Dave Kalman

Children's intellectual function in relation to arsenic exposure.

Background: Very little evidence exists concerning the possible impairment of childrens intellectual function in relation to arsenic exposure in utero and during childhood. Methods: We conducted a cross-sectional study among 351 children age 5 to 15 years who were selected from a source population of 7683 people in West Bengal, India, in 2001–2003. Intellectual function was assessed with 6 subtests from the Wechsler Intelligence Scale for Children as well as with the Total Sentence Recall test, the Colored Progressive Matrices test, and a pegboard test. Arsenic in urine and lifetime water sources (including during the pregnancy period) were assessed using measurements of samples from 409 wells. The test scores were analyzed with linear regression analyses based on the method of generalized estimating equations incorporating relevant covariates. Results: Stratifying urinary arsenic concentrations into tertiles, we found associations between arsenic and reductions in the adjusted scores of the vocabulary test (0, −0.14, −0.28; P for trend = 0.02), the object assembly test (0, −0.16, −0.24; P for trend = 0.03), and the picture completion test (0, −0.15, −0.26; P for trend = 0.02). These findings correspond to relative declines of 12% (95% confidence interval =0.4% to 24%) in the vocabulary test, 21% (−0.8% to 42%) in the object assembly test, and of 13% (0.3% to 24%) in the picture completion test in the upper urinary arsenic tertile. However, we did not find evidence of an association between test results and arsenic water concentrations during pregnancy or childhood. Conclusions: Current arsenic concentrations in urine, which reflect all sources of recent exposure, including water and food, were associated with small decrements in intellectual testing in school-aged children in West Bengal. We did not see associations between long-term water arsenic concentrations and intellectual function.

Arsenic Methylation and Bladder Cancer Risk in Case-Control Studies in Argentina and the United States

Objective: We sought to assess whether the metabolism of arsenic impacts a persons susceptibility to bladder cancer. Methods: Urinary methylation products were measured in subjects from Argentina (114 cases and 114 controls) and the United States (23 cases and 49 controls). Results: In Argentina, the adjusted odds ratio (OR) for subjects with a high proportion of ingested arsenic excreted as monomethylarsonate (%MMA) was 2.17 (95% confidence interval [CI] = 1.02–4.63) in smokers and 0.48 (95% CI = 0.17–1.33) in nonsmokers. In the United States, the adjusted ORs for high %MMA in subjects with arsenic intakes less than and greater than 100 &mgr;g/d were 1.20 (95% CI = 0.27–5.38) and 2.70 (95% CI = 0.39–18.6). Conclusions: Overall, these results are consistent with data from Taiwan suggesting that some individuals who excrete a higher proportion of ingested arsenic as MMA are more susceptible to arsenic-related cancer.

Dietary Intake and Arsenic Methylation in a U.S. Population

Millions of people worldwide are exposed to arsenic-contaminated drinking water, and ingestion of inorganic arsenic (InAs) has been associated with increased risks of cancer. The primary metabolic pathway of ingested InAs is methylation to monomethyl arsenic (MMA) and dimethyl arsenic (DMA). However, people vary greatly in the degree to which they methylate InAs, and recent evidence suggests that those who excrete high proportions of ingested arsenic as MMA are more susceptible than others to arsenic-caused cancer. To date, little is known about the factors that determine interindividual differences in arsenic methylation. In this study, we assessed the effect of diet on arsenic metabolism by measuring dietary intakes and urinary arsenic methylation patterns in 87 subjects from two arsenic-exposed regions in the western United States. Subjects in the lower quartile of protein intake excreted a higher proportion of ingested InAs as MMA (14.6 vs. 11.6%; p = 0.01) and a lower proportion as DMA (72.3 vs. 77.0%; p = 0.01) than did subjects in the upper quartile of protein intake. Subjects in the lower quartile of iron, zinc, and niacin intake also had higher urinary percent MMA and lower percent DMA levels than did subjects with higher intakes of these nutrients. These associations were also seen in multivariate regression analyses adjusted for age, sex, smoking, and total urinary arsenic. Given the previously reported links between high percent MMA and increased cancer risks, these findings are consistent with the theory that people with diets deficient in protein and other nutrients are more susceptible than others to arsenic-caused cancer.

Individual differences in arsenic metabolism and lung cancer in a case-control study in Cordoba, Argentina

In humans, ingested inorganic arsenic is metabolized to monomethylarsenic (MMA) then to dimethylarsenic (DMA), although in most people this process is not complete. Previous studies have identified associations between the proportion of urinary MMA (%MMA) and increased risks of several arsenic-related diseases, although none of these reported on lung cancer. In this study, urinary arsenic metabolites were assessed in 45 lung cancer cases and 75 controls from arsenic-exposed areas in Cordoba, Argentina. Folate has also been linked to arsenic-disease susceptibility, thus an exploratory assessment of associations between single nucleotide polymorphisms in folate metabolizing genes, arsenic methylation, and lung cancer was also conducted. In analyses limited to subjects with metabolite concentrations above detection limits, the mean %MMA was higher in cases than in controls (17.5% versus 14.3%, p=0.01). The lung cancer odds ratio for subjects with %MMA in the upper tertile compared to those in the lowest tertile was 3.09 (95% CI, 1.08-8.81). Although the study size was too small for a definitive conclusion, there was an indication that lung cancer risks might be highest in those with a high %MMA who also carried cystathionine beta-synthase (CBS) rs234709 and rs4920037 variant alleles. This study is the first to report an association between individual differences in arsenic metabolism and lung cancer, a leading cause of arsenic-related mortality. These results add to the increasing body of evidence that variation in arsenic metabolism plays an important role in arsenic-disease susceptibility.

Intraindividual Variability in Arsenic Methylation in a U.S. Population

Several recent investigations have reported associations between a reduced capacity to fully methylate inorganic arsenic and increased susceptibility to arsenic-caused cancer. In these studies, methylation patterns were based on a single assessment of urinary arsenic metabolites collected at the time of cancer diagnosis. However, the latency of arsenic-caused cancer may be several decades, and the extent to which a recent measurement can be used to estimate a persons past methylation pattern is unknown. In this investigation, the distribution of urinary inorganic arsenic, monomethylarsonate, and dimethylarsinate was used to assess intraindividual variation in methylation capacity in 81 subjects with low to moderate arsenic exposures. Multiple urine samples were collected from each subject over a 1-year period. Duplicate analyses done on 27 samples were used to assess laboratory measurement imprecision. The intraclass correlation coefficients (ICC) for the proportion of urinary arsenic as inorganic arsenic, monomethylarsonate, and dimethylarsinate in samples taken an average of 258 days apart, were 0.45 [95% confidence interval (95% CI), 0.23-0.63] 0.46 (95% CI, 0.24-0.64), and 0.49 (95% CI, 0.28-0.66). In analyses of duplicate samples, ICCs for the concentration of arsenic species ranged from 0.87 to 0.93, whereas ICCs for species proportions ranged from 0.63 to 0.76. These data suggest that individual methylation patterns remain fairly stable over time, although variability due to measurement imprecision or intraindividual changes over time does occur. This variability could lead to misclassification of methylation patterns and could bias relative risk estimates in studies of methylation and cancer towards the null.

Farmworker Exposure to Organophosphorus Pesticide Residues During Apple Thinning in Central Washington State

The purpose of this study was to characterize worker exposure to azinphos-methyl (Guthion) over an entire 4-6 week apple-thinning season. Twenty workers from three work sites in the Chelan-Douglas County region of Washington state were recruited for the study. Exposure potential was estimated by dislodgeable foliar residue measurements, and individual exposures were estimated by biological monitoring through urinary metabolites. Measureable azinphos-methyl residues were found on apple foliage at all sites throughout the six-week sampling period, indicating continuous exposure potential (median residue level of 0.5 microgram/cm2). Measurable levels of the urinary dialkylphosphate metabolite, DMTP, were found in virtually all urine samples (limit of detection = 0.04 microgram/mL). Mean DMTP concentrations differed significantly across sites (0.53, 0.29, and 0.90 microgram/mL for Sites 1-3, respectively; analysis of variance, p < .002), and intraindividual variability was much greater than interindividual differences. Group mean DMTP concentrations at each site fluctuated according to foliar residue levels. Measurable DMTP concentrations were found in 9% of reference workers, ranging from 0.04-0.18 microgram/mL. Cholinesterase activity levels monitored with a field test kit were not considered reliable due to temperature changes of the instrument.

Comparative functional genomic analysis identifies distinct and overlapping sets of genes required for resistance to monomethylarsonous acid (MMAIII) and arsenite (AsIII) in yeast.

Arsenic is a human toxin and carcinogen commonly found as a contaminant in drinking water. Arsenite (As(III)) is the most toxic inorganic form, but recent evidence indicates that the metabolite monomethylarsonous acid (MMA(III)) is even more toxic. We have used a chemical genomics approach to identify the genes that modulate the cellular toxicity of MMA(III) and As(III) in the yeast Saccharomyces cerevisiae. Functional profiling using homozygous deletion mutants provided evidence of the requirement of highly conserved biological processes in the response against both arsenicals including tubulin folding, DNA double-strand break repair, and chromatin modification. At the equitoxic doses of 150 microM MMA(III) and 300 microM As(III), genes related to glutathione metabolism were essential only for resistance to the former, suggesting a higher potency of MMA(III) to disrupt glutathione metabolism than As(III). Treatments with MMA(III) induced a significant increase in glutathione levels in the wild-type strain, which correlated to the requirement of genes from the sulfur and methionine metabolic pathways and was consistent with the induction of oxidative stress. Based on the relative sensitivity of deletion strains deficient in GSH metabolism and tubulin folding processes, oxidative stress appeared to be the primary mechanism of MMA(III) toxicity whereas secondary to tubulin disruption in the case of As(III). Many of the identified yeast genes have orthologs in humans that could potentially modulate arsenic toxicity in a similar manner as their yeast counterparts.