IRIS STEP 6 INTERAGENCY COMMENTS (OMB)

OMB Followup Comments on Inorganic Arsenic Assessment (page numbers refer to pages in redline draft dated March 2009)

General Comments:

• We thank EPA staff for their responsiveness to our first round comments. The clarity, transparency and readability of the document is greatly improved. Our remaining comments are presented below. We are happy to work quickly with EPA to address the comments.

• We have heard that Dr.Vanessa Vu at SAB may have discussed with the previous ORD AA ways for the SAB to quickly and efficiently do a quick review of the draft assessment to ensure that SAB was satisfied with the way its comments have been addressed. Has ORD staff spoken recently to Dr. Vu about her ideas or suggestions? Considering the importance of this assessment, a quick check back with SAB would likely help st rengthen this document. Can you share with us the options Dr. Vu may have and ORD’s thoughts on conducting such a review for this particular assessment?

• We have received copies of 3 letters sent to EPA by different stak eholder groups regarding
comments related to this assessment. We trust that staff have seen and considered these letters, but please confirm.

• Most recent assessments circulated for intera gency review have contained a chapter in
Section 5 entitled “uncertainties in the cancer ri sk values”. It would be useful to have a
similar section here that discusses uncertainties and implications of so me of the assumptions that EPA made and the likely impact of those assumptions.

• Section 5 in multiple places mentions the Arse nic Rule. This seems inconsistent with EPA’s previous approach to IRIS assessments, which separate the science from any risk management decisions. We also note that previo usly EPA has not presented information that
comes from sources other than sc ientific journal articles and has referred readers generally to other sources for this type of information.

• While we do not comment specifically on the IRIS summary, we hope that EPA will make conforming changes there as you address our comments on the assessment.

Specific Comments:

• Section 5.3.1 The addition of this section is very helpful. The SAB comments are summarized in text as requesting only a furthe r sensitivity analysis of modeling methods and choices. This approach may miss other SA B recommendations. A more complete presentation of their recommendations, in text, may be useful. For example:

o In response to Charge C2, SAB suggested that EPA use a uniform set of evaluation criteria to assess other epidem iology studies from the U.S. and other countries exposed to lower arsenic concen trations. SAB stated that “comparative analysis could lead to further insight s into the possible influence of these differences on population response to arsenic in drinking water.”IRIS STEP 6 INTERAGENCY COMMENTS (OMB)

o SAB suggested that EPA: “ also conduct adjunct analyses to test the robustness of results against their assumptions, determine the impact of variability in some parameters, compare the results against those from othe r data sets, and provide a transparent assessment of the available epidemiological data using a consistent set of criteria.”

o SAB recommended that “ the other relevant epidemiologic databases from studies of arsenic-exposed populations be used to compare the unit risks at high exposure levels that emerge from the Taiwan data.”

o SAB also recommended that “results on bladder cancer risk from published epidemiology studies of U.S. and other populations chronically exposed to arsenic levels ranging from 0.5 to 160 μ g/L inorganic arsenic in drinking water, be critically
evaluated.”

• Table 5-1.

o It would be useful to add the SAB 2007 review and its recommendations to the table. Otherwise it could appear as th ough there has been no effort since 2005,
and the fact that SAB made recommenda tions regarding the assessment is not transparently presented. Pages 103-105 do discuss some of the implemented SAB 2007 recommendations; thus, seeing them in the table would be helpful.

o In order for readers to fully understand how the assessments have evolved over time, after an added SAB 2007 column, it w ould be useful to add the parameters for this final assessment. This would greatly improve clarity and would make it easy to see all the changes over time and their implications--including the information presented in this final assessment.

o In the endpoints calculated section, it woul d be useful to present the oral slope factor, unit risk and drinking water concentrations at 10 -4 and 10 -6 risk levels. This
is consistent with section II.B.I of the IRIS summary and this would be extremely helpful here. It is unclear why one of th e metrics EPA presents is incidence at 10ug/L in drinking water as this is not consistent with typical IRIS summary
information.

• In the response to interagency comments on page 14 EPA states: “ As discussed in revised Section 5.3.8.2,.....Adoption of more recent bac kground U.S. mortality and cancer incidence data may have resulted in the current risk estimates being about 50% increased compared to what the

would have been if older data had been used.” In section 5.3.8.2, we were unable to find transparent discussion of the impact of U.S. mo rtality and cancer incidence data leading to a 50% increase compared to older da ta. It would be useful to pres ent these data in this section.

• Appendix B: it is helpful that EPA added fr ont matter discussion to Appendix B describing
the factors SAB asked to have considered. However, as EPA mentions, all of this information is not in the table, and when we look to section 4.1 we can not uniformly find how this information was considered. In partic ular, for many studies we are unable to locate: a) estimates of the level of exposure misclassifi cation; b) temporal variability in assigning past arsenic levels from recent measurements; c) the extent of reliance on imputed exposure levels; d) the number of persons exposed at various estimated levels of wa terborne arsenic; e) study response/participation rates; f) estimates of exposure vari ability; g) cont rol selection methods in case-control studies; and, h) the resulting influence of these factors on the magnitude and statistical stabilit y of cancer risk estimates. As these are the issues that SABIRIS STEP 6 INTERAGENCY COMMENTS (OMB)

suggested EPA consider, is there a way to more clearly present this information either in the
table or text of section 4.1? We note that SAB suggested a tabular format; thus, perhaps adding this information to the table may meet SAB’s concern. SAB also suggested that the strengths and weaknesses be described in re lation to each of the criterion above and suggested that the caveats and a ssumptions “be presented so that they are apparent to anyone
who uses these data.” Is there a wa y to better present this evaluation?

• Our first set of comments asked whether EPA could use a Monte Carlo approach, or distributions, rather than a point estimate for water consumption. EPA responded that it would be misleading to apply a Monte Carlo ap proach to only one exposure variable and not
others. If EPA is clear about th e approach and explains why it was done for just one variable, why would this be misleading? We note that it is not uncommon in Monte Carlo analysis to use distributions for some parameters and point estimates for others.

• We appreciate EPA’s responsiveness and the ne w presentation for sl ope factors that are gender specific. Did EPA use gender specific cons umption rates for males and females or did EPA use the population (both genders combin ed) value? This was unclear. We would recommend using gender specific values wherever possible.

• Page 107, the last paragraph discusses the NAS recommendations and mentions that SAB also reviewed the modeling. However, it do es not provide the SA B recommendation. It would be useful to provide a sentence or two describing the SAB recommendation.

• Page 109, 2 nd paragraph, EPA states that they have assumed that the ratios of cancer mortality to incidence for arsenic related can cers are the same for the U.S. and Taiwanese populations. Can EPA discuss the effects of this assumption to give a sense of its magnitude? If the ratio is lower in the U.S., what would th e overall impact be? Are there any general data regarding cancer incidence and mo rtality in the U.S. vs Taiwan to help inform the effects of this assumption? Does EPA expect that change s to this assumption would have a small or large effect on the final outcome. Discussion of this would be helpful and informative.

• Page 109, 5.3.5, 2 nd paragraph. EPA used 10ug/day as the non-water arsenic intake for both reference and exposed populations . EPA also states (page 110) that NRC in 1999 reported 50 ug/day in 1999 and used 30 ug/day in 2001 for exposed populations. In 2005, EPA used 0, 30 and 50 ug/day for exposed populations. It is not clear why EPA now finds 10 ug/day to be the best estimate for both populations. More clar ity here would be useful. Did SAB make any suggestion for the value for the exposed populat ion? The implications of varying this parameter should be clearly discussed in a final section on uncertainties.

• Page 115, 5.3.7.3, 2 nd to last sentence, why were intakes resulting in 10 -2 lifetime risks estimated? Why not 10 -4 through 10 -6 ?

• Page 116, 5.3.8.1 text and tables, please present risk for 10 -4 to 10 -6 as this is consistent with presentation in all IRIS summaries. It is al so unclear why inciden ce at 10 ug/L in drinking water is presented. If EPA’s intent is to tie this information to a regulation (that may changeIRIS STEP 6 INTERAGENCY COMMENTS (OMB)

over time), it seems inappropriate for the IR IS tox review docume nt (as per previous statements EPA has made regarding in cluding this type of information).

• Page 118, 5.3.8.2, in the first paragraph, it would also be helpful to discuss why the results in this assessment are so different from those pr esented in the 2005 draf t assessment. For both
assessments internal cancers were used and the same modeling approach was used. More clarity in explaining how and why the assessment has changed since 2005 would be useful. Similar discussion in section 6.2 would also be helpful.

• Page 119, EPA states that conver ting mortality estimates to in cidence adds uncertainty. Can EPA say anything more about the impact or dir ection of this uncertainty and its potential
effect? Discussion of this in an unc ertainty section would be useful.

• Page 122, 1 st full paragraph, states that the BEIR IV more recent da ta likely contribute to the
risk differences in table 5-6. Can EPA say anything about the impacts of the new data (e.g. percent change in va lue due to its use) on the final outcome?

• Page 125, now very nicely discusses the impacts of non-water intake on the final values. This
discussion should be considered in an uncer tainty section where EPA talks about the confidence in the assumption (e.g. 10 ug/day) chosen for exposed and reference populations.

• Page 131, EPA states: “A key assumption underlying this model is that the risk of arsenicrelated cancer is a constant multiplicative functi on of the “background” age profile of cancer risks in the target U.S. popul ation.” EPA should addi tionally discuss the implications of this assumption on the final value.

Editorial Comments:

• Page 98, 3 rd full paragraph. Was the application of the cancer slope factors in the OPP RED externally peer reviewed? If s o, it would be helpful to mention that here. REDs typically go through a robust public comment period, but if this was also peer reviewed, this would be good supporting information to add.

• Page 108, section 5.3.4, 1 st paragraph. Did SAB also reco mmend using lung and bladder cancer mortality? If so, the SAB citation shoul d be added. This paragraph also talks about mortality and we note that EPAs final estima tes are for incidence, not mortality. Is the transition from mortality to incidence, and th e implications of changi ng the endpoint, clearly discussed in the chapter? If EPA has transiti oned from mortality to incidence, it would be helpful to clarify the implica tions of changing the endpoint.

• Page 109, 1 st paragraph, last sentence. Please clarify whether or not SAB 2007 also supported linear extrapolation from the point of departure.

• Page 111, 5.3.6, 2 nd paragraph. It would be useful to mention where the sensitivity analysis using different well concen trations is presented.IRIS STEP 6 INTERAGENCY COMMENTS (OMB)

• Page 113, 5.3.7.1. Where can readers find the actual modeling data as well as results from different models tested, the resulting impact s and details of the goodne ss of fit and parsimony criteria applied to the different models? Simila rly, where are the conf idence limit calculations (discussed in section 5.3.7.2) presented?

• Page 113, footnote 5 appears to be missing in the redline draft.

• Page 118 suggested edit: “the combined cancer slope factor for women (25.7 per mg/kg-day) is appropriate chosen for use in establishing health crit eria, since, based on the available data, women appear to be the more sensitive group”

• Page 119, 1 st paragraph, refers to “the Rule”. EPA should clarify what this is.

• Page 119, table 5-5, it is unclear where the values from the current analysis come from. Are the calculations presented anyw here? Are all the values in th e table incidence values? This should be clarified. On page 120 EPA states that the Chen results are mo rtality -- thus is it appropriate to compare mortalit y and incidence? Are the Chen results for lung cancer also mortality? What would be the impact of adju sting them to incidence and then how would they compare with the current analysis values?

• Page 120, table 5-6 and in text, EPA should clar ify why they are presenting a comparison at 10 ug/L arsenic in drinking water. This type of comparison is not typical in IRIS tox reviews.

• Page 125, line 1, suggest replacing “small or mode rate” with specific numbers. Similarly in
the 2 nd sentence, suggest deleting “small” and s imply present the value. Similar edits throughout this discussion (see also the 3 rd paragraph on page 125) would be useful.

• Page 126, footnote 8, EPA talks about how the data fit less well for some models. It would be useful to provide information on the criter ion EPA used for good model fit. Are these modeling data presented in the document?

• Page 127, 2 nd paragraph, suggest replacing “very si milar risks” with actual values.

• The introduction to Appendix A states that the summary of comments and responses is
inclusive of issues ra ised by public commenters. Does th is mean that all public comments
were similar to SAB comments? We do not see any public comments specifically mentioned in this appendix.