1.       If uncertainty in the RDX body of research is such a factor of concern, why hasn’t the Army simply 
repeated the original Lish and Levine studies of 1983/1984 to attempt to replicate or scale them up?  
Response:  Much of what was lacking in the RDX toxicity database went beyond a single rodent study.  
Information on the mechanism of toxicity and kinetics (i.e., how exposure to RDX in the feed was much 
lower than toxicity of RDX in a gavage bolus) was unknown.  There were many other knowledge gaps 
and the science has progressed significantly since the Lish and Levine studies. The cost of repeating any 
2-year cancer studies could be up to several million dollars and for this reason it is rare to repeat such 
studies for any chemical.  Instead, smaller less expensive studies such as genotoxicity or mutageniticy 
studies can answer questions regarding the potential for a substance to be carcinogenic.  While the 
studies mentioned were instrumental in helping us to understand effects of RDX in the diet, there were 
many more data gaps that those studies did not address, such as variation in exposure that could occur 
from RDX in the water and studies to help determine what exactly the mechanism of toxicity for RDX 
was.  These data would help us extrapolate, with less uncertainty, between effects in rodents and those 
that could be expected in humans.   
2.       What would be entailed in repeating the original Lish/Levine rat and mice studies? What would it 
cost, how long would it take?  
Response: Another chronic study (2 years in-life portion) where rodents would get daily exposures to 
RDX through drinking water, rather than through the food or gavage would take approximately 5 years 
and cost between $2-3 million dollars. Currently, there is no funding to support it and even if results 
were negative, the equivocal results from previous studies remain. 
3.       Regarding the 1983/84 Lish and Levine studies and the cancer issues raised by them, is there a 
better way to re-examine a dose-response cancer reaction from RDX than to repeat this study? Many 
critics of the Army’s research have asserted that this study should be repeated, and that the DoD’s 
decision not to do so represents a bias or attempt to focus the scientific questions around RDX on other 
topics, such as uncertainty.  
Response: Typically, chronic studies in two species (mice, rats) for any substance of concern are 
considered sufficient for regulatory purposes.  Currently, the decision to do cancer studies on other 
substances at APHC involves a phased approach where mutagenic or genotoxic screening assays that 
have high false positive rates are conducted first.  These assays are relatively inexpensive and quick. If 
these are positive then other, newer methods can be used.  These screening assays were conducted 
after the Lish studies and were predominantly negative.  The positive result in the Lish studies were not 
robust, and are suggestive of variation in background incidence or those that could occur by chance. 
Cancer in rodents occurs at background levels (not related to the dosing chemical) as it does in humans, 
and results in rodents are not always correlated with those that occur in humans especially when the 
incidences of cancer in the rodent studies are close to the background incidences. Repeating these 
studies using drinking water as the exposure media could be worthwhile; however, these studies are 
very expensive and take years (5 yrs) to complete.  And again even if negative, these results do not 

 nullify previous results in the overall cancer assessment.  We simply have not found a sponsor to fund 
these studies.   
We in the Army Public Health Center have a mission to protect the Soldier, their families, Army workers 
and support the installations and that mission is supported through Army Regulation 40-5 where we are 
expected to provide information to help ensure environmental and occupational health of our Army. 
There has never been a strategy to manipulate RDX regulation by deciding not to do studies, as is 
suggested here; our interest has always been to provide as much information as possible so that the 
best possible science can be used to reduce uncertainty associated with establishing safe levels of 
exposure for decision-making, and where we could, we have supported our sister federal agencies with 
providing them with any information we have, including raw data.    
 
4.       Why has so much of the Army and Navy’s research into RDX since about 2003 focused on revealing 
the degree of uncertainty in existing research into RDX (essentially, raising questions about older 
research) and on either reinterpreting existing data (Reddy, 2006 re-examining Lish/Levine), or 
reinterpreting other EPA data (Sweeney, 2011/12) rather than initiating completely new studies?  
Response: I would disagree with that assertion.  EPA reevaluates chemicals of concern every 5-10 years 
as new data becomes available.  Also, the old assessment would not have included the criteria in the 
more recent EPA Cancer Guidelines (2005) which required more narrative statements on the nature of 
the cancer, dose-response, and potential mode of action.  Much of the research has been focused on 
helping us understand the mechanism of toxicity (neurological effects), kinetics (i.e. why gavage low 
doses cause neurological effects and only high exposures of RDX in feed does), interaction with DNA, 
and other aspects to help us understand whether exposure to RDX is a health problem of concern.  
Much has been learned since those studies were conducted in the 1970's and 1980's that suggested the 
nervous system is the target from subchronic and chronic exposures, likely not prostate inflammation or 
testicular atrophy that was noted in the original assessment.  
 
5.       I’d like your group’s response to the general assertion that the DoD funded research into RDX, 
while technically sound on a study-by-study bases, on the whole represents a bias against regulation 
because it is funded by an agency with a stake in the regulatory outcome of the EPA’s tox review, and 
because, as critics point out, the body of research appears to have skipped over some of the most 
important questions. (ie, repeating Lish/Levine).  
Response:. In the Army Public Health Center, our mission is to protect the health of the Soldier, their 
families, and the environment and as mentioned before is very similar to the mission of our other 
federal agencies (e.g., EPA, FDA, OSHA) and we try to be as objective as we can in the evaluation of the 
data and in study conduct to fulfill our mission.  This criticism may seem logical from those who take a 
simplistic view of the military and its overall mission; however, the Army is a relatively large organization 

 with many parts all functioning together to keep our nation safe.  Safeguarding the health of the Soldier, 
their families and the environment on installations is vital to keeping a ready force. 
I would remind the author that submission to the FDA for new drugs are made by the manufacturing 
companies based on a required set of studies.  The same is required for manufacturers of new chemicals 
through the Toxic Substance Control Act.  That we use the very same Good Laboratory Practices that 
other federal agencies require helps to ensure our data are accurate and defensible. 
We also attempted to fulfil the requirements for a complete set of studies to do a comprehensive risk 
assessment of RDX; this included chronic and subchronic studies, immunotoxicology studies, 
reproductive and developmental studies, genotoxicity studies, and mechanistic studies.  We would 
fundamentally disagree that we have “skipped” over any important studies. However, funding for 
toxicology has always been limited and decisions to undertake studies are based on determining hazard, 
filling data gaps, and providing information that can be used to help understand where toxicity occurs. 
There has never been a strategy to not repeat the Lish/Levine studies, or any studies; however, the 
prohibitive costs of such studies were more likely determinants.  Our stated mission compels us to 
produce the best possible science within the rigors of our budget and personnel.  However, we 
recognize that we are all cognizant of the responsibilities the armed forces have to protect our nation 
and think it would be logical to be as objective as possible in understanding, as best we can, what the 
effects could be from exposure and precisely where the threshold for disease lies.  
 
6.       Dr. Reddy, in an internal PowerPoint presentation made to Army staff, expressed the view that his 
research should be interpreted for the purpose of relaxing standards for RDX, and that over-regulating 
RDX would endanger military readiness and waste money. Critics of the process are describing that 
example, and also a very similar statement by Sweeney in her 2011 paper, as evidence of a bias that 
reveals the Army’s interest in presenting research with the goal of downplaying RDX’s dangers. Could 
you respond to this concern and explain why it is not the case, or explain if indeed the research is being 
done with a specific goal? (Please respond separately from the above question – this is a specific 
allegation about Dr. Reddy’s and Sweeney’s interests that I’d like a response to in my story text). 
Response: There is a risk from setting values too low and too high.  The more toxicology data that are 
available for a substance, the less uncertainty is involved in extrapolating to doses that are safe.  When 
there is less uncertainty (more information on toxicology) this is reflected in lower default factors.  Our 
goal was simply to reduce the uncertainty associated with extrapolating toxicity information from 
animals to humans. The best available science can then be used to protect people, the environment and 
potentially enable the demands of our National security.     
 
7.       Estimating dose levels and prescribing lifetime exposure levels for RDX is normally the purview of 
the EPA. Why have Defense-funded researchers so often stepped into that effort and offered specific 
dose/exposure suggestions that would appear to be better suited for policymakers/regulators?  

 Response: As mentioned, protecting the Soldier, their families (often on installations), workers, and the 
environment in which they operate is our mission at APHC (see AR 40-5).  We strive to work with our 
federal partners where we can to help provide as much information as possible in helping us be 
successful in our combined goals.  The act of establishing safe thresholds for exposure is carried out by 
many organizations in the federal and state governments.  Where publications suggest regulatory 
values, the EPA assesses these publications in the normal course of events of hazard identification of a 
substance and makes an independent decision.   This does not mean that these publications drive the 
risk assessment or policy.    EPA recognizes that stakeholder involvement is important in the regulatory 
process.   
 
8.       Why did so much of Dr Reddy’s research into RDX in particular, but also Defense research into RDX, 
pick up in momentum and frequency around and after 2005, when it had been a subject of interest since 
the 1970s?  
Response: What and when research gets conducted is a factor of funding.  The EPA informed the DoD 
around this time that they would reassess the values of RDX in the IRIS database and that new studies 
were welcome. The DoD then attempted to fill data gaps in the prior RDX assessment.  But this effort is 
always a judgement call based on available funding, other chemical priorities, available personnel and 
technical capacity.  
 
9.       My article will explore the question of whether RDX may be carcinogenic (not just the EPA’s asking 
of that same question). In very lay terms, what key findings suggest that RDX does NOT cause cancer, 
and which specific studies are best referenced for that?  
Response: We agree with the EPA’s determination of “suggestive evidence of carcinogenic potential” 
based on the evidence.   
A central tenet of toxicology is that the dose determines whether a substance can become toxic or not. 
Therefore, labeling a substance as “carcinogenic” is rarely helpful as exposure to so many 
chemicals/other factors are suggestive of cancer with sufficient dose (e.g., sunlight, radiation from cell 
phones, nitrosoamines found in bacon and hot dogs, etc.). Our more recent work took a retrospective 
review of the previous studies and used more recent in vitro and in vivo scientific methods to help us 
understand if RDX was mutagenic or genotoxic since there was a general lack of a robust dose-response 
relationship in the Lish and Levine studies.  Results from these in vitro and in vivo assays were largely 
negative, which suggests RDX is not mutagenic or genotoxic or acting in an underlying way that could 
cause neoplasms.  
However, there is another mechanism that can increase the likelihood of cancer - promotion.  Some 
chemicals can cause cells to rapidly divide without being directly mutagenic, so when a mutation occurs, 

 they can enhance its proliferation.  However, there has been no evidence that RDX could act as a 
promotor. 
Finally, there is no evidence that humans in occupational settings that have worked with RDX since 
WWII have had unusually high cancers such as has been the case with mesothelioma in asbestos 
workers or angiosarcoma of the liver cancer among PVC workers.  In fact, the main concern through the 
years from RDX has been neurologic, not carcinogenic.  Because of this, the EPA has changed their noncancer regulatory value in the new draft assessment to base it on seizures, not on prostatitis in rats.   
Reddy, G., Erexson, G.I., Cifone, M. A., Major, M.A., and G.J. Leach. 2005. Genotoxicity assessment of 
RDX.  Int. J. Toxicol. 24: 427-434. 
 
10.   From my reporting, RDX’s breakdown products, the nitrosamine compounds, may present the 
greatest cancer risk. Perhaps I am missing key studies, but it appears that far less research has been 
done by the DoD to examine the affect of RDX-specific nitroso compounds on cancer effect. Am I wrong 
(can you point me to a chronic toxicity study?)? Or why is this the case? Is this an important gap in the 
body of research in your view?  
Response: We endeavored to investigate metabolites from RDX exposure and did so in several 
publications and physiologically-based, pharmacokinetic models (see below).  The bulk of those 
metabolites in rodents and more importantly in primates were the oxidative metabolites MEDINA and 
NDAB (this makes sense as RDX is an oxidizer/energetic); however, the nitroso metabolites you mention 
have been found in very small quantities in the pig and out-bred mice (e.g., Peromyscus). But if reductive 
metabolites were acting via a mutagenic mechanism, they would be mostly likely to exert effects 
directly in the gut, where there is a reductive environment.  However, no evidence of cancer associated 
with the gut (e.g., colon) observed in 2-year studies in rats or mice.  
Krishnan, K., Crouse, L. C., Bazar, M. A., Major, M.A., and Reddy, G. 2009. Physiologically based  
pharmacokinetic modeling of cyclortmethylenetrinitramine in male rats. J. Appl. Toxicol. 29: 629-637. 
Major, M.A., Reddy, G., Berge, M.A., Patzer, S.S., Li, A.C. and Gohdes, M. 2007. Metabolite Profiling of 
14C-RDX in minipigs. J. Toxicol. Envron. Health 70: 1191-1202.