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PROPOSED CARCINOGENIC MECHANISMS FOR ARSENIC
Citation:
Kitchin, K T. AND S Ahmad. PROPOSED CARCINOGENIC MECHANISMS FOR ARSENIC. Presented at Int'l Symposium on Carcinogenic Metals, Australia, July 1-5, 2001.
Description:
PROPOSED CARCINOGENIC MECHANISMS FOR ARSENIC.
Arsenic is a human carcinogen in skin, lung, liver, urinary bladder and kidney. In contrast,
there is no accepted experimental animal model of inorganic arsenic carcinogenesis.
Proposed mechanisms/modes of action for arsenic carcinogenesis include but are not limited to clastogenic effects, mutation, oxidative stress, gene amplification, aItered DNA methylation, cell proliferation, promotion, effects on the progression stage, inhibition of DNA repair and interaction with important cellular proteins. At this time, there is not a scientific consensus on the mechanism/modes for arsenic carcinogenesis. In regulating human exposure to arsenic, this uncertainty in ru-senic's carcinogenic mechanisms/modes of action makes biologically based risk assessment and extrapolation model selection difficult. Therefore, arsenate, arsenite, monomethylarsonic acid (MMA(V) and dimethylarsinic acid (DMA(V) were administered to rats to determine their biochemical effects. In our laboratory, DMA(V) at 387 mg/kg caused DNA damage in rat lungs, but not in rat liver. Neither arsenate or arsenite damaged rat DNA. Sodium arscnite at doses of 1.6, 8.2 and 24.6 mg/kg increased rat hepatic ornithine decarboxylase activity by 40 to 140%. DNA damage and ornithine decarboxylase induction are interpreted as indicators of initiation and promotion of cancer, respectively. Experiments were also performed to evaluate the possible role of oxidative stress in arsenic carcinogenesis. Trivalent arsenicals were better releasers of iron from ferritin than the corresponding pentavalent arsenic forms. In particular, DMA(III) released more than 8 times as much iron as did equimolar arsenite. When ferritin was exposed to both DMA(III) and ascorbic acid at the same time, a more than 4 times greater than additive release of iron from ferritin occurred. DMA(III), either with or without ascorbic acid, damaged both calf thymus DNA and PBR322 plasmid DNA in vitro. DMA(III) was more DNA damaging than DMA{V), MMA(V), MMA(III), arsenite or arsenate to plasmid PBR322 DNA- Recently, DMA(V) has showed either promotional or complete carcinogcnic activity in rats (bladder, kidney and liver) and mice (lung and skin). The trivalent forms of methylated arsenicals have recently been shown to have biological effects at low concentrations on several systems-inhibition of mouse liver thioredoxin reductase activity (MMA(III) and DMA(III) and cytotoxicity to human hepatocytes (MMA(III)). The reactivity of trivalent arsenic's unshared s orbital electron pair together with the diminished negative charge due to the presence of methyl groups and the absence of ionized hydroxy groups may account for the substantial biological activities that trivalent methylated arsenic species have demonstrated. Based on recent experimental findings. for carcinogcnesis, methylation of inorganic arsenic may be a (toxification-) pathway. The arsenic metabolites MMA(III) and or DMA(III) may be or may generate the active promoting/carcinogenic arsenic chemicall form.
This is an abstract of a proposed presentation and does not necessarily reflect EPA policy.