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Framework for Determining a Mutagenic Mode of Action for Carcinogenicity (External Review Draft)

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Framework for Determining a Mutagenic Mode of Action for Carcinogenicity: Using EPA’s 2005 Cancer Guidelines and Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens

This document is intended to help EPA risk assessors determine whether data support a finding of a mutagenic mode of action (MOA) for carcinogenicity. This draft document, Framework for Determining a Mutagenic Mode of Action for Carcinogenicity: Using EPA’s 2005 Cancer Guidelines and Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens (or Framework), deals only with MOA for carcinogenicity and not with other adverse endpoints that involve mutations.

EPA’s 2005 Guidelines for Carcinogen Risk Assessment (or Cancer Guidelines) emphasize using MOA information in interpreting and quantifying the potential cancer risk to humans.

EPA’s Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens (or Supplemental Guidance) also relies on assessing the MOA. In particular, the Supplemental Guidance advises that age-dependent adjustment factors (ADAFs) be used with the cancer slope factors and age-specific estimates of exposure in the development of risk estimates, if the weight of evidence (WOE) supports a mutagenic MOA for carcinogenicity. This default approach is used only when appropriate chemical-specific data are not available on susceptibility from early-life exposures.

The analysis in this Framework expands and clarifies discussions found in the Cancer Guidelines and Supplemental Guidance on characteristics to be evaluated for a chemical’s potential for a mutagenic MOA. It is meant to be used with those documents. Thus, the reader should be familiar with the framework for determining a mode of action in EPA’s Cancer Guidelines, as well as the discussion of the mutagenic MOA in the Supplemental Guidance, before using this Framework. In order to use the Framework properly, the chemical of interest must already have a WOE determination for carcinogenicity. Nothing in this document should be interpreted as superseding either the Cancer Guidelines or the Supplemental Guidance. Related information on these documents can be obtained at www.epa.gov/cancerguidelines.

Background

In response to requests from numerous stakeholders, this Framework expands and clarifies discussions on characteristics to be evaluated to determine a chemical’s potential for a “mutagenic mode of action for carcinogenicity.” This phrase is used in EPA’s 2005 Cancer Guidelines and Supplemental Guidance and affects consideration of adjusting cancer potencies (via the age-dependant adjustment factors or ADAFs) when exposures to these carcinogens occur in children. The Framework is meant to complement the Cancer Guidelines and Supplemental Guidance, and it assumes that the reader is familiar with the framework for determining a mode of action, as presented in section 2.4 of the Cancer Guidelines, as well as the discussion of the mutagenic MOA, as presented in section 2.2 of the Supplemental Guidance (available in the Related Documents section).

Another document that provides useful information as to whether a chemical causes mutations is the EPA’s 1986 Guidelines for Mutagenicity Risk Assessment (or Mutagenicity Guidelines). The Mutagenicity Guidelines focus on heritable (germ cell) mutagenicity, i.e., the risk of passing new mutations to future generations. While heritable mutation is a different adverse health outcome than cancer, both adverse health outcomes involve mutation as a part of their etiology. This document may be useful to the cancer MOA assessment because it provides a summary of endpoints that are useful in assessing the ability of a chemical to induce mutation.

Chronology of Events

September 2007 External Review Draft of Framework for Determining a Mutagenic Mode of Action for Carcinogenicity made available for public comment.

March 2005 EPA releases Guidelines for Carcinogen Risk Assessment (or Cancer Guidelines) and Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens (or Supplemental Guidance). These documents, related documents, and further information on these topics are available at: www.epa.gov/cancerguidelines.

2004/05 In response to an SAB recommendation, EPA extended the analysis supporting the Supplemental Guidance. The National Institute of Environmental Health Sciences (NIEHS) journal, Environmental Health Perspectives, peer reviewed this analysis and accepted it for publication. A separate peer review of this analysis was also conducted.

Mar 2004 EPA received SAB comments on the Supplemental Guidance.

Mar 2003 EPA released the Draft Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens for public comment. At this time, the SAB reviewed the Draft Supplemental Guidance.

Mar 2003 EPA released Draft Final Cancer Guidelines to the SAB for comment.

Nov 2001 EPA solicited public comment on the finalized Cancer Guidelines and extended the opportunity to provide additional information and comment (66 FR 59593, November 29, 2001). This Notice also identified the July 1999 Draft Revised Guidelines for Carcinogen Risk Assessment as interim guidance pending issuance of final guidelines.

Jul 1999 The SAB and Children's Health Protection Advisory Committee (CHPAC) reviewed the Draft Final Revised Guidelines for Carcinogen Risk Assessment for their protection of children.

Jan 1999 The SAB reviewed revisions of key sections of the proposed guidelines per previous SAB and public comments.

1996 EPA published the Proposed Guidelines for Carcinogen Risk Assessment for public comment. This "proposed" guideline underwent Science Advisory Board (SAB) review in 1997.

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