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Drs. Vicki Dellarco Anna Lowit Health Effects Division Office of Pesticide Programs

Slide 2 of 38. Uses of Mechanistic Data in Risk Assessment . Identify Key biological (precursor) events leading to adverse toxicities (Mode of Action)InformHuman relevance of animal findingsDose response extrapolationLife stage susceptibilitiesUnderstandCommon pathways of toxicity (cumulativ

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Drs. Vicki Dellarco Anna Lowit Health Effects Division Office of Pesticide Programs

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    1. Slide 1 of 38 Drs. Vicki Dellarco & Anna Lowit Health Effects Division Office of Pesticide Programs Mode of Action/ Human Relevance Analysis For Incorporating Mechanistic Data in Human Health Risk

    2. Slide 2 of 38 Uses of Mechanistic Data in Risk Assessment Identify Key biological (precursor) events leading to adverse toxicities (Mode of Action) Inform Human relevance of animal findings Dose response extrapolation Life stage susceptibilities Understand Common pathways of toxicity (cumulative risk assessment) Promote Consistent harmonized approach to risk assessment for all health endpoints

    3. Slide 3 of 38 II

    4. Slide 4 of 38 Mode of Action Framework EPA’s Guidelines for Carcinogen Risk Assessment 1996 Proposed Revisions put forth the notion of understanding mode of action versus mechanism of action 1999 Interim Guidance introduced mode of action framework 2005 Final Guidance minor rewording of MOA framework

    5. Slide 5 of 38 Mode of Action Framework Postulated mode of action Identify sequence of key events on the path to cancer Experimental support Concordance of dose-response for key events with that for tumors Temporal relationships for key events & tumors Biological plausibility & Coherence Strength, consistency & specificity Other modes of action Identify uncertainties Conclusion

    6. Slide 6 of 38 Human Relevance Framework Risk Sciences Institute-ILSI Comparability or concordance analysis of the key events & relevant biology between the laboratory species & humans Tumor Responses: Meek et al., 2003, Critical Reviews in Toxicology Vol 33/Issue 6, 581-653 Reproductive, Developmental, Neurtoxocity Responses: Seed et al., 2005 Critical Reviews in Toxicology Vol 35/Issue 8-9, 63-781 extended human relevance analysis to include mutagenic carcinogens & noncancer end points WHO/IPCS Human Relevance Framework (in preparation)

    7. Slide 7 of 38 Human Relevance Framework Based on three analyses: Is the Weight of Evidence sufficient to establish a MOA in animals (MOA Framework)? Are the key events in the animal MOA plausible in humans? Taking into account kinetic/dynamic factors, is the animal MOA plausible in humans?

    8. Slide 8 of 38

    9. Slide 9 of 38 Assessing an Animal Mode of Action General Points: Applicable to all chemicals, to all endpoints, and to all modes of action Evaluation of MOA for tumors or (other adverse effects) in different organs MOA in different organs may or may not be the same Site concordance between animals & humans

    10. Slide 10 of 38 Assessing an Animal Mode of Action General Points: When a substance operates via a novel MOA, the analysis is focused on the chemical & entails a detailed evaluation via the MOA Framework When a substance produces an adverse effect consistent with an already established & peer reviewed MOA through which other chemicals have been shown to operate, the analysis is focused on the established MOA & a determination of whether the substance operates via the same key events established for the pathway

    11. Slide 11 of 38 Assessing an Animal Mode of Action for Human Relevance General Points: Concordance Analysis of key events is for the MOA & is not necessarily a chemical specific evaluation. Chemical specific & generic information relevant to the toxicity process can be valuable

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    14. Slide 14 of 38 Case Study Cacodylic Acid (Dimethylarsinic acid)

    15. Slide 15 of 38 DMAV Mode of Action Science Issue Paper: “Mode of Carcinogenic Action for Cacodylic Acid (Dimethylarsinic Acid, DMAV) and Recommendations for Dose Response Extrapolation” (July 26, 2005) http://www.epa.gov/oppsrrd1/reregistration/cacodylic_acid/ Revised issue paper will be publicly available this spring. EPA’s Science Advisory Board (SAB) reviewed the special issue paper in September, 2005 Draft SAB report December 27, 2005

    16. Metabolism of Arsenic

    17. Slide 17 of 38 DMAV: MODE OF ACTION ANALYSIS Extensive experimental cellular and laboratory animal data

    18. Slide 18 of 38 DMAV: Available Cancer Data No epidemiology data Standard rodent bioassay Bladder carcinogen in rats via feed -100 ppm (9.4 mg/kg bw per day) via drinking water- 50 & 200 ppm females more sensitive than males Not carcinogenic in mice Up to 500 ppm in B6C3F (Gurr et al., 1989) 121 ppm in C57 XC3H/Anf or AKR (NCI 1969)

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    22. Slide 22 of 38 Cacodylic Acid: Key Events Temporal Relationship

    23. Slide 23 of 38 Cacodylic Acid: Key Events Cytotoxicity/Regenerative Proliferation Strength, Consistency & Specificity Consistency of association found in repeated experiments within a lab & among different labs Inhibition of DMAV ?DMAIII reduced cytotoxicity Cessation of exposure to DMAV results in recovery of tissue (i.e., hyperplasia) Biological Plausibility & Coherence Regenerative proliferation associated with persistent toxicity appears to be a risk factor for bladder cancer in humans

    24. Slide 24 of 38 Characterization of Cacodylic Acid’s Genotoxicity Neither DMAV or DMAIII are direct acting point/gene mutagens Both are clastogenic but DMAIII is the more potent In vitro data only DNA damage appears to result from an indirect mechanism (ROS/oxidative damage) DMAIII ? DMAV

    25. Slide 25 of 38 Chromosomal Aberrations For the oxidative DNA damage to be relevant to the carcinogenic process (i.e., clonally expanded), stable chromosomal mutations must be formed Formation of chromosomal mutations requires DNA replication because chromosomal alterations are produced by errors of replication on a damaged DNA template. frequency of chromosomal mutations will be a function of the regenerative proliferative response. All these events--genetic errors, cytotoxicity, stimulation in cell proliferaiton -- must occur to result in bladder tumors.

    26. Slide 26 of 38 Other Modes of Action or Key Events No other MOA with sufficient scientific support Direct DNA reactivity Formation of solids Changes in urinary chemistry & physiology

    27. Slide 27 of 38 Mode of Action Conclusions Sequence of key events leading to bladder tumors measurable & supported by robust data Biologically plausible Uncertainties do not discount scientific support cellular target for cytotoxicity not understood unknown cytotoxic metabolites found in urine (after drinking water exposure)

    28. Slide 28 of 38 Human Relevance of DMAV’s Mode of Action

    29. Slide 29 of 38 Concordance Analysis of Key Events in Rats & Humans: Qualitative & Quantitative Plausibility

    30. Slide 30 of 38 DMAV Mode of Action (MOA) The SAB concurred with EPA’s conclusions Rat data developed for DMAV most appropriate data for quantifying cancer risk MOA for the development of bladder tumors in rats established The rat MOA is expected to be plausible in humans The MOA supports nonlinear extrapolation of cancer risk to DMAV

    31. Slide 31 of 38 Dose response extrapolation approach Dose response extrapolation should be based on considerations of MOA which supports nonlinearity Must be sufficient DMAIII to produce cell killing & sufficient cell killing to lead to regenerative proliferation Cytotoxicity & enhanced proliferation need to be sustained Frequency of chromosomal mutations dependent on enhanced proliferation & on generation of ROS (DMAIII ?DMAV) Point of Departure based on cell proliferation should be protective of DMA’s carcinogenic & promoting effects

    32. Slide 32 of 38 Dose Response Considerations Cancer Guidelines describe a two-step dose-response process which separates Modeling the observable range of data Extrapolation to lower doses Nonlinear extrapolation Preferred approaches PBPK Model--internal dosimetry at the target tissue e.g. DMAIII BBDR Model—predict biological effect e.g., two stage clonal growth Interim approach Identify a point of departure (POD) based on benchmark dose modeling Apply uncertainty and safety factors

    33. Slide 33 of 38

    34. Slide 34 of 38 Benchmark Dose Modeling: Regenerative Proliferation

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    37. Slide 37 of 38 Summary Human Relevance Framework Identify key events Assist in dose response assessment Assist in rodent to human extrapolation Promote harmonization of risk assessment for all endpoints

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