Cell proliferation in the bladder and implications for cancer risk assessment

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Chemicals can increase carcinogenic risk by either directly damaging DNA or increasing cell replication or they can do both. These effects have different implications for a biologically-based extrapolation from rodent bioassays to humans. 2-Acetylaminofluorene (2-AAF) administered at low doses to mice for a lifetime has a different dose-response for the liver (approximately linear) compared to the urinary bladder (apparent no effect dose of 45 ppm with a sigmoidal dose response at 60-150 ppm), which can be explained if carcinogen metabolism, DNA adduct formation and cell proliferation effects are considered. In contrast to 2-AAF and other genotoxic chemicals, chemicals which form calculi in the urine do not generally damage DNA directly but increase cell proliferation dramatically by eroding the bladder surface, leading to regenerative hyperplasia. This occurs only at doses at which calculi form; lower doses do not produce calculi and, therefore, do not increase cell proliferation or cause tumors. Extrapolation to humans from the rodent bioassay should be dependent on dose requirements for formation of calculi rather than any type of statistical extrapolation to lower doses. Saccharin and other sodium salts administered at high doses to rats also produce bladder cancer by increasing cell proliferation. These salts do not effect mice, hamsters, guinea pigs or monkeys. Based on dose and mechanistic considerations, saccharin and these other sodium salts are unlikely to be human carcinogens. Extrapolation to possible human cancer risk requires biological determinations rather than simply using statistical formulations.

Original languageEnglish (US)
Pages (from-to)149-159
Number of pages11
JournalToxicology
Volume102
Issue number1-2
DOIs
StatePublished - Sep 1 1995

Fingerprint

Calculi
Cell proliferation
Urinary Bladder Neoplasms
Extrapolation
Risk assessment
Cell Proliferation
2-Acetylaminofluorene
Saccharin
Salts
Bioassay
Biological Assay
Carcinogens
Rodentia
Urinary Bladder
Sodium
DNA Adducts
DNA
Metabolism
Cricetinae
Liver

Keywords

  • 2-Acetylaminofluorene
  • Bladder cancer
  • Calculi
  • Cell proliferation
  • Risk assessment
  • Saccharin

ASJC Scopus subject areas

  • Toxicology

Cite this

Cell proliferation in the bladder and implications for cancer risk assessment. / Cohen, Samuel Monroe.

In: Toxicology, Vol. 102, No. 1-2, 01.09.1995, p. 149-159.

Research output: Contribution to journalArticle

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