Factors influencing the metabolism of inorganic arsenic in humans

Inorganic arsenic (iAs), a naturally occurring drinking water contaminant, is a potent human carcinogen and toxicant. It is believed that in humans, as well as in most mammals, inorganic arsenic is biotransformed via reduction and methylation using onecarbon metabolism with S-adenosyl methionine (SAM) as methyl donor, and is excreted mainly in urine as dimethylarsinate (DMA) and methylarsonate (MA) as well as some unmethylated iAs (arsenate (As(V)) and arsenite (As(III)). There is a wide variation in susceptibility to arsenic induced health effects, which, in part, may be due to the large inter-individual variation in arsenic metabolism. The main aim of the present study was to elucidate the mechanisms behind the marked inter-individual variation in the metabolism of inorganic arsenic in humans in two different populations, one from Central Europe including Hungary, Romania and Slovakia and the other from Bangladesh. As part of the work a comparison of the most commonly used analytical methods for determination of arsenic metabolites in urine was performed. Inorganic arsenic exposure was assessed based on measurements of inorganic arsenic and its metabolites in urine and total arsenic in drinking water. Arsenic concentrations in urine were determined either as the sum of arsenic metabolites (SumAs; iAs+MA+DMA) by hydride generation atomic absorption spectrometry (HG-AAS) or by speciation analysis using high performance liquid chromatography coupled to either inductively coupled plasma mass spectrometry or atomic fluorescence spectrometry via hydride generation (HPLC-HG-ICPMS and HPLC-HG-AFS). Total arsenic concentrations in drinking water were analyzed using HG-AAS. The results of the present study show that most of the individuals in the Matlab area, Bangladesh and a large part of the individuals in Bekes, Csongrad and Jasz-NagykunSzolnok counties in Hungary were exposed to elevated arsenic levels in drinking water, but with a large variation. It was also found that food was an important source of arsenic exposure in both study areas. HPLC-HG-AFS was shown to be a good alternative to HPLC-HG-ICPMS for speciation analysis of arsenic in urine in highly exposed areas where the requirements of low detection limits are not needed. Considerable inter-individual variations in the distribution of inorganic arsenic and its metabolites in urine were found. The exposure level of arsenic was found to be the strongest influencing factor on arsenic metabolism, except at low exposure levels (below about 50 μg/L). The association was negative, indicating an inhibition of the methyltransferases involved in arsenic methylation. Demographic factors such as age and gender were also found to influence the metabolism of arsenic, with men having a higher proportion of MA in urine than women. Interestingly, this was only seen between 20 and 60 years of age, indicating an effect of sex hormones on arsenic methylation. Polymorphisms in the genes arsenic (III) methyltransferase (AS3MT) and methylene tetrahydrofolate reductase (MTHFR), but not in glutathione-S-transferase omega 1 (GSTO1), had a negative influence on arsenic methylation. Nutritional status did not influence arsenic methylation as much as previously hypothesized. Only about 20% of the variation in arsenic methylation was explained by the factors studied. The rest of the variation is probably explained by e.g. polymorphisms in genes coding for other methyltransferases backing up the methylation of arsenic.