Comments on EPA's Science Issue Paper: Mode of Carcinogenic Action for Cacodylic Acid and Recommendations for Dose Response Extrapolation

Executive Summary Based on studies in rats, it is clear that the mode of action (MOA) for DMA V-induced bladder tumors is cytotoxicity, resulting in persistent regenerative proliferation, leading to development of bladder tumors. This MOA has no mutagenic component and has a nonlinear dose response. The toxicokinetics of DMA V is different from the toxicokinetics of DMA V in other species, including humans, rendering the rat uniquely susceptible to DMA V carcinogenicity. In a recent report, "Science Issue Paper: Mode of Carcinogenic Action for Cacodylic Acid and Recommendations for Dose Response Extrapolation", the EPA Office of Pesticide Programs (OPP) uses a reference dose approach to estimate the daily exposure to DMA V that is not associated with any increased cancer risk. The reference dose, 7 x 10-5 mg/kg/day is based on the BMDL 1 (i.e. the lower 95% confidence limit on the benchmark dose (BMD) that is associated with 1% of the maximum cell proliferation rate above background) and a composite Uncertainty Factor (UF) of 1000, composed of three 10-fold UFs-for intraspecies variability, interspecies variability, and the FQPA safety factor for special sensitivity of early life stages. While OPP's framework is reasonable, several aspects of OPP's analysis are overly conservative and not based on the best available scientific data: • The BMD 10 rather than the BMD 1 is more appropriate as a point of departure (POD) • The interspecies UF should be 1-fold at the most, since the model species, the rat, is more sensitive than humans to DMA V. • The FQPA UF should be 1-fold since there are data showing there is no increased sensitivity to DMA V in early life stages compared to adults. A more appropriate reference dose, based on sound scientific evidence, can be calculated as 2.9 x 10-2 mg/kg/day. This value is greater than that proposed by OPP, but is still protective of public health. When comparing this revised cancer reference dose to EPA's estimated daily intake of DMA V due to agricultural use, the resulting margin of exposure (MOE) is over 100,000-fold.