IRIS STEP 3 INTERAGENCY COMMENTS 

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OMB Staff Working Comments on EPA’s Hexavalent Chromium draft 

Toxicological Review (page numbers refer to the draft dated April 2010) and Draft 

Charge to External Reviewers

May 10, 2010

General Science Comments:

• We applaud EPA for providing a document that is concise, transparent, and easy to 

follow. In particular, the presentation of the epidemiology studies was particularly 

informative and useful. For instance, where there were doubts or concerns about 

exposures in a particular Provence of China, EPA very clearly presented the impact of 

keeping this population in the overall analysis and the impact of removing it from 

consideration. This type of consideration and treatment of uncertain information was 

extremely informative. If peer reviewers should determine that human data may be 

more informative than animal data for the cancer quantification, this information 

should prove helpful. EPA may want to include a charge question regarding the 

determination not to exclude the more uncertain information, just in case reviewers 

suggest that EPA use this dataset.

• We are pleased to see that EPA has collaborated with other Federal (ATSDR) and 

State Agencies (Cal EPA and NJDEP) in producing this document. Consistent with 

the OMB Guidance on Peer Review (and likely conforming EPA guidance), while 

EPA typically has employees from State agencies on their peer review panels, to 

prevent any real or perceived conflicts of interest or concerns regarding 

independence, EPA should ensure that employees from collaborating agencies do not 

serve as expert reviewers.

• Page X, mentions that the intent of Section 6 is to characterize overall confidence by 

addressing the quality of data and related uncertainties and to convey limitations to 

aid and guide risk assessors. It was not clear to us that Section 6 addressed 

confidence, uncertainties and limitations. EPA may want to consider adding this 

information to Section 6, as is typical for most IRIS assessments.

• In discussing the results of the non-neoplastic lesions in the NTP 2007 and 2008 

studies, Section 4 does present, in tables, the severity of these lesions. In almost all 

cases, the severity was minimal to mild and occasionally moderate at the highest 

doses. As EPA relies on these endpoints for the RfD determination, it would be useful 

in Sections 4, 5, and 6 to include discussion regarding the severity of the lesions at the 

point of departure (in most cases the BMDL). This should be an important part of the 

discussion of the RfD determination and subsequent description of the RfD endpoint. 

Similarly, discussion of whether or not these lesions are considered to be adverse 

effects, adaptive changes (as NTP refers to diffuse epithelial hyperplasia) biologically 

significant changes, biomarkers of another endpoint (eg malignant neoplastic tumors),

and/or perhaps precursors to adverse effects would also be helpful. EPA may want to 
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consider a specific charge question on both these aspects as the reviewers consider 

the RfD determination. 

• EPA has determined that the mutagenic effects of hexavalent chromium are due to its 

reduction within the cell to trivalent chromium (see section 4.4.2). As the current 

IRIS summary file for trivalent chromium does not have a significant discussion of its 

mutagenic effects (except for a sentence which cites Nakamura 1978 which finds that 

trivalent chromium mutagenicity was low compared to compounds of hexavalent 

chromium), and classifies the compound as a group D carcinogen, is EPA now 

revising its views regarding the carcinogenicity of trivalent chromium? If so, does 

EPA plan to update its IRIS file for trivalent chromium? EPA may want to consider 

updating the trivalent chromium file first as this may then inform the hexavalent 

chromium update (rather than doing hexavalent chromium first since EPA is stating 

that its mutagenicity is due to the trivalent form). Discussion of any plans for 

updating the trivalent chromium file could be informative to this assessment.

• In discussing mutagenicity, in Section 4.6.2, as EPA is quantifying cancers in 

B6C3F1 mice, EPA may want to provide some discussion of the in vivo genotoxicity 

results in this strain. It seems a bit inconsistent that the studies presented in Table 4-

23 were negative or equivocal (as depicted by +) in this strain, yet EPA is 

hypothesizing a mutagenic mode of action. More discussion of these data, and 

perhaps a charge question to expert reviewers, may be helpful.

• In Section 5.1.2, it would be helpful for EPA to more clearly present when dose 

groups were dropped in the BMD modeling. EPA relies on a POD based on diffuse 

epithelial hyperplasia (as shown in Table 5-2). In the appendix it becomes clear that 

in order to make the model fit, EPA dropped the 2 highest dose groups. It would be 

helpful to explain, in Section 5, the justification for dropping dose groups. A robust 

statistical approach involves determining what data are relevant and sound before 

beginning a modeling exercise. Expert reviewers have commented on this issue in 

previous assessments (see Dr. Dale Hattis and Dr. Bruce Allen comments on 1,1,2,2 

Tetrachloroethane available at: 

http://cfpub.epa.gov/ncea/iris_drafts/recordisplay.cfm?deid=56732 ). As Dr. Hattis 

stated, in the context of BMD modeling, “In the light of Dr. Allen’s pre-meeting 

comments I would recommend that EPA at least show earlier results with the highest 

doses and show the lack of fit that led the analyst to make the dose exclusions that 

were made. I agree that it is probably not correct to exclude the higher doses for all 

endpoints in summary fashion without analyzing the specific fits for different 

endpoints, if that is what was done in this case.” A specific charge question about not 

using the two highest dose groups in the final model may be useful.

• In Section 5.1.2, it may be useful for EPA to describe how the best fitting model was 

determined, providing specific details on what standards for adequate fit were used. 

Looking at Appendix B, it is unclear if EPA chose values based on the highest x

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pvalue or based on the lowest AIC value. 
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• In Table 5.2, for endpoints where a BMD/BMDL was not determined, it may be 

helpful for EPA to provide the NOAEL/LOAEL values. In some recent assessments, 

EPA seems to not show a preference for the BMD approach over the 

NOAEL/LOAEL approach. If this is the case, showing the comparable values for all 

endpoints may be useful. Similarly, in cases where EPA dropped dose groups, it may 

be helpful to present the NOAEL/LOAEL value as a comparison.

• In Section 5.3.5, as the ADAF guidance recommends that information specific to the 

exposure scenarios of concern be used in case-specific evaluations, we recommend 

that EPA refer readers to the guidance for examples on how to apply the factors, 

rather than creating a full life time exposure value in this assessment. If the life-time 

exposure value is retained, EPA should remind risk managers to apply case specific 

exposure values that are appropriate to the particular risk management scenario under 

consideration. 

Editorial Comments (with Scientific Impacts):

• Page 10, line 7/8, please add a citation for this sentence.

• In discussing studies, EPA often states “results of this study identified..” a NOAEL 

and/or LOAEL value. It would be useful to clarify if the values have been identified 

by study authors or EPA. This is particularly important in chapter 5 when EPA refers 

back to these studies as having identified such values. Understanding where the 

determination came from would be helpful.

• In section 4.3, it would be very useful to provide a table (perhaps one for 4.3.1 and 

one for 4.3.2) which presents a summary of the reproductive and developmental 

summary citing the dose levels at which effects were seen, the statistical significance, 

and any limitations and uncertainties associated with the study.

• Page 179, line 6/7, it may be helpful to clarify who has made the proposal that is 

discussed. If there is peer reviewed literature, EPA may want to cite it.

• Page 181, line 10, it is not clear what data and discussion have been provided to 

support the determination that the mutagenic mode of action is applicable to all tumor 

types. Section 4.6.3.5 discusses different routes of exposure, but not different tumor 

types.

• Page 188, EPA may want to clarify that the BMD Technical Guidance is a draft. 

Citation should also be 2000b.
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Comments on the Draft Charge:

(Note: some suggestions for charge questions are provided in comments in the above 

sections. Many of those comments have not been reiterated here, but should be 

considered as equally important.)

• Since the development of Agency Information Quality (IQ) guidelines required by 

statute, many agencies have been using charge language that tracks with the standards 

of their own IQ guidelines. For example, such language often focuses on whether or 

not the information in question is accurate, clear, complete, transparently and 

objectively described, and scientifically justified. We believe it may be useful for 

EPA to follow a similar approach and incorporate some of the language from your IQ 

guidelines into the formulation of the charge questions. It may also be helpful for 

EPA to ask reviewers to comment on both the objectivity of the presentation and the 

objectivity of the substance regarding the critical decisions. 

• Under the general questions, it is unclear why EPA is no longer asking reviewers to 

comment on future research needs that may decrease uncertainties. Similarly, it is 

unclear why EPA is no longer taking comment on the characterization and 

identification of uncertainties. 

• In Q A2, as per comments above, EPA may want to describe whether or not this 

effect is considered adverse and ask the reviewers to comment on the determination.

• It may be helpful to have a specific charge question regarding EPA’s review of 

epidemiology data and whether the human data should be considered for cancer 

and/or non cancer quantification.

• While EPA asks, in Q B2, if a mutagenic mode of action is supported, it may also be 

helpful for EPA to have a specific charge question requesting comment on EPA”s 

mode of action and key events discussion in Section 4.6.3. EPA may also want to 

specifically take comment on the determination that intracellular reduction to trivalent 

chromium is necessary for a mutagenic mode of action.