Arsenic and diabetes and hypertension in human populations: a review

Long-term exposure to ingested arsenic from drinking water has been well documented to be associated with an increased risk of diabetes mellitus and hypertension in a dose-response relationship among residents of arseniasis-endemic areas in southwestern Taiwan and Bangladesh. An increased risk of self-reported hypertension but not diabetes was reported in a community-based study of residents who consumed drinking water with a low level of arsenic. Increased glycosylated hemoglobin level and systolic blood pressure were observed in workers occupationally exposed to arsenic. Inconsistent findings of arsenic and diabetes in occupational studies may result from the healthy worker effect and the variation in exposure measurement, age composition, number of patients, accuracy in diagnosis and classification of underlying causes of death, competing causes of death, and method to detect diabetes. The dose-response relationship and toxicological mechanisms of arsenic-induced diabetes and hypertension need further elucidation.     

Arsenic health risk assessment in drinking water and source apportionment using multivariate statistical techniques in Kohistan region,northern Pakistan

The present study was conducted in Kohistan region, where mafic and ultramafic rocks (Kohistan island arc and Indus suture zone) and metasedimentary rocks (Indian plate) are exposed. Water samples were collected from the springs, streams and Indus river and analyzed for physical parameters, anions, cations and arsenic (As³⁺, As⁵⁺ and arsenic total). The water quality in Kohistan region was evaluated by comparing the physio-chemical parameters with permissible limits set by Pakistan environmental protection agency and world health organization. Most of the studied parameters were found within their respective permissible limits. However in some samples, the iron and arsenic concentrations exceeded their permissible limits. For health risk assessment of arsenic, the average daily dose, hazards quotient (HQ) and cancer risk were calculated by using statistical formulas. The values of HQ were found >1 in the samples collected from Jabba, Dubair, while HQ values were <1 in rest of the samples. This level of contamination should have low chronic risk and medium cancer risk when compared with US EPA guidelines. Furthermore, the inter-dependence of physio-chemical parameters and pollution load was also calculated by using multivariate statistical techniques like one-way ANOVA, correlation analysis, regression analysis, cluster analysis and principle component analysis.     

An approach for assessing human exposures to chemical mixtures in the environment

Humans are exposed daily to multiple chemicals, including incidental exposures to complex chemical mixtures released into the environment and to combinations of chemicals that already co-exist in the environment because of previous releases from various sources. Exposures to chemical mixtures can occur through multiple pathways and across multiple routes. In this paper, we propose an iterative approach for assessing exposures to environmental chemical mixtures; it is similar to single-chemical approaches. Our approach encompasses two elements of the Risk Assessment Paradigm: Problem Formulation and Exposure Assessment. Multiple phases of the assessment occur in each element of the paradigm. During Problem Formulation, analysts identify and characterize the source(s) of the chemical mixture, ensure that dose-response and exposure assessment measures are concordant, and develop a preliminary evaluation of the mixture's fate. During Exposure Assessment, analysts evaluate the fate of the chemicals comprising the mixture using appropriate models and measurement data, characterize the exposure scenario, and estimate human exposure to the mixture. We also describe the utility of grouping the chemicals to be analyzed based on both physical-chemical properties and an understanding of environmental fate. In the article, we also highlight the need for understanding of changes in the mixture composition in the environment due to differential transport, differential degradation, and differential partitioning to other media. The Results section describes the application of the method to various chemical mixtures, highlighting issues associated with assessing exposures to chemical mixtures in the environment.     

Residential exposure to drinking water arsenic in Inner Mongolia, China

In the Ba Men region of Inner Mongolia, China, a high prevalence of chronic arsenism has been reported in earlier studies. A survey of the arsenic contamination among wells from groundwater was conducted to better understand the occurrence of arsenic (As) in drinking water. A total of 14,866 wells (30% of all wells in the region) were analyzed for their arsenic-content. Methods used to detect arsenic were Spectrophotometric methods with DCC-Ag (detection limit, 0.5 microg of As/L); Spot method (detection limit, 10 microg of As/L); and air assisted Colorimetry method (detection limit, 20 microg of As/L). Arsenic-concentrations ranged from below limit of detection to 1200 microg of As/L. Elevated concentrations were related to well depth (10 to 29 m), the date the well was built (peaks from 1980-1990), and geographic location (near mountain range). Over 25,900 individuals utilized wells with drinking water arsenic concentrations above 20 microg of As/L (14,500 above 50 microg of As/L-the current China national standard in drinking water and 2198 above 300 microg of As/L). The presented database of arsenic in wells of the Ba Men region provides a useful tool for planning future water explorations when combined with geological information as well as support for designing upcoming epidemiological studies on the effects of arsenic in drinking water for this region.     

Arsenic exposure at low-to-moderate levels and skin lesions, arsenic metabolism, neurological functions, and biomarkers for respiratory and cardiovascular diseases: Review of recent findings from the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh

The contamination of groundwater by arsenic in Bangladesh is a major public health concern affecting 35-75 million people. Although it is evident that high levels (> 300 μg/L) of arsenic exposure from drinking water are related to adverse health outcomes, health effects of arsenic exposure at low-to-moderate levels (10-300 μg/L) are not well understood. We established the Health Effects of Arsenic Longitudinal Study (HEALS) with more than 20,000 men and women in Araihazar, Bangladesh, to prospectively investigate the health effects of arsenic predominately at low-to-moderate levels (0.1 to 864 μg/L, mean 99 μg/L) of arsenic exposure. Findings to date suggest adverse effects of low-to-moderate levels of arsenic exposure on the risk of pre-malignant skin lesions, high blood pressure, neurological dysfunctions, and all-cause and chronic disease mortality. In addition, the data also indicate that the risk of skin lesion due to arsenic exposure is modifiable by nutritional factors, such as folate and selenium status, lifestyle factors, including cigarette smoking and body mass index, and genetic polymorphisms in genes related to arsenic metabolism. The analyses of biomarkers for respiratory and cardiovascular functions support that there may be adverse effects of arsenic on these outcomes and call for confirmation in large studies. A unique strength of the HEALS is the availability of outcome data collected prospectively and data on detailed individual-level arsenic exposure estimated using water, blood and repeated urine samples. Future prospective analyses of clinical endpoints and related host susceptibility will enhance our knowledge on the health effects of low-to-moderate levels of arsenic exposure, elucidate disease mechanisms, and give directions for prevention.     

Arsenic dose in patients with cutaneous carcinomata and hepatic haemangio-endothelioma after environmental and occupational exposure

A total of 16 male cases with malignant tumours associated with arsenic-polluted water were observed in Tarapacá and Antofagasta Provinces, northern Chile. Fifteen of them had skin carcinomata and the remaining one a haemangio-endothelioma of liver. The 15 skin cancer cases had latent periods ranging from 12–45 years. Three patients were studied in detail. The first one (skin cancer) had a latent period of 20 years with a weighted mean dose of 1.2 mg/day (total dose for latent period 8.4 g). The second one (skin cancer) had a latent period of 23 years with a weighted mean dose of 1.0 mg/day (total dose for latent period 8.3 g). The third case (liver tumour) exhibited a latent period of 14 years with a weighted mean of 0.6 mg/day (total dose for latent period 3.1 g).Fifteen of the 16 cancer patients were labourers. For normal subjects of different ages and both sexes (n=290) and ingesting arsenic-polluted water (0.60 ppm), the relationship between mean age and mean arsenic dose is expressed by a weighted least square polynomial regression, of second degree: (y) = _o + ₁ ^t + ₂ ^{t 2} where y is mean arsenic dose (mg/person/day) and t is mean age (years). For the general male population and for male labourers, the respective equations are presented.Deceased. National Academy of Medicine, Santiago, Chile     

Low-level arsenic exposure in drinking water and bladder cancer: a review and meta-analysis

Although exposure to high levels of arsenic in drinking water is associated with excess cancer risk (e.g., skin, bladder, and lung), lower exposures (e.g., <100–200 μg/L) generally are not. Lack of significant associations at lower exposures may be attributed to methodologic issues (e.g., inadequate statistical power, exposure misclassification), or to differences in the dose–response relationship at high versus low exposures. The objectives of this review and meta-analysis were to evaluate associations, examine heterogeneity across studies, address study design and sample size issues, and improve the precision of estimates. Eight studies of bladder cancer and low-level arsenic exposure met our inclusion criteria. Meta-analyses of never smokers produced summary relative risk estimates (SRREs) below 1.0 (highest versus lowest exposure). The SRRE for never and ever smokers combined was elevated slightly, but not significantly (1.11; 95% CI: 0.95–1.30). The SRRE was somewhat elevated among ever smokers (1.24; 95% CI: 0.99–1.56), and statistical significance was observed in some subgroup analyses; however, heterogeneity across studies was commonly present. Although uncertainties remain, low-level arsenic exposure alone did not appear to be a significant independent risk factor for bladder cancer. More studies with detailed smoking history will help resolve whether smoking is an effect modifier.     

A review of epidemiologic studies of low-level exposures to organophosphorus insecticides in non-occupational populations

Abstract

This paper systematically reviews epidemiologic studies related to low-level non-occupational exposures to organophosphorus (OP) insecticides. Many of the studies evaluate levels of maternal OP metabolites and subsequent health outcomes in offspring. The studies focused primarily on birth outcomes (e.g., infant body weight or head circumference) and neurodevelopmental (e.g., mental and psychomotor) testing results. The evidence from these studies was reviewed under the Bradford Hill guidelines. Most of the studies assessing exposure based on urinary levels of OP insecticide metabolites used only one or two measurements during pregnancy. The potential for exposure misclassification with this method is largely due to (1) preformed metabolites that are ingested with food, (2) the short elimination half-life of OP insecticides, and (3) lack of specificity to particular OP insecticides for many of the metabolites. For birth outcomes, the majority of reported results are not statistically significant, and the associations are inconsistent within and across studies. There is more within-study consistency for some of the neurodevelopmental testing results, although few associations were examined across several studies. These associations are generally weak, have been replicated only to a limited extent, and require further confirmation before they can be considered established. The OP insecticide levels measured in the epidemiologic studies are too low to cause biologically meaningful acetylcholinesterase inhibition, the most widely used metric for OP insecticide toxicity. Overall, the available evidence does not establish that low-level exposures to OP insecticides cause adverse birth outcomes or neurodevelopmental problems in humans.     

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 β-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.     

Human exposure to bisphenol A by biomonitoring: methods, results and assessment of environmental exposures

Human exposure to bisphenol A is controversially discussed. This review critically assesses methods for biomonitoring of bisphenol A exposures and reported concentrations of bisphenol A in blood and urine of non-occupationally ("environmentally") exposed humans. From the many methods published to assess bisphenol A concentrations in biological media, mass spectrometry-based methods are considered most appropriate due to high sensitivity, selectivity and precision. In human blood, based on the known toxicokinetics of bisphenol A in humans, the expected very low concentrations of bisphenol A due to rapid biotransformation and the very rapid excretion result in severe limitations in the use of reported blood levels of bisphenol A for exposure assessment. Due to the rapid and complete excretion of orally administered bisphenol A, urine samples are considered as the appropriate body fluid for bisphenol A exposure assessment. In urine samples from several cohorts, bisphenol A (as glucuronide) was present in average concentrations in the range of 1-3 microg/L suggesting that daily human exposure to bisphenol A is below 6 microg per person (<0.1 microg/kg bw/day) for the majority of the population.     

原子荧光光谱法同时测定饮用水中的砷和硒

目的：采用氢化物发生-原子荧光光谱法测定饮用水中的砷和硒。方法：用硝酸、高氯酸混合溶液消解水样,在5%盐酸介质中,加入硫脲-抗坏血酸混合试剂,以20g/L NaBH4溶液为还原剂,测定砷、硒荧光强度。结果：在最佳实验条件下,检出限砷为0.526μg/L,硒为0.452μg/L。回收率砷为94.8%～100.3%;硒为95.1%～99.0%。结论：此方法简便,快速,准确。     

Rising level of arsenic in water and fodder: a growing threat to livestock and human populations in Pakistan

Arsenic (As) is considered to be one of the top environmental contaminants of concern worldwide. In many regions in Pakistan, there are reports of increased levels of As in the environment, and this metalloid remains a major source of contamination of soil, water and fodder. This pathway of exposure has emerged as a new threat for both wildlife and the surrounding human communities because of the mobilization and accumulation of As via the food chain. The objective of this critical review is to synthesize historical information about As levels in the environmental resources of Pakistan to better characterize the risk to livestock and humans in the region. The South Punjab and Sindh are the dominant areas which are reported to contain the highest As contamination compared to other regions. This is a concern as millions of animals as well as the human population are facing significant health issues due to As. For example, some of the population of Sindh province are potentially faced with As levels ～10–50?μg/L in drinking water, which is well above safe drinking limits of 10?μg/L outlined by the World Health Organization. These collective data on As are anticipated to be a useful source of information for decisions by the environmental protection agency in Pakistan regarding the adoption of preventive measures against its adverse impacts and toxicity.     

Arsenic accumulation, elimination, and interaction with copper, zinc and manganese in liver and kidney of rats

The arsenic accumulation, distribution and influences on metallothionein-1 (MT-1) expression and other trace elements in various organs were examined in rats orally exposed to sodium arsenate (iAs(V)). Rats received a dose of 0, 1, 10 and 100ppm of iAs(V) in drinking water daily for 4- and 16-weeks. Arsenic seems to be distributed in all of the tissues, and was accumulated relatively higher in the spleen, lung and kidney compared to the liver, and much lower in skin and cerebrum. High dose of iAs(V)-exposure significantly increased the concentration of copper in the kidney, but did not influence other trace elements such as zinc and manganese in the liver. The mRNA expression of MT-1 was dose-dependently increased by iAs(V)-exposure in the liver whereas it was decreased in the kidney. These data indicate that arsenic is widely distributed and significantly accumulated in various organs and influences on other trace elements, and also modulates MT-1 expression in the liver and kidney.     

A review and rationale for studying the cardiovascular effects of drinking water arsenic in women of reproductive age

Drinking water arsenic has been shown to be associated with a host of adverse health outcomes at exposure levels >300 microg of As/L. However, the results are not consistent at exposures below this level. We have reviewed selected articles that examine the effects of drinking water arsenic on cardiovascular outcomes and present a rationale for studying these effects on women of reproductive age, and also over the course of pregnancy when they would potentially be more susceptible to adverse cardiovascular and reproductive outcomes. It is only recently that reproductive effects have been linked to drinking water arsenic. However, there is a paucity of information about the cardiovascular effects of drinking water arsenic on women of reproductive age. Under the cardiovascular challenge of pregnancy, we hypothesize that women with a slightly elevated exposure to drinking water arsenic may exhibit adverse cardiovascular outcomes at higher rates than in the general population. Studying sensitive clinical and sub-clinical indicators of disease in susceptible sub-populations may yield important information about the potentially enormous burden of disease related to low-level drinking water arsenic exposure.     

Dietary n-6 and n-3 polyunsaturated fatty acids and colorectal carcinogenesis: results from cultured colon cells, animal models and human studies

During the past few decades, many studies have been conducted to evaluate the effects of n-6 and n-3 polyunsaturated fatty acids (PUFAs) on colorectal carcinogenesis. This report provides a brief overview of the recent studies that have been performed in cultured colon cells, animal models as well as of the population-based and short-term biomarker studies with humans. No differential effect between n-6 and n-3 PUFAs has been observed in vitro. Results from animal models indicate that n-6 PUFAs have a tumor enhancing effect, predominantly during the post-initiation phase. n-3 PUFAs may protect against colorectal carcinogenesis during both the initiation and post-initiation phase. Population-based human studies show little or no associations between n-6 or n-3 PUFA intake and colorectal cancer. Short-term biomarker studies in humans suggest though that fish oil (FO) supplementation with high amounts of n-3 PUFAs may protect against colorectal carcinogenesis and that n-6 PUFA supplementation may increase the risk.     

Dietary n-6 and n-3 polyunsaturated fatty acids and colorectal carcinogenesis: results from cultured colon cells, animal models and human studies

During the past few decades, many studies have been conducted to evaluate the effects of n-6 and n-3 polyunsaturated fatty acids (PUFAs) on colorectal carcinogenesis. This report provides a brief overview of the recent studies that have been performed in cultured colon cells, animal models as well as of the population-based and short-term biomarker studies with humans. No differential effect between n-6 and n-3 PUFAs has been observed in vitro. Results from animal models indicate that n-6 PUFAs have a tumor enhancing effect, predominantly during the post-initiation phase. n-3 PUFAs may protect against colorectal carcinogenesis during both the initiation and post-initiation phase. Population-based human studies show little or no associations between n-6 or n-3 PUFA intake and colorectal cancer. Short-term biomarker studies in humans suggest though that fish oil (FO) supplementation with high amounts of n-3 PUFAs may protect against colorectal carcinogenesis and that n-6 PUFA supplementation may increase the risk.     

Assessment of the health risks related to the presence of drug residues in water for human consumption: application to carbamazepine

Pharmaceutical residues have been detected at low (usually ng/L) concentrations in drinking water sources. The detection of drugs in water intended for human consumption (WIHC) has raised questions of safety. In the absence of regulatory or other official guidance, water utilities are faced with a problem of which pharmaceutical residues should be monitored and the toxicological limits that should be required. In this essay, we define an approach for the assessment of health risks related to chemicals found in drinking water. We use the examples of carbamazepine and its main metabolite 10,11-epoxycarbamazepine to demonstrate our approach, which involves application of the following algorithm: (1) when there is human or animal toxicity data, a toxicity reference value (TRV) can be calculated; (2) when this is not applicable, an attempt should be made to derive the TRV using known information about the minimum therapeutic dose (MTD); and (3) when no applicable data is available, at all, a threshold of toxicological concern (TTC) should be estimated. In the case of carbamazepine, where relevant toxicological data exists, we derived a TRV, based on the known minimum therapeutic dose (MTD). For carbamazepine's metabolite 10,11-epoxycarbamazepine, there is no toxicological data, so we applied the TTC approach. Using this approach, and combining our estimates with what is known about these chemicals' margin of exposure (MOE), suggests that there is likely to be no appreciable risk to human health exposure to carbamazepine or its major metabolite, even given the inevitable uncertainties in exposure scenarios.     

不同产地当归中砷暴露对小鼠肝肾毒性损伤的研究

目的研究不同产地当归中重金属砷暴露对小鼠肝肾的损伤情况,并探讨其毒性.方法35只昆明种成年小鼠随机分为正常对照组、当归组(产地分别为云南、四川和陕西)和雄黄组共5组.小鼠灌胃给药72h 后处死,取血,肝脏和肾脏组织,全自动生化分析仪检测血清丙氨酸转氨酶(ALT)、天门冬氨酸转氨酶(AST)、尿素氮(UREA)和肌酐(CREA)含量,观察肝肾组织病理学变化;原子荧光光谱测定肝肾组织中的砷蓄积量;实时荧光定量(RT-PCR)检测砷毒性敏感基因金属硫蛋白-1(Metallothionein,MT-1)mRNA 和肿瘤坏死因子-α(TNF-α)mRNA 的表达水平.结果与对照组相比,雄黄组血清 ALT、AST、CREA 浓度水平和肝肾组织中砷蓄积量显著升高(P<0.05),并可能伴随肝肾功能的损伤, MT-1 mRNA 和 TNF-αmRNA 表达量升高但无统计学意义.当归组只在肝组织中检测到微量砷,肝肾功能病理学检查与正常对照组相似,MT-1 mRNA 和 TNF-αmRNA 表达量无显著升高(P>0.05).结论不同产地当归所含砷的毒性远小于雄黄毒性,高剂量雄黄给药对小鼠肝肾组织可能产生影响,但它们在一定剂量下被用于中药仍然是相对安全的.     

Human health risk assessment from the presence of human pharmaceuticals in the aquatic environment

Assessments for potential impact to human health from environmental exposures were carried out for 44 active pharmaceutical ingredients (APIs) marketed by GlaxoSmithKline (GSK), representing approximately 22 general pharmacological classes exhibiting a broad spectrum of therapeutic activities. These assessments use the considerable amount of information available on the human pharmacology and toxicology of the APIs to develop acceptable daily intakes (ADIs) which are believed to be without pharmacological or toxicological effect. With the exception of the anti-cancer drugs and some antibiotics, the minimum dose producing the intended therapeutic effect was typically used as the point of departure for calculation of ADIs. The ADI values were used to generate predicted no effect concentrations from environmental exposure for human health (PNEC_HHs) from drinking water or fish consumption. These PNECs were compared to predicted environmental concentrations (PECs) calculated using the regional assessment models PhATE™ for North America and GREAT-ER for Europe. Risk was characterized by calculating the ratio of the 90th percentile PECs to the PNEC_HHs. For the APIs reported here, these ratios are less than one for all of the compounds, varying from 7 × 10⁻² to 6 × 10⁻¹¹, indicating that based upon currently available data, these compounds do not appear to pose an appreciable risk to human health from potential environmental exposure from drinking water and fish consumption.