1. A Small Dose of Risk Assessment – 2/27/04 An Introduction To Risk Assessment, Risk Management & Precautionary Principle A Small Dose of Risk Assessment Steven G. Gilbert, PhD, DABT www.asmalldoseof.org ENV H 472 A - ENVIRONMENTAL RISK AND SOCIETY Class 4

2. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Outline  Risk in context of society  Risk Management examples  Principles of risk assessment  Precautionary Principle  Seattle and WA State efforts

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

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

5. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Child Health

6. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Decision Making Risk Assessment and Risk Management in Context of Societal Issues

7. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Socially Responsibility What is social responsibility? What are our responsibilities to society?

8. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Socially responsible white guys?

9. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology "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 Risk Assessment – 2/27/04 A Small Dose of Toxicology “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 Risk Assessment – 2/27/04 A Small Dose of Toxicology “The Commons” The Tragedy of the Commons By Garrett Hardin, Science, 1968

12. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology The Tragedy Cattle Farmers Return on Investment Return for me Not the commons Society suffers

13. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology No Technical Solutions “It is our considered professional judgment that this dilemma has no technical solution.”

14. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Problems – Solutions?  Tick-tack-toe  Nuclear disarmament  Bioterrorism  Fish from the sea  Cancer  Lead and kids  Fetal alcohol syndrome  Commons ….

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

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

17. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Toxicology Issues / Solutions?  Cancer (soot & benzene ….)  Radiation exposure  Plant and animal toxins  Pesticides  Drugs  Lead and Mercury  Fetal alcohol syndrome  ….

18. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Freedom? Restriction of Freedom? Responsibility knowing the problem? What does toxicology say about managing the commons?

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

20. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Examples of Risk Risk Management Examples Alcohol Lead Mercury

21. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Ethyl Alcohol C H H H OHC H H

22. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology FAS Child

23. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Effects of Prenatal Alcohol

24. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Fetal Alcohol Syndrome (FAS) 1968 - Researchers at the Univ. of Nantes Early 1970’s FAS – Univ. of Washington 4,000-12,000 infants per year in US 1 to 3 births per 1,000 world wide?? Most common preventable cause of adverse CNS development

25. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Fetal Alcohol Effect (FAE) Milder form of FAS 7,000-36,000 infants per year in US World wide? Characteristics Growth deficiency Learning dysfunction Nervous systems disabilities

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

27. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Lead In Homes

28. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Lead in Families

29. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Recycling Lead

30. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Agency Blood Lead Levels

31. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Fetal Effects of MeHg

32. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Life-Long Effects of MeHg

33. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology The Mercury Cycle

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

35. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Precautionary Principle "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

36. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Key Words of Toxicology Hazard X Exposure = Risk Individual Susceptibility Dose / Response

37. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Early Risk Assessment “What is food to one man may be fierce poison to others.” Lucretius (c. 99 B.C.–c. 55 B.C.)

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

39. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology “One death is a tragedy. A million deaths is a statistic.” Joseph Stalin Perspective

40. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology  1775 – Percivall Pott – Occupational – cancer of scrotum in chimney sweeps  1895 – Bladder cancer in workers in aniline dye industry Historical Awareness

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

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

43. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Risk of What? Obvious Death, Cancer, Acid burn, Birth defect, asthma, Subtle Decreases in learning and memory (lead), Sensitivity of the individual (child)

44. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Risk Assessment Process of estimating association between an exposure to a chemical or physical agent and the incidence of some adverse outcome.

45. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Policy developed to deal with hazards identified through risk assessment Process of evaluating alternative regulatory options and selecting among them Risk Management

46. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Framework for RA and RM Identify hazards Characterize risks Control risks Epidemiology Toxicology In vitro tests Structure/Activity Analysis Potency Exposure Susceptibility Information Regulation Substitution

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

48. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Steps in Risk Assessment  Hazard Identification  Exposure Assessment  Dose-Response Assessment  Risk Characterization

49. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Hazard Identification Review human and animal data to determine if a chemical or agent has biological effects

50. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Hazard Identification  Research  Structure-Activity Analysis  Short-term Screening Tests  Animal Bioassays  Human Epidemiological Data

51. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Structure-Activity Analysis Does structure resemble that of a known toxic agent? Computer modeling

52. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Short-term Screening Tests Cell Culture, Tissue Culture Does the chemical or agent adversely effects cells?

53. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Animal Bioassays Animal Studies Does the chemical or agent causes effect animals? What is the potentially for human toxicity?

54. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Toxicity Endpoints  Carcinogenicity  Mutations  Altered immune function  Teratogenicity  Altered reproductive function  Neuro-behavioral toxicity  Organ-specific effects  Ecological effects (wildlife, environmental persistence)

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

56. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Human Epidemiological Human Studies Does the chemical or agent causes adverse effect in human populations?

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

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

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

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

61. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Exposure Assessment  Route of exposure (skin, oral, inhalation)  Amount of exposure (dose)  Duration of exposure  To whom (animals, humans, environment)

62. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Home environment Current events Workplace School Government Decisions (war) Global and local environment Exposure Issues

63. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Dose-Response Assessment How much exposure to a chemical or agent will cause what effect?

64. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Chemical Potency Dose Response Threshold (NOAEL ED50

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

66. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology  Uncertainty  Perception  Comparison  Education  Regulation Risk Management

67. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology How do you know? How good is the data? Uncertainty

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

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

70. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Reducing Uncertainty Upstanding mechanism of action Physiologically based pharmacokinetic models (distribution and metabolism) Sample size

71. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Comparing Risks  By probability  By expected value  By outrage  By exposure  By experts

72. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Annual Risk Of Death In The U.S. HAZARDRISK PER MILLION All causes9,000.0 Motor vehicle accidents210.0 Work accidents150.0 Homicides93.0 Drowning37.0 Poisoning, Solids/liquids17.0 Railroads0.9 Civil aviation0.8 Bits and stings0.2 “TO LIVE, IS TO RISK DYING”

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

74. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology  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  Lead Unknown Known DreadedLittle Dread

75. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Adapted from Slovic et al. (1979), Environ., 21: 14. Differences in Risk Perception Activity/Agent Rank by Risk Analyst Rank by non- Risk Analyst Motor Vehicles12 Smoking24 Alcohol36 Handguns43 Surgery510 Motorcycles65 X-rays722 Pesticides89 Electric Power918 Swimming1019 Nuclear Power201

76. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Structure of PBDEs X & Y are number of Bromine atoms Common Penta, Octa, and Deca PolyBrominated Diphenyl Ether O Br x Br y

77. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology PBDEs in House Dust (ppb) From EWG - Toxic Fire Retardants Contaminate American Homes - http://www.ewg.org/reports/inthedust/summary.php

78. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology PBDEs in Breast Milk (ppb) From EWG - Toxic Fire Retardants in Breast Milk from American Mothers - http://www.ewg.org/reports/mothersmilk/es.php

79. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Developmental Data 2863 above 1 Million pounds 78.2% no data 21.4% some data 12 or 0.4% good data www.preventingharm.org

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

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

82. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology The challenge “the knowledge of how to use knowledge for the social good” Knowledgeable Bioethics

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

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

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

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

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

88. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology  Improve decision making  Promote integrated assessments  Promote transparency  Promote sharing of information  Examine alternatives  Examine uncertainties  Encourage discussion among stake holders Purpose/Objectives

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

90. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Seattle Precautionary Principle White Paper (www.asmalldoseof.org) Inclusion of PP in Comp Plan Environment Element (http://www.seattle.gov/dpd/Planning/Seattle's_Compr ehensive_Plan/DPD_001178.asp) LinkLink Result of Effort

91. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology “Protecting Public Health by Adopting the Precautionary Principle as an Approach to Decision Making” Resolution Submitted to Washington State Public Health Association WSPHA Resolution

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

93. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Testifying Writing review papers K-12 class room teaching Adding expertise to community groups Education Mentoring Speakers Bureau Socially Responsible Actions

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

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

96. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology The Potential of Children

97. A Small Dose of Risk Assessment – 2/27/04 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)  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

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

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

100. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Authorship Information For Additional Information Contact Steven G. Gilbert, PhD, DABT E-mail: smdose@asmalldoseof.org Web: www.asmalldoseof.org This presentation is supplement to “A Small Dose of Toxicology”

101. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Statistical Model Fundamental Types of Uncertainty

102. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Easiest to examine & reduce Not knowing the exact value of a variable (inter and intra subject variance) Sample size Statistical Uncertainty

103. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Not fully understanding the relations between variables (mechanism of action) Which variables are most important (high dose vs low dose) Model or System Uncertainty

104. A Small Dose of Risk Assessment – 2/27/04 A Small Dose of Toxicology Not knowing the right questions to ask Most sensitive end point “we don’t know what we don’t know” Fundamental Uncertainty

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

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