An Introduction To Risk Assessment, Risk Management

1
An Introduction To Risk Assessment,Risk
Management Precautionary Principle
A Small Dose of Risk Assessment
DEOHS Summer 511July 11, 2005Steven G. Gilbert,
PhD, DABTwww.asmalldoseof.org LINK
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Outline

• Risk in context of society
• Risk Management examples
• Principles of risk assessment
• Lead Risk CDC 10 to 2 mcg/cl?
• Mercury cap and trade
• Precautionary Principle
• Seattle and WA State efforts

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A Small Dose of Toxicology
See www.asmalldoseof.org -- smdose
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NW Public Health
Public Health and the Precautionary Principle By
Steven G. Gilbert
See http//healthlinks.washington.edu/nwcphp/nph/
nwph
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Doubt / Uncertainty
"Doubt is our product since it is the best means
of competing with the 'body of fact' that exists
in the mind of the general public. 1969 an
executive at Brown Williamson owned by R. J.
Reynolds Tobacco Company (Doubt Is Their Product
by David Michaels in Scientific American, June
15, 2005)
6
Current Bioethical Issues

• Check the local news paper
• Stem cells (state, national, international)
• Genetically Engineered Organisms
• Knowing your genes
• In vetro fertilization choosing your child's
  genes and characteristics
• Global warming
• Nanotechnology
• Environmental health
• Chemicals exposures human health

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Child Health
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Decision Making
Risk Assessment and Risk Management in Context of
Societal Issues
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Socially Responsibility
What is social responsibility? What are our
responsibilities to society?
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Socially responsible white guys?
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The First Bioethicist
Aldo Leopold
"A thing is right when it tends to preserve the
integrity, stability, and beauty of the biotic
community. It is wrong when it tends otherwise."
- Aldo Leopold, 1949, A Sand County Almanac
---------- 1887 - 1948 ----------
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Limits on Freedom
An ethic, ecologically, is a limitation on
freedom of action in the struggle for
existence Aldo Leopold
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The Commons
The Tragedy of the Commons By Garrett Hardin,
Science, 1968
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The Tragedy
Cattle Farmers Return on Investment Return for
me Not the commons Society suffers
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No Technical Solutions
It is our considered professional judgment that
this dilemma has no technical solution.
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Problems Solutions?

• Tick-tack-toe
• Nuclear disarmament
• Bioterrorism
• Fish from the sea
• Cancer
• Lead and kids
• Fetal alcohol syndrome
• Commons .

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Toxicology Issues / Solutions?

• Cancer (soot benzene .)
• Radiation exposure
• Plant and animal toxins
• Pesticides
• Drugs
• Lead and Mercury
• Fetal alcohol syndrome
• .

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Freedom?
What does toxicology say about managing the
commons?
Restriction of Freedom? Responsibility knowing
the problem?
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Environmental Health
What is the goal of risk management? Conditions
that ensure that all living things have the best
opportunity to reach and maintain their full
genetic potential. Steven G. Gilbert, 1999
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Examples of Risk
Risk Management Examples Alcohol Lead Mercury
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Ethyl Alcohol
H
H
C
H
OH
C
H
H
22
FAS Child
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Effects of Prenatal Alcohol
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Fetal Alcohol Syndrome (FAS)
1968 - Researchers at the Univ. of Nantes Early
1970s FAS Univ. of Washington 4,000-12,000
infants per year in US 1 to 3 births per 1,000
world wide?? Most common preventable cause of
adverse CNS development
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Fetal Alcohol Effect (FAE)
Milder form of FAS 7,000-36,000 infants per year
in US World wide? Characteristics Growth
deficiency Learning dysfunction Nervous systems
disabilities
26
Awareness of Lead

• 6500 BC. - Lead discovered in Turkey
• 500 BC-300 AD.- Roman lead smelting produces
  dangerous emissions (wine)
• 100 BC. - Greek physicians give clinical
  description of lead poisoning
• 2 BC "Lead makes the mind give way.
• 1920s - Lead in gasoline, lead in paint

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Lead In Homes
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Lead in Families
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Recycling Lead
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Agency Blood Lead Levels
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Fetal Effects of MeHg
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Life-Long Effects of MeHg
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The Mercury Cycle
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WA State Advisory
Limit the amount of canned tuna you eat, based on
your bodyweight. Guidelines are Women of
childbearing age should limit the amount of
canned tuna they eat to about one can per week
(six ounces.) A woman who weighs less than 135
pounds should eat less than one can of tuna per
week. Children under six should eat less than
one half a can of tuna (three ounces) per week.
Specific weekly limits for children under six
range from one ounce for a twenty pound child, to
three ounces for a child weighing about sixty
pounds.
http//www.doh.wa.gov/fish/FishAdvMercury.htm
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Precautionary Principle
"When an activity raises threats of harm to the
environment or human health, precautionary
measures should be taken even if some cause and
effect relationships are not fully established
scientifically." - Wingspread Statement on the
Precautionary Principle, Jan. 1998
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Key Words of Toxicology
Dose / Response

• Hazard X Exposure Risk

Individual Susceptibility
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Early Risk Assessment

• What is food to one man may be fierce poison to
  others.
• Lucretius (c. 99 B.C.c. 55 B.C.)

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Perspective
"If someone had evaluated the risk of fire right
after it was invented, they may well have decided
to eat their food raw." Julian Morris of the
Institute of Economic Affairs in London
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Perspective
One death is a tragedy. A million deaths is a
statistic. Joseph Stalin
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Historical Awareness

• 1775 Percivall Pott Occupational cancer of
  scrotum in chimney sweeps
• 1895 Bladder cancer in workers in aniline dye
  industry

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Recent Awareness

• 1938 - Founding of American Conference of
  Governmental Industrial Hygienists (ACGIH).
• 1941 - Chemical Substances Committee established
  to investigate and recommend exposure limits for
  chemical substances.
• Threshold Limit Values (TLVs) for 148 chemicals
  (exposure limits)

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Superman
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Risk of What?
Obvious Death, Cancer, Acid burn, Birth defect,
asthma, Subtle Decreases in learning and
memory (lead), Sensitivity of the individual
(child)
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Risk Assessment
Process of estimating association between an
exposure to a chemical or physical agent and the
incidence of some adverse outcome.
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Risk Management
Policy developed to deal with hazards identified
through risk assessment Process of evaluating
alternative regulatory options and selecting
among them
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Framework for RA and RM
Epidemiology Toxicology In vitro
tests Structure/Activity Analysis Potency Exposu
re Susceptibility Information Regulation Substit
ution
Identify hazards Characterize risks Control
risks
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Objective of Risk Assessment

• Evaluate the risks
• Environmental contaminant, drugs, pesticides,
  industrial chemical
• Evaluate uncertainty of data
• Set target levels of exposure
• Food, air, water, work place
• Provide information to agencies
• Regulatory agencies, Manufacturers,
  Environmental/Consumer Agencies

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Steps in Risk Assessment

• Hazard Identification
• Exposure Assessment
• Dose-Response Assessment
• Risk Characterization

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Hazard Identification
Review human and animal data to determine if a
chemical or agent has biological effects
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Hazard Identification

• Research
• Structure-Activity Analysis
• Short-term Screening Tests
• Animal Bioassays
• Human Epidemiological Data

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Structure-Activity Analysis
Does structure resemble that of a known toxic
agent? Computer modeling
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Short-term Screening Tests
Cell Culture, Tissue Culture Does the chemical
or agent adversely effects cells?
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Animal Bioassays
Animal Studies Does the chemical or agent causes
effect animals? What is the potentially for
human toxicity?
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Toxicity Endpoints

• Carcinogenicity
• Mutations
• Altered immune function
• Teratogenicity
• Altered reproductive function
• Neuro-behavioral toxicity
• Organ-specific effects
• Ecological effects (wildlife, environmental
  persistence)

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Pros and Cons - Animals

• Advantages
• Monitor progress of toxicity/carcinogenicity
• Can directly link with exposure
• Can be used to predict human risks

• Disadvantages
• Can be very expensive (1 M)
• Can take many years

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Human Epidemiological
Human Studies Does the chemical or agent causes
adverse effect in human populations?
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Pros and Cons - Humans

• Advantages
• Yields information in humans
• Yields associations relevant to real world
  exposures

• Disadvantages
• Can be very expensive (large N, many years)
• Lack control relative to lab
• Many confounding variables

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Human Variability

• Human Subject Variability
• Lifestyle risk of exposure to .
• Occupation risk of exposure to .
• Breathing digestion uptake of chemicals
• Metabolism kidney function elimination
• Age, gender disease susceptibility to toxicity

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Examples of Variability

• Children spend more time on floor more hand to
  mouth behavior than adults
• Occupation exposure to other chemicals
• Rate of breathing higher in children than adults
• Lung function and susceptibility are altered by
  smoking or asthma
• Disease effects liver function
• The overall dose-response behavior is subject to
  both intra-individual and inter-individual
  variability.

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Uncertainty

• Measurements error in experiments
• Extrapolation from animal studies to human
• Sample sizes for animal and human studies
• Selection of endpoint
• Intra and inter subject variability

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Exposure Assessment

• Route of exposure (skin, oral, inhalation)
• Amount of exposure (dose)
• Duration of exposure
• To whom (animals, humans, environment)

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Exposure Issues

• Home environment
• Current events
• Workplace
• School
• Government Decisions (war)
• Global and local environment

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Dose-Response Assessment
How much exposure to a chemical or agent will
cause what effect?
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Chemical Potency
ED50
Response
Threshold (NOAEL
Dose
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Risk Characterization
Risk Hazard X Exposure

• Hazard (including sensitive populations)
• May require low dose extrapolation
• Exposure
• Route of exposure, amount, duration
• dermal, oral, inhalation, injection

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Risk Management

• Uncertainty
• Perception
• Comparison
• Education
• Regulation

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Uncertainty
How do you know? How good is the data?
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Use of Uncertainty Factors

• Divide Dose by Power of 10
• Human variability
• Interspecies extrapolation
• Children
• Subchronic to chronic extrapolation
• Absence of a NOAEL
• Database uncertainty

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Use of Uncertainty Factors
Animal Dose Response Data NOAEL (No Observed
Adverse Effect Level) Divide by 10 (Account for
inadequate animal data) Divide by 10 (Animal to
Human Extrapolation) Divide by 10 (Human
Variability or Individual Sensitivity) Reference
Dose (RfD) Or Acceptable Daily Intake (ADI)
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Reducing Uncertainty

• Upstanding mechanism of action
• Physiologically based pharmacokinetic models
  (distribution and metabolism)
• Sample size

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Comparing Risks

• By probability
• By expected value
• By outrage
• By exposure
• By experts

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Annual Risk Of Death In The U.S.
HAZARD RISK PER MILLION All causes 9,000.0 Mo
tor vehicle accidents 210.0 Work
accidents 150.0 Homicides 93.0 Drowning 37
.0 Poisoning, Solids/liquids 17.0 Railroads 0.
9 Civil aviation 0.8 Bits and stings 0.2
TO LIVE, IS TO RISK DYING
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Characteristics of Risk
Characteristic Level Examples
Knowledge Little known Food additives Much
known Alcoholic drinks Newness Old Guns New
Space travel Voluntariness Not
voluntary Crime Voluntary Rock
climbing Control Not controllable Natural
disasters Controllable Smoking Dreadedness Li
ttle dread Vaccination Great dread Nerve
gas Catastrophic Not likely Sunbathing potential
Likely War Equity Distributed Skiing Und
istributed Hazardous dump
Adapted from Kraus and Slovic (1988), Risk Anal.,
8 435.
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Risk Perceptions
Unknown
w
Lead
w
w
Food coloring
DNA Research
Knowable
w
w
Nuclear Power
Saccharin
Newness Lack of scientific knowledge Exposure is
unknown/unknowable
w
Microwave ovens
w
Asbestos
w
Aspirin
w
Herbicides
w
Dread
Pesticides
Dreaded
Little Dread
Catastrophic potential Involuntariness Personal
risk Inequity
w
Anesthetics
w
Power Tools
w
Smoking
w
Dynamite
w
Alcohol
w
w
Warfare
Motor vehicles
w
Handguns
Known
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Differences in Risk Perception
Rank by non-Risk Analyst
Rank by Risk Analyst
Activity/Agent
Motor Vehicles 1 2 Smoking 2 4 Alcohol 3 6
Handguns 4 3 Surgery 5 10 Motorcycles 6 5
X-rays 7 22 Pesticides 8 9 Electric
Power 9 18
Swimming 10 19 Nuclear Power 20 1
Adapted from Slovic et al. (1979), Environ., 21
14.
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Case Study
LEAD
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Ancient Awareness
"Lead makes the mind give way."
Greek Dioscerides - 2nd BC
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Agency Blood Lead Levels
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Canfield et al, 2003
Conclusions Blood lead concentrations, even
those below 10 mgc/dL, are inversely associated
with childrens IQ scores at three and five years
of age, and associated declines in IQ are greater
at these concentrations than at higher
concentrations. These findings suggest that more
U.S. children may be adversely affected by
environmental lead than previously
estimated. Canfield et al. 2003, NEJM, 384
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Half-life Of Lead
25 DAYS -- BLOOD 40 DAYS -- SOFT TISSUE 20
YEARS -- BONE
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Lead - Absorption
ORALLY CONSUMED LEAD ABSORBED CHILDREN 30-50
OF LEAD ADULTS 5-10 OF LEAD Increased During
Pregnancy
82
Needleman, NEJM, 1979
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Lead Based Paint
1887 - US medical authorities diagnose childhood
lead poisoning 1904 - Child lead poisoning linked
to lead-based paints 1909 - France, Belgium and
Austria ban white-lead interior paint 1914-
Pediatric lead-paint poisoning death from eating
crib paint is described 1921 - National Lead
Company admits lead is a poison 1922 - League of
Nations bans white-lead interior paint US
declines to adopt 1943- Report concludes eating
lead paint chips causes physical and neurological
disorders, behavior, learning and intelligence
problems in children 1971- Lead-Based Paint
Poisoning Prevention Act passed
84
Lead Industry Advertisements
History of Lead Industry Advertisements
(LINK) http//www.cincinnatichildrens.org/research
/project/enviro/hazard/lead/lead-advertising/defau
lt.htm
http//www.cincinnatichildrens.org/research/projec
t/enviro/hazard/lead/lead-advertising/default.htm
85
Lead-associated Reading Deficits in U.S. Children
Reading Score
Blood lead levels (?g/dl)
Lanphear BP, et al. Public Health Reports
2000115521-529. (BLs slide)
86
IQ and Blood Lead

• Life time overall
• Increase in 1 mcg/dl 0.87 IQ drop
• Covariates - 1 mcg/dl 0.46 IQ drop
• 1 to 10 mcg/dl (bigger drop)
• Increase in 1 mcg/dl 1.37 IQ drop
• Non-linear - 1 mcg/dl 7.4 IQ drop

Canfield R, et al. NEJM 20033481517-1526
87
Societal Consequences
(Curtsey Bernard Weiss)
88
Cost of Childhood Lead

• Assumptions in calculating costs
• All lead is harmful and from environment
• Blood lead of children age 5 2.7 ug/dl (CDC)
• 5-year old boys (1,960,200) and girls (1,869,800)
• 1 ug/dl of lead 0.25 IQ point reduction
• Cost boys 27.8 and girls 15.6 Billion
• Total Costs 43.4 Billion

Environmental Pollutants and Disease in American
Children Estimates of Morbidity, and Costs for
Lead Poisoning, Asthma, Cancer, and Developmental
Disabilities, by Landrigan, P. et al. EHP, 110,
July 2002, 721-728.
89
Current CDC Policy
90
Proposed CDC Policy
91
Recycling Lead
92
Case Study
Mercury
93
Hg Like Water
94
Hg Solid Enough to Sit On
95
Outbreaks of MeHg Poisoning
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Iraq Infant - Effects of Mercury
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Mercury to Methyl Mercury
Inorganic - elemental mercury vapor Hg0
Biotransformation
Organic - Methylmercury - CH3Hg
Bioaccumulation
98
Mercury Release
50-75 mercury of released in the environment
related to human activities
99
Atmospheric Hg
100
Biotransformation of Mercury
Inorganic Mercury
Discharge
Ambient Water Sediments
Biomethylation
Methyl-Mercury
Bioaccumulation
Edible Fish
Exposure
Methyl-Mercury In Humans
101
Neurobehavioral Effects

• Blindness - Deafness
• Cerebral Palsy - Seizures
• Abnormal reflexes muscle tone
• Retarded motor development
• Visual and Auditory Deficits
• Delayed motor development
• Altered DRH performance

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Effects On The Brain

• Decrease in Brain Size
• Cell loss
• Disorganization of cells
• Cell migration failures

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Animal - Risk Assessment

• MONKEY - 25 µg/kg - LOAEL
• RAT - 10 µg/kg - LOAEL
• RAT - 50 µg/kg - replicated

104
Animal - Risk Assessment

• 2.5 µg/kg - NOAEL (animals)
• 0.25 µg/kg - Human
• 0.025 µg/kg - Sensitive populations

(the rule of dividing by 10)
105
Human - Risk Assessment
10-20 ppm hair - LOAEL 40-80 ppb blood -
LOAEL 0.645 µg/kg 0.06 µg/kg - RfD
106
Mercury Fishing Advisories

• In 2000, 41 States have over 2000 fish
  consumption advisories
• An increase form 27 in 1993
• Pregnant women, nursing mothers, women who intend
  to have children, and children under 15

107
Recommendations

• Reduce environmental release
• Restrict global production and sale
• Advise women of child bearing age
• Research mechanisms of action
• Assess neurodegenerative effects

108
MeHg Consumption Limits
US EPA 0.1 ug/kg-day US FDA 1 ppm (mg/kg) in
tuna
109
Mercury A Global Issue
Mercury distribution and exposure is a global
problem
110
Structure of PBDEs
PolyBrominated Diphenyl Ether
X Y are number of Bromine atoms Common Penta,
Octa, and Deca
111
PBDEs in House Dust (ppb)
From EWG - Toxic Fire Retardants Contaminate
American Homes - http//www.ewg.org/reports/inthed
ust/summary.php
112
PBDEs in Breast Milk (ppb)
From EWG - Toxic Fire Retardants in Breast Milk
from American Mothers - http//www.ewg.org/reports
/mothersmilk/es.php
113
Developmental Data
2863 above 1 Million pounds
12 or 0.4 good data
21.4 some data
78.2 no data
www.preventingharm.org
114
The Consequences

• Nearly 12 million children (17) under age 18 in
  the US suffer from one or more developmental
  disabilities
• Learning disabilities 5-10 of kids in public
  school
• ADHD 3-6 of all school kids, maybe higher

115
Genomic and Ecological Bioethics
The challenge To develop an individual and
societal ethical framework for decision making
that supports the long term maintenance of a
globally sustainable ecology
116
Knowledgeable Bioethics
The challenge the knowledge of how to use
knowledge for the social good
117
Sir Austin Bradford Hill
"All scientific work is incomplete - whether it
be observational or experimental. All scientific
work is liable to be upset or modified by
advancing knowledge. That does not confer upon us
a freedom to ignore the knowledge we already have
or postpone the action that it appears to demand
at a given time. " Sir Austin Bradford Hill
(1965)
118
Determining Causation

• Strength of association
• Consistency of findings
• Biological gradient
• Temporal sequence
• Biologic or theoretical plausibility
• Coherence with established knowledge
• Specificity of association
• Sir Austin Bradford Hill (1965)

119
Precautionary Principle
When an activity raises threats of harm to human
health or the environment, precautionary measures
should be take even if some cause and effect
relationships are not fully established
scientifically. Wingspread Conference, 1998.
120
Safety Efficacy vs Harm

• FDA regulations of Drugs (1938)
• FDA regulations of Dietary Supplements (Dietary
  Supplement Health and Education Act of 1994
  (DSHEA))
• Ephedra present an unreasonable risk of illness
  or injury (Dec, 2003)

121
Central components

• Taking preventive action in the face of
  uncertainty
• Shifting the burden of proof/responsibility to
  the proponents of an activity
• Exploring a wide range of alternatives to
  possibly harmful actions
• Increasing public participation in decision
  making (environmental justice)
• Wingspread Conference, 1998.

122
Purpose/Objectives

• Improve decision making
• Promote integrated assessments
• Promote transparency
• Promote sharing of information
• Examine alternatives
• Examine uncertainties
• Encourage discussion among stake holders

123
Seattle Initiative

• City Comprehensive Plans
• Every citizen of Seattle has an equal right to a
  healthy and safe environment.
• Seattle sees the Precautionary Principle approach
  as its policy framework to develop laws for a
  healthier and more just Seattle.
• Seattle PP working group

124
Result of Effort

• Seattle Precautionary Principle White Paper
  (www.asmalldoseof.org)
• Inclusion of PP in Comp Plan Environment Element
• (http//www.seattle.gov/dpd/Planning/Seattle's_Com
  prehensive_Plan/DPD_001178.asp) Link

125
WSPHA Resolution
Protecting Public Health by Adopting the
Precautionary Principle as an Approach to
Decision Making Resolution Submitted to
Washington State Public Health Association
126
Citizen Toxicologist
Socially Responsible Toxicologist
The citizen toxicologist is a thoughtful advocate
for human and environmental health, who strives
to share their scientific knowledge with the
public, speaking to public interests rather than
private or special interests.
127
Socially Responsible Actions

• Testifying
• Writing review papers
• K-12 class room teaching
• Adding expertise to community groups
• Education
• Mentoring
• Speakers Bureau

128
SOT - ELSI Specialty Section

• Forum in which to discuss the ethical
  implications of results from our science as well
  as the resulting legal and social implications.
• 2005 SOT meeting workshop on Conflict of
  Interest

http//www.toxicology.org/memberservices/specsecti
on/specsection.html
129
Knowledge - Responsibility

• Children have a right to a safe, fair and healthy
  environment
• Ethical Responsibility to share and use of
  knowledge
• Duty to promote health and well being of children
• Thoughtful public health advocate

130
The Potential of Children
131
Additional Information

• The Science and Environmental Health Network
  (SEHN) (www.sehn.org)
• Late lessons from early warnings the
  precautionary principle 1896-2000 European
  Environment Agency (free)
• Garrett Hardin - The Tragedy of the Commons
  (Science, 1968)
• Ethics and Environmental Health Mini Monograph
  - Environmental Health Perspectives (November
  2003)
• Ethical, legal, and social issues our children's
  future. Steven G. Gilbert. Neurotoxicology, in
  press, 2005

132
A Small Dose of Risk Assessment
133
Additional Information

• Web Sites
• World Health Organization - The International
  Programme on Chemical Safety (IPCS) Risk
  Assessment http//www.who.int/pcs/ra_main.html
• U.S. Environmental Protection Agencies - National
  Center for Environmental Assessment (NCEA)
  Access http//cfpub.epa.gov/ncea/

134
Authorship Information
This presentation is supplement to A Small
Dose of Toxicology
For Additional Information Contact Steven G.
Gilbert, PhD, DABT E-mail smdose_at_asmalldoseof.org
Web www.asmalldoseof.org
135
Precautionary Principle
"When an activity raises threats of harm to the
environment or human health, precautionary
measures should be taken even if some cause and
effect relationships are not fully established
scientifically." - Wingspread Statement on the
Precautionary Principle, Jan. 1998
136
Scientific Process
Variability Uncertainty
137
Types of Uncertainty

• Statistical
• Model
• Fundamental

138
Statistical Uncertainty

• Easiest to examine reduce
• Not knowing the exact value of a variable (inter
  and intra subject variance)
• Sample size

139
Model or System Uncertainty

• Not fully understanding the relations between
  variables (mechanism of action)
• Which variables are most important (high dose vs
  low dose)

140
Fundamental Uncertainty

• Not knowing the right questions to ask
• Most sensitive end point
• we dont know what we dont know

141
Sir Austin Bradford Hill
"All scientific work is incomplete - whether it
be observational or experimental. All scientific
work is liable to be upset or modified by
advancing knowledge. That does not confer upon us
a freedom to ignore the knowledge we already have
or postpone the action that it appears to demand
at a given time. " Sir Austin Bradford Hill
(1965)
142
Determining Causation

• Strength of association
• Consistency of findings
• Biological gradient
• Temporal sequence
• Biologic or theoretical plausibility
• Coherence with established knowledge
• Specificity of association
• Sir Austin Bradford Hill (1965)