dioxins: are we all at risk? linda. s. birnbaum, phd, dabt national health and environmental effects...
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DIOXINS: ARE WE ALL AT RISK?
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
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?
• 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
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
Bases for Standard Setting
• Science = Risk Assessment
• Economic
• Legal
• Social
• Political
• Technological
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”
• Prototype for family of structurally related compounds
• Common mechanism of action
• Common spectrum of biological responses
• Environmentally and biologically persistent
(Basis for TEQ approach)
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
““Dioxins”Dioxins”Polyhalogenated Dibenzo-p-dioxins and furans
Never produced intentionallyUnwanted byproducts of industrial and combustion
processes
Polyhalogenated Biphenyls, Naphthalenes, Azo/azoxybenzenes
Commercially producedMajor industrial chemicals
Only a few chemicals from these large classes have dioxin-like toxicity!
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
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
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
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)
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
33’44’5-PeCB(126) 0.1 95.0 15
23’44’5-PeCB(118) .0001 35.7 6.5
233’44’5-HCB(156 .0005 64.3 12
Contribution of 7 88.5
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
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
Reentrainment
SOURCESTRANSPORT
DEPOSITION
FOODSUPPLY
RunoffErosion
Combustion
Industrial Processes
DirectDischarge
Sources and Pathways to Human Exposures
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
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
65 pg TEQDFP-WHO98/day
21%16%
19%
14%
5%
4%
7%
6%
1%
Soil ingestionSoil dermal contact
Freshwater fish andshellfish
Marine fish and shellfish
Inhalation
Milk
Dairy
Eggs
Beef
Pork
Poultry
Other meats Vegetable fat
U.S. Adult Average Daily Intake of CDDs/CDFs/ Dioxin - Like PCBs
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
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
Mean and Range of TEQs By Age Group
0
5
10
15
20
25
30
35
40
12-19 20-39 40-59 60+
Age Group (Number of Pools)
TE
Q
4.5
6.2
9.0
(17) (13) (10) (11)
13.7
10
6.6
23.5
19.3
15.8
34.4
25.6
41.7
12-19 20-39 40-59 60+
Age Group (years)
(Needham, 2005)
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
Effects of Dioxins
• Multiple Effects• Multiple Tissues• Both Sexes• Multiple Species• Throughout
Vertebrata
• Molecular/ Biochemical
• Metabolic/ Cellular
• Tissue/Organ• Growth/
Differentiation• Wasting/Death
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
Adverse Effects in Animals
Wildlife and Domestic Wildlife and Domestic AnimalsAnimals
Great Lakes fish, birds, mammals
Baltic seals, Dolphins
(Effects observed at environmental levels)
Cows, Horses, Sheep, Chickens
(Effects observed during poisoning episodes)
Laboratory AnimalsLaboratory Animals
Fish
Amphibians
Turtles
Birds
Rats
Mice
Guinea Pigs
Hamsters
Rabbits
Dogs
Non-human primates
Developmental/Reproductive/Immunological EffectsEndocrine/Multiple Organ-System Effects
Nearly All Vertebrate Animals Nearly All Vertebrate Animals
Examined Respond to DioxinsExamined 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!
Unfortunate Poisoning Episodes
• PCBs/PCDFs Japan (“Yusho”) Taiwan (“Yucheng”)
• PBBs/PBNs Michigan
• TCDD Seveso, Italy Vienna, Austria Ukraine
• Clear Evidence of Adverse Health Effects
Viktor Yushchenko(Before and After)
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
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
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
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
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
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
Are Health Effects Occurring in the General
Population?
• What Effects?
• Are they Adverse?
• Who are most Susceptible?
• Can we Predict the Future?
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
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.
Key to Epidemiology Studies on Dioxins
• Multiple chemicals
• EVERYONE has Some Exposure
• Approach to Consider Distribution of Populations Altered Sensitivity/Susceptibility
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
SummarySummary
• 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
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
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
Thank-you
• To all of my students and to my colleagues, world-wide