Exposure and Human Health Reassessment of 2,3,7,8-

0,86

MB

Tetrachlorodibenzo-p-Dioxin (TCDD) and Related Compounds

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Part III: Integrated Summary and Risk Characterization for

2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) and Related

5916

ID

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

2000

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CONTENTS

1. INTRODUCTION 1

1.1. DEFINITION OF DIOXIN-LIKE COMPOUNDS . 3

1.2. TOXIC EQUIVALENCY FACTORS 4

1.3. UNDERSTANDING EXPOSURE/DOSE RELATIONSHIPS FOR DIOXIN-LIKE COMPOUNDS . 8

1.3.1. Administered Dose . 9

1.3.2. Area Under the Curve 10

1.3.3. Plasma or Tissue Concentrations 12

1.3.4. Steady-State Body Burdens 13

1.3.5. Mechanistic Dose Metrics . 14

1.3.6. Summary 14

2. EFFECTS SUMMARY . 14

2.1. BIOCHEMICAL RESPONSES 16

2.2. ADVERSE EFFECTS IN HUMANS AND ANIMALS 19

2.2.1. Cancer 19

2.2.1.1. Epidemiologic Studies . 19

2.2.1.2. Animal Carcinogenicity . 24

2.2.1.3. Plausible Mode(s) of Carcinogenic Action . 27

2.2.1.4. Other Data Related to Carcinogenesis 29

2.2.1.5. Cancer Hazard Characterization 30

2.2.2. Reproductive and Developmental Effects 31

2.2.2.1. Human 32

2.2.2.2. Experimental Animal . 34

2.2.2.3. Other Data Related to Developmental and Reproductive Effects . 37

2.2.2.4. Developmental and Reproductive Effects Hazard Characterization . 39

2.2.3. Immunotoxicity . 40

2.2.3.1. Epidemiologic Findings . 40

2.2.3.2. Animal Findings . 41

2.2.3.3. Other Data Related to Immunologic Effects 42

2.2.3.4. Immunologic Effects Hazard Characterization 43

2.2.4. Chloracne . 44

2.2.5. Diabetes 45

2.2.6. Other Effects . 47

2.2.6.1. Elevated GGT . 47

2.2.6.2. Thyroid Function 48

2.2.6.3. Cardiovascular Disease . 49

2.2.6.4. Oxidative Stress . 49

3. MECHANISMS AND MODE OF DIOXIN ACTION 50

3.1. MODE VERSUS MECHANISM OF ACTION 51

3.2. GENERALIZED MODEL FOR DIOXIN ACTION 52

3.2.1. The Receptor Concept . 52

3.2.2. A Framework to Evaluate Mode of Action 54

3.2.3. Mechanistic Information and Mode of Action; Implications for Risk Assessment 55

4. EXPOSURE CHARACTERIZATION 58

4.1. SOURCES 59

4.1.1. Inventory of Releases . 60

4.1.2. General Source Observations . 63

4.2. ENVIRONMENTAL FATE 66

4.3. ENVIRONMENTAL MEDIA AND FOOD CONCENTRATIONS . 68

4.4. BACKGROUND EXPOSURES . 70

4.4.1. Tissue Levels . 70

4.4.2. Intake Estimates 71

4.4.3. Variability in Intake Levels 72

4.5. POTENTIALLY HIGHLY EXPOSED POPULATIONS OR DEVELOPMENTAL STAGES 73

5. DOSE-RESPONSE CHARACTERIZATION 77

5.1. DOSE METRIC(s) . 79

5.1.1. Calculations of Effective Dose (ED) . 81

5.2. EMPIRICAL MODELING OF INDIVIDUAL DATA SETS 82

5.2.1. Cancer 83

5.2.1.1. Estimates of Slope Factors and Risk at Current Background Body Burdens Based on

Human Data . 88

5.2.1.2. Estimates of Slope Factors and Risk at Current Background Body Burdens Based on

Animal Data . 90

5.2.1.3. Estimates of Slope Factors and Risk at Current Background Body Burdens Based on a

Mechanistic Model . 92

5.2.2. Noncancer Endpoints . 93

5.3. MODE-OF-ACTION BASED DOSE-RESPONSE MODELING 94

5.4. SUMMARY DOSE-RESPONSE CHARACTERIZATION . 95

6. RISK CHARACTERIZATION . 99

GLOSSARY AND DEFINITIONS 159

REFERENCES FOR RISK CHARACTERIZATION 165