DIOXINS: ARE WE ALL AT RISK? Linda. S. Birnbaum, PhD, DABT National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency.

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