ELSI & DART 10/1/04

Ethical, Legal, and Social Issues Related to DART

ELSI – Children & Toxicology

Reproductive & Developmental Toxicology:

Pharmaceutical, Environmental, and Legal Considerations

Northern and Southern California Chapters of the Society of Toxicology - Fall 2004 Meeting

Sept 30 – Oct 1, 2004

Steven G.Gilbert, PhD, DABT

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Child Health

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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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WHO Vision for Child Health

A World Fit for Children • Promoting healthy lives• Providing quality education• Protecting against abuse,

exploitation and violence• Combating HIV/AIDS.

http://www.unicef.org/why/why_worldgoals.html

ELSI & DART 10/1/04

CDC Vision for Child Health

“Environmental Health at CDC strives to promote health and quality of life by preventing or controlling those diseases or deaths that result from interactions between people and their environment.”

http://www.cdc.gov/node.do?id=0900f3ec8000e044

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American Academy of Pediatrics

Mission and vision

To attain optimal physical, mental and social health and well-being for all infants, children, adolescents and young adults.

http://www.aap.org/member/memcore.htm

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American Academy of Pediatrics

The APA goes on to state: “To this purpose, the AAP and its members dedicate their efforts and resources.

The vision: 1) to advocate for infants, children, adolescents, and young adults and provide for their care; 2) to collaborate with others to assure child health; and ….

http://www.aap.org/member/memcore.htm

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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.”

Vision of Environmental Health

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• Dose Response Issues

• Higher metabolic rate

• Different nutritional requirements

• Rapidly dividing & migrating cells

• Immature organs

Susceptibility of Children

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Sequence of Human Development

1 2 3 4 5 6 7 8 12 16 20 38

Implantation

Prenatal Death

Emryonic period

Major Morphological abnormalities

Fetal Period

Physiological and Functional Defects

Central Nervous System

Heart

Ears

Eyes

Limbs

Palate

External Genetalia

Red - most sensitive, Gray - Less

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Many ancient cultures had fertility goddess Many ancient documentation of

malformations Malformations rich aspect of mythology 6500 BC – Turkey - figurine of conjoined

twins 4000-5000 BC – Australia drawings of twins 2000 BC - Tablet of Nineveh – describes 62

malformations and predicts the future

Ancient Awareness

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15th-16th centuries malformations caused by the devil, mother and child killed

1830’s - Etienne Geoffroy Saint-Hilaire experimented with chicken eggs

1900’s began acceptance of malformations related to genetics

1940’s - Josef Warkany – environmental factors affect rat development

Historical Awareness

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1941 – Human malformations linked to rubella virus

1960’s – Thalidomide (a sedative and anti-nausea drug) found to cause human malformations

1950’s – Methylmercury recognized as developmental toxicant

1970’s – Alcohol related to developmental effects – Fetal Alcohol Syndrome (FAS)

Historical Events

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Case Studies

Thalidomide Methylmercury Lead Ethanol (Alcohol) PBDEs

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Thalidomide

Introduced in 1956 as sedative (sleeping pill) and to reduce nausea and vomiting during pregnancy

Withdrawn in 1961

Discovered to be a human teratogen causing absence of limbs or limb malformations in newborns

5000 to 7000 infants effected Resulted in new drug testing rules

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Fetal Effects of MeHg

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The Mercury Cycle

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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

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San Francisco Bay Regional Water

Quality Control Board. San Francisco Bay Mercury Total Maximum

Daily Load (TMDL)

Numeric targets for mercury concentrations in

suspended sediment fish tissue, and berg eggs

San Francisco – Hg TMDL

http://www.swrcb.ca.gov/rwqcb2/sfbaymercurytmdl.htm

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Lead In Homes

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Lead History

6500 BC. - Lead discovered in Turkey, first mine. 500 BC-300 AD.- Roman lead smelting produces

dangerous emissions. 100 BC. - Greek physicians give clinical description of

lead poisoning. “Lead makes the mind give way.” 1904 - Child lead poisoning linked to lead-based paints. 1922 - League of Nations bans white-lead interior paint;

U.S. declines to adopt 1923 - Leaded gasoline goes on sale in selected markets 1971- U.S. Lead-Based Paint Poisoning Prevention Act

passed 1923 - Leaded gasoline goes on sale in selected markets 1986 - Primary phase out of leaded gas in US completed

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Workplace Lead

Health of lead exposure on workers in London - “Steel dust, stone dust, clay dust, alkali dust, fluff dust, fiber dust- all these things kill, and they are more deadly than machine-guns and pom-poms. Worst of all is the lead dust in the white lead trades”.

1903 book “The People of the Abyss” Jack London

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Agency Blood Lead Levels

40

30

25

20

15

10

0

5

10

15

20

25

30

35

40

Blo

od

Lea

d (

ug

/dl)

CDC1973

CDC1975

CDC1985

WHO1986

EPA1986

CDC1990

Agency and Year

Acceptable Childhood Blood Lead Levels

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Alcohol

CH

H

H

OHC

H

H

(CH3-CH2-OH)

ELSI & DART 10/1/04FAS Child

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FAS & FAE

Most common preventable cause of adverse CNS development

Fetal Alcohol Syndrome (FAS)4,000-12,000 infants per year in US

Fetal Alcohol Effect (FAE)7,000-36,000 infants per year in US

1 to 3 infants per 1,000 world wide??

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• 1981 - U.S. Surgeon General first advised that women should not drink alcoholic beverages during pregnancy.

• 1988 - U.S. requires warning labels on all alcoholic beverages sold in the United States.

• 1990 - U.S. Dietary Guidelines state that women who are pregnant or planning to become pregnant should not drink alcohol.

• 1998 - 19 states require the posting of alcohol health warning signs where alcoholic beverages are sold

Policy Approaches

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Structure of PBDEs

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

PolyBrominated Diphenyl Ether

O

BrxBry

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PBDEs in House Dust (ppb)

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

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PBDEs in Breast Milk (ppb)

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

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Legislation to ban - Penta and Octa-PBDE

Did not ban Deca-PBDEMust report amount of electronic

waste and toxic chemicals in waste such as PBDEs, metals

PBDEs – California Status

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Scientific Process

VariabilityUncertainty

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• Statistical

• Model

• Fundamental

Types of Uncertainty

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• Easiest to examine & reduce

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

• Sample size

Statistical Uncertainty

Reducing Variability

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

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

Model or System Uncertainty

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• Not knowing the right questions to ask

• Most sensitive end point

• “we don’t know what we don’t know”

Fundamental Uncertainty

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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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Socially responsible white guys?

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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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“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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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

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• 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

Wingspread Conference, 1998.

Central components

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1) Respect - for the needs and rights of this and future generations as well as others who cannot speak for themselves

2) Humility - towards the natural world and our ability to understand it through science

3) Democracy - giving people a voice in matters that affect their lives

4) Responsibility - government’s public trust responsibility to manage the commonwealth for this and future generations.

- Individuals’ including industry, obligation to take responsibility for their actions in the world.

Values of the precautionary principle

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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 Initiative

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• 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

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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

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• Testifying

• Writing review papers

• K-12 class room teaching

• Adding expertise to community groups

• Education

• Mentoring

• Speakers Bureau

Socially Responsible Actions

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• 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 - ESLI Specialty Section

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

ELSI & DART 10/1/04

The Potential of Children

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ELSI - Children & Toxicology

Questions or Comments?

Download Presentation from www.asmalldoseof.org

ELSI & DART 10/1/04

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)

(http://reports.eea.eu.int/environmental_issue_report_2001_22/en)

Garrett Hardin - The Tragedy of the Commons (Science, 1968)

Ethics and Environmental Health – Mini Monograph - Environmental Health Perspectives (November 2003)

ELSI & DART 10/1/04

Authorship Information

Steven G. Gilbert, PhD, DABTDirector, INND

8232 14th Ave NE Seattle, WAPh: 206.527.0926Fx: 206.525.5102

E-mail: sgilbert@innd.org

www.asmalldoseof.org