Metabolism of inorganic arsenic and biomarkers of exposure

Sammanfattning: Humans as well as most mammals metabolize inorganic arsenic (Inorg As), a recognized human carcinogen, by methylation. The end-metabolites methylarsonic acid (MMA) and dimethylarsinic acid (DMA) are less toxic and more readily excreted in the urine than Inorg As. Generally, people exposed to arsenic have 10-30% Inorg As, 10- 20% MMA and 60-80% DMA in urine, with considerable interindividual variation. Little is known about factors influencing the metabolism in humans. The aim of the present study was to investigate such factors e.g. age, ethnicity, and pregnancy in people chronically exposed to arsenic via drinking water in two villages in northern Argentina. Also, transfer of arsenic to the fetus and human milk was studied. For assessment of arsenic exposure, total arsenic concentrations in drinking water, food, breast milk and blood (B- As) were determined using hydride generation atomic absorption spectrophotometry (HGAAS), after dry ashing. Concentrations of arsenic metabolites in urine (U-Asmet, i.e. Inorg As+MMA+DMA; direct HG-AAS) and B- As were used as biomarkers of exposure to Inorg As. In order to assess methylation capacity, arsenic metabolites in urine and plasma were speciated. using ionexchange chromatography and HG-AAS. Fetal exposure was investigated by determination of arsenic concentrations in cord blood, placenta, matemal blood and urine. The concentration of arsenic in drinking water in the villages was about 200 µg As/L, which is considerably higher than the drinking water guideline of 10 µg As/L recommended by the WHO. The staple food soup and maize porridge had the highest concentrations of arsenic (300-400 µg As/kg). The high arsenic exposure caused clearly elevated B-As and U-Asmet, in the investigated children (n=57, age 3-15 yrs) and women (n=39, age 18-66 yrs). The B-As (10 µg As/L) was 10 times higher and the U-Asmet (300-440 µg AsAL) was 30 times higher than in the control area, where the water contained <1 µg As/L. There was a unique pattern of arsenic metabolites in the urine, characterized by the low urinary excretion of MMA (about 3%), compared to more than 10% (often 10-20%) in other population groups studied. The data indicate the existence of genetic polymorphism in the methylation of arsenic. Interestingly, the individuals with low % MMA were of native Andean origin and they seemed to retain less arsenic than people with more MMA in urine. Studies of intra- and inter-individual variation in the metabolism of Inorg As showed a remarkably stable methylation from day-to-day, but a slight diurnal variation. A pronounced inter-individual variation in methylation (%DMA 51-8 1 %) was observed. Thus, the genetic influence seemed to be more important than the environmental. Another important finding was that children had significantly lower % DMA (50%) and higher urinary % inorganic arsenic (about 47%) compared to the women, but similar low %MMA. Thus, the results indicate lower arsenic methylating capacity in children, and that children retain more arsenic than adults. The concentration of arsenic in cord blood was almost as high as, and significantly correlated to, that in matemal blood in late gestation (9 and 11 µg As/L, respectively; r = 0.79). Thus, arsenic was readily transferred to the human fetus. Essentially all arsenic in maternal plasma and urine, cord plasma and infant urine was in the form of DMA, indicating an increase in the arsenic methylation in late gestation and that the fetus was mostly exposed to DMA prior to birth. This is important from a toxicological point of view, as experimental studies have indicated that DMA is less toxic to the embryo and fetus than Inorg As. In spite of the high concentrations of arsenic in maternal blood and urine, the concentrations of arsenic in breast milk were low, on average 3 µg As/L. Breast feeding led to a decrease in the arsenic concentrations in the urine of the infants during the nursing period.