Arsenic-Induced Enhancement of Ultraviolet Radiation Carcinogenesis in Mouse Skin: A Dose-Response Study
Burns, Fredric J., Uddin, Ahmed N., Wu, Feng, Nadas, Arthur, Rossman, ToG., Environmental Health Perspectives
The present study was designed to establish the form of the dose-response relationship for dietary sodium arsenite as a co-carcinogen with ultraviolet radiation (UVR) in a mouse skin model. Hairless mice (strain Skh1) were fed sodium arsenite continuously in drinking water starting at 21 days of age at concentrations of 0.0, 1.25, 2.5, 5.0, and 10 mg/L. At 42 days of age, solar spectrum UVR exposures were applied three times weekly to the dorsal skin at 1.0 kJ/[m.sup.2] per exposure until the experiment ended at 182 days. Untreated mice and mice fed only arsenite developed no tumors. In the remaining groups a total of 322 locally invasive squamous carcinomas occurred. The carcinoma yield in mice exposed only to UVR was 2.4 [+ or -] 0.5 cancers/mouse at 182 days. Dietary arsenite markedly enhanced the UVR-induced cancer yield in a pattern consistent with linearity up to a peak of 11.1 [+ or -] 1.0 cancers/mouse at 5.0 mg/L arsenite, representing a peak enhancement ratio of 4.63 [+ or -] 1.05. A decline occurred to 6.8 [+ or -] 0.8 cancers/mouse at 10.0 mg/L arsenite. New cancer rates exhibited a consistent-with-linear dependence on time beginning after initial cancer-free intervals ranging between 88 and 95 days. Epidermal hyperplasia was elevated by arsenite alone and UVR alone and was greater than additive for the combined exposures as were growth rates of the cancers. These results demonstrate the usefulness of a new animal model for studying the carcinogenic action of dietary arsenite on skin exposed to UVR and should contribute to understanding how to make use of animal data for assessment of human cancer risks in tissues exposed to mixtures of carcinogens and cancer-enhancing agents. Key words: arsenic, arsenite, cancer, hairless, mouse, radiation, skin, ultraviolet, UV.
Although elevated cancer risk has been demonstrated in people exposed to arsenic in drinking water, the data generally cannot distinguish between various possible dose-response relationships, such as linear, quadratic, or hockey stick (Buchet and Lison 2000). However, studies of skin or bladder cancer among persons consuming arsenic-contaminated drinking water in Taiwan were consistent with linearity, although other forms could not be ruled out (Brown et al. 1989, 1997; Chiou et al. 2001). Lung cancer in smelter workers was consistent with linear when analyzed according to the excess mortality approach but not when analyzed according to the standard mortality approach (Viren and Silvers 1999).
In other studies, dose-response tended to be hockey stick shaped at low levels of arsenic (~ < 100 ppb) in drinking water for skin cancer and for non-neoplastic end points, such as hyperpigmentation and keratosis (Tucker et al. 2001). Males were considerably more susceptible than females, and low body weight, presumably a result of poor nutrition, was predisposing (Guha Mazumder et al. 1998). Although solar keratosis is a benign neoplastic condition thought by some to be a precursor of squamous cell carcinomas, no direct linkage was apparent in these studies. Overall, the human data are not yet sufficient to contest the low-dose linearity default form of the dose-response relationship for cancer induction by arsenite (Huff et al. 1998).
Numerous ideas have been put forward to explain arsenic's carcinogenic activity (Abernathy et al. 1999; Corsini et al. 1999; Germolec et al. 1997; Rossman 2003; Rossman et al. 2002; Simeonova and Luster 2000; Yager and Wiencke 1993, 1997). Possible mechanisms include reduced DNA repair, altered DNA methylation, increased growth factors, enhanced ceil proliferation, induction of gene amplification (an indication of genomic instability), and suppressed p53 expression leading to faulty DNA damage signaling (which also affects repair). In support of the latter, it was recently found that arsenite prevented S-phase arrest in human lung tumor cells irradiated with ultraviolet C radiation (UV-C; Hartwig et al. …