Human Health Risk Assessment: Moving from Policy to Science

1. Human Health Risk Assessment: Moving from Policy to Science Michael Dourson Toxicology Excellence for Risk Assessment (TERA)

2. Toxicology Excellence for Risk Assessment (TERA) • Toxicology Excellence for Risk Assessment (TERA) is a non-profit, 501(c)(3) corporation organized for scientific and educational purposes.  • The mission of TERA is to support the protection of public health by… • developing,reviewing and communicating risk assessment valuesand analyses, • improving risk assessment methods through research, • and educating risk assessors and managers and the public on risk assessment issues.

3. Risk Assessment/Management BEST AVAILABLE TECHNOLOGY DOSE RESPONSE ASSESSMENT PUBLIC RESPONSE RISK CHARACTERIZ- ATION HAZARD IDENTIFICATION KIDS COST POLITICAL CONSIDERATIONS EXPOSURE ASSESSMENT ENGINEERING OPTIONS (National Academy of Sciences, 1983)

4. Risk Assessment/Management BEST AVAILABLE TECHNOLOGY DOSE RESPONSE ASSESSMENT MOS HI PUBLIC RESPONSE RISK CHARACTERIZATION COST HAZARD IDENTIFICATION MOE KISS MCLG NSRL POLITICAL CONSIDERATIONS Peer Review EXPOSURE ASSESSMENT ENGINEERING OPTIONS (National Academy of Sciences, 1983)

5. an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily oral (for RfD) or continuous inhalation (for RfC) exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. As Defined by EPA an Reference Dose (RfD) or Reference Concentration (RfC) Is……

6. RfDs and RfCs are considered to be accurate estimates of doses below a toxicity threshold, because they are based on a review of all toxicity data and individual uncertainty factors are considered to be somewhat protective. ....If you play golf, accurate drives are generally those that land in the fairway, although they may be scattered over a wide area. HOW ACCURATE ARE THESE ESTIMATES?

7. How Precise Are These Estimates? • Not very! Each uncertainty factor varies with ranges up to about 10-fold. Several factors are generally multiplied to estimate a subthreshold dose and some factors overlap, thereby increasing variability and decreasing precision. • .....If you play golf, precise drives are those that consistently land in one area of the fairway (or the creek).

8. Default Categorical Data Derived UFs Default Presumed Protective Biologically-based Protective New Concepts • Over the last several years, scientists have begun using more data when extrapolating dose response and choosing uncertainty factors • Methods range from default (“presumed protective”) to those incorporating more biological data (“biologically-based protective”) Meek et al, 2001

9. SLIGHT BODY WEIGHT DECREASE FAT IN LIVER CELLS (CRITICAL EFFECT) CONVULSIONS % Response ENZYME CHANGE Dose New Concepts Benchmark Dose Chemical Specific Adjustment Factors (CSAF) Categorical Regression Mode of Action

10. Benchmark Dose/Concentration • What is a Benchmark Dose/Concentrations (BMD/C)? • The dose/concentration producing a predetermined level of adverse effect. • For example, a 10% increase in animals developing liver necrosis. • A BMD/C is calculated by fitting a mathematical dose-response model to data.

11. 1 0.8 0.6 0.4 0.2 0 0 50 100 Example of Calculation of a BMD for a Given Incidence or Tumor Response BMD BMD Lower Bound % animals responding NOAEL BMDL BMD 150 200 dose

12. New Concepts:Example of Default UF Hg Oral RfD EPA, 2001

13. Observed Range of CNS Effects in Faroe Children Percent Children With CNS Effects Methyl Mercury Dose (µg/kg-day) 10

14. Kinetics Dynamics 4.0 2.5 Interspecies Intraspecies 3.2 3.2 New Concepts:Chemical Specific Adjustment Factors (CSAFs) • Renwick (1993) proposed breaking the interspecies and intraspecies UFs into toxicokinetic (TK) and toxicodynamic (TD) components • This approach was modified by World Health Organization- International Programme on Chemical Safety as follows: IPCS, 1994; 2001

15. New Concepts: Interindividual Variability in Ingested Hg a Corresponding to either 1ppm Hg in hair or 1ppb in blood NAS, 2001

16. Kinetics Dynamics 1 1 Interspecies Intraspecies 3.2 1.8 New Concepts:Example of Chemical Specific Adjustment Factors (CSAF) & Categorical Default for Hg Total UF = 5.8 Methyl Hg RfD = 2 E-4 mg/kg-day Dourson et al., 2001

17. New Concepts: Ingested Hg NAS, 2001 Predicted mean probability of MeHg intake corresponding to 11ppm MeHg in hair.

18. New Concepts: Compare ingestion rates (g/kg/day) of Seychelles studies from either deterministic approach or Monte Carlo approach (ICF Kaiser. 1998)

19. Distribution of RfD Values Percentile RfD(g/kg/day) 1 0.29 5 0.35 10 0.38 25 0.44 50 0.53 75 0.63 90 0.77 95 0.86 99 1.10 Methylmercury ingestion associated with BMDL in Seychelles population. New Concepts:RfD Based on a Monte Carlo 1st 2nd ÷ 3 UF for database 3rd

20. Summary of Hg Example • Limited scientific data supports use of default uncertainty factor for intra-species variability of 10 (Hg RfD = 1 E-4) (EPA, 2001). • Newer methods on categorical defaults allow replacement of defaults with compound specific data (Hg RfD = 2 E-4) (Dourson et al., 2001). • Monte Carlo Analysis requires more data but allows probabilistic approach to RfD determination (1st percentile Hg RfD = 3 E-4) (ICF Kaiser. 1998).

21. Categorical Regression RfD Definition Regression model "without appreciable risk" r < 10-2 "is likely to be" P(*) > 0.95 "deleterious effect" severity = moderate or frank New RfD Definition P ( r < 10-2 at dose<RfD ) > 0.95 where r = P (severity >1)

22. Aldicarb Clinical Studies

23. Effect Categories of Aldicarb Exposure in Humans

24. Probability of Effects with Aldicarb

27. Under the EPA (2005) Guidelines for Carcinogen Risk Assessment: • Chloroform is likely to be carcinogenic to humans by all routes of exposure under high-exposure conditions that lead to cytotoxicity and regenerative hyperplasia in susceptible tissues. • Chloroform is not likely to be carcinogenic to humans by any route of exposure under exposure conditions that do not cause cytotoxicity and cell regeneration. • EPA has determined that the RfD can be considered protective against increased risk of cancer.

29. Detailed Graphical Representation of Chloroform Extrapolations BMDL

30. EPA’s Postulated Mode Of Action Chloroform CYP2E1 Metabolism Oxidative Phosgene Sustained Toxicity Regenerative Cell Proliferation Key Events Tumor Development

31. Mutagenicity: Conclusions • Weight of Evidence • Mutagenicity is not a component of chloroform induced neoplasia

32. Metabolism: Conclusions • Predominate pathway • P450 (CYP2E1)-mediated oxidative pathway • Phosgene key reactive metabolite • The following play little, if any role in chloroform induced tumors-- • Reductive P450 metabolism & free radical production • GST catalyzed conjugation

33. Toxicity-Regenerative Proliferation • Strong association of doses that cause sustained toxicity-proliferation & tumors • No persistent toxicity-proliferation in organs that do not show tumors • Tumors are preceded by toxicity-proliferation Conclusions

34. Mode of Action: Human Relevance Key steps are basic biochemical and cellular events in common to rodents & humans Oxidative CYP2E1 Metabolism Cell Injury & Death Regenerative Proliferation

35. MOA Conclusions for Chloroform Postulated MOA Well Supported Other MOAs NOT Well Supported Human Relevance Presumed Applies to Children (but not more susceptible) Consistent with Nonlinear Dose Response Risk Approach Based on Protection Against Sustained Toxicity/Proliferation

36. Summary of Traditional Approach & New Methods • Estimates of “safe” doses/concentrations are... • accurate but imprecise • believed to be without risk, but cannot estimate risk • Benchmark Dose, Chemical Specific Adjustment Factors (CSAF) Categorical Regression & Mode of Action analysis • ask different questions of the data • are not alternatives to each other • nor are they alternatives to the current “Safe” dose • Methods of combining two or more of these approaches are being used.

37. What is Peer Review? • Involves review of a draft product for quality by specialists who were not involved in its preparation. • Evaluation of assumptions, alternate interpretations, methodologies, and conclusions. • Reviewers have training & experience = to authors. • Peer reviewers should be independent of authors and sponsoring organizations. • Review serves to ensure that quality meets the standards of the scientific community. • Peer Review is not the same as public comment.

38. For a Peer Review to be Credible, it Must be Independent • Authors/sponsors should not participate in selection of peer reviewers. • Candidates should be carefully screened for conflict of interest and biases. • Panels should include reviewers with diverse perspectives and backgrounds. • List of questions (charge) for reviewers should cover key issues and be objective. • Reviewers must be provided with necessary documentation. • Process should be public and transparent. • Sponsors and authors should have limited interaction with the reviewers.

39. Conflict of Interest (COI) National Academy of Sciences (NAS) procedures for panel selection NAS defines a conflict of interest as “any financial or other interest which conflicts with the service of the individual because it… • could significantly impair the individual’s objectivity • could create an unfair competitive advantage for any person or organization. …” The term ‘conflict of interest’ means something more than individual bias. There must be an interest, ordinarily financial, that could be directly affected by the work of the committee.”

40. Bias NAS procedures for panel selection onbias… “Questions of lack of objectivity and bias ordinarily relate to views stated or positions taken that are largely intellectually motivated or that arise from the close identification or association of an individual with a particular point of view or the positions or perspectives of a particular group.” • Biases are not necessarily disqualifying, but a balance of potentially biasing backgrounds or professional or organization perspectives is needed. • Some potential sources of bias may be so substantial that they would prevent an individual from considering others perspectives or relevant evidence contrary to their strongly held position.

41. Panel Selection Procedures • Identification of scientific expertise necessary to address key issues. • Search for appropriate candidates, evaluate credentials. • Contact most promising candidates for interest and availability. Query them on conflicts of interest and biases. Avoid candidates with conflicts and substantial biases. • Select a panel of independent experts, that is balanced with regard to necessary disciplines, biases, and has a diversity of perspectives.

42. Some Independent Peer ReviewsOrganized by TERA • Captan carcinogenicity classification. • Resorcinol safe dose for Pennsylvania clean up. • World Trade Center Residential Clean up Levels. • Voluntary Children’s Chemical Evaluation Program. • Texas CEQ review of methods for estimating values See http://www.tera.org/peer for meeting reports

43. World Trade Center Residential Assessment  • Meeting held in NYC, October 2002. • Document prepared by federal, state and city agencies: U.S. EPA, NYC, ATSDR. • TERA selected panel and organized meeting. • Public invited to nominate experts, attend meeting to observe, submit oral and written comments. • Final report summarized discussions, and conclusions. Included copies of public comments.

44. Texas Commission on Environmental Quality (TCEQ) • A panel of expert scientists conducted a Peer Review of a technical guidance document prepared by the (TCEQ), State of Texas. • Technical guidance describes the process used by staff of the Toxicology Section to develop Effects Screening Levels, Inhalation Reference Values, and Unit Risk Factors. • Panel made numerous recommendations for improvements. • TCEQ revised its methods. http://www.tceq.state.tx.us/implementation/tox/esl/peer_rev/PRmain.html

45. Alliance for Risk Assessment (ARA) • Partnership with the National Library of Medicine • Serves as shared resource to facilitate collaborative risk issue resolution among stakeholders. • Designed with input from colleagues from over 30 States, federal agencies, tribes, and NGOs, who need a more timely & constructive way to resolve issues.  • Example: uncertainty in determining appropriate risk values to use for chemicals like TCE has spurred interest from state and local risk assessment colleagues.

46. Alliance for Risk Assessment (ARA) Stakeholder Process Alliance “Menu” Options States, Fed. Agencies, Public Interests, Industry Steering Committee Risk Document Development Initiation of Risk Issue Training and Certification Non-profit Collaborators Risk Information Exchange (RiskIE) Risk Communication Document Draft Risk Research And Tools Peer Reviews Peer Consult Peer Review Release to Public ITER

47. International Toxicity Estimates for Risk (ITER) Database • Part of the National Library of Medicine. • Free web-based data. • Contains peer-reviewed risk values for more than 600 chemicals from 5 agencies, plus independent groups. Agencies include: ATSDR, EPA IRIS, Health Canada, RIVM (the Netherlands), NSF Int. • Used by over 500 risk assessors daily. • Provides a central source for peer-reviewed risk values to foster data sharing. http://www.tera.org/iter

48. NLM’s Toxnet

49. Extra Slides

50. Pennsylvania-Resorcinol • A reference dose (RfD) for resorcinol was prepared by AMEC Earth and Environmental, Inc for Beazer East, Inc. • RfD (safe dose) developed to inform risk-based clean up decisions under Pennsylvania Department of Environmental Protection (DEP) regulations. • Authors revised assessment with peer review panel recommendations. • Panel’s recommendations accepted by the Science Advisory Board of PA DEP.