Department of Defense (DOD) Comments on the Interagency Science Consultation Draft IRIS Assessment of RDX (dated September 2014)

Date: October 28, 2014

_______________________________________________________________________________________________________________________________________

Department of Defense Comments on 

RDX_Interagency Consultation draft Charge to External Reviewers_9-30-14.pdf

Comments submitted by: Chemical Material Risk 

Management Program Organization: Department of Defense Date Submitted: 10/27/2014

*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E); or Other (O). Also please indicate if Major i.e. affects the 

outcome, conclusions or implementation of the assessment.

Comment 

No.

Section Pages Comment Suggested Action, Revision and References 

(if necessary) *Category

1 2c

DoD appreciates that EPA provided the 

question asking whether the choice of dose 

metric is appropriate. However, DoD feels that 

this is a critical aspect of the dose-response 

assessment and requests that a more thorough 

question be developed and perhaps separated 

as a subquestion to 2c.

Consider asking: “Do the animal and human 

data support using the AUC rather than peak 

plasma RDX concentrations in the PBPK 

model? Are the impacts of using AUC rather 

than peak plasma RDX concentrations on the 

final RfD adequately described and scientifically 

supported?” 

S/M

2 3a

DoD appreciates that EPA asks external 

reviewers whether the available studies support 

the conclusion that nervous system toxicity is a 

human health hazard of RDX exposure. Given 

that this is the critical endpoint for RfD 

development, DoD feels that additional 

questions related to whether scientifically 

accurate and appropriate descriptions and 

considerations of mode of action and 

Please consider additional questions on the 

interpretation of nervous system toxicity, 

including explicitly asking whether the reviewers 

believe that the differences between the 

toxicokinetics of gavage versus feeding studies, 

and whether interpretation of the mode of action 

for RDX neurological effects, are appropriately 

and accurately considered and incorporated 

S/M
toxicokinetic differences between gavage and 

feeding studies are warranted (either here or in 

question 4a).

into the hazard identification subsequent dose-

response modeling. 

3 3e

DoD appreciates that EPA provided the 

question “Do the available...studies support this 

conclusion?” for the “suggestive evidence of 

carcinogenic potential” designation. However, 

we feel the opposing questions should also be 

provided for unbiased questioning of the 

external reviewers. 

Please consider adding the additional question 

to 3e: “Conversely, could the carcinogenic 

weight of evidence, including no statistically 

significant dose-dependent increases in tumors 

from animal studies, and negative genotox data, 

support a finding that RDX is unlikely to be 

carcinogenic?”

S/M

4 4a Please consider asking an explicit question on 

the use of the Crouse et al. gavage study.

DoD recommends asking: “Is the use of the 

Crouse et al. study, which uses a bolus 

(gavage) dosing regimen, appropriate and 

scientifically accurate for derivation of the 

RfD?”  

S/M

5 4a

Please consider asking an explicit question 

regarding the assumption/interpretation that 

seizure incidence is “severe” due to 

equivalence to mortality.

DoD recommends asking: “Does the weight of 

evidence including the overt evaluation of 

mortality/lethality from RDX exposure to 

humans, and the quantitative evaluation of 

mortality following convulsions in rodent 

studies, support the determination that seizures 

are a sever endpoint equivalent to mortality?” 

S/M

6 4a

DoD feels that the calculation of a BMDL (95% 

CI) at the 1% level is a critical decision within 

the RfD derivation for RDX. As such, more 

thorough and explicit questions are warranted. 

If the BMDL at the 1% BMR is retained, DoD 

requests that external reviewers are asked the 

following question: “Is calculation of a BMDL 

(95% CI) at the 1% level scientifically accurate 

per EPA BMD Guidance and technically 

supported, considering both statistical 

requirements (i.e. precision of the data) and 

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biological plausibility (i.e. EPA’s determination 

that the severity of seizures warrants additional 

protection via a more conservative BMR)?” 

7 4a DoD feels specific questions of the UFD and 

UFH are warranted.

Please consider adding explicit charge 

questions on the technical accuracy and 

appropriateness of the UFD and UFH 

determinations. Including: “EPA chose to use a 

default UFH rather than chemical-specific 

information derived from analysis of 

toxicokinetic data via the available PBPK 

models. Is this decision scientifically defensible 

and appropriate? Would the use of PBPK 

models to derive a data-derived uncertainty 

factor for human variability improve the RfD 

derivation?”  and “ 

UFD=3. Is this decision scientifically defensible 

and appropriate?”

S/M

8 4c

DoD requests additional, more specific, 

questions should be provided to the external 

reviewers related to EPA’s oral slope factor 

derivation.

Please consider asking the following questions: 

“Are the RDX cancer data (considering the 

entire weight of evidence) sufficient to support a 

quantitative oral slope factor derivation and is it 

appropriate to do so?” “Has EPA chosen an 

appropriate study (Lish et al. 1984) from which 

to calculate the oral slope factor, per 

established EPA guidance and guidelines?” 

“Has EPA accurately and appropriately 

evaluated and interpreted results from Lish et 

al., considering statistical tests and biological 

plausibility?” 

S/M
9 6

DoD commends EPA for specifically requesting 

that the experts review EPA's response to 

public comments. DoD asks if the interagency 

comments supplied at this time will be included 

in this response.

DoD strongly suggests that these interagency 

comments be included in this section of the 

report.

S/M

10 General

The charge questions ask whether the various 

parts of the assessment are "appropriate". DoD 

suggests that this term is vague and open to 

multiple interpretations. DoD suggests that the 

experts be also asked to opine as to whether 

the parts of the assessment are "accurate" or 

"sufficiently accurate".

DoD suggests that in addition to “appropriate,” 

“accuracy” is a major issue on which the 

experts should be asked to consider.

S