# Consolidated Comments from IRIS Interagency Reviewers

on the Format and Preamble in the Science Consultation Draft Ammonia Assessment

**June 2012** 

In 2011, t he National Research Council (NRC) recommended 1 

## that EPA make changes in the development and presentation of Integrated Risk Information System (IRIS) assessments. The implementation of the NRC recommendations is following a phased approach that is consistent with the ir report

. Along with streamlining assessments and incre asing the use of tables, figures, and appendices , EPA has also changed the format of assessment s and added a preamble. Prior to releasing the External Review Draft IRIS Toxicological Review of Ammonia , EPA circulated a previous version of the draft IRIS a ssessment preamble and assessment format to other Federal health agency scientists for their review and comment. The previous version was circulated as a part of Interagency Science Consultation 2 

## for an assessment other than ammonia, but the comments are applicable to the preamble and format in the draft IRIS Toxicological Review of Ammonia.

This document contains the comments provided by Federal health scientists outside of EPA on the previous draft version of the IRIS assessment preamble and format. Comments were received from the Council on Environmental Quality, Department of Defense, and the National Toxicology Program. These comments are being made publicly available to ensure transparency in the IRIS assessment development process.

1 

### National Research Council, 2011. Review of the Environmental Protection Agency’s Draft IRIS Assessment of Formaldehyde.
2 

### Interagency Science Consultation is step 3 of the IRIS assessment development process. For more in formation,

see http://www.epa.gov/IRIS/process.htm

.


## 1

# Interagen **cy Comments**

Council on Environmental Quality:

“The IRIS Program is to be commended on the new format for the toxicological reviews. The document is more accessible, easier to read, and there is greater transparency in the presentation of key assumpti ons. The effective use of figures and tables are also notable.”

“In the preamble, we suggest adding some additional information (i.e., internet addresses) to the second paragraph in order to facilitate the reader’s ability to locate assessments for the ch emicals that are not covered by the IRIS program. We also suggest that you replace “White House offices” with Executive Office of the President offices.”

“ Finally, we recommend that the IRIS program consider modifying th e new IRIS assessment format
to inc lude a section focused on the critical (or co

- critical) study. For exa mple, we think that some of the information about the critical study that presented in Appendix A could be moved into the main document and expanded upon. ”

Department of Defense :

Comments submitted by: Chemical Material Risk Management Program Organization: Department of Defense Date Submitted: 2/9/2012

*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E); or Other (O). Also please indicate if Major i.e. affects the outcome, conclusions or implementation of the assessment.

Section Comment Suggested Action, Revision and References (if necessary) *Category

Preamble 2 EPA 2009 is not included in the list of references. Add the reference to the list in Section
3. E

Preamble,
3.3 Although this section explains the preferred types of exposures, the section does not contain definitions or examples. These definitions in the IRIS glossary are subject to change without notice. DoD would like to see contemporaneous definitions of "acut e", "subchronic" and "chronic" exposures for both commonly used laboratory animals and people; these could be presented in a table. Please supply definitions and examples of acute, subchronic, and chronic exposures for people and for all of the species that are used in the quantitative analysis of these
chemicals. S



## 2Preamble,

4.2 In evaluating the quality of an epidemiological study, EPA
does not include the need to demonstrate a reasonable
dose

- response relationship. As dose

- response relationships are f undamental to all, high quality toxicological studies, this requirement, and whether the data must show a positive trend, a statistically significant increase, a biologically significant change, and/or other criteria should be presented in this section. EP A should discuss its criteria with regard to dose

- response observations for epidemiological studies. DoD notes in particular an over

- reliance on statistics rather than biologically informative information, as well as an
absence of a discussion about dose

response criteria. S/M

Preamble,
4.3 In the third paragraph, EPA should state that it will clearly identify that its interpretation of the data differ from the scientists who conducted the study, as well as discussing why its conclusions differ. DoD would prefer if EPA would also commit to trying to contact at least one of the
authors to determine their reaction to EPA's interpretation, and to allow those authors to comment on EPA's interpretation of the data, as they may have additional information about the study that was not published. Disagreeing with the conclusions of the scientists who designed and conducted an experiment should only be done when there are clear and undisputed

reasons. We suggest that EPA consider discussing its intended
reint erpretation of the data with the authors before relying on a different interpretation for estimating toxicity of a
chemical. S

Preamble 5.2 DoD disagrees with EPA's statement that "causality is not at issue in controlled experiments". Unless a well designed experiment has been replicated exactly (often not the case for the critical experiment on which EPA bases its RfDs, RfC, and cancer potency values) statistically significant results can be false positives. At p = 0.05, there is a 1 in 20 probability of a false positive, even in a well controlled experiment. EPA should delete this clause or provide at least one independent
reference that would support its
assertion. S/M

Preamble 5.3 EPA's use of the term "genetic toxicity" is not defined and is neither clear nor transparent, especially in a section on mode of action (MOA). EPA's 2005 cancer guidelines and guidance do not use this term, but rather refer to a "mutagenic mode of action"

. Frequently, genetic toxicity includes effects that are not considered mutations, the term used in the rest of the document. DoD has previously mentioned EPA's tendency to use the terms "genotoxic" and "mutagenic" loosely, and as these terms have signif icant implications within EPA's guidelines and guidance, we would like to see more precision in their use. We highly recommend that EPA define "genetic toxicity" and "mutagenicity" (or variants of those words), as they have significant implications within EPA's guidelines and guidance. The IRIS glossary does not include a reference for "genetic toxi8city" or "genotoxic";
and it does not always agree with definitions in other parts of EPA's web sites and can be changed without
notice or review. S/M

Preambl e 5.4 The text does not mention a critical clause of the 2005 cancer guidelines: That the WOE for a chemical's MOA can vary by route of exposure or by level of exposure,

etc. This section would be interpreted by many individuals as asserting that only one WOE is possible EPA should include important options within this WOE section to clearly and accurately represent what is in its guidelines. The text should explicitly
state that there can be more that one S



## 3per chemical per endpoint. WOE for carcinogeni city, e.g., a chemical's MOA can vary by route of exposure or by level of exposure, etc.

Preamble,
7.3 EPA states that the choice of point of departure (POD) is based on statistical and biological factors and cites the draft BMD guidance (U.S. EPA 2000b) and EPA's 2005 guidelines for carcinogen risk assessment. The

text goes on to state that for dichotomous responses, a 10% response will be used for "minimally adverse
effects" and "5% or lower for more severe effects."
Neither of the cited referen ces have statements that agree with EPA's assertion. Both documents indicate that the benchmark response (BMR) that determines the POD should be near the low end of the range of data and that a 10% BMR should also be estimated for facilitating This language should be removed from
the current Preamble and instead
included in the BMD guidance document; such recommendations can be proposed by EPA and formally S/M

comparisons across chemicals. These concepts are also applied to the suggested methods for calculating the
POD from continuous data. We know of no such severity

- related guidance regarding the POD for nonlinear extrapolations in either of these documents. The definition of "minimally adverse" or "more severe" is a key aspect of the POD, but there is no available guidance as to how different effects should be categorized. Furthermore, the BMD guidance is listed in the references as U.S. EPA 2000a, rather than 2000b. evaluated by the scientific and regulatory community. EPA should
also correct the citati ons of EPA2000a
vs. 2000b.

Preamble 7.3
and 7.4 These sections, that cover standard procedures used, contain several statements that are not consistent with EPA's 2005 cancer guidelines. If IRIS is proposing that these statements are standard practi ce within its toxicological review, it should both state that these are deviations and should provide a rationale for its deviation from guidelines. We believe that the cancer guidelines are applicable to the entire agency.

1. None of the cited EPA guidelines or guidance suggests use of a "standard value" for a point of departure for extrapolation, much less "(10% response for animal data, 1% for epidemiologic data, depending on the observed response rates)." These values are recommended as frequently used based on historical observations of results and the power of the
standard studies. They are also recommended to be estimated and reported for the purposes This section should be carefully reviewed to ensure consistency with EPA guidance and the references
cited.

1. Please delete any reference to a standard response level
or value for a POD for extrapolation. EPA's draft BMD and cancer guidelines
refer to use of standard values for the purposes of comparisons among chemicals, and in that case
the best estimate, not the lower confidence value, is
recommended for use.

2. The use of the lower bound should be qualified, as it is in S/M



## 4of comparing potencies across chemicals. the cited references. The phrase that is in EPA's guidance is "near 3. According to EPA's cancer the low end of the observable range is used" guidelines, use of a which will differ by experimental design. biologically based model

2. The statement that "For dichotomous obviates extrapolation; linear responses, the point of departure is the 95% or nonlinear. The
lower bound on the dose associated with a statement should either be small increase of a biological ly significant deleted or clearly explain effect." requires addition of the qualifier that IRIS is deviating from "generally" or "usually" to be consistent with EPA guidance and provide a
the cited sources. In particular, the BMD draft rationale for this deviation.
indicates that the maximum likelihood estimate 4. The concept of a "linear should be used for some purposes. component" or "other
3. EPA's guidelines discuss use of a biologically activity" as a criterion for based model to extrapolate to lower doses. determining whether th e They do not advocate "Below the range where extrapolation is linear or confidence bounds on the predictions are nonlinear should be deleted reasonably precise, extrapolation may continue as inconsistent with EPA's using a linear model."

4. EPA's 2005 cancer guidelines differentiate low dose extrapolation procedures for MOAs that are linear at low doses, MOAs that are guidance. Otherwise, the

text should clearly explain that IRIS is deviating from EPA guidance and provide a nonlinear (including nonlinear, no threshold) at rationale for this deviation. low doses, and chemicals for which the MOA 5. The suggestion that cannot be determined. They do not provide for exposure levels are a criteria a linear extrapolation "the dose response curve is expected to have a linear component below the point of departure. [emphasis added]"

. As for type of extrapolation
should either be deleted or EPA clearly explain that IRIS many highly nonlinear function have a "linear is deviating from EPA component" or can be fit to curves that have a guidance and provide a linear component, this statement direc tly rationale for this deviation.
contradicts both the text and the intent of 6. IRIS documents should EPA's cancer guidelines. (DoD notes that the define the terms "genetic concept of a linear component is discussed toxicity" and "mutagenicity", with regard to chemicals with multiple MOAs, h ow they differ (if IRIS
but does not make that a condition that scientists believe they do), requires a linear extrapolation.) and how these definitions

5. EPA's assertion that "Agents or their relate to EPA's mutagenic metabolites for which human exposures or mode of action. body burdens are near doses associated with key events leading to an effect." is not included in the cited guidelines. IRIS has often asserted that IRIS documents do not consider exposure
levels. If this is accurate, such a consideration
is not relevant to this document. If IRIS documents do consider exposure levels, this



## 5introduction should discuss those aspects of EPA's cancer guidelines that do refer to exposure, e.g., different WOEs for different levels of exposure.
6. The statement that "the agent does not demonstrate mutagenic or other activity consistent with linearity at lower doses." is not part of the criteria in EPA's cancer guidelines for using a non

- linear extrapolat ion. The guidelines state that chemicals with a mutagenic MOA, not just mutagenic activity, are expected to have a linear extrapolation.
This statement asserts a much lower criterion for imposing a linear extrapolation. Nor do the guidelines reference "other activity consistent with linearity" as a measure. The guideline only discusses such concepts within the context of the MOA, not individual key events
of the MOA.

Preamble 7.5 Statement #3 is incorrect. The cited EPA guidance document recommends use of the age

- dependent adjustment factors ONLY for chemicals that have been demonstrated to have a mutagenic MOA that do not have
chemical

- specific data on early

- life exposure, not "suspected carcinogens" as stated here. EPA should correct this misstatement of policy. S/M

Preamble 7.6 EPA states that "if the point of departure is based on toxicokinetic modeling, dosimetry modeling or allometric scaling", UFA = 10^0.5 is applied to account for "the remaining uncertainty involving toxicodynamic
differences." The U.S. EPA (2011b) guidance states (p 21) that "processes pertinent to the consideration of this UF are recognized to include both toxicokinetics and toxicodynamics." While IR IS has instituted a "common practice" of asserting such a division after PBPK modeling, it should either provide a written citation for this practice, and indicate whether it has been externally peer reviewed, or explicitly state that this is an IRIS

devel oped policy that has or has not been externally peer
reviewed. If such a guidance document is prior to 2011, it should also provide a rationale for not following the more recent guidance. EPA should revise the text to accurately reflect U.S. EPA (2011b)

g uidance. S



## 6

## National Toxicology Program:

“ This IRIS draft was prepared using a new format that has substantially decreased the unnecessary repetitions. The preamble section is extremely helpful for new readers and even the regulars. However, the formatting changes have also resulted into limited information on the studies that are critical and supportive of the guidance values derived. Therefore it is difficult to fully ascertain the scientific strengths or weaknesses from the summaries of the data presented. Also, the order of the sections in the document does not flow logically. Hopefully, these minor formatting issues would be sorted out with time. ”

7