1

EPA’s Response to Selected Major Interagency Commen ts on the Interagency Science

Consultation Draft IRIS Toxicological Review of Acr ylonitrile June 30, 2011

History of Interagency Science Consultation (Step 3 of the IRIS Process) for the draft IRIS Toxicological Review of Acrylonitrile:

• February 2008 – Interagency review began in February, 2008; comm ents were received from the Office of Management and Budget (OMB), the National Institute of Environmental Health Sciences (NIEHS), and the Agen cy for Toxic Substances and Disease Registry (ATSDR). The interagency review st ep was not completed. Comments on the February, 2008 draft were received before the May, 2009 IRIS review process was implemented and, therefore, are not subject to the 2009 provision for public release of interagency review comments. Comments from the 2008 interagency review are not included in this disposi tion of major interagency

comments.

• January 2010 – Under the May, 2009 IRIS process, the interagenc y science consultation step was re-initiated in January 2010; comments wer e received from OMB and NIEHS. EPA’s response to selected major interagency commen ts is found below. The complete original comments are in an Appendix to this docume nt.

• June 2010 – The draft Toxicological Review of Acrylonitrile was placed on hold in June, 2010 following the release of a report by the Natio nal Toxicology Program outlining their review of pathology findings from the Ramazzini Ins titute. The draft assessment relied on a Ramazzini Institute study – Maltoni et al. (19 88) – for quantification.

• June 2011 – Upon further analysis, EPA determined that the Ma ltoni study was not critical for estimating the potential cancer risks associated wi th acrylonitrile exposure. The assessment was revised accordingly and the revised sections (Sections 4.8.1 and 5.4.4.3) were distributed for review to interagency reviewer s; comments in support of the

revisions were received from the Council on Environ mental Quality (CEQ) and are appended below. – The Interagency Science Consultation draft Toxico logical Review of Acrylonitrile (dated January 2010), Interagency Science Consultat ion draft external peer review charge questions, interagency comments on these draft docu ments, and EPA’s Disposition of Selected Major Interagency Science Consultation com ments are posted on the IRIS website (www.epa.gov/iris). All interagency commen ts provided were taken into consideration in revising the Interagency Science C onsultation draft. The subsequent External Peer Review draft Toxicological Review of Acrylonitrile (dated June 2010) is currently being provided for public comment and ext ernal peer review.

For a complete description of the IRIS process, inc luding Interagency Science Consultation, visit

the IRIS website at www.epa.gov/iris

.

The following are EPA’s responses to selected major interagency review comments received during Interagency Science Consultation. The compl ete set of all interagency comments is attached as an appendix to this document.2

January 2010 Interagency Science Consultation Draft IRIS Assessment—Selected Major Comments and Responses:

1. OMB Comment: 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 the se endpoints. As the RfD is based on forestomach lesions, it may be helpful to have a di scussion of this mode of action.

EPA Response: Section 4.5.1.1, “Mechanistic Data and Other Studi es in Support of the Mode of Action—Noncancer Endpoints” was organized a round the mechanistic studies that were available in the acrylonitrile literature. Th e absence of a section specifically on forestomach lesions reflects the limited experiment al investigation of mechanisms by which acrylonitrile induces noncancer effects in the fore stomach. The title of Section 4.5.1.1.1 has been changed from “GI Hemorrhaging” to “GI Effects” to better reflect the content of this section. In addition, a summary of the study by Gh anayem et al. (1997) on proliferative changes in the forestomach has been added (with cro ss reference to Section 4.5.1.2.4). The summary of the mechanistic study of Ghanayem and Ah med (1983), which investigated acrylonitrile-induced GI hemorrhage, has been revis ed to specifically state that bleeding was evaluated in rat stomach (forestomach and glandular stomach) and intestine to better highlight information on the critical target organ.

2. OMB Comment: Page 417, in citing NAS, the page citation should b e page 143. EPA, in shortening this parenthetical, deletes some clauses of some sentences which may change meaning. It would be better to present full sentenc es with qualifiers. Thus we suggest lengthening this quote to capture the full NAS stat ement (including the citations). It may be best to put this in a footnote. We also note that t his 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 this section, the EPA 2005 Cancer Guidelines which talk about considering the biological

relevance of animal tumors and how each should be c onsidered 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 ap ply the mode of action framework and discuss how it supports the relevance of each of th e tumors found only in animals. This analytical approach may help to increase EPA’s scie ntific justification for considering these

tumors. We note that EPA has a mode of action discu ssion for the forestomach tumors but not the Zymbal or Harderian gland tumors.

EPA Response: Section 4.7.2 of the Toxicological Review was revi sed to present the full quote from NAS (2008) regarding site concordance of tumors between animals and humans; the page citation for this quote was corrected. EP A agrees that it would be useful to cite and include a discussion of the Agency’s 2005 Guidelines for Carcinogen Risk Assessment (“Cancer Guidelines”) in Section 4.7.2; as such, ci tation to the guidelines was added. As noted in the Cancer Guidelines, site concordance “i s not always assumed between animals and humans” because “there is evidence that growth control mechanisms at the level of the cell are homologous among mammals, but there is no evidence that these mechanisms are site concordant. Moreover, agents observed to prod uce tumors in both humans and animals3

have produced tumors either at the same site (e.g., vinyl chloride) or different sites (e.g., benzene) (NRC, 1994).” Regarding Zymbal gland and Harderian gland tumors, EPA would have conducted a mode of action analysis applying t he framework from the Cancer Guidelines to each tumor type if data for these tum ors were available to support such an analysis; however, for these and certain other tumo rs, the information was insufficient to apply the framework. The text has been revised to state more clearly that these data are not

available.

3. OMB Comment: Page 486, in discussing the co-exposures to Cyanid e (CN) and methyl methacrylate (MM) in the Lu study chosen for the Rf C derivation, EPA seems to presume

that the CN concentration will be lower than the ac rylonitrile 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 o f today’s modeling approaches, which may show MM as more toxic than it was thought in 19 98. Was neurobehavioral performance

evaluated for MM? As the RfC is based on a differen t endpoint, EPA may want to look at

studies that examined MM neurobehavioral effects. I f no studies exist then it seems that there

could be a lack of data and it’s not clear that EPA can so easily discount the confounders. While the results from this study are consistent wi th others, they are also the lowest, and 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 (inc luding 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 stud y.

EPA Response: EPA obtained additional information on potential c yanide and methyl methacrylate exposures from the first author of the Lu et al. (2005a) study, Dr. Rongzhu Lu. In the production of acrylic fiber, the ratio of ac rylonitrile (primary monomer) to methyl methacrylate (second monomer) and methylenesuccinic acid (third monomer) is approximately 90-94 to 5-8 to 0.3-2, depending on t he technology used. The second and third monomers are used for improving softness of t he fibers and do not present a significant exposure potential. Because ambient concentrations of these monomers in the workplace are too low to be detected, no workplace monitoring dat a are collected; the study author identified methyl methacrylate and methylenesuccini c acid as potential trace exposures. Cyanide is one of the by-products in the production of acrylonitrile by oxidation of ammonia; this byproduct is recycled from the process to prod uce sodium cyanide. The concentration of cyanide was also reported by Dr. Lu to be too low t o be detected, and therefore workplace monitoring is not performed. Because cyanide and m ethacrylate occurred only at trace levels, if at all, EPA does not considered them to be confounding exposures. Additional information related to the presence of these chemic als in the workplace (citing communication with the study author) was added to t he summary of Lu et al. (2005a) in the Toxicological Review. In light of the additional i nformation provided on these monomers and cyanide, EPA did not identify this issue as a m ajor uncertainty in the Lu et al. study. EPA agrees that it will be important to have a neur otoxicologist as one of the peer reviewers of the acrylonitrile assessment; this expertise wil l be represented on the peer review panel.

4. OMB Comment: In appendix B, for modeling of the rodent data, in some cases it appears4

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 datase t for modeling as a strength of the BMD approach is that it takes into account the full dat aset rather than just point estimates. Ideally, EPA should only be excluding data from modeling if an evaluation of the data, before statistical analyses 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.

EPA Response: Dose-response assessments in IRIS toxicological re views always begin with

an evaluation of the data to determine their suitab ility for BMD modeling. Once deemed amenable to modeling, the dropping of high-dose gro ups generally arises only when attempts

to fit BMD models to the full data set are not succ essful. That is, the BMD models used by EPA in BMDS are found not to provide adequate fits to the data (as judged by the p -value of the chi-square goodness-of-fit statistic and visual examination of the fit, especially in the low-dose region of the dose-response curve). In th is situation, a common and valuable analytical approach is to determine whether an adeq uate fit can be obtained if the high-dose

data are omitted. Because human health risk assess ment is focused on estimating responses at low-dose levels, the high-dose group, rather tha n low or intermediate dose groups, is typically dropped. This approach allows for use of the most relevant data and is more statistically sound than the NOAEL/LOAEL approach. Dropping a dose group that is relatively distant from the region of interest (i.e ., low-dose risk estimation) is a reasonable and statistically defensible approach to modeling. This approach is reflected in the Agency’s

External Peer Review Draft of the BMD Technical Gui dance (U.S. EPA, 2000) that is currently being finalized.

The text in Section 5 of the Toxicological Review o f Acrylonitrile identifies those endpoints for which it was not possible to conduct BMD modeli ng using the full data set and the reason why a model fit could not be obtained. The draft p eer review charge includes a specific question regarding whether BMD modeling was appropr iately conducted.5 Appendix Comments on the Interagency Science Consultation Dr aft IRIS Toxicological Review of Acrylonitrile6

Office of Management and Budget (OMB) Comments on t he Interagency Science Consultation Draft IRIS Toxicological Review of Acr ylonitrile (dated January 2010)

OMB Staff Working Comments on EPA’s Acrylonitrile ( AN) draft Toxicological Review (page numbers refer to the redline draft dated Janu ary 2010 and refer to pages of the PDF [eg page x of 976], not the actual page numbers as thes e are highly variable) and Draft Charge to

External Reviewers

General Science Comments:

• We appreciate the many clarifying changes EPA ma de in response to our earlier March 2008 comments and are pleased to see this assessment mov ing forward.

• To ensure a robust review, we hope EPA will incl ude multiple biostatisticians and PBPK modelers on the panel to help address questions rel ated to the modeling and early-life exposure analysis.

Specific Science Comments: • It appears as if EPA had an internal group revie w the PBPK models used in this assessment and EPA has modified some of the parameters. Have t hese parameter changes been peer reviewed or does EPA plan to take peer review on th ese 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 t he modifications.

• The sections reviewing the epidemiological studi es could be interpreted to presume a priori

that there must be associations between AN and canc er and non-cancer endpoints. For example, the write-up appears to assume that confou nders and/or the healthy worker effect or study design masked effects. Perhaps a reorganizati on here might be helpful. For example, the human studies are presented before the animal liter ature. Reversing this order might help the reader to understand more about possible effects be fore 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 these chemicals was not assessed. However, in the exposur e assessment by Stewart et al. (1998) on this cohort, these chemicals were not singled out a s 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 these other exposures ar e present, shouldn’t this also be discussed

in the context of Blair and mentioned when describi ng the methods? It may be helpful to

describe how Blair 98 controlled for these other ex posures 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 in7

the lung-cancer case control study of Scélo et al. (2004) provides weight for this association. This study adjusted for effects related to individu al smoking history and to a number of potential coexposures found in a subject’s occupati onal setting.” The previous discussion of the Scelo study mentions co-exposures to styrene an d vinyl chloride, but there is no discussion of how the study adjusted for these confounding exp osures. 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 workers and lung cancer diagnosis. It is unclear ho w 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 t hat a LOAEL was identified for reasons including decreased survival. Where are data on dec reased 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 can cer focuses on GI hemorrhaging, hemoglobin metabolism, neurotoxicity, oxidative stress and imm unotoxicity. It may be helpful to explain why EPA focuses on these endpoints. As the RfD is b ased on forestomach lesions, it may be helpful to have a discussion of this mode of action

.

• Page 417, in citing NAS, the page citation shoul d be page 143. EPA, in shortening this parenthetical, deletes some clauses of some sentenc es which may change meaning. It would be better to present full sentences with qualifiers . Thus we suggest lengthening this quote to capture the full NAS statement (including the citat ions). It may be best to put this in a

footnote. We also note that this is a statement mad e in passing by the NAS but it is not necessarily a final conclusion of their report as i t was not a question they were asked to address. In addition, it may also be helpful to als o cite and discuss, in this section, the EPA 2005 Cancer Guidelines which talk about considering the biological relevance of animal tumors and how each should be considered and weighe d 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 frame work and discuss how it supports the relevance of each of the tumors found only in anima ls. This analytical approach may help to increase EPA’s scientific justification for conside ring these tumors. We note that EPA has a

mode of action discussion for the forestomach tumor s but not the Zymbal or Harderian gland

tumors.

• Page 472 (and similar comment for the RfC sectio n and cancer derivations, eg table 5-12), it may be helpful to show a summary table of the model ed BMD and BMDL values, along with the AIC values and goodness of fit values, in chapt er 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?).

• Page 486, in discussing the co-exposures to Cyan ide (CN) and methyl methacrylate (MM) in8

the Lu study chosen for the RfC derivation, EPA see ms 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 R fC. However EPA may want to look at the data in light of today’s modeling approaches, w hich may show MM as more toxic than it was thought in 1998. Was neurobehavioral performanc e 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 then i t seems that there could be a lack of data and its not clear that EPA can so easily discount the c onfounders. While the results from this study are consistent with others, they are also the lowes t, and this could possibly be due to the confounders. It may be helpful for EPA to also ensu re that there is a neurobehavioral toxicologist on the panel who will be able to answe r questions related to the choice of the Lu study and its limitations (including the cultural d esign issue that is mentioned by Lu). It may also be helpful to mention the potential confoundin g exposures on page 496 when discussing limitations of the Lu study.

• Page 491, table 5-2., in previous assessments th is 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. Seeing 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 t han the full dataset. It is unclear why EPA would not use the full dataset for modeling as a st rength of the BMD approach is that it takes into account the full dataset rather than just poin t estimates. Ideally, EPA should only be excluding data from modeling if an evaluation of th e data, before statistical analyses begin, shows that they should be excluded for methodologic al 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 140, sentence grammatically unclear: “Nearl y half of the exposed group worked with AN for at least 5 years, and 26% of the unexposed g roup was both observations significantly lower than expected.”

• Page 172, table 4-16, please revise title to ref lect that this represents exposures to vinyl chloride and styrene, as well as AN. The summary pa ragraph should also reflect this.

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

• Page 415, EPA states that there “is suggestive e vidence of a possible association between occupational exposure to AN and increased risk of l ung cancer”. EPA refers back to section 4.1.2.2. It may be helpful to also provide the cita tions 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.9

Comments on the Draft Charge: (Note: some suggestions for charge questions are pr ovided in comments in the above sections. Many of those comments have not been reiterated her e, but should be considered as equally important in ensuring a rigorous peer review of thi s highly technical document.)

• Since the development of Agency Information Qual ity (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 focuse s on whether or not the information in question is accurate, clear, complete, transparentl y and objectively described, and scientifically justified. We believe it may be usef ul for EPA to follow a similar approach and incorporate some of the language from your IQ guide lines into the formulation of the charge questions. It will also be helpful for EPA to ask r eviewers to comment on both the objectivity of the presentation and the objectivity of the subs tance regarding the critical decisions.

• As has been done in some previous IRIS reviews, it may be helpful to ask expert reviewers to comment on research needs which may likely inform f uture assessments and decrease uncertainties in the database. It may also be usefu l 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 ju stified. It may be helpful to also ask about EPA’s approach for adding it to the model and the s pecific 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 t he full model. EPA may also want to ask reviewers if they think the model is appropriate fo r use without further peer review.

• B3, EPA presents a nice discussion of uncertaint ies associated with the model and also presents some sensitivity analyses in the appendix. It may be helpful for EPA to also ask

reviewers to comment on the identification and char acterization 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 us e an epidemiology study for the RfC, to ask

reviewers to comment on whether the limitations of the study have been sufficiently considered. EPA may also want to ask reviewers if t hey agree with EPA’s determination to

use the human data instead of the animal data.

• D2, from the tox review, it seems that the criti cal 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 provide comments.

• E1, in addition to the general question about th e cancer classification, it may be helpful to have some very specific questions that ask the revi ewers to comment on EPA’s classification determination. For instance, EPA could add the foll owing: • EPA notes that the epidemiological studies do no t provide strong or consistent10 evidence for a causal association. Please comment o n 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 comm ent on the rigor of the cancer weight of the evidence characterization.

• E4, As EPA is combining some tumors for which th ere is no human counterpart (eg forestomach or zymbal gland) it may be helpful to s pecifically ask reviewers about 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 th ey took to the modeling. Current questions only ask about the choice of study and th e combining of tumors.

• E5 mentions that EPA estimated the IUR using bot h the animal data and the epidemiology data. EPA should clarify what the preferred final c hoice is and ask for explicit comment on this choice. EPA may also want to consider the foll owing additional questions regarding the Blair study:

o Conversion of occupational exposures to continuous environmental exposures was accomplished by adjusting for differences in the am ount of air inhaled during an eighthour work day versus a 24-hour day (10 m3/day vs. 2 0 m3/day, respectively). Given that Blair et al. 1998 only identified statisticall y significant relationships in the most highly exposed groups, do you think that there is s ufficient data to support a linear extrapolation to low levels? Are there any other ap proaches or data sources that you would recommend to inform the extrapolation from th e 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 t han white males sex-race groups, so

sex and race were not included as covariates. Pleas e comment on the potential implications of taking this approach, rather than t hat used in Starr 2004 (which only looked at white males).

o Does the analysis technique adequately account for the healthy worker effect?

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

• E6, as this is the first time EPA is deriving ch emical-specific data-derived, early-life susceptibility factors within the context of a chem ical assessment, it may be helpful for EPA to take comment on the approach. Alternatively, EPA could have a separate peer review process, with appropriate experts to review this de rivation. It may be useful for EPA to ask the reviewers the following questions:

o A specific question about whether or not all the tu mors in these studies, particularly the mammary tumors, are known to act through a mutageni c mode of action. This is

critical.

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

o A specific question regarding whether this one inha lation study should be used to adjust11

both the oral and inhalation values.

o A specific question about using the default values in the supplemental guidanceassuming 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 an alysis that was conducted.

• In addition a previous draft contained the follo wing question which we thought was useful. It is unclear why EPA deleted it in the current versio n. The question reads: • Please comment on the scientific justification f or the application of this early-life susceptibility factor 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 expos ure to acrylonitrile only in earlylife?12

National Institute of Environmental Health Sciences (NIEHS) Comments on the Interagency Science Consultation Draft IRIS Toxicol ogical Review of Acrylonitrile (dated January 2010)

February 26, 2010

NOTE TO: Norm Birchfield

RE: Acrylonitrile

I received the attached comments from the National Institute of Environmental Health Sciences concerning the EPA draft review of acrylonitrile. Thank you for the opportunity to participate in

this review.

Sandra N. Howard Office of the Assistant Secretary For Planning and Evaluation U.S. Department of Health and Human Services13

Dear Dr. Howard:

Thank you for giving us opportunity to participate in finalization of IRIS documents. The following are my comments on draft toxicology r eview for acrylonitrile.

General: The revised draft is very well prepared an d has incorporated most of the suggestions from the first round. It is an excellen t draft for the external peer-review panel; EPA should be commended for its efforts. I h ave some mino r points for EPA’s

consideration:

1. As suggested by OMB, it is better to have the da ta on experimental animals described first followed by the information on huma n studies 2. Page 126, the NTP studies in mice cited were sub chronic, not range finding 3. Page 290, under the mode of action subsection, t he human relevance should be elaborated including the description of common path ways among experimental

animal and humans
4. Sections 4.7.3.5

, 4.7.3.6 and 4.7.3.7 do not add much to the text and could be deleted or consolidated under a single subsection

Draft Charge list for External Reviewers: In my op inion, the list covers all the pertinent aspects of the toxicological review. I do not have any additional suggestions.

Please let me know if you have any questions regard ing the above comments.

Thanks.

Raj Rajendra S. Chhabra, PhD., DABT

NIEHS14

Council on Environmental Quality (CEQ) Comments on the Interagency Science Consultation Draft IRIS Toxicological Review of Acr ylonitrile (dated June 2011)

CEQ reviewed the forwarded document that highlighte d the most recent revisions to the Acrylonitrile Tox Assessment. EPA has proposed a m utagenic mode of action for acrylonitrile carcinogenicity and the application of early-life a ge dependent adjustment factors (ADAF) when assessing cancer risk associated with early-life ex posures. This is consistent with EPA guidance.

Given NTP's concerns with the evaluation of tumors at the Ramazzini Institute, EPA has decided not to rely on these data to calculate data-derived ADAFs for use in the assessment of cancer risk. Instead, the EPA will recommend the use of t he default ADAFs. Given the limitations of

the Ramazzini data and the need to move forward wit h this assessment, CEQ supports this change and EPA's intention to release the draft for external peer review and public comment.

Greg Miller Deputy Associate Director for Chemical Regulations White House Council on Environmental Quality

www.whitehouse.gov/ceq