Arsenic, mode of action at biologically plausible low doses : what are the implications for low dose cancer risk?

Snow, Elizabeth T., Sykora, Peter, Durham, Troy R. and Klein, Catherine B. 2005, Arsenic, mode of action at biologically plausible low doses : what are the implications for low dose cancer risk?, Toxicology and applied pharmacology, vol. 207, no. 2 Supplement 1, pp. 557-564, doi: 10.1016/j.taap.2005.01.048.

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Title Arsenic, mode of action at biologically plausible low doses : what are the implications for low dose cancer risk?
Author(s) Snow, Elizabeth T.
Sykora, Peter
Durham, Troy R.
Klein, Catherine B.
Journal name Toxicology and applied pharmacology
Volume number 207
Issue number 2 Supplement 1
Start page 557
End page 564
Publisher Academic Press
Place of publication San Diego, Calif.
Publication date 2005-09
ISSN 0041-008X
Keyword(s) inorganic arsenic
gene expression
DNA repair
Summary Arsenic is an established human carcinogen. However, there has been much controversy about the shape of the arsenic response curve, particularly at low doses. This controversy has been exacerbated by the fact that the  mechanism(s) of arsenic carcinogenesis are still unclear and because there are few satisfactory animal models for arsenic-induced carcinogenesis. Recent epidemiological studies have shown that the relative risk for cancer among populations exposed to ≤60 ppb As in their drinking water is often lower than the risk for the unexposed control population. We have found that treatment of human keratinocyte and fibroblast cells with 0.1 to 1 μM arsenite (AsIII) also produces a low dose protective effect against oxidative stress and DNA damage. This response includes increased transcription, protein levels and enzyme activity of several base excision repair genes, including DNA polymerase β and DNA ligase I. At higher concentrations (> 10 μM), As induces down-regulation of DNA repair, oxidative DNA damage and apoptosis. This low dose adaptive (protective) response by a toxic agent is known as hormesis and is characteristic of many agents that induce oxidative stress. A mechanistic model for arsenic carcinogenesis based on these data would predict that the low dose risk for carcinogenesis should be sub-linear. The threshold dose where toxicity outweighs protection is hard to predict based on in vitro dose response data, but might be estimated if one could determine the form (metabolite) and concentration of arsenic responsible for changes in gene regulation in the target tissues.
Language eng
DOI 10.1016/j.taap.2005.01.048
Field of Research 111502 Clinical Pharmacology and Therapeutics
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2005, Elsevier Inc
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Document type: Journal Article
Collection: School of Biological and Chemical Sciences
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