Progress Report:  Arsenic Health Effects Research 
Clewell HJ, et al.  “Research toward the development of a biologically based dose response assessment for inorganic arsenic carcinogenicity:  A progress report,” Toxicology and Applied Pharmacology, 222 (2007), 388–398.  EPRI is participating in collaborative research to develop a biologically based dose-response model that can be used to estimate the carcinogenicity of inorganic arsenic at the low doses commonly encountered by U.S. populations.  Possible overestimates of low-dose ingestion cancer risk—based on the current linear dose-response model—could have far-reaching implications for U.S. water standards and exposure guidance values, including ambient water quality criteria and related regulatory requirements for remediation of arsenic-contaminated sites owned by electric power companies.  Since inhalation cancer risk is also based on linear extrapolation, results from the current study may ultimately apply to it as well.  Key areas of collaborative research include:

• Physiologically based pharmacokinetic (PBPK) modeling.  Researchers are refining comparable models that predict dose to target tissues based on the kinetics (chemical reaction rates) of inorganic arsenic and its metabolites in mice and humans.
• Cancer modeling.  The research paper presents a hierarchy of cellular responses across a range of doses of inorganic arsenic.  With each dose, a cell enters a different state with new properties that are reflected by the alteration of genes in key signal pathways.  Since—regardless of exposure route—inorganic arsenic acts through interaction with proteins rather than DNA, a model of inorganic arsenic carcinogenesis must describe both mutagenic and cell regulatory changes.
• Literature review of genomic responses to arsenic.  Published studies have reported a consistent pattern of gene changes involving seven categories of cellular response to inorganic arsenic.  In general, the effects of inorganic arsenic can be seen as highly specific direct interactions of arsenite (the trivalent form of arsenic) with critical proteins, superimposed on a background of chemical stress.  At low exposure concentrations (0.01 μM), cells apparently enter an adaptive state.  At high concentrations (> 5 μM), they exhibit increased toxicity shown by cell cycle stasis, apoptosis (programmed cell death), and inhibition of DNA repair.  An observed reversal of gene responses at concentrations below 0.1 μM supports a nonlinear threshold model.  Reported gene changes are consistent with epidemiologic and in vitro effects of arsenic seen under different exposure conditions. 
• Arsenic genomic dose-response studies.  The bladder is one of the human target tissues for arsenic carcinogenesis.  The bladder was selected as the initial focus for study for technical reasons.  Assuming adequate resources, the lung as a target tissue will be evaluated next.  In work reported here, researchers found no significant gene expression changes in the bladder tissue of a low-dose (0.05 mg/l) group of mice exposed to inorganic arsenic in drinking water, compared with controls.  Significant changes were seen in the high-dose group (50 mg/l).  A 12-week follow-up study employing multiple concentrations will document changes in gene expression related to dose over time.
• Application of biologically based dose-response model to arsenic low-dose nonlinear cancer risk assessment.  As an alternative to a linear extrapolation approach, a nonlinear margin-of-exposure approach that maintains a biological basis will be developed.  This margin-of-exposure approach will be built on the relatively uncomplicated biologically based dose-response (BBDR) model developed by this project.  The BBDR model incorporates multiple gene expressions associated with events that must occur for tumors to develop as a result of inorganic arsenic exposure.

This research is being performed under a Memorandum of Understand among EPRI, The Hamner Institute (formerly CIIT Centers for Health Research), and USEPA.  For more information, contact John W. Goodrich-Mahoney, (202) 293-7516, jmahoney@epri.com.