The scientific basis, inference assumptions, regulatory uses, and research needs in risk assessment are considered in this two-part volume. The first part, Use of Maximum Tolerated Dose in Animal Bioassays for Carcinogenicity, focuses on whether the maximum tolerated dose should continue to be used in carcinogenesis bioassays. The committee considers several options for modifying current bioassay procedures. The second part, Two-Stage Models of Carcinogenesis, stems from efforts to identify improved means of cancer risk assessment that have resulted in the development of a mathematical dose-response model based on a paradigm for the biologic phenomena thought to be associated with carcinogenesis. Table of Contents Front Matter Executive Summary USE OF THE MAXIMUM TOLERATED DOSE IN ANIMAL BIOASSAYS FOR CARCINOGENICITY THE TWO-STAGE MODEL OF CARCINOGENESIS A PARADIGM FOR ECOLOGIC RISK ASSESSMENT Issues In Risk Assessment Use Of Maximum Tolerated Dose in Animal Bioassays for Carcinogenicity BACKGROUND SCOPE OF REPORT DEFINITIONS AND BACKGROUND CORRELATIONS RELATIONSHIP BETWEEN TOXICITY AND CARCINOGENICITY OBSERVED AT MTD QUALITATIVE INFORMATION QUANTITATIVE INFORMATION OPTION 1 OPTION 2 OPTION 3 Option 4A Option 4B 5 Conclusions and Recommendations REFERENCES BACKGROUND DEFINING AND DETERMINING THE MTD Appendix B Organizing Subcommittee Appendix C Federal Liaison Group Appendix D Workshop Program Appendix E Workshop Attendees 1. INTRODUCTION 2.1 Measures of Carcinogenic Potency 2.2 Carcinogenic Potency Database (CPDB) 2.3 Variation in Carcinogen Potency 2.4 Classification of Carcinogens 3.1 Empirical Correlations 3.2 Range of Possible TD50 Values 3.3 Analytical Correlations 3.4 Model Dependency 3.5 Genotoxic vs. Nongenotoxic Carcinogens 4.1 Predictions Based on the MDT 4.2 Predictions Based on Mutagenicity and Acute Toxicity 5.1 Correlation Between Upper Bounds On the Low Dose Slope and MTD 5.2 Correlation Between q1* and the TD50 5.3. Preliminary Estimate of Risk 6. INTERSPECIES EXTRAPOLATION 6.1 Extrapolation from Rats to Mice 6.2 Extrapolation from Rodents to Humans 7. CONCLUSIONS 8. ACKNOWLEDGEMENTS 9. REFERENCES ANNEX A: MAXIMUM LIKELIHOOD METHODS FOR FITTING THE WEIBULL MODEL ANNEX B. SHRINKAGE ESTIMATORS OF THE DISTRIBUTION OF CARCINOGENIC POTENCY ANNEX C: ADJUSTMENT OF POTENCY VALUES FOR LESS THAN LIFETIME EXPOSURE ANNEX D: CORRELATION BETWEEN TD50 AND MTD ANNEX E: CORRELATION BETWEEN TD50S FOR RATS AND MICE Appendix G Informal Search for ''Supercarcinogens" CRITERIA AND CANDIDATE CHEMICALS DATA RESULTS DISCUSSION Issues in Risk Assessment The Two-Stage Model Of Carcinogenesis INTRODUCTION BIOLOGIC CONSIDERATIONS THE TWO-STAGE MODEL APPLICATIONS OF THE TWO-STAGE MODEL TO ANIMAL DATA Data Needs Criteria for Adoption Prospects CONCLUSIONS AND RECOMMENDATIONS REFERENCES BIOLOGICAL FACTORS IN TWO-STAGE MODELS TWO-STAGE MODEL OF CLONAL EXPANSION APPLICATION OF THE TWO-STAGE MODEL TO ANIMAL DATA Appendix B Workshop Program Appendix C Workshop Federal Liaison Group TOPIC GROUP MEMBERS Appendix E Workshop Organizing Task Group Isuees In Risk Assessment A Paradigm for Ecological Risk Assessment 1 Introduction 2 Scope of Ecological Risk Assessment COMPONENTS OF THE 1983 FRAMEWORK CONSISTENCY OF CASE STUDIES WITH THE 1983 FRAMEWORK INTEGRATION OF ECOLOGICAL RISK INTO THE 1983 FRAMEWORK DEFINITION OF FRAMEWORK COMPONENTS FOR ECOLOGICAL RISK ASSESSMENT EXTRAPOLATION ACROSS SCALES QUANTIFICATION OF UNCERTAINTY VALIDATION OF PREDICTIVE TOOLS VALUATION 5 Conclusions 6 Recommendations REFERENCES Appendix A Workshop Participants Appendix B Workshop Organizing Subcommittee and Federal Liaison Group Appendix C Workshop Introduction TERRY F. YOSIE BUILDING ECOLOGICAL RISK ASSESSMENT AS A POLICY TOOL D. WARNER NORTH: RELATIONSHIP OF WORKSHOP TO NRC'S 1983 RED BOOK REPORT MICHAEL SLIMAK: U.S. ENVIRONMENTAL PROTECTION AGENCY ACTIVITIES IN ECOLOGICAL RISK ASSESSMENT CASE STUDY 1: TRIBUTYLTIN RISK MANAGEMENT IN THE UNITED STATES Discussion CASE STUDY 2: ECOLOGICAL RISK ASSESSMENT FOR TERRESTRIAL WILDLIFE EXPOSED TO AGRICULTURAL CHEMICALS CASE STUDY 3A: MODELS OF TOXIC CHEMICALS IN THE GREAT LAKES: STRUCTURE, APPLICATIONS, AND UNCERTAINTY ANALYSIS CASE STUDY 3B: ECOLOGICAL RISK ASSESSMENT OF TCDD AND TCDF Discussion CASE STUDY 4: RISK ASSESSMENT METHODS IN ANIMAL POPULATIONS: THE NORTHERN SPOTTED OWL AS AN EXAMPLE Discussion CASE STUDY 5: ECOLOGICAL BENEFITS AND RISKS ASSOCIATED WITH THE INTRODUCTION OF EXOTIC SPECIES FOR BIOLOGICAL CONTROL OF A... Discussion CASE STUDY 1: UNCERTAINTY AND RISK IN AN EXPLOITED ECOSYSTEM: A CASE STUDY OF GEORGES BANK Discussion Generic Issues Analysis of Case Studies DOSE-RESPONSE ASSESSMENT Selection of End Points Consideration of Nonlinearities And Discontinuities Understanding the Stressor Additions to the 1983 Paradigm Needed for Ecological Risk Assessment Modeling Needs for Stress-Response Relationships Methods of Measuring Stressors for Ecological Exposure Assessment Definition of Risk Characterization Components of Risk Characterization Organization and Presentation Differences from and Similarities To the 1983 Report Application to the Case Studies Agricultural Chemicals Northern Spotted Owl General Discussion: Models and Risk Assessment Uncertainties Identified In the Case Studies Implications of Uncertainty for Ecological Risk Assessment VALUATION Risk Assessment Has Many Uses Different Risk Assessment Methods Are Suited to Different Risk Assessment Needs Risk Assessors and Risk Managers Need to Communicate Credibility is Crucial Appendix G Contemplations on Ecological Risk Assessment Appendix H Workshop Summary Appendix I References for Appendixes Appendix J Workshop Program

• 1 Front Matter
• 2 Executive Summary
• 3 USE OF THE MAXIMUM TOLERATED DOSE IN ANIMAL BIOASSAYS FOR CARCINOGENICITY
• 4 THE TWO-STAGE MODEL OF CARCINOGENESIS
• 5 A PARADIGM FOR ECOLOGIC RISK ASSESSMENT
• 6 Issues In Risk Assessment Use Of Maximum Tolerated Dose in Animal Bioassays for Carcinogenicity
• 7 BACKGROUND
• 8 SCOPE OF REPORT
• 9 DEFINITIONS AND BACKGROUND
• 10 CORRELATIONS
• 11 RELATIONSHIP BETWEEN TOXICITY AND CARCINOGENICITY OBSERVED AT MTD
• 12 QUALITATIVE INFORMATION
• 13 QUANTITATIVE INFORMATION
• 14 OPTION 1
• 15 OPTION 2
• 16 OPTION 3
• 17 Option 4A
• 18 Option 4B
• 19 5 Conclusions and Recommendations
• 20 REFERENCES
• 21 BACKGROUND
• 22 DEFINING AND DETERMINING THE MTD
• 23 Appendix B Organizing Subcommittee
• 24 Appendix C Federal Liaison Group
• 25 Appendix D Workshop Program
• 26 Appendix E Workshop Attendees
• 27 1. INTRODUCTION
• 28 2.1 Measures of Carcinogenic Potency
• 29 2.2 Carcinogenic Potency Database (CPDB)
• 30 2.3 Variation in Carcinogen Potency
• 31 2.4 Classification of Carcinogens
• 32 3.1 Empirical Correlations
• 33 3.2 Range of Possible TD50 Values
• 34 3.3 Analytical Correlations
• 35 3.4 Model Dependency
• 36 3.5 Genotoxic vs. Nongenotoxic Carcinogens
• 37 4.1 Predictions Based on the MDT
• 38 4.2 Predictions Based on Mutagenicity and Acute Toxicity
• 39 5.1 Correlation Between Upper Bounds On the Low Dose Slope and MTD
• 40 5.2 Correlation Between q1* and the TD50
• 41 5.3. Preliminary Estimate of Risk
• 42 6. INTERSPECIES EXTRAPOLATION
• 43 6.1 Extrapolation from Rats to Mice
• 44 6.2 Extrapolation from Rodents to Humans
• 45 7. CONCLUSIONS
• 46 8. ACKNOWLEDGEMENTS
• 47 9. REFERENCES
• 48 ANNEX A: MAXIMUM LIKELIHOOD METHODS FOR FITTING THE WEIBULL MODEL
• 49 ANNEX B. SHRINKAGE ESTIMATORS OF THE DISTRIBUTION OF CARCINOGENIC POTENCY
• 50 ANNEX C: ADJUSTMENT OF POTENCY VALUES FOR LESS THAN LIFETIME EXPOSURE
• 51 ANNEX D: CORRELATION BETWEEN TD50 AND MTD
• 52 ANNEX E: CORRELATION BETWEEN TD50S FOR RATS AND MICE
• 53 Appendix G Informal Search for "Supercarcinogens"
• 54 CRITERIA AND CANDIDATE CHEMICALS
• 55 DATA
• 56 RESULTS
• 57 DISCUSSION
• 58 Issues in Risk Assessment The Two-Stage Model Of Carcinogenesis
• 59 INTRODUCTION
• 60 BIOLOGIC CONSIDERATIONS
• 61 THE TWO-STAGE MODEL
• 62 APPLICATIONS OF THE TWO-STAGE MODEL TO ANIMAL DATA
• 63 Data Needs
• 64 Criteria for Adoption
• 65 Prospects
• 66 CONCLUSIONS AND RECOMMENDATIONS
• 67 REFERENCES
• 68 BIOLOGICAL FACTORS IN TWO-STAGE MODELS
• 69 TWO-STAGE MODEL OF CLONAL EXPANSION
• 70 APPLICATION OF THE TWO-STAGE MODEL TO ANIMAL DATA
• 71 Appendix B Workshop Program
• 72 Appendix C Workshop Federal Liaison Group
• 73 TOPIC GROUP MEMBERS
• 74 Appendix E Workshop Organizing Task Group
• 75 Isuees In Risk Assessment A Paradigm for Ecological Risk Assessment
• 76 1 Introduction
• 77 2 Scope of Ecological Risk Assessment
• 78 COMPONENTS OF THE 1983 FRAMEWORK
• 79 CONSISTENCY OF CASE STUDIES WITH THE 1983 FRAMEWORK
• 80 INTEGRATION OF ECOLOGICAL RISK INTO THE 1983 FRAMEWORK
• 81 DEFINITION OF FRAMEWORK COMPONENTS FOR ECOLOGICAL RISK ASSESSMENT
• 82 EXTRAPOLATION ACROSS SCALES
• 83 QUANTIFICATION OF UNCERTAINTY
• 84 VALIDATION OF PREDICTIVE TOOLS
• 85 VALUATION
• 86 5 Conclusions
• 87 6 Recommendations
• 88 REFERENCES
• 89 Appendix A Workshop Participants
• 90 Appendix B Workshop Organizing Subcommittee and Federal Liaison Group
• 91 Appendix C Workshop Introduction
• 92 TERRY F. YOSIE BUILDING ECOLOGICAL RISK ASSESSMENT AS A POLICY TOOL
• 93 D. WARNER NORTH: RELATIONSHIP OF WORKSHOP TO NRC'S 1983 RED BOOK REPORT
• 94 MICHAEL SLIMAK: U.S. ENVIRONMENTAL PROTECTION AGENCY ACTIVITIES IN ECOLOGICAL RISK ASSESSMENT
• 95 CASE STUDY 1: TRIBUTYLTIN RISK MANAGEMENT IN THE UNITED STATES
• 96 Discussion
• 97 CASE STUDY 2: ECOLOGICAL RISK ASSESSMENT FOR TERRESTRIAL WILDLIFE EXPOSED TO AGRICULTURAL CHEMICALS
• 98 CASE STUDY 3A: MODELS OF TOXIC CHEMICALS IN THE GREAT LAKES: STRUCTURE, APPLICATIONS, AND UNCERTAINTY ANALYSIS
• 99 CASE STUDY 3B: ECOLOGICAL RISK ASSESSMENT OF TCDD AND TCDF
• 100 Discussion
• 101 CASE STUDY 4: RISK ASSESSMENT METHODS IN ANIMAL POPULATIONS: THE NORTHERN SPOTTED OWL AS AN EXAMPLE
• 102 Discussion
• 103 CASE STUDY 5: ECOLOGICAL BENEFITS AND RISKS ASSOCIATED WITH THE INTRODUCTION OF EXOTIC SPECIES FOR BIOLOGICAL CONTROL OF A..
• 104 Discussion
• 105 CASE STUDY 1: UNCERTAINTY AND RISK IN AN EXPLOITED ECOSYSTEM: A CASE STUDY OF GEORGES BANK
• 106 Discussion
• 107 Generic Issues
• 108 Analysis of Case Studies
• 109 DOSE-RESPONSE ASSESSMENT
• 110 Selection of End Points
• 111 Consideration of Nonlinearities And Discontinuities
• 112 Understanding the Stressor
• 113 Additions to the 1983 Paradigm Needed for Ecological Risk Assessment
• 114 Modeling Needs for Stress-Response Relationships
• 115 Methods of Measuring Stressors for Ecological Exposure Assessment
• 116 Definition of Risk Characterization
• 117 Components of Risk Characterization
• 118 Organization and Presentation
• 119 Differences from and Similarities To the 1983 Report
• 120 Application to the Case Studies
• 121 Agricultural Chemicals
• 122 Northern Spotted Owl
• 123 General Discussion: Models and Risk Assessment
• 124 Uncertainties Identified In the Case Studies
• 125 Implications of Uncertainty for Ecological Risk Assessment
• 126 VALUATION
• 127 Risk Assessment Has Many Uses
• 128 Different Risk Assessment Methods Are Suited to Different Risk Assessment Needs
• 129 Risk Assessors and Risk Managers Need to Communicate
• 130 Credibility is Crucial
• 131 Appendix G Contemplations on Ecological Risk Assessment
• 132 Appendix H Workshop Summary
• 133 Appendix I References for Appendixes
• 134 Appendix J Workshop Program