1. Risk Assessment – 12/05/06 A Small Dose of Toxicology Risk Assessment and Risk Communication Steven G. Gilbert, PhD, DABT www.asmalldoseof.org www.toxipedia.org How Chemicals Affect Your Health December 5, 2006 A Small Dose of Toxicology

2. Risk Assessment – 12/05/06 Benefits & Risk

3. A Small Dose of Toxicology Risk Assessment – 12/05/06 Child Health

4. A Small Dose of Toxicology Risk Assessment – 12/05/06 Outline Risk Assessment – Arbitrary and Capricious??  Ethics and Risk  Principles of Risk Assessment  Risk Assessment - examples  Weaknesses of Risk Assessment

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

6. A Small Dose of Toxicology Risk Assessment – 12/05/06 “Children can develop and mature in an environment that allows them to reach and maintain their full potential.” Vision for Child Health

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

8. A Small Dose of Toxicology Risk Assessment – 12/05/06 Socially responsible white guys?

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

10. A Small Dose of Toxicology Risk Assessment – 12/05/06 “An ethic, ecologically, is a limitation on freedom of action in the struggle for existence” Aldo Leopold Limits on Freedom

11. A Small Dose of Toxicology Risk Assessment – 12/05/06 “The Commons” The Tragedy of the Commons By Garrett Hardin, Science, 1968

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

13. A Small Dose of Toxicology Risk Assessment – 12/05/06 Problems – Solutions?  Lead and kids  Fetal alcohol syndrome  Nuclear disarmament  Bioterrorism  Ocean Fisheries  Persistent chemicals  The Commons

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

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

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

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

18. A Small Dose of Toxicology Risk Assessment – 12/05/06 Key Words of Toxicology Hazard X Exposure = Risk Individual Susceptibility Dose / Response

19. A Small Dose of Toxicology Risk Assessment – 12/05/06 Early Risk Assessment “What is food to one man may be fierce poison to others.” Lucretius (c. 99 B.C.–c. 55 B.C.)

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

21. A Small Dose of Toxicology Risk Assessment – 12/05/06  Developed in 1960-1970s  Concern over increased cancer rates  Expanded to non-cancer effects Modern Risk Assessment

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

23. A Small Dose of Toxicology Risk Assessment – 12/05/06 Steps in Risk Assessment  Hazard Identification  Exposure Assessment  Dose-Response Assessment  Risk Characterization

24. A Small Dose of Toxicology Risk Assessment – 12/05/06 What Hazard? Obvious Death, Cancer, Acid burn, Birth defect, asthma ….. Subtle Decreases in learning and memory (lead) Loss of potential Sensitivity of the individual (child)

25. A Small Dose of Toxicology Risk Assessment – 12/05/06 Hazard Identification Review human and animal data to determine if a chemical or agent has biological effects.

26. A Small Dose of Toxicology Risk Assessment – 12/05/06 Toxicity Endpoints  Carcinogenicity  Mutations  Altered immune function  Teratogenicity  Altered reproductive function  Neuro-behavioral toxicity  Organ-specific effects  Ecological effects (wildlife, environmental persistence)

27. A Small Dose of Toxicology Risk Assessment – 12/05/06 Exposure Assessment  Route of exposure (skin, oral, inhalation)  Amount of exposure (dose)  Duration of exposure  To whom (animals, humans, environment)  Children, other sensitive individuals

28. A Small Dose of Toxicology Risk Assessment – 12/05/06 Home environment Workplace (occupational) School Food Consumer products Global and local environment Exposure Issues

29. A Small Dose of Toxicology Risk Assessment – 12/05/06 Dose-Response Assessment How much exposure to a chemical or agent will cause what effect? Dose – Response

30. A Small Dose of Toxicology Risk Assessment – 12/05/06 Some Jargon LOAEL – Lowest Observed Adverse Effect Level (mg/kg) NOAEL – No Observed Adverse Effect Level (mg/kg) RfD – Reference Dose (mg/kg-day)

31. A Small Dose of Toxicology Risk Assessment – 12/05/06 Greater Dose – Greater Response Dose Response Threshold (NOAEL) ED50 LOAEL

32. A Small Dose of Toxicology Risk Assessment – 12/05/06  Hazard (including sensitive populations) –Low dose extrapolation  Exposure –Route of exposure, amount, duration dermal, oral, inhalation, injection –To Whom? Sensitive Individuals? Risk Characterization Risk = Hazard X Exposure

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

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

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

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

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

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

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

40. A Small Dose of Toxicology Risk Assessment – 12/05/06 Mercury & Toxicology

41. A Small Dose of Toxicology Risk Assessment – 12/05/06 The Mercury Cycle

42. A Small Dose of Toxicology Risk Assessment – 12/05/06 Atmospheric Hg

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

44. A Small Dose of Toxicology Risk Assessment – 12/05/06  Decrease in Brain Size  Cell loss  Disorganization of cells  Cell migration failures  Behavioral effects – learning and memory Effects On The Brain

45. A Small Dose of Toxicology Risk Assessment – 12/05/06 Fetal Effects of MeHg

46. A Small Dose of Toxicology Risk Assessment – 12/05/06  MONKEY - 25 µg/kg - LOAEL  RAT - 10 µg/kg - LOAEL  RAT - 50 µg/kg - replicated Animal - Risk Assessment

47. A Small Dose of Toxicology Risk Assessment – 12/05/06  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)

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

49. A Small Dose of Toxicology Risk Assessment – 12/05/06 MeHg Consumption Limits US EPA – 0.1 ug/kg-day US FDA – 1 ppm (mg/kg) in tuna

50. A Small Dose of Toxicology Risk Assessment – 12/05/06 "Lead makes the mind give way." Ancient Awareness Greek Dioscerides - 2nd BC

51. A Small Dose of Toxicology Risk Assessment – 12/05/06 Agency Blood Lead Levels

52. A Small Dose of Toxicology Risk Assessment – 12/05/06 Recycling Lead

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

54. A Small Dose of Toxicology Risk Assessment – 12/05/06 Developmental Data 2863 above 1 Million pounds 78.2% no data 21.4% some data 12 or 0.4% good data www.preventingharm.org

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

56. A Small Dose of Toxicology Risk Assessment – 12/05/06 Estimated Costs - National Best Estimate Low EstimateHigh Estimate Lead Poisoning $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)

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

58. A Small Dose of Toxicology Risk Assessment – 12/05/06 Adapted from Kraus and Slovic (1988), Risk Anal., 8: 435. Characteristics of Risk Characteristic Level Examples KnowledgeLittle knownFood additives Much knownAlcoholic drinks NewnessOldGuns NewSpace travel VoluntarinessNot voluntaryCrime VoluntaryRock climbing ControlNot controllableNatural disasters ControllableSmoking DreadednessLittle dreadVaccination Great dreadNerve gas CatastrophicNot likelySunbathing potentialLikelyWar EquityDistributedSkiing UndistributedHazardous dump

59. A Small Dose of Toxicology Risk Assessment – 12/05/06  Food coloring                 Saccharin Microwave ovens Aspirin Anesthetics Power Tools Alcohol Motor vehicles DNA Research Nuclear Power Asbestos Herbicides Pesticides Smoking Dynamite Warfare Handguns Risk Perceptions Catastrophic potential Involuntariness Personal risk Inequity Dread Newness Lack of scientific knowledge Exposure is unknown/unknowable Knowable Unknown Known DreadedLittle Dread

60. A Small Dose of Toxicology Risk Assessment – 12/05/06 The Potential of Children

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

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