Susceptibility To Skin Cancer

Undernourishment

Among the residents aged 60 or more years in the BFD-endemic area, the prevalence of skin cancer was 4.8%, 16.5% and 25.6%, respectively, for males whose drinking water had arsenic concentrations of <300, 300-599 and >600 Mg/l (Tseng et al., 1968). The corresponding figures for females were 0.9%, 6.2% and 11.0%, respectively. However, the status of undernourishment in the development of arsenic-induced skin cancer was not examined in this study. In a recent survey in the BFD-hyperendemic villages, the prevalence of skin cancer was found to increase with the duration of consuming sweet potato in a dose-response relationship (Hsueh et al., 1995). The multivariate-adjusted odds ratios were 5.5 and 8.5, respectively, for those who consumed sweet potato for 10-19 and >20 years compared with those that had a consumption duration of <10 years. In another nested case-control study in BFD-hyperendemic villages, the incidence of arsenic-induced skin cancer was found to increase with the decrease in serum p-carotene level (Hsueh et al., 1997). The odds ratio for those who had a serum p-carotene level in the lowest tertile was around eleven-fold as compared with those who had higher levels after adjustment for age, sex, cumulative arsenic exposure and arsenic methylation capability.

Liver dysfunction

In the prevalence survey in the BFD-endemic area, both hepatitis B virus (HBV) chronic infection and liver dysfunction indexed by an elevated serum level of alanine transaminase were associated with an increased prevalence of skin cancer (Hsueh et al., 1995). The multivariate-adjusted odds ratio was 6.6 for HBV surface antigen carriers with liver dysfunction compared with non-carriers with normal liver function. It was hypothesized that liver dysfunction may reduce the methylation of inorganic arsenic in the liver and thus increase the deposition of inorganic arsenic in the skin. The detailed mechanism needs further elucidation.

Inorganic Arsenic Methylation Capability

In the nested case-control study aimed to examine the association between arsenic methyl-ation capability and skin cancer risk, a higher MMA percentage and a lower DMA percentage in the total urinary inorganic arsenic metabolites level was observed among skin cancer patients than among healthy controls (Hsueh et al., 1997). The multivariate-adjusted odds ratio for those that had a cumulative arsenic exposure of >20.0 mg/l per year and a percentage of MMA > 26.7% was around 24-fold, as compared with those that had a cumulative arsenic exposure of <20.0 mg/l per year and a percentage of MMA < 26.7%.

Family History of Skin Cancer

The prevalence of arsenic-induced skin cancer in BFD-endemic areas was higher for those who had a family history of skin cancer among first-degree relatives than for those without such history (Hsueh et al., 1995). The age-sex-adjusted odds ratio was as high as four-fold, but it was not statistically significant due to the small sample size in the study.

Genetic Polymorphism of Glutathione S-transferases andp53

In a recent nested case-control study, a significant association with arsenic-induced skin cancer was observed for the combination of three GST genotypes (Tseng, 1999). For those who had at least one null or variant genotype of GST M1, T1 or P1, the risk of developing skin cancer was around five-fold as compared with those with wild genotypes of all three GST. There was a significant interaction between cumulative arsenic exposure, GST genetic polymorphisms and arsenic methylation capability. For those who had a cumulative arsenic exposure > 14 mg/l per year, a poor inorganic arsenic methylation capability, and at least one null or variant genotypes of three GST, the risk of developing skin cancer was around 15-fold as compared with those with a cumulative arsenic exposure < 14 mg/l per year, a normal arsenic methylation capability, and wild genotypes of three GST. There was no association between skin cancer risk and genetic polymorphism of p53 codon 72.

Genetic Polymorphisms ofDNA Repair Enzymes

In a most recent nested case-control study, arsenic-induced skin cancer was found to be associated with genetic polymorphisms of DNA repair enzymes XPD and XRCC1 (Lin, 2000). The age-sex-adjusted odds ratios of developing skin cancer were 2.0 and 1.7, respectively, for the AA/AC genotypes (versus CC genotype) of XPD exon 6 and the Arg/Arg genotype (versus Arg/His or His/His genotypes) of XRCC1 exon 9. There were significant interactions between genetic polymorphisms of GST and DNA repair enzymes in the determination of arsenic-induced skin cancer. Further studies on genetic polymorphisms of other enzymes involved in DNA repair, xenobiotic metabolism and cell cycle regulation may provide better understanding of gene-gene and gene-environment interactions in arsenic-induced skin carcinogenesis.

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