Transcript Persistent Contaminants: New Priorities, New Concerns

DIOXINS: ARE WE ALL AT
RISK?
Linda. S. Birnbaum, PhD, DABT
NHEERL/US EPA
Research Triangle Park, NC
Saginaw, MI – April 13, 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: 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
Risk
Assessment
Risk
Management
DoseResponse
Assessment
Actions
Hazard
Risk
Identification
Characterization
Issues
Economics
Exposure
Assessment
Legal
Social
Political
Engineering
None
Public
Information
Ambient
Standards
Control
Devices
Emission
Limitations
Ban
What Are “Dioxins”?
A family of structurally related
chemicals which have a common
mechanism of action and induce a
common spectrum of biological
responses
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
“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
Limited number of congeners have dioxin-like properties
Lateral halogenation
> 3 Halogens
Chlorinated, brominated, and mixed chloro-bromo
congeners
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: Broad Specturm
of Chemicals with
Unknown Toxicity but with
Striking SAR
• 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)
• 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)
• ∑([Chemical] x TEF)PCDD/PCDF/PCB=TEQ
Five Compounds Make up
about 80+% of the Total
TEQ in Human Tissues
• Four of 17 Toxic PCDD/PCDF
Congeners
 2,3,7,8-TCDD
 1,2,4,7,8,-PeCDD
 1,2,3,6,7,8-HxCDD
 2,3,4,7,8-PeCDF
• One of the 12 Toxic PCBs
 PCB 126
Major Past Sources of
Dioxins (20th Century
Problem)
• 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
• Open Burning of Household
Waste
• Uncontrolled Combustion
 Forest Fires and Volcanos
• Metal Refining
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Major US Dioxin Sources
9000.0
8000.0
7000.0
6000.0
5000.0
4000.0
3000.0
2000.0
1000.0
0.0
Sources and Pathways to Human Exposures
SOURCES
TRANSPORT
Reentrainment
DEPOSITION
Industrial
Processes
Combustion
Direct
Discharge
FOOD
SUPPLY
Runoff
Erosion
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 omnipresent
• 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
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
• Dioxins are well absorbed from
the GI tract and lungs
 Skin absorption is limited and slow
• Dioxins primarily lodge 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
Higher Trophic Organisms have Higher
Concentrations
 Older Organisms have Higher Body
Burdens than Young
Half-Life Varies with Body Burden
and Body Composition (Emond et al.,
2004)
250.00
Experimental exposure
Background Human exposure
217.71
209.79
215.88
Occupational exposure
212.75
206.29
203.00
200.00
194.25
171.75
157.67
T1/2 (day)
150.00
114.54
104.17
100.00
61.50
50.00
50.69
6.9% FAT
33.96
27.96
25% FAT
18.63
22.29
13.57
0.00
1.00E-07
1.00E-06
1.00E-05
1.00E-04
1.00E-03
1.00E-02
1.00E-01
Dose ug/kg de BW
1.00E+00
1.00E+01
18.33
10.88
1.00E+02
17.2916.58
9.46 8.71
1.00E+03
Background Serum Levels in the
United States 1995 - 1997 (CDC, 2000)
60
TEQ, pg/g lipid
50
40
30
20
10
0
10
20
30
40
50
Age
60
70
80
90
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
Dioxin TEQ Levels
(PCDDs/PCDFs) in U.S.
Residents Have Fallen
from 1960s
(Lorber, 2002)
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+
Adverse Effects
Wildlife and Domestic
Animals
Great Lakes fish, birds,
mammals
Baltic seals, Dolphins
Developmental/reproductiv
e effects
Immunological effects
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
Effects of Dioxins
BIOCHEMICAL
• Induction of Drug
Metabolizing Genes

Cyp1A1/2, 1B1; GST;
UDPGT; ALDH…
• Induction of Proliferation
Genes
• Induction of Cytokines

TNF, IL-6, IL-1β
• Induction of Oxidative
Stress
• Induction of Growth
factors/receptors

TGFs, EGFR…
• Modulation of
Hormones/Receptors
TOXIC
• LethalityWasting
• Gonadal/Lymphoid
Atrophy
• Hyperplasia/Metaplasia
• Endocrine Disruption
• Carcinogenicity
• Repro/Developmental
toxicity
• Functional Devpt.
Toxicity
• Dermal Toxicity
• Immunotoxicity
• Neurotoxicity
• Hepatic Toxicity
• Cardiovascular Toxicity
• Bone/Teeth Toxicity
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
“Ah Receptor”
• 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
Mechanism of Action
hsp90
AIP,..
Cl O Cl
O Cl
TCDD, ...Cl
Cl O Cl
Cl O Cl
Other Proteins
hsp90 AIP,..
Rb, RelA,…
Arnt
Cl O Cl
Cl O Cl
HIFa,
Sim,...
phosphorylation/
dephosphorylation
hsp90
DRE
BTFs
Cl O Cl
Cl O Cl
BTFs
Co-activators
Co-repressors
Arnt
Differentiation
and
Proliferation
chromatin
TATA
Changes in protein levels
(e.g., CYPIA1, IL-1, ...)
Altered gene expression
mRNA
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
Devpt
Chloracne
Classic Toxic Effect
•
•
•
•
“Hallmark of Dioxin Toxicity”
High-Dose Response
Genetic Polymorphism
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
0000
Peak Dioxin Body Burden Levels in Background
Populations and Epidemiological Cohorts
14000
1000
Mean_
Median
Median
g-Mean
100
Median
g-M/Med
Median
g-M/Med
Mean_
10
M/Med
Median
Median
Median
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????
All Cancer ED01 and Slope Factor
Calculations from Published Studies
STUDY
ED01/LED01 (95%
lower bound) ng/kg
(Body Burden)
Slope Factor, All
Cancer
risk/pg/kg/day (95%
upper bound)
Hamburg cohort,
Becher et al. 1998
6.0 – 32.2
0.9 – 5.1 x 10-3
NIOSH cohort,
Steenland et al. 2001
18.6 (11.5)
1.5 x 10 –3 (2.5 x 10 –
3)
BASF cohort, Ott and
Zober 1996
50.9 (25.0)
0.57 x 10-3 (1.2 x 103)
Meta-Analysis,
Crump et al. 2003
51 (33)
91 (47)
0.6 x 10-3 (0.9 x10-3)
0.3 x 10-3 (0.6x10-3)
US EPA (2000)
47 (30)
1.0 x 10-3
SD rats, Kociba et al.
1978, Goodman and
Sauer 1992
(pathology)
38 (27.5)
0.80 x 10-3 (1.1 x 103)
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
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
 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
Body Burdens Associated with Effects
in Animals
Body Burden (ng/kg)
ADVERSE EFFECTS
Margin of Exposure
(Effect level/current
av. US BB, 5ng/kg)
Developmental
Neurotoxicity
22
4
Developmental
reproductive toxicity
0.7 –42
0.1 - 8
Developmental
immunotoxicity
50
10
Adult immunotoxicity 1.6 – 12
0.3 - 2
Endometriosis
22
4
Cancer
3.3 - 80
0.6 - 16
CYP1A1 induction
0.6 -33
0.1 - 7
CYP1A2 induction
2.1 - 83
0.4 - 17
Oxidative stress
10
2
BIOCHEM. EFFECTS
Dose/Response
Relationships
•
Biochemical Effects Occur in Animals
Within Range of General Population
Body Burdens
Within 10X of Current Body Burdens
•


•
Endometriosis and Immune Suppression
in Adults
Developmental Problems – learning,
immune, reproductive, teeth
Within 100X of Body Burdens


Porphyrin Accumulation
Cancer
Integrating Exposure
and Effects
M-O-E =
exposure of interest
low effect level
Avg. Daily Intake = 1-2 pg TEQ/kg/day
WHO TDI (1998) = 1-4 pg TEQ/kg/day
Cancer (A&H)
Altered Glucose Tolerance,
Insulin Metabolism, Diabetes
* Dev.Eff. (Dutch, Japanese, Finnish, German Studies)
Low Dose Animal Effects1
Average Body Burden
--------------------------------------10-2
10-1
A = Animal
1
100
101
102
103
104
Body Burden (ng/kg)
H = Human
enzyme induction, cellular effects, viral susceptibility, oxidative damage,
developmental effects, endometriosis
Margin of Exposure
• Ratio of Body Burden where
Effects occur to Background Body
Burden
• No MOE for Biochemical Effects
• MOE <10 for clearly Adverse NonCancer Responses
• MOE ~10-100 for Cancer
 Excess Risk ~1/1000
Integrating Exposure
and Effects
• Dioxins affect multiple tissues and
organ systems
 The embryo/fetus may be especially
susceptible
• Dioxins result in a plethora of 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?
• Regulations have had the desired
results
• Levels are coming down in the
environment
• Levels are coming down in people
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
What Are Current Human
Exposure Levels?
• Daily exposure in the US, about 1-2 pg
dioxins/kg/day
• Current body burden
 ~5 ng dioxin/kg body weight
 ~25 pg dioxins/g fat
Environmental Health Risk
Assessment
• How do we identify potential
hazards to human health?
• How do we understand how
serious such problems are?
We all know that certain
things are bad for us….
•
•
•
•
Cigarette smoke
Alcohol
Lead
Ozone (too much – and too little!)
What about other
substances in our
environment?
•
•
•
•
•
•
•
Gasoline Fumes?
Dry Cleaning fluids?
Pesticides
Wood Smoke
Heavy Metals
UV Light
Etc… should be we concerned?