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

10,0

Tetrachlorodibenzo-p-Dioxin (TCDD) and Related Compounds -

1101

stron

Part II: Health Assessment for 2,3,7,8-Tetrachlorodibenzo-p-

dioxin (TCDD) and Related Compounds

5921

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

2004

rok

CONTENTS

1. DISPOSITION AND PHARMACOKINETICS 1-1

1.1. ABSORPTION/BIOAVAILABILITY FOLLOWING EXPOSURE 1-1

1.1.1. Oral 1-1

1.1.1.1.Gastrointestinal Absorption in Animals 1-1

1.1.1.2. Gastrointestinal Absorption in Humans . 1-3

1.1.1.3. Bioavailability Following Oral Exposure 1-5

1.1.2. Dermal Absorption . 1-6

1.1.2.1. Bioavailability Following Dermal Exposure 1-8

1.1.3. Transpulmonary Absorption 1-9

1.1.4. Parenteral Absorption 1-11

1.2. DISTRIBUTION . 1-11

1.2.1. Distribution in Blood and Lymph 1-11

1.2.2. Tissue Distribution 1-13

1.2.2.1. Tissue Distribution in Humans . 1-16

1.2.3. Time-Dependent Tissue Distribution . 1-18

1.2.4. Dose-Dependent Tissue Distribution . 1-23

1.2.5. Potential Mechanisms for Dose-Dependent Tissue Distribution . 1-25

1.3. METABOLISM AND EXCRETION 1-29

1.3.1. Structure of Metabolites 1-30

1.3.2. Toxicity of Metabolites . 1-32

1.3.3. Autoinduction of Metabolism 1-33

1.3.4. Excretion in Animals . 1-37

1.3.5. Excretion in Humans . 1-40

1.4. PHARMACOKINETICS AND EXPOSURE 1-45

1.4.1. Introduction . 1-45

1.4.2. Estimating Daily Intake of TCDD . 1-46

1.4.3. Daily Intake of Congeners . 1-48

1.4.4. Induction of Liver Binding Proteins and Resultant Distribution . 1-51

1.4.5. Pregnancy and Lactation (Exposure of Offspring) . 1-51

1.4.6. Pharmacokinetics and Aging . 1-60

1.5. SELECTION OF DOSE SURROGATE 1-61

1.5.1. Administered Dose 1-62

1.5.2. Area Under the Curve 1-63

1.5.3. Plasma or Tissue Concentrations 1-64

1.5.4. Steady-State Body Burdens 1-65

1.5.5. Mechanistic Dose Metrics . 1-66

1.5.6. Summary 1-66

REFERENCES FOR CHAPTER 1 1-95

2. MECHANISM(S) OF ACTION . 2-1

2.1. INTRODUCTION . 2-1

2.2. THE "RECEPTOR" CONCEPT . 2-2

2.3. THE Ah (DIOXIN) RECEPTOR 2-4

2.4. THE ARNT PROTEIN 2-8

2.5. OTHER PROTEINS THAT PARTICIPATE IN THE RESPONSE

TO DIOXIN . 2-10

2.6. ACTIVATION OF GENE TRANSCRIPTION BY DIOXIN 2-12

2.6.1. In Vitro Studies 2-12

2.6.2. In Vivo Studies . 2-15

2.7. EVIDENCE FOR DIFFERENT MECHANISMS OF TOXICITY. 2-17

2.8. FUTURE RESEARCH . 2-21

2.9. MECHANISTIC INFORMATION AND RISK ASSESSMENT 2-25

REFERENCES FOR CHAPTER 2 2-31

3. ACUTE, SUBCHRONIC, AND CHRONIC TOXICITY . 3-1

3.1. SCOPE AND LIMITATIONS 3-1

3.2. ACUTE TOXICITY 3-1

3.2.1. Signs and Symptoms of Toxicity . 3-4

3.2.2. Studies In Vitro 3-5

3.2.3. Appraisal . 3-6

3.3. SUBCHRONIC TOXICITY 3-6

3.3.1. Appraisal . 3-8

3.4. CHRONIC TOXICITY 3-9

3.4.1. Appraisal 3-10

3.5. SPECIFIC EFFECTS 3-10

3.5.1. Wasting Syndrome . 3-10

3.5.2. Hepatotoxicity 3-13

3.5.3. Epidermal Effects . 3-16

3.5.4. Enzyme Induction . 3-17

3.5.4.1. Appraisal . 3-20

3.5.5. Endocrine Effects . 3-20

3.5.6. Vitamin A Storage . 3-23

3.5.7. Lipid Peroxidation . 3-25

3.5.8. Neurotoxicity 3-27

3.6. MECHANISMS OF TOXICITY 3-28

3.7. SUMMARY . 3-32

REFERENCES FOR CHAPTER 3 3-41

4. IMMUNOTOXICITY . 4-1

4.1. INTRODUCTION . 4-1

4.2. ROLE OF THE AH LOCUS IN PHAH IMMUNOTOXICITY 4-3

4.3. SENSITIVE TARGETS FOR PHAH IMMUNOTOXICITY . 4-9

4.4. INFLUENCE OF TCDD ON HOST RESISTANCE TO DISEASE . 4-14

4.5. ROLE OF THE THYMUS IN PHAH IMMUNOTOXICITY 4-17

4.6. IMMUNOTOXICITY FOLLOWING PRENATAL/NEONATAL EXPOSURE TO PHAHS . 4-19

4.7. IMMUNOTOXICITY OF PHAHS IN NONHUMAN PRIMATES . 4-22

4.8. IMMUNOTOXICITY OF PHAHS IN HUMANS: IN VIVO EXPOSURE . 4-24

4.9. IMMUNOTOXICITY OF PHAHS IN HUMANS: IN VITRO EXPOSURE 4-33

4.10. SUMMARY . 4-34

REFERENCES FOR CHAPTER 4 4-42

5. DEVELOPMENTAL AND REPRODUCTIVE TOXICITY 5-1

5.1. INTRODUCTION . 5-1

5.2. DEVELOPMENTAL TOXICITY . 5-3

5.2.1. Death/Growth/Clinical Signs 5-3

5.2.1.1. Fish 5-3

5.2.1.2. Birds . 5-4

5.2.1.3. Laboratory Mammals 5-7

5.2.1.4. Structure-Activity Relationships in Laboratory Mammals 5-14

5.2.1.5. Humans 5-15

5.2.2. Structural Malformations 5-17

5.2.2.1. Cleft Palate . 5-19

5.2.2.2. Hydronephrosis 5-27

5.2.2.3. Tooth Development 5-30

5.2.3. Postnatal Effects 5-30

5.2.3.1. Eye Opening 5-30

5.2.3.2. Male Reproductive System . 5-31

5.2.3.3. Female Reproductive System . 5-58

5.2.3.4. Neurobehavior 5-63

5.2.3.5. Thermoregulation 5-72

5.2.3.6. Auditory Function and Thyroid Hormones . 5-73

5.2.3.7. Night Vision 5-75

5.2.4. Cross-Species Comparison of Effect Levels 5-76

5.3. REPRODUCTIVE TOXICITY . 5-78

5.3.1. Female . 5-78

5.3.1.1. Reproductive Function/Fertility 5-78

5.3.1.2. Ovarian Function . 5-80

5.3.1.3. Reproductive Capability of Ah Receptor Knockout Mice 5-80

5.3.1.4. Endometriosis . 5-81

5.3.1.5. Mammary Gland . 5-82

5.3.1.6. Alterations in Hormone Levels 5-86

5.3.1.7. Antiestrogenic Action . 5-86

5.3.2. Male . 5-91

5.3.2.1. Reproductive Function/Fertility 5-91

5.3.2.2. Alterations in Hormone Levels 5-92

5.3.2.3. Target Organ Responsiveness . 5-92

5.4. SUMMARY . 5-95

5.4.1. Human . 5-95

5.4.2. Experimental Animal . 5-96

5.4.2.1. Developmental Toxicity . 5-96

5.4.2.2. Adult Female Reproductive Toxicity 5-98

5.4.2.3. Adult Male Reproductive Toxicity . 5-98

5.4.3. Conclusion 5-99

REFERENCES FOR CHAPTER 5 . 5-110

6. CARCINOGENICITY OF TCDD IN ANIMALS 6-1

6.1. INTRODUCTION . 6-1

6.2. ANIMAL BIOASSAYS FOR CANCER . 6-2

6.2.1. Kociba Study 6-3

6.2.2. NTP Study 6-5

6.2.3. Syrian Golden Hamster 6-6

6.2.4. B6C3 and B6C Mice 6-6

6.2.5. Fish . 6-7

6.2.6. Carcinogenicity of Related Compounds 6-7

6.3. INITIATION/PROMOTION STUDIES . 6-8

6.3.1. TCDD Is Not a Direct Genotoxic Agent . 6-9

6.3.2. Two-Stage Models of Liver Tumor Promotion by TCDD . 6-10

6.3.3. Lung . 6-12

6.3.4. Mouse Skin 6-13

6.3.5. Transgenic Models 6-14