IRIS STEP 3 INTERAGENCY COMMENTS

OMB Staff Working Comments on EPA’s Acrylonitrile (AN) draft Tox icological

Review (page numbers refer to the redline draft dated January 2010 and refer to pages of the PDF [eg page x of 976], not the actual page numbers as these are highly variable ) and

Draft Charge t o External Reviewers

General Science Comments:

**•** We appreciate the many clarifying changes EPA made in response to our earlier

March 2008 comments and are pleased to see this assessment moving forward.

**•** To ensure a robust review, we hope EPA will include multiple biost atisticians and

PBPK modelers on the panel to help address questions related to the modeling and early

- life exposure analysis.

Specific Science Comments:

**•** It appears as if EPA had an internal group review the PBPK models use d in this assessment and EPA has modified some of the parameters. Have these parameter changes been peer reviewed or does EPA plan to take peer review on these modifications during the current peer review? If the plan is to have the PBPK peer

review take place concurrent with the review of the toxicological review, it may be helpful to have multiple modeling experts on the panel and to ask them specific detailed questions regarding the modifications.

**•** The sections reviewing the epidemiological studies could be interpreted to presume a priori that there must be associations between AN and cancer and non

- cancer endpoints. For example, the write

- up appears to assume that confounders and/or the healthy worker effect or study design masked effects. Perhaps a reorganization here might be helpful. For example, t he human studies are present ed before the animal

literature. Reversing this order might help the reader to understand more about possible effects before getting to the summaries of the epi literature.

**•** Page 157 , in discussing Marsh, EPA states that “Other known potential occupational hazards at the plant included asbestos, 1,3

- butadiene, and depleted uranium; exposure

to the se chemicals was not assessed. However, in the exposure assessment by Stewart et al. (1998) on this cohort, these chemicals were not singled out as impactful potential occupational hazards.” Does this mean that Stewart didn’t focus on them or

did he evaluate them and find that the exposures were minimal ? If t he se other

exposures are present, s houldn’t this also be discussed in the context of Blair and mentioned when describing the methods? It may be helpful to describe how Blair 98 controlled for these other exposures and how these co

- exposures were taken into

account when stating that Blair provides ‘suggestive evidence’ with regards to lung

cancer.

**•** Page 184 states: “Furthermore, the statistically significant increased OR for AN exposure in the lung

- cancer case control study of Scélo et al. (2004) provides weight

for this association. This study adjusted for effects related to individual smokingIRIS STEP 3 INTERAGENCY COMMENTS

history and to a number of potential coexposures found in a subject’s occupational setting.” The previous discussion of the Scelo study mentions co

- exposures to styrene
and vi nyl chloride, but there is no discussion of how the study adjusted for these confounding exposures. It may be helpful to add this to the discussion of Scelo.

**•** Page 184, discusses a 1992 Selikoff and Seidman study looking at histopathology of

asbestos worke rs and lung cancer diagnosis. It is unclear how this study leads to a conclusion that the Blair cohort may have 10% of internal controls with lung cancer.

**•** Page 217, in summarizing Quast 2002 EPA states that a LOAEL was identified for reasons including dec reased survival. Where are data on decreased survival presented? This is not clear. It may be useful to add this information to a relevant

table.

**•** Page 324, the mode of action section for non cancer focuses on GI hemorrhaging, hemoglobin metabolism, neurotoxicity, oxidative stress and immunotoxicity. It may be helpful to explain why EPA focuses on these endpoints. As the RfD is based on forestomach lesions, it may be helpful to have a discussion of this mode of action.

**•** Page 417, in citing NAS, the page citation should be page 143. EPA

, in shortening this parenthetical, deletes some clauses of some sentences which may change meaning. I t w ould be better to pre sent full sentences with qualifiers . Thus we suggest lengthening this quote to capture the full NAS statement (including the citations ). It may be best to put this in a footnote. We also note that this is a statement made in passing by the NAS but it is not necessarily a final conclusion of their report as it was not a question they were asked to address. In addition, it may also be helpful to also

cite and discuss, in t his section, the EPA 2005 Cancer Guidelines which talk about considering the biological relevance of animal tumors and how each should be considered and weighed on its own merits. The EPA Cancer Guidelines also discuss

how evaluation of the mode of action of each tumor is important and thus EPA may want to apply the mode of action framework and discuss how it supports the relevance of each of the tumors found only in animals. This analytical approach may help to increase EPA’s scientific justification for c onsidering these tumors. We note

that EPA has a mode of action discussion for the forestomach tumors but not the Zymbal or Harderian gland tumors.

**•** Page 472 (and similar comment f or the RfC section and cancer derivations, eg table

5

- 12 ) , it may be helpful to show a summary table of the modeled BMD and BMDL values, along with the AIC values and goodness of fit values, in chapter 5. EPA typically does this and it is very helpful in allowing readers/reviewers to easily see how EPA came to their determination of the best fitting model and choice of BMD and BMDL. It may also be useful to clarify how EPA determined if AIC values were different enough to be considered separately, rather than treating them as similar (eg. is 44.5 meaningfully lower than 44.9 or did EPA use the mean of both values?).IRIS STEP 3 INTERAGENCY COMMENTS

**•** Page 486, in discussing the co

- exposures to Cyanide (CN) and methyl methacrylate (MM) in the Lu study chosen for the RfC derivation, EPA seem s to presume that the CN concentration will be lower than the AN concentration. It may be helpful to clarify what this assumption is based on. For MM, EPA compares toxicity to a 1998 RfC. However EPA may want to look at the data in light of today ’ s modeling approaches, which may show MM as more toxic than it was thought in 1998. Was neurobehavioral performance evaluated for MM? As the RfC is based on a different endpoint, EPA may want to look at studies that examined MM neurobehavioral

effects. If no studies exist th e n it seems that there could be a lack of data and its not clear that EPA can so easily discount the confounders. While the results from this study are consistent with others, they are also the lowest, a nd this could possibly be due to the confounders. It may be helpful for EPA to also ensure that there is a neurobehavioral toxicologist on the panel who will be able to answer questions related to the choice of the Lu study and its limitations (includin g the cultural design issue that is mentioned by Lu). It may also be helpful to mention the potential confounding exposures on page 496 when discussing limitations of the Lu study.

**•** Page 491, table 5

- 2., in previous assessments this type of table has also included the possible RfC value by including UF’s that would be applied. In addition, as EPA provides comparisons in text to values that would be derived from animal studies, it may be helpful to also show the comparative array including the animal data. S eeing NOAEL information may also be useful.

**•** In appendix B, for modeling of the rodent data, in some cases it appears that BMD modeling was conducted using only some of the data, rather than the full dataset. It is unclear why EPA would not use the full da taset for modeling as a strength of the BMD approach is that it takes into account the full dataset rather than just point estimates. Ideally, EPA should only be excluding data from modeling if an evaluation of the data, before statistical analy ses begin, shows that they should be excluded for methodological or other reasons. A question about not using the full range of data may be very useful in the charge so that EPA can get the input of the expert

reviewers.

Editorial Comments (with Scientific Impacts) :

**•** Page 1 40 , sentence grammatically unclear: “Nearly half of the exposed group worke d with AN for at least 5 years, and 26% of the unexposed group was both observations significantly lower than expected. ”

**•** Page 1 72

, table 4

- 16, please revise title to reflect that this represents exposures to vinyl chloride and styrene, as well as AN. The summary paragraph should also reflect

this.

**•** Page 251, typos in section 4.2.2.1 header, also in 1 st sentence of section.

**•** Page 415, EPA states that there “is suggestive evidence of a possible association between occupational exposure to AN and increased risk of lung cancer”. EPA refersIRIS STEP 3 INTERAGENCY COMMENTS

back to section 4.1.2.2. It may be helpful to also provide the citations to the specific

studies EPA is relying upon for this finding.

**•** Page 539, chooses the IUR from human data based on Blair, however it is unclear

where the derivation of this value is provided in the text.

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 import ant in ensuring a rigorous peer review of this highly

technical document

. )

**•** 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 informat ion 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 form ulation of the charge questions. It will 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.

**•** As has been done in some previous IRIS revi ews, it may be helpful to ask expert reviewers to comment on research needs which may likely inform future assessments and decrease uncertainties in the database. It may also be useful for EPA to have a question asking reviewers to comment on the existing EPA evaluation of

uncertainties.

**•** B1 asks if the addition of EH to the model is justified . It may be helpful to also ask

about EPA ’ s approach for add ing it to the model and the specific values used. Because this question focuses only on the EH aspect of the model, EPA may also want to have a charge question asking reviewers for other suggestions related to the full model. EPA may also want to ask reviewers if they thi nk the model is appropriate for use without further peer review.

**•** B3

, EPA presents a nice discussion of uncertainties associated with the model and also presents some sensitivity analyses in the appendix. I t may be helpful for EPA to

also ask revi ewers to comment on the identification and characterization of the uncertainties as EPA presents them.

**•** C, questions on the RfD, it may be helpful to add a question that asks specifically about the choice of species and strain used for the critical effect.

**•** D1, it may be useful, since EPA has chosen to use an epidemiology study for the RfC, to ask reviewers to comment on whether the limitations of the study have beenIRIS STEP 3 INTERAGENCY COMMENTS

sufficiently considered. EPA may also want to ask reviewers if they agree with

EPA’s determination to use the human data instead of the animal data.

**•** D2, from the tox review, it seems that the critical effect EPA has chosen was

considered to be minimal (as stated by EPA, but not defined) . It may be useful to describe what EPA means by this so that the reviewers can provid e comments.

**•** E1, in addition to the general question about the cancer classification, it may be helpful to have some very specific questions that ask the reviewers to comment on EPA’s classification determination. For instance, EPA could add the following:

**•** EPA notes that the epidemiological studies do not provide strong or consistent

eviden ce for a causal association. Please comment on the role that you would give to the epidemiological evidence in drawing conclusions regarding potential carcinogenicity.

**•** Do you find that the conclusions drawn from the animal data are consistent with those drawn from the epidemiological studies? Please comment on the rigor of the cancer weight of the evidence characterization.

**•** E4, As EPA is combining some tumors for which there is no human counterpart (eg forestomach or zymbal gland) it may be helpful to specifically ask reviewers ab out the inclusion of these tumors. In addition for the oral slope factor, EPA may want to include a more general question about the overall approach they took to the modeling. Current questions only ask about the choice of study and the combining of tumors

.

**•** E5 mentions that EPA estimated the IUR using both the animal data and the epidemiology data. EPA should clarify what the preferred final choice is and ask for explicit comment on this choice. EPA may also want to consider the following additional questi ons regarding the Blair study:

o Conversion of occupational exposures to continuous environmental exposures was accomplished by adjusting for differences in the amount of air inhaled during an eight

- hour work day versus a 24

- hour day (10 m3/day vs. 20

m3/da y, respectively). Given that Blair et al. 1998 only identified statistically significant relationships in the most highly exposed groups, do you think that there is sufficient data to support a linear extrapolation to l ow levels? Are there any oth er approaches or data sources that you would recommend to inform the extrapolation from the relatively high industrial exposures in these studies of the past to the types of ambient exposures that EPA regulates?

o There were not enough lung cancer deaths in other than white males sex

- race groups, so sex and race were not included as covariates. Please comment on the potential implications of taking this approach, rather than that used in Starr 2004 (which only looked at white males).

o Does the analysis techni que adequately account for the healthy worker effect?

**•** For both the IUR and the slop e , EPA provides advice to not use the animal derived values above a certain exposure level . EPA may want to take comment on this advice

.IRIS STEP 3 INTERAGENCY COMMENTS

**•** E6, as this is the first time EPA is derivin g chemical

- specific data

- derived, early

- life susceptibility factors within the context of a chemical assessment, it may be helpful for EPA to take comment on the approach. Alternatively, EPA could have a separate peer review process, w ith appropriate experts to review this derivation. It may be useful for EPA to ask the reviewers the following questions:

o A specific question about whether or not all the tumors in these studies, particularly the mammary tumors

, are known to act through a mutagenic mode

of action. This is critical.

o A specific question about whether or not the one study available for quantification provides sufficient weight of evidence to reliably quantify an appropriate factor.

o A specific ques tion regarding whether this one inhalation study should be used to adjust both the oral and inhalation values.

o A specific question about using the default values in the supplemental guidance

- assuming there is a known mutagenic mode of action for AN , in light of the lack of data available.

o A specific question about using the 15

- week data to inform an adjustment factor for less than chronic exposure.

o A specific question about the quantification and analysis that was conducted.

**•** In addition a previous draft contained the following question which we thought was useful. It is unclear why EPA deleted it in the current version. The question

reads:

**•** Please comment on the scientific justification for the application of this early

life susceptibility facto r as suggested. Should an early

- life adjustment factor be applied for less than chronic exposures starting in early

- life? Can available data be used for an estimate of early

- life adjustment factor with exposure to acrylonitrile only in early

- life?