Transcript DIOXINS: ARE WE ALL AT RISK? Linda. S. Birnbaum, PhD, DABT

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?
• 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”
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!
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
of group 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
Sources and Pathways to Human Exposures
SOURCES
TRANSPORT
Reentrainment
FOOD
SUPPLY
DEPOSITION
Industrial
Processes
Combustion
Direct
Discharge
Runoff
Erosion
16
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
U.S. Adult Average Daily Intake of
CDDs/CDFs/ Dioxin - Like PCBs
65 pg TEQDFP-WHO98/day
Vegetable fat Soil ingestion
Soil dermal contact
Other meats
Poultry
Freshwater fish and
shellfish
6%
Pork
5%
19%
Marine fish and shellfish
Beef
7%
14%
1%
4%
Eggs
16%
21%
Milk
Dairy
Inhalation
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
41.7
40
35
34.4
30
TEQ
25
23.5
20
19.3
15
13.7
9.0
10
5
25.6
15.8
10
6.6
6.2
4.5
0
12-19
(17)
12-19
20-39
(13)
20-39
40-59
(10)
40-59
Age Group (Number of Pools)
Age Group (years)
(Needham, 2005)
60+
(11)
60+
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
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
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!
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
Summary
• Dioxins affect multiple tissues and
organ systems
 The embryo/fetus may be especially
susceptible
• Dioxins result in a many different noncancer 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