A Small Dose of Risk Assessment – 2/27/04 An Introduction To Risk Assessment, Risk Management & Precautionary Principle A Small Dose of ™ Risk Assessment

A Small Dose of Risk Assessment – 2/27/04

An Introduction To Risk Assessment,Risk Management &

Precautionary Principle

A Small Dose of ™ Risk Assessment

DEOHS Summer 511July 11, 2005

Steven G. Gilbert, PhD, DABTwww.asmalldoseof.org LINK

A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology

Outline

Risk in context of societyRisk Management examplesPrinciples of risk assessmentLead Risk – CDC 10 to 2 mcg/cl?Mercury – cap and tradePrecautionary PrincipleSeattle and WA State efforts


A Small Dose of Toxicology

See: www.asmalldoseof.org -- smdose


NW Public Health

See: http://healthlinks.washington.edu/nwcphp/nph/

nwph

Public Health and the Precautionary

Principle

By Steven G. Gilbert


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)


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


Child Health


Decision Making

Risk Assessment and Risk Management in Context of

Societal Issues


Socially Responsibility

What is social responsibility?

What are our responsibilities to society?


Socially responsible white guys?


"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


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

existence”Aldo Leopold

Limits on Freedom


“The Commons”

The Tragedy of the CommonsBy Garrett Hardin, Science, 1968


The Tragedy

CattleFarmers

Return on InvestmentReturn for me

Not the commonsSociety suffers


No Technical Solutions

“It is our considered professional judgment that

this dilemma has no technical solution.”


Problems – Solutions?

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


Toxicology Issues / Solutions?

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


Freedom?

Restriction of Freedom?Responsibility knowing the

problem?

What does toxicology say about managing the

commons?


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

Environmental Health


Examples of Risk

Risk Management Examples

AlcoholLead

Mercury


Ethyl Alcohol

CH

H

H

OHC

H

H

A Small Dose of Risk Assessment – 2/27/04 A Small Dose of ToxicologyFAS Child


Effects of Prenatal Alcohol


Fetal Alcohol Syndrome (FAS)

1968 - Researchers at the Univ. of NantesEarly 1970’s FAS – Univ. of Washington

4,000-12,000 infants per year in US1 to 3 births per 1,000 world wide??

Most common preventable cause of adverse CNS development


Fetal Alcohol Effect (FAE)

Milder form of FAS

7,000-36,000 infants per year in USWorld wide?

CharacteristicsGrowth deficiency

Learning dysfunctionNervous systems disabilities


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.“ 1920’s - Lead in gasoline, lead in paint

Awareness of Lead


Lead In Homes


Lead in Families


Recycling Lead


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


Fetal Effects of MeHg


Life-Long Effects of MeHg


The Mercury Cycle


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.

WA State Advisory

http://www.doh.wa.gov/fish/FishAdvMercury.htm



"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


Key Words of Toxicology

Hazard X Exposure = Risk

Individual Susceptibility

Dose / Response


Early Risk Assessment

“What is food to one man may be fierce poison to others.”

Lucretius (c. 99 B.C.–c. 55 B.C.)


"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


“One death is a tragedy.

A million deaths is a statistic.”

Joseph Stalin

Perspective


1775 – Percivall Pott – Occupational – cancer of scrotum in chimney sweeps

1895 – Bladder cancer in workers in aniline dye industry

Historical 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)

Recent Awareness

A Small Dose of Risk Assessment – 2/27/04 A Small Dose of ToxicologySuperman


Risk of What?

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

SubtleDecreases in learning and memory (lead), Sensitivity of the individual (child)


Risk Assessment

Process of estimating association between an

exposure to a chemical or physical agent and the

incidence of some adverse outcome.


Policy developed to deal with hazards identified through risk

assessment

Process of evaluating alternative regulatory options and selecting

among them

Risk Management


Framework for RA and RM

Identify hazards

Characterize risks

Control risks

EpidemiologyToxicologyIn vitro testsStructure/Activity Analysis

PotencyExposureSusceptibility

InformationRegulationSubstitution


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


Steps in Risk Assessment

Hazard IdentificationExposure AssessmentDose-Response AssessmentRisk Characterization


Hazard Identification

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


Hazard Identification

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


Structure-Activity Analysis

Does structure resemble that of a known toxic agent?

Computer modeling


Short-term Screening Tests

Cell Culture, Tissue Culture

Does the chemical or agent adversely effects cells?


Animal Bioassays

Animal Studies

Does the chemical or agent causes effect animals?

What is the potentially for human toxicity?


Toxicity Endpoints

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

environmental persistence)


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


Human Epidemiological

Human Studies

Does the chemical or agent causes adverse effect in human

populations?


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


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


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.


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


Exposure Assessment

Route of exposure (skin, oral, inhalation)

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

environment)


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

Exposure Issues


Dose-Response Assessment

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


Chemical Potency

Dose

Res

po

nse

Threshold (NOAEL

ED50


• Hazard (including sensitive populations)– May require low dose extrapolation

• Exposure– Route of exposure, amount, duration

• dermal, oral, inhalation, injection

Risk Characterization

Risk = Hazard X Exposure


Uncertainty Perception Comparison Education Regulation

Risk Management


How do you know?How good is the data?

Uncertainty


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


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)


Reducing Uncertainty

• Upstanding mechanism of action• Physiologically based

pharmacokinetic models (distribution and metabolism)

• Sample size


Comparing Risks

By probability

By expected value

By outrage

By exposure

By experts


Annual Risk Of Death In The U.S.

HAZARD RISK PER MILLIONAll causes 9,000.0Motor vehicle accidents 210.0Work accidents 150.0Homicides 93.0Drowning 37.0Poisoning, Solids/liquids 17.0Railroads 0.9Civil aviation 0.8Bits and stings 0.2

“TO LIVE, IS TO RISK DYING”

A Small Dose of Risk Assessment – 2/27/04 A Small Dose of ToxicologyAdapted 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


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

LeadUnknown

Known

DreadedLittle Dread

A Small Dose of Risk Assessment – 2/27/04 A Small Dose of ToxicologyAdapted from Slovic et al. (1979), Environ., 21: 14.

Differences in Risk Perception

Activity/AgentRank by Risk

AnalystRank by non-Risk Analyst

Motor Vehicles 1 2Smoking 2 4Alcohol 3 6

Handguns 4 3Surgery 5 10Motorcycles 6 5

X-rays 7 22Pesticides 8 9Electric Power 9 18

Swimming 10 19Nuclear Power 20 1


Case Study

LEAD


"Lead makes the mind give way."

Ancient Awareness

GreekDioscerides - 2nd BC


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


“Conclusions: Blood lead concentrations, even those below 10 mgc/dL, are inversely

associated with children’s 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

Canfield et al…, 2003


• 25 DAYS -- BLOOD• 40 DAYS -- SOFT TISSUE • 20 YEARS -- BONE

Half-life Of Lead


Lead - Absorption

ORALLY CONSUMED LEAD ABSORBED

CHILDREN – 30-50% OF LEADADULTS – 5-10% OF LEAD

Increased During Pregnancy


Needleman, NEJM, 1979


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


Lead Industry Advertisements

http://www.cincinnatichildrens.org/research/project/enviro/hazard/lead/lead-advertising/default.htm

History of Lead Industry Advertisements (LINK)

http://www.cincinnatichildrens.org/research/project/enviro/hazard/lead/lead-advertising/default.htm


Lead-associated Reading Deficits in U.S. Children

75

80

85

90

95

100

105

<2.5 2.5 5 7.5 10

Blood lead levels (g/dl)

Rea

ding

Sco

re

Lanphear BP, et al. Public Health Reports 2000;115:521-529. (BL’s slide)


Canfield R, et al. NEJM 2003;348:1517-1526

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


Societal Consequences

(Curtsey Bernard Weiss)


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.

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


Current CDC Policy

Blood lead level µg/dL)b Actions

Time frame for beginning intervention

10-14 Provide caregiver lead education. Provide follow-up testing. Refer the child for social services if necessary.

Within 30 days

15-19 Above actions, plus:If BLLs persist (i.e., 2 venous BLLs in this range at least 3 months apart) or increase, proceed according to actions for BLLs 20-44.

Within 2 weeks

20-44 Above actions, plus:Provide coordination of care (case management).Provide clinical evaluation and care.c

Provide environmental investigation and control currentlead hazards.

Within 1 week

45-70 Above actions. Within 48 hours

70 or higher Above actions, plus hospitalize child for chelation therapy immediately.

Within 24 hours


Proposed CDC PolicyBlood lead level (µg/dL)

Actions Time frame for beginning intervention

<2 No action

2-5 Provide caregiver lead education. Provide follow-up testing. Refer the child for social services to investigate possible sources of lead exposure.

Within 30 days

5-10 Above actions, plus:If BLLs persist (i.e., 2 venous BLLs in this range at least 3 months apart) or increase, proceed according to actions for BLLs 10-20.

Within 2 weeks

10-20 Above actions, plus: Provide coordination of care (case management). Provide clinical evaluation and care. Provide environmental investigation and control current lead hazards.

Within 1 week

20-70 Above actions. Within 24 hours

70 or higher Above actions, plus hospitalize child for chelation therapy immediately.

Within 24 hours


Recycling Lead


Case Study

Mercury


Hg – Like Water


Hg – Solid Enough to Sit On


Outbreaks of MeHg Poisoning

Place Year CasesMinamata 1953-60 1000

Nigata 1964-65 646

Guatemala 1963-65 45

Ghana 1967 144

Pakistan 1969 100

Iraq 1956 100

Iraq 1960 1,002

Iraq 1971 40,000

On-going 2001 ???


Iraq Infant - Effects of Mercury


Inorganic - elemental mercury vapor Hg0

Inorganic - elemental mercury vapor Hg0

Biotransformation

Organic - Methylmercury - CH3Hg+

Bioaccumulation

Mercury to Methyl Mercury


Mercury Release

50-75% mercury of released in the environment related to human activities


Atmospheric Hg


Ambient WaterSediments

Edible Fish

Inorganic Mercury

Methyl-Mercury

Methyl-MercuryIn Humans

Biomethylation

Bioaccumulation

Exposure

Discharge

Biotransformation of Mercury


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

Neurobehavioral Effects


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

Effects On The Brain


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

Animal - Risk Assessment


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)


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

• 0.645 µg/kg •• 0.06 µg/kg - RfD •

Human - Risk Assessment


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


• Reduce environmental release

• Restrict global production and sale

• Advise women of child bearing age

• Research mechanisms of action

• Assess neurodegenerative effects

Recommendations


MeHg Consumption Limits

US EPA – 0.1 ug/kg-day

US FDA – 1 ppm (mg/kg) in tuna


Mercury A Global Issue

Mercury distribution and exposure is a global problem


Structure of PBDEs

X & Y are number of Bromine atomsCommon Penta, Octa, and Deca

PolyBrominated Diphenyl Ether

O

BrxBry


PBDEs in House Dust (ppb)

From EWG - Toxic Fire Retardants Contaminate American Homes - http://www.ewg.org/reports/inthedust/summary.php


PBDEs in Breast Milk (ppb)

From EWG - Toxic Fire Retardants in Breast Milk from American Mothers - http://www.ewg.org/reports/mothersmilk/es.php


Developmental Data

2863 above 1 Million pounds

78.2% no data

21.4% some data

12 or 0.4% good data

www.preventingharm.org


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


The challenge

To develop an individual and societal ethical framework for

decision making that supports the long term maintenance of a globally

sustainable ecology

Genomic and Ecological Bioethics


The challenge

“the knowledge of how to use knowledge for the social

good”

Knowledgeable Bioethics


"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


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


Determining Causation


“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.



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)

Safety & Efficacy vs Harm


• 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.

Central components


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

stake holders

Purpose/Objectives


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

Seattle Initiative


• Seattle Precautionary Principle White Paper (www.asmalldoseof.org)

• Inclusion of PP in Comp Plan Environment Element

(http://www.seattle.gov/dpd/Planning/Seattle's_Comprehensive_Plan/DPD_001178.asp) Link

Result of Effort


“Protecting Public Health by Adopting the Precautionary Principle as an Approach to Decision Making”

Resolution Submitted to Washington State Public Health Association

WSPHA Resolution


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.

Citizen Toxicologist

Socially Responsible Toxicologist


• Testifying

• Writing review papers

• K-12 class room teaching

• Adding expertise to community groups

• Education

• Mentoring

• Speakers Bureau

Socially Responsible Actions


• 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

SOT - ELSI Specialty Section

http://www.toxicology.org/memberservices/specsection/specsection.html


• 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

Knowledge - Responsibility


The Potential of Children


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


A Small Dose of ™ Risk Assessment


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/


Authorship Information

For Additional Information ContactSteven G. Gilbert, PhD, DABT

E-mail: [email protected]: www.asmalldoseof.org

This presentation is supplement to “A Small Dose of Toxicology”



"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


Scientific Process

VariabilityUncertainty


• Statistical

• Model

• Fundamental

Types of Uncertainty


• Easiest to examine & reduce

• Not knowing the exact value of a variable (inter and intra subject variance)

• Sample size

Statistical Uncertainty


• Not fully understanding the relations between variables (mechanism of action)

• Which variables are most important (high dose vs low dose)

Model or System Uncertainty


• Not knowing the right questions to ask

• Most sensitive end point

• “we don’t know what we don’t know”

Fundamental Uncertainty


"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


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


Determining Causation

Documents

A Small Dose of Risk Assessment – 2/27/04 An Introduction To Risk Assessment, Risk Management & Precautionary Principle A Small Dose of ™ Risk Assessment