DIOXINS: ARE WE ALL AT RISK?

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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

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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

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2,3,7,8-Tetrachlorodibenzo-p-dioxinThe 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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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 1st US EPA health assessment of TCDD
• 1991 NIOSH cancer mortality study of US workers
• 1999 Belgium dioxin poisoning Viennese
  poisoning
• 2004 Viktor Yushenko

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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)

• 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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7 Congeners Responsible for Most of TEQ
Concentration in US Serum Samples (Needham, 2005)
Congener TEFs TEQ of group of whole TEQ
2378-TCDD 1.0 14.1 7
12378-PeCDD 1.0 43.1 21
123678-HxCDD 0.1 31.6 16
23478-PeCDF 0.5 75.8 11
33445-PeCB(126) 0.1 95.0 15
23445-PeCB(118) .0001 35.7 6.5
233445-HCB(156 .0005 64.3 12
Contribution of 7 88.5
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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

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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

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

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How are People Exposed?

• Dioxins are everywhere
• Majority of exposure (gt95) 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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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?

• 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
12-19 20-39 40-59 60 Age Group
(years) (Needham, 2005)
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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

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Effects of Dioxins

• Molecular/ Biochemical
• Metabolic/ Cellular
• Tissue/Organ
• Growth/ Differentiation
• Wasting/Death

• Multiple Effects
• Multiple Tissues
• Both Sexes
• Multiple Species
• Throughout Vertebrata

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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

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Adverse Effects in Animals
Developmental/Reproductive/Immunological
Effects Endocrine/Multiple Organ-System Effects

• 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

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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!

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Unfortunate Poisoning Episodes

• 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(Before and After)
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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 Development

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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

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HEALTH EFFECTS IN HIGHLY EXPOSED POPULATIONS

• Exposures Are Not As High As We Once
  Thought10-100X 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

• 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

• 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

• 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?

• 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!

• 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!

• 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

• Multiple chemicals
• EVERYONE has Some Exposure
• Approach to Consider
• Distribution of Populations
• Altered Sensitivity/Susceptibility

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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

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Summary

• Dioxins affect multiple tissues and organ systems
  
• The embryo/fetus may be especially susceptible
• Dioxins result in a many different 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

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Whats 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

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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

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Thank-you

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