DO NOT QUOTE OR CITE
June 1994
External Review Draft
Health Assessment Document for 2,3,7,8-Tetrachlorodibenzo-p-dioxin(TCDD) and Related Compounds

Contents - Overview EPA/600/BP-92/001a,b,c

CONTENTS - VOLUME I
SELECT Tables
SELECT Figures
SELECT Abbreviations and Acronyms
SELECT Preface
SELECT Authors, Contributors, and Reviewers
Chapter go to 1.0: DISPOSITION AND PHARMACOKINETICS  
  • 1.1.    ABSORPTION/BIOAVAILABILITY FOLLOWING EXPOSURE
    • 1.1.1.   Oral
      • 1.1.1.1.  Gastrointestinal Absorption in Animals
      • 1.1.1.2.  Gastrointestinal Absorption in Humans
      • 1.1.1.3.  Bioavailability  Following Oral Exposure
    • 1.1.2.   Dermal Absorption
      • 1.1.2.1.  Bioavailability  Following Dermal Exposure
    • 1.1.3.   Transpulmonary Absorption
    • 1.1.4.   Parenteral Absorption
  • 1.2.    DISTRIBUTION
    • 1.2.1.   Distribution in Blood and Lymph
    • 1.2.2.   Tissue Distribution
      • 1.2.2.1.  Tissue Distribution  in Humans
    • 1.2.3.   Time-Dependent Tissue Distribution
    • 1.2.4.   Dose-Dependent Tissue Distribution
    • 1.2.5.   Potential Mechanisms for the Dose-Dependent Tissue Distribution
  • 1.3.    METABOLISM AND EXCRETION
    • 1.3.1.   Structure of Metabolites
    • 1.3.2.   Toxicity of Metabolites
    • 1.3.3.   Autoinduction of Metabolism
    • 1.3.4.   Excretion in Animals
    • 1.3.5.   Excretion in Humans
  • 1.4.   PHYSIOLOGICALLY BASED PHARMACOKINETIC (PB-PK) MODELS
  • 1.5.   PHARMACOKINETICS IN SPECIAL POPULATIONS
    • 1.5.1.  Pregnancy and Lactation (Prenatal and Postnatal Exposure of Offspring)
    • 1.5.2.  Aging
  • REFERENCES FOR CHAPTER
Chapter go to 2.0: MECHANISM(S) OF ACTION  
  • 2.1.   INTRODUCTION
  • 2.2.   THE "RECEPTOR" CONCEPT
  • 2.3.   THE Ah (DIOXIN) RECEPTOR
  • 2.4.   THE Arnt PROTEIN
  • 2.5.   OTHER PROTEINS THAT PARTICIPATE IN THE RESPONSE TO DIOXIN
  • 2.6.   ACTIVATION OF GENE TRANSCRIPTION BY DIOXIN
    • 2.6.1.  In Vitro Studies
    • 2.6.2.  In Vivo Studies
  • 2.7.   FUTURE RESEARCH
  • 2.8.   MECHANISTIC INFORMATION AND RISK ASSESSMENT
  • REFERENCES FOR CHAPTER 2
Chapter go to 3.0: ACUTE, SUBCHRONIC, AND CHRONIC TOXICITY  
  • 3.1.   SCOPE AND LIMITATIONS
  • 3.2.   ACUTE TOXICITY
    • 3.2.1.  Signs and Symptoms of Toxicity
    • 3.2.2.  Studies In Vitro
    • 3.2.3.  Appraisal
  • 3.3.   SUBCHRONIC TOXICITY
    • 3.3.1.  Appraisal
  • 3.4.   CHRONIC TOXICITY
    • 3.4.1.  Appraisal
  • 3.5.   SPECIFIC EFFECTS
    • 3.5.1.  Wasting Syndrome
    • 3.5.2.  Hepatotoxicity
    • 3.5.3.  Epidermal Effects
    • 3.5.4.  Enzyme Induction
    • 3.5.5.  Appraisal
    • 3.5.6.  Endocrine Effects
    • 3.5.7.  Vitamin A Storage
    • 3.5.8.  Lipid Peroxidation
  • 3.6.   MECHANISMS OF TOXICITY
  • 3.7.   CONCLUSIONS
  • REFERENCES FOR CHAPTER 3
Chapter go to 4.0: IMMUNOTOXICITY  
  • 4.1.   INTRODUCTION
  • 4.2.   ROLE  OF THE Ah LOCUS IN HAH IMMUNOTOXICITY
  • 4.3.   TOXIC EQUIVALENCY FACTORS FOR IMMUNOTOXICITY
  • 4.4.   INTERACTIONS BETWEEN HAHs
  • 4.5.   SENSITIVE TARGETS FOR HAH IMMUNOTOXICITY
  • 4.6.  INFLUENCE OF TCDD ON HOST RESISTANCE TO DISEASE
  • 4.7.  IN VITRO IMMUNOTOXIC EFFECTS OF HAHs
  • 4.8.  INDIRECT MECHANISMS OF HAH IMMUNOTOXICITY
  • 4.9.  ROLE OF THE THYMUS IN HAH IMMUNOTOXICITY
  • 4.10.  IMMUNOTOXICITY FOLLOWING PRENATAL/NEONATAL EXPOSURE TO HAHs
  • 4.11.  IMMUNOTOXICITY OF HAHs IN NONHUMAN PRIMATES
  • 4.12.  IMMUNOTOXICITY OF HAHs IN HUMANS
  • REFERENCES FOR CHAPTER 4
Chapter go to 5.0: DEVELOPMENTAL AND REPRODUCTIVE TOXICITY  
  • 5.1.  INTRODUCTION
  • 5.2.  DEVELOPMENTAL TOXICITY
    • 5.2.1. Death/Growth/Clinical Signs
      • 5.2.1.1. Fish
      • 5.2.1.2. Birds
      • 5.2.1.3. Laboratory Mammals
      • 5.2.1.4. Structure-Activity Relationships in Laboratory Mammals
      • 5.2.1.5. Humans
    • 5.2.2. Structural Malformations
      • 5.2.2.1. Cleft Palate
        • 5.2.2.1.1. Characterization of TCDD effects
        • 5.2.2.1.2. Evidence for an Ah receptor mechanism
          • 5.2.2.1.2.1. Genetic
          • 5.2.2.1.2.2. Structure activity
        • 5.2.2.1.3. Species Differences
      • 5.2.2.2. Hydronephrosis
        • 5.2.2.2.1. Characterization of TCDD effects
        • 5.2.2.2.2. Evidence for an Ah receptor mechanism
          • 5.2.2.2.2.1. Genetic Structure activity
          • 5.2.2.2.2.2. Structure activity
        • 5.2.2.2.3. Species Differences
    • 5.2.3. Postnatal Effects
      • 5.2.3.1. Male Reproductive System
        • 5.2.3.1.1. Overt toxicity assessment
        • 5.2.3.1.2. Androgenic status
        • 5.2.3.1.3. Spermatogenesis
        • 5.2.3.1.4. Epididymis
        • 5.2.3.1.5. Reproductive capability
        • 5.2.3.1.6. Sexual differentiation of the CNS
          • 5.2.3.1.6.1. Demasculinization of sexual behavior
          • 5.2.3.1.6.2. Feminization of sexual behavior
          • 5.2.3.1.6.3. Feminization of LH secretion regulation
          • 5.2.3.1.6.4. Comparison to other Ah reseptor-mediated responses
          • 5.2.3.1.6.5. Possible mechanisms and significance
      • 5.2.3.2. Female Reproductive System
      • 5.2.3.3. Neurobehavior
        • 5.2.3.3.1. Mice.
        • 5.2.3.3.2. Monkeys.
        • 5.2.3.3.3. Humans.
    • 5.2.4. Cross-Species Comparison of Effect Levels
  • 5.3.   REPRODUCTIVE TOXICITY
    • 5.3.1.  Female
      • 5.3.1.1.  Reproductive Function/Fertility
      • 5.3.1.2.  Alterations in Hormone Levels
      • 5.3.1.3.  Antiestrogenic Action
        • 5.3.1.3.1. In Vivo
        • 5.3.1.3.2. In Vitro
        • 5.3.1.3.3. Evidence for an Ah receptor mechanism
          • 5.3.1.3.3.1. Ah receptor mutants
          • 5.3.1.3.3.2. Structure-activity relationships in vivo
          • 5.3.1.3.3.3. Genetic evidence.
          • 5.3.1.3.3.4. Structure-activity relationships in vitro
    • 5.3.2.  Male
      • 5.3.2.1.  Reproductive Function/Fertility
      • 5.3.2.2.  Alterations in Hormone Levels
      • 5.3.2.3.  Target Organ Responsiveness
        • 5.3.2.3.1. Inhibition of testicular steroidogenesis
        • 5.3.2.3.2. Altered regulation of pituitary LH secretion.
        • 5.3.2.3.3. Differential responsiveness of androgen target organs
        • 5.3.2.3.4. Relative sensitivity
  • REFERENCES FOR CHAPTER 5
Chapter go to 6.0: CARCINOGENICITY OF TCDD IN ANIMALS  
  • 6.1.   INTRODUCTION
  • 6.2.   ANIMAL BIOASSAYS FOR CANCER
    • 6.2.1.  Kociba Study
    • 6.2.2.  NTP Study
    • 6.2.3.  Syrian Golden Hamster
    • 6.2.4.  B6C3 and B6C Mice
    • 6.2.5.  Carcinogenicity of Related Compounds
  • 6.3.   MECHANISMS OF  TCDD CARCINOGENICITY
  • 6.4.   INITIATION/PROMOTION STUDIES
    • 6.4.1.  Two-Stage Models in Rat Liver
    • 6.4.2.  Rat Lung
    • 6.4.3.  Mouse Skin
  • 6.5.   BIOCHEMICAL RESPONSES
    • 6.5.1.  CYP1A1 and 1A2
    • 6.5.2.  Epidermal Growth Factor Receptor
    • 6.5.3.  UDP-Glucuronosyltransferases
    • 6.5.4.  Estrogen Receptor
    • 6.5.5.  Other Biochemical End Points
  • 6.6.  SUMMARY AND WEIGHT OF EVIDENCE FROM ANIMAL STUDIES
  • REFERENCES FOR CHAPTER 6