Mode of action studies for assessing carcinogenic risks posed by inorganic arsenic

Mode of action (MOA) is emphasized as a unifying concept in new U.S. EFA carcinogen risk assessment guidelines. Optimally, MOA hypotheses relate carcinogenicity to obligatory precursor effects, link cancer and non-cancer responses through common pathways, and predict dose-response relationships via biologically-based dose-response (BBDR) models. Inorganic arsenic (As-i) increases skin lesions, cardiovascular disease, and several types of cancers in humans. The MOA or MOAs for As-i toxicity/carcinogenicity is poorly understood. Multiple effects may be idiosyncratic, each with a distinct MOA. Alternatively, only a limited number of precursor steps may be involved in all tissues. This paper outlines proposed MOAs of As-i carcinogenesis-impaired DNA repair, altered DNA methylation, increased growth factor synthesis, and increased oxidative stress. Increasingly, MOA hypotheses are suggesting that concentrations of critical gene products, including growth factors, redox-sensitive proteins, and DNA repair/DNA methylating enzymes, may be altered by As-i. These alterations would enhance tumor promotion or progression. A potential MOA for As-i acting as a late-stage tumor progressor is evaluated in relation to specific data needs for an As-i risk assessment and to the development of a BBDR model for As-i-induced internal tumors in humans. MOA studies of transcriptional processes, measurements of As-i dosimetry in humans, and dose-response evaluations for precursor endpoints appear important for supporting public health decisions about the risks posed by human As-i exposures. Studies of the transcriptional/ post-translational activities of arsenite and metabolites are likely to prove especially valuable for both cancer and non-cancer risk assessments.