Susceptibility To Blackfoot Disease

Arsenic-induced Skin Lesion

Among the residents aged 60 or more years in the BFD-endemic area, the prevalence of BFD was 2.0%, 3.2% and 6.1%, respectively, for those whose drinking water had arsenic concentrations of <300, 300-599 and >600 Mg/l (Tseng, 1977). In this prevalence study, skin lesions including hyperpigmentation, hyperkeratosis and various cancers were found to coexist with BFD showing relative risks of 9.7, 14.0 and 62.4, respectively, compared with those without the lesions. Arsenic-induced skin lesion may be considered a long-term biomarker of cumulative arsenic exposure and/or individual susceptibility to arseniasis. The arsenic level in drinking water was not adjusted in the estimation of relative risks of developing BFD for various arsenic-induced skin lesions in the previous study. In a recent case-control study, an increased risk of BFD was observed among those who had skin hyperkeratosis and/or cancer after adjustment for duration of consuming high-arsenic artesian well water and other risk factors (Chen et al., 1988b). The multivariate-adjusted odds ratio was around three-fold.

Undernourishment

An earlier study on the diet of residents in the BFD-endemic area found that the diet commonly consumed was dominated by sweet potato, intakes of fresh vegetables and fruits were markedly low, and fish was the only notable source of animal protein (Yang and Blackwell, 1961). The diet was adequate with respect to calories, high in carbohydrates, low in protein and extremely low in fat, which might include a deficient intake of essential unsaturated fatty acids. The intake of indispensable amino acids appeared to be above the minimum requirements with the exception of methionine and tryptophan. Although no attempt was made to evaluate vitamin and mineral intakes in the study, it appeared likely that vitamin intake was marginal. The dietary deficiencies were considered to be one of several factors required to induce BFD in susceptible individuals. An early case-control study showed that BFD patients had a lower socioeconomic status than matched controls showing odds ratios of 3.3 and 4.5, respectively, for those who had an average and below-average socioeconomic status as compared with those with an above-average socioeconomic status (Chi and Blackwell, 1967). A recent case-control study found that BFD patients had a significantly lower intake of meat, eggs and vegetables than matched controls (Chen et al., 1988b). Consumption of sweet potato as food staple was associated with an increased risk of BFD showing an odds ratio around two-fold as compared with consumption of rice. In our recent study on 29 patients affected with peripheral vascular disease and 198 healthy controls in the BFD-endemic area, low serum levels of a-and P-carotene were associated with an increased risk of the disease showing odds ratios (lowest quartile versus others) of 2.9 and 2.4, respectively.

Inorganic Arsenic Methylation Capability

Ingested and inhaled inorganic arsenic is methylated into monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in humans. As MMA and DMA are less toxic than arsenite and arsenate, the methylation is considered a detoxification process of inorganic arsenic. The arsenic methylation capability of an individual may be reflected by the relative proportions of inorganic arsenic, MMA and DNA in urine measured by high-performance liquid chromatography (HPLC)-hydride generation-atomic absorption spectrometry. In our recent study on 29 patients affected with BFD and 289 healthy controls, a higher percentage of inorganic arsenic and a lower percentage of DMA in urine were observed in BFD patients than in healthy controls. The high percentage of inorganic arsenic in urine (>6.7%) was associated with a two-fold risk of BFD compared with the low percentage (<6.7%) after adjustment for age, sex, and duration of consuming high-arsenic artesian well water and serum carotene level.

Family History of Blackfoot Disease

In an early prevalence survey, a significant familial aggregation of BFD was observed (Wu et al., 1961). More than 15% of BFD patients had family members affected with BFD, while the BFD prevalence of the surveyed population was only 2%. The familial aggregation of BFD may be attributable to common genes and/or environments shared by family members. No adjustment for drinking high-arsenic artesian water was made in this study. In a recent case-control study (Chen et al., 1988b), a much higher proportion of BFD patients (7.6%) had a family history of BFD among first-degree relatives than matched controls (0.7%). The odds ratio of developing BFD was around three-fold after multivariate adjustment for risk factors including the duration of consuming artesian well water and the arsenic-induced skin hyperpigmentation and/or cancer. Further elucidation of genetic susceptibility to BFD will clarify the underlying mechanism of this familial aggregation.

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