Developing Relative Potency Factors for Pesticide Mixtures:

1,21

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Biostatistical Analyses of Joint Dose-Response

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5906

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

2003

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TABLE OF CONTENTS

FOREWORD iii

RESEARCHERS . iv

LIST OF ABBREVIATIONS vii

KEY DEFINITIONS. viii

EXECUTIVE SUMMARY xiii

1. INTRODUCTION . 1

2. DOSE ADDITION CONCEPTS 9

3. RELATIVE POTENCY FACTORS 12

3.1. JUDGMENTS OF COMMON TOXICOLOGIC ACTION 15

4. CHOICE OF DOSE METRIC IN CHARACTERIZING MIXTURE TOXICITY BY DOSE ADDITION .

20

4.1. RPF DOSE ISSUES . 20

4.1.1. Administered Dose . 21

4.1.2. Internal Dose . 21

4.1.3. Mixtures Exposures Through Multiple Exposure Routes 21

4.1.4. Mixtures Exposures Though a Single Exposure Route in Different Species 22

4.2. CHOICE OF DOSE MEASURES . 25

5. BIOSTATISTICAL DOSE-RESPONSE MODELING FOR CUMULATIVE RISK 26

5.1. DOSE-RESPONSE MODEL FOR COMBINED EXPOSURES . 27

5.1.1. Constant Relative Potency . 30

5.1.2. Nonconstant Relative Potency 31

5.1.3. Constant and Nonconstant Relative Potencies in the Same Mixture . 32

5.2. STATISTICAL ALGORITHMS FOR SUBCLASS GROUPS WITHIN A MIXTURE. 34

5.2.1. Top-Down Approach 36

5.2.2. Bottom-Up Approach . 39

5.3. CUMULATIVE RISK ASSESSMENT 42

5.3.1. Mixtures Reference Dose 43

6. CONCLUSIONS 45

7. REFERENCES 48

APPENDIX A: Chen et al., 2001. Using Dose Addition to Estimate Cumulative Risks from

Exposures to Multiple Chemicals . A-1

APPENDIX B: Chen et al., 2003 (In Press). Cumulative Risk Assessment for Quantitative

Response Data B-1