Health Assessment, Volume III: Risk Characterization

DRAFT EPA/600/BP-92/001c

DO NOT QUOTE OR CITE August 1994

External Review Draft

NOTICE

THIS DOCUMENT IS A PRELIMINARY DRAFT. It has not been formally released by the U.S. Environmental Protection Agency and should not at this stage be construed to represent Agency policy. It is being circulated for comment on its technical accuracy and policy implications.

Office of Health and Environmental Assessment

Office of Research and Development

U.S. Environmental Protection Agency

Washington, D.C.

DISCLAIMER

This document is an external draft for review purposes only and does not constitute Agency policy. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.

Volume I

1. DISPOSITION AND PHARMACOKINETICS

2. MECHANISM(S) OF ACTION

3. ACUTE, SUBCHRONIC, AND CHRONIC TOXICITY

4. IMMUNOTOXICITY

5. DEVELOPMENTAL AND REPRODUCTIVE TOXICITY

6. CARCINOGENICITY OF TCDD IN ANIMALS

Volume II

7. EPIDEMIOLOGY/HUMAN DATA

PART A. CANCER EFFECTS

PART B. EFFECTS OTHER THAN CANCER

8. DOSE-RESPONSE MODELING

Volume III

9. RISK CHARACTERIZATION OF 2,3,7,8-TETRACHLORODIBENZO-p-DIOXIN (TCDD) AND RELATED COMPOUNDS

and Related Compounds

CONTENTS - VOLUME III

List of Tables III-vi

List of Figures III-vi

List of Abbreviations and Acronyms III-vii

Preface III-xv

Authors, Contributors, and Reviewers III-xix

9. RISK CHARACTERIZATION OF 2,3,7,8-TETRACHLORODIBENZO-p-DIOXIN (TCDD) AND RELATED COMPOUNDS 9-1

9.1. INTRODUCTION 9-1

9.2. CHEMICAL STRUCTURE AND PROPERTIES 9-3

9.3. ENVIRONMENTAL FATE 9-7

9.4. SOURCES 9-8

9.4.1. Levels in the Environment and in Food 9-13

9.4.2. Background Exposure Levels 9-14

9.4.3. Highly Exposed Populations 9-19

9.5. DISPOSITION AND PHARMACOKINETICS 9-23

9.6. MECHANISMS OF DIOXIN ACTION 9-30

9.7. TOXIC EFFECTS OF DIOXIN 9-36

9.7.1. General Comments 9-36

9.7.2. Chloracne 9-38

9.7.3. Carcinogenicity 9-39

9.7.4. Reproductive and Developmental Effects 9-44

9.7.5. Immunotoxicity 9-48

9.7.6. Other Effects 9-50

9.7.6.1. Circulating Reproductive Hormones 9-51

9.7.6.2. Diabetes and Fasting Serum Glucose Levels 9-51

9.7.6.3. Enzyme Induction 9-51

9.7.6.4. Gamma Glutamyl Transferase (GGT) Activity 9-52

9.7.6.5. Endometriosis 9-52

9.8. DOSE-RESPONSE CONSIDERATIONS 9-53

9.9. USE OF TOXICITY EQUIVALENCE 9-69

9.10. KEY ASSUMPTIONS AND INFERENCES 9-70

9.11. OVERALL CONCLUSIONS REGARDING THE IMPACT OF DIOXIN AND RELATED COMPOUNDS ON HUMAN HEALTH 9-74

REFERENCES FOR CHAPTER 9 9-89

LIST OF TABLES

9-1. Toxicity Equivalency Factors (TEF) for CDDs and CDFs 9-5

9-2. Effects of TCDD and Related Compounds in Different Animal Species 9-37

9-3. Estimated Body Burdens of Experimental Animals and Humans Exposed to Dioxins: Responses in Humans Causally Associated With Exposure to Dioxins and Comparable Effects in Experimental Animals 9-55

9-4. Estimated Body Burdens of Experimental Animals and Humans Exposed to Dioxins: Responses in Humans Associated With Dioxin Exposure and Comparable Effects in Experimental Animals 9-59

9-5. Estimated Body Burdens of Experimental Animals and Humans Exposed to Dioxins: Low-Dose Effects in Animals Exposed to Dioxins and Their Relationship to Background Human Exposure 9-62

9-6. Comparison of the Effects of TCDD Exposure on Human and Animal Tissue In Vitro 9-64

LIST OF FIGURES

9-1. Dioxin and similar compounds--chemical structure 9-4

9-2. Schematic representation of the complex sequence of molecular and biological events involved in dioxin-mediated toxicants 9-33

 

 

 

 

 

 

 

 

 

 

 

 

LIST OF ABBREVIATIONS AND ACRONYMS

ACTH Adrenocorticotrophic hormone

Ah receptor Aryl hydrocarbon receptor

AHH Aryl hydrocarbon hydroxylase

ALA Aminolevulinic acid

ALT L-alanine aminotransferase

AOR Adjusted odds ratio

APC Antigen-presenting cells

AST L-aspartate aminotransferase

ATPase Adenosine triphosphatase

BDD Brominated dibenzo-p-dioxin

BDF Brominated dibenzofuran

BCF Bioconcentration factor

BGG Bovine gamma globulin

bHLH Basic helix-loop-helix

bw Body weight

cAMP Cyclic 3,5-adenosine monophosphate

CDC Centers for Disease Control and Prevention

CDD Chlorinated dibenzo-p-dioxin

CDF Chlorinated dibenzofuran

cDNA Complementary DNA

cl Confidence level

CMI Cornell Medical Index

CNS Central nervous system

CSM Cerebrospinal malformation

CTL Cytotoxic T lymphocyte

DCDD 2,7-Dichlorodibenzo-p-dioxin

DEN Diethylnitrosamine

DHT 5a -Dihydrotestosterone

DIS Diagnostic Interview Schedule

DMBA Dimethylbenzanthracene

DMSO Dimethyl sulfoxide

DNA Deoxyribonucleic acid

DRE Dioxin-responsive enhancers

DTH Delayed-type hypersensitivity

EC₅₀ Concentration effective for 50% of organisms tested

EC₁₀₀ Concentration effective for 100% of organisms tested

ED₅₀ Dose effective for 50% of recipients

ECOD 7-Ethoxycoumarin-O-deethylase

EEG Electroencephalogram

EGF Epidermal growth factor

EGFR Epidermal growth factor receptor

ER Estrogen receptor

EROD 7-Ethoxyresorufin-O-deethylase

EOF Enzyme altered foci

EOI Exposure opportunity index

FEV Forced expiratory volume

FIQ Full-scale IQ

FSH Follicle-stimulating hormone

FTI Free thyroxine index

FVC Forced vital capacity

GC-ECD Gas chromatograph-electron capture detection

GC/MS Gas chromatograph/mass spectrometer

GGT Gamma glutamyl transpeptidase

GnRH Gonadotropin-releasing hormone

GST Glutathione-S-transferase

GVH Graft versus host

HAH Halogenated aromatic hydrocarbons

HCB Hexachlorobenzene

HCDD Hexachlorodibenzo-p-dioxin

HDL High density lipoprotein

HLH Helix-loop-helix

HPAH Halogenated polycyclic aromatic hydrocarbon

HpCDD Heptachlorinated dibenzo-p-dioxin

HpCDF Heptachlorinated dibenzofuran

HPLC High performance liquid chromatography

HRB Halstead-Reitan Battery

HRGC/HRMS High resolution gas chromatography/high resolution mass spectrometry

HTL Human tonsillar lymphocytes

HxBB Hexabrom-biphenyl

HxCB Hexachlorobiphenyl

HxCDD Hexachlorinated dibenzo-p-dioxin

HxCDF Hexachlorinated dibenzofuran

ICD-9 International Classification of Diseases 9

ID₅₀ Dose infective to 50% of recipients

I-TEF International TCDD-toxic-equivalency

KVK Kemisk Vaerk Køge

LADD Lifetime average daily dose

LD₅₀ Dose lethal to 50% of recipients (and all other subscripter dose levels)

LDH L-lactate dehydrogenase

LH Luteinizing hormone

LDL Low density liproprotein

LMS Linearized multistage

LPL Lipoprotein lipase activity

LOAEL Lowest-observable-adverse-effect level

LOEL Lowest-observed-effect level

LPS Lipopolysaccharide

MACDP Metropolitan Atlanta Congenital Defects Program

3-MC 3-Methylcholanthrene

MCDF 6-Methyl-1,3,8-trichlorodibenzofuran

MCF-7 (breast cancer cell)

MCMI Millon Clinical Multiaxial Inventory

MCPA (4-Chloro-2-methylphenoxy)acetic acid

MCPB 2-Methyl-4-chlorophenoxybutyric acid

MCPP 2-(4-Chloro-2-methylphenoxy)-propanoic acid

MFO Mixed function oxidase

MMPI Minnesota Multiphase Personality Inventory

MLE Maximum likelihood estimate

mRNA Messenger RNA

MNNG N-methyl-N-nitrosoguanidine

NADP Nicotinamide adenine dinucleotide phosphate

NADPH Nicotinamide adenine dinucleotide phosphate (reduced form)

NaTCP Sodium 2,4,5-trichlorophenate

NHL Non-Hodgkin's lymphoma

NIEHS National Institute of Environmental Health Sciences

NIOSH National Institute for Occupational Safety and Health

NK Natural killer

NOAEL No-observable-adverse-effect level

NOEL No-observed-effect level

NTP National Toxicology Program

OCDD Octachlorodibenzo-p-dioxin

OCDF Octachlorodibenzofuran

OR Odds ratio

OVX Ovariectomized

PAA Phenoxyacetic acid

PAH Polyaromatic hydrocarbon

PBA Phenoxybutyric acid

PBB Polybrominated biphenyl

PBF Percent body fat

PBL Peripheral blood lymphocytes

PB-PK Physiologically based pharmacokinetic

PCB Polychlorinated biphenyl

PCBA Phenoxybutyric acid

PCDD Polychlorinated dibenzodioxin

PCDF Polychlorinated dibenzofuran

PCP Pentachlorophenol

PCPA Parachlorophenoxyacetic acid

PCQ Quaterphenyl

PCT Porphyria cutanea tarda

PeCDD Pentachlorinated dibenzo-p-dioxin

PeCDF Pentachlorinated dibenzo-p-dioxin

PEPCK Phosphoenol pyruvate carboxykinase

PFC Plaque-forming cell

PGE₂ Prostaglandin E₂

PGF_2a Prostaglandin F_2a

PGST Placental glutathione-S-transferase

PGT Placental glutathione transferase

PHA Phytohemagglutinin

PIQ Performance IQ

PKC Protein kinase C

PNS Peripheral nervous system

POMS Profile of Mood States

ppb Parts per billion

ppm Parts per million

ppt Parts per trillion

PRR Prevalence risk ratio

PWM Pokeweed mitogen

RNA Ribonucleic acid

RR Relative risk

SAR Structure-activity relationships

SB-IQ Standford Binet IQ

SCL-90-R Self-Report Symptom Checklist-90-Revised

SD Standard deviation

SE Standard error

SEA Southeast Asia

SGOT Serum glutamic oxaloacetic transaminase

SGPT Serum glutamic pyruvic transaminase

SIR Standard incidence ratio

SMR Standardized mortality ratio

SRBC Sheep erythrocytes (red blood cells)

STS Soft tissue sarcoma

t_½ Half-time

TBB Tetrabromobiphenyl

TBDD Tetrabrominated dibenzo-p-dioxin

TBDF Tetrabrominated dibenzo-p-furan

TBG Thyroxine-binding globulin

TBP Thyroxine-binding protein

TCAOB Tetrachloroazoxybenzene

TCB Tetrachlorobiphenyl

TCDD Tetrachlorodibenzo-p-dioxin

TCDF Tetrachlorodibenzofuran

TCP Trichlorophenol

TEF Toxic equivalency factors

TEQ Toxic equivalents

TGF Thyroid growth factor

TI T helper cell independent

TNF Tumor necrosis factor

tPA Tissue plasminogen activator

TPA Tetradecanoyl phorbol acetate

TSH Thyroid-stimulating hormone

TT Tetanus toxoid

TTR Transthyretrin

TxB₂ Thromboxane B₂

UDP Uridine diphosphate

UDPGT UDP-glucuronosyltransferase

URO-D Uroporphyrinogen decarboxylase

VIQ Verbal IQ

VLDL Very low density lipoprotein

v/v Volume per volume

w/w Weight by weight

WAIS Wechsler Adult Intelligence Scale

WISC-R Wechsler Intelligence Scale for Children, Revised

PREFACE

In April 1991, the U.S. Environmental Protection Agency (EPA) announced that it would conduct a scientific reassessment of the health risks of exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and chemically similar compounds collectively known as dioxin. The EPA has undertaken this task in response to emerging scientific knowledge of the biological, human health, and environmental effects of dioxin. Significant advances have occurred in the scientific understanding of mechanisms of dioxin toxicity, of the carcinogenic and other adverse health effects of dioxin in people, of the pathways to human exposure, and of the toxic effects of dioxin to the environment.

In 1985 and 1988, the Agency prepared assessments of the human health risks from environmental exposures to dioxin. Also, in 1988, a draft exposure document was prepared that presented procedures for conducting site-specific exposure assessments to dioxin-like compounds. These assessments were reviewed by the Agency's Science Advisory Board (SAB). At the time of the 1988 assessments, there was general agreement within the scientific community that there could be a substantial improvement over the existing approach to analyzing dose response, but there was no consensus as to a more biologically defensible methodology. The Agency was asked to explore the development of such a method. The current reassessment activities are in response to this request.

The scientific reassessment of dioxin consists of five activities:

1. Update and revision of the health assessment document for dioxin.

2. Laboratory research in support of the dose-response model.

3. Development of a biologically based dose-response model for dioxin.

4. Update and revision of the dioxin exposure assessment document.

5. Research to characterize ecological risks in aquatic ecosystems.

The first four activities have resulted in two draft documents (the health assessment document and exposure document) for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. These companion documents, which form the basis for the Agency's reassessment of dioxin, have been used in the development of the risk characterization chapter that follows the health assessment. The process for developing these documents consisted of three phases which are outlined in later paragraphs.

The fifth activity, which is in progress at EPA's Environmental Research Laboratory in Duluth, Minnesota, involves characterizing ecological risks in aquatic ecosystems from exposure to dioxins. Research efforts are focused on the study of organisms in aquatic food webs to identify the effects of dioxin exposure that are likely to result in significant population impacts. A report titled, Interim Report on Data and Methods for the Assessment of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) Risks to Aquatic Organisms and Associated Wildlife (EPA/600/R-93/055), was published in April 1993. This report will serve as a background document for assessing dioxin-related ecological risks. Ultimately, these data will support the development of aquatic life criteria which will aid in the implementation of the Clean Water Act.

The EPA had endeavored to make each phase of the current reassessment of dioxin an open and participatory effort. On November 15, 1991, and April 28, 1992, public meetings were held to inform the public of the Agency's plans and activities for the reassessment, to hear and receive public comments and reviews of the proposed plans, and to receive any current, scientifically relevant information.

In the Fall of 1992, the Agency convened two peer-review workshops to review draft documents related to EPA's scientific reassessment of the health effects of dioxin. The first workshop was held September 10 and 11, 1992, to review a draft exposure assessment titled, Estimating Exposures to Dioxin-Like Compounds. The second workshop was held September 22-25, 1992, to review eight chapters of a future draft Health Assessment Document for 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and Related Compounds. Peer-reviewers were also asked to identify issues to be incorporated into the risk characterization, which was under development.

In the Fall of 1993, a third peer-review workshop was held on September 7 and 8, 1993, to review a draft of the revised and expanded Epidemiology and Human Data Chapter, which also would be part of the future health assessment document. The revised chapter provided an evaluation of the scientific quality and strength of the epidemiology data in the evaluation of toxic health effects, both cancer and noncancer, from exposure to dioxin, with an emphasis on the specific congener, 2,3,7,8-TCDD.

As mentioned previously, completion of the health assessment and exposure documents involves three phases: Phase 1 involved drafting state-of-the-science chapters and a dose-response model for the health assessment document, expanding the exposure document to address dioxin related compounds, and conducting peer review workshops by panels of experts. This phase has been completed.

Phase 2, preparation of the risk characterization, began during the September 1992 workshops with discussions by the peer-review panels and formulation of points to be carried forward into the risk characterization. Following the September 1993 workshop, this work was completed and was incorporated as Chapter 9 of the draft health assessment document. This phase has been completed.

Phase 3 is currently underway. It includes making External Review Drafts of both the health assessment document and the exposure document available for public review and comment.

Following the public comment period, the Agency's Science Advisory Board (SAB) will review the draft documents in public session. Assuming that public and SAB comments are positive, the draft documents will be revised, and final documents will be issued.

The Health Assessment Document for 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and Related Compounds has been prepared under the direction of the Office of Health and Environmental Assessment, Office of Research and Development, which is responsible for the report's scientific accuracy and conclusions. A comprehensive search of the scientific literature for this document varies somewhat by chapter but is, in general, complete through January 1994.

AUTHORS, CONTRIBUTORS, AND REVIEWERS

This draft Health Assessment Document was prepared under the leadership and direction of the Office of Health and Environmental Assessment (OHEA) within EPA's Office of Research and Development (ORD). The overall coordination and leadership of the activities associated with EPA's reassessment of dioxin, which includes the development of this draft document, is Dr. William H. Farland, Director of OHEA.

Authors and chapter managers for the Health Assessment Document are listed below. Early drafts of some chapters were prepared by Syracuse Research Corporation under EPA Contract No. 68-CO-0043. Other chapters were authored totally or in part by scientists within EPA and other agencies within the federal government. The ORD chapter managers were responsible for providing oversight, review, and technical editing of successive drafts, and incorporating comments from reviewers to develop a comprehensive and consistent document. In some cases, the chapter managers also authored sections or parts of the chapter.

REVIEWERS

Early drafts of Chapters 1 through 8 of this health assessment were reviewed by a panel of experts at a peer-review workshop held September 22-25, 1992. Members of the Peer Review Panel for this workshop were as follows:

Edward Bresnick Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH

M. Judith Charles Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC

Michael Denison Department of Biochemistry, Michigan State University, East Lansing, MI

Phillip Enterline Emeritus Professor of Biostatistics, University of Pittsburgh, Pittsburgh, PA

Mark Feeley Toxicity Evaluation Division, Bureau of Chemical Safety, Health, and Welfare, Ottawa, Ontario, Canada

Thomas A. Gasiewicz Department of Biophysics, University of Rochester,

Rochester, NY

James Gillette Laboratory of Chemical Pharmacology, National Heart, Lung, and Blood Institute, National Institutes of Health,

Bethesda, MD

Claude Hughes Duke University Medical Center, Durham, NC

Curtis D. Klaassen Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS

Daniel Krewski Biostatistics and Computer Applications, Environmental Health Centre, Ottawa, Ontario, Canada

Suresh Moolgavkar Professor of Epidemiology and Biostatistics, The Fred Hutchinson Cancer Research Center, Seattle, WA

Jay Silkworth Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany, NY

Thomas Webster Center for the Biology of Natural Systems, Queens College, City University of New York, Flushing, NY

On September 7 and 8, 1993, a peer-review workshop was held to review a greatly revised and expanded draft Chapter 7 (Epidemiology/ Human Data). Members of the Peer Review Panel for this workshop are as follows:

John Andrews Associate Administrator for Science, Agency for Toxic Substances and Disease Registry, Atlanta, GA

Germaine Buck Clinical Assistant Professor, Department of Social and Preventive Medicine, State University of New York, Buffalo, NY

Harvey Checkoway Professor, Department of Environmental Health, University of Washington, Seattle, WA

Phillip Enterline Emeritus Professor of Biostatistics, University of Pittsburgh, Pittsburgh, PA

M. Gerald Ott Director of Epidemiology, BASF Corporation, Parsippany, NJ

Allan H. Smith Professor of Epidemiology, University of California, Berkeley, CA

Anne Sweeney Assistant Professor of Epidemiology, School of Public Health, University of Texas, Houston, TX

Karen Webb Medical Director, HealthLine Corporation Health, St. Louis, MO

In addition, during the development of this draft Health Assessment Document, selected sections, chapters, or volumes were peer reviewed by scientists and experts within EPA and other federal agencies, as well as by experts in academia and the private sector.

A draft of Chapter 9, the risk characterization, was reviewed by an interagency workgroup comprising scientists from the following agencies of the federal government:

Department of Agriculture

Department of Defense

Department of Health and Human Services^*

Department of Labor (Occupational Safety and Health Administration)

Department of Veterans Affairs

Executive Office of the President

Office of Science and Technology Policy

Council of Economic Advisors