A Population-based Case–Control Study of Urinary Arsenic Species and Squamous Cell Carcinoma in New Hampshire,USA

Background: Chronic high arsenic exposure is associated with squamous cell carcinoma (SCC) of the skin, and inorganic arsenic (iAs) metabolites may play an important role in this association. However, little is known about the carcinogenicity of arsenic at levels commonly observed in the United States.Objective: We estimated associations between total urinary arsenic and arsenic species and SCC in a U.S. population.Methods: We conducted a population-based case–control SCC study (470 cases, 447 controls) in a U.S. region with moderate arsenic exposure through private well water and diet. We measured urinary iAs, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA), and summed these arsenic species (ΣAs). Because seafood contains arsenolipids and arsenosugars that metabolize into DMA through alternate pathways, participants who reported seafood consumption within 2 days before urine collection were excluded from the analyses.Results: In adjusted logistic regression analyses (323 cases, 319 controls), the SCC odds ratio (OR) was 1.37 for each ln-transformed microgram per liter increase in ln-transformed ΣAs concentration [ln(ΣAs)] (95% CI: 1.04, 1.80). Urinary ln(MMA) and ln(DMA) also were positively associated with SCC (OR = 1.34; 95% CI: 1.04, 1.71 and OR = 1.34; 95% CI: 1.03, 1.74, respectively). A similar trend was observed for ln(iAs) (OR = 1.20; 95% CI: 0.97, 1.49). Percent iAs, MMA, and DMA were not associated with SCC.Conclusions: These results suggest that arsenic exposure at levels common in the United States relates to SCC and that arsenic metabolism ability does not modify the association.Citation: Gilbert-Diamond D, Li Z, Perry AE, Spencer SK, Gandolfi AJ, Karagas MR. 2013. A population-based case–control study of urinary arsenic species and squamous cell carcinoma in New Hampshire, USA. Environ Health Perspect 121:1154–1160; http://dx.doi.org/10.1289/ehp.1206178     

高砷暴露致皮肤损伤人群尿砷代谢产物分析

目的 探讨高砷暴露致皮肤损伤人群尿砷代谢的特点.方法 应用氢化物发生.冷阱捕获.原子吸收分光光度法测定高砷暴露地Ⅸ(水砷浓度分别为0.21、0.24、0.36 mg/L)皮肤损伤组人群(77人)和未见皮肤损伤对照组人群(77人,性别、年龄1:1配比)尿中无机砷(iAs)、一甲基胂酸(MMA)和二甲基胂酸(DMA)含量.以iAs、MMA及DMA的总和表示总砷(tAs)水平;以iAs/tAs、MMMtAs和DMA/tAs分别计算iAs%、MMA%、DMA%;以(MMA+DMA)/tAs及DMM(MMA+DMA)分别计算一甲基化率(FMR)和二甲基化率(SMR)水平.结果 皮肤损伤组人群与对照组人群相比尿中各形态砷化合物及总砷含量差异无统计学意义(JD>0.05),而皮肤损伤组尿iAs%水平高于对照组,DMA%、FMR和SMR水平低于对照组差异均有统计学意义(P<0.05).皮肤损伤组人群中男性SMR水平显著低于女性,且尿中MMA%显著高于女性(P<0.05).结论 高砷暴露情况下,出现皮肤损伤症状的人群对砷的甲基化能力较低.

Abstract：

Objective To explore the characteristics of urine arsenic metabolism of people with skin lesion. Methods The levels of inorganic arsenic (iAs), monomethylated arsenic (MMA), dimethylated arsenic (DMA) in urine were detected with hydride generation-cold trap-atomic absorption spectroscopy among population exposed to higher levels of arsenide (0.24 ,0.36,0.21 mg/L), which consisted of skin lesion group(n=77) and non-skin lesion group (n=77,control group) in Apr.,2009 . Total arsenic (tAs) , iAs %, MMA%, DMA%, the first methylation ratio (FMR) and the secondary methylation ratio (SMR) were calculated as iAs + MMA+ DMA , iAs/tAs, MMA/tAs, DMA/tAs, (MMA + DMA)/ tAs and DMA/(MMA + DMA), respectively. Results No significant difference was observed in urinary concentrations of arsenic species and tAs between two groups (P>0.05), iAs% was much higher and the levels of FMR, SMR and DMA% were significantly lower in skin lesion group compared with the control (P<0.05). There were statistically significant differences in iAs% and SMR between males and females of the skin lesion group(P<0.05). Conclusion The arsenic methylation capacity of the persons with skin lesions is lower at high arsenic exposure.     

饮水型砷暴露对人群甲基化代谢能力的影响

目的探讨饮水型砷暴露对人群甲基化代谢能力的影响。方法以带有砷化物预处理装置的原子吸收分光光度计测定砷暴露人群及无砷暴露对照人群血、尿中无机砷(iAs)、甲基胂(MMA)、二甲基胂(DMA)含量。以iAs、MMA及DMA的总和表示总胂(tAs)水平;以(MMA+DMA)/tAs及DMA/(MMA+DMA)分别计算一甲基化率(PMI)和二甲基化率(SMI)水平。结果砷暴露人群血中iAs、MMA、DMA、tAs及PMI水平均显著高于相应对照人群的水平,而SMI水平显著低于对照人群。尿中MMA水平分别与血中PMI及SMI水平呈显著正相关(r=0.419,P<0.01)及负相关(r=-0.326,P<0.05)。暴露组和对照组血中各种砷化物水平及甲基化率水平在男女间差异无显著性。结论砷暴露人群与无砷暴露人群相比甲基化率有差异,PMI显著增高,SMI显著降低。人群甲基化率无显著性别差异。     

Profile of urinary arsenic metabolites during pregnancy

Chronic exposure to inorganic arsenic (In-As) from drinking water is associated with different health effects, including skin, lung, bladder, and kidney cancer as well as vascular and possibly reproductive effects. In-As is metabolized through the process of methylation, resulting in the production and excretion of methylated species, mainly monomethylarsenate (MMA) and dimethylarsenate (DMA). Because a large percentage of the dose is excreted in urine, the distribution of urinary In-As, MMA, and DMA is considered a useful indicator of methylation patterns in human populations. Several factors affect these patterns, including sex and exposure level. In this study, we investigated the profile of urinary In-As, MMA, and DMA of pregnant women. Periodic urine samples were collected from early to late pregnancy among 29 pregnant women living in Antofagasta, Chile, who drank tap water containing 40 micro g/L In-As. The total urinary arsenic across four sampling periods increased with increasing weeks of gestation, from an initial mean value of 36.1 to a final value of 54.3 micro g/L. This increase was mainly due to an increase in DMA, resulting in lower percentages of In-As and MMA and a higher percentage of DMA. Our findings indicate that among women exposed to moderate arsenic from drinking water during pregnancy, changes occur in the pattern of urinary arsenic excretion and metabolite distribution. The toxicologic significance of this is not clear, given recent evidence suggesting that intermediate methylated species may be highly toxic. Nevertheless, this study suggests that arsenic metabolism changes throughout the course of pregnancy, which in turn may have toxicologic effects on the developing fetus. Key words: arsenic, arsenic metabolism, arsenic methylation, Chile, pregnancy, urinary arsenic.     

Intra-individual variation in the metabolism of inorganic arsenic

OBJECTIVE: Inorganic arsenic is metabolized to methylarsonic acid (MMA) and dimethylarsinic acid (DMA), which are excreted in the urine. Previous studies have shown a marked inter-individual variation in the metabolism, but the within-person variation is unknown. Therefore, we determined the variation in the relative amount of urinary arsenic metabolites, i.e., inorganic arsenic, MMA and DMA, over time in women living in an Andean village with elevated arsenic levels in drinking water. METHODS: For our investigation of the individual day-to-day variation, daily spot urine samples were collected (at the same time of the day) for 5 consecutive days by 15 women. For our investigation of the within-day variation, seven women collected all the urine voided over a 72-h period, each voided into a separate container. RESULTS: Repeated measures analysis of variance (ANOVA) revealed no significant day-to-day variation, either in the relative distribution of inorganic arsenic metabolites (inorganic arsenic, MMA and DMA), or in the concentration of the metabolites. However, the percentage of DMA was slightly higher (on average 5.0%; P=0.003) and the percentage of inorganic arsenic lower (on average 5.8%; P=0.001) during the morning/day (03:00-15:00) compared with the evening/night (15:00-03:00). No within-day variation in the percentage of MMA was observed. CONCLUSION: The arsenic methylation efficiency of an individual is remarkably stable over time.     

Folate and arsenic metabolism: a double-blind, placebo-controlled folic acid-supplementation trial in Bangladesh

BACKGROUND: Populations in South and East Asia and many other regions of the world are chronically exposed to arsenic-contaminated drinking water. To various degrees, ingested inorganic arsenic (InAs) is methylated to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) via folate-dependent one-carbon metabolism; impaired methylation is associated with adverse health outcomes. Consequently, folate nutritional status may influence arsenic methylation and toxicity. OBJECTIVE: The objective of this study was to test the hypothesis that folic acid supplementation of arsenic-exposed adults would increase arsenic methylation. DESIGN: Two hundred adults in a rural region of Bangladesh, previously found to have low plasma concentrations of folate (相似文献   

Family correlations of arsenic methylation patterns in children and parents exposed to high concentrations of arsenic in drinking water

We investigated the evidence of a familial contribution to urinary methylation patterns in families ingesting arsenic in drinking water. Arsenic methylation can be assessed by measuring urinary levels of inorganic arsenic (InAs) and its methylated metabolites, monomethylarsonate (MMA), and dimethylarsinate (DMA). Methylation activity is reflected in the ratios: InAs/methylated arsenic (InAs/metAs) and MMA/DMA. Eleven families from Chile were selected because of their long-term exposure to very high levels of arsenic in drinking water (735-762 microg/L). Each family consisted of a father, a mother, and two children. We measured urinary arsenic and its methylated metabolites for each participant (n = 44). The intraclass correlation coefficients showed that 13-52% of the variations in the methylation patterns were from being a member of a specific family. Family correlations were calculated for father-mother, parent-child, and sibling-sibling pairs. Methylation patterns correlated strongly between siblings [r = 0.78 for InAs/metAs, 95% confidence interval (CI), 0.34-0.94; r = 0.82 for MMA/DMA, 95%CI, 0.43-0.95] compared to lower correlations in father-mother pairs (r = 0.18, r = -0.01, respectively), after adjustment for total urinary arsenic, age, and sex. Family correlations were not notably altered when adjustments were made for specific blood micronutrients (methionine, homocysteine, folate, vitamin B6, selenium, and vitamin B12 potentially related to methylation. We also report on a family pedigree with high prevalence of arsenic-induced effects. Participants from this family had low InAs/metAs values, which is consistent with increased toxicity of trivalent methylated arsenic species. Despite our small sample size, we observed that methylation patterns aggregate in families and are correlated in siblings, providing evidence of a genetic basis for the variation in arsenic methylation. Larger studies with more extensive pedigrees will need to be conducted to confirm these findings.     

A Prospective Study of Arsenic Exposure,Arsenic Methylation Capacity,and Risk of Cardiovascular Disease in Bangladesh

Background: Few prospective studies have evaluated the influence of arsenic methylation capacity on cardiovascular disease (CVD) risk.Objective: We evaluated the association of arsenic exposure from drinking water and arsenic methylation capacity with CVD risk.Method: We conducted a case–cohort study of 369 incident fatal and nonfatal cases of CVD, including 211 cases of heart disease and 148 cases of stroke, and a subcohort of 1,109 subjects randomly selected from the 11,224 participants in the Health Effects of Arsenic Longitudinal Study (HEALS).Results: The adjusted hazard ratios (aHRs) for all CVD, heart disease, and stroke in association with a 1-SD increase in baseline well-water arsenic (112 µg/L) were 1.15 (95% CI: 1.01, 1.30), 1.20 (95% CI: 1.04, 1.38), and 1.08 (95% CI: 0.90, 1.30), respectively. aHRs for the second and third tertiles of percentage urinary monomethylarsonic acid (MMA%) relative to the lowest tertile, respectively, were 1.27 (95% CI: 0.85, 1.90) and 1.55 (95% CI: 1.08, 2.23) for all CVD, and 1.65 (95% CI: 1.05, 2.60) and 1.61 (95% CI: 1.04, 2.49) for heart disease specifically. The highest versus lowest ratio of urinary dimethylarsinic acid (DMA) to MMA was associated with a significantly decreased risk of CVD (aHR = 0.54; 95% CI: 0.34, 0.85) and heart disease (aHR = 0.54; 95% CI: 0.33, 0.88). There was no significant association between arsenic metabolite indices and stroke risk. The effects of incomplete arsenic methylation capacity—indicated by higher urinary MMA% or lower urinary DMA%—with higher levels of well-water arsenic on heart disease risk were additive. There was some evidence of a synergy of incomplete methylation capacity with older age and cigarette smoking.Conclusions: Arsenic exposure from drinking water and the incomplete methylation capacity of arsenic were adversely associated with heart disease risk.     

Genetic variants associated with arsenic susceptibility: study of purine nucleoside phosphorylase, arsenic (+3) methyltransferase, and glutathione S-transferase omega genes

BACKGROUND: Individual variability in arsenic metabolism may underlie individual susceptibility toward arsenic-induced skin lesions and skin cancer. Metabolism of arsenic proceeds through sequential reduction and oxidative methylation being mediated by the following genes: purine nucleoside phosphorylase (PNP), arsenic (+3) methyltransferase (As3MT), glutathione S-transferase omega 1 (GSTO1), and omega 2 (GSTO2). PNP functions as arsenate reductase; As3MT methylates inorganic arsenic and its metabolites; and both GSTO1 and GSTO2 reduce the metabolites. Alteration in functions of these gene products may lead to arsenic-specific disease manifestations. OBJECTIVES: To find any probable association between arsenicism and the exonic single nucleotide polymorphisms (SNPs) of the above-mentioned arsenic-metabolizing genes, we screened all the exons in those genes in an arsenic-exposed population. METHODS: Using polymerase chain reaction restriction fragment length polymorphism analysis, we screened the exons in 25 cases (individuals with arsenic-induced skin lesions) and 25 controls (individuals without arsenic-induced skin lesions), both groups drinking similar arsenic-contaminated water. The exonic SNPs identified were further genotyped in a total of 428 genetically unrelated individuals (229 cases and 199 controls) for association study. RESULTS: Among four candidate genes, PNP, As3MT, GSTO1, and GSTO2, we found that distribution of three exonic polymorphisms, His20His, Gly51Ser, and Pro57Pro of PNP, was associated with arsenicism. Genotypes having the minor alleles were significantly overrepresented in the case group: odds ratio (OR) = 1.69 [95% confidence interval (CI), 1.08-2.66] for His20His; OR = 1.66 [95% CI, 1.04-2.64] for Gly51Ser; and OR = 1.67 [95% CI, 1.05-2.66] for Pro57Pro. CONCLUSIONS: The results indicate that the three PNP variants render individuals susceptible toward developing arsenic-induced skin lesions.     

吸烟对人类砷代谢和甲基化影响的Meta分析

目的 探讨吸烟是否影响人类对砷的代谢和甲基化.方法 检索纳入有关吸烟和砷代谢产物关系的1994-2008年发表的文献6篇,应用随机效应模型和同定效应模型对吸烟与人尿中无机砷(iAs)、一甲基胂酸(MMA)、二甲基胂酸(DMA)含量占总砷百分比的关系进行综合的定量分析.结果 吸烟组尿中iAs百分比的合并加权均数差(weight meandifference,WMD)为0.59(95%CI:-0.01～1.18);吸烟组尿中MMA百分比的合并WMD为2.44(95%CI:1.95～2.94);吸烟组尿中DMA百分比的合并WMD为-3.04(95%CI:-4.01-2.07). Meta分析提示吸烟组尿中MMA百分比高于非吸烟组,而吸烟组尿中DMA百分比低于非吸烟组.结论 吸烟可能是人类对砷代谢和甲基化影响因素之一.

Abstract：

Objective To investigate whether smoking affects metabolism and methylation of arsenic. Methods Six papers about the relation between smoking and arsenic metabolism, methylation were collected until December,2008, and the data were quantitatively analyzed with random and fixed effect models. Results In the group of smoking, the summary weighted mean difference of percent of inorganic in urinary was 0.59 (95% CI:-0.01 - 1.18). The summary weighted mean difference of percent of MMA in urinary was 2.44 (95%CI:1.95 - 2.94). The summary weighted mean difference of percent of DMA in urinary was -3.04 (95%CI:-4.01 --2.07). Current evidence suggested that percent of MMA was higher, percent of DMA was lower in smoking or ever smoking group compared with nonsmoking group. Conclusion Smoking may be considered a risk factor for metabolism and methylation of arsenic on human.     

Comparison of health effects between individuals with and without skin lesions in the population exposed to arsenic through drinking water in West Bengal, India

A study was conducted to explore the effect of arsenic causing conjunctivitis, neuropathy and respiratory illness in individuals, with or without skin lesions, as a result of exposure through drinking water, contaminated with arsenic to similar extent. Exposed study population belongs to the districts of North 24 Parganas and Nadia, West Bengal, India. A total of 725 exposed (373 with skin lesions and 352 without skin lesions) and 389 unexposed individuals were recruited as study participants. Participants were clinically examined and interviewed. Arsenic content in drinking water, urine, nail and hair was estimated. Individuals with skin lesion showed significant retention of arsenic in nail and hair and lower amount of urinary arsenic compared to the group without any skin lesion. Individuals with skin lesion also showed higher risk for conjunctivitis ((odd's ratio) OR: 7.33, 95% CI: 5.05-10.59), peripheral neuropathy (OR: 3.95, 95% CI: 2.61-5.93) and respiratory illness (OR: 4.86, 95% CI: 3.16-7.48) compared to the group without any skin lesion. The trend test for OR of the three diseases in three groups was found to be statistically significant. Again, individuals without skin lesion in the exposed group showed higher risk for conjunctivitis (OR: 4.66, 95% CI: 2.45-8.85), neuropathy (OR: 3.99, 95% CI: 1.95-8.09), and respiratory illness (OR: 3.21, 95% CI: 1.65-6.26) when compared to arsenic unexposed individuals. Although individuals with skin lesions were more susceptible to arsenic-induced toxicity, individuals without skin lesions were also subclinically affected and are also susceptible to arsenic-induced toxicity and carcinogenicity when compared to individuals not exposed to arsenic.     

The impact of diet and betel nut use on skin lesions associated with drinking-water arsenic in Pabna, Bangladesh

An established exposure-response relationship exists between water arsenic levels and skin lesions. Results of previous studies with limited historical exposure data, and laboratory animal studies suggest that diet may modify arsenic metabolism and toxicity. In this study, we evaluated the effect of diet on the risk of arsenic-related skin lesions in Pabna, Bangladesh. Six hundred cases and 600 controls loosely matched on age and sex were enrolled at Dhaka Community Hospital, Bangladesh, in 2001-2002. Diet, demographic data, and water samples were collected. Water samples were analyzed for arsenic using inductively coupled plasma mass spectroscopy. Betel nut use was associated with a greater risk of skin lesions in a multivariate model [odds ratio (OR) = 1.67; 95% confidence interval (CI), 1.18-2.36]. Modest decreases in risk of skin lesions were associated with fruit intake 1-3 times/month (OR = 0.68; 95%CI, 0.51-0.89) and canned goods at least 1 time/month (OR = 0.41; 95% CI, 0.20-0.86). Bean intake at least 1 time/day (OR = 1.89; 95% CI, 1.11-3.22) was associated with increased odds of skin lesions. Betel nut use appears to be associated with increased risk of developing skin lesions in Bangladesh. Increased intake of fruit and canned goods may be associated with reduced risk of lesions. Increased intake of beans may be associated with an increased risk of skin lesions. The results of this study do not provide clear support for a protective effect of vegetable and overall protein consumption against the development of skin lesions, but a modest benefit cannot be excluded.     

Comparison of the urinary excretion of arsenic metabolites after a single oral dose of sodium arsenite,monomethylarsonate, or dimethylarsinate in man

Summary The urinary elimination of the metabolites of arsenic has been followed up as a function of time in volunteers who ingested a single oral dose of arsenic (500 g As) either as sodium arsenite (As_i), monomethylarsonate (MMA), or cacodylate (DMA). The excretion rate increased in the order As_i < DMA < MMA. After 4 days, the amount of arsenic excreted in urine represents 46, 78, and 75% of the ingested dose in the case of As_i, MMA and DMA, respectively. With regard to the in vivo biotransformations, it is concluded that DMA is excreted unchanged; MMA is slightly (13%) methylated into DMA while roughly 75% of the arsenic excreted after ingestion of As_i is methylated arsenic (about 1/3 as MMA and about 2/3 as DMA).This study was supported by a grant from the Commission of the European Communities     

Decrements in lung function related to arsenic in drinking water in West Bengal, India

During 1998-2000, the authors investigated relations between lung function, respiratory symptoms, and arsenic in drinking water among 287 study participants, including 132 with arsenic-caused skin lesions, in West Bengal, India. The source population involved 7,683 participants who had been surveyed for arsenic-related skin lesions in 1995-1996. Respiratory symptoms were increased among men with arsenic-caused skin lesions (versus those without lesions), particularly "shortness of breath at night" (odds ratio (OR) = 2.8, 95% confidence interval (CI): 1.1, 7.6) and "morning cough" (OR = 2.8, 95% CI: 1.2, 6.6) in smokers and "shortness of breath ever" (OR = 3.8, 95% CI: 0.7, 20.6) in nonsmokers. Among men with skin lesions, the average adjusted forced expiratory volume in 1 second (FEV1) was reduced by 256.2 ml (95% CI: 113.9, 398.4; p < 0.001) and the average adjusted forced vital capacity (FVC) was reduced by 287.8 ml (95% CI: 134.9, 440.8; p < 0.001). In men, a 100-microg/liter increase in arsenic level was associated with a 45.0-ml decrease (95% CI: 6.2, 83.9) in FEV1 (p = 0.02) and a 41.4-ml decrease (95% CI: -0.7, 83.5) in FVC (p = 0.054). Women had lower risks than men of developing skin lesions and showed little evidence of respiratory effects. In this study, consumption of arsenic-contaminated water was associated with respiratory symptoms and reduced lung function in men, especially among those with arsenic-related skin lesions.     

Physical activity and common mental disorder: results from the Caerphilly study

The authors examined associations between leisure-time and occupational physical activity and common mental disorder (CMD), defined as anxiety and depression, using data from a cohort of middle-aged men in Caerphilly, South Wales, United Kingdom, who were followed for 5 years (1989-1993) and 10 years (1993-1997). CMD was measured using the General Health Questionnaire. Total leisure-time activity and percentage of time spent in heavy-intensity activity were estimated from self-reports (Minnesota Leisure Time Physical Activity Questionnaire). Men were classified into four classes of occupational activity. Among 1,158 men with complete data, those who participated in any heavy-intensity leisure-time activity had reduced odds of CMD 5 years later (below median vs. none: adjusted odds ratio (OR(adj)) = 0.61, 95% confidence interval (CI): 0.40, 0.93); median or above vs. none: OR(adj) = 0.54, 95% CI: 0.35, 0.83). Analyses using multiple imputation to deal with missing data found weaker evidence for an association (OR(adj) = 0.79 (95% CI: 0.54, 1.15) and OR(adj) = 0.73 (95% CI: 0.49, 1.09), respectively). There was little evidence that men in the most physically demanding jobs had reduced odds of CMD after 5 years, and there was no association between physical activity and CMD 10 years later. Among these men, heavy-intensity leisure-time physical activity was associated with a small reduction in CMD over 5 years.     

Creatinine, diet, micronutrients, and arsenic methylation in West Bengal, India

Background: Ingested inorganic arsenic (InAs) is methylated to monomethylated (MMA) and dimethylated metabolites (DMA). Methylation may have an important role in arsenic toxicity, because the monomethylated trivalent metabolite [MMA(III)] is highly toxic.Objectives: We assessed the relationship of creatinine and nutrition—using dietary intake and blood concentrations of micronutrients—with arsenic metabolism, as reflected in the proportions of InAS, MMA, and DMA in urine, in the first study that incorporated both dietary and micronutrient data.Methods: We studied methylation patterns and nutritional factors in 405 persons who were selected from a cross-sectional survey of 7,638 people in an arsenic-exposed population in West Bengal, India. We assessed associations of urine creatinine and nutritional factors (19 dietary intake variables and 16 blood micronutrients) with arsenic metabolites in urine.Results: Urinary creatinine had the strongest relationship with overall arsenic methylation to DMA. Those with the highest urinary creatinine concentrations had 7.2% more arsenic as DMA compared with those with low creatinine (p < 0.001). Animal fat intake had the strongest relationship with MMA% (highest tertile animal fat intake had 2.3% more arsenic as MMA, p < 0.001). Low serum selenium and low folate were also associated with increased MMA%.Conclusions: Urine creatinine concentration was the strongest biological marker of arsenic methylation efficiency, and therefore should not be used to adjust for urine concentration in arsenic studies. The new finding that animal fat intake has a positive relationship with MMA% warrants further assessment in other studies. Increased MMA% was also associated, to a lesser extent, with low serum selenium and folate.     

Variability in human metabolism of arsenic

Estimating the nature and extent of human cancer risks due to arsenic (As) in drinking water is currently of great concern, since millions of persons worldwide are exposed to arsenic, primarily through natural enrichment of drinking water drawn from deep wells. Humans metabolize and eliminate As through oxidative methylation and subsequent urinary excretion. While there is debate as to the role of methylation in activation/detoxification, variations in arsenic metabolism may affect individual risks of toxicity and carcinogenesis. Using data from three populations, from Mexico, China, and Chile, we have analyzed the distribution in urine of total arsenic and arsenic species (inorganic arsenic (InAs), monomethyl arsenic (MMA), and dimethyl arsenic (DMA). Data were analyzed in terms of the concentration of each species and by evaluating MMA:DMA and (MMA+DMA):InAs ratios. In all persons most urinary As was present as DMA. Male:female differences were discernible in both high- and low-exposure groups from all three populations, but the gender differences varied by populations. The data also indicated bimodal distributions in the ratios of DMA to InAs and to MMA. While the gene or genes responsible for arsenic methylation are still unknown, the results of our studies among the ethnic groups in this study are consistent with the presence of functional genetic polymorphisms in arsenic methylation leading to measurable differences in toxicity. This analysis highlights the need for continuing research on the health effects of As in humans using molecular epidemiologic methods.     

Arsenic exposure from drinking water and risk of premalignant skin lesions in Bangladesh: baseline results from the Health Effects of Arsenic Longitudinal Study

Millions of persons around the world are exposed to low doses of arsenic through drinking water. However, estimates of health effects associated with low-dose arsenic exposure have been extrapolated from high-dose studies. In Bangladesh, many persons have been exposed to a wide range of doses of arsenic from drinking water over a significant period of time. The authors evaluated dose-response relations between arsenic exposure from drinking water and premalignant skin lesions by using baseline data on 11,746 participants recruited in 2000-2002 for the Health Effects of Arsenic Longitudinal Study in Araihazar, Bangladesh. Several measures of arsenic exposure were estimated for each participant based on well-water arsenic concentration and usage pattern of the wells and on urinary arsenic concentration. In different regression models, consistent dose-response effects were observed for all arsenic exposure measures. Compared with drinking water containing <8.1 microg/liter of arsenic, drinking water containing 8.1-40.0, 40.1-91.0, 91.1-175.0, and 175.1-864.0 microg/liter of arsenic was associated with adjusted prevalence odds ratios of skin lesions of 1.91 (95% confidence interval (CI): 1.26, 2.89), 3.03 (95% CI: 2.05, 4.50), 3.71 (95% CI: 2.53, 5.44), and 5.39 (95% CI: 3.69, 7.86), respectively. The effect seemed to be influenced by gender, age, and body mass index. These findings provide information that should be considered in future research and policy decisions.     

Pregnancy outcomes, infant mortality, and arsenic in drinking water in West Bengal, India

Between 2001 and 2003, the authors studied pregnancy outcomes and infant mortality among 202 married women in West Bengal, India. Reproductive histories were ascertained using structured interviews. Arsenic exposure during each pregnancy, including all water sources used, was assessed; this involved measurements from 409 wells. Odds ratios for spontaneous abortion, stillbirth, neonatal mortality, and infant mortality were estimated with logistic regression based on the method of generalized estimating equations. Exposure to high concentrations of arsenic (> or =200 microg/liter) during pregnancy was associated with a sixfold increased risk of stillbirth after adjustment for potential confounders (odds ratio (OR) = 6.07, 95% confidence interval (CI): 1.54, 24.0; p = 0.01). Arsenic-related skin lesions were found in 12 women who had a substantially increased risk of stillbirth (OR = 13.1, 95% CI: 3.17, 54.0; p = 0.002). The odds ratio for neonatal death was 2.81 (95% CI: 0.73, 10.8). No association was found between arsenic exposure and spontaneous abortion (OR = 1.01, 95% CI: 0.38, 2.70) or overall infant mortality (OR = 1.33, 95% CI: 0.43, 4.04). This study adds to the limited evidence that exposure to high concentrations of arsenic during pregnancy increases the risk of stillbirth. However, there was no indication of the increased rates of spontaneous abortion and overall infant mortality that have been reported in some studies.     

Associations between drinking water and urinary arsenic levels and skin lesions in Bangladesh

The present study examined the associations between drinking water and urinary arsenic levels and skin lesions among 167 residents of three contiguous villages in Bangladesh. Thirty-six (21.6%) had skin lesions (melanosis, hyperkeratosis, or both), of which 13 (36.1%) occurred in subjects who were currently drinking water containing concentrations of arsenic < 50 micrograms/L. The risk for skin lesions in relation to the exposure estimates based on urinary arsenic was elevated more than 3-fold, with the odds ratios for the highest versus the lowest quartiles being 3.6 (95% confidence interval, 1.2 to 12.1) for urinary total arsenic and 3.2 (95% confidence interval, 1.1 to 10.0) for urinary creatinine-adjusted total arsenic. The risks for skin lesions in relation to the exposure estimates based on arsenic in drinking water were less strongly elevated, with the odds ratios for the highest versus the lowest quartiles of exposure being 1.7 (95% confidence interval, 0.6 to 5.1) for drinking-water arsenic and 2.3 for cumulative arsenic index. The study suggests that arsenic exposure is associated with skin lesions in the Bangladesh population and that urinary arsenic may be a stronger predictor of skin lesions than arsenic in drinking water in this population.