIA 0C5 Edificc Vanguard Pi?ce 7'01 1'71 rue Slater Ottawa.(0ntario) KIA 0C5 (615) 990-1437 (613) 990-1625 fax Canada" The report includes several key proposals: shared responsibility for making decisions on pesticides by the Ministers of Environment, Health and Welfare and Agriculture; significantly improved opportunity for public input throughout the process, including specific pesticide registration decisions; mechanisms to encourage the development of new pest management technologies that may reduce risk of harm to human health. safety and the environment; enhanced predictability and accountability of the federal regulatory system; more adaptiveness and responsiveness to changing science. technology and expectations of stakeholders including the general public; mechanisms to foster pesticide pricing discipline in the Canadian market. Following the public meetings, the final report will be presented to the Minister of Agriculture and released to the public. -30- For further lnfonnation. media may contact: Ghislain Leblond Chairman (613) 990-1437 or Hajo Versteeg Executive Secretary (613) 990?1437' Copies of the report. and further information on pUblic participation may be obtained from: The Secretariat Pesticide Registration Review 171 Slater Street, Suite 701 Ottawa. Ontario K1A 005 (613) 990-1437 Attachment: Dates and locations of public meetings SCHEDULE OF PUBLIC CONSULTATION MEETINGS Monday, September 24 2:00 pm. - 5:00 pm. 7:00 pm. 10:00 pm. Tuesday, September 25 2:00 pm. 5:00 pm. 7:00 pm. - 10:00 pm. Wednesday, September 26 2:00 pm. - 5:00 pm. 7:00 pm. - 10:00 pm. Thursday, September 27 2:00 pm. - 5:00 pm. 7:00 pm. - 10:00 pm. Tuesday, October 2 2:00 pm. -- 5:00 pm. 7:00 pm. - 10:00 pm. Wednesday, October 3 2:00 pm. - 5:00 pm. 7:00 pm. - 10:00 pm. Wednesday, October 10 2:00 pm. - 5:00 pm. Thursday, October 11 2:00 pm. 5:00 pm. 7:00 pm. 10:00 pm. Friday, October 12 2:00 5:00 pm. Monday, October 15 2:00 pm. - 5:00 pm. 7:00 pm. - 10:00 pm. Wednesday, October 17 2:00 pm. - 5:00 pm. 7:00 pm. - 10:00 pm. Thursday, October 18 2:00 pm. - 5:00 pm. 7:00 pm. - 10:00 pm. The following dates and cities have been selected for public meetings to be held in the fall of 1990: St. John's, Nfld. Northwest Altantic Fisheries Centre White Hills Charlottetown, P.E.I. Dutch Inn 4 Fredericton, NB. Fredericton Inn Ltd. 1315 Regent St. Halifax, N.S. Halifax Hilton 1181 Hollis St. Quebec City, Oue. Hotel Plaza Universe! 3031 Blvd. Laurier Ste.?Foy Toronto, Ont. Days Inn 7 Toronto Airport 6257 Airport Rd. Yellowknife, The Explorer Inn Postal Service 7000 Edmonton, Alta. Edmonton Inn . 11830 Kingsway Ave. Whitehorse, ?Yukon Westmark Klondike Inn 2288 - 20d Ave. Vancouver, B.C. Holiday Inn Vancouver Centre 711 West Broadway Regina, Sask. Hotel Saskatchewan 2121 Victoria Ave. Winnipeg, 'Man. Radisson Suite Hotel - ng. Airport 1780 Wellington Ave. News Release Communique Diffusion immediate Oblet: PUBLICATION DU RAPPORT PRELIMINAIRE sun LA REVISION DU PROCESSUS DES PESTICIDES I OTTAWA. le 11 )uillet 1990 L'Equipe d'examen du processus f?d?ral d?homologation des pesticides a publi? aujourd?hIJi son rapport pr?liminaire exposant les grandes lignes d'une proposition pour r?viser Ie systeme federal de lutte antiparasitaire. Ce rapport pr?liminaire a pour but d?inviter les Canadians a exprimer leur point de vue a I?Equipe avant que celle? ci ne soumette ses recommendations au ministre de i'AgricUlture, en d?cembre 1990. L'Equipe d?examen. qui est ind?p?ndante du gouvernement f?d?ral, r?unit douze membres repr?sentant utilisateursagricoles, leS consommateurs, les groupes environnementaux, les utilisateurs forestiers; Ies travailleurs, I'industrie des pesticides et les intervenants en sant? publique. "Des n?goclations et des discussions intensives ont eu lieu au cours de l?ann?e ?coul?e. En d?plt de leurs int?r?ts tres diversities, les membres de I'Equipe ont d?montr?' un esprit de coop?ration hors de i'ordinaire et une volont? peu commune de s?acquitter de cette t?che complexe. L?Equipe croit qu'elle a developp? un nouveau systems qui repr?sente une amelioration significative par rapport au Syst?me actuel". a d?clar? Ghislaln Leblond, president de I'Equipe d'examen. Tous les membres de I'Equipe d'examen, a l?exception du repr?sentant du Congres du Travail du Canada, ont appos? IeUr signature at cette proposition. L'Equipe a insist? sur la n?cessit? d'assurer la participation du public tout au long de I?examen. Le public est donc invite a presenter deS m?moires ?crits ou a faire des interventions orales aux rencontres publiques qui auront lieu a l?automne 1990. ?Nous avons hate de connai?tre le point de vue des Canadiens aux rencontres publiques pr?vues, cat automne. danS chaque province et dans .chacun deS territoires," a indiqu? M. Leblond. GISTHAT QQE-BE [04/19 egi In; Vanguard Building Room 701 1?1 Slater Street Ottawa, Ontario KIA Edifice Vanguard Pi?ee 701 17'] rue Slater Ottawa (Ontario) KIA 0C5 (615.) 990-1457 (615) 990-1625 fax Canard}; Le rapport contient plusieurs propositions-Clea:- une responsabilit? d?cisionnelle conjointe des ministres de I?Environnement, de la Sant? et Bien??tre social et de I?Agriculture en ce qui concerne l?homologation des pesticides;- une occasion slgnificativement meilleure de participation du public a .l?ensemble du processus et, en particulier. aux decisions d?homologatlon des pesticides; des m?canismes qui incitent le d?veloppement de nouvelles strategies de lutte antiparasitaire qui peuvent r?duire ies risques d'effets nuislbles pour la s?curit? des travailleurs, la sant? humaine et I?environnement; un systems r?glementaire f?d?ral dont Ia pr?visibilit? et l'imputabilit? reverent une importance d?terminante; un systeme plus souple, qui s?adapte mieux a I'?voiution scienti?que et technologique alnsi qu'aux attentes des groupes d'lnt?r?t et du' grand public; des m?canismes qui incitent a Line discipline des prix sur le march? canadien. A la suite des rencontres publiques, le rapport final sera remis au Ministre de I?Agriculture et diffuse dans la public. 30 - Pour plus de renseignements, ies m?dias sont invites a communiquer avec: Ghislain Lebiond Pr?sident (6i3) 990-1437 ou Hajo Versteeg Secr?taire administratif (6l3) 990-1437 Pour obtenir d'autres exemplaires du rapport ou des renseignements suppi?mentaires sur la participation du public, veuillez communiquer avec: Le Secr?tariat Processus d?examen de l'homologation des pesticides 171, rue Slater, Piece 701 OttaWa (Ontario) K1A 005 (613) 990-1437 Piece inciuse Lieux 9! dates des rencontres publiques Voici Ia liste des dates l'automne: CALEN DRIER DES RENCONTRES ES. Lundi, 24-septembre de 14h00 a 17h00. de '19h00 a22h00 Mardi, 25 septembre de 14h00 17h00 de 19h00 22h00 Mercredi, 26 septembre de 14h00 a 1_7h00 de 19h00 a 22h00 27 septembre de 14h00 a 17h00 dejehoo a 22hoo .Mardi, 2 octobre de 14h00. a 17h00 de 19h00 at 22h00? -. Merc'redi, 3 octobre de 14h00 :21 mm de tehoo a 22h00 Mer?cre'di, 10 octo'bre 'de_14h.00 51 171100 Jeudi, 11 octobre de 14h00 a 17h00 de 19mg 91 22h00 Vendredi, 12.0ctobre 14h00 a 17h00 Lundi,.15 octobre de 14h00 9: mm de 19h00 a22h00 Mercredi; 17 octobre de 14h00 a 17mm de 19h00 a'22h00 Jeudi, 18 octobre - de'14h00 a 17h00 de 19h00 a 22h00- St. John?s (II-N.) Northwest Atlantic Fisheries Centre - White 'Hills Charlottetown Dutch Inn. . FLR. 4 Fredericton (N.-B.) Fredericton Inn. It?e 1315, rue Regent Halifax, (N.-E.) . Halifax Hilt0n 1181 rue Hollis? Quebec (Quebec) - Hotel Plaza Universel 3031, boul. Laurier Ste-Foy Toronto Days Inn, a?roport de Toronto 6257, rte de I'a?roport Yellowknife (T The EXplorer Inn B.P. 7000 Edmonton (Alb.) Edmonton Inn .- 11 830', av. Kingsway Whitehorse (Yn) I Westmark Klondike Inn 2288, 29 av. Vancouver (C.-B.) Holiday Inn Vancouver Centre 711, West Broadway . Regina (Sask.) Hotel Saskatchewan 2121, a'v. Victoria; Winnipeg (Mam) Hotel Radisson, a?roport de Winnipeg 1780, av. Wellington et des endroits choisis pour la tenue des renco'ntres phbliqties qui abront lieu a. Da?girA' To: From: HOUSE OF COMMONS CHAMBRE DES COMMUNES FAX TRANSIISSION SHEET .94 ?93- ?70- PML Fax number: Ross Harvey M.P., Edmonton East New Democrat Energy Critic Room 635-8, Centre Block House of Commons Ottawa, Ontario K1A 0A6 Phone: (613) 992?2289 Fax: (613) 992-6864 Pages to followmore: wa?uw ,hnzi?) ak,lil?y xw?l?w?e W243 750 4 9x4! r/jrj?, 51 (7m31 a41k?tl auh,_ can?! Good #6-on ?lamentary OJICB rh Roon1635-S *3 Center Biock House of Commons 11? K1AOA6 ?ggag? phone?6131992-2289 faxl613)992-6864 engage Community O?uce HOUSE OF 11809 65 Sweet CHAMBHE DES EQmonton. Alberta CANADA m?wz phone (403) 495-6588 fax {403) 495-6751 ROSS HARVEY M.P.. Edmonton East 15 June 1990 Honourable Don Mazankowski Delivered by Messenger Minister of Agriculture Room 209-8, Centre Block House of Commons Ottawa Dear Mr. Mazankowski, RE: DIOXIN CONTAMINATION OF HOUSEHOLD CLEANSERS Oral Question Period; May 9, 1990 Hansard pp. 11187?8 During the past month, I have been hoping that you woui; have clarified answers that you gave during Oral Question Period on May 9, 1990. However, no such clarification has been forthcoming in the House of Commons. As a result, and given the technical nature of the subject matter, I am writing now to request that you clarify in writing the government's position on the important issue of dioxin contamination of household cleansers. In response to my first question concerning when the government knew "of the presence of TCDD in Santophen?I and, hence in Lysol", you referred to "the particular contaminant that he is referring to, namely Santophen." You then went on to state that use in Lysol was discontinued in the early 19808, shortly after it was detected as being a contaminant and harmful (I)t is no longer used in Lysol." It seems reasonable to conclude from your answer that there must have been some confusion here between Santophen?I (one of the active ingredients of Lysol) and TCDD (a contaminant of Santophen-I). Assuming this to be the case, I respectfully ask: (1) Has the use of Santophen-I in Lysol been discontinued in Canada, and if so, when? In response to my statement that "Monsanto's Santophen?I was only one of the brands of 2?benzyl?4?chlorophenol in Canada, and Agriculture Canada lists 56 pest control products containing you indicated that "(t)here may be 10 that have this contaminant, not 56." Given the aforementioned confusion, it is not clear whether- yOu are referring to Santophen?I or to TCDD as "this contaminant". This naturally raises the following questions: (2) How many pest control products listed by Agriculture Canada currently contain Santophen?I? (2a) What are the names, manufacturers, and distributors of those products? (3) How many pest control products listed by Agriculture Canada currently contain (Be) What are the names, manufacturers, and distributors of those products? You stated further that those chemicals ?that have this contaminant were grandfathered under the 1980 regime and they are now being analysed further" (emphasis added). It is my information that as of May 10, 1990, the Pesticides Directorate had performed no tests for the presence of dioxin either on 2?benzyl-4-chlorophenol or on Santophen~l. (4) Could you tell me what analyses are currently underway on these chemicals? (4a) Specifically, can you tell me if both 2-benzyl- 4?chlor0phenol and Santophen?I or any products containing these chemicals have yet been analysed in Goverment of Canada laboratories for the presence of TCDD or other dioxins? (4b) If so, what analytical techniques were employed and what are the results of these analyses? You also state in your reply that has not been detected because it is in such minute quantities, that is less than one part per billion (emphasis added), that we do not have the mechanisms and the machinery to detect it." I have enclosed for your information a copy of a paper written by Health and Welfare Canada employee John J. Ryan and others in 1983 entitled "Intralaboratory Study on Determination . . 1/3 of in Fish", which describes a study carried out over seven years ago to estimate the reliability of analyses for TCDD. The-detection limits of the seven laboratories tested including four in Canada ranged between 1 and 10 parts per trillion. In light of this evidence, your statement is clearly incorrect and besmirches the otherwise excellent reputation of Government of Canada experts. I would ask that you withdraw you statement in the House of Commons at the earliest opportunity. In any event, you comment suggests another question? (5) Have tests for TCDD been conducted by Government-of Canada employees on any pest control products, or on any active ingredients contained in any pest control products, listed by Agriculture Canada? (5a) If so, when were these tests conducted, on what active ingredients or products were they performed, what analytical techniques were employed, and what were the results of these testS? Finally, after suggesting that TCDD, in concentrations of "less than one part per billion", constituted "minute quantities" you stated that TCDD "in so infinitesimally small quantities would probably not be harmful" (emphasis added). Enclosed is a copy of an important article by Carol Van Strum?and Paul Merrell entitled "Fraud alleged in key dioxin human health studies" which contains new and apparently well?founded allegations that several key studies that have been relied upon for years were fraudulant and seriously understated the true danger that dioxins in minute quantities pose to human health. In light of this new information, I am very interested in receiving your answer to the following: (6) What is the scientific basis for your statement suggesting that concentrations of TCDD of one part per billion ?would probably not be harmful?? Thank you in advance for taking the time to provide thoughtful answers to these important questions. I look forward to receiving a reSponse from you soon. Yours sincerely, Ross Harvey M.P., Edmonton East Minister of Agriculture Ministre de I'Agrioulture 2% 1.990 Please Quote: 221603 Dear Mr.'Harvey: Thank you for your letter of June 15, 1990 concerning.dioxin contamination of household cleansers. Santophen?l is one of the trade names for the active ingredient (pesticide) In the summer of 1983, Monsanto, the basic manufacturer of SantOphen?l, voluntarily announced that they would no longer be marketing this active ingredient. In 1985 Sterling Drugs, the registrant of the Lysol products, applied to change the source of the ortho?benzyl?para~ chlorophenol in their products. The application was approved that same year in August. Attached is a list of the currently registered products which contain the active ingredient ortho? benzyl?para?Chlorophenol. . In 1980, Agriculture Canada instituted a procedure which required the basic manufacturers of pesticide active ingredients to update the chemistry information on our files. This included information on manufacturing and analytical methods. This information has been used by Departmental chemistry experts to predict the probability of dioxin contamination in the various registered active ingredients. - Mr. Ross Harvey, M.P. House of Commons Ottawa, Ontario K1A 0A6 Ottawa. Canada K1A 005 My officials indicate that the basic conditions for producing in chlorinated phenolics include high temperature and high pH. As the manufacturing methods for ortho?benzyl?para? chlorophenol do not include these reaction conditions, the probability that is formed in this case is remote. Product specifications submitted by the two current suppliers of ortho?benzyl?para?chlorophenol have confirmed this assessment. I can, therefore, confirm your statement that no testing of Santophen?l or of other sources of ortho?benzyl?para?chlorophenol for dioxins, has been carried out in Agriculture Canada laboratories. Departmental resources have, however, been devoted to analysing those active ingredients where the likelihood of finding contaminants is more significant. Please find attached Volumes 1 and 2 of the publication Portfolio of Recent Reports and Publications Relating to Pesticide Analysis? (1986 and 1988). These publications should answer your questions concerning TCDD testing, since they cover the work carried out by my Department's laboratories. In response to your final point concerning the toxicity of dioxins you may wish to consult the following publications: Dibenzo?p?Dioxins?: Criteria for their Effects on Man and his Environment, National Research Council of Canada Publication No. 18574, 1981. "Report of the Ministers' Expert Advisory Committee on Dioxins?, Health and Welfare Canada and Environment Canada, 1983. Thank you for bringing your concerns to my attention. Please do not hesitate to write again should the need arise. Yours sincerefy, Attachments NEW if" YORK TIMES Date 22 Page 4 A-zs are all hostages now. and by our own consent. it is our addiction to imported oil that has undone us. ?Just say no." Nancy Reagan used to advise the young tempted by drugs. Neither her husband nor anyone else of public consequence dared issue the same good advice to a vast public of all ages that was hapelessly hooked on oil. Jimmy Carter had tried something like it during his own Presidency and Reagan had ?attened him for it in the election of 1980. The Reagan people had recognized that Americans had a bad, bad oil habit. so bad that they were ready to kill for it. and certainly ready to shuclt off any President who tried to ease them toward a cure. The Reagan people chose to get ahead by going along. To be sure. even Carter's medicine had been feeble stuff. He asked every- body to set the thermostat lower. leaned on Detroit to make the cars a little more efficient. persuaded Con- gress to put up a little money for re- search on solar energy. He appeared on television sitting in the White House wearing a heavy wool sweater. A lot of us jolted or winced at that. Next thing you knew he'd be urging us to put on long johns for the winter. as though we were farmers or, worse. Britishers. Americans were delighted by the chance to put him away in 1980. When they did. the one feeble attempt to stop the big oil binge ended. After the Reagan landslide. research on solar energy was closed down The ancient American lust for his cars was per- Slaves to Oil ?the Japanese had successfully in- vaded America by offering low-cost. low-weight. fuel-efficient cars Detroit couldn?t match. But as the oil spree got bigger in the 30?s. so did Japanese cars. Bigger. heavier. more expen- sive. more like the old Detroit guz- zlers and more profitable to both dealers and Japan. By the late and Lin- coln were running television com- mercials in which uptown swells en- gaged in boasting competitions about whose car was bigger, longer. heav- ier, more mastodonic and. therefore, more appropriate for the very finest Americans to drive to the country club. The policy was It?s morning in America; live it up. Thus we made the entire country available to hostage-takers like Sad- dam Hussein whose threat to our oil supply now enables him to force us to choose among options in matters of war, diplomacy and economic stabil- ity, all of them decidedly nasty. if Saddam had not talten advantage of us. sooner or later someone else surely would have. and may yet, if the Saddam businw ends happily. When you are as vulnerable as we have made ourselves because of our oil habit. it is only a matter of time be- fore dangerma or foolish adventurers will dare have a go at you. The big men say. of course, that oil is not the only explanation for our war footing. Saddamlasaidtobeanother Adolf Hitler (sure. and John Dillinger wuanotherAttilathellin).andhia thd'tof Kuwait unidtobethesortof brutal emerald: against which we must be prepared to use all our might if necessary to avert bloody chaos. This call to serve principle and ternational morality is ennooii.z;. bu: if no oil were at risk would we really be putting armies and navies into Arabia? Drop the oil from the equation and the thuggish Saddam?s seizure of Ku- wait would be. to the United States. just another uninteresting incident in the tiresome tribal quarrels that divided the Arabs of the old Ottoman Empire before the British made such a mess of it in the First World War. Of course. without the oil all that money! Kuwait might not have at- tracted Saddam. Certainly nothing in the Middle East attracted the United States until there was oil. it is hard to believe that before the Middle East and oil became synonymous. ti: United States would have even a note of reprimand cs. 9. bore Chieftain like Saddam .21: 5.1231- izing one of the weaker art: as. President Bush says the American way of life is threatened. Lie appar- ently means our ability to pic?.: up :he carry-out fried chicken in the drive- by lane at the fast-food shop. as well as our power to sit one?commuter- per-car for 45 minutes every day on the way home from work. Hooked as we are on such joys. we may end by finding ourselves at war to preserve them. If not this time. then maybe next time. When you've- got to have oil or die. you put your destiny in the hands of the oil dealers- just as surely as the drug axis-.5 make themselves hostage- to the peo? ple Nancy Reagan wants you to ju. . 1 new YORK TIMES . - a Date my. . Oil and Gas Prices RISL page dDona-s Iy MATTHII mu.) Prices for oil and rue' yesterday after sharply during the day. earlyinthedaybutthen ilback- after a statement by President Sadi- damHusaeindlraqthatu-adersald' was less aggressivethanaxpectod. Crude oil for October delivery $28.71. having bounced from $23 to $29.45. But that was placid compared :ithdg?toline. tunic?; traded over a ma ante-gs range, equiva- lent to $4.82 a barrel. it closed at 2? no'llm em 1 n1 a??f "acted like a gorilla in a trampo- line." He added that in the current at- mosphere of uncertainty. speculators were afraid to sell 011 short. which means to promise delivery of ollthey donothaveAsareauLwhenothet-a who are ?big" decide to take agorofit by selling contracts for oil they not need. there are no ready buyem ?59. you get these quick whooehee down: he said. After trading ended yesterday. the- American Petroleum institute. the ins dustry's main trade association. re- leased inventory figures that will add ?bump- and.? and even if the ether OPEC members go to full capacity, there is Still a dif- ference between production and con- sumption of two million barrels a day." Withdrawn From Stocks . Demand is usually highest in the fourth quarter, because it is winter in the importing countries. but the ex- cess of demand over supply in that pe?od is usually only 500,000 barrels a day. said Mr. Verleger. who is a Visiting fellow at the Institute for In- ternational Economics in Washing- ton. The difference is withdrawn from stocks. he added. The gasoline market. meanwhile. UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460 July 20, 1994 OFFICE OF SOLID WASTE AND MEMORANDUM Subject: The Monsanto Investigation - From: William Sanjour, Policy Analyst To: David Bussard, Director Characterization and Assessment Division This is an analysis of the failure of EPA to investigate allega? tions that the Monsanto Company had falsified scientific studies on the carcinogenicity of dioxin. Background and summary Dioxins are highly toxic unwanted byproducts of certain industri- al operations including the manufacture of some pesticides. Dioxins are unintentionally created in chemical manufacturing processes when chlorine combines with other chemicals at high temperatures. - Agent Orange, a defoliant widely used during the Viet Nam war by the United States to eradicate jungle hiding places of the Viet Cong, contained trace amounts of dioxin. Since dioxin was known to cause cancer and birth defects in some animals, veterans, who had contracted cancer and who had been in areas sprayed with Agent Orange, attempted to obtain compensation from the Veterans Administration and from the manufacturers of Agent Orange. These manufacturers included Monsanto, Dow, Uniroyal and Diamond Shamrock. Since the chemical manufacturers were aware of the presence and toxicity of dioxin in Agent Orange and since the presence of dioxin could have been greatly reduced by more careful production techniques, a successful lawsuit by the veterans could have bankrupted some of the world's largest chemical manufacturing companies, just as a similar problem with asbestos had bankrupted the giant Johns Manville Corporation some years ago. However, the veterans won very little from the Veterans Adminis? tration and less from their lawsuits against the manufacturers. Their principal problem was the insufficient scientific data showing that dioxin caused cancer in humans. Even more damaging to their suit was the fact that, of the few studies of human exposure to dioxin in existence at the time, the ones where there were the greatest exposure to dioxin showed no significant increase in cancer. These included Monsanto sponsored studies of Monsanto workers inadvertently exposed to dioxin. Because of the sparsity of positive human data and the existence of the negative Monsanto data, the veterans, in 1984, had to accept a token "nuisance value" settlement. Eventually, scien- tific studies came to light which unambiguously identified dioxin as a human carcinogen, but it was too late for the veterans as the courts had closed the door on any further settlements. In February 1990, Dr. Cate Jenkins, a chemist at the U.S. Envi- ronmental Protection Agency, wrote to the EPA Science Advisory Board that there was evidence that the Monsanto studies were fraudulently done and that if the studies had been done correct? ly, they would have shown the connection between dioxin and cancer in humans. This accusation received considerable press attention. In August, 1990 EPA decided to launch a criminal investigation of Monsanto.1 Amid a furor of publicity and cries of foul and intensive lobby- ing by Monsanto the criminal investigation went on for two years. However, despite the government's assurances that it would "investigate any allegations of fraud and, if appropriate, evaluate the full range of enforcement options" it did nothing of the kind. Instead it investigated and illegally harassed the whistleblower, Cate Jenkins. In August of 1992, EPA quietly closed the criminal investigation without ever determining or even attempting to determine if the Monsanto studies were valid or invalid, let alone fraudulent. However, the investigation itself and the basis for closing the investigation were fraudulent. Jenkins' harassment was subsequently halted by order of the Secretary of Labor. The veterans were able to use her report to obtain increased Agent Orange benefits from Congress for Viet Nam cancer victims. Recent EPA reports say that there is now con? vincing human evidence of the carcinogenicity of dioxin, in contradiction to the Monsanto studies. This investigation has left the unanswered question: did Monsanto manipulate their studies in order to play down the danger of dioxin so as to reduce their liability to the Viet Nam veterans? And it has raised two more questions. Are t0p EPA officials more concerned with protecting their employment prospects with the industries they regulate than in protecting human health and the environment? And, are EPA law enforcement officials being used as an internal KGB to silence dissent? The Monsanto studies The story starts in Nitro, West Virginia at a Monsanto chemical plant which was manufacturing the herbicide (the princi- pal ingredient of Agent Orange, which contains traces of dioxin). In 1949, a runaway reaction at the plant caused an explosion releasing reaction material, resulting in many workers being doused with dioxin. In 1978, when concern about dioxin was on the rise and EPA was considering banning Monsanto sponsored several studies of the long range health effects of the workers exposed to dioxin, both from the 1949 incident and from workers otherwise involved in production, comparing their health with the health of workers who were not exposed. These studies were published in medical and scientific journals between 1980 and 1984 . Publication of the first study, in 1980, coincided with a time when Monsanto was defending itself in three different legal actions relating to dioxin exposure from their products. Monsanto issued a press release headlined "Study Fails to Link 'Agent Orange' to Deaths of Industrial Workers". All of these studies showed no statistically significant increase in cancers among the exposed workers. Because of the high exposures, these studies contributed to the conclusion drawn in EPA and elsewhere that: [T]he human evidence supporting an association between [dioxin] and cancer is considered inade- quate.? Monsanto's studies would promote the idea that human beings, unlike other animals, are relatively immune to this man?made chemical. Kemner V. Monsanto The story moves next to Sturgeon, Missouri, 1979. A freight train derailment caused the spill of a tank car, containing 19,000 gallons of a Monsanto chlorophenol intermediate called OCP-crude, used in making wood preservatives and contaminated with dioxin. Frances Kemner and others exposed to the spill filed suit in Missouri state court in 1980 (Kemner et al v. Monsanto Company?). The trial lasted three years and eight months. At the end, the jury found for the plaintiffs with a most bizarre award; nominal awards as low as one dollar for actual damages and more than sixteen million dollars punitive damages! The jury did not believe the plaintiffs had proven that they had suffered any harm to date, but they were outraged at the egregious behavior of the Monsanto Company. These are some of the allegations made by plaintiffs attorneysfz 3 Monsanto failed to notify and lied to its workers about the presence and danger of dioxin in its chlorophenol plant, so that it would not have to bear the expense of changing its manufacturing process or lose customers, Monsanto knew how to make chlorophenol with significantly less dioxin content but did not do so until after the Stur- geon spill. Monsanto knowingly dumped 30 to 40 pounds of dioxin a day into the Mississippi River between 1970 and 1977 which could enter the St. Louis food chain. Monsanto lied to EPA that it had no knowledge that its plant effluent contained dioxin. Monsanto secretly tested the corpses of people killed by accident in St. Louis for the presence of dioxin and found it in every case. Lysol, a product made from Monsanto's Santophen, was contam- inated with dioxin with Monsanto's knowledge. Lysol is recommended for cleaning babies' toys and for other cleaning activities involving human contact. The manufacturer of Lysol was not told about the dioxin by Monsanto for fear of losing his business. Other companies using Santophen, who specifically asked about the presence of dioxin, were lied to by Monsanto. Monsanto was aware that dioxin contaminated their lawn care products (which were eventually banned by EPA). Monsanto sold these and many other consumer products know- ingly contaminated with dioxin without warning the public for over thirty years. Shortly after a spill in the Monsanto chlorophenol plant, OSHA measured dioxin on the plant walls. Monsanto conducted its own measurements, which were higher than OSHA's, but they issued a press release to the public and they lied to OSHA and their workers saying they had failed to confirm OSHA's findings. Exposed Monsanto workers were not told of the presence of dioxin and were not given protective clothing even though the company was aware of the dangers of dioxin. Even though the Toxic Substances Control Act requires chemi- cal companies to report the presence of hazardous substances in their products to EPA, Monsanto never gave notice and 4 lied to EPA in reports. 0 At one time Monsanto lied to EPA saying that it could not test its products for dioxin because dioxin was too toxic to handle in its labs. 0 At the trial a Monsanto executive argued that it did not report what it considered very low levels of dioxin to EPA because it would merely "add fuel to the media fires." Of particular relevance to this report were the allegations that two of the Monsanto studies mentioned earlier, which showed no increase in cancer as a result of high levels of dioxin exposure, were fraudulent. At the time these studies were published, there was increasing concern about the carcinogenicity of dioxin as a result of animal tests. Plaintiff's attorney, however, argued that the data in the 1980 Zack and Gaffey and the 1985 Suskind and Hertzberg studies were finagled and if used correctly, would have shown a definite increase in cancers in the exposed workers. At one point, the plaintiffs-appellees' brief says: Dr. Suskind was cross-examined and shown to be such a fraud that he refused to return to the State of Illi- nois for completion of his cross-examination.7 Such allegations were argued in front of a jury for more than three and a half years, the longest running trial in history at the time. Monsanto fought these charges with the best lawyers and expert witnesses that money could buy. They had to; the downside risk to Monsanto was enormous. If the plaintiffs in the Kemner case could collect damages, then every user of Lysol, Weed-B?Gone, and dozens of other consumer products using chemi- cals containing traces of dioxin might collect damages and put Monsanto and other chemical companies into bankruptcy. In the end, Monsanto won the big issue. Since plaintiffs could not prove to the jury that they were harmed by the spill, the jury awarded them only nominal damages. Yet, despite Monsanto's parade of expert witnesses, the jury expressed its opinion of Monsanto's honesty and integrity by the unusual award of more than sixteen million dollars in punitive damages. Plaintiffs lost on appeal on the technical legal ground that a punitive award could not be made in the absence of actual damages regardless of the facts in the case. Only one of the three appellate judges discussed the facts at all. He upheld the jury's Opinion of Monsanto's behavior saying: By finding for the plaintiffs, the jury found that the misconduct alleged had been proved, and such finding was eminently reasonable and based on the evidence. It is not the purpose of this paper to re-examine this evidence. Given the time and effort that went into this trial, one is hardly likely to find a more through examination of these allega- tions into Monsanto's conduct. Monsanto studies fraud allegations raised at EPA Several years later, Cate Jenkins, a chemist at EPA was working on a project to develop regulations to control hazardous waste originating in the wood preserving industry. While col- lecting data on damages caused by these wastes, her acquaintances at Greenpeace brought the 1979 Sturgeon, Missouri spill to her attention. This introduced her to the Kemner Monsanto case along with its accusations of fraud in the Monsanto studies. Jenkins was aware that in 1988, EPA had published a risk assess? ment of dioxin?. This assessment contrasted the Monsanto stud- ies, which showed no human cancer, with other studies which did show cancers resulting from exposure to dioxin. The EPA risk assessment concluded that, in Jenkins' words, "the existing epidemiologic studies were conflicting, and did not provide definitive data on human health effects of dioxins, and thus EPA should continue to utilize animal toxicological data as a basis for dioxin assessments."9 Jenkins recognized that if the Monsanto studies were fraudulent, and were shown to be positive rather than negative, EPA would have concluded that there was human data, albeit limited, showing that dioxin causes cancer, rather than just animal data. This view was also held by Dr. William H. Farland, director of EPA's Office of Health and Environmental Assessment under whose juris- diction the risk assessment was developed. He wrote in 1993: In essence, the overall data base of human (epidemio- logic) studies was considered [in 1988] to be "inade- quate" for determining a cause and effect relationship between dioxin exposure and human cancer potential. If the [Monsanto] studies under discussion had been shown to be positive, the human data might have been consid? ered "limited" for making such a determination.10 (EPA uses a weight of evidence classification system for carcino? gens adopted from the International Agency for Research on Cancer (IARC). Carcinogens are classified into five groups based on decreasing weight of evidence: Group A, Human Carcinogens; Group B, Probable Human Carcinogens: Group C, Possible Human Carcino- gens; Group D, Not Classifiable as to Human Carcinogenicity, and; Group E, Evidence of Non-Carcinogenicity for Humans. Group is further divided into Group Bl, for which there is limited human evidence of carcinogenicity, and 32 for which there is inadequate human evidence but sufficient animal evidence.? EPA's Office of Health and Environmental Assessment had classified dioxin as Group BZ. Jenkins and Farland believed that if the Monsanto studies had been positive, the classification would have been Bl.) EPA's classification of carcinogens is not juSt for internal EPA use, it is relied on throughout the world, in governmental, health care and legal circles, as one of the prime sources of this kind of information. In many situations, a substance is treated as a human carcinogen only if it is in Group lower. Because of the apparent conflicts in human data, the idea began circulating that dioxin is not the big problem with humans that it was previously thought to be based on animal studies. Dr. Jenkins was aware of this growing groundswell of opinion and saw its adverse effects in her regulatory work and in litigation concerning dioxin emissions in the pulp and paper industry. Thus, when she saw the Kemner brief, she immediately understood its significance, and on February 23, 1990, Jenkins sent a memorandum to the EPA Science Advisory Board entitled "Newly Revealed Fraud by Monsanto in an Epidemiological Study Used by EPA to Assess Human Health Effects from Dioxins", attaching a copy of part of the Kemner Plaintiffs?Appellees? brief dealing with the Monsanto studies. She requested that the Board or the EPA Office of Research and Development, audit the records of these studies to see if they were flawed. Almost immediately, on March 9, 1990, Monsanto Vice President, James H. Senger, wrote to the chairman of the EPA Science Adviso- ry Board complaining about Jenkins' memo and offering proof of its falsity. (He did not explain how Monsanto had obtained a copy of the memo.) His concern, however, was unnecessary since the day before, the Board had written to Jenkins, rejecting her request, informing her that they do not conduct study audits and forwarded her memo, without comment, to the National Institute for Occupational Safety and Health (NIOSH) and the EPA Office of Toxic Substances. Within a few weeks, the story began appearing in the press. On April 6, Newsday ran a story headlined Questions Dioxin? Cancer Study". The Charleston Gazette of March 23 carried the headline "Key dioxin study a fraud, EPA says". This last brought a letter from the CEO of Monsanto to EPA Administrator William Reilly? calling for the Agency to publicly announce that Jenkins does not speak for EPA. EPA complied and in a letter to Monsanto's CEO, EPA Assistant Administrator Don Clay expressed his regrets for "any problems that Monsanto may have had as a result of the news medias's use of this memorandum."13 Veterans organizations reading the story, recognized its signifi- cance to the Agent Orange controversy. The Veterans Administra? 7 tion does not generally accept animal data in determining veter- ans benefits from exposure to carcinogens. The VA's position, stated in the Federal Register, is that the: VA does not believe it would be appropriate to adopt the IARC model, especially those portions which would apply "in the absence of adequate human data."? Thus, the difference between the El and 32 classification of the Monsanto studies meant the denial of VA benefits to thousands of Viet Nam veterans and their dependents. Criminal investigation of Monsanto In March, 1990 the EPA Office of Criminal Enforcement (OCE) also began to look into the criminal aspect of the fraud charges. In July, 1990, OCE instructed the Office of Criminal Investigation (OCI) to evaluate the material to see if a criminal investigation was warranted. A seven page response from OCI, written August 8, 1990 was very positive and recommended "a full field criminal investigation". The summary of allegations repeated just about everything in the Kemner brief. Potential criminal violations of three laws were cited; (1) the Toxic Substances Control Act (TSCA) which requires persons to report any substantial risk of their products to EPA and provides criminal penalties for knowing violation (15 USC 2615(b)), (2) conspiracy to defraud the United States (18 USC 371), and (3) making a false statement on a matter within the jurisdiction of any agency of the United States (18 USC 1001). On August 20, 1990, the criminal investigation was officially opened. The case "Opening Statement" concentrated on the charges of fraud in the Zack and Suskind study, though all other charges in the Kemner brief were included. Running the investigation was John West, Special Agent in Charge, Office of Criminal Investiga- tions assisted by Special Agent Kevin Guarino, both out of the Denver office. Completion was anticipated by March, 1991. Two days later, OCI informed OCE15 that they had opened the investigation, saying: Information in the plaintiffs brief indicates a poten? tial conspiracy, between Monsanto and its officers and employees, exists or has existed to defraud the Us EPA, in violation of 18 USC 371. The means of conspiracy appears to be by (1) providing misleading information to the (2) intentional failure by Monsanto to fully disclose all pertinent TSCA related information to the EPA: (3) false statements in notices and reports to (4) the use of allegedly fraudulent research to erroneously convince the EPA, and the scientific commu? 8 nity, that Dioxin is less harmful to health and the environment. The enthusiasm shown in these first three documents from OCI is short lived. One gets the impression, on reviewing the record, that as soon as the criminal investigation began, a whole bunch of wet blankets were thrown over it. Almost nothing appears in the record about the first three charges once the investigation began. The investigation concentrated on criminal fraud in the Monsanto studies. It is interesting to note that Jenkins never asked for a criminal investigation. She only requested a scientific audit of the Monsanto papers. Although she alleged fraud, which in legal terms is a criminal offence, not being a lawyer, she probably used the word in the common English sense of "cheating". It makes no sense at all to conduct a criminal investigation of allegedly fraudulent studies right off the bat. The logical steps are: step 1) A scientific investigation to see if the studies are flawed. If so, then_step 2. step 2) A scientific investigation to see if the studies would have yielded positive results if the data were used correctly. If so, then step 3. step 3) Scientific peers judge if it is "more likely than not" that the kinds of errors found could be honest mistakes made by competent professionals. I.e. whether the studies are fraudulent in the "English" sense. The decision of the Office of Criminal Enforcement to go right to a criminal investigation without having gone through these steps would prove to be a major stumbling block to the investigation. Its like trying to make tiger stew without first catching a tiger. The record shows repeated attempts by the DOE to get the Science Advisory Board or the Office of Research and Development involved, to no avail. None of the scientific groups in EPA, it seems, wanted to touch this hot potato, and no one in position of authority was instructing them to do so. Another wet blanket was the five year federal statute of limita- tions. The record is replete with concerns that the statute of limitations may have expired and the need to see if Monsanto had submitted these studies to the Agency in the last five years. For example, the August 8, 1990 memo says: One important issue in proving a criminal case is to determine what Monsanto has reported to the EPA during the last five years in regards to dioxin. Nevertheless, there is nothing in the detectives' reports of investigation or their status reports to indicate that any attempt was made to look for such submissions, even though, as we will see later, they do exist. Still another self-imposed impediment to the investigation was the fact that almost as soon as the investigation began, the investigators limited themselves to looking at only how the Monsanto studies may have affected EPA regulations. There is nothing in the statutes which says that providing misinformation to the government or conspiring to defraud the government applies only to regulations. To prove criminal fraud, given that cheat- ing has been established, it is only necessary to show that the U.S. Government (not only EPA) relied on these studies in some substantial way (not just for regulations) and that Monsanto tried to convince the U.S. Government to do so. A clue to the timing of this investigative reversal is provided in the Status Report for September, 1990. The report says: During the week of September 17th, [West/Guarino?] met with the following EPA Headquarters personnel regarding this matter: Though the names were struck out, the document lists two enforce? ment attorneys, two persons from the Office of Compliance Moni? toring of the Office of Toxic Substances, one person from the Inspector General's Office, and one from the Office of Solid Waste (OSW, Dr. Jenkins' office).' Although a record must have been made of these interviews, none accompanied the FOIA re- sponse, leaving one to speculate about what may have transpired. Following that, the status report says the investigators tried to set up a meeting with [Jenkins?] but were unable to. Dr. Jenkins says10 that she got a phone call from either West or Guarino trying to set up a meeting after office hours on her own time. She found this request rather strange and insisted that any interview would have to be on official time. This incident along with the other "mood" changes referred to above, gives one a clue as to what may have transpired during those meetings on the week of September 17th. First, it is reasonable to assume that the persons from the Office of Compliance Monitoring told the investigators that the charges relating to violations of TSCA were in the jurisdiction of the Office of Toxic Substances and were under investigation by them?. This may be why the investigators only looked at the charges relating to fraudulent studies. Second, the attorneys from the Office of Enforcement, one of whom was with the Toxics Litigation Division, may have emphasized the 10 statute of limitation problems and they may have given the investigators the idea that only the influence on regulatory matters was relevant. This speculation is based on a memo written by [Michael J. Walker?, Director,] Toxics Litigation Division about the Monsanto studies5 which says: The study may be 30 [sic] years old. This may preclude EPA taking action under existing statutes unless the study has been "presented" in the context of some request for regulatory action. (The memo adds the note that "If there is a criminal case being developed, we need to ensure that contacts are limited.") And lastly, one can guess that the person from OSW (probably Jenkins? supervisor, Michael Petruska, or his supervisor, David Bussard) must have told the investigators that Dr. Jenkins has a reputation as a troublemaker and whistleblower and that her memo to the Science Advisory Board was not part of her assigned duties and that he would not want her spending official time on this investigation. During this time, Monsanto continued its campaign against Jenkins. In October, an angry Monsanto vice president wrote to Assistant Administrator Don Clay"9 (to whom the Office of Solid Waste reported): The gross inaccuracy of these charges have been the subject of prior correspondence to the Agency by myself and by Monsanto's Chairman, Richard Mahoney. Notwith- standing our efforts to correct the record, these baseless charges have been widely repeated in newspaper accounts and even before a Congressional Subcommittee where the charges are portrayed as fact, thus giving the incorrect impression that it is the government?s view that the studies are misleading.? This too may have been part of the education the two detectives from Denver received at EPA headquarters in Washington. If this speculation is correct, then it would certainly account for their change in attitude. In any event, when West and Guarino finally got around to inter- viewing Dr. Jenkins (on official time) on November 14, they were just going through the motions. They pointed out the difficul? ties at every turn but did not follow up on any offers of Jenkins to supply information to overcome the difficulties. For example, she offered them the transcript of Kemner plaintiff's attorney Rex Carr's cross examination of Monsanto's expert witnesses which convinced a jury of Monsanto's guilt, but they weren't interest? ed. At the end of the interview, Jenkins, concerned at their lack of enthusiasm, told them that their investigation would be 11 closely watched by Congress and veterans groups.? Still concerned, Jenkins sent a follow-up memorandum to West and Guarino the next day. The subject was: "Criminal Investigation of Monsanto Corporation It began: You said that pursuing a criminal prosecution against Monsanto would require a prior determination of the significance of the fraud. In order for proceedings to be initiated by EPA, the fraud would need to have affected the regulatory process at EPA, and Monsanto would need to have knowingEly] submitted the falsified data and health studies to EPA in order to affect the regulatory process. The memo then proceeded to outline information which satisfies that need and offered to make the supporting documents available. Although Jenkins says she was not responsible for the leaking of her earlier meme? she made sure that this one received wide distribution by formally copying it to veterans groups, members of Congress, and environmental organizations, in order to shore up a sagging investigation. This was the first public announce- ment that Monsanto was under criminal investigation. On November 17, Jenkins accepted an award from the National Viet Nam Veterans Coalition where she also revealed the fact that EPA was conduct- ing a criminal investigation of Monsanto. Dr. Jenkins? memo and speech did indeed generate publicity. Although it was her wish that the public attention would put some backbone into the investigation, it had just the opposite result. The law enforcement officials were horrified that anyone would reveal the existence of a criminal investigation. Such behavior was contrary to the entire ethic of the law enforcement community where secrecy is a way of life. Dr. Jenkins was unaware of this concern until she received a phone call from Special Agent Guarino on November 20, asking her to refrain from revealing the that there was an ongoing criminal investigation. She told him it was too late, "the cat's already out of the bag you should have told me this when we first talked."? Apparently Guarino and West must have been under some heat from their management for the Jenkins revelations. Being unaware that Jenkins had tape recorded both the interview and the phone call, they falsified their Status Report for November, 1990, saying that they had advised Jenkins on November 14th "not to disclose, to the public, the existence of an ongoing criminal investigation" and that she had proceeded to distribute her memorandum of November 15th to the public after she had been requested not to do so. The report also says that "this matter 12 has been brought to the attention of the Office of Enforcement." Thus agents West and Guarino may have committed a felony by knowingly making a false statement on a matter within the juris- diction of the United States (47 USC 1001) and may have violated EPA ethics standards by making false and malicious statements about a fellow employee. After this EPA's enforcement interest focused on Jenkins rather than Monsanto, as shall be seen later. Meanwhile, towards the end of 1990, things were heating up. Greenpeace issued a detailed 44 page critique of the Monsanto studies by Joe Thornton entitled "Science for Sale"? which repeated Jenkins' allegations and added several more, followed by a petition to EPA to investigate the studies, and held a well publicized press conference. The Washington Post reported that: said yesterday it is looking into Greenpeace's charg- es." The Environmental and Natural Resources Division of the Depart- ment of Justice notified the EPA Inspector General that an "employee may have improperly disclosed confidential government investigatory information".? This was probably reaponsible for the?investigation of Jenkins launched by the Inspector Gener- al. The law firm which represented the Viet Nam veterans in their class action suit against Monsanto wrote to the judge to re-Open the suit based on Jenkins' memo.29 Office of Enforcement representatives were called to brief House and Senate staffs on the criminal investigation of Monsanto. They assured the staffs of EPA's commitment to look into Jenkins' allegations, a commitment which turned to be false. EPA also assured them that they would not harass Dr. Jenkins, which also turned out to be untrue.30 EPA Assistant Administrator Don Clay (who had previously apolo- gized to Monsanto for Jenkins' memo) accepted Monsanto's invita- tion to appear on the program for their annual Environmental Meeting in St. Louis although he said that on advice of counsel, he could not discuss dioxin or any "personnel issues".? On January 24, 1991, Jenkins wrote another memorandum? to West and Guarino in response to a newspaper article. In it she said: [T]his should correct certain misinformation being disseminated by an unidentified EPA official claim? ing that even if the Monsanto human studies on dioxins effects were fraudulent, this had no impact on protect- ing the public. This is not true. This memorandum outlines the direct changes in the environmental regu? lations, as well as compensation by the government and court systems, that would result if dioxins were clas? l3 sified as human, not just animal, carcinogens. The Monsanto studies subject to your investigation have played a major role in preventing the classification of dioxins as human carcinogens, Dr. Jenkins then proceeded to give a ten page factual summary, extensively footnoted, supporting her assertions of the impor- tance of the dioxin classification. But the only interest shown in her memo by the investigators in the Status Report for February, 1991, was that "a number of individuals and organi- zations outside of EPA were sent copies. [John West?] and EPA Headquarters, Office of Enforcement, were informed of this matter." They reported no other relevant activity for several months. However, there was considerable related activity elsewhere in EPA. The Inspector General was apparently investigating whether Jenkins had violated any EPA rules in divulging the fact that there was an ongoing criminal investigation (even though nothing was happening in that investigation). The Office of Enforcement was working on a new agency policy to prevent such disclosures in the future.33 And a Work Group had been set up to respond to the Greenpeace petition. The Greenpeace petition was denied? on technical grounds, but EPA Administrator William Reilly tried to smooth over hard feelings by writing a personal letter to Greenpeace's Pat Costner with a hand written note at the bottom saying: "We want to keep the lines of communication open. Best regards".35 However a different view of EPA's interest was revealed in a document never intended for public eyes. It was the Greenpeace petition Work Group's outline of the issues, which was inadvertently left in the docket.?b The last line says: How can we respond appropriately to the petition from a legal and substantive standpoint and not unnecessarily contribute to the Greenpeace publicity campaign? Although EPA denied Greenpeace's petition it nevertheless assured the public in the Federal Register that: As a matter of Policy, EPA does investigate allegations of false statements and/or misrepresentation, and if appropriate, will evaluate the full range of enforce? ment options available to address legitimate charges of misconduct. These bold words notwithstanding, the investigation into Monsanto's alleged false statements and/or misrepresentations was going nowhere. The only action reported for March was a contact with someone in Dr. Jenkins' division about "the release of information concerning this criminal investigation to outside 14 sources by [Dr. Things appeared to pick up in April. The Status Report said that [Dr. Hugh McKinnon?] of EPA Headquarters would be assigned to lend Technical assistance in this investigation. Dr. McKinnon is an epidemiologist and director of the Human Health Assessment Group within the Office of Health and Environ? mental Assessment. This is the first indication on the record of any scientific input to the investigation. As mentioned earlier, the investigation of Criminal fraud is meaningless until there is first a scientific determination that the studies are flawed. The appearance that an investigation might finally be getting under way, however, was an illusion. There is no subsequent mention of Dr. McKinnon. In fact there is no investigative activity reported at all from May of 1991 until May of 1992. Lack of activity was later explained as being "due to organiza- tional changes and transfers during this period"?. While no one in the scientific community was willing to tell the investigators on the record whether the studies were flawed, apparently they were not so reluctant to talk to Science maga? zine. A February, 1991, article by Leslie Roberts? says; Everyone Science spoke to who is familiar with the Monsanto studies agrees that they are flawed, but probably not as a result of criminal intent. Among the people interviewed by Ms. Roberts and presumably included in "everyone Science spoke to are: Dr. Michael Gallo, Robin Wood Johnson Medical School Dr. Linda Birnbaum, Director of EPA's Environmental Toxicol- ogy Division of the Health Effects Research Laboratory Dr. George Lucier, Chief, Laboratory of Biological Risk Analysis, National Institute of Environmental Health Scienc- es Dr. Ellen Silbergeld, University of Maryland Dr. Michael Gough, Program Manager, Biological and Behavior- al Sciences, Congressional Office of Technology Assessment Dr. Maryilyn Fingerhut, Chief, Studies Branch, National Institute for Occupational Safety and Health Dr. William H. Farland, Director of EPA's Office of Health and Environmental Assessment Dr. Donald Barnes, Director, EPA Science Advisory Board 15 Dr. Eric Bretthauer, EPA Assistant Administrator for Re- search and Development. While it is possible that not every scientist mentioned was "familiar with the Monsanto studies", certainly most were. Nevertheless, Monsanto continued to argue the correctness of its studies and to vilify Dr. Jenkins. In April, 1991, James Moore, an attorney for Monsanto, formerly with wrote to the EPA Assistant Administrator for Enforcement, Raymond Ludwiszewski?, complaining that: [Tjhis investigation has become a media event through the unprofessional efforts of a single EPA employee The agency has been unsuccessful in halting this im- proper conduct, despite the clear impropriety and the fact that such information releases are highly damaging to Monsanto's reputation. The government and its employees have a responsibility to protect those being investigated from unfair "official" public accusations. Moore wrote again to EPA criminal attorney Howard Berman on November, 15 saying Jenkins' behavior: is highly inappropriate and a violation of the agency's responsibility, under the [American Bar Association] code of ethics the agency should take definitive action to prevent this kind of ethics violation from recurring. The next letter from Moore to Berman?2 on March 12, 1992, reveals something of the relationship between Monsanto and EPA. As a follow up to our telephone conversation of last week For all the reasons I have previously dis- cussed with you, there is no basis for a conclusion that fraud was perpetrated. The inquiry by criminal unit should be concluded expeditiously so that Monsanto can clear its good name and such references to the alleged criminal nature of the studies will cease. In our last conversation you indicated that you would get back to me quickly on the status of the scientific review of the studies and, if possible, what body is doing the review. It is clear from the FOIA record that Monsanto had access and communications with EPA that were not available to the general public. What the record does not and cannot show are the phone calls and private meetings that may have also taken place. Furthermore, there is no reason to expect that Monsanto's lobby- ing was limited to EPA. It is not unreasonable to suspect that 16 Monsanto may have also made contact within Congress and the White House. In May of 1992, it again looked as if the investigation might be getting off the ground. The Report of Investigation says: "Assistance from the EPA Science Advisory Board will be sought." But, as reported in a July 7, Report of Interview, the SAB dashed that hope, saying they are not revisiting the dioxin issue. Finally, on August 4, 1992, scientific help arrived in the person of Dr. William Farland, but only to nail the lid shut on the coffin of a long dead investigation. The criminal investigation's Report of Interview of Dr. Farland says: The 1980-85 Analysis of dioxin data by EPA was ulti- mately used to establish drinking water guidance, assist superfund site specific cleanup decisions and in state regulatory decisions. However, there are NO direct regulations that have been speCifically sat as a _result of this data assessment. Dr. Farland stated that if it were to ever turn out that the results of the Zack/Suskind and Suskind/Hertzberg were positive, this would only result in there being limited human evidence of carcinogenici? ty the results would still be the same. [E]ven if the human data were falsified by the researchers, there would have been little implications in the end because these studies were essentially disregarded in the regulatory decisions. Based on this, on August 7, 1992, EPA closed the criminal inves- tigation, saying: This investigation is closed. The submission of alleg- edly fraudulent studies to the EPA were determined to be immaterial to the regulatory process. Further, allegations made in the Kemner litigation appear to be beyond the statute of limitations.? The abrupt closing left many issues unaddressed: The agents did not respond to, and indeed, did not appear to have read Dr. Jenkins memos of November 15, 1990 and January 24, 1991 which were written to refute the very arguments raised by Dr. Farland as to the relevance of the Monsanto studies. 0 In Dr. Jenkins experience, the classification of dioxin as a B2 carcinogen (animal data only) has had a significant 17 negative effect on EPA regulation of dioxin. Dr. Farland is an office director in research and development and as such is remote from the business of writing regulations whereas Dr. Jenkins has been intimately involved in regulation writing for fifteen years. 0 Dr. Farland may be disingenuous or ignorant when he does not mention the very significant effect of dioxin classification on the Veterans Administration's determinations about Agent Orange benefits and on the veteran?s litigation against Monsanto, but these factors were all pointed out to the investigators by Dr. Jenkins. 0 All that aside, why did the investigators believe that the influences that Dr. Farland did mention, namely: "to estab- lish drinking water guidance, assist superfund site specific cleanup decisions and in state regulatory decisions", were of no importance? 0 If the Monsanto studies were fraudulent to begin with, then the statute of limitations would not have expired because the letters, written by Monsanto and their attorneys as late as 1992, defending the studies would have constituted an ongoing conspiracy to defraud the government and to conceal evidence of the fraud. Thus the investigation was closed in August 1992. It had gone on for two years without having investigated anything. No one blushed at the memory of Administrator Reilly 's assurances in the Federal Register that: - As a matter of Policy, EPA does investigate allegations of false statements and/or misrepresentation, and if appropriate, will evaluate the full range of enforce- ment options available to address legitimate charges of misconduct. In this case they decided on the enforcement option without conducting the investigation. There was no public announcement that the investigation was closed. Dr. Jenkins didn't learn about it until fifteen months later. Yet Monsanto knew within a few days of EPA's closure. A note from someone high up in the Office of Enforcement to someone else, probably his boss, dated August 26, 1992, says: Today I spoke with Jim Moore, attorney for Weyerhaeuser and Monsanto he said he has talked with who told him that the case was "dropped." Now Jim Moore wants to talk about what might or should say to .set the record straight. I must agree with him that it was certainly unfortunate that an EPA employee 18 revealed the existence of a criminal investigation[.] It is my view that it would be appropriate in these unique circumstances to seriously entertain a proposal to set the record straight by untarnishing the company's reputation. [N]o doubt Jim Moore would have some specific thoughts to offer[.] At the very least, I would think that he would be entitled to a letter saying that the investigation was closed by OCE for lack of evidence sufficient to support a criminal prosecution. He would probably want more than this.? The harassment of Cate Jenkins Dr. Cate Jenkins has been an environmental scientist with EPA since 1979. Before getting involved with Monsanto and the Kemner brief in 1990, she had, by 1987, already become a well known whistleblower over, what she felt was fraud, waste, or abuse in the agency?s handling of dioxin laden wastes from the wood preserving industry and EPA's regulatory decisions on the syn? thetic plant hormone Alar. During the months of March through August 1990, copies of corre- spondence between Jenkins immediate supervisor Mike Petruska and his associates and his immediate supervisor reflect EPA manage- ment's disturbance with Jenkins involvement in whistleblowing activities.45 For example her former manager, Ed Abrams, when asked what he thought should be done with Jenkins, wrote: I don't think Cate should be involved with anything that puts her in direct contact with the regulated community or the general public. If we insist on retaining her, place her in some administrative or staff position (like Bill Sanjour) and not worry about whether she is happy."0 Within days of learning that the Office of Enforcement had initiated a criminal investigation of Monsanto based on Jenkins' allegations, her job duties were withdrawn without warning. She was not given any assignments from August 30, 1990 until she was reassigned on April 8, 1992? to a job which was primarily admin- istrative or clerical?. Just as Ed Abrams had recommended. During this time, the agency spent considerable energy research? ing anything they could find to discipline her, including her sending letters to Congress?, using EPA stationery50 and disclos- ing the existence of a criminal investigation, only to find that there was nothing illegal or contrary to government rules about any of these activities.? Shortly after she was reassigned, Dr. Jenkins filed a complaint with the Department of Labor claiming that she was being harassed for carrying out perfectly legal activities. 19 Investigation of Jenkins' complaint During May 1992, an examiner from the Department of Labor inter- viewed some of her present and former managers. In the examin- er's write-up?, the most interesting quotes came from Ed Abrams. Among them are: Cate appears to be on a mission to eliminate dioxins wherever they may be. Cate Jenkins has a very intelligent mind and it's a shame it can't be focused differently. [MJanagement has been too soft in the past in dealing with Cate's activities[.] The examiner concluded by agreeing with Dr. Jenkins' allegations that EPA discriminated against her due to her protected whistleblowing activities[.] The Feb., 1990 letters do appear to have been the initial trigger for her None of the rationales [explaining her transfer] given by EPA via Bussard appear valid. Recommendation: Jenkins be re-instated reimbursed for any legal fees and costs.53 The Department of Labor District Director concurred?, but EPA chose to appeal for a formal hearing before an administrative law judge. This gave Jenkins' lawyers the opportunity to take depositions of all the key players and to question them under oath and to bring in their own witnesses. Some of the facts which emerged and are listed in the Complainant's Post-Hearing Brief are: - 0 Dr. Jenkins received several cash awards for performance which "exceeded expectations? for the two years preceding the date her assignments were removed (pg. 4). 0 She was never criticized or disciplined for the way she interacted with the regulated community, the public, or any other outside parties (pg. 4). 0 Mr. Bussard testified that he had a direct conversation with Monsanto concerning Jenkins? allegations of fraud (pg. 9). Bussard said that peOple in EPA were concerned about litiga- tion from Monsanto over Jenkins' communications (pg. 9). 0 Mike Petruska ruled out any assignments for Jenkins which would involve Monsanto (pg. 10). 20 0 Ed Abrams testified that "but for her crusade on dioxins", Dr. Jenkins would be a very valuable member of his team (99. 12). Dr. Jenkins? lawyer brought in a witness to counteract EPA's criticism of her ability to appropriately interact with the public. He was John Thomas Burch, Jr., an attorney, a Viet Nam veteran and the chairman of the National Viet Nam Veterans Coalition. He testified that other people in EPA had referred him to Jenkins and that she was the only person in EPA who was reaponsive to his inquiries. He said she was friendly, helpful, unbiased, approachable, a seeker of truth, but yet, not a zealot. Mr. Burch testified that Dr. Jenkins' memos about the Monsanto studies "broke a roadblock" to additional legislation in Congress which "meant thousands of [veterans] getting medical care who wouldn't have gotten it otherwise." For this she was awarded a plaque for exemplary service to Viet Nam veterans.? The judge ruled in Jenkins' favor.56 For the third time, EPA refused to accept the decision and continued to use taxpayer funds to appeal the case to the Secretary of Labor, who also ruled for Jenkins."T This was the second EPA whistleblower case in less than a year that went all the way up to the Secretary and in both cases the Secretary ruled against EPA. The agency was getting a bad reputation with the Labor Department, so after two years of fruitless litigation, EPA management threw in the towel and promised to restore Jenkins to her old job. Although she had committed no crime, Jenkins had been vilified and harassed for the sin of wanting to protect the public from dioxin. Many wrongs, including violations of EPA's own regula- tions, were committed by those who illegally harassed her, but no one has suggested punishment for them. And while many EPA officials were willing, even anxious, to apologize to Monsanto, none has come forward to apologize to Dr. Jenkins. Conclusions It was probably foolish to launch a criminal rather than a civil investigation. The level of proof required for a civil judgement is that it was "more likely than not" that an offense was commit- ted, whereas a criminal conviction requires a burden of proof that is "beyond a reasonable doubt". It would be almost impossi? ble to satisfy the level of certainty required for a criminal conviction in a case involving differences of opinions between qualified scientists. On the other hand, the Kemner trial demonstrated that a civil judgement might be obtained. One has to feel sorry for agents West and Guarino. They started out with enthusiasm in a whole different kind of investigation 21 which could prove to be very important, only to find that their chief source of information was a pariah, despised by EPA manage- ment, and that the EPA science community wanted nothing to do with their investigation. Without the scientific support of the agency, they were left "turning slowly in the wind". How does one explain the disinterest, even hostility of the agency's science community? There are several epidemiologist in EPA and more in other government agencies who were familiar with the Monsanto studies because these stUdies had to be considered in their own research. In light of all the publicity, they must also have been familiar with Jenkins' memo and the even more detailed Greenpeace study "Science for Sale", by Joe Thornton. They must then have formed a conclusion, at least in their own minds, about the validity of the controversial studies. If their conclusion was that the case made by Jenkins and Thornton, was unconvincing and that they could see nothing significantly wrong with the Monsanto studies, wouldn't they have told investigators not to waste their time? Agreeing with the validity of the studies would have been the simplest and most direct way to close the case. Yet Dr. Farland, in the case closing interview with the detectives, side?stepped the issue. Why would he do that if he thought the studies were valid? If the studies were valid, he would not have had to resort to the questionable argument that their validity was irrelevant. On the other hand, there are many reasons for believing that the studies may be flawed. At least two different government epide- miologist involved in dioxin research have written letters questioning the way Monsanto did some of their studies. These are Marilyn Fingerhut of and David Bayliss of EPA's Office of Health and Environmental Assessment?. Dr. Fingerhut and her colleagues at NIOSH published a study of major importance which re-examined data on workers exposed to dioxin, including the Monsanto data, and concluded that there was a definite link between dioxin and several forms of cancer?. In the process, NIOSH classified several of the Monsanto workers differently than Monsanto did, all of which tended to reverse Monsanto's conclu- sions. Based on this and other studies, EPA's Office of Health and Environmental Assessment has recently concluded that the human data base now supports "an association between exposure to dioxin and increased cancer mortality".bl Add this to the Sci? ence magazine article and the Kemner decision and it is reason- able to Speculate that a proper scientific review would show the Monsanto studies to be flawed. The Office of Health and Environmental Assessment, Dr. Farland's office, is usually in the forefront in EPA in defining new chemical threats to human health and the environment. In inter- nal EPA work groups, OHEA frequently finds itself battling 22 program offices, such as air and pesticides, who resist attempts to introduce new substances for them to regulate. In addition, the office has to battle industry every time a new substance is discovered to be harmful. Therefore, it is understandable that OHEA would not want to get into battle with Monsanto over some studies which OHEA had already decided not to use.? Considering the importance of the issue to Monsanto, one can assume that they would struggle mightily to defend their studies, and if OHEA were to come up with some formal assessment which decided the studies were flawed, the agency and OHEA would run the risk of being tied up in litigation and recriminations and everything else that Monsanto could throw at them for years to come. From OHEA's viewpoint, there is nothing to be gained by such a struggle and a great deal to be lost. The issue one is faced with is more fundamental than any possible dereliction by any one EPA office. By now Americans have seen many examples of corporations secretly weighing the cost of correcting some great harm their products may be causing versus the cost of continuing the harm Johns Manville with asbes- tos and the Ford Motor Company with the Pinto). This kind of cold-blooded analysis is bad enough when the product is used by the general public, but it is insufferable when used on our own armed forces who were exposed in combat. But this is exactly the kind of behavior that the Jenkins memo had raised. The issue wasn't false science, but allegedly using false science to cover-up a callous hard-hearted decision to continue poisoning our GIs and their children because it was cheaper to do so. When Jenkins made her allegations, and when the veterans groups made known the full implication of those allegations, a govern- ment with a decent respect for the welfare of its armed forces would have publicly ordered a full and impartial investigation with all the resources and support necessary and let the chips fall where they may. Instead, our tOp government officials were silent or even worse, they let it be known that they despised the messenger and had nothing but friendly feelings for the accused. The United States government gave no support or encouragement to a scientific, civil, or criminal investigation of Monsanto. No mere office director in EPA is big enough or strong enough to take on an influential giant like Monsanto without that support and encouragement. Recommendations What should have been done and what still can be done is what was suggested earlier. Convene a panel of disinterested scientists, with the full support and authority of the U.S. government, to 23 determine if the studies are valid, and if not then determine whether the results would have been positive if the studies were done correctly. If the answers to the first two questions are yes, then the panel should determine if it is more likely than not that the kinds of errors found by the panel could be honest mistakes made by competent professionals. The panel's findings should then be made public. If the answer to the last question is no, then the Justice Department should review the panel's findings to determine what, if any, enforcement action should be taken. This is what the government promised the American people it would do, but never did. Our veterans deserve nothing less. Other recommendations are: 0 EPA should stop running a KGB type operation that tries to control anyone who calls attention to waste, fraud, and abuse by high ranking officials and powerful private inter? ests. The agency should pay attention instead to the mes? sage of these whistleblowers. Failed attempts at suppres- sion only increase the public?s distrust of its government. 0 To achieve this, senior EPA executives, especially political appointees, should undergo training in the implications of such laws as the Freedom of Information Act, the Privacy Act, various whistleblower protection provisions, and the False Claims Act which have increasingly thwarted manage- ment's ability to control whistleblowers. 0 EPA and the scientific community should take a more skepti- cal view of self?serving industry sponsored studies. 0 Many EPA executives, especially political appointees and attorneys, use public service as a mere stepping stone to high paying positions by courting the favor of private interests when they are supposed to be regulating in the public interest. They should not be allowed to become consultants to or accept positions with the corporations the agency regulates for some years after they leave. cc: Inspector General 24 ms 1. The allegations in Dr. Jenkins' memo and later by Greenpeace, charging fraud by Monsanto, were picked up by newspapers around the world including The Washington Post, Newsday, The Atlanta Constitution and The St. Louis Post?Dispatch. Nevertheless, when Dr. Gaffey, one of the authors of the studies in question and recently retired from Monsanto, chose to sue someone for libel, he chose the minuscule Environmental Research Foundatidn (ERF), a three person operation which publishes a one page weekly environ- mental newsletter with a circulation of 1,700. In order to prepare for its defense, ERF sent a Freedom of Information Act (FOIA) request to EPA for all the documentation concerning EPA's criminal investigation of Monsanto based on the Jenkins memo. Some of the material in this report is from that FOIA response. EPA replied with a one and a half foot stack of censored docu- ments in which the agency blanked out the names of individuals and replaced them with brackets, thus In some cases it was possible to guess whose name was removed and in these cases I have indicated the name as, for example, [John Smith?] but in other cases I am forced to show the name as 2. J.A. Zack, and R. Suskind, "The Mortality Experience of Workers Exposed to Tetrachlorodibenzodioxin in a Trichlorophenol Process Accident," J. of Occupational Medicine, Vol. 22 (1980), pgs. 11-14. J.A. Zack, and w. R. Gaffey, Mortality Study Of Workers Employed At The Monsanto Company Plant In Nitro, West Virginia," Environmental Science Research, Vol. 26 (1983), pgs. 575?591. R.R. Suskind, and v.3. Hertzberg, "Human Health Effects Of And Its Toxic Contaminants," Journal of the American Medical Association, Vol. 251, No. 18 (1984), pgs. 2372?2380. R.R. Suskind, "Chloracne, 'The Hallmark 0f Dioxin Intoxication,'" Scandinavian Journal of Work, Environment and Health, Vol. 11, No. 3 (1985), pgs. 165-171. R.R. Suskind, "Long-Term Health Effects Of Exposure To And/Or Its Contaminants," Chemosphere, Vol. 12, No. 4?5 (1983). pg. 769. 3. U.S. Environmental Protection Agency, A Cancer?Risk Specific Dose for External Review Draft and appendices, Washington DC, June, 1988. 25 4. Kemner, et al Monsanto Co., Civil No. 80-L-970, Circuit Court of the twentieth Judicial Circuit, St. Clair County, Illinois. 5. Kemner, et al Monsanto Co., No. 80-L-970, In the Appellate Court of Illinois Fifth District, Plaintiffs-Appellees' Brief, October 3, 1989. 6. Kemner Monsanto, Plaintiffs brief, previously cited, pg. 29. 7. 160 111. Dec. 192, 576 1146 (111. App. 5 Dist. 1991). 8. U.S. Environmental Protection Agency, 1988, previously cited. 9. Cate Jenkins, "Newly Revealed Fraud by Monsanto in an Epidemi- ological Study Used by EPA to Assess Human health Effects from Dioxins", EPA memorandum to Raymond Loehr, Chairman, Executive Committee, EPA Science Advisory Board, February 23, 1990. 10. H. Farland, Director?,] EPA Office of Health and Environ? mental Assessment, "Report of Interview on Monsanto Case", EPA memorandum to [John West or Kevin Guarino?], EPA Office of Criminal Enforcement, February 18, 1993. 11. U.S. Environmental Protection Agency, The Risk Assessment Guidelines of 1986, Washington, DC, August, 1987, pg. 1?12. 12. Richard J. Mahoney, CEO, Monsanto Co., Letter to William Reilly, EPA Administrator, March'26, 1990. 13. Don R. Clay, EPA Assistant Administrator for Solid Waste and Emergency Response, EPA letter to Richard J. Mahoney, Chairman and CEO, Monsanto Company, May 4, 1990. 14. Federal Register, Vol. 54, pg. 40389, October 2, 1989. This is in the preamble to the VA's final rule on "Evaluation of Studies Relating to Health Effects of Dioxin and Radiation Exposure". 15. NEIC Investigative Unit, "Monsanto Chemical Company (90? EPA memorandum to Office of Criminal Enforce? ment, August 22, 1990. 16. Personal conversation with Dr. Jenkins. [Frank K0ver?], Compliance - - TIP EPA form memo to Chemical Screening Branch, July 2, 1990. 18. [Michael J. Walker, Director,?] EPA Toxics Litigation Divi- sion, "False Study Involving Monsanto Dioxin Data To Be Investi- gated By University", EPA memo to May 18, 1990. 26 19. J. Senger, Monsanto Co., Letter to Don Clay, EPA Assistant Administrator, October 1, 1990. 20. Monsanto also requested, in this letter, that the studies in question undergo a scientific audit, which is precisely what Jenkins requested. 21. Tape recording of the interview made by Dr. Cate Jenkins. 22. C. Jenkins, "Criminal Investigation of Monsanto Corporation Cover-up of Dioxin Contamination in Products - Falsification of Dioxin Health Studies", EPA memorandum to John West, EPA NEIC, and Kevin Guarino, EPA NEIC, November 15, 1990. 23. Jenkins believes that the wide distribution of her February 23rd memo was undertaken by Greenpeace. She had sent them a courtesy copy as they were the source of the information used in the memo. 24. Transcript of tape recording of the conversation made by Dr. Jenkins. 25. J. Thornton, Science for Sale, Greenpeace, Washington, DC, November 29, 1990. 26. Malcolm Gladwell, "Greenpeace Digs Deep Into Dioxin Debate", The Washington Post, November 30, 1990, pg. A27. 27. Office of the Assistant Attorney General, letter to John Martin, EPA Inspector General on letterhead of U.S. Department of Justice, Environment and Natural Resources Division, December 3, 1990. 28. Cate Jenkins EPA, Case No. 92-CAA-6 before the Dept. of Labor Office of Administrative Law Judges, Complainant's Post? Hearing Brief, November 23, 1992, pg. 13. 29. Victor John Yannacone, Jr., attorney, letter to Judge Jack B. Weinstein, U.S. District Court for Eastern District of New York on letterhead of Yannacone Yannacone, attorneys, Patchogue, NY, December 4, 1990. 30. EPA Office of Enforcement, "Briefing of House/Senate Staff on Monsanto Investigation", EPA memo to The File, December 6, 1990. 31. Don Clay, EPA Assistant Administrator, Letter to J. Senger, vice president, Monsanto Co., December 10, 1990. On leaving EPA, Clay formed an industry sponsored organization called the RCRA Policy Forum which brings together EPA hazardous waste regulators with industries producing hazardous wastes to 27 discuss EPA's plans for regulation. 32. Cate Jenkins, "Impact of Falsified Monsanto Human Studies on Dioxin Regulations by EPA and Other Agencies January 24, 1991 NIOSH Study Reverses Monsanto Study Findings and Exposes Certain Fraudulent Methods", EPA memorandum to John West, EPA NEIC, and Kevin Guarino, EPA NEIC, January 24, 1991. 33. Office of Criminal Enforcement Counsel, "Action Plan for Agency-wide Policy Addressing Responsibilities and Obligations of EPA Employees Concerning Ongoing Enforcement Actions", EPA memorandum to Office of Enforcement, January 31, 1991. 34. Federal Register, Vol. 56, pg. 19999, May 1, 1991. 35. William Reilly, EPA Administrator, letter to Pat Costner, Greenpeace, April 23, 1991. 36. Found in the Greenpeace Petition docket (Docket Number OPTS- 211029) stapled to item 24. 37. [Kevin Guarino?], Status Report for March, 1991, U.S. EPA, NEIC Investigative Unit, Control number signed April 1, 1991. 38. [Kevin Guarino?], Status Report for July, 1991 through May, 1992, U.S. EPA, NEIC Investigative Unit, Control number signed May 27, 1992. 39. Leslie Roberts, "Dioxin Risk Revisited", Science, Vol. 251, pg. 624, (February 8, 1991). 40. James Moore was a prot?g? of former EPA administrator William Ruckelshaus and was, during period under discussion, a partner in Ruckelshaus' old law firm of Perkins Coie. Ruckelshaus was a director of Monsanto between his two terms as administrator of EPA. After his second term, Ruckelshaus was a paid consultant to Monsanto. Ruckelshaus is generally credited with installing two other prot?g?s, William Reilly, as administrator of EPA and Henry Habicht, as deputy administrator, both of whom served during period discussed here. 41. Raymond Ludwiszewski left the agency to become a partner, specializing in environmental regulation, in the law firm of Gibson, Dunn Crutcher which places particular emphasis on representation of clients before regulatory agencies. 42. Howard Berman is now with the Jefferson Group, a Washington public relations and lobbying firm. 28 43. [Kevin Guarino?], Report of Investigation, for the period June 1, 1992 Through August 7, 1992, NEIC Investigative Unit, Control number signed August 7, 1992. 44. There is no evidence that this advice was followed. 45. Diane C. Koplewski, Dept. of Labor Examiner, "Narrative Report", May 21, 1992, pg. 6. Attached to letter from Travis M. Campbell, Dept. of Labor District Director to EPA, May 26, 1992. 46. Jenkins EPA, Complainant's Post-Hearing Brief, previously cited, pg. 15. 47. Koplewski, previously cited, pg. 5. 48. Jenkins EPA, Complainant's Post-Hearing Brief, previously cited, pg. 17. 49. Koplewski, previously cited, pg. 6. 50. Jenkins EPA, Complainant's Post-Hearing Brief, previously cited, pg. 15. 51. Jenkins EPA, Complainant's Post-Hearing Brief, previously cited, pgs. 12?15. 52. Koplewski, previously cited, attachment. 53. Koplewski, previously cited, pgs. 12?13. 54. Letter from Travis M. Campbell, Dept. of Labor District Director to EPA, May 26, 1992. 55. Jenkins EPA, transcript September 29, 1992. 56. Jenkins EPA, Recommended Decision and Order. 57. Jenkins EPA, Before the Secretary of Labor, Decision and Order, May 18, 1994. 58. Marilyn Fingerhut, NIOSH, Letter to James Collins, Director of Epidemiology, Monsanto Co., April 24, 1990. 59. David Bayliss, Epidemiologist, EPA Office of Health and Environmental Assessment, Letter to James Collins, Director of Epidemiology, Monsanto Co., November 10, 1993. .60. Fingerhut, M. et al.. "Cancer Mortality in Workers Exposed to New England Journal Of Medicine, Vol. 324, No. 4 (January 24, 1991), pgs. 212-218. 29 61. Draft Chapter on Dioxin Risk Characterization Dated May 2, 1994", Daily Environment Report, Bureau of National-Affairs, Washington, DC, May 12, 1994, pg. E-l. 62. Health Assessment for (TCDD) and Related Compounds, Chapter 7. Epidemiology/Human Data", Office of Health and Environmental Assessment, Office of Research and Development, U.S. EPA, Wash- ington, DC, Draft revised June, 1993, p. 7-9. "This cohort [the 172 members of the NIOSH study by Fingerhut et al., 1991] subsumed, and thereby supplanted, company-specific cohorts from Dow Chemical USA and the Monsanto Company (Zack and Gaffey, 1983: Zack and Suskind, 1980) that had been the subject of previous reports". 30 EIEJIL Wednesday, April 6, 1983 The Miami Herald . Section data Did fake studies 0K ?safe chemicals? By KEITH SCHNEIDER 'Special to The Herald in the past decade. Industrial Bio-Test Laboratories near Chicago has condilcted thousands of critical research projects for American chemical and drug manufacturers. Nearly half of its studies were used to support federal registrations for an array of products: insecticides. herbicides. food additives. chemi- cals for water treatment. cosmetics.? pharmaceuticals. soaps. bleaches and even coloring for ice cream. This week. lBT?s president and three of- his top associates are on trial. charged with conducting and distributing fake scientific research -- data that has put a number of chemicals in daily contact with most Americans. The trial began in Chicago Mon- day. seven years after federal inves- tigators uncovered what they allege is the most massive scientific fraud ever committed in the U. 5. Opening arguments by both sides' attorneys are expected today. Established in 1953. IBT was not only one of the nation' 5 oldest inde- pendent laboratories. but during its last decade it was Also the largest. The lab employed 350 people and collected revenues close to ?$10 million for research performed at the main facility in 25 miles north of Chicago. and in two satellite laboratories -- one in Neillsville. Wis.. and another in Decatur. Ill. According to officials of the us. Primarily, the saga of demise is a disturbing tale of scientific ethics giving way to business greed. Food and Drug Administration (FDA). IBT conducted more than 22.000 research projects for nearly every major American chemical and drug manufacturer. dozens of for- eign concerns and several federal agencies as well It's been estimated that between 35 and 40 per cent of all toxicology tests in the country were conducted by in May. 1981. after a five-year joint FDA-U. S. Justice Department. pro'ue. Dr. Joseph C. Calandra. 65. lBT?s president. and three associ- ates were indicted in Chicago by a special federal grand jury. Calandra and his co-workers Dr. Paul Wright. 44. Dr. Moreno L. Kepling- er. 54. and James B. Plank. 39 are each charged with eight counts scientific research and then of at- tempting to cover up -the scheme. If- convicted. each defendant faces up to 40 years in prison and fines total- ing more than 540.000. The-trial. say federal prosecutors. is expected to last at least six weeks. Each defendant has continuously maintained his innocence. though they have refused. through their at- torneys. to comment on the charges. . Frederick Branding. a former federal prosecutor who recently left the Chicago Attorney's 'staff. called the 113T prosecution. ?one of the most important cases ever. in- vest] gated out of this office." During the trial prosecutors say they hope not only to prove the de- fendants?. guilt. but they. will also outline a pattern of chemical com- pany knowledge of the fraudulent research taking place at IBT. and in some cases. promotion of those practices by chemical company ex- ecutives in order to secure the kind of results they knew would pass - registration standards Environmental Protec- _tion Agency (EPA). of conducting and distributing fake Said one Justice Department in- vestigator: became the largest testing lab in the country hecauae companies knew this was the place to get the results they wanted. A primary example. prosecutors allege. is the case of defendant Paul Wright. Before he joined IBT in March. 1971. Wright was employed as a toxicologist by Monsanto Corp. in St. Louis. FDA investigatorh say Wright went to to manage Monsanto's contract with 1131' to test the safety of the company's anti-bacterial agent TCC which is widely used in popular deodorant soaps such as Dial. Zest and Safe- guard. TCC was under suspicion by the FDA of causing lesions-in laborato- ry rats fed the compound. At the same time. Monsanto was counting - on TCC as a major product to re- place hexachlorophene. another anti-bacterial chemical jsut with- drawn from'the American market. Monsanto. said investigators. need- ed a "clean"'iBT study to convince the FDA that TCC was safe so the .agency would allow increased lev- els of TCC in some deodorant soaps. Wright stayed. on IBT's payroll for 18 months. according to govern- ment documents. long enough to su- pervise most of the TCC research. He then returned to Monsanto where he was named Manager of Toxicology for the flrm?s depart- ment of medicine and environmen- tal health. While at Monsanto. ac-- cording to prosecutors and witness-' es. Wright wrote several critical sections of the final TCC summary report and pressured a key iBT'sci- enlist Into changing his finding that TCC did. in fact. cause dangerous lesions In laboratory rats. The sections Wright authored were included in summary re- port which was mailed to the FDA in 1976. The agency eventually ap- proved ralsing the levels of TCC in some soaps. Attorneys for the com- pany said Monsanto officials would not comment on the charges "at this time." Primarily. the saga of iBT?s de- mise is a disturbing tale of scientific ethics giving way to business greed. The? pages of grand jury testimony in the case are swollen with lurid images bf an overworked staff toil- ing in cramped and filthy facilities. and watching, as massive rodent deaths went unreported and sum- mary tables were magicaliy filled In with phony. numbers. Within the re- search buildings of technicians quietly witnessed scientific accura- cy fade away to. a welter of forg- ery. trickery and lies. "We did a large volume of stud- ies: no sooner would one study end. than another would start." technl-. cian Manny Reyna told the grand jury. ?it seemed that conditions were just so stressed in doing stud- ies. and finishing studies and start- ing new studies." - The most notorious place inside according to witness testimo- ny. was a room technicians called ?the swamp." in 1970. directors installed an automatic watering system in a Please turn to TRIAL 1' Thalia-innit! Solace/Indiana ?Invalid? Studies' chemicals iE rodent cages. the equipment rarely worked properly. Faulty nozzles spr?ayedthemomwithacontinmus chilly mist; showering the caged animals. Water-streamed off cages Ratsdied of, lhtheir feedingtroughahlotechni- entered the swamp without rubber boots. and many wore masks to protect themselves from the stench of disease and death. Dining the course of a two-year feeding study. involving over 200 animals. the mortality rate of the .?awamp"reached80percent. Worst of all was cleaning the cages. Dead rats and mice. techni- cians told federal investigators. de- composed so rapidly in the ?swamp" that their bodies oozed through wire cage bottom and lay in purple puddles on the droppings mill. The Justice Department Brasseri- tion covers the paid en 1970 and 1978 and involves fraudu- mducted on four compounds: the Insecticide Nemacur 'and the herbi- cide Sencor produced by Chemagrn Corp. now owned by Mobay Chemi- cal 00.: the drug Naprosyn manu- factured by Syntex Corp. to treat arthritis swelling: and Monsanto Corp.'s anti-becteriai agent TCC. The government charges that: a Oiemagro paid for two 18- month mouse studies which were conducted for just 14 months by 1131'. Throughout the studies. large numbers of mice died and were re placed without hein'gl?roperly rec- orded. The final mo ty summary 1 tables for both reports were faked. Moreover. was supposed to feed a control group of mice a known animal carcinogen in order tempura" Altseffectswiththoaeof" the Nemacur and Sencor study group. The results from this test for an 18-month study with conducted instead for 22 months. A whichdetaiiedbloodandurinedata greet says the lab neither; a Monsanto signed with [31' for a two-year rat feeding study on wasundersuspiclonby? the FDA for causing testicular atro- ,phyinlaboratoryratsfed the com- pound. During the course of the shady. which wasoonductedinthe- ?swamp." hordesof rats died with- outbeing recordedYetiBTreport- examined. 50 many rats died that 131' was forced toestablis'h an extra masts. calling them the ?research Since late 1979. pathologists at' the FDA. the EPA. and In Canada have undertaken an immense and complex program of auditing [81' studies. They have determined that more than 10.000 were used to reg- ister products for the American market. and they consider nearly" 2.000 as primary research. meaning they were the most important stud- ies supporting registration. Most of these were for 325 Insecticides and: herbiddes. The vast majority of the 131? studies have been declared by American and Canadian scientists to be ?invalid." The manufacturers of the chemicals have been asked to repeat the studies. and the results for most will not be ready for re- view until after next year. On this continent and in Europe. health authorities have begun to take regulatory action against chemicals registered 1131? data Sweden recently outlawed eight iBT-studied pesticides. Last year. after studying data on 113 pesti- cides, Canada outlawed sis and se- verely restricted application of the I'm. ?dm. in the US. the EPA's final report on 212 more pesticides registered withiBTdataisduetobereleased in May. awording to Kevin Kesny. an official with the Office of Pesti- cide Programs. in other actions. the EPA suspended the use of theherhi- tide silvex. and most uses of the Insecticides tonphene and ,aharardtohumanheaithaudthe environment. All threewere regis- tered with extendve 131? data which declared them ?safe." Yet most alarming. say many re- scandal. There are few Ameri- ans who don?t make daily contact with chemicals [31' tested and de- clared safe. chiefly from pesticide re?dues contained in food and water. Since the 131? scandal was uncovered. several of these chemi- cals have been declared by federal agendes to be hazardous to human health and the environment. Many others are accused by researchers across the country of causing ill- nesses and environmental contami- nation [31? still lives. though barely. Nine people work at ,the North- brook facili research for clients. still have questions. The satellite Iahs have been sold. nemsinlablsonthemsrketAsk- ing price: 82.7 million. The rats- have been shipped out and the ?swamp" is just a room with a con- crete floor. Regardless of what hap- pens in court, federal investigators admit that only one conclusion is really clear about the [31' scandal: the magnitude of what occurred may never be known. audits effect is likely to be felt for generations.