1	DIOXINS: ARE WE ALL AT RISK? Linda. S. Birnbaum, PhD, DABT NHEERL/US EPA Research Triangle Park, NC Saginaw, MI – April 13, 2005
2	What is Environmental Risk? The likelihood of injury, disease, or death resulting from human exposure to a potential environmental hazard Human Health Risk Assessment The process by which we evaluate the likelihood and nature of public health effects of environmental pollution
3	Risk Assessment: Basis for Standard Setting Exposure Assessment Who? What? When? Where? Why? How? Hazard Identification Potential for a problem Dose/Response Assessment Relationship between amount of exposure and observed effects Risk Characterization Critical evaluation of all the data and uncertainties
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5	What Are “Dioxins”? A family of structurally related chemicals which have a common mechanism of action and induce a common spectrum of biological responses
6	2,3,7,8-Tetrachlorodibenzo-p-dioxin “The Most Toxic Man-Made Compound” Prototype for family of structurally related compounds Common mechanism of action Common spectrum of biological responses Environmentally and biologically persistent (Basis for TEQ approach)
7	Why the Interest in Dioxins??? 1899 – Chloracne Characterized 1929 – PCBs produced commercially 1947 – “X” Disease in cattle 1949 – Nitro, West Virginia 1957 – Chick Edema Disease; TCDD identified in TCPs 1962-1970 – Agent Orange use in Southeast Asia 1968 – “Yusho” oil disease 1971 – Times Beach; TCDD causes birth defects in mice 1973 – PBB contamination in Michigan 1976 – Seveso, Italy 1978 – Kociba rat cancer study 1979 – “Yucheng” oil dieases 1981 – Capacitor fire in Binghamton, NY 1985 – 1^st US EPA health assessment of TCDD 1991 – NIOSH cancer mortality study of US workers 1999 – Belgium dioxin poisoning; Viennese poisoning
8	“Dioxins” Polyhalogenated Dibenzo-p-dioxins and furans Never produced intentionally Unwanted byproducts of industrial and combustion processes Polyhalogenated Biphenyls, Naphthalenes, Azo/azoxybenzenes Commercially produced Major industrial chemicals Limited number of congeners have dioxin-like properties Lateral halogenation > 3 Halogens Chlorinated, brominated, and mixed chloro-bromo congeners
9	PCBs Large Family of Chemicals 209 Possible Congeners Small Subset Are “Dioxins” NEVER have PCBS without Dioxin-like PCBs Majority Have Own, Inherent, Toxicities Multiple, Overlapping, Structural Classes Can Interact Additively, Synergistically, and/or Antagonistically With Dioxins and With Other PCB Congeners
10	TCDD is NEVER Found Alone Complex Mixtures Exist both Environmentally and in Animal and Human Tissues TCDD is only a Small Part of Total Chemical Mass We have the Most Toxicological Information about TCDD
11	Problem: Broad Specturm of Chemicals with Unknown Toxicity but with Striking SAR 3 Regulatory Approaches Treat All as Equi-toxic to TCDD Ignore all those lacking Definitive Toxicological Data Develop a Relative Potency Ranking Scheme which utilizes Existing Data and Expert Scientific Judgment
12	Toxic Equivalency Factors (TEFs) Developed for Risk Assessment Interpret Complex Database Derived from Analysis of Samples Containing Mixtures of Dioxin-like Chemicals Express Quantitatively the Toxicity of a Chemical in terms of an Equivalent concentration of TCDD (Relative Potency) ∑([Chemical] x TEF)_{PCDD/PCDF/PCB}=TEQ
13	Five Compounds Make up about 80+% of the Total TEQ in Human Tissues Four of 17 Toxic PCDD/PCDF Congeners 2,3,7,8-TCDD 1,2,4,7,8,-PeCDD 1,2,3,6,7,8-HxCDD 2,3,4,7,8-PeCDF One of the 12 Toxic PCBs PCB 126
14	Major Past Sources of Dioxins (20^th Century Problem) Chloralkali Facilities Chlorinated herbicide and biocide Production Leaded Gasoline Municipal, Medical, and Hazardous Waste Incineration Chlorine Bleaching of Paper and Pulp Products
15	Recently Identified Sources Open Burning of Household Waste Uncontrolled Combustion Forest Fires and Volcanos Metal Refining
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18	How do Dioxins Move in the Environment If emitted into air, undergo atmospheric transport and deposition on land or water If emitted into water, bind to sediment Recycle in environment Bioaccumulate up the food chain Resistance to physical, chemical, and biological degradation
19	How are People Exposed? Dioxins are omnipresent Majority of exposure (>95%) is via microcontamination of food Meat, fish, dairy Sensitive Subpopulations with High Exposure Subsistence Fishers and Hunters Nursing Infants Occupational Workers Oral, dermal, and inhalation exposures
20	U.S. Adult Average Daily Intake of CDDs/CDFs/ Dioxin - Like PCBs
21	How You are Exposed Makes Little Difference Dioxins are well absorbed from the GI tract and lungs Skin absorption is limited and slow Dioxins primarily lodge in the liver and fat Dioxins are primarily eliminated after metabolism, which is VERY slow
22	Why do the Body Burdens Increase Over Time? Persistence Resistance to Biological, Chemical, and Physical Degradation Long Half-Lives in Animals and People More Body Fat-àLonger Half-Life Half-Life is Dose-Dependent Bioaccumulation Due to Persistence in Animal tissues Higher Trophic Organisms have Higher Concentrations Older Organisms have Higher Body Burdens than Young
23	Half-Life Varies with Body Burden and Body Composition (Emond et al., 2004)
24	Background Serum Levels in the United States 1995 - 1997 (CDC, 2000)
25	Dioxin/PCB Exposure Trends Environmental Levels Peaked in late ’60s/early ’70s – decline since confirmed by sediment data Decline also supported by Emissions Inventory – shows significant decrease from ’87 to ‘;95 (~80%) Human tissue data suggest mid-90s levels approximately half of 1980 55 à 25 ppt TEQ lipid (~5ng/kg ww) Decrease continues Success of Regulatory Agenda
26	Dioxin TEQ Levels (PCDDs/PCDFs) in U.S. Residents Have Fallen from 1960s
27	Mean and Range of TEQs By Age Group
28	Adverse Effects Wildlife and Domestic Animals Great Lakes fish, birds, mammals Baltic seals, Dolphins Developmental/reproductive effects Immunological effects Effects observed at environmental levels Cows, Horses, Sheep, Chickens Effects observed during poisoning episodes Laboratory Animals Fish Amphibians Turtles Birds Rats Mice Guinea Pigs Hamsters Rabbits Dogs Non-human primates
29	Effects of Dioxins BIOCHEMICAL Induction of Drug Metabolizing Genes Cyp1A1/2, 1B1; GST; UDPGT; ALDH… Induction of Proliferation Genes Induction of Cytokines TNF, IL-6, IL-1_β Induction of Oxidative Stress Induction of Growth factors/receptors TGFs, EGFR… Modulation of Hormones/Receptors TOXIC LethalityWasting Gonadal/Lymphoid Atrophy Hyperplasia/Metaplasia Endocrine Disruption Carcinogenicity Repro/Developmental toxicity Functional Devpt. Toxicity Dermal Toxicity Immunotoxicity Neurotoxicity Hepatic Toxicity Cardiovascular Toxicity Bone/Teeth Toxicity
30	Effects of Dioxins Multiple Effects Multiple Tissues Both Sexes Multiple Species Throughout Vertebrata Molecular/ Biochemical Metabolic/ Cellular Tissue/Organ Growth/ Differentiation Wasting/Death
31	Dioxin Effects Require the “Ah Receptor” Highly conserved protein throughout Vertebrates Related Proteins in Invertebrates Member of Growing Family of Key Regulatory Proteins Development, Aging, Hypoxia, Daily Rhythms Necessary, but Not Sufficient, for All of the Effects of Dioxins
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33	Nearly All Vertebrate Animals Examined Respond to Dioxins What about People? People have the Ah Receptor and the other members of its signaling complex. Human cells and organs in culture respond to Dioxins. Biochemical Responses have been Measured in Exposed People. Subtle effects have been detected in the General Population. Adverse Effects have been seen in highly exposed populations. THE REAL QUESTION IS NOT CAN PEOPLE RESPOND TO DIOXINS, BUT AT WHAT DOSES THEY RESPOND!
34	Unfortunate Poisoning Episodes PCBs/PCDFs Japan (“Yusho”) Taiwan (“Yucheng”) PBBs/PBNs Michigan TCDD Seveso, Italy Vienna, Austria Ukraine Clear Evidence of Adverse Health Effects
35	Viktor Yushchenko (Before and After)
36	Dioxins’ Effects in People Cardiovascular Disease Diabetes Cancer Porphyria Endometriosis Decreased Testosterone Chloracne Biochemical Enzyme Induction Receptor Changes Developmental Thyroid Status Immune Status Neurobehavior Cognition Dentition Reproductive Effects Altered Sex Ratio Delayed Breast Devpt
37	Chloracne Classic Toxic Effect “Hallmark of Dioxin Toxicity” High-Dose Response Genetic Polymorphism Occurs in People, Monkeys, Cows, Rabbits, and Mice Associated with multiple problems with skin, teeth, hair and nails following prenatal exposure
38	HEALTH EFFECTS IN “HIGHLY” EXPOSED POPULATIONS Exposures Are Not As High As We Once Thought:10-100X Background (“Ambient”) Occupational Populations Chloracne, Cancer, Heart Disease, Diabetes, ... Poisoning Episodes Chloracne. Cancer, Heart Disease, Diabetes, Reproductive, Developmental, Hormonal and Immune Effects
39	Peak Dioxin Body Burden Levels in Background Populations and Epidemiological Cohorts
40	EFFECTS SEEN IN ADULTS AT BACKGROUND EXPOSURES Type II Diabetes Decreased Glucose Tolerance Hyperinsulinemia Mechanistic Plausibility Endometriosis Hormone Disruption and Immune Suppression Animal Models Cancer????
41	All Cancer ED₀₁ and Slope Factor Calculations from Published Studies
42	HEALTH OUTCOMES IN PRENATALLY-EXPOSED CHILDREN Studies in the US (Michigan, North Carolina, Lake Oswego); Japan; the Netherlands; Sweden; Finland Low Birthweight Cognitive and Behavioral Impairment Immune System Effects Hormonal Changes (Thyroid Effects) Altered Dentition
43	Dioxin Effects of Greatest Concern Developmental Alterations Occurring at “High End” of Background Population Decreased neuro-optimality and IQ Altered Behavior Altered Immune System Altered Hormone Systems Altered Growth
44	Are Health Effects Occurring in the General Population? What Effects? Are they Adverse? Who are most Susceptible? Can we Predict the Future?
45	What You See Depends on How and Where you Look! Subclinical Effects Can have Population Impacts Think of the “LEAD” Example “Second Generation” Effects Exposed Mothers Can Result in Developmental Neurological, Reproductive and Immune Effects in Children Exposed Fathers Can Result in Fewer Boys
46	Benefits of Nursing Outweigh the Risks! Majority, if not all, of the effects are associated with in utero exposure. Nursing infants do better than those who are bottle-fed (Given the same level of prenatal exposure). Nursing leads to greater infantile exposure, but this does not have long term effects on the adult body burden.
47	Key to Epidemiology Studies on Dioxins Multiple chemicals EVERYONE has Some Exposure Approach to Consider Distribution of Populations Altered Sensitivity/Susceptibility
48	Body Burdens Associated with Effects in Animals
49	Dose/Response Relationships Biochemical Effects Occur in Animals Within Range of General Population Body Burdens Within 10X of Current Body Burdens Endometriosis and Immune Suppression in Adults Developmental Problems – learning, immune, reproductive, teeth Within 100X of Body Burdens Porphyrin Accumulation Cancer
50	Integrating Exposure and Effects Avg. Daily Intake = 1-2 pg TEQ/kg/day WHO TDI (1998) = 1-4 pg TEQ/kg/day
51	Margin of Exposure Ratio of Body Burden where Effects occur to Background Body Burden No MOE for Biochemical Effects MOE <10 for clearly Adverse Non-Cancer Responses MOE ~10-100 for Cancer Excess Risk ~1/1000
52	Integrating Exposure and Effects Dioxins affect multiple tissues and organ systems The embryo/fetus may be especially susceptible Dioxins result in a plethora of non-cancer effects Dioxins are human carcinogens Dose/Response Assessments, both empirical and modeling, demonstrate that effects may be occurring in the high end of the general population
53	What’s the Good News? Regulations have had the desired results Levels are coming down in the environment Levels are coming down in people
54	PUBLIC HEALTH POSITION Current Levels in the Environment Are Associated With Body Burdens in the High End of the General Population Which Are at or Near the Point Where Effects May Be Occurring. Continue to Reduce Sources and Environmental Levels à Decreased Exposure
55	Thank-you To all of my students and to my colleagues, world-wide
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57	What Are Current Human Exposure Levels? Daily exposure in the US, about 1-2 pg dioxins/kg/day Current body burden ~5 ng dioxin/kg body weight ~25 pg dioxins/g fat
58	Environmental Health Risk Assessment How do we identify potential hazards to human health? How do we understand how serious such problems are?
59	We all know that certain things are bad for us…. Cigarette smoke Alcohol Lead Ozone (too much – and too little!)
60	What about other substances in our environment? Gasoline Fumes? Dry Cleaning fluids? Pesticides Wood Smoke Heavy Metals UV Light Etc… should be we concerned?