Ethical, Legal, and Social Issues Related to DART

1. 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

2. Child Health

3. Convergence of Issues • 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

4. 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

5. 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

6. 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

7. 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

8. Vision for Child Health “Children can develop and mature in an environment that allows them to reach and maintain their full potential.”

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

10. Susceptibility of Children • Dose Response Issues • Higher metabolic rate • Different nutritional requirements • Rapidly dividing & migrating cells • Immature organs

11. Sequence of Human Development Red - most sensitive, Gray - Less

12. Ancient Awareness • 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

13. Historical Awareness • 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

14. Historical Events • 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)

15. Case Studies • Thalidomide • Methylmercury • Lead • Ethanol (Alcohol) • PBDEs

16. 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

17. Fetal Effects of MeHg

18. The Mercury Cycle

19. 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

20. San Francisco – Hg TMDL 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 http://www.swrcb.ca.gov/rwqcb2/sfbaymercurytmdl.htm

21. Lead In Homes

22. 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

23. 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

24. Agency Blood Lead Levels

25. H H C C OH H H H Alcohol (CH3-CH2-OH)

26. FAS Child

27. 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??

28. Policy Approaches • 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

29. Structure of PBDEs O Bry Brx PolyBrominated Diphenyl Ether X & Y are number of Bromine atoms Common Penta, Octa, and Deca

30. PBDEs in House Dust (ppb) From EWG - Toxic Fire Retardants Contaminate American Homes - http://www.ewg.org/reports/inthedust/summary.php

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

32. PBDEs – California Status • Legislation to ban - Penta and Octa-PBDE • Did not ban Deca-PBDE • Must report amount of electronic waste and toxic chemicals in waste such as PBDEs, metals

33. Scientific Process Variability Uncertainty

34. Types of Uncertainty • Statistical • Model • Fundamental

35. Statistical Uncertainty Reducing Variability • Easiest to examine & reduce • Not knowing the exact value of a variable (inter and intra subject variance) • Sample size

36. Model or System Uncertainty • Not fully understanding the relations between variables (mechanism of action) • Which variables are most important (high dose vs low dose)

37. Fundamental Uncertainty • Not knowing the right questions to ask • Most sensitive end point • “we don’t know what we don’t know”

38. 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)

39. 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)

40. Socially responsible white guys?

41. “The Commons” The Tragedy of the Commons By Garrett Hardin, Science, 1968

42. Technical Solutions “It is our considered professional judgment that this dilemma has no technical solution.” The Tragedy of the Commons By Garrett Hardin, Science, 1968

43. Problems – Solutions? • Lead and kids • Fetal alcohol syndrome • Nuclear disarmament • Bioterrorism • Ocean Fisheries • Persistent chemicals • The Commons

44. 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.

45. 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)

46. 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 • Wingspread Conference, 1998.

47. Values of the precautionary principle 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.

48. 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.

49. 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

50. 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.