Developing a Quantitative Dose-Response Model for Arsenic Carcinogenicity. M. E. Andersen and H. J. Clewell, III, KS Crump Division, ICF Kaiser Engineers, Inc., PO Box 14348, Research Triangle Park, NC 27709
Arsenic (As) exposures in humans have been associated with increases in skin and internal cancers. However, this metal does not cause tumors in laboratory animals in most test protocols. While most human carcinogens are strong mutagens, As is not mutagenic at single gene loci in various organisms. In vitro arsenite does serve as a co-mutagen both for treatment of cells with ionizing radiation and for treatment with genotoxic compounds. We are quantitatively evaluating a hypothesis that As acts at a late stage of the carcinogenic process in humans on intermediate transformed cells that are involved in human carcinogenesis, but less likely to be involved in the shorter lived experimental animals. Specifically, As may act to accelerate the conversion of slowly growing precursor lesions to more aggressive cancers that are a hallmark of human carcinogenesis, but less frequently found in most rodent studies. A late effect might occur after the appearance of a mutator cell phenotype, deficient in cell cycle control, but preceding an invasive, rapidly growing stage of the tumor. We have developed a multipathway dose-response model for late stage carcinogenicity of As that links specific stages in the model to As co-mutagenesis. The model follows from an approximation to the two-stage cancer model developed previously (Clewell et al., J. Risk) carcinogens are strong mutagens, As is not mutagenic at single gene loci in various organisms. In vitro arsenite does serve as a co-mutagen both for treatment of cells with ionizing radiation and for treatment with genotoxic compounds. We are quantitatively evaluating a hypothesis that As acts at a late stage of the f carcinogenic process in humans on intermediate transformed cells that are involved in human carcinogenesis, . . . . . . [RiskWorld Note: Submitted abstract incomplete]