Consolidated Comments from IRIS Interagency Reviewers

on the Format and Preamble in 

the Science Consultation Draft Ammonia Assessment
 

June 2012 

In 2011, the National Research Council (NRC) recommended1 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 

their report. Along with streamlining assessments and increasing the use of tables, figures, and 

appendices, EPA has also changed the format of assessments 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 assessment 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 

Consultation2 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 information, 

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

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Interagency 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 assumptions. 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 chemicals 

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 the new IRIS assessment format 

to include a section focused on the critical (or co-critical) study. For example, 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 "acute", "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 

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Preamble, 

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 fundamental 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. 

EPA 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 doseresponse 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 

reinterpretation 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 significant 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 

Preamble 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 

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per chemical per endpoint. WOE for carcinogenicity, 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 references 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 citations 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 practice 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 

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of 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 biologically 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 the 

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 directly 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, how 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 

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introduction 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 extrapolation. 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 IRIS 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 IRISdeveloped 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) 

guidance. 

S 

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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.” 

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