Issues in Risk Assessment

The scientific basis, inference assumptions, regulatory uses, and research needs in risk assessment are considered in this two-part volume. The first part is Use of Maximum Tolerated Dose in Animal Bioassays for Carcinogenicity; and the second is Two-Stage Models of Carcinogenesis.

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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