Arsenic-induced bladder cancer in an animal model

Samuel Monroe Cohen, Takamasa Ohnishi, Lora L Arnold, X. Chris Le

Research output: Contribution to journalArticle

95 Citations (Scopus)

Abstract

Dimethylarsinic acid (DMAV) is carcinogenic to the rat urinary bladder, but not in mice. The carcinogenic mode of action involves cytotoxicity followed by regenerative cell proliferation. Dietary DMAV does not produce urinary solids or significant alterations in urinary composition. The cytotoxicity is due to formation of a reactive metabolite, likely dimethylarsinous acid (DMAIII), concentrated and excreted in the urine. Urinary concentrations of DMAIII 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 DMAIII, 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 DMAIII, regardless of the arsenical being administered. Monomethylarsonic acid (MMAV) 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 DMAV-induced bladder carcinogenesis in the rat involves generation of a reactive metabolite (DMAIII) 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.

Original languageEnglish (US)
Pages (from-to)258-263
Number of pages6
JournalToxicology and Applied Pharmacology
Volume222
Issue number3
DOIs
StatePublished - Aug 1 2007

Fingerprint

Arsenicals
Arsenic
Cytotoxicity
Urinary Bladder Neoplasms
Animals
Animal Models
Rats
Urinary Bladder
Metabolites
Cacodylic Acid
No-Observed-Adverse-Effect Level
Drinking Water
Cysteine
Carcinogenesis
Hemoglobins
Cell proliferation
Antioxidants
Cell Proliferation
Urine
Extrapolation

Keywords

  • Arsenic
  • Bladder cancer
  • Dimethylarsinic acid
  • Monomethylarsonic acid
  • Urothelial cytotoxicity
  • Urothelial hyperplasia

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

Arsenic-induced bladder cancer in an animal model. / Cohen, Samuel Monroe; Ohnishi, Takamasa; Arnold, Lora L; Le, X. Chris.

In: Toxicology and Applied Pharmacology, Vol. 222, No. 3, 01.08.2007, p. 258-263.

Research output: Contribution to journalArticle

Cohen, Samuel Monroe ; Ohnishi, Takamasa ; Arnold, Lora L ; Le, X. Chris. / Arsenic-induced bladder cancer in an animal model. In: Toxicology and Applied Pharmacology. 2007 ; Vol. 222, No. 3. pp. 258-263.
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