INTRODUCTION TO RISK ASSESSMENT

1. INTRODUCTION TO RISK ASSESSMENT THE RISK ASSESSMENT/RISK MANAGEMENT PARADIGM ASPH ENVIRONMENTAL HEALTH CONFERENCE, Minneapolis 12 July, 2004 Gilbert S. Omenn, M.D.,Ph.D. University of Michigan

3. “The Perils of Wizardry”(Judge David Bazelon, ~1979) • Premise: regulatory issues tend to recur, so it is important to build a useful record • Technical experts (inside & outside the agency) should: -- stay away from the ultimate policy decision, not their charge or special expertise -- delineate the specific elements of the risk characterization -- focus on those specific elements/build the record -- expect to be asked again!

4. “The Red Book” (1983) • Should regulatory-relevant research be organizationally separated from regulatory policy-based decision-making? Recognize different models: NIOSH/OSHA, CPSC reliance on outside (NAS), considerable scientific capability within FDA and EPA • Red Book embraced variety, but favored more interaction, rather than less, between research and regulatory programs and offices, as in EPA and FDA • Red Book promulgated the hazard identification, risk characterization, risk management framework instead

5. Presidential/Congressional Commission on Risk Assessment and Risk Management (1994-97) Peter Y. Chiu, MD, Kaiser Permanente, San Francisco Alan C. Kessler, LLB, Buchanan Ingersoll, Philadelphia Sheila McGuire, PhD, Iowa Health Research Inc, Boone, IA Norman Anderson, American Lung Assn, Augusta, Maine David P. Rall, MD, PhD, former director, NIEHS;Washington, DC John Doull, PhD, Toxicologist, Kansas Univ, Kansas City, KS Joshua Lederberg, PhD, former president, Rockefeller Univ, NYC Gilbert Omenn, MD, PhD, Dean, Univ of Washington SPH, Seattle Virginia V. Weldon, PhD, VP Monsanto Company, St. Louis, MO Bernard Goldstein, MD, Univ Med/Dentistry, Piscataway, NJ Staff: Gail Charnley, PhD; Sharon Newsome; Joanna Foellmer

7. Mandate Uses and limitations of risk assessment in decision-making Appropriate exposure scenarios Uncertainty and risk communication Risk management policy issues Consistency across agencies

8. Topic Areas Addressed by the Commission Risk assessment science & models Risk-management framework Communicating uncertainty Peer review Inter- and intra-agency consistency “Bright lines” Sensitive subpopulations Ecologic risk assessment Comparative risk assessment Economic analysis Judicial review

9. Objectives of Risk Assessment 1.Balance risks and benefits Drugs Pesticides 2. Set target levels of risk Food contaminants Water pollutants 3. Set priorities for program activities Regulatory agencies Manufacturers Environmental/consumer organizations 4. Estimate residual risks and extent of risk reduction after steps are taken to reduce risks

10. Major Hazardous Chemical Laws in the United States EPA: Air Pollutants Clean Air Act 1970, 1977, 1990 Water Pollutants Fed WP Control Act 1972, 1977 Safe Drinking Water Safe DW Act 1974, 1996 Pesticides FIFRA 1972 Food Quality & Protection FQPA, 1996 Ocean Dumping Marine Protection Act, 1995 Toxic Chemicals TSCA 1976 Hazardous Wastes RCRA 1976 Hazardous Waste Cleanup CERCLA (Superfund) 1980, 1986 FDA: Foods, Drugs, Cosmetics FDC Acts, 1906, 1938, 1962, 1977, 1997 CEQ: Envtl Impacts NEPA, 1972 OSHA: Workplace OSH Act, 1970 CPSC: Dangerous Consumer Products CPS Act, 1972 DOT: Transport of Haz Materials THM Act, 1975-79, 1984, 1990

11. Cancers Mutations Birth defects Reproductive toxicity Immunological toxicity Biological End-Points Neurobehavioral toxicity Organ-specific effects Endocrine modulation / disruption Ecosystem effects

12. Context • Multiple sources of same agent • Multiple media/pathways of exposure • Multiple risks/effects of same agent • Multiple agents causing same effects • Public health: status / trends • Ecological health • Social, cultural, environmental justice considerations

13. Context Move beyond one chemical, one environmental medium (air, water, soil, food), one health effect (cancer, birth defect…) at a time in risk assessment and risk management: requires comprehensive public health view

14. Framework for Regulatory Decision-Making Epidemiology Hazard Identification Lifetime rodent bioassays Short-term, in vitro/in vivo tests Structure / activity Potency (dose/response) Risk Characterization Exposure analysis Variation in susceptibility Information Risk Reduction Substitution Regulation / Prohibition

15. Data Gaps: “Toxic Ignorance” • Only 7% of high production volume (HPV) chemicals have full set of studies for 6 basic endpoints, while 43% of HPV chemicals have no publicly available studies for any of 6 basic toxicity endpoints (EPA, 1998) • Environmental Defense Fund report “Toxic Ignorance” and OECD stimulated new commitments to test (SIDS)

16. Epidemiology •  Analyzes human effects; requires human exposures •  Avoids extrapolation from animals; requires • exclusion of confounding factors •  Usually insensitive -- limited sample size, as well as • uncertainties… • Occupational populations -- higher exposures, better exposure estimates, small numbers •  General population -- lower exposures, more • uncertainties, larger numbers (potentially)

17. A.B. Hill Criteria to Evaluate Epidemiological Associations • Strength of association • Consistency • Specificity • Temporality • Biologic gradient • Biologic plausibility and coherence • Experimental evidence • Analogy

18. The Crucial Influence of Heterogeneity • Important to research strategies on mechanisms, diagnosis, treatments, preventive interventions, and testing • Need to speak of “cancers” in the plural: the illusion of “The War on Cancer” (1970) • Emergence of new signaling pathways, receptors, molecular targets, and mRNA and protein expression patterns • Ramifications of subpopulation analysis: pharmaco-genomics and personalized medicine

19. The Current Transformation of Epidemiology MOVE BEYOND STATISTICAL ASSOCIATIONS Etiology: Test hypotheses of mechanism Link to similar studies in animals Use biomarkers -- of exposure -- of effect -- of susceptibility Use gene expression & proteomic arrays Reduce latent period for cancers if intermediate endpoints can be validated.

20. The Current Transformation of Epidemiology Validate Hypothesis: modify or remove risk factors Chemoprevention & behavior change trials • Anti-oxidant vitamins: beta-carotene, C, E (CARET, ATBC, PHS) • Vitamin A, retinoids • Folate •  GSH Need validated intermediate endpoints Monitor emissions, exposures, effects after risk reduction actions

21. Animal Bioassays Standard protocols Experimental control of variables Limitations  Statistical criteria - determine “positive” / “negative”  Mechanisms of action and differences in metabolism seldom investigated: “black box”, odd sites  Choice of species, strains, dose, route of exposure, time course of exposure, exposure mixtures…  Extrapolations required - animal to humans, high dose to low dose  High costs and many years required

22. Developments in Rodent Studies • Focus on toxicity and proliferation Recognize non-linear D/R curve for certain cancers Apply molecular biology to address mechanisms Use transgenics and other new rodent models for tests • Use physiologically-based pharmaco-kinetic (PBPK) models • Add biomarkers: target dose, early effect, susceptibility • Weigh evidence • Apply “Value-of-information model (Lave & Omenn) • interpretation of results • strategies for testing • Consider multiple exposures and interactions (relevant to humans)

23. Problems with Lifetime Rodent Bioassay • Many compounds carcinogenic only at doses at or near maximal tolerated dose • Concordance of results only 70% between rats and mice: unlikely that concordance with humans would be higher • Observable range for cancer endpoint: 12- 100% incidence, but regulatory requirement to protect below 0.0001% upper-bound estimated risk: modes of action and extrapolation models crucial

24. Rodent Carcinogenic Responses Not Likely to Apply in Humans Tumor Site Illustrative Chemical Agents Male Rat Kidney D-limonene, unleaded gasoline Male Bladder Saccharin, nitrilotriacetic acid Rat Thyroid EBDC fungicides, goitrogens Forestomach-only (after gavage) BHA, propionic acid, ethyl acrylate Mouse Liver Certain classes of liver carcinogens (McClain, 1994; EPA, 1996; Risk Commission, 1997)

25. Potency/Dose-Response  Determination of critical health effect  Evaluation of strength-of-evidence  Choice of data set(s) - for quantitative analyses of effects in relation to exposure doses  Essential extrapolation from observations at high dose to exposure at low dose: assumptions and policies  Linear or linearized multistage model  95% UCL “worst case”  Benign, as well as malignant, tumors  Use of strikingly positive data set

26. Toxicogenomics and Toxicoproteomics: NIEHS Environmental Genome Project • Develop molecular signatures for effects of carcinogenic, mutagenic, teratogenic, and other toxic agents • Test known carcinogens for distinctive patterns--benzidines, beta-naphthylamine, benzene, bis-chloromethyl ether, nitrosamines, ?asbestos, …in animal models • Test chemopreventive agents in animal models and organ and cell cultures

27. A Golden Age for the Public Health Sciences Sequencing the human genome will generate an avalanche of genetic information to be linked with information about: • Nutrition and metabolism • Lifestyle behaviors • Diseases and medications • Microbial, chemical, physical exposures

28. The Post-Genomic Era Will Depend Upon the Public Health Sciences • Epidemiology -- All the factors that play upon/determine the expression of genetic variation identified in sequences; role of biomarkers • Biostatistics & Bioinformatics -- Platforms and methods for designing studies and for analyzing the avalanche of data • Environmental Health Sciences / “Eco-Genetics” -- Understanding the host variation in host/agent interactions; risk assessment/risk management

29. Post-Genomic Era (con’t) • Pathobiology / Infectious Diseases • Host-pathogen genomic interactions • Host-pathogen-environmental interactions • Behavioral Sciences • Genetic predispositions to aspects of smoking behavior and other unhealthful behaviors • Health Services Research Fields • Designing and assessing well-targeted, cost-effective genetic clinical and preventive services that improve quality of life

30. Both Genetics and Public Health • Focus on populations • Need more information about heterogeneity of genetic predispositions, environmental exposures, disease risks, and responses to interventions. • Explicitly recognize cultural, societal, ethnic, and racial contexts. • Are sensitive to risks of discrimination.

31. Lave-Omenn Value-of-Information (VOI) Model (Nature, 1986; Nature 1988; Mut Res 1988) • Strategies for testing chemicals • Modeling for social costs of testing and of consequences of false-positives and false- negatives • Implications for risk management: Quantitative risk estimation versus • ALARA (as low as reasonably achievable)

32. VOI Model Applied to Rodent Bioassay and Risk Management for Humans If concordance of rodent bioassay to true effect in humans is below 70%, or likelihood of chemical being carcinogenic is below 10%, social cost is less if classify all as non-carcinogenic. If likelihood chemical is carcinogenic is 50% or more, use of the rodent bioassay (@$1M/bioassay) is more costly than classifying the chemical as a carcinogen without further testing IARC listed 26 chemicals or groups of chemicals as showing definite evidence of carcinogenicity for humans: either few chemicals are carcinogens, or few of the carcinogens are potent enough and reach enough people to have been recognized in humans as carcinogenic.

33. Short-Term Tests Advantages: short time, low cost, information about mechanisms; can apply new toxicogenomics approaches Need scientific and regulatory strategies to develop test batteries and tier testing schemes that will assist decisions Limitations •  Validity •  Variety •  Lack of decision rules/ “cut points” • to evaluate +/- results • to make decisions • to weight for false-positive and false-negative consequences •  Will short-term tests simply add to regulatory requirements, • or will these tests replace bioassays?

34. NIEHS/NTP Carcinogen Prediction Challenge (Ashby, Tennant, 1990, 1994; Omenn 1996) • 40 chemicals; 10 sets of predictions • All 10 chemicals nearly everyone predicted would be carcinogenic proved positive in the rodent bioassay • Of 9 chemicals nearly unanimously predicted to be noncarcinogenic, 6 were and other 3 had equivocal results • But 21 of the 40 had highly variable correlations and predictions

35. Exposure Analysis  Sources  Pathways  Environmental transformations  Routes of entry  Time course of exposures  Concept of total exposure  Need for translation from ambient levels to target tissue effective dose  New methods for tissue burdens and dosimetry

36. Mixtures  Test real world chemical mixtures: diesel exhaust urban smog actual effluents pesticide combinations workplaces  Assume additivity of risks as default; use mechanisms, if known  Pay attention to radiation and microbial exposures/risks

37. Impetus for Susceptibility Analysis • Clinical Occupational Medicine - “Why me, Doc?” • OSH Act requires that standards be set “so that no worker…shall suffer adverse effects.” • Clean Air Act requires standards set to protect “most susceptible subgroups.” • Food Quality & Protection Act requires protection of children and other vulnerable subpopulations. • To discover mechanisms or markers for diseases that may appear only years later -- and could be prevented: getting inside the “black box”

38. Eco-Genetics Known inherited predispositions to: Drug chemicals Pesticides Inhaled pollutants Foods Food additives Sensory stimuli Allergic & sensitizing agents Infectious agents

39. Eco-Genetic Polymorphisms Tissue susceptibility G6PD deficiency Alpha-1 anti-trypsin deficiency Biotransformation enzymes Acetylator phenotype Debrisoquine hydroxylation (Carbon oxidation - P450) Paraoxonase activity

40. Acetylator Phenotype: bimodal distribution of plasma level of active drug (INH) @ 6 hours after standard dose Genetics: Single gene Enzyme: N-acetyl-transferase in liver Other drugs that require acetylation hydralazine dapsone & other sulfas phenalzine cyclophosphamide What about occupational or environmental chemicals that are detoxified by acetylation? Industrial anti-oxidants Beta-naphthylamine Benzidines, biphenyls

41. Genetic Toxicology Mutagens Ames tests Adducts Mutations Chromosomal aberrations Sister chromatid exchange (SCE) Oncogene activation  DNA repair

42. Various Risk Mgt/Risk Communication Approaches Engagement of stakeholders: learning the issues and questions; finding what might be “acceptable”Risk-based (chemicals): de minimus Maximal contaminant levels (foods, water): bright linesComparisons of similar risksPrecautionary principle: Hippocrates’ “Do No Harm”ALARA: As-low-as-reasonably-achievable Substantial equivalence (recombinant DNA)Best-available technology (Clean Air Act)Benefit-cost analysis

43. “ I know no safe depository of the ultimate powers of society but the people themselves; if we think them not enlightened enough to exercise their control with a wholesome discretion, the remedy is not to take it away from them, but to inform their discretion.” - Thomas Jefferson

44. Reducing risk by orders of magnitude is not equivalent to linear reductions Risk Commission, Final Report, 1997

45. The Rush to Substitutes  TRIS--flammable sleepwear Red dye 2/red dye 40 Cyclamates/saccharin Nitrilotriacetic acid/phosphate detergents Gasoline/MTBE (fuel oxygenates)

46. Estimates of Median Cost per Year of Life Saved INTERVENTION COST Childhood immunizations Saves $ Prenatal care Saves $ Flu shots $600 Water chlorination $4,000 Pneumonia vaccination $12,000 Breast cancer screening $17,000 Construction safety rules $38,000 Home radon control $141,000 Asbestos controls $1.9 million Radiation controls $27.4 million Wall Street Journal 7/6/94, Tengs et al, Risk Analysis, 1995:

47. Current Issues, Bush Administration • Arsenic in Drinking Water Bush Administration/EPA Administrator Whitman: Pull the regulation to re-study via NRC • Global Warming/Kyoto Agreement Admit uncertainties Point to context of conservation of energy resources and need for efficient energy conversion (Evans Report 1991) • Mercury emissions to air (and water) from power plants and hospitals

48. Medical School Administration: Precautionary Principle • According to Treaty on European Union (1992), basis for European environmental law: beware new technologies with uncertain effects. Numerous definitions/formulations. • Rio Declaration (1992): “Lack of full scientific certainty shall not be used as a reason for postponing cost-effective measures to prevent environmental degradation.” • Initial application: prevention of ocean dumping of pollutants. • Point of view may depend upon application: prevention of introduction of hormone-treated beef or genetically-modified crops/foods versus desire to require environmental remediation. • 1998-99: Italian, Swiss, New Zealand policies for radio frequency fields, starting with international exposure guidelines without any consistent evidence of hazard at low levels of exposure

49. European Commission Communication on Precautionary Principle Brussels, 2 Feb 2000 Builds on US NRC “Red Book” framework for Risk Assessment Requires identification of a potentially hazardous effect to trigger Seeks assessment of uncertainties and wide range of actions Guidelines: Provisional decisions under uncertainty Proportionality---actions related to desired level of protection Non-discrimination--comparable and different situations Consistency--lessons from situations with ample science Analysis of benefits and costs Scientific research should be continued to gain needed data

50. A Public Health View on the “Precautionary Principle” The environmental regulatory agencies are dominated by attorneys, engineers, environmental exposure assessors, and economists, with relatively few, if any, public health and preventive medicine professionals. The traditional PREVENTIVE approach at all levels of public health is often lacking…Two solutions are training in public health and disease prevention for staff of environmental agencies and adequate leadership in these agencies from public health and preventive medicine specialists. -----former UC Berkeley SPH Dean, Dr. Patricia Buffler