IRIS STEP 3 INTERAGENCY COMMENTS 

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

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 to 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 biostatisticians 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 used 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, the human studies are presented 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 these 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 these other

exposures are present, shouldn’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 smoking 
IRIS 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 vinyl 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 workers 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 decreased 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. It would be better to present 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 this 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 considering 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 for 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 seems 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 then 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, 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 (including 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. 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 than the full dataset. It is 

unclear why EPA would not use the full dataset 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 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.

Editorial Comments (with Scientific Impacts):

• Page 140, sentence grammatically unclear: “Nearly half of the exposed group worked 

with AN for at least 5 years, and 26% of the unexposed group was both observations 

significantly lower than expected.”

• Page 172, 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 1st 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 refers 
IRIS 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 important 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 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 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 reviews, 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 adding 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 think 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. It may be helpful for EPA to 

also ask reviewers 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 been 
IRIS 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 provide 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 

evidence 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 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 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 questions 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/day, 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 low levels? Are 

there any other 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 technique adequately account for the healthy worker effect?

• For both the IUR and the slope, 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 deriving 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, with 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 question 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 earlylife 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 exposure to 

acrylonitrile only in early-life?