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 Supplemental Information_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 D General

As noted in specific comments herein, there are 

several errors, issues and inconsistencies 

within EPA’s dose-response modeling.

Please ensure a careful review and quality 

control of the documents prior to public release. 

S

2 D D-1

Line 4: There is an error within the document’s 

internal referencing. 

Please correct. E

3 1.1.1 D-1

EPA provides no information regarding the 

combined data except that they can be 

combined statistically. Since the individual data 

do not demonstrate a statistically significant 

increase in tumors, i.e., since all of the tumor 

incidences are consistent with controls, it would 

be expected that the combined data would also 

be not different than controls. However, it is not 

indicated if the combined data (1) had any 

doses that resulted in tumors that were 

Please clearly demonstrate the statistical 

evaluation of the combined data. In the absence 

of any indication -- even the limited indication of 

a positive trend -- that the combined data show 

an increase in tumor incidence over controls, 

DoD does not feel that quantitative analyses of 

the data should be performed. Additionally, 

please discuss how (1) type 1 error (false 

positive associations), including the use of 

normal ranges (historical data) from laboratory 

S/M
statistically significantly increased over controls 

or (2) if there were a statistically significant 

trend.

animals are considered, and (2) which tests to 

assess statistical fit (e.g. least square error) 

have been applied, either to the combined or 

individual data sets. 

4 D.1. D-2

In Table D-1. Noncancer endpoints selected for 

dose-response modeling for RDX, footnote "b" 

is not used.

Please indicate the study from which the 

highest dose was dropped before modeling.

S

5 D.1.2. D-3

"If the BMDL estimates were not sufficiently 

close, the lowest BMDL was selected as the 

POD." As mentioned in other DoD comments, 

the lowest BMDL may result from the most 

uncertainty, i.e., the lowest quality study. One of 

the stated advantages for using BMD 

methodology was to encourage the use of 

better study designs; the quoted practice does 

the opposite of that goal.

DoD recommends that EPA examine the BMD, 

not the BMDL, to determine which study has the 

lowest BMD, and then select the corresponding 

BMDL. Selection of the lowest BMDL may be 

unnecessarily increasing the uncertainty and 

imprecision of the estimate.

S/M

6 D.1.3 D-19 to D-25

The increasing statistical uncertainty of the 

point of departure with decreasing BMR can be 

clearly observed by looking at the BMD/BMDL 

ratios for convulsions in male and female F344 

rats in the Crouse study. The Multistage 2 

model (which was the model selected for BMR 

= 1%) is selected as an example. The 

BMD/BMDL ratios are 1.3, 1.6, and 2.8 for 

BMRs of 10, 5, and 1% respectively. 

The BMR 10 exhibits the lowest statistical 

uncertainty, demonstrated by an evaluation of 

the BMD/BMDL. Following EPA’s BMD 

Guidance, EPA should evaluate statistical 

information when selecting the BMR. DoD 

recommends that EPA use a BMR of 10% for 

seizures in rats. (Note additional comments 

from DoD on this topic throughout the various 

RDX documents.)

S/M

7 D.1.3. D-23

While DoD agrees with EPA's decision not to 

choose the Quantal-Linear model in Table D-9, 

DoD notes that EPA did not follow the 

appropriate selection rules by making this 

The EPA choice of model-selection should be 

made based on biological consistency and 

plausibility as well as statistical considerations. 

DoD suggests that the selection of doseS
choice. The BMDL of the Quantal-Linear model, 

0.860, is greater than 3-fold lower than other 

BMDLs, specifically, the BMDL of the selected 

model, i.e., 3 x 0.86 = 2.58 is less than 2.66. 

DoD notes that this is inconsistent with 

decisions EPA made with similar values for 

other data sets, e.g., Table D-2. 1. DoD 

recommends that EPA use the totality of the 

information provided by the use of multiple 

models to select and provide justification for the 

selection of the most statistically AND 

biologically justifiable model. 

response models is an inconsistency within 

EPA, especially within this particular document, 

but also found between IRIS documents.

8 D.1.3. Modeling 

Results

D-23

In Table D-9, it is unclear why if three of the 

multistage models reduced to the same model, 

the reported BMDLs differ.

There is either an error in the footnote, EPA's 

software, or the reporting of the results. Please 

correct the error. 

S

9 D.1.3. D-25

As stated in other comments, DoD disagrees 

with EPA’s choice of BMDL01. Given that the 

BMDL10 for noncancer risks is almost 10-fold 

higher than the BMDL01 that EPA chose to use 

for RDX, the RfD would also be substantially 

changed. At the very least, this difference in 

ultimate RfD should be presented for 

comparison. 

As not all of the procedures are linear, DoD 

recommends that EPA also derive an RfD from 

the BMDL10 so that the public and the external 

peer reviewers can determine the quantitative 

effect of EPA's decision. By presenting this 

information, EPA will also provide a measure of 

the uncertainty in the RfD as currently 

estimated.

S/M

10 D.1.3. D-31

In Table D-13, the reason for the choice of the 

Quantal-Linear model is that it has the "lowest 

AIC". However, the AIC of that model is 

reported to be 42.077, and the LogLogistic (AIC 

= 41.996), LogProbit (AIC = 41.963), Weibull 

(AIC = 42.026), and Gamma (AIC = 42.003) 

Please correct and please review all of the data 

in Appendix D to ensure the model selection is 

both accurately explained and either follows 

EPA decision rules as stated in this document, 

or explains why the decision rules were not 

followed. 

S
models have lower AICs. The selected model 

has the lowest BMDL. In Table D-9, it is unclear 

why if three of the multistage models reduced to 

the same model, the reported BMDLs differ.