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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. What is Environmental Risk?.

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Dioxins are we all at risk l.jpg

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


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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


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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


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Bases for Standard Setting

  • Science = Risk Assessment

  • Economic

  • Legal

  • Social

  • Political

  • Technological


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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


2 3 7 8 tetrachlorodibenzo p dioxin the most toxic man made compound l.jpg
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)


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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???


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“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!


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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


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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


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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


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Toxic Equivalency Factors (TEFs) Striking Structural Similarities

  • 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)



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Major Past Sources of Dioxins Serum Samples (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


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Recently Identified Sources Serum Samples (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


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Sources and Pathways to Human Exposures Serum Samples

SOURCES

TRANSPORT

FOOD

SUPPLY

Reentrainment

DEPOSITION

Industrial

Processes

Combustion

Runoff

Erosion

Direct

Discharge


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How do Dioxins Move in the Environment Serum Samples

  • 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


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How are People Exposed? Serum Samples

  • 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


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Soil ingestion Serum Samples

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


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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


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Why do the Body Burdens Increase Over Time? Affect You

  • 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


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Mean and Range of TEQs By Age Group Affect You

12-19 20-39 40-59 60+

Age Group (years)

(Needham, 2005)


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National Dioxin/PCB Exposure Trends Affect You

  • 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


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Multiple Effects Affect You

Multiple Tissues

Both Sexes

Multiple Species

Throughout Vertebrata

Molecular/ Biochemical

Metabolic/ Cellular

Tissue/Organ

Growth/ Differentiation

Wasting/Death

Effects of Dioxins


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Dioxin Effects Require the “Dioxin Receptor” Affect You

  • 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


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Wildlife and Domestic Animals Affect You

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


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Nearly All Vertebrate Animals Examined Respond to Dioxins Affect YouWhat 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!


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Unfortunate Poisoning Episodes Affect You

  • PCBs/PCDFs

    • Japan (“Yusho”)

    • Taiwan (“Yucheng”)

  • PBBs/PBNs

    • Michigan

  • TCDD

    • Seveso, Italy

    • Vienna, Austria

    • Ukraine

  • Clear Evidence of Adverse Health Effects


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Viktor Yushchenko Affect You(Before and After)


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Cardiovascular Disease Affect You

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


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Chloracne Affect YouClassic 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


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HEALTH EFFECTS IN “HIGHLY” EXPOSED POPULATIONS Affect You

  • 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


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EFFECTS SEEN IN ADULTS AT BACKGROUND EXPOSURES Affect You

  • 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


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HEALTH OUTCOMES IN PRENATALLY-EXPOSED CHILDREN Affect You

  • 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


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Dioxin Effects of Greatest Concern Affect You

  • 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


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Are Health Effects Occurring in the General Population? Affect You

  • What Effects?

  • Are they Adverse?

  • Who are most Susceptible?

  • Can we Predict the Future?


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What You See Depends on How and Where you Look! Affect You

  • 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


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Benefits of Nursing Outweigh the Risks! Affect You

  • 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.


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Key to Epidemiology Studies on Dioxins Affect You

  • Multiple chemicals

  • EVERYONE has Some Exposure

  • Approach to Consider

    • Distribution of Populations

    • Altered Sensitivity/Susceptibility


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Dose/Response Relationships Affect You

  • 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


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Summary Affect You

  • 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


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What’s the Good News Nationally? Affect You

  • 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


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PUBLIC HEALTH POSITION Affect You

  • 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


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Thank-you Affect You

  • To all of my students and to my colleagues, world-wide


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