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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.

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Suggested Citation

National Research Council. 1993. Issues in Risk Assessment. Washington, DC: The National Academies Press. https://doi.org/10.17226/2078.

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Publication Info

374 pages |  6 x 9 |  Paperback
ISBN: 978-0-309-04786-9
DOI: https://doi.org/10.17226/2078
Chapters skim
Front Matter i-xviii
Executive Summary 1-2
USE OF THE MAXIMUM TOLERATED DOSE IN ANIMAL BIOASSAYS FOR CARCINOGENICITY 3-8
THE TWO-STAGE MODEL OF CARCINOGENESIS 9-9
A PARADIGM FOR ECOLOGIC RISK ASSESSMENT 10-12
Issues In Risk Assessment Use Of Maximum Tolerated Dose in Animal Bioassays for Carcinogenicity 13-14
BACKGROUND 15-17
SCOPE OF REPORT 18-20
DEFINITIONS AND BACKGROUND 21-23
CORRELATIONS 24-32
RELATIONSHIP BETWEEN TOXICITY AND CARCINOGENICITY OBSERVED AT MTD 33-42
QUALITATIVE INFORMATION 43-48
QUANTITATIVE INFORMATION 49-52
OPTION 1 53-53
OPTION 2 54-54
OPTION 3 55-56
Option 4A 57-58
Option 4B 59-60
5 Conclusions and Recommendations 61-66
REFERENCES 67-78
BACKGROUND 79-79
DEFINING AND DETERMINING THE MTD 80-90
Appendix B Organizing Subcommittee 91-92
Appendix C Federal Liaison Group 93-94
Appendix D Workshop Program 95-96
Appendix E Workshop Attendees 97-110
1. INTRODUCTION 111-112
2.1 Measures of Carcinogenic Potency 113-115
2.2 Carcinogenic Potency Database (CPDB) 116-116
2.3 Variation in Carcinogen Potency 117-118
2.4 Classification of Carcinogens 119-120
3.1 Empirical Correlations 121-124
3.2 Range of Possible TD50 Values 125-125
3.3 Analytical Correlations 126-127
3.4 Model Dependency 128-129
3.5 Genotoxic vs. Nongenotoxic Carcinogens 130-130
4.1 Predictions Based on the MDT 131-131
4.2 Predictions Based on Mutagenicity and Acute Toxicity 132-134
5.1 Correlation Between Upper Bounds On the Low Dose Slope and MTD 135-135
5.2 Correlation Between q1* and the TD50 136-138
5.3. Preliminary Estimate of Risk 139-139
6. INTERSPECIES EXTRAPOLATION 140-140
6.1 Extrapolation from Rats to Mice 141-143
6.2 Extrapolation from Rodents to Humans 144-145
7. CONCLUSIONS 146-148
8. ACKNOWLEDGEMENTS 149-149
9. REFERENCES 150-159
ANNEX A: MAXIMUM LIKELIHOOD METHODS FOR FITTING THE WEIBULL MODEL 160-161
ANNEX B. SHRINKAGE ESTIMATORS OF THE DISTRIBUTION OF CARCINOGENIC POTENCY 162-163
ANNEX C: ADJUSTMENT OF POTENCY VALUES FOR LESS THAN LIFETIME EXPOSURE 164-165
ANNEX D: CORRELATION BETWEEN TD50 AND MTD 166-168
ANNEX E: CORRELATION BETWEEN TD50S FOR RATS AND MICE 169-172
Appendix G Informal Search for ''Supercarcinogens" 173-174
CRITERIA AND CANDIDATE CHEMICALS 175-176
DATA 177-180
RESULTS 181-181
DISCUSSION 182-184
Issues in Risk Assessment The Two-Stage Model Of Carcinogenesis 185-186
INTRODUCTION 187-187
BIOLOGIC CONSIDERATIONS 188-189
THE TWO-STAGE MODEL 190-195
APPLICATIONS OF THE TWO-STAGE MODEL TO ANIMAL DATA 196-211
Data Needs 212-212
Criteria for Adoption 213-213
Prospects 214-214
CONCLUSIONS AND RECOMMENDATIONS 215-216
REFERENCES 217-222
BIOLOGICAL FACTORS IN TWO-STAGE MODELS 223-225
TWO-STAGE MODEL OF CLONAL EXPANSION 226-227
APPLICATION OF THE TWO-STAGE MODEL TO ANIMAL DATA 228-232
Appendix B Workshop Program 233-234
Appendix C Workshop Federal Liaison Group 235-236
TOPIC GROUP MEMBERS 237-238
Appendix E Workshop Organizing Task Group 239-240
Isuees In Risk Assessment A Paradigm for Ecological Risk Assessment 241-242
1 Introduction 243-246
2 Scope of Ecological Risk Assessment 247-248
COMPONENTS OF THE 1983 FRAMEWORK 249-250
CONSISTENCY OF CASE STUDIES WITH THE 1983 FRAMEWORK 251-253
INTEGRATION OF ECOLOGICAL RISK INTO THE 1983 FRAMEWORK 254-254
DEFINITION OF FRAMEWORK COMPONENTS FOR ECOLOGICAL RISK ASSESSMENT 255-258
EXTRAPOLATION ACROSS SCALES 259-260
QUANTIFICATION OF UNCERTAINTY 261-261
VALIDATION OF PREDICTIVE TOOLS 262-262
VALUATION 263-264
5 Conclusions 265-266
6 Recommendations 267-268
REFERENCES 269-272
Appendix A Workshop Participants 273-278
Appendix B Workshop Organizing Subcommittee and Federal Liaison Group 279-280
Appendix C Workshop Introduction 281-282
TERRY F. YOSIE BUILDING ECOLOGICAL RISK ASSESSMENT AS A POLICY TOOL 283-285
D. WARNER NORTH: RELATIONSHIP OF WORKSHOP TO NRC'S 1983 RED BOOK REPORT 286-288
MICHAEL SLIMAK: U.S. ENVIRONMENTAL PROTECTION AGENCY ACTIVITIES IN ECOLOGICAL RISK ASSESSMENT 289-292
CASE STUDY 1: TRIBUTYLTIN RISK MANAGEMENT IN THE UNITED STATES 293-293
Discussion 294-294
CASE STUDY 2: ECOLOGICAL RISK ASSESSMENT FOR TERRESTRIAL WILDLIFE EXPOSED TO AGRICULTURAL CHEMICALS 295-296
CASE STUDY 3A: MODELS OF TOXIC CHEMICALS IN THE GREAT LAKES: STRUCTURE, APPLICATIONS, AND UNCERTAINTY ANALYSIS 297-298
CASE STUDY 3B: ECOLOGICAL RISK ASSESSMENT OF TCDD AND TCDF 299-299
Discussion 300-300
CASE STUDY 4: RISK ASSESSMENT METHODS IN ANIMAL POPULATIONS: THE NORTHERN SPOTTED OWL AS AN EXAMPLE 301-301
Discussion 302-302
CASE STUDY 5: ECOLOGICAL BENEFITS AND RISKS ASSOCIATED WITH THE INTRODUCTION OF EXOTIC SPECIES FOR BIOLOGICAL CONTROL OF A... 303-303
Discussion 304-304
CASE STUDY 1: UNCERTAINTY AND RISK IN AN EXPLOITED ECOSYSTEM: A CASE STUDY OF GEORGES BANK 305-306
Discussion 307-308
Generic Issues 309-309
Analysis of Case Studies 310-310
DOSE-RESPONSE ASSESSMENT 311-311
Selection of End Points 312-312
Consideration of Nonlinearities And Discontinuities 313-313
Understanding the Stressor 314-314
Additions to the 1983 Paradigm Needed for Ecological Risk Assessment 315-315
Modeling Needs for Stress-Response Relationships 316-316
Methods of Measuring Stressors for Ecological Exposure Assessment 317-317
Definition of Risk Characterization 318-318
Components of Risk Characterization 319-319
Organization and Presentation 320-320
Differences from and Similarities To the 1983 Report 321-321
Application to the Case Studies 322-323
Agricultural Chemicals 324-324
Northern Spotted Owl 325-325
General Discussion: Models and Risk Assessment 326-326
Uncertainties Identified In the Case Studies 327-327
Implications of Uncertainty for Ecological Risk Assessment 328-328
VALUATION 329-330
Risk Assessment Has Many Uses 331-332
Different Risk Assessment Methods Are Suited to Different Risk Assessment Needs 333-333
Risk Assessors and Risk Managers Need to Communicate 334-334
Credibility is Crucial 335-336
Appendix G Contemplations on Ecological Risk Assessment 337-342
Appendix H Workshop Summary 343-346
Appendix I References for Appendixes 347-350
Appendix J Workshop Program 351-356

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