Arsenic-induced bladder cancer in an animal model.
Dimethylarsinic acid (DMA(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(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(III)), concentrated and excreted in the urine. Urinary concentrations of DMA(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(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(III), regardless of the arsenical being administered. Monomethylarsonic acid (MMA(V)) is not carcinogenic in rats or mice. In short term experiments (< or =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(V)-induced bladder carcinogenesis in the rat involves generation of a reactive metabolite (DMA(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.
Cohen
Samuel M
SM
Department of Pathology and Microbiology and Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198-3135, USA. scohen@unmc.edu
Ohnishi
Takamasa
T
Arnold
Lora L
LL
Le
X Chris
XC
D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D001152:Arsenicals; D002101:Cacodylic Acid / Q000031:analogs & derivatives / Q000633:toxicity; D002273:Carcinogens; D004195:Disease Models, Animal; D006454:Hemoglobins / Q000378:metabolism; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D013438:Sulfhydryl Compounds / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced* / Q000473:pathology
D001152:Arsenicals; D002273:Carcinogens; D006454:Hemoglobins; D013438:Sulfhydryl Compounds; C472511:dimethylarsinous acid; D002101:Cacodylic Acid; C020300:monomethylarsonic acid; D001151:Arsenic