No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Field Researches on Chronical Arsenic Poisoning in Inner Mongolia, China: Biological Effects and Preventive Measures
Abstract
Chronic arsenic (As) poisoning in China as endemic disease observed in local residents is summarized with reference to the field research reports. The importance of choosing the appropriate parameter for As exposure based on the property of each field in the analytical research on the relationship between As exposure level and As-related diseases is discussed. Our field cohort study of chronic waterborne As poisoning established in Inner Mongolia is introduced as one of the leading models demonstrating that it is possible to evaluate the improvement of As-related diseases including skin lesions and to validate the attenuation of carcinogenesis by the mitigation of As exposure. Our cohort study reveals that the improvement of skin lesions due to chronic As poisoning occurred in the early phase as 1 or 2 years after the mitigation of As exposure, and then slow alleviation continued for long periods. On the other hand, after long, more than 25 years As exposure period, and even if the exposure had mitigated, the number of As-induced malignancy including skin cancer is expected to rise. So for well-directed screening to find the As-related malignancy cases, the use of appropriate parameters for identifying high-risk subjects is needed.
... These patients were followed up for an additional 5, 10, and 15 years. A fast improvement in hyperkeratosis was observed in the first year, but, unexpectedly, successive improvement was found to be slow [41]. ...
Large-scale chronic arsenic poisoning in several areas worldwide has not been eradicated. Adverse health effects of inorganic arsenic (iAs) exposure are associated with decreased arsenic methylation capacity (AMC). The AMC results from 21 children and 39 adults with acute arsenic poisoning support and effectively guide the analysis and evaluation of AMC in chronic arsenic poisoning. Results of the 65th-year follow-up for 6223 cases of infants, who survived subacute arsenic poisoning, contribute to future projections against health effects (cancer and cognitive dysfunction). Currently, arsenolipids from fish and shellfish are attracting attention because of their direct association with brain dysfunction. Accordingly, the European Food Safety Authority is considering legal restrictions on their dietary intake. Modern society overlooks the environmental contamination and health hazards caused by arsenic chemical weapons mainly produced during World War II. This review aims to evaluate the various health effects of AMC reduction in acute, subacute, and chronic arsenic poisoning, in addition to the methylarsenic compounds such as arsenolipids, arsenosugars, and arsenobeta-ine, as well as arsenic chemical weapons such as lewisite, diphenylchloroarsin, and diphenylcyanoarsine.
... Chronic exposure of human and animal populations to high concentrations of arsenic have been reported in arsenic endemic areas of Iran (Mosaferi et al., 2003), Bangladesh (Mori et al., 2018) and Yellowknife (Canada) (Amuno et al., 2018;Clark and Raven, 2004). Such chronic exposures have been associated with multiorgan damage, including skin lesions, peripheral vascular disease (PVD), blackfoot disease, cataracts, cancers and metabolic syndrome including bone abnormalities and osteoporosis (Tseng et al., 2005;Chen and Chiou, 2011;Yoshida et al., 2019;Amuno et al., 2018). ...
The brain is one of the critical organs particularly susceptible to the damaging effects of chronic arsenic poisoning and there is a growing body of evidence that suggest that oxidative stress plays a key role in the pathogenesis of neurodegenerative disorders. The aim of this present work was to comparatively assess biomarkers of oxidative stress and status of antioxidant enzyme activities in the brains of muskrats and squirrels breeding in arsenic endemic areas, specifically near the vicinity of the abandoned Giant mine site (~2 km radius), and an intermediate location approximately 20 km from the mine area and in reference locations spanning 52-105 km from the city of Yellowknife, Northwest Territories (Canada). Analysis included measurement of total arsenic and cadmium concentration in the nails, brain, and stomach content of muskrats and squirrels, in addition to biochemical evaluation of lipid peroxidation levels and antioxidant enzymes defense: catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the brain tissues. The results revealed that arsenic concentration in the nails of muskrats collected closest to the vicinity of the mine area was in the range of 11 to 35.1 times higher than those from the reference site. The maximum concentration of arsenic in the nails of muskrats from the intermediate location was 47.6 times higher than the maximum concentration observed in the reference muskrats. Cadmium was generally undetected in the nails of muskrats and squirrels from the three sampling locations. Arsenic in the gut contents of muskrats from the arsenic affected area was 4.5 to 49.1 times higher than those from the reference site. Cadmium levels in the guts of muskrats from the mine area almost doubled those from the reference site. Arsenic accumulated in the nails of squirrels from the areas closest to the mine but was undetected in the squirrel nails from the reference location. The maximum arsenic levels in the stomach content of squirrels from the mine area was ~40 times higher than those from the reference site. Arsenic did not accumulate in the brains of muskrats, but cadmium was detected in a few brains of muskrats. Brains of squirrels from the mine area and intermediate locations accumulated both arsenic and cadmium. The brains of squirrels and muskrats from the arsenic affected area showed no evidence of increased lipid peroxidation compared to the animals from the reference site. However, SOD, CAT and GPx activities in the brains of animals from the arsenic endemic areas tended to be higher compared to the control sites. This is the first study documenting evidence of oxidative stress and altered antioxidant enzyme activities in brains of wild rodent population in arsenic endemic areas of Canada.
Arsenic (As) contamination of soil and water poses a serious threat to the health of ecosystems and human beings, causing widespread concern. The main arsenic species in soil and water are arsenite [As(III)] and arsenate [As(V)]. Because As(III) is more toxic and often more mobile than As(V), many remediation strategies aim to oxidize As(III) to As(V). In the environment, the reduction of As(V) under anaerobic conditions is mainly mediated by microorganisms, but the oxidation of As(III) under aerobic conditions may be mainly a chemical process. This article first reviews the chemical oxidation of As(III) in the environment, with emphasis on the role of iron and manganese oxides. Then, the application of iron and manganese oxides in the remediation of arsenic-contaminated soil and water is summarized. The oxidation of As(III) by O2 is very slow without catalysts. Many manganese oxides, on the other hand, can efficiently oxidize As(III). Although the oxidation of As(III) by Fe(III) is also slow, this process can be accelerated by light or Fe(II). Iron and manganese oxides are widely used for the remediation of arsenic-contaminated soil and water, with iron oxides generally acting as absorbents while manganese oxides as oxidants. For better understanding and regulating arsenic transformation and transport in the environment, further study in the mechanisms and influencing factors of As(III) oxidization by iron and manganese oxides is needed, and innovative methods and materials based on iron and manganese oxides are desired.
Endemic arsenism is widely distributed in the world, which can damage multiple organs, especially in skin and liver. The etiology is clear, but the mechanisms involved remain unknown. Ubiquitin-proteasome pathway (UPP) is the main pathway regulating protein degradation of which proteasome subunit beta type-5(PSMB5) plays a dominant role. This paper aims to study the role and mechanism of PSMB5 in sodium arsenite (NaAsO2)–induced oxidative stress liver injury in L-02 cells. Firstly, L-02 cells were exposed to different concentrations of NaAsO2 to establish a liver injury model of oxidative stress, and then mechanisms of oxidative stress were studied with carbobenzoxyl-leucyl-leucl-leucll-line (MG132) and knockdown PSMB5 (PSMB5-siRNA). The oxidative stress indicators, levels of 20S proteasome, the transcription and protein expression levels of PSMB5, Cu-Zn superoxide dismutase (SOD1), and glutathione peroxidase 1 (GPx1) were detected. The results demonstrated that NaAsO2 could induce oxidative stress–induced liver injury and the activity of 20S proteasome and the protein expression of PSMB5, SOD1, and GPx1 decreased. After MG132 or PSMB5-siRNA pretreatment, the gene expression of PSMB decreased. After MG132 or PSMB5-siRNA pretreatment, and then L-02 cells were treated with NaAsO2, the gene expression of PSMB remarkably decreased; however, the protein expression of SOD1 and GPx1 increased. Overall, NaAsO2 exposure could induce oxidative stress liver injury and low expression of PSMB5 in L-02 cells, and PSMB5 might play an important role in the regulation of oxidative stress by regulating the expression of SOD1 and Gpx1.
Objective:
The effects of arsenic exposure from drinking water, arsenic metabolism, and arsenic methylation on blood pressure (BP) were observed in this study.
Methods:
The BP and arsenic species of 560 participants were determined. Logistic regression analysis was applied to estimate the odds ratios of BP associated with arsenic metabolites and arsenic methylation capability.
Results:
BP was positively associated with cumulative arsenic exposure (CAE). Subjects with abnormal diastolic blood pressure (DBP), systolic blood pressure (SBP), and pulse pressure (PP) usually had higher urinary iAs (inorganic arsenic), MMA (monomethylated arsenic), DMA (dimethylated arsenic), and TAs (total arsenic) than subjects with normal DBP, SBP, and PP. The iAs%, MMA%, and DMA% differed slightly between subjects with abnormal BP and those with normal BP. The PMI and SMI were slightly higher in subjects with abnormal PP than in those with normal PP.
Conclusion:
Our findings suggest that higher CAE may elevate BP. Males may have a higher risk of abnormal DBP, whereas females have a higher risk of abnormal SBP and PP. Higher urinary iAs may increase the risk of abnormal BP. Lower PMI may elevate the BP. However, higher SMI may increase the DBP and SBP, and lower SMI may elevate the PP.
In order to figure out the prevalence of skin lesions and methylation capacity for migrant and native adult women in an endemic area for arsenic poisoning in Inner Mongolia, China, 207 adult women were selected for study subjects. The results showed that the prevalence of skin lesions for the external group, provincial group and native group was 36.54, 26.15 and 35.56 %, respectively. The nail content of arsenic and urinary concentrations of dimethylarsenic (DMA), monomethylarsenic (MMA) and inorganic arsenic (iAs) were significantly higher in women with skin lesions than in those without skin lesions. The highest urinary concentrations of DMA, MMA and iAs were 213.93, 45.72 and 45.01 μg/L in the native group. The arsenic methylation capacity index revealed that the external group had the greatest capacity, while the native group had the lowest. The odds ratios of skin lesions in relation to arsenic metabolites and arsenic methylation capacity varied widely among the three groups. Urinary MMA and iAs concentrations were positively associated with risk of skin lesions in the three groups of adult women, while primary and secondary methylation capacities were negatively related to risk of skin lesions in native and provincial groups. The external group might be more susceptible to MMA and iAs, while the provincial and native groups were more tolerance to MMA and iAs. Lower primary and secondary arsenic methylation capacities increased the risk of skin lesions in native and provincial groups. Moreover, higher nail arsenic concentration increased the risk of skin lesions of adult women.
Deficiency in the capability of xenobiotic detoxification and arsenic methylation may be correlated with individual susceptibility to arsenic-related skin cancers. We hypothesized that glutathione S-transferase (GST M1, T1, and P1), reactive oxygen species (ROS) related metabolic genes (NQO1, EPHX1, and HO-1), and DNA repair genes (XRCC1, XPD, hOGG1, and ATM) together may play a role in arsenic-induced skin carcinogenesis. We conducted a case-control study consisting of 70 pathologically confirmed skin cancer patients and 210 age and gender matched participants with genotyping of 12 selected polymorphisms. The skin cancer risks were estimated by odds ratio (OR) and 95% confidence interval (CI) using logistic regression. EPHX1 Tyr113His, XPD C156A, and GSTT1 null genotypes were associated with skin cancer risk (OR = 2.99, 95% CI = 1.01-8.83; OR = 2.04, 95% CI = 0.99-4.27; OR = 1.74, 95% CI = 1.00-3.02, resp.). However, none of these polymorphisms showed significant association after considering arsenic exposure status. Individuals carrying three risk polymorphisms of EPHX1 Tyr113His, XPD C156A, and GSTs presented a 400% increased skin cancer risk when compared to those with less than or equal to one polymorphism. In conclusion, GSTs, EPHX1, and XPD are potential genetic factors for arsenic-induced skin cancers. The roles of these genes for arsenic-induced skin carcinogenesis need to be further evaluated.
Inefficient arsenic methylation capacity has been associated with various health hazards induced by arsenic. In this study, we aimed to explore the interaction effect of lower arsenic methylation capacity with demographic characteristics on hypertension risk. A total of 512 adult participants (126 hypertension subjects and 386 non-hypertension subjects) residing in an arsenic-endemic area in Inner Mongolia, China were included. Urinary levels of inorganic arsenic (iAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) were measured for all subjects. The percentage of urinary arsenic metabolites (iAs%, MMA%, and DMA%), primary methylation index (PMI) and secondary methylation index (SMI) were calculated to assess arsenic methylation capacity of individuals. Results showed that participants carrying a lower methylation capacity, which is characterized by lower DMA% and SMI, have a higher risk of hypertension compared to their corresponding references after adjusting for multiple confounders. A potential synergy between poor arsenic methylation capacity (higher MMA%, lower DMA% and SMI) and older age or higher BMI were detected. The joint effects of higher MMA% and lower SMI with cigarette smoking also suggest some evidence of synergism. The findings of present study indicated that inefficient arsenic methylation capacity was associated with hypertension and the effect might be enhanced by certain demographic factors.
Chronic arsenic exposure through drinking water has been a vigorously studied and debated subject. However, the existing literature does not allow for a thorough examination of the potential regional discrepancies that may arise among arsenic-related health outcomes. The purpose of this article is to provide an updated review of the literature on arsenic exposure and commonly discussed health effects according to global geographical distribution. This geographically segmented approach helps uncover the discrepancies in the health effects of arsenic. For instance, women are more susceptible than men to a few types of cancer in Taiwan, but not in other countries. Although skin cancer and arsenic exposure correlations have been discovered in Chile, Argentina, the United States, and Taiwan, no evident association was found in mainland China. We then propose several globally applicable recommendations to prevent and treat the further spread of arsenic poisoning and suggestions of future study designs and decision-making.
Arsenic exposure from burning high arsenic-containing coal has been associated with human skin lesion and cancer. However, the mechanisms of arsenic-related carcinogenesis are not fully understood. Inactivation of critical tumor suppression genes by epigenetic regulation or genetic modification might contribute to arsenic-induced carcinogenicity. This study aims to clarify the correlation between arsenic pollution and functional defect of p15
INK4b
gene in arsenic exposure residents from a region of Guizhou Province, China. To this end, 103 arsenic exposure residents and 105 control subjects were recruited in this study. The results showed that the exposure group exhibited higher levels of urinary and hair arsenic compared with the control group (55.28 vs 28.87 μg/L, 5.16 vs 1.36 μg/g). Subjects with higher arsenic concentrations are more likely to have p15
INK4b
methylation and gene deletion (χ2 = 4.28, P = 0.04 and χ2 = 4.31, P = 0.04). We also found that the degree of p15
INK4b
hypermethylation and gene deletion occurred at higher incidence in the poisoning cases with skin cancer (3.7% and 14.81% in non-skin cancer group, 41.18% and 47.06 in skin cancer group), and were significantly associated with the stage of skin lesions (χ2 = 12.82, P < 0.01 and χ2 = 7.835, P = 0.005). These observations indicate that inactivation of p15
INK4b
through genetic alteration or epigenetic modification is a common event that is associated with arsenic exposure and the development of arsenicosis.
Incomplete arsenic (As) methylation has been considered a risk factor of As-related diseases. This study aimed to examine the difference of urinary As metabolites and the methylation capacity between subjects with and without skin lesions. Urinary inorganic arsenic (iAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) were analyzed. The percentage of each As species (iAs%, MMA%, and DMA%), the primary methylation index (PMI) and secondary methylation index (SMI) were calculated. The results showed that subjects with skin lesions have higher levels of urinary iAs (99.08 vs. 70.63 μg/g Cr, p = 0.006) and MMA (69.34 vs. 42.85 μg/g Cr, p = 0.016) than subjects without skin lesions after adjustment for several confounders. Significant differences of urianry MMA% (15.49 vs. 12.11, p = 0.036) and SMI (0.74 vs. 0.81, p = 0.025) were found between the two groups. The findings of the present study suggest that subjects with skin lesions may have a lower As methylation capacity than subjects without skin lesions.
Arsenic-contaminated groundwater used for drinking in China is a health threat that was first recognized in the 1960s. However,
because of the sheer size of the country, millions of groundwater wells remain to be tested in order to determine the magnitude
of the problem. We developed a statistical risk model that classifies safe and unsafe areas with respect to geogenic arsenic
contamination in China, using the threshold of 10 micrograms per liter, the World Health Organization guideline and current
Chinese standard for drinking water. We estimate that 19.6 million people are at risk of being affected by the consumption
of arsenic-contaminated groundwater. Although the results must be confirmed with additional field measurements, our risk model
identifies numerous arsenic-affected areas and highlights the potential magnitude of this health threat in China.
Hyperpigmentation, hyperkeratoses, and Bowen's disease are hallmarks of chronic arsenic exposure. The association between arsenic-induced skin lesions and subsequent internal cancers is examined by using a community-based prospective study. The cohort was enrolled from an arseniasis-endemic area in southwestern Taiwan, where 2,447 residents participated in skin examinations during the late 1980s. The number of participants diagnosed with hyperpigmentation was 673; with hyperkeratosis, 243; and with skin cancer (Bowen's disease or non-melanoma skin cancer), 378. Newly diagnosed internal cancers were ascertained through linkage with National Cancer Registry profiles. Cox regression was performed to estimate hazard ratios with 95% confidence intervals for potential risk predictors. Compared with participants without skin lesions, patients affected with skin cancers had a significantly increased risk of lung cancer (hazard ratio = 4.64, 95% confidence interval: 2.92, 7.38) and urothelial carcinoma (hazard ratio = 2.02, 95% confidence interval: 1.23, 3.30) after adjustment for potential confounders and cumulative arsenic exposure. Hyperkeratosis is significantly associated with an increased lung cancer risk (hazard ratio = 2.76, 95% confidence interval: 1.35, 5.67). A significant interactive effect on lung cancer risk between hyperkeratosis and cigarette smoking was identified, which suggests that patients with hyperkeratosis who have been exposed to arsenic should cease smoking.
It was estimated that, nearly 100 million people are at risk for drinking arsenic (As)-contaminated drinking water. Although the WHO guideline recommends that levels of As in drinking water should not exceed 10 μm/L, it was estimated that more than 30 million people drink As-containing water at levels more than 50 μm/L in Bangladesh and India alone. Therefore, the adverse health effects resulting from chronic As exposure pose a global threat. In Taiwan, studies focusing on the health effects resulting from chronic As exposure through contaminated drinking water have been ongoing for more than 50 years. During the past half century, it was recognized that the impact of high As exposure on human health is much more complicated than originally anticipated. Chronic As exposure resulted in infamous blackfoot disease, which is unique to As endemic areas in Taiwan, and various diseases including cancers and non-cancers. Although the potential-biological outcomes have been well-documented, the pathomechanisms leading from As exposure to occurrence and development of the diseases remain largely unclear. One of the major obstacles that hindered further understanding regarding the adverse health effect resulting from chronic As exposure is documentation of cumulative As exposure from the distant past, which remains difficult as the present technologies mostly document relatively recent As exposure. Furthermore, the susceptibility to As exposure appears to differ between different ethnic groups and individuals and is modified by lifestyle factors including smoking habits and nutrition status. No consensus data has yet been reached even after comparing the study results obtained from different parts of the world focusing on associations between human As toxicity and genetic polymorphisms in terms of cellular detoxification enzymes, tumor suppressor proteins, and DNA repair pathway. With the availability of the new powerful "OMIC" technologies, it may now be possible to gain new path-breaking insights regarding this important environmental health issue. The lessons learned from the past half-century placed Taiwan in an experienced position to actively participate in the international collaborative projects using these novel technologies and standardized methods.
This article provides the history of arsenicosis in Mainland China and the research situation in the recent 10 years. The first large area of arsenicosis caused by high levels of arsenic in drinking water in Mainland China was discovered in Kuitun, Xinjiang Province, in 1983. The government attached great importance to arsenicosis and finally regarded it as the epidemic disease throughout the nation in 1994. Until 2006, the survey areas of wells with arsenic concentration greater than 50 μg/L in drinking water have involved 16 provinces in Mainland China. The molecular epidemiological studies on relationship between arsenic metabolism and manifestations of arsenicosis caused by chronic exposure to high level of arsenic in drinking water and the studies on arsenic exposure and related health effects in different arsenic exposure populations are summarized in this review.
In contrast to arsenic (As) poisoning caused by naturally occurring inorganic arsenic-contaminated water consumption, coal arsenic poisoning (CAP) induced by elevated arsenic exposure from coal combustion has rarely been reported. In this study, the concentrations and distributions of urinary arsenic metabolites in 57 volunteers (36 subjects with skin lesions and 21 subjects without skin lesions), who had been exposed to elevated levels of arsenic present in coal in Changshapu village in the south of Shaanxi Province (China), were reported. The urinary arsenic species, including inorganic arsenic (iAs) [arsenite (iAsIII) and arsenate (iAsV)], monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV), were determined by high-performance liquid chromatography (HPLC) combined with inductively coupled plasma mass spectroscopy (ICP-MS). The relative distributions of arsenic species, the primary methylation index (PMI=MMAV/iAs) and the secondary methylation index (SMI=DMAV/MMAV) were calculated to assess the metabolism of arsenic. Subjects with skin lesions had a higher concentration of urinary arsenic and a lower arsenic methylation capability than subjects without skin lesions. Women had a significantly higher methylation capability of arsenic than men, as defined by a higher percent DMAV and SMI in urine among women, which was the one possible interpretation of women with a higher concentration of urinary arsenic but lower susceptibility to skin lesions. The findings suggested that not only the dose of arsenic exposure but also the arsenic methylation capability have an impact on the individual susceptibility to skin lesions induced by coal arsenic exposure.
We conducted a retrospective mortality study in an Inner Mongolian village exposed to well water contaminated by arsenic since the 1980s. Deaths occurring between January 1, 1997 and December 1, 2004 were classified according to underlying cause and water samples from household wells were tested for total arsenic. Heart disease mortality was associated with arsenic exposure, and the association strengthened with time exposed to the water source. Cancer mortality and all-cause mortality were associated with well-water arsenic exposure among those exposed 10-20 years. This is the first study to document increased arsenic-associated mortality in the Bayingnormen region of Inner Mongolia.
Residents of the Bayingnormen region of Inner Mongolia have been exposed to arsenic-contaminated well water for over 20 years, but relatively few studies have investigated health effects in this region. We surveyed one village to document exposure to arsenic and assess the prevalence of arsenic-associated skin lesions and self-reported morbidity. Five-percent (632) of the 12,334 residents surveyed had skin lesions characteristics of arsenic exposure. Skin lesions were strongly associated with well water arsenic and there was an elevated prevalence among residents with water arsenic exposures as low as 5 uμg/L-10 uμg/L. The presence of skin lesions was also associated with self- reported cardiovascular disease. [email protected]
/* */;.
Arsenic exposure is associated with human cancer. Telomerase-containing human telomerase reverse transcriptase (hTERT) can extend telomeres of chromosomes, delay senescence, and promote cell proliferation leading to tumorigenesis.
The goal of this study was to investigate the effects of As on hTERT mRNA expression in humans and in vitro.
A total of 324 Inner Mongolia residents who have been exposed to As via drinking water participated in this study. Water and toenail samples were collected and analyzed for As. Blood samples were quantified for hTERT mRNA expression using real-time polymerase chain reaction. The hTERT mRNA levels were linked to water and nail As concentrations and skin hyperkeratosis. Human epidermal keratinocytes were treated with arsenite to assess effects on cell viability and hTERT expression in vitro.
hTERT mRNA expression levels were significantly associated with As concentrations of water (p<0.0001) and nails (p=0.002) and also associated with severity of skin hyperkeratosis (p<0.05), adjusting for age, sex, smoking, and pesticide use. Females showed a higher slope than males (females: 0.126, p=0.0005; males: 0.079, p=0.017). In addition to water and nail As concentrations, age (p<0.0001) and pesticide use (p=0.025) also showed significant associations with hTERT expression. The hTERT expression levels decreased with age. Tobacco smoking did not affect hTERT expression (p=0.13). hTERT expression was significantly correlated with OGG1 and ERCC1 expression. The in vitro results also showed a dose-response relationship between arsenite concentrations and hTERT expression and reached the peak at 1 microM.
hTERT expression was associated with As exposure in vivo and in vitro. The increased hTERT expression may be a cellular response to genomic insults by As and may also indicate that As may function as a tumor promoter in carcinogenesis in humans.
In order to evaluate the prevalence and multiple risk factors of arsenic-induced skin cancer among residents in Taiwanese villages in which chronic arseniasis is hyperendemic, a total of 1571 subjects aged 30 or more years were recruited between September 1988 and March 1989. All of them were interviewed personally by a public health nurse using a structured questionnaire, and 1081 interviewed study subjects, including 468 men and 613 women, participated in physical examination, giving a participation rate of 68.8%. The overall prevalence of skin cancer was as high as 6.1%, showing an increase with age in both men and women. There was a significant dose-response relation between skin cancer prevalence and chronic arsenic exposure as indexed by duration of residence in the endemic area, duration of consumption of high-arsenic artesian well water, average arsenic exposure in parts per million (p.p.m.) and cumulative arsenic exposure in p.p.m.-years. Chronic carriers of hepatitis B surface antigen with liver dysfunction had an increased prevalence of skin cancer. Undernourishment, indexed by a high consumption of dried sweet potato as a staple food, was also significantly associated with an increased prevalence of arsenic-induced skin cancer. All these risk factors remained statistically significant in the multiple logistic regression analysis. Consistent with animal experiments, the findings imply that liver function and nutritional status may affect the metabolism of inorganic arsenic and the development of subsequent skin cancers.
Domestic coal combustion has had profound adverse effects on the health of millions of people worldwide. In China alone several hundred million people commonly burn raw coal in unvented stoves that permeate their homes with high levels of toxic metals and organic compounds. At least 3,000 people in Guizhou Province in southwest China are suffering from severe arsenic poisoning. The primary source of the arsenic appears to be consumption of chili peppers dried over fires fueled with high-arsenic coal. Coal samples in the region were found to contain up to 35,000 ppm arsenic. Chili peppers dried over high-arsenic coal fires adsorb 500 ppm arsenic on average. More than 10 million people in Guizhou Province and surrounding areas suffer from dental and skeletal fluorosis. The excess fluorine is caused by eating corn dried over burning briquettes made from high-fluorine coals and high-fluorine clay binders. Polycyclic aromatic hydrocarbons formed during coal combustion are believed to cause or contribute to the high incidence of esophageal and lung cancers in parts of China. Domestic coal combustion also has caused selenium poisoning and possibly mercury poisoning. Better knowledge of coal quality parameters may help to reduce some of these health problems. For example, information on concentrations and distributions of potentially toxic elements in coal may help delineate areas of a coal deposit to be avoided. Information on the modes of occurrence of these elements and the textural relations of the minerals and macerals in coal may help predict the behavior of the potentially toxic components during coal combustion.
Arsenic is a notorious environmental toxicant known as both a carcinogen and an atherogen in human beings, but the pathogenic mechanisms are not completely understood. In cell culture studies, trivalent arsenic enhanced oxidative stress in a variety of mammalian cells, and this association may be closely associated with the development of arsenic-related diseases. To investigate the effect of arsenic exposure on oxidative stress in humans, we conducted a population study to determine the relationships of blood arsenic to reactive oxidants and antioxidant capacity at the individual level. We recruited 64 study subjects ages 42-75 years from residents of the Lanyang Basin on the northeast coast of Taiwan, where arsenic content in well water varies from 0 to > or = 3,000 microg/L. We used a chemiluminescence method, with lucigenin as an amplifier for measuring superoxide, to measure the plasma level of reactive oxidants. We used the azino-diethyl-benzthiazoline sulphate method to determine the antioxidant capacity level in plasma of each study subject. We determined arsenic concentration in whole blood by hydride formation with an atomic absorption spectrophotometer. The average arsenic concentration in whole blood of study subjects was 9.60 +/- 9.96 microg/L (+/- SD) with a range from 0 to 46.50 microg/L. The level of arsenic concentration in whole blood of study subjects showed a positive association with the level of reactive oxidants in plasma (r = +0.41, p = 0.001) and an inverse relationship with the level of plasma antioxidant capacity (r = -0.30, p = 0.014). However, we found no significant association (p = 0.266) between levels of plasma reactive oxidants and antioxidant capacity. Our results also show that the lower the primary arsenic methylation capability, the lower the level of plasma antioxidant capacity (p = 0.029). These results suggest that ingestion of arsenic-contaminated well water may cause deleterious effects by increasing the level of reactive oxidants and decreasing the level of antioxidant capacity in plasma of individuals. Persistent oxidative stress in peripheral blood may be a mechanism underlying the carcinogenesis and atherosclerosis induced by long-term arsenic exposure.
Arsenic is an environmental hazard and the reduction of drinking water arsenic levels is under consideration. People are exposed to arsenic not only through drinking water but also through arsenic-contaminated air and food. Here we report the health effects of arsenic exposure from burning high arsenic-containing coal in Guizhou, China. Coal in this region has undergone mineralization and thus produces high concentrations of arsenic. Coal is burned inside the home in open pits for daily cooking and crop drying, producing a high concentration of arsenic in indoor air. Arsenic in the air coats and permeates food being dried producing high concentrations in food; however, arsenic concentrations in the drinking water are in the normal range. The estimated sources of total arsenic exposure in this area are from arsenic-contaminated food (50-80%), air (10-20%), water (1-5%), and direct contact in coal-mining workers (1%). At least 3,000 patients with arsenic poisoning were found in the Southwest Prefecture of Guizhou, and approximately 200,000 people are at risk for such overexposures. Skin lesions are common, including keratosis of the hands and feet, pigmentation on the trunk, skin ulceration, and skin cancers. Toxicities to internal organs, including lung dysfunction, neuropathy, and nephrotoxicity, are clinically evident. The prevalence of hepatomegaly was 20%, and cirrhosis, ascites, and liver cancer are the most serious outcomes of arsenic poisoning. The Chinese government and international organizations are attempting to improve the house conditions and the coal source, and thereby protect human health in this area.
Chronic arsenic exposure causes vascular diseases associated with systematic dysfunction of endogenous nitric oxide. Replacement of heavily arsenic-contaminated drinking water with low-arsenic water is a potential intervention strategy for arsenosis, although the reversibility of arsenic intoxication has not established. In the present study, we examined urinary excretion of cyclic guanosine 3 ,5 -monophosphate (cGMP), a second messenger of the vasoactive effects of nitric oxide, and signs and symptoms for peripheral vascular function in 54 arsenosis patients before and after they were supplied with low-arsenic drinking water in an endemic area of chronic arsenic poisoning in Inner Mongolia, China. The arsenosis patients showed a marked decrease in urinary excretion of cGMP (mean +/- SEM: male, 37.0 +/- 6.1; female, 37.2 +/- 5.4 nmol/mmol creatinine), and a 13-month period of consuming low-arsenic drinking water reversed this trend (male, 68.0 +/- 5.6; female, 70.6 +/- 3.0 nmol/mmol creatinine) and improved peripheral vascular response to cold stress. Our intervention study indicates that peripheral vascular disease in arsenosis patients can be reversed by exposure cessation and has important implications for the public health approach to arsenic exposure.
Chronic arsenicosis is a newly-emerged public-health issue in China and many other Asian countries. Over 200 million people are estimated to be at the risk of high arsenic exposure from drinking-water in the Asian region. To protect people from the hazards of chronic arsenic poisoning, the Chinese Government has been providing low-arsenic drinking-water to some seriously-affected rural areas, such as Inner Mongolia autonomous province. Results of follow-up studies showed that both the average values of arsenic, including inorganic arsenic (iAs), monomethylated arsenic, dimethylated arsenic and trimethylated arsenic, and 8-hydroxydeoxyguanine in urine, decreased significantly after drinking low-arsenic water for one year, and arsenic-specific skin lesions also improved to some extent. However, a five-year follow-up study showed no more significant improvement of skin lesions, while the potential risk of arsenic-induced cancers after cutting off high-arsenic exposure was still uncertain and indefinite. The susceptibility of children compared to adults to chronic arsenic exposure and the need to re-evaluate the appropriate standard of arsenic in drinking-water were also discussed in this paper.
Arsenic exposure from burning coal with high arsenic contents occurs in southwest Guizhou, China. Coal in this region contains extremely high concentrations of inorganic arsenic. Arsenic exposure from coal-burning is much higher than exposure from arsenic-contaminated water in other areas of China. The current status and prevention strategies for arsenic poisoning from burning high-arsenic coal in southwest Guizhou, China, is reported here. Over 3,000 arsenic-intoxicated patients were diagnosed based on skin lesions and urinary arsenic excretion. Non-cancerous toxicities and malignancies were much more common and severe in these patients than in other arsenic-affected populations around the world. The high incidence of cancer and arsenic-related mortality in this cohort is alarming. Chelation therapy was performed but the long-term therapeutic effects are not satisfactory. The best prevention strategy is to eliminate arsenic exposure. Funds from the Chinese Government are currently available to solve this arsenic exposure problem. Strategies include the installation of vented stoves, the use of marsh gas to replace coal, health education, the improvement of nutritional status, and the use of various therapies to treat arsenic-induced skin and liver diseases.
We report the concentrations and distributions of urinary arsenic (As) metabolites in 233 residents exposed to 20, 90, or 160 microg/L inorganic arsenic (iAs) in drinking water from three villages in Hohhot, Inner Mongolia, China, that formed one control and two exposed groups.
We used hydride generation-atomic absorption spectrometry (HGAAS) to determine iAs, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA).
The concentrations of each urinary As species in the two exposed groups were significantly higher than in the control group for both children and adults. Both children and adults in exposed groups had higher percent iAs and MMA and lower percent DMA, and low primary and secondary methylation indices (PMI and SMI, respectively) than those in the control group. However, children showed significant increases in percent DMA and the SMI as well as decreases in the percent MMA when the iAs exposure level increased from 90 to 160 microg/L. In addition, children in the two exposed groups showed lower percent MMA but higher percent DMA and higher SMI than adults in the same exposed group. No significant differences in As metabolite concentrations and distributions were found between males and females in each group. A significant correlation was also found in the SMI between 11 pairs of children and their mothers from the 160-microg/L-exposed group.
Children had higher a capacity for secondary methylation of As than adults when exposed to the same concentrations of iAs in drinking water. Exposure to As may increase the capacity for methylation in children to some extent.
The associations between arsenic exposure, arsenic methylation, and the prevalence of skin lesions and hypertension are investigated. The results indicate that the HS (hypertension and skin lesions) group and the S (skin lesions) group have higher urinary concentrations of iAs (inorganic arsenic), MMA (monomethylarsonic acid), DMA (dimethylarsinous acid) and %MMA, and lower SMI (secondary arsenic methylation index) compared to the H (hypertension) and N (without both hypertension and skin lesions) groups. The arsenic content in water which caused H may be lower than that which caused HS and S. In addition, the odds ratios suggest that higher urinary concentrations of iAs and MMA, %iAs, %MMA and PMI elevate the prevalence of only hypertension and skin lesions, and both hypertension and skin lesions. However, higher %DMA and SMI, and lower %MMA increase the prevalence of both hypertension and skin lesions compared to that of only skin lesions. It can be concluded that skin lesions subjects have higher prevalence of hypertension. Hypertension subjects may have higher prevalence of skin lesions. Lower %DMA and SMI, higher %iAs, %MMA and PMI enhance the prevalence of only hypertension and skin lesions, and both hypertension and skin lesions. Moreover, iAs and MMA may have higher toxicity and lead to both hypertension and skin lesions than to only hypertension.
Humans are exposed to arsenic via drinking water, dietary intake and inhaled particulates. Endemic chronic arsenic exposure related reproductive toxicity is well documented, but the effect of low-level general environmental arsenic exposure on unexplained male infertility (UMI) remains unclear.
In this case-control study, we aimed to investigate the relationship between non-geogenic environmental arsenic exposure and UMI risk. One hundred and one infertile men with normal semen as cases and sixty one fertile men as controls were recruited. Five urinary arsenic species: pentavalent arsenate (AsiV), trivalent arsenite (AsiIII), methylated to monomethylarsonic acid (MMAV), dimethylarsinic acid (DMAV), arsenobetaine (AsB) were quantitatively measured by liquid chromatography-inductively coupled plasma-mass spectrometry (LC-ICP-MS). To assess the semen quality, semen volume, sperm concentration, total motility, and progressive motility were measured.
The nonparametric Mann-Whitney U test was used to compare the differences of arsenic species and index between the case and the control group; we observed that concentrations of AsiV, AsB, MMAV, DMAV, total inorganic As and total As were significantly higher in the cases than the controls. The urine AsiV level increased more than twenty folds in case group. Moreover, higher redox index (AsiV/AsiIII) and lower primary arsenic methylation index (PMI = MMAV/Asi) were observed for case group. Furthermore, through the logistic regression analysis, we observed that the urine AsiV level and PMI were most significantly associated with UMI risk among the observations. Specifically, in comparison to the first quartile, the subjects with higher AsiV levels were more likely to exhibit UMI with increasing adjusted odds ratios (AORs) (adjusted by age, body mass index, drinking status and smoking status) of 8.39 [95% confidence interval (CI), 2.59–27.17], 13.12 (95% CI, 3.44–50.12) and 36.51 (95% CI, 8.25–161.66) at the second, third and fourth quartiles, respectively. Also a concentration-dependent decrease of AOR was also observed for PMI in comparison to the fourth quartile: 15.43 [95% CI, 4.28–55.69], 9.69 (95% CI, 2.78–33.78) and 6.93 (95% CI, 2.21–21.76) at the first, second and third quartiles, respectively. These findings provide evidences that low-level environmental arsenic exposure was positively associated with UMI risk.
To investigate the interaction between skin lesion status and arsenic methylation profiles, the concentrations and proportions of arsenic metabolites in urine and arsenic methylation capacities of study subjects were determined. The results showed that the mean urinary concentrations of iAs (inorganic arsenic), MMA (monomethylarsonic acid), DMA (dimethylarsinic acid), and TAs (total arsenic) were 75.65, 68.78, 265.81, and 410.24 μg/L, respectively, in the skin lesions subjects. The highest values were observed in the multiple skin lesions subjects. Higher %iAs and %MMA, and lower %DMA, PMI (primary methylation index), and SMI (secondary methylation index) were found in skin lesions subjects. The multiple skin lesions subjects had highest %iAs and %MMA, and lowest %DMA, PMI, and SMI. The prevalence of skin lesions strongly, positively correlated with arsenic levels in drinking water. The elder persons also had higher frequency of skin lesions compared with younger persons. It can be concluded that arsenic levels in drinking water significantly affected the prevalence of skin lesions. Male subjects usually had higher proportions of skin lesions when compared with female subjects. Moreover, it may be concluded that MMA was significantly related to single skin lesion, whereas DMA and iAs were associated with multiple skin lesions. It seemed that MMA had greater toxicity to hyperkeratosis, whereas DMA and iAs had higher toxicity to depigmentation or pigmentation. © 2015 Wiley Periodicals, Inc. Environ Toxicol, 2015.
A lower arsenic methylation capacity is believed to be associated with various arsenic-related diseases. However, the synergistic effect of the arsenic methylation capacity and potential modifiers on arsenicosis risk is unclear. The current study evaluated the joint effect of the arsenic methylation capacity with several risk factors on the risk of arsenicosis characterized by skin lesions. In total, 302 adults (79 arsenicosis and 223 non-arsenicosis) residing in an endemic arsenism area in Huhhot Basin were included. Urinary levels of inorganic arsenic (iAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) were determined, and the percentages of arsenic species (iAs%, MMA%, and DMA%), as well as two methylation indices (primary methylation index, PMI, and secondary methylation index, SMI), were calculated to assess the arsenic methylation capacity of individuals. The results showed that a lower methylation capacity, which is indicated by higher MMA% values and lower DMA% and SMI values, was significantly associated with arsenicosis after the adjustment for multiple confounders. The relative excess risk for interactions between higher MMA% values and older age was 2.35 (95% CI: -0.56, 5.27), and the relative excess risk for interactions between higher MMA% values and lower BMI was 1.08 (95% CI: -1.20, 3.36). The data also indicated a suggestive synergistic effect of a lower arsenic methylation capacity (lower DMA% and SMI) with older age, lower BMI, and male gender. The findings of the present study suggest that a lower arsenic methylation capacity was associated with arsenicosis and that certain risk factors may enhance the risk of arsenic-induced skin lesions.
Environmental exposure to lead or mercury can cause neurodevelopmental damage. Arsenic is another neurotoxicant that can affect intellectual function in children. This study was designed to explore the difference of arsenic methylation capacity indices between with and without developmental delay in preschool children. We also aimed to identify whether blood levels of lead or mercury modify the effect of arsenic methylation capacity indices. A cross sectional study was conducted from August 2010 to March 2012. All participants recruited from the Shin Kong Wu Ho-Su Memorial Teaching Hospital. >In all, 63 children with developmental delay and 35 children without developmental delay were recruited. Urinary arsenic species, including arsenite (AsIII), arsenate (AsV), monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) were measured with a high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Lead and mercury levels of red blood cells were measured by inductively coupled mass spectrometry. All participants underwent developmental assessments to confirm developmental delays, including evaluations of gross motor, fine motor, speech-language, cognition, social, and emotional domains. Urinary total arsenic and MMAV percentage were significantly positively associated and DMAV percentage was negatively associated with the risk of developmental delay in a dose-dependent manner after adjustment for blood lead or mercury levels and other risk factors. A multivariate regression analysis indicated that blood lead level and arsenic methylation capacity each independently contributed to the risk of developmental delay. This is the first study to show that arsenic methylation capacity is associated with developmental delay, even without obvious environmental arsenic exposure.
Statistical modeling has been used to predict high risk area of arsenic (As) hazard, but information about its application on endemic arsenism is limited. In this study, we aim to link the prediction model with population census data and endemic arsenicosis in Shanxi Province, Northern China. 23 explanatory variables from different sources were compiled in the format of grid at 1km resolution in a GIS environment. Logistic regression was applied to describe the relationship between binary-coded As concentrations data and the auxiliary predictors. 61 endemic arsenism villages were geo-located and combined with output maps of the prediction model. Linear regression was used to identify the relationship between arsenicosis occurrence rate and predictive As probability at village level. Our results show that 6 explanatory environmental variables were significantly contributed to the final model. Area of 3000km(2) was found to have high risk of As concentrations above 50μgL(-1). The linear regression indicates that 13% of the variation in arsenicosis occurrence rate can be predicted using predictive probability of As concentration above 50μgL(-1) in Shanxi Province. These results suggest that As prediction model may be helpful for identifying As-contaminated area and endemic arsenism village.
Though oxidative stress is recognized as an important pathogenic mechanism of arsenic, and arsenic methylation capacity is suggested to be highly involved in arsenic-related diseases, the association of arsenic methylation capacity with arsenic-induced oxidative stress remains unclear. To explore oxidative stress and its association with arsenic methylation, cross-sectional studies were conducted among 208 high and 59 low arsenic-exposed subjects. Levels of urinary arsenic species [inorganic arsenic (iAs), monomethylated arsenic (MMA) and dimethylated arsenic (DMA)] were determined by hydride generation atomic absorption spectrometry. Proportions of urinary arsenic species, the first methylation ratio (FMR) and the secondary methylation ratio (SMR) were used as indicators for arsenic methylation capacity. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) concentrations were analyzed by enzyme-linked immunosorbent assay kits. Reduced glutathione (GSH) levels and superoxide dismutase (SOD) activity in whole blood were determined to reflect anti-oxidative status. The high arsenic-exposed children and adults were significantly increased in urinary 8-OHdG concentrations but decreased in blood GSH levels compared with the low exposed children and adults. In multiple linear regression models, blood GSH levels and urinary 8-OHdG concentrations of arsenic-exposed children and adults showed strong associations with the levels of urinary arsenic species. Arsenic-exposed subjects in the lower and the upper quartiles of proportions of urinary arsenic species, FMR or SMR were significantly different in urinary 8-OHdG, blood GSH and SOD. The associations of arsenic methylation capacity with 8-OHdG, GSH and SOD were also observed in multivariate regression analyses. These results may provide linkage between arsenic methylation capacity and oxidative stress in humans and suggest that adverse health effects induced by arsenic are related to arsenic methylation through oxidative stress.
Chronic exposure to excess level of arsenic through contaminated drinking water is associated with many injuries, among which skin lesions are the most prominent. In this study, we measured the concentrations of inorganic arsenic (iAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) in the blood of the residents of arsenicosis area, who demonstrated different skin lesion grade from mild, moderate to advanced. We evaluated the individual methylation capacity by two indices of the first and secondary methylation ratio (FMR and SMR). We found that SMR of moderate and advanced groups were markedly lower than that of mild group. Significant negative correlation was found between SMR of all the subjects and the grade of skin lesion, with Spearman's correlation coefficient of -0.429 (P = 0.016). Moreover, blood MMA proportion of moderate and advanced groups was found to be significantly higher than that of the mild group. These results suggest that low secondary arsenic methylation capacity and high MMA proportion are associated with the severity of arsenic-related skin lesions. Our findings evaluated by blood speciation is consistent with that evaluated by the generally accepted urinary arsenic speciation in the relationship between arsenic methylation capacity and arsenic-related lesions.
Long-term exposure to inorganic arsenic from artesian drinking well water is associated with carotid atherosclerosis in the Blackfoot Disease (BFD)-hyperendemic area in Taiwan. The current study examined the arsenic methylation capacity and its risk on carotid atherosclerosis. A total of 304 adults (158 men and 146 women) residing in the BFD-hyperendemic area were included. The extent of carotid atherosclerosis was assessed by duplex ultrasonography. Chronic arsenic exposure was estimated by an index of cumulative arsenic exposure (CAE) and the duration of artesian well water consumption. Urinary levels of inorganic arsenite [As(III)], arsenate [As(V)], monomethylarsonic acid [MMA(V)] and dimethylarsinic acid [DMA(V)] were determined by high performance liquid chromatography linked on-line to a hydride generator and atomic absorption spectrometry (HPLC-HG-AAS). The percentage of arsenic species, primary methylation index [PMI=MMA(V)/(As(III)+As(V)] and secondary methylation index [SMI=DMA(V)/MMA(V)] were calculated and employed as indicators of arsenic methylation capacity. Results showed that women and younger subjects had a more efficient arsenic methylation capacity than did men and the elderly. Carotid atherosclerosis cases had a significantly greater percentage of MMA(V) [%MMA(V)] and a lower percentage of DMA [%DMA (V)] compared to controls. Subjects in the highest two tertiles of PMI with a median of CAE >0 mg/L-year had an odds ratio (OR) and a 95% confidence interval (CI) of carotid atherosclerosis of 2.61 and 0.98-6.90 compared to those in the highest two tertiles of PMI with a CAE=0 mg/L-year. We conclude that individuals with greater exposure to arsenic and lower capacity to methylate inorganic arsenic may be at a higher risk to carotid atherosclerosis.
Subjects exposed to arsenic show significant inter-individual variation in urinary patterns of arsenic metabolites but insignificant day-to-day intra-individual variation. The inter-individual variation in arsenic methylation can be partly responsible for the variation in susceptibility to arsenic toxicity. Wide inter-ethnic variation and family correlation in urinary arsenic profile suggest a genetic effect on arsenic metabolism. In this paper the environmental factors affecting arsenic metabolism are reviewed. Methylation capacity might reduce with increasing dosage of arsenic exposure. Furthermore, women, especially at pregnancy, have better methylation capacity than their men counterparts, probably due to the effect of estrogen. Children might have better methylation capacity than adults and age shows inconsistent relevance in adults. Smoking and alcohol consumption might be associated with a poorer methylation capacity. Nutritional status is important in the methylation capacity and folate may facilitate the methylation and excretion of arsenic. Besides, general health conditions and medications might influence the arsenic methylation capacity; and technical problems can cause biased estimates. The consumption of seafood, seaweed, rice and other food with high arsenic contents and the extent of cooking and arsenic-containing water used in food preparation may also interfere with the presentation of the urinary arsenic profile. Future studies are necessary to clarify the effects of the various arsenic metabolites including the trivalent methylated forms on the development of arsenic-induced human diseases with the consideration of the effects of confounding factors and the interactions with other effect modifiers.
Age-adjusted mortality rates were analyzed to examine the dose-response relation between ingested arsenic levels and risk of cancers and vascular diseases among residents in the endemic area of blackfoot disease, a unique peripheral vascular disease associated with long-term exposure to high-arsenic artesian well water and confined to the southwestern coast of Taiwan. The arsenic levels in well water determined in 1964-1966 were available in 42 villages of the study area, while mortality and population data during 1973-1986 were obtained from the local household registration offices and Taiwan Provincial Department of Health. Age-adjusted mortality rates from various cancers and vascular diseases by sex were calculated using the 1976 world population as the standard population. A significant dose-response relation was observed between arsenic levels in well water and cancers of the bladder, kidney, skin, and lung in both males and females, and cancers of the prostate and liver in males. However, there was no association for cancers of the nasopharynx, esophagus, stomach, colon, and uterine cervix, and for leukemia. Arsenic levels in well water were also associated with peripheral vascular diseases and cardiovascular diseases in a dose-response pattern, but not with cerebrovascular accidents. The dual effect of arsenic on carcinogenesis and arteriosclerosis and the interrelation between these two pathogenic mechanisms deserve more intensive study.
The objective of this study is to elucidate the association between high-arsenic artesian well water and cancers in endemic area of blackfoot disease, a unique peripheral vascular disease related to continuous arsenic exposure. As compared with the general population in Taiwan, both the standardized mortality ratio (SMR) and cumulative mortality rate were significantly high in blackfoot disease-endemic areas for cancers of bladder, kidney, skin, lung, liver, and colon. The SMRs for cancers of bladder, kidney, skin, lung, liver, and colon were 1100, 772, 534, 320, 170, and 160, respectively, for males, and 2009, 1119, 652, 413, 229, and 168, respectively, for females. A dose-response relationship was observed between SMRs of the cancers and blackfoot disease prevalence rate of the villages and townships in the endemic areas. SMRs of cancers were greater in villages where only artesian wells were used as the drinking water source than in villages using both artesian and shallow wells, and even greater than in villages using shallow wells only.
In ecologic studies, participants are studied by groups, and the exposure status of each group is usually represented by a single indicator, mostly the mean exposure. In this paper, we propose using multiple variables derived from dummy variables at the individual level to describe the exposure. An analysis of the association between arsenic in drinking water and skin cancer was used as an example. Well water arsenic levels and skin cancer incidence from 1980 to 1987 were assessed for 243 townships in Taiwan. We first analyzed the data using the mean arsenic concentration in each township as the only exposure variable. The second analysis used multiple variables to describe arsenic exposure; each variable denoted the percentage of wells with arsenic levels within a specific range in each township. Although the first approach did not identify associations between arsenic levels and skin cancer, the multiple-variable approach identifies a positive association at the highest arsenic exposure category (>0.64 mg/L) in both men and women. Therefore, using multiple variables to describe an exposure in ecologic studies may facilitate a better description of the exposure status and thereby lead to more accurate risk assessment, especially when the dose-response relationship is not linear.
Prolonged exposure to arsenic results in peripheral and cardiovascular manifestations, as does impaired production of endothelial nitric oxide (NO). In vitro studies have indicated that endothelial cells undergo damage by arsenic. However, no information has been available on the relationship between NO synthesis and chronic arsenic poisoning in humans. The present study was designed to reveal this question. The subjects were 33 habitants who continued to drink well water containing high concentrations of inorganic arsenic (mean value = 0.41 microg/ml) for about 18 years in Inner Mongolia, China, and 10 other people who lived in this area but exposed to minimal concentrations of arsenic (mean value = 0.02 microg/ml) were employed as controls. Mean blood concentration of total arsenic was six times higher in exposed subjects than controls; 42.1 vs. 7.3 ng/ml, p <.001. Mean serum concentration of nitrite/nitrate, stable metabolites of endogenous NO, was lower in arsenic-exposed subjects than in controls: 24.7 vs. 51.6 microM, p<.001. In total samples, an inverse correlation with serum nitrite/nitrate levels was strong for blood inorganic arsenic (r = -0.52, p <.001) and less strong for its metabolites, monomethyl arsenic (r = -0.45, p<.005) and dimethyl arsenic (r = -0.37, p<.05). Furthermore, serum nitrite/nitrate concentration was significantly correlated with nonprotein sulfhydryl level in whole blood (r = 0.58, p<.001). In an in vitro study, we demonstrated that inorganic arsenite or arsenate suppresses the activity of endothelial NO synthase in human umbilical vein endothelial cells. These results suggest that long-term exposure to arsenic by drinking well water possibly reduces NO production in endothelial cells, resulting in a decrease in reduced nitrite/nitrate concentrations. Peripheral vascular disorders caused by arsenic may be attributable in part to impairment of NO production in vivo.
The arsenic-related peripheral vascular disease found to be endemic along the southwestern coast of Taiwan is reviewed. In the early 20th century a strange disease involving the lower extremities characterized by typical clinical symptoms and signs of progressive arterial occlusion was reported in a confined area located along the southwestern coast of Taiwan. The disease was locally called "blackfoot disease" because of its gangrenous appearance involving the feet of the patients. The prevalence of this disease ranged from 6.51 to 18.85 per 1,000 population in different villages. Epidemiologic studies revealed that blackfoot disease was associated with the consumption of artesian well water containing high levels of arsenic. High co-occurrence of blackfoot disease and arsenic-related skin lesions such as hyperpigmentation, hyperkeratosis, and skin cancer was also observed. Recent studies also confirmed the association of preclinical peripheral vascular disease with arsenic exposure in a dose-response pattern. Subclinical arterial insufficiency and defects in cutaneous microcirculation can also be demonstrated in seemingly normal subjects living in the endemic villages. The incidence of clinical manifestation of blackfoot disease decreased dramatically after the implementation of tap water in these villages over the past 2-3 decades. The atherogenicity of arsenic could be associated with its effects on hypercoagulability, endothelial injury, smooth muscle cell proliferation, somatic mutation, oxidative stress, and apoptosis. However, its interaction with some trace elements and its association with hypertension and diabetes mellitus could also explain part of its higher risk of developing atherosclerosis.
Chronic endemic arsenism via drinking water was first found in Taiwan in 1968, and reported in Xinjiang Province in mainland China in the 1980s. Arsenism has become one of the most serious endemic diseases in China in the last two decades. Up to now, the disease has been found in Inner Mongolia, Shanxi, Ningxia, Jilin and Qinghai provinces. According to the Chinese maximum limit standard of arsenic (As) in drinking water, over 2 millions people have been exposed to high arsenic and about 10,000 persons were diagnosed as arsenism patients. There are different As concentrations in the water of different sites, even in the same area. Most of the As concentrations range from 0.05 to 2.0mg/l. The incidence of arsenism increases as As concentrations in drinking water and the drinking time increase. The age distribution of patients with arsenism ranged from 3 to 80 years old with peak prevalence in adults. A dose-effect relationship between the status of arsenism and arsenic level and drinking time has been shown. New high-arsenic areas in China have been discovered during recent investigations. In order to reduce the adverse health effects of arsenism, the central and local governments of China have provided significant funds to change water levels of As and at the same time take general measures to "reduce arsenic intake, remove arsenic from the body and treat the patients". After the implementation of these control measures in certain regions, the clinical symptoms and signs of 30% of the patients were improved. There was no change in 52% of patients and only 18% of patients got worse. It is suggested that future work in the research and control of arsenism in China should include: (1) identify all the high arsenic areas in China, (2) study the association of arsenism with fluorosis, (3) determine individual susceptibility, (4) select biomarkers for diagnosis in the early stage of a arsenism, and (5) investigate the molecular mechanisms of carcinogenesis.
Arsenicosis is a serious environmental chemical disease in China mainly caused by drinking water from pump wells contaminated by high levels of arsenic. Chronic exposure of humans to high concentrations of arsenic in drinking water is associated with skin lesions, peripheral vascular disease, hypertension, blackfoot disease, and high risk of cancers. Lead by the Ministry of Health of China, we carried out a research about arsenicosis in China recently. Areas contaminated with arsenic from drinking water are determined by 10% pump well water sample method while areas from burning coal are determined by existing data. Two epidemic areas of Shanxi Province and Inner Mongolia are investigated for the distribution of pump wells containing high arsenic. Well water in all the investigated villages of Shanxi Province showed polluted by high arsenic, and the average rate of unsafe pump well water is 52%. In Inner Mongolia, the high percentage of pump wells containing elevated arsenic is found only in a few villages. The average rate of unsafe pump well water is 11%. From our research, we find that new endemic areas are continuously emerging in China. Up to now, epidemic areas of arsenicosis mainly involve eight provinces and 37 counties in China. In the affected areas, the discovery of wells and coal with high levels of arsenic is continuing sporadically, and a similar scattered distribution pattern of patients is also being observed.
Chronic arsenic (As) poisoning has become a worldwide public health issue. Most human As exposure occurs from consumption of drinking water containing high amounts of inorganic As (iAs). In this paper, epidemiological studies conducted on the dose-response relationships between iAs exposure via the drinking water and related adverse health effects are reviewed. Before the review, the methods for evaluation of the individual As exposure are summarized and classified into two types, that is, the methods depending on As concentration of the drinking water and the methods depending on biological monitoring for As exposure; certain methods may be applied as optimum As exposure indexes to study dose-response relationship based on various As exposure situation. Chronic effects of iAs exposure via drinking water include skin lesions, neurological effects, hypertension, peripheral vascular disease, cardiovascular disease, respiratory disease, diabetes mellitus, and malignancies including skin cancer. The skin is quite sensitive to arsenic, and skin lesions are some of the most common and earliest nonmalignant effects related to chronic As exposure. The increase of prevalence in the skin lesions has been observed even at the exposure levels in the range of 0.005-0.01 mg/l As in drinking waters. Skin, lung, bladder, kidney, liver, and uterus are considered as sites As-induced malignancies, and the skin is though to be perhaps the most sensitive site. Prospective studies in large area of endemic As poisoning, like Bangladesh or China, where the rate of malignancies is expected to increase within the next several decades, will help to clarify the dose-response relationship between As exposure levels and adverse health effects with enhanced accuracy.
Long-term exposure to ingested inorganic arsenic is associated with peripheral vascular disease (PVD) in the blackfoot disease (BFD)-hyperendemic area in Taiwan. This study further examined the interaction between arsenic exposure and urinary arsenic speciation on the risk of PVD. A total of 479 (220 men and 259 women) adults residing in the BFD-hyperendemic area were studied. Doppler ultrasound was used to diagnose PVD. Arsenic exposure was estimated by an index of cumulative arsenic exposure (CAE). Urinary levels of total arsenic, inorganic arsenite (As(III)) and arsenate (As(V)), monomethylarsonic acid (MMA(V)), and dimethylarsinic acid (DMA(V)) were determined. Primary methylation index [PMI = MMA(V)/(As(III) + As(V))] and secondary methylation index (SMI = DMA(V)/MMA(V)) were calculated. The association between PVD and urinary arsenic parameters was evaluated with consideration of the interaction with CAE and the confounding effects of age, sex, body mass index, total cholesterol, triglycerides, cigarette smoking, and alcohol consumption. Results showed that aging was associated with a diminishing capacity to methylate inorganic arsenic and women possessed a more efficient arsenic methylation capacity than men did. PVD risk increased with a higher CAE and a lower capacity to methylate arsenic to DMA(V). The multivariate-adjusted odds ratios for CAE of 0, 0.1-15.4, and >15.4 mg/L x year were 1.00, 3.41 (0.74-15.78), and 4.62 (0.96-22.21), respectively (P < 0.05, trend test); and for PMI < or = 1.77 and SMI > 6.93, PMI > 1.77 and SMI > 6.93, PMI > 1.77 and SMI < or = 6.93, and PMI < or = 1.77 and SMI < or = 6.93 were 1.00, 2.93 (0.90-9.52), 2.85 (1.05-7.73), and 3.60 (1.12-11.56), respectively (P < 0.05, trend test). It was concluded that individuals with a higher arsenic exposure and a lower capacity to methylate inorganic arsenic to DMA(V) have a higher risk of developing PVD in the BFD-hyperendemic area in Taiwan.
Blackfoot disease (BFD) is an endemic peripheral vascular disease confined to the southwestern coast of Taiwan. This article reviews the epidemiology, clinical manifestations and diagnosis, pathology, etiology and pathogenesis of this disease. Sporadic cases of BFD occurred as early as in the early 20th century, and peak incidence was noted between 1956 and 1960, with prevalence rates ranging from 6.51 to 18.85 per 1,000 population in different villages. Typical clinical symptoms and signs of progressive arterial occlusion mainly found in the lower extremities, but in rare cases, the upper extremities might also be involved. Ulceration, gangrene and spontaneous or surgical amputation were typical fate. An extensive pathological study concluded that 30% of the BFD patients had histologic lesions compatible with thromboangiitis obliterans and 70% showed changes of arteriosclerosis obliterans. Epidemiologic studies carried out since mid-20th century revealed that BFD was associated with the consumption of inorganic arsenic from the artesian wells. Recent studies confirmed the existence of preclinical peripheral vascular disease, subclinical arterial insufficiency and defects in cutaneous microcirculation in the residents of the endemic villages. A more recent study suggested that the methylation capacity of arsenic can interact with arsenic exposure in the development of peripheral vascular disease among residents of BFD-endemic areas. The incidence of BFD decreased dramatically after the implementation of tap water in these villages over the past 2-3 decades. The atherogenicity of arsenic could be associated with its effects of hypercoagulability, endothelial injury, smooth muscle cell proliferation, somatic mutation, oxidative stress, and apoptosis. However, its interaction with some trace elements and its association with hypertension and diabetes mellitus could also explain part of its higher risk of developing atherosclerosis. Although humic substances have also been suggested as a possible cause of BFD, epidemiologic studies are required to confirm its etiologic role.
Exposure to arsenic through domestic burning arsenic-containing coal causes various tumors in a population of Guizhou, China. The glycophorin A (GPA) assay is a human mutation assay detecting somatic variation in erythrocytes expressing the MN blood type, and was used to assess genotoxicity of arsenic-exposed patients. Peripheral blood was collected from 18 adult healthy subjects and 40 arsenic-exposed patients in heparin-treated tubes. Erythrocytes were isolated, fixed in formalin and immuno-labeled with fluorescent antibodies against GPA, followed by flow cytometry analysis. Arsenic exposure increased the variant frequency (expressed as the number of variant red cells per 10(6) erythrocytes): NN, 3.7 in healthy subjects versus 21.2 in arsenic-exposed patients; N phi, 12.6 versus 33.1; MM, 13.1 versus 110; and M phi, 5.2 versus 20.3. The total GPA variant frequency was increased about five-fold (34.7 in healthy subjects versus 185 in arsenosis patients). Furthermore, the variant frequency was significantly higher in skin tumor-bearing patients: NN, 19.4 in arsenic-exposed non-tumor patients versus 31.5 in tumor-bearing patients; N phi, 29.5 versus 54.5; MM, 102 versus 159; M phi, 15.9 versus 45.1. Total GPA variant frequency in arsenic-exposed patients bearing skin tumors was significantly increased compared to patients without skin tumors (167 versus 290). The relationship between arsenic exposure history and GPA variant frequency was less evident. These data demonstrate that arsenic exposure is associated with mutations at the GPA locus, an effect exaggerated in patients bearing arsenic-induced skin tumors. The variant frequency of GPA could be a useful biomarker for arsenic exposure and arsenic carcinogenesis.
The most common health effects from drinking-water containing dissolved arsenic are skin abnormalities and lesions that are typically diagnosed as keratosis and pigment disorder. It was previously reported that the prevalence of cutaneous lesions was about 44% in arsenic-affected villages. However, there has been little research on the relationship between levels of arsenic in drinking-water and cutaneous lesions in Inner Mongolia. One study examined the association between the prevalence of keratosis and levels of arsenic exposure and the relationship between pigment disorder and levels of arsenic exposure among villagers aged 18 years or older in the arsenic-affected village of Hetao Plain in Inner Mongolia, PR China. The study included 227 participants who were affected by cutaneous lesions and 221 participants who were not affected by cutaneous lesions diagnosed in 1996 and 1998. Well-water drunk by the participants was collected to analyze arsenic content. Adjusting for age, sex, and smoking, logistic regression was applied to calculate the risks that arsenic in drinking-water will lead to cutaneous lesions. The results from the logistic regression showed that, with the increase of arsenic concentration in water, the risk of pigment disorder also increased (odds ratio [OR]=5.25, 95% confidence interval [CI] 1.32-83.24 for 50-199 microg/L; OR=10.97, 95% CI 1.50-79.95 for 200-499 [microg/L; OR=10.00, 95% CI 1.39-71.77 for > or = 500 microg/L (p=0.000), but the association between risk of keratosis and levels of arsenic was not significant (p=0.346). The findings suggest that keratosis is an early feature of arsenic poisoning, and the development of pigment disorder depends on higher doses of arsenic intake rather than keratosis. Further studies are needed to confirm that cutaneous lesions and other adverse health effects occur at low levels of arsenic exposure.
This study was directed to ascertain the mortality of a group of arseniasis patients in an endemic rural township in Southwest China, where the residents were exposed for decades to indoor combustion of high arsenic coal.
All the diagnosed arseniasis cases registered in 1991 were defined as the target population, which were assigned to three symptom subgroups by the severity of dermal lesions. The death cases were surveyed and checked. The follow-up period was 12.5 years. The standardized mortality ratio (SMR) of all death causes combined, all cancers combined, and the cancers at every site were analyzed. The age standardized mortality rates (ASMRs) were calculated in three subgroups using the procedure of standardization.
One hundred and six death cases were recorded. Liver cirrhosis, non-melanotic skin cancer, lung and liver cancer were the four most prevalent death causes and referred to 70.8% (75/106) of the total death cases. The mortality of all death causes combined was not higher than that of the whole of China in 2001 (SMR = 0.76, 95% CI 0.63-0.93). The crude mortality rate of non-melanotic skin cancer in males reached up to 128.66/10(5). SMRs of lung cancer and larynx cancer in males (SMRs 2.84 and 27.27, 95% CIs 1.51-4.86 and 5.61-79.62, respectively) significantly exceeded the levels for all male Chinese. ASMRs of all death causes combined, all cancers combined and non-melanotic skin cancer in males of the severe dermal symptoms subgroup were significantly higher than those in medium and/or mild dermal symptom subgroups.
A significantly increased mortality due to lung cancer and non-melanotic skin cancer was confirmed, alike the situation in other arseniasis endemic areas in the world. No significant elevation of mortality due to liver cancer and bladder cancer was observed. Male arseniasis patients diagnosed with severe skin lesions face higher risks of malignancies and of non-melanotic skin cancer in particular in the following years.