Science Issue Paper: Mode of Carcinogenic Action for Cacodylic Acid (Dimethylarsinic Acid, DMAV) and Recommendations for Dose Response Extrapolation July 26, 2005 Prepared by: Health Effects Division Office of Pesticide Programs US Environmental Protection Agency DMA MOA Page 1 of 201 DISCLAIMER This document is a preliminary draft: It has not been formally released by the U.S. Environmental Protection Agency and should not at this stage be construed to represent Agency policy, and should not be interpreted as intent to regulate. It is being circulated for comment on its technical accuracy. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. DMA MOA Page 2 of 201 PREFACE By August 2006, under the Food Quality Protection Act of 1996, EPA’s Office of Pesticide Programs must review the safety of all existing pesticide tolerances (the legal limit set on the maximum amount of pesticides that may remain in or on foods). As part of this tolerance reassessment process, the risk assessment on cacodylic acid is being updated. For ease of discussion, cacodylic acid will be referred to as DMAV (dimethylarsinic acid). Cacodylic acid and its sodium salt (sodium cacodylate) are organic arsenical nonselective contact herbicides which defoliate or dessicate a wide variety of plant species. Cacodylic acid and its sodium salt are used in combination, primarily as cotton defoliants, but also for weed control around non-bearing citrus, lawn renovation and edging, and weed control around buildings, sidewalks and driveways, and along utility lines. The only agricultural uses of cacodylic acid are on cotton and non-bearing citrus (i.e. applied when the citrus trees are not bearing their fruit). There are residential exposures to homeowners and children (e.g. toddlers) from the use of cacodylic acid on ornamentals, during lawn renovation and weed control, and around buildings and walkways. Much of this document will focus on and highlight issues related to the cancer hazard assessment of DMAV. EPA will also be developing a risk assessment for exposures to monomethylarsinic acid (MMAV). It is important to note that following pesticide applications of MMAV to citrus and/or cotton plants, residues measured in the fruit and plants are predominately DMA. Thus, whether DMAV or MMAV are used as herbicides, the general population is principally exposed to DMAV in foods. As part of the reassessment of cacodylic acid, new studies on the metabolism and the animal cancer mode of action were evaluated. These studies are the focus of this special issue paper. A complete health risk assessment developed by OPP includes: hazard identification, dose response assessment, exposure assessment and risk characterization. The current paper focuses only on the carcinogenic mode of action in animals and whether the rat tumor data should be used to estimate human potential risk and if so how does the mode of action understanding informs the dose response extrapolation for cancer risk assessment. A complete hazard characterization including non-cancer endpoints unrelated to the cancer process, exposure assessment, and risk characterization are not included here. Thus, this paper does not represent a complete assessment for evaluating the potential health impacts (for both noncancer and cancer endpoints). These remaining components will be included in EPA’s health risk assessment of cacodylic acid expected to be available to the public in late 2005. The Office of Pesticide Programs (OPP) has provided its analysis and prespective on cacodylic acid’s carcinogenic mode of action (Section 3), its relevance to humans (Section 4) and dose response extrapolation approaches for estimating carcinogenic risk (Sections 5 and 6). The SAB should also refer to additional discussion on the mode of carcinogenic action for DMAV in Appendix E. It should be noted that the parts of Appendix E that refer to the OPP document on cacodyic acid were based on an earlier draft of the OPP paper. Given the issues raised regarding the metabolism and mode of carcinogenic action for arsenicals, OPP is at a point in its assessment of cacodylic acid where external peer review by the Science Advisory Board (SAB) would DMA MOA Page 3 of 201 facilitate further development and refinement of OPP’s health assessment document. The aim of the SAB review is to obtain advice and comment on whether the conclusions drawn in OPP’s analysis of metabolism and cancer mode of action are consistent with the current science. This external scientific peer review is viewed as a significant and critical step as OPP proceeds to develop a sound and scientifically credible health risk assessment on cacodylic acid. OPP intends to use the SAB’s comments, as well as public comments that are received to further refine this preliminary cancer hazard and dose response analysis. DMA MOA Page 4 of 201 TABLE OF CONTENTS 1. Background ........................................................................................................... 9 2. Data for Evaluating Potential Cancer Risk to DMAV......................................... 12 2.A. Introduction ................................................................................................. 12 2.B. Available Cancer Studies in Humans and Animals.................................. 14 2.B.1. Inorganic Arsenic .................................................................................. 14 2.B.2. Monomethylarsonic Acid (MMAV)......................................................... 14 2.B.3. Dimethylarsonic Acid (DMAV) ............................................................... 15 2.B.4. Trimethanearsinic oxide (TMAO).......................................................... 15 2.C. Toxicokinetics and Metabolism ................................................................. 15 2.C.1. Metabolism Scheme .............................................................................. 16 2.C.2. In vivo Metabolism Studies................................................................... 18 2.C.3. In vitro Studies....................................................................................... 28 2.D. Toxicodynamic Considerations ................................................................. 29 2.D.1. In vivo Toxicities Associated With Arsenical Compounds ................ 29 2.D.2. Relative Toxicity of Various Arsenical Compounds In vitro .............. 30 2.D.3. Complicated Mixtures of Metabolites................................................... 33 2.E. Weight of the evidence and Summary: Data for evaluating potential cancer risk to DMAV .................................................................................... 34 3. Mode of Action Analysis for DMAV .................................................................... 36 3.A. Summary of Carcinogenic Effects............................................................. 36 3.A.1. Epidemiologic Studies .......................................................................... 36 3.A.2. Laboratory Animal Cancer Bioassay Studies ..................................... 37 3.B. Summary Description of Postulated Mode of Carcinogenic Action in Rats .............................................................................................................. 40 3.B.1. Identification of Key Events.................................................................. 41 3.B.2. Dose-Response Concordance of Key Events with Tumor Response49 2.B.3. Temporal Association ........................................................................... 52 3.B.4. Genotoxicity ........................................................................................... 52 3.B.5. Initiation and Promotion Studies.......................................................... 59 3.B.6. Strength, Consistency, and Specificity of Association of Tumor Response with Key Events ................................................................... 59 3.B.7. Biological Plausibility and Coherence................................................. 62 3.B.8. Other Modes of Carcinogenic Action................................................... 62 3.B.9. Uncertainties and Limitations............................................................... 63 3.B.10. Mode of Action Conclusions ................................................................ 64 4. Human Relevance ............................................................................................... 67 4.A. Human Relevance of Bladder Cancer Produced in Rodents By Xenobiotics: Generic Considerations ....................................................... 67 4.B. Human Relevance of Bladder Cancer Produced in Rats by DMA........... 68 4.C. Relevance of Bladder Cancer to Sensitive Human Subpopulations or Lifestages .................................................................................................... 71 5. Dose-response assessment............................................................................... 72 5.A. Introduction ................................................................................................. 72 5.B. Biologically-Based Dose Response Modeling.......................................... 72 5.C. Physiologically-Based Pharmacokinetic Modeling.................................. 73 5.D. Empirical Modeling ..................................................................................... 74 DMA MOA Page 5 of 201 5.D.1. Introduction...........................................................................................