Dma Carcinogenesis In Rats

A major impediment to furthering our understanding of the mechanisms by which arsenic causes cancer in humans has been the lack of appropriate animal models (IARC, 1980; Huff et al., 2000). Despite its recognition as a human carcinogen, the various forms of arsenic have not been widely tested in animal models, including in standard two-year bioassays. However, recently, administration of relatively high doses of dimethylarsinic acid (DMA) were demonstrated to produce an increased incidence of cancer of the urinary bladder in rats, with females apparently more susceptible than males (van Gemert and Eldan, 1998; Wei et al., 1999). Bladder tumors were induced whether the chemical was administered in the diet (van Gemert and Eldan, 1998) or in the drinking water (Wei et al., 1999). Administration of DMA in drinking water appeared to produce a significantly greater toxicity at comparable doses. Nevertheless, the only tissue showing any incidence of tumors after two years in the rat was the urinary bladder, and the incidences were relatively low. Higher incidences of urothelial hyperplasia were detected.

Following dietary administration, there was hyperplasia observed at a dose of 40 mg/kg and bladder tumors were present at a dose of 100 mg/kg. Doses of 2 and 10 mg/kg of the diet did not produce any effect on the urothelium in the rat (van Gemert and Eldan, 1998). When administered in the drinking water to male rats, bladder tumors and hyperplasia were observed at doses of 50 and 200 mg/l of the drinking water. No increased incidences of urothelial lesions were detected at 12.5 mg/l, compared to controls (Wei et al., 1999).

In contrast, bioassays of DMA administered in the diet and drinking water to mice have been negative with respect to carcinogenicity (van Gemert and Eldan, 1998; Fukushima et al., 2000). DMA was administered in the diet at doses of 8, 40, 200, and 500 mg/kg to of male and female CD-1 mice (van Gemert and Eldan, 1998), and it was administered in the drinking water at doses of 50 and 200 mg/l to male C57BL wild-type mice and p53(+/—) mice for 90 weeks (Fukushima et al., 2000). There was no increased incidence of tumors in these bioassays involving mice. In addition, Tice et al. (2000) administered sodium arsenite to C57BL/6 p53(+/—) male mice for 26 weeks, at a dose of 50 mg/l of the drinking water, and did not detect any increased incidence of tumors. They also found no increase in tumor incidences in mice when DMA was administered in a choline deficient diet or when it was co-administered with p-cresidine or 4-vinyl-1-cyclohexene diepoxide, known bladder and skin carcinogens, respectively.

Yamamoto et al. (1995) administered DMA in the drinking water to male F344 rats after pretreatment with a complex protocol involving the administration of five known carcinogens, including diethylnitrosamine, N-methyl-N-nitrosourea, 1,2-dimethylhydrazine, N-butyl-N-(4-hydroxybutyl) nitrosamine, and N-bis(2-hydroxypropyl) nitrosamine. DMA was administered at doses of 50, 100, 200, or 400 mg/l in the drinking water. The incidences of tumors of the bladder, kidney, liver, and thyroid gland were increased, but only at the highest dose, which was well in excess of a maximally tolerated dose and produced significant toxicities. Because of the extraordinarily high, toxic doses used in this study, interpretation of the results are difficult.

Administration of DMA in the drinking water at doses of 0, 2, 10, 25, 50, and 100 mg/l for 32 weeks following pre-administration with BBN produced an increased incidence of urinary bladder tumors at doses of 25 mg/l and higher (Wanibuchi et al., 1996). There was a suggestion of a slight effect at 10 mg/l. Again, significant toxicity was seen at the highest dose (100 mg/l), but tumors were seen at lower doses, also. No effects on the urothelium were seen at a dose of 2 mg/l in the drinking water.

DMA administered as 100 mg/l of the drinking water following pretreatment with BBN produced a similar incidence of bladder tumors in NCI-Black-Reiter male rats as in F344 male rats (Li et al., 1999). This strain of rats does not produce or excrete alpha2u-globulin in the urine. A lack of difference of results with DMA in the NCI-Black-Reiter rat compared to the F344 rats suggests that this male rat protein is not involved in the mode of action of DMA in bladder carcinogenesis in rats. In general, experiments in mice have been negative. However, DMA has recently been shown to promote skin carcinogenesis in keratin (K6)/ODC transgenic female mice following initiation with 7,12-dimethylbenz(a)anthracene (DMBA). Treatment with DMA alone had no effect on these mice. However, in strains of mice more commonly utilized for skin initiationpromotion experiments, DMA and other arsenicals, including inorganic arsenic, have been negative (IARC, 1980; Huff et al., 2000; Morikawa et al., 2000; Tice et al., 2000).

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