Risk Assessment – 12/05/06 A Small Dose of Toxicology Risk Assessment and Risk Communication...

Risk Assessment – 12/05/06 A Small Dose of Toxicology

Risk Assessment and Risk Communication

Steven G. Gilbert, PhD, DABT

www.asmalldoseof.orgwww.toxipedia.org

How Chemicals Affect Your HealthDecember 5, 2006

A Small Dose of Toxicology

A Small Dose of Toxicology Risk Assessment – 12/05/06

Benefits & Risk

A Small Dose of Toxicology Risk Assessment – 12/05/06

Child Health

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Outline

Risk Assessment – Arbitrary and Capricious??

Ethics and Risk Principles of Risk Assessment Risk Assessment - examples Weaknesses of Risk Assessment

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• Vision of Child Health

• Knowledge of Reproductive and Developmental Toxicology

• Policy Approach within an ethical framework• Social responsibilities• No technical solutions• Restriction of freedoms• Precautionary Principle

Convergence of Issues

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“Children can develop and mature in an

environment that allows them to reach and maintain their full

potential.”

Vision for Child Health

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“Conditions that ensure that all living things have the best opportunity to reach and maintain their full genetic potential.”

S. Gilbert (1999)

Human & Environmental Health

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Socially responsible white guys?

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"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

The First Bioethicist

---------- 1887 - 1948 ----------

Aldo Leopold

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“An ethic, ecologically, is a limitation on freedom of action in the struggle for

existence”Aldo Leopold

Limits on Freedom

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“The Commons”

The Tragedy of the CommonsBy Garrett Hardin, Science, 1968

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Technical Solutions

“It is our considered professional judgment that

this dilemma has no technical solution.”

The Tragedy of the CommonsBy Garrett Hardin, Science, 1968

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Problems – Solutions?

Lead and kids Fetal alcohol syndrome Nuclear disarmament Bioterrorism Ocean Fisheries Persistent chemicals The Commons

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"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)

Sir Austin Bradford Hill

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1. Strength of association

2. Consistency of findings

3. Biological gradient

4. Temporal sequence

5. Biologic or theoretical plausibility

6. Coherence with established knowledge

7. Specificity of association

Sir Austin Bradford Hill (1965)

Determining Causation

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“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.

Precautionary Principle

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• Setting goals (Health indicators)• Taking preventive action in the face of

uncertainty• Shifting the burden of responsibility to the

proponents of an activity (Who benefits?)• Exploring a wide range of alternatives to

possibly harmful actions (Is it necessary?)• Increasing public participation in decision

making (transparency of information & environmental justice)

Central components

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Key Words of Toxicology

Hazard X Exposure = Risk

Individual Susceptibility

Dose / Response

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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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"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

Perspective

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Developed in 1960-1970s Concern over increased cancer ratesExpanded to non-cancer effects

Modern Risk Assessment

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Quantitative Risk Assessment

Process of estimating association between an

exposure to a chemical or physical agent and the

incidence of some adverse outcome.

National Research Council, Risk Assessment in the Federal Government: Managing the Process. National Academy Press,

Washington, DC, 1983

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Steps in Risk Assessment

Hazard IdentificationExposure AssessmentDose-Response AssessmentRisk Characterization

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What Hazard?

ObviousDeath, Cancer, Acid burn, Birth defect, asthma …..

SubtleDecreases in learning and memory (lead)

Loss of potential

Sensitivity of the individual (child)

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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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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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Exposure Assessment

Route of exposure (skin, oral, inhalation)

Amount of exposure (dose)Duration of exposureTo whom (animals, humans,

environment) Children, other sensitive individuals

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• Home environment• Workplace (occupational)• School• Food• Consumer products• Global and local environment

Exposure Issues

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Dose-Response Assessment

How much exposure to a chemical or agent will cause what effect?

Dose – Response

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Some Jargon

LOAEL – Lowest Observed Adverse Effect Level (mg/kg)

NOAEL – No Observed Adverse Effect Level (mg/kg)

RfD – Reference Dose (mg/kg-day)

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Greater Dose – Greater Response

Dose

Res

po

nse

Threshold (NOAEL)

ED50

LOAEL

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Hazard (including sensitive populations)

–Low dose extrapolationExposure

– Route of exposure, amount, duration• dermal, oral, inhalation, injection

– To Whom? Sensitive Individuals?

Risk Characterization

Risk = Hazard X Exposure

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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)

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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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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• Socio/economic facts

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Examples of Variability

• Children spend more time on floor – more hand to mouth behavior than adults

• Rate of breathing higher in children than adults

• Occupation – exposure to other chemicals• 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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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) or LOAEL

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)

A Small Dose of Toxicology Risk Assessment – 12/05/06Superman

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Mercury & Toxicology

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The Mercury Cycle

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Atmospheric Hg

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• Blindness - Deafness• Cerebral Palsy - Seizures• Abnormal reflexes & muscle tone• Retarded motor development• Visual and Auditory Deficits• Delayed motor development• Human and animal data

Neurobehavioral Effects

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Decrease in Brain Size Cell loss Disorganization of cells Cell migration failures Behavioral effects –

learning and memory

Effects On The Brain

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Fetal Effects of MeHg

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MONKEY - 25 µg/kg - LOAELRAT - 10 µg/kg - LOAELRAT - 50 µg/kg - replicated

Animal - Risk Assessment

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

Animal - Risk Assessment

(the rule of dividing by 10)

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• 10-20 ppm hair - LOAEL •• 40-80 ppb blood - LOAEL •

• 0.645 µg/kg •• 0.06 µg/kg - RfD •

Human - Risk Assessment

Gilbert, S.G., and Grant-Webster, K.S. Neurobehavioral effects of developmental methylmercury exposure. Env. Health Persep. 103(Suppl 6), 135-142, 1995.

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MeHg Consumption Limits

US EPA – 0.1 ug/kg-day

US FDA – 1 ppm (mg/kg) in tuna

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"Lead makes the mind give way."

Ancient Awareness

GreekDioscerides - 2nd BC

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Agency Blood Lead Levels

60

40

3025

2015

10

20

10

20

30

40

50

60

Blo

od

Lea

d (

ug

/dl)

CDC1960

CDC1973

CDC1975

CDC1985

WHO1986

EPA1986

CDC1990

CDC2006?

Agency and Year

Acceptable Childhood Blood Lead Levels

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Recycling Lead

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Limitations of Risk Assessment

Lack of adequate data Most sensitive endpoint Low dose extrapolation Exposure information Multiple chemical exposures Complex – expert driven –

undemocratic Individual sensitivity Narrow perspective – Ethical??

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Developmental Data

2863 above 1 Million pounds

78.2% no data

21.4% some data

12 or 0.4% good data

www.preventingharm.org

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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

The Consequences

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Estimated Costs - National

Best Estimate

Low Estimate High Estimate

Lead Poisoning   $43.4 $43.4 $43.4

Asthma  $2.0 $0.7 $2.3

Cancer  $0.3 $0.2 $0.7

Neurobehavioral Disorders

$9.2 $4.6 $18.4

TOTAL $54.9 $48.8 $64.8

Estimated Costs of Pediatric Disease of Environmental Origin, United States,1997 (billions)

(From “Environmental Pollutants and Disease in American Children,” Landrigan, Schechter, et.al., 2002)

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Estimated Costs - Washington

Diseases and disabilities (asthma, cancer, lead exposure, birth defects, and neurobehavioral effects) attributable to environmental contaminants.

Best Estimate

Direct Costs

Indirect Costs

Range

Childhood $1,875 $310.6 $1,565

$1,600-$2,200

Adult & child $2,734 $782.1 $1,953

$2,800-$3,500

Disease/Disability (2004 $ million)

Kate Davies Economic costs of diseases and disabilities attributable to environmental contaminants in Washington State. Antioch University Seattle 2005. http://washington.chenw.org/pdfs/EnvironmentalCosts.pdf

A Small Dose of Toxicology Risk Assessment – 12/05/06Adapted from Kraus and Slovic (1988), Risk Anal., 8: 435.

Characteristics of RiskCharacteristic Level Examples

Knowledge Little known Food additivesMuch known Alcoholic drinks

Newness Old GunsNew Space travel

Voluntariness Not voluntary CrimeVoluntary Rock climbing

Control Not controllable Natural disastersControllable Smoking

Dreadedness Little dread VaccinationGreat dread Nerve gas

Catastrophic Not likely Sunbathingpotential Likely WarEquity Distributed Skiing

Undistributed Hazardous dump

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Food coloring

Saccharin

Microwave ovens

Aspirin

Anesthetics

Power Tools

Alcohol

Motor vehicles

DNA Research

Nuclear Power

Asbestos

HerbicidesPesticides

Smoking

Dynamite

Warfare

Handguns

Risk Perceptions

Catastrophic potentialInvoluntariness

Personal riskInequity

Dread

NewnessLack of scientific knowledge

Exposure is unknown/unknowable

Knowable

Unknown

Known

DreadedLittle Dread

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The Potential of Children

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Additional Information

National Research Council, Risk Assessment in the Federal Government: Managing the Process. National Academy Press, Washington, DC, 1983

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) – http://cfpub.epa.gov/ncea/

A Small Dose of Toxicology – Risk Assessment - http://www.asmalldoseof.org/toxicology/risk_assessment.php

A Small Dose of Toxicology Risk Assessment – 12/05/06

Risk Assessment