Arsenic-induced bladder cancer in an animal model

Journal Article · Wed Aug 01 04:00:00 EDT 2007 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2006.10.010· OSTI ID:21077756

Ohnishi, Takamasa ^[1]

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1. Department of Pathology and Microbiology and Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198-3135 (United States)

Dimethylarsinic acid (DMA{sup V}) is carcinogenic to the rat urinary bladder, but not in mice. The carcinogenic mode of action involves cytotoxicity followed by regenerative cell proliferation. Dietary DMA{sup V} does not produce urinary solids or significant alterations in urinary composition. The cytotoxicity is due to formation of a reactive metabolite, likely dimethylarsinous acid (DMA{sup III}), concentrated and excreted in the urine. Urinary concentrations of DMA{sup III} are dose-dependent, and the urinary concentrations are at cytotoxic levels based on in vitro studies. The no observed effect level (NOEL) in these rat dietary studies for detectable levels of DMA{sup III}, cytotoxicity, and proliferation is 2 ppm, with marginal changes at 10 ppm. The tumorigenic dose is 100 ppm. Recent investigations have demonstrated that arsenicals administered to the rat result in binding to a specific cysteine in the hemoglobin alpha chain as DMA{sup III}, regardless of the arsenical being administered. Monomethylarsonic acid (MMA{sup V}) is not carcinogenic in rats or mice. In short term experiments ({<=} 10 weeks), sodium arsenate in the drinking water induces significant cytotoxicity and regenerative proliferation. There is little evidence that the cytotoxicity produced following administration of arsenicals is caused by oxidative damage, as antioxidants show little inhibitory activity of the cytotoxicity of the various arsenicals either in vitro or in vivo. In summary, the mode of action for DMA{sup V}-induced bladder carcinogenesis in the rat involves generation of a reactive metabolite (DMA{sup III}) leading to cytotoxicity and regenerative proliferation, is a non-linear process, and likely involves a threshold. Extrapolation to human risk needs to take this into account along with the significant differences in toxicokinetics and toxicodynamics that occur between different species.

• OSTI ID: 21077756
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 222; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANTIOXIDANTS
ARSENATES
ARSENIC
BLADDER
CARCINOGENESIS
CELL PROLIFERATION
CYSTEINE
DRINKING WATER
EXTRAPOLATION
HEMOGLOBIN
IN VITRO
IN VIVO
MICE
NEOPLASMS
OXIDATION
RATS
SODIUM
TOXICITY
URINE