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Framework for Determining a Mutagenic

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Framework for Determining a Mutagenic DISCLAIMER: THIS INFORMATION IS DISTRIBUTED SOLELY FOR THE PURPOSE OF EXTERNAL REVIEW UNDER APPLICABLE INFORMATION QUALITY GUIDELINES. IT HAS NOT BEEN FORMALLY DISSEMINATED BY THE EPA AND SHOULD NOT BE CONSTRUED TO REPRESENT ANY AGENCY DETERMINATION OR POLICY. Page 1 1 EPA 120/R-07/002-A 2 External Peer Review Draft 3 September 2007 4 5 6 7 8 9 10 Framework for Determining a 11 Mutagenic Mode of Action for Carcinogenicity: 12 Using EPA’s 2005 Cancer Guidelines and Supplemental Guidance for 13 Assessing Susceptibility from Early-Life 14 Exposure to Carcinogens 15 16 17 Risk Assessment Forum Technical Panel on Mutagenic Mode of Action 18 Rita S. Schoeny, Chair, Office of Water 19 Margaret M. Chu, Office of Research and Development 20 Michael C. Cimino, Office of Prevention, Pesticides and Toxic Substances 21 Kerry L. Dearfield, U.S. Department of Agriculture, Food Safety and Inspection Service 22 Andrew Kligerman, Office of Research and Development 23 Channa Keshava, Office of Research and Development 24 Nagalakshmi Keshava, Office of Research and Development 25 Nancy McCarroll, Office of Prevention, Pesticides and Toxic Substances 26 Russell D. Owen, Office of Research and Development 27 28 Contributor 29 Martha M. Moore, U.S. Food and Drug Administration, 30 National Center for Toxicological Research 31 32 Risk Assessment Forum Staff 33 Resha M. Putzrath, Health Science Coordinator 34 Elizabeth Lee Hofmann, Executive Director, Risk Assessment Forum 35 36 37 38 DISCLAIMER: THIS INFORMATION IS DISTRIBUTED SOLELY FOR THE PURPOSE OF EXTERNAL REVIEW UNDER APPLICABLE INFORMATION QUALITY GUIDELINES. IT HAS NOT BEEN FORMALLY DISSEMINATED BY THE EPA AND SHOULD NOT BE CONSTRUED TO REPRESENT ANY AGENCY DETERMINATION OR POLICY. Page 2 1 Table of Contents 2 3 Preface.......................................................................................................................................... 4 4 1.0 Introduction.......................................................................................................................5 5 1.1 Background.................................................................................................................. 5 6 1.2 Regulatory Uses of Genetic Toxicology Data.............................................................. 6 7 1.3 Mutation as a Mode of Action (MOA) for Cancer....................................................... 7 8 1.4 “Mutagenicity” in the Context of a Mutagenic MOA for Cancer................................ 8 9 2.0 Process: Determining if the Chemical Has a Mutagenic MOA for Carcinogenicity.10 10 2.1 Assemble the Relevant Data........................................................................................10 11 2.2 Evaluate the Data against Current Acceptance and Quality Criteria...........................14 12 2.3 Judge WOE that the Chemical Has a Mutagenic Activity ..........................................14 13 2.3.1 Categorize the Data ......................................................................................15 14 2.3.2 Describe the WOE for Mutagenicity............................................................15 15 2.3.2.1 Conclusions for Individual Assay Types or Endpoints.................15 16 2.3.2.2. Evaluating Results across Endpoints ...........................................17 17 2.3.2.3 WOE Conclusions for Mutagenic Activity.................................. 18 18 2.4 Apply the MOA Framework .......................................................................................19 19 2.4.1 Key Events ...................................................................................................22 20 2.4.2 Strength, Consistency, and Specificity of Association ............................... 25 21 2.4.3 Site Concordance between Mutagenicity and Cancer ................................ 25 22 2.4.4 Dose-response Relationships .......................................................................25 23 2.4.5 Temporality ................................................................................................. 26 24 2.4.6 Biological Plausibility and Coherence ........................................................ 26 25 2.4.7 Other Modes of Action ............................................................................... 27 26 2.4.8 Uncertainties, Inconsistencies, and Data Gaps ........................................... 27 27 2.4.9 Is the Mutagenic MOA for Carcinogenesis Supported in Animals or In 28 Vitro? ..…………………………………………………………………… 28 29 2.4.10 Is the Mutagenic MOA for Carcinogenesis Supported in Humans?..........29 30 3.0 Implications of Determining that the WOE Supports a Mutagenic MOA for 31 Carcinogenicity .............................................................................................................. 31 32 4.0 Glossary and Acronyms ................................................................................................ 32 33 5.0 References ...................................................................................................................... 33 34 35 Appendix A. Suggested Format for Organizing the Assays of Mutagenicity ........................... 39 36 Appendix B. Mutagenicity Testing Schemes in Use at EPA .................................................... 41 37 Appendix C. Examples of the Use of Structure-Activity Relationships in Assessing 38 Mutagenicity ........................................................................................................ 45 39 Appendix D. Concordance Between Specific Mutagenicity Assays and Observation of Cancer 40 Outcomes ............................................................................................................. 47 DISCLAIMER: THIS INFORMATION IS DISTRIBUTED SOLELY FOR THE PURPOSE OF EXTERNAL REVIEW UNDER APPLICABLE INFORMATION QUALITY GUIDELINES. IT HAS NOT BEEN FORMALLY DISSEMINATED BY THE EPA AND SHOULD NOT BE CONSTRUED TO REPRESENT ANY AGENCY DETERMINATION OR POLICY. Page 3 1 Table of Contents (continued) 2 3 List of Figures 4 5 Figure 1 v 1 .............................................................................................................................. 11 6 Figure 1 v 2 page 1 ................................................................................................................... 12 7 Figure 1 v 2 page 2 ................................................................................................................... 13 8 Figure B-1 OPPTS Mutagenicity Testing Scheme for Existing Chemical & Pesticides ......... 43 9 Figure B-2 OPPT Mutagenicity Testing Scheme for New Chemicals ..................................... 44 DISCLAIMER: THIS INFORMATION IS DISTRIBUTED SOLELY FOR THE PURPOSE OF EXTERNAL REVIEW UNDER APPLICABLE INFORMATION QUALITY GUIDELINES. IT HAS NOT BEEN FORMALLY DISSEMINATED BY THE EPA AND SHOULD NOT BE CONSTRUED TO REPRESENT ANY AGENCY DETERMINATION OR POLICY. Page 4 1 Preface 2 3 This document is intended to help EPA risk assessors determine whether data support a 4 mutagenic mode of action (MOA) for carcinogenicity. This document (Framework for 5 Determining a Mutagenic Mode of Action for Carcinogenicity) deals only with MOA for 6 carcinogenicity and not for other adverse endpoints that involve mutations. EPA’s 2005 7 Guidelines for Carcinogen Risk Assessment (or “Cancer Guidelines”) emphasize using MOA 8 information in interpreting and quantifying the potential cancer risk to humans (U.S. EPA, 9 2005a). EPA’s Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to 10 Carcinogens (or “Supplemental Guidance”) also relies on assessing the MOA. In particular, the 11 Supplemental Guidance advises that age-dependent adjustment factors (ADAFs) be used with the 12 cancer slope factors and age-specific estimates of exposure in the development of risk estimates if 13 the weight of evidence (WOE) supports a mutagenic MOA. This default approach is used only 14 when appropriate chemical-specific data are not available on susceptibility from early-life 15 exposures (U.S. EPA, 2005b; see also discussion of analysis of the data in Barton et al., 2005). 16 Given the potentially broad impact of judging an agent to have a mutagenic MOA, it is important 17 that EPA’s risk assessors approach the identification of a mutagenic MOA for carcinogenicity in 18 a consistent, objective, transparent, and scientifically sound manner. 19 20 The analysis in this Framework for Determining a Mutagenic Mode of Action for 21 Carcinogenicity (or "Framework") expands and clarifies discussions found in the Cancer 22 Guidelines and Supplemental Guidance on characteristics to be evaluated for a chemical’s 23 potential for a mutagenic MOA. It is meant to be used with those documents. Thus, the reader 24 should be familiar with the framework for determining a mode of action in EPA’s Cancer 25 Guidelines as well as the discussion of the mutagenic MOA in the Supplemental Guidance before 26 using this Framework. Nothing in this document should be interpreted as superseding either 27 the Cancer Guidelines or the Supplemental Guidance. Related information on these 28 documents can be obtained at www.epa.gov/cancerguidelines. 29 30 The members of the Risk Assessment Forum (RAF) Technical Panel on Mutagenic Mode 31 of Action emphasize that the information offered here is neither a checklist nor specific set of 32 criteria that must be met for determining if the WOE supports a mutagenic MOA. Instead it 33 provides a framework for organizing data, determining relevance of those data and
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