Summary
The mode of carcinogenic action as well as metabolic disposition are both important decision elements when choosing the appropriate approach for conducting high-to-low dose human cancer risk assessment with respect to inorganic arsenic (As). Conflicting opinions exist whether or not a dose threshold should be applied for this human carcinogen, and/or if metabolic overloading with respect to methylation to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) occurs at elevated exposures that might potentiate the carcinogenic action of As. Unfortunately, progress has been hampered by the fact that neoplasia cannot be induced consistently by As in experimental animals, and that no appropriate animal model has yet been found that adequately mimics its metabolism in most humans. The latter also includes the Chimpanzee, in as much as we have demonstrated that this primate does not metabolize As.
As inhibits DNA-repair, and our investigations on the effect of As(III) on UV-induced nucleotide excision repair in repair proficient human cells, and partly repair deficient xeroderma pigmentosum cultivated human fibroblasts indicate incision to be the most sensitive step. Inhibition occurs at concentrations that are relevant with respect to cancer induction in humans. At higher concentrations ligation is also inhibited. The global genome repair as well as the transcription-coupled repair pathway are both affected, and exposure to As may, thus, induce a partially repair deficient condition similar to that seen in xeroderma, where additional promotive action such as keratotic changes will determine the site of tumor appearance.
Although As does not induce point mutations per se, it is pro-mutagenic in many in vitro systems, including human cell lines. It is a clastogen and an aneugen in cultured mammalian cells, as well as in peripheral lymphocytes from exposed humans from northwestern Argentina: In an isolated native Indian settlement in the Andean region, as well as in a mestizo population in the lower Chaco region, Salta Province, where both populations are exposed to As in drinking water at about the same level (200ug/L), there was a highly significant increase in the frequency of micronuclei (MN) as well as of aneuploidy in lymphocytes from exposed individuals, but no notable effects were found on sister chromatid exchanges, specific chromosomal translocations, or on cell cycle progression. As supported by fluorescence in situhybridization (FISH), at least a proportion of MN appears to originate from whole chromosome loss. The incidence of MN was similar to that found previously by us for women from a heavily contaminated area around the Srednogorie copper smelter, Bulgaria, and these findings are also supported by similar findings with respect to exfoliated bladder cells in an exposed cohort in Nevada. The induction of MN appears to constitute the most sensitive toxicological endpoint for exposure to As so far been described. These findings support the hypothesis, that As exerts its carcinogenic effects by an indirect mechanism, that may exhibit a dose threshold.
The exposed native population in the Andes had a different metabolic disposition than previously found for populations in Europe, U.S., and Japan, in as much as these individuals mainly excrete arsenic as DMA and inorganic As, with very little MMA. Further, whereas none of the typical signs of systemic As intoxication could be seen among the Indians studied in the Puna region—who have been exposed for a very long time in history —hyperkeratoses and skin cancer were present among the investigated mestizos exposed to about the same concentration of As in drinking water from the Chaco area. The observed ethnic differences most probably have a genetic background.
Keywords
- Chromosomal Aberration
- Nucleotide Excision Repair
- Sister Chromatid Exchange
- Inorganic Arsenic
- Sodium Arsenite
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Nilsson, R., Natarajan, A.T., Hartwig, A., Dulout, F., De la Rosa, M.E., Vahter, M. (1999). Clastogenic Effects and Influence of Inorganic Arsenic on DNA-Repair in Mammalian Systems. In: Sarkar, B. (eds) Metals and Genetics. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-4723-5_3
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