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High Content Screening Analysis to Evaluate the Toxicological Effects of Harmful and Potentially Harmful Constituents (HPHC)
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Published on: May 10, 2016

Implications of arsenic genotoxicity for dose response of carcinogenic effects

R Rudel1, T M Slayton, B D Beck

  • 1Silent Spring Institute, Inc., 29 Crafts Street, Newton, Massachusetts, 02158, USA.

Regulatory Toxicology and Pharmacology : RTP
|April 1, 1996
PubMed

Insights

Arsenic exposure and cancer risk may follow a sublinear dose-response relationship, meaning higher doses don't proportionally increase cancer risk. This suggests linear models may overestimate cancer risks at lower arsenic exposure levels.

Area of Science:

  • Environmental Health
  • Toxicology
  • Molecular Biology

Background:

  • Epidemiological studies suggest a sublinear or threshold relationship between arsenic ingestion and cancer risk.
  • Physiological saturation of arsenic detoxification pathways is a proposed mechanism for sublinear responses.

Purpose of the Study:

  • To evaluate the molecular mechanisms underlying sublinear dose-response relationships for arsenic genotoxicity and carcinogenesis.
  • To review arsenic's dose-response effects in genotoxicity assays and DNA repair inhibition.

Main Methods:

  • Review of existing genotoxicity assay data for arsenic.
  • Analysis of arsenic's effects on chromosomal aberrations, clastogenicity, mutagenicity, and DNA ligase inhibition.
  • Evaluation of dose-response relationships in mammalian and human cell systems.

Main Results:

  • Sublinear dose-response relationships were consistently observed for arsenic-induced chromosomal aberrations (except sister chromatid exchanges).
  • Arsenic enhanced the genotoxicity of other agents with a sublinear dose response.
  • Arsenic inhibited DNA ligases I and II, crucial for DNA repair, also with a sublinear dose response.

Conclusions:

  • Arsenic likely induces genetic damage indirectly via a sublinear dose-response mechanism in humans.
  • This provides a biological basis for sublinear cancer risk relationships.
  • Linear dose-response modeling may overestimate cancer risks at low arsenic exposure levels.

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