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.     

GSTO基因多态性与燃煤污染型砷中毒易感性的关系

[目的]探讨GSTO基因多态性与燃煤污染型砷中毒易感性的关系.[方法]应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术检测130名燃煤型砷中毒患者和140名健康个体GSTO1 Ala140Asp和GSTO2Asn142Asp基因两个位点的多态性,并分析不同基因型与砷中毒发病风险的关系.[结果]病例组中携带GSTO2 142Asn/Asp Asp/Asp(杂合型 突变纯合型)基因型个体的比例显著高于对照组,携带该基因型的个体较携带GSTO2 142Asn/Asn(野生纯合型)基因型个体发生砷中毒的风险升高1.18倍(ORadj=1.18,95%CI:1.02～1.37);而病例组中携带GSTO1140Ala/Asp Asp/Asp(杂合型 突变纯合型)基因型个体的比例仅略高于对照组,差异无统计学意义(ORadj=0.98,95%CI:0.51～1.91);但同时携带GSTO1 140Ala/Asp Asp/Asp和GSTO2 142Asn/Asp Asp/Asp基因型的个体砷中毒的发病风险显著增加(ORadj=2.48,95%CI:1.14～5.40).[结论]携带GSTO2Asn142Asp基因型个体有较高的砷中毒发病风险;而同时携带GSTO1 140Ala/Asp Asp/Asp和GSTO2 142Asn/Asp Asp/Asp的个体可能更容易发生砷中毒.     

Association between GSTO2 polymorphism and the urinary arsenic profile in copper industry workers

Two members of the recently identified Omega class glutathione S-transferase enzymes (GSTO1 and GSTO2) have been proposed to play a role in the response to arsenic exposure. Therefore, polymorphisms in these genes could be related with variations in the arsenic excretion profile and, consequently, with the individual response to chronic exposure. Exons and flanking regions of GSTO2 gene have been screened in two different ethnic groups (20 Europeans and 20 Chilean Indians), and the urinary arsenic patterns and the GSTO2 Asn142Asp polymorphism have been investigated in 207 copper mine workers occupationally exposed to arsenic. Three polymorphisms of GSTO2 already described were detected in Europeans and Chilean Indians, although with significant different allele frequencies. The genotyping for the Asn142Asp polymorphism revealed that almost no significant association exists between this change and the arsenic excretion profile. However, 142Asp change seems to be correlated with an increase in DMA excretion after age and total urinary arsenic adjustment (OR=3.61; P=0.05). Altogether, our findings indicate that ethnical differences should be taken into account for correlation studies between GST Omega polymorphisms and arsenic susceptibility, and that the 142Asp allozyme could modulate arsenic biotransformation and thereby arsenic toxicity.     

不同人群GSTO1 mRNA表达及与砷甲基化关系

目的 观察谷胱甘肽-S-转移酶(GSTO1)mRNA在砷中毒患者、病区对照和非病区对照人群中的表达及其与尿砷甲基化水平的关系.方法 选取饮水型砷中毒重度患者、轻度患者、病区对照和非病区对照各6例,采用实时定量RT-PCR技术测定研究对象的淋巴细胞中GSTO1 mRNA表达,采用AFS-9130、SAP-10检测尿无机砷(iAS)、一甲基胂酸(MMA)、二甲基胂酸(DMA)、尿总砷TAs含量.结果 中重度组,轻度组、病区对照组人群iAs,MMA,DMA,TAs一甲基化指数(PMI)均明显高于非病区对照人群(P<0.05);中重度组(P_(50)=1.96),轻度组(P_(50)=1.31)、病区对照组人群(P_(50)=1.23)GSTO1mRNA表达高于非病区对照人群(P_(50)=1.015)(P<0.05);GSTO1 mRNA表达与MMA%(r=0.206,P=0.112)、DMA%(r=0.098,P:0.700),PMI(r=0.127,P=0.615)和SMI(r=0.192,P=0.445)无相关性.结论 GSTO1 mRNA表达与砷甲基化无明显关系,砷中毒引起的损伤可能与砷暴露引起GSTO1mRNA表达增高,并将五价砷化物还原为三价砷化物增多有关.     

砷代谢相关酶及其基因多态性研究进展

地方性砷中毒是一种严重危害健康的地方病,研究发现,高砷暴露环境下的个体并不都患病,提示除环境因素外,个体的遗传易感性在砷中毒的发病过程中可能也起着重要作用。砷在体内的代谢过程涉及许多酶促和/或非酶促反应过程,现在研究较多的砷代谢酶促反应3种相关酶是谷胱甘肽S转移酶(GSTO 1-1)、嘌呤核苷磷酸化酶(PNP)、三价砷甲基转移酶(CYT19/AS3MT),围绕上述酶及其基因多态性展开综述。     

Metabolism of low-dose inorganic arsenic in a central European population: influence of sex and genetic polymorphisms

BACKGROUND: There is a wide variation in susceptibility to health effects of arsenic, which, in part, may be due to differences in arsenic metabolism. Arsenic is metabolized by reduction and methylation reactions, catalyzed by reductases and methyltransferases. OBJECTIVES: Our goal in this study was to elucidate the influence of various demographic and genetic factors on the metabolism of arsenic. METHODS: We studied 415 individuals from Hungary, Romania, and Slovakia by measuring arsenic metabolites in urine using liquid chromatography with hydride generation and inductively coupled plasma mass spectrometry (HPLC-HG-ICPMS). We performed genotyping of arsenic (+III) methyltransferase (AS3MT), glutathione S-transferase omega 1 (GSTO1), and methylene-tetrahydrofolate reductase (MTHFR). RESULTS: The results show that the M287T (T-->C) polymorphism in the AS3MT gene, the A222V (C-->T) polymorphism in the MTHFR gene, body mass index, and sex are major factors that influence arsenic metabolism in this population, with a median of 8.0 microg/L arsenic in urine. Females < 60 years of age had, in general, higher methylation efficiency than males, indicating an influence of sex steroids. That might also explain the observed better methylation in overweight or obese women, compared with normal weight men. The influence of the M287T (T-->C) polymorphism in the AS3MT gene on the methylation capacity was much more pronounced in men than in women. CONCLUSIONS: The factors investigated explained almost 20% of the variation seen in the metabolism of arsenic among men and only around 4% of the variation among women. The rest of the variation is probably explained by other methyltransferases backing up the methylation of arsenic.     

Genetic polymorphisms influencing arsenic metabolism: evidence from Argentina

The susceptibility to arsenic-induced diseases differs greatly between individuals, possibly due to interindividual variations in As metabolism that affect retention and distribution of toxic metabolites. To elucidate the role of genetic factors in As metabolism, we studied how polymorphisms in six genes affected the urinary metabolite pattern in a group of indigenous women (n = 147) in northern Argentina who were exposed to approximately 200 microg/L As in drinking water. These women had low urinary percentages of monomethylated As (MMA) and high percentages of dimethylated As (DMA). MMA has been associated with adverse health effects, and DMA has the lowest body retention of the metabolites. The genes studied were arsenic(+III)methyltransferase (AS3MT), glutathione S-transferase omega 1 (GSTO1), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), methylenetetrahydrofolate reductase (MTHFR), and glutathione S-transferases mu 1 (GSTM1) and theta 1 (GSTT1). We found three intronic polymorphisms in AS3MT (G12390C, C14215T, and G35991A) associated with a lower percentage of MMA (%MMA) and a higher percentage of DMA (%DMA) in urine. The variant homozygotes showed approximately half the %MMA compared with wild-type homozygotes. These polymorphisms were in strong linkage, with high allelic frequencies (72-76%) compared with other populations. We also saw minor effects of other polymorphisms in the multivariate regression analysis with effect modification for the deletion genotypes for GSTM1 (affecting %MMA) and GSTT1 (affecting %MMA and %DMA). For pregnant women, effect modification was seen for the folate-metabolizing genes MTR and MTHFR. In conclusion, these findings indicate that polymorphisms in AS3MT-and possibly GSTM1, GSTT1, MTR, and MTHFR-are responsible for a large part of the interindividual variation in As metabolism and susceptibility.     

Developmentally restricted genetic determinants of human arsenic metabolism: association between urinary methylated arsenic and CYT19 polymorphisms in children

We report the results of a screen for genetic association with urinary arsenic metabolite levels in three arsenic metabolism candidate genes, PNP, GSTO, and CYT19, in 135 arsenic-exposed subjects from the Yaqui Valley in Sonora, Mexico, who were exposed to drinking water concentrations ranging from 5.5 to 43.3 ppb. We chose 23 polymorphic sites to test in the arsenic-exposed population. Initial phenotypes evaluated included the ratio of urinary inorganic arsenic(III) to inorganic arsenic(V) and the ratio of urinary dimethylarsenic(V) to monomethylarsenic(V) (D:M). In the initial association screening, three polymorphic sites in the CYT19 gene were significantly associated with D:M ratios in the total population. Subsequent analysis of this association revealed that the association signal for the entire population was actually caused by an extremely strong association in only the children (7-11 years of age) between CYT19 genotype and D:M levels. With children removed from the analysis, no significant genetic association was observed in adults (18-79 years). The existence of a strong, developmentally regulated genetic association between CYT19 and arsenic metabolism carries import for both arsenic pharmacogenetics and arsenic toxicology, as well as for public health and governmental regulatory officials.     

Genetic variation in Glutathione S-Transferase Omega-1, Arsenic Methyltransferase and Methylene-tetrahydrofolate Reductase, arsenic exposure and bladder cancer: a case-control study

ABSTRACT: BACKGROUND: Ingestion of groundwater with high concentrations of inorganic arsenic has been linked to adverse health outcomes, including bladder cancer, however studies have not consistently observed any elevation in risk at lower concentrations. Genetic variability in the metabolism and clearance of arsenic is an important consideration in any investigation of its potential health risks. Therefore, we examined the association between genes thought to play a role in the metabolism of arsenic and bladder cancer. METHODS: Single nucleotide polymorphisms (SNPs) in GSTO-1, As3MT and MTHFR were genotyped using DNA from 219 bladder cancer cases and 273 controls participating in a case-control study in Southeastern Michigan and exposed to low to moderate (<50 mug/L) levels of arsenic in their drinking water. A time-weighted measure of arsenic exposure was constructed using measures from household water samples combined with past residential history, geocoded and merged with archived arsenic data predicted from multiple resources. RESULTS: While no single SNP in As3MT was significantly associated with bladder cancer overall, several SNPs were associated with bladder cancer among those exposed to higher arsenic levels. Individuals with one or more copies of the C allele in rs11191439 (the Met287Thr polymorphism) had an elevated risk of bladder cancer (OR = 1.17; 95% CI = 1.04-1.32 per 1 mug/L increase in average exposure). However, no association was observed between average arsenic exposure and bladder cancer among TT homozygotes in the same SNP. Bladder cancer cases were also 60% less likely to be homozygotes for the A allele in rs1476413 in MTHFR compared to controls (OR = 0.40; 95% CI = 0.18-0.88). CONCLUSIONS: Variation in As3MT and MTHFR is associated with bladder cancer among those exposed to relatively low concentrations of inorganic arsenic. Further investigation is warranted to confirm these findings.     

Risk factors for increased urinary inorganic arsenic concentrations from low arsenic concentrations in drinking water

A large number of drinking water supplies worldwide have greater than 50 microg l(- 1) inorganic arsenic in drinking water, and there is increasing pressure to reduce concentrations. Few studies have specifically considered low concentrations of arsenic in water supplies and the significance of other factors which may contribute to increased exposure. This study aimed to investigate risk factors for increased urinary inorganic arsenic concentrations, in a population exposed to 10 - 100 microg l(- 1) of arsenic in drinking water, as well as a control population with lower arsenic concentrations in their drinking water. Inorganic arsenic in urine was used as the measure of exposure. The median drinking water arsenic concentration in the exposed population was 43.8 microg l(- 1) (16.0 - 73 microg l(- 1)) and less than the analytical limit of detection of 1 microg l(- 1) (相似文献   

Airborne arsenic and urinary excretion of metabolites of inorganic arsenic among smelter workers

Summary The relationship between airborne concentrations of arsenic and the urinary excretion of inorganic arsenic metabolites (inorganic arsenic + methylarsonic acid + dimethylarsinic acid) have been studied among smelter workers exposed to arsenic trioxide. The urinary concentrations of arsenic metabolites were found to increase steadily during the first day of the working week (after 2–3 d off from work), whereafter they reached a steady state. The concentration in the late evening after a day of exposure was very similar to that in the early morning after. Both were well correlated to the total daily excretion. In the second part of the study, comprising 18 subjects, the first-void morning urine of each participant was collected for 2 to 3 d during the steady-state phase. Total concentration of arsenic in the breathing zones was measured by personal air samplers. Airborne arsenic (8-h values) varied between 1 and 194 g As/m³, and urinary arsenic between 16 and 328 g As/g creatinine. With the urinary arsenic concentrations (mean values of 2–3 d for each subject) plotted against the corresponding airborne arsenic concentrations, the best fit was obtained by a power curve with the equation y = 17 x x^0.56. However, four of the participants were found to excrete far more (105–260%) arsenic in the urine than possibly could have been inhaled, most likely due to oral intake of arsenic via contaminated hands, cigarettes or snuff. If these four were excluded, the best fit was obtained by a straight regression line with the slope 2.0 and the intercept 29 g As/g creatinine (coefficient of correlation 0.92; P < 0.001).     

Microtubules as a critical target for arsenic toxicity in lung cells in vitro and in vivo

To understand mechanisms for arsenic toxicity in the lung, we examined effects of sodium m-arsenite (As3?) on microtubule (MT) assembly in vitro (0-40 μM), in cultured rat lung fibroblasts (RFL6, 0-20 μM for 24 h) and in the rat animal model (intratracheal instillation of 2.02 mg As/kg body weight, once a week for 5 weeks). As3? induced a dose-dependent disassembly of cellular MTs and enhancement of the free tubulin pool, initiating an autoregulation of tubulin synthesis manifest as inhibition of steady-state mRNA levels of βI-tubulin in dosed lung cells and tissues. Spindle MT injuries by As3? were concomitant with chromosomal disorientations. As3? reduced the binding to tubulin of [3H]N-ethylmaleimide (NEM), an -SH group reagent, resulting in inhibition of MT polymerization in vitro with bovine brain tubulins which was abolished by addition of dithiothreitol (DTT) suggesting As3? action upon tubulin through -SH groups. In response to As3?, cells elevated cellular thiols such as metallothionein. Taxol, a tubulin polymerization agent, antagonized both As3? and NEM induced MT depolymerization. MT-associated proteins (MAPs) essential for the MT stability were markedly suppressed in As3?-treated cells. Thus, tubulin sulfhydryls and MAPs are major molecular targets for As3? damage to the lung triggering MT disassembly cascades.     

Low-level arsenic excretion in breast milk of native Andean women exposed to high levels of arsenic in the drinking water

Objective: To investigate the excretion of arsenic in breast milk of lactating native Andean women living in a village in northwestern Argentina with high concentrations of arsenic in the drinking water (about 200 μg/l) and to assess the exposure of children to arsenic during the very first period of life. Methods: The study included ten lactating women and two nursing babies. Hydride-generation atomic absorption spectrometry (HG-AAS) was used to determine the concentration of arsenic in samples of human milk, drinking water, blood, and urine. Results: The concentrations of arsenic detected in maternal blood (total arsenic) and urine (metabolites of inorganic arsenic) were high, averaging 10 and 320 μg/l, respectively. In subjects without known exposure to arsenic the average concentrations found in blood and urine are 1–2 and about 10 μg/l, respectively. The metabolites of inorganic arsenic constituted more than 80% of the total arsenic in the urine, which shows that inorganic arsenic was the main form of arsenic ingested. The average concentration of arsenic detected in human milk was 2.3 μg/kg fresh weight (range 0.83–7.6 μg/kg). Although data on background levels of arsenic in human breast milk are scarce, the present concentrations seem to be slightly elevated. However, considering the high levels of arsenic exposure in the mothers, the total arsenic concentrations measured in human milk were low. In concordance with the low concentrations of arsenic found in the milk, the concentrations of arsenic metabolites measured in the urine of two of the nursing babies were low: 17 and 47 μg/l, respectively. Conclusions: The low concentrations of arsenic detected in the breast milk and urine of the two nursing babies in relation to the high level of maternal exposure to arsenic indicate that inorganic arsenic is not excreted in breast milk to any significant extent. This is a very important reason for long breast-feeding periods. Received: 27 February 1997 / Accepted: 6 June 1997     

Seafood intake and urine concentrations of total arsenic, dimethylarsinate and arsenobetaine in the US population

Background

Seafood is the main source of organic arsenic exposure (arsenobetaine, arsenosugars and arsenolipids) in the population. Arsenosugars and arsenolipids are metabolized to several species including dimethylarsinate (DMA).

Objective

Evaluate the association of seafood intake with spot urine arsenic concentrations in the 2003–2006 National Health Nutrition and Examination Survey (NHANES).

Methods

We studied 4276 participants ≥6 years. Total arsenic was measured using inductively coupled plasma dynamic reaction cell mass spectrometry (ICPMS). Urine DMA and arsenobetaine were measured by high-performance liquid chromatography coupled with ICPMS.

Results

Participants reporting seafood in the past 24-h had higher urine concentrations of total arsenic (median 24.5 vs. 7.3 μg/L), DMA (6.0 vs. 3.5 μg/L), arsenobetaine (10.2 vs. 0.9 μg/L) and total arsenic minus arsenobetaine (11.0 vs. 5.5 μg/L). Participants reporting seafood ≥2/wk vs. never during the past year had 2.3 (95% confidence interval 1.9, 2.7), 1.4 (1.2, 1.6), 6.0 (4.6, 7.8) and 1.7 (1.4, 2.0) times higher (p-trend <0.001) concentrations of total arsenic, DMA, arsenobetaine and total arsenic minus arsenobetaine, respectively. In participants without detectable arsenobetaine and in analyses adjusted for arsenobetaine, seafood consumption in the past year was not associated with total arsenic or DMA concentrations in urine.

Conclusion

Seafood intake was a major determinant of increased urine concentrations of total arsenic, DMA, arsenobetaine and total arsenic minus arsenobetaine in the US population. Epidemiologic studies that use total arsenic, DMA, the sum of inorganic arsenic, methylarsonate and DMA, and total arsenic minus arsenobetaine as markers of inorganic arsenic exposure and/or metabolism need to address seafood intake.     

Gender and age differences in mixed metal exposure and urinary excretion

Background

Little is known about the variation in exposure to toxic metals by age and gender and other potential modifying factors. We evaluated age and gender differences by measurements of metal/element concentrations in urine in a rural population in Matlab, Bangladesh, in three age groups: 8–12 (N=238), 14–15 (N=107) and 30–88 (N=710) years of age, living in an area with no point sources of metal exposure but where elevated water arsenic concentrations are prevalent.

Results

We found marked differences in urine concentrations of metals and trace elements by gender, age, tobacco use, socioeconomic and nutritional status. Besides a clearly elevated urinary arsenic concentration in all age groups (medians 63–85 μg As/L), and despite the low degree of contamination from industries and traffic, the urine concentrations of toxic metals such as cadmium and lead were clearly elevated, especially in children (median 0.31 μg Cd/L and 2.9 μg Pb/L, respectively). In general, women had higher urinary concentrations of toxic metals, especially Cd (median 0.81 μg/L) compared to men (0.66 μg/L) and U (median 10 ng/L in women, compared to 6.4 ng/L in men), while men had higher urinary concentrations of the basic and essential elements Ca (69 mg/L in men, 30–50 years, compared to 52 mg/L in women), Mg (58 mg/L in men compared to 50 mg/L in women), Zn (182 μg/L in men compared to 117 μg/L in women) and Se (9.9 μg/L in men compared to 8.7 μg/L in women). Manganese was consistently higher in females than in males in all age groups, suggesting a biological difference between females and males in Mn metabolism. Increasing socioeconomic status decreased the toxic metal exposure significantly in children and especially in men. Poor iron status was detected in 17% of children, adolescents and women, but only in 6% of men. Also zinc deficiency was more prevalent in females than in males.

Conclusions

Women and children seemed to be more at risk for toxic metal exposure than men and at the same time more vulnerable to micronutrient deficiency. Higher concentrations of the toxic metals in urine in women are likely to reflect an increased gastrointestinal absorption of these metals at micronutrient deficiency, such as low body iron stores and Zn deficiency. Higher urinary concentrations of the essential elements in men likely reflect a better nutritional status. There is a need for information on exposure, lifestyle and socioeconomic factors, stratified by gender and age, for the purpose of conducting balanced risk assessment and management that considers such differences.     

Mortality by cancer in groups of the Belgian population with a moderately increased intake of arsenic

Object: The dose-response relationship for lung carcinoma and other cancers at low doses of As is highly uncertain because it is based on modeling data collected in populations with a high daily intake of the element. The finding of a slightly increased exposure to arsenic in certain groups of the Belgian general population prompted us to examine whether this had repercussions on the causes of mortality. Method: Statistics of mortality by causes with a possible link to exposure to the element (standardized mortality ratio) were analyzed in groups of the Belgian population previously shown to have been exposed to As from natural (drinking water) and/or industrial (nonferrous metal smelter emissions) sources. Results: A moderately increased absorption of As, leading to a 3- to 4- fold higher urinary excretion (35 μg/day as compared with 6–10 μg As/day in nonexposed subjects) did not enhance the mortality by diseases of the nervous system, liver and heart, and cancers. An increase in mortality by lung cancer, however, was observed in men but not women living around zinc smelters and might be related to past occupational exposure and/or smoking habits. Conclusion: A low to moderate level of environmental exposure to inorganic arsenic (0.3 μg As/m³ of air; 20–50 μg As/l of drinking water) does not seem to affect the causes of mortality, suggesting in particular nonlinearity of the dose-response relationship for arsenic and cancer. Received: 16 December 1996 / Accepted: 2 July 1997     

Assessment of cancer risk and environmental levels of arsenic in New Hampshire

The Agency for Toxic Substances and Disease Registry (ATSDR) and the United States (US) Environmental Protection Agency (EPA) Office of Solid Waste and Emergency Response (OSWER) list arsenic as a major concern for Superfund sites and the environment at large. Arsenic is clearly linked to skin, bladder, and lung cancer occurrence in populations highly exposed to arsenic occupationally, medicinally, or through contaminated drinking water (Agency for Toxic Substances and Disease Registry, 1999; IARC, 1987). While these studies have identified important adverse health effects, they cannot provide risk information at lower levels of exposure such as those commonly found in the US. Additionally, precise measurement of exposure is critical to assessing risk in populations consuming relatively trace amounts of arsenic. In New Hampshire, domestic wells serve roughly 40% of the population, and about 10% of these contain arsenic concentrations in the controversial range of 10 to 50 micrograms/l. New Hampshire, along with other states in New England, has among the highest bladder cancer mortality rates in the country. Therefore, we are conducting a population-based epidemiologic study in New Hampshire (1) to assess the risk of skin and bladder cancer associated with arsenic exposure in a US population, (2) to evaluate methods of quantifying individual exposure to arsenic at low to moderate levels, and (3) to explore alternative models of determining the dose-response relationship at the lower end of exposure. Our findings to date indicate that toenail arsenic concentrations are a reliable, long-term biomarker of total arsenic exposure and reflect arsenic intake by drinking water containing 1 microgram/l or more. We found that urinary arsenic cannot be detected consistently in a population for which drinking water arsenic is primarily below 50 micrograms/l. Lastly, our data suggest that use of a biologic marker along with alternative statistical approaches may aid detection of the levels at which arsenic may affect cancer occurrence in the US.     

Surveillance on chronic arsenic exposure in the Mekong River basin of Cambodia using different biomarkers

Thousands of Cambodia populations are currently at high risks of both toxic and carcinogenic effects through drinking arsenic-rich groundwater. In order to determine and assess the use of arsenic contents in different biological samples as biomarkers of chronic arsenic exposure from drinking arsenic-rich groundwater in Cambodia, individual scalp hair, fingernail and toenail were collected from three different provinces in the Mekong River basin of Cambodia. After washing and acid-digestion, digestate was analyzed for total arsenic by an inductively coupled plasma mass spectrometry. Chemical analysis of the acid-digested hair revealed that among 270 hair samples cut from Kandal, 78.1% had arsenic content in scalp hair (As_h) greater than the typical As_h (1.00 μg g⁻¹), indicating possible arsenic toxicity. Concurrently, 1.2% and 0.6% were found elevated in Kratie (n = 84) and Kampong Cham (n = 173), respectively. Similarly, the upper end of the ranges for arsenic contents in fingernail (As_fn) and toenail (As_tn) clipped from Kandal (fingernail n = 241; toenail n = 187) were higher than the normal arsenic content in nail (0.43–1.08 μg g⁻¹), however, none was observed elevated in both Kratie (fingernail n = 76, toenail n = 42) and Kampong Cham (fingernail n = 83; toenail n = 52). Significant positive intercorrelations between groundwater arsenic concentration (As_w), average daily dose (ADD) of arsenic, As_h, As_fn and As_tn suggest that As_h, As_fn and As_tn can be used as biomarkers of chronic arsenic exposure from drinking arsenic-rich groundwater, in which As_h is more favorable than As_fn and As_tn due to the ease of sample processing and analytical measurements, respectively.     

Lung function in adults following in utero and childhood exposure to arsenic in drinking water: preliminary findings

Purpose  

Evidence suggests that arsenic in drinking water causes non-malignant lung disease, but nearly all data concern exposed adults. The desert city of Antofagasta (population 257,976) in northern Chile had high concentrations of arsenic in drinking water (>800 μg/l) from 1958 until 1970, when a new treatment plant was installed. This scenario, with its large population, distinct period of high exposure, and accurate data on past exposure, is virtually unprecedented in environmental epidemiology. We conducted a pilot study on early-life arsenic exposure and long-term lung function. We present these preliminary findings because of the magnitude of the effects observed.     

Urinary arsenic species, toenail arsenic, and arsenic intake estimates in a Michigan population with low levels of arsenic in drinking water

The large disparity between arsenic concentrations in drinking water and urine remains unexplained. This study aims to evaluate predictors of urinary arsenic in a population exposed to low concentrations (≤50?μg/l) of arsenic in drinking water. Urine and drinking water samples were collected from a subsample (n=343) of a population enrolled in a bladder cancer case-control study in southeastern Michigan. Total arsenic in water and arsenic species in urine were determined using ICP-MS: arsenobetaine (AsB), arsenite (As[III]), arsenate (As[V]), methylarsenic acid (MMA[V]), and dimethylarsenic acid (DMA[V]). The sum of As[III], As[V], MMA[V], and DMA[V] was denoted as SumAs. Dietary information was obtained through a self-reported food intake questionnaire. Log(10)-transformed drinking water arsenic concentration at home was a significant (P<0.0001) predictor of SumAs (R(2)=0.18). Associations improved (R(2)=0.29, P<0.0001) when individuals with less than 1?μg/l of arsenic in drinking water were removed and further improved when analyses were applied to individuals who consumed amounts of home drinking water above the median volume (R(2)=0.40, P<0.0001). A separate analysis indicated that AsB and DMA[V] were significantly correlated with fish and shellfish consumption, which may suggest that seafood intake influences DMA[V] excretion. The Spearman correlation between arsenic concentration in toenails and SumAs was 0.36 and between arsenic concentration in toenails and arsenic concentration in water was 0.42. Results show that arsenic exposure from drinking water consumption is an important determinant of urinary arsenic concentrations, even in a population exposed to relatively low levels of arsenic in drinking water, and suggest that seafood intake may influence urinary DMA[V] concentrations.