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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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Issues in Risk Assessment (1993)

Chapter: Analysis of Case Studies

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Issues in Risk Assessment (1993)

Chapter: Analysis of Case Studies