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PART 2 SETTING PRIORITIES FOR TOXICITY TESTING CONTENTS 1. INTRODUCTION DESIGN OF THE PRIORITY-SETTING SYSTEM Goal of Priority-Setting Chemicals Considered Structure of the System Analysis of Information Estimating Exposure Estimating Toxic Effects Assessment and Decision-Making Design Factors Describing the Priority-Setting System Accuracy of Stages or Tests Measuring Performance Cost 3. BRIEFLY FOLLOWING A CHEMICAL THROUGH AN ILLUSTRATIVE SYSTEM Stage 1 Stage 2 Stage 3 Stage 4 4. DETAILED DESCRIPTION OF THE OPERATION OF AN ILLUSTRATIVE SYSTEM Introduction Elements of Design Goal Universe Assessment Structure Rules for Selection Design Parameters Stage 1 Exposure Data Elements Toxicity Data Elements Selection Rules Stage 2 Exposure Data Elements Toxicity Data Elements Selection Rules 199 Page 205 207 208 208 210 213 215 218 221 222 222 222 223 226 227 227 232 234 235 237 237 237 237 237 238 238 238 239 239 240 243 255 258 258 267 270

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Stage 3 Exposure Data Elements Toxicity Data Elements Selection Rules Stage 4 5. FUTURE DEVELOPMENT, IMPLEMENTATION, AND REFINE MENT OF THE SYSTEM Development Implementation Further Refinement Evaluation Possible New Data ELements The Use of Surveys and Epidemiologic Information Developing Very-Low-Cost (VLC) Tests Random Sampling 6. CONCLUSIONS AND RECOMMENDATIONS REFERENCES 270 272 273 275 275 lo_ 200 285 285 286 288 289 290 290 291 293 295 297

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Tables Target Organs and Chemically Induced Effects in Humans 2. Possible Results of Test Having Three Results: High, Medium, and Low Illustrative Stage 1 Estimates of Probability of Exposure in Relation to Use and Production Page 220 224 241 4. Illustrative Estimates of Distribution of Production Volumes in Relation to Use Categories 242 Chemical Groups Associated with Human Health Effects~Either Directly or After Metabolic Activation 6. Significance of Ranking of RTECS Codes for Car- cinogenic Potential 7. Estimated Proportions of Chemicals with Given Carcinogenic Potency, by RTECS Code 8. Estimated Proportions of Chemicals with RTECS Codes Related to Cancer 9. Selected Sources of Exposure Information by Use Class 10. Data Needs for Use Classes 11. Hypothetical Estimates of Probability Distributions of Degree of Exposure Generated in Stage 2 in Relation to Estimated Degrees of Concern and Confidence 12. Hypothetical Percentages of Chemicals as Estimated by Assessor to Have Given Degrees of Concern and Confidence in Estimate 13. Selected Sources of Toxicity Information by Effect 14. Hypothetical Estimates of Probability Distributions of Carcinogenic Potency as Generated in Stage 2, in Relation to Assigned Degree of Concern about Carcino- genicity and.Degree of Confidence in Assignment 201 245 256 257 257 260 264 265 267 268 271

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15. Hypothetical Estimates of Probability Distributions of Degree of Exposure Generated in Stage 3, in Re- lation to Assigned Degree of Confidence in Assignment 272 16. Hypothetical Estimates of Probability Distributions of Carcinogenic Potency as Generated in Stage 3, in Relation to Assigned Degree of Concern about Carcino- genicity and Degree of Confidence in Assignment 274 17. Estimates of Costs of Some Carcinogenicity Tests 276 18. Correlation among Results of Salmonella/microsome Tests Performed by 12 Investigators 19. Predictive Accuracy of Various Short-Term Tests for Carcinogenicity 20. Predictive Accuracy of Several Short-Term Tier Testing Regimens 21. Chemicals Analyzed by Short-Term Tests (International Collaborative Study) 202 278 279 282 283

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Figures Page le Example of one stage or building block in process of investigation and control of toxic substances. 211 Illustration of misclassification 3. Stage 1 of illustrative system. 4. Stage 2 of illustrative system. 5. Stages 3 and 4 of illustrative system. Be Decision rules used in processing example chemical bispbenol A. 7. Sample checklist for Stage 2 exposure assessment, to be filled out by assessor reviewing dossier. 203 225 228 Age 230 233 266

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Page Appendix A Review of Selected Priority-Setting Systems 301 Appendix B Mathematical Modeling of the Priority Setting Process and Resulting Decision Rules 319 Appendix C Expert Judgment and the Treatment of Uncertainty 347 Appendix D The Analysis of Structure-Activity Relation ships in Selecting Potentially Toxic Compounds for Testing 355 Appendix E Costs of Misclassification 363 Appendix F Differences Between Part 1 and Part 2 381 204