DIOXINS: ARE WE ALL AT RISK?

1. DIOXINS: ARE WE ALL AT RISK? Linda. S. Birnbaum, PhD, DABT National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency Research Triangle Park, NC Midland, MI – July 12, 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: Scientific 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

4. Bases for Standard Setting • Science = Risk Assessment • Economic • Legal • Social • Political • Technological

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 • Never produced intentionally • Unwanted byproducts of industrial and combustion processes

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. 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 – 1st US EPA health assessment of TCDD 1991 – NIOSH cancer mortality study of US workers 1999 – Belgium “dioxin” poisoning; Viennese poisoning 2004 – Viktor Yushenko Why the Interest in Dioxins???

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 Only a few chemicals from these large classes have dioxin-like toxicity!

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: Many Chemicals with Unknown Toxicity but with Striking Structural Similarities • 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) • Relative Potency Ranking Scheme • 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)

13. 7 Congeners Responsible for Most of TEQ Concentration in US Serum Samples (Needham, 2005)

14. Major Past Sources of Dioxins (20th Century Problem – Addressed by Regulations) • 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(Minor Compared to those in 20th Century) • Open Burning of Household Waste • Uncontrolled Combustion • Forest Fires and Volcanoes • Metal Refining • Reservoirs – contaminated soils and sediments from past releases

16. Sources and Pathways to Human Exposures SOURCES TRANSPORT FOOD SUPPLY Reentrainment DEPOSITION Industrial Processes Combustion Runoff Erosion Direct Discharge

17. 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

18. How are People Exposed? • Dioxins are everywhere • 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 • Local elevated sources –fish/wildgame advisories, other untested foods

19. Soil ingestion Vegetable fat Soil dermal contact Other meats Poultry Freshwaterfish and shellfish 6% Pork 5% 19% Marine fish and shellfish Beef 7% 14% 1% Inhalation 4% 16% Eggs 21% Milk Dairy U.S. Adult Average Daily Intake of CDDs/CDFs/ Dioxin - Like PCBs 65 pg TEQDFP-WHO98/day

20. How You are Exposed Makes Little Difference in How Dioxins Affect You • Dioxins are well absorbed from the GI tract and lungs • Skin absorption is limited and slow • Dioxins primarily build up in the liver and fat • Dioxins are primarily eliminated after metabolism, which is VERY slow

21. 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-Longer Half-Life • Half-Life is Dose-Dependent • Bioaccumulation • Due to Persistence in Animal tissues • Animals Higher in Food Chain have Higher Concentrations • Older Organisms have Higher Body Burdens than Young

22. Mean and Range of TEQs By Age Group 12-19 20-39 40-59 60+ Age Group (years) (Needham, 2005)

23. National 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  25 ppt TEQ lipid (~5ng/kg ww) • Decrease continues • Success of Regulatory Agenda

24. Multiple Effects Multiple Tissues Both Sexes Multiple Species Throughout Vertebrata Molecular/ Biochemical Metabolic/ Cellular Tissue/Organ Growth/ Differentiation Wasting/Death Effects of Dioxins

25. Dioxin Effects Require the “Dioxin Receptor” • Dioxin Receptor = “Lock”; Dioxin = Key • 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

26. Wildlife and Domestic Animals Great Lakes fish, birds, mammals Baltic seals, Dolphins (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 Adverse Effects in Animals Developmental/Reproductive/Immunological Effects Endocrine/Multiple Organ-System Effects

27. Nearly All Vertebrate Animals Examined Respond to DioxinsWhat 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!

28. Unfortunate Poisoning Episodes • PCBs/PCDFs • Japan (“Yusho”) • Taiwan (“Yucheng”) • PBBs/PBNs • Michigan • TCDD • Seveso, Italy • Vienna, Austria • Ukraine • Clear Evidence of Adverse Health Effects

29. Viktor Yushchenko(Before and After)

30. 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 Development Dioxins’ Effects in People

31. Chloracne Classic Toxic Effect • “Hallmark of Dioxin Toxicity” • High-Dose Response • Genetic Susceptibility • Occurs in People, Monkeys, Cows, Rabbits, and Mice • Associated with multiple problems with skin, teeth, hair and nails following prenatal exposure

32. 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

33. 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???? • Human Epidemiology and Rodent Studies show similar Body Burdens and Cancer Potency Values

34. 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

35. 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 • Subclinical Effects are Hard to Measure

36. Are Health Effects Occurring in the General Population? • What Effects? • Are they Adverse? • Who are most Susceptible? • Can we Predict the Future?

37. What You See Depends on How and Where you Look! • Subclinical Effects Can have Population Impacts • Think of the “LEAD” Example • “Second Generation” Effects of Dioxins • Exposed Mothers Can Result in Developmental Neurological, Reproductive and Immune Effects in Children • Exposed Fathers Can Result in Fewer Boys

38. 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.

39. Key to Epidemiology Studies on Dioxins • Multiple chemicals • EVERYONE has Some Exposure • Approach to Consider • Distribution of Populations • Altered Sensitivity/Susceptibility

40. Dose/Response Relationships • Biochemical Effects Occur in Animals Within the Range of General Population Body Burdens • Adverse Effects Occur in Animals Within 10X of Current National Average Body Burdens • Endometriosis and Immune Suppression in Adults • Developmental Problems – learning, immune, reproductive, teeth • Adverse Effects Occur Within 100X of National Average Body Burdens • Porphyrin Accumulation • Cancer

41. Summary • Dioxins affect multiple tissues and organ systems • The embryo/fetus may be especially susceptible • Dioxins result in a many differentnon-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

42. What’s the Good News Nationally? • Regulations have had the desired results • Levels are coming down in the environment • Levels are coming down in people • Bad News: Still need to Reduce Reservoir Sources

43. 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  Decreased Exposure

44. Thank-you • To all of my students and to my colleagues, world-wide