Chronic arsenic exposure and its adverse health effects in Taiwan: A paradigm for management of a global environmental problem

Abstract

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.

Introduction

Arsenic (As) is among the most toxic metals (metalloids) derived from the earth's crust [1]. Although organic As is non‐toxic, inorganic As is ubiquitously found in the environment and has been classified as a Class I carcinogen according to the International Agency for Research on Cancer [1]. Arsenic occurs in two oxidative forms including the trivalent arsenite (As^III) and the pentavalent arsenate (As^V) states, with arsenite being much more toxic than the arsenate [2]. As early as 1879, inorganic As was proposed to be responsible for causing the high rates of lung cancer among the German miners by means of inhalation route [3]. Subsequently, studies from different parts of the world found associations between As exposure and internal cancers by means of inhalation or ingestion [[3], [4], [5], [6], [7]].

Of the various sources of As in the environment, drinking water probably poses the greatest threat to human health [8]. Drinking water is derived from a variety of sources including surface water (rivers, lakes, reservoirs, and ponds), rain water, and groundwater. Alongside the obvious point sources of As contamination, high concentrations are mainly found in groundwater. Consequently, human beings who rely on groundwater supplies were at risk for inadvertent As exposure. In fact, groundwater obtained from Bangladesh, India (West Bengal), China (Inner Mongolia), parts of the United States (California, Nevada, Alaska, and Utah), smaller areas of Argentina, Australia, Chile, Mexico, Viet Nam, and Taiwan (mostly Southwest coast) has been shown to contain high levels of As (Fig. 1) [9]. It was estimated that nearly to 100 million people are at risk of drinking As‐contaminated drinking water [[10], [11]]. Although the WHO guideline recommends that levels of As in drinking water should not exceed 10 μg/L, it was estimated that more than 30 million people drink As‐containing water at levels more than 50 μg/L in Bangladesh and India alone [1]. Therefore, the adverse health effects resulting from chronic As exposure pose a global threat. This review focused on the lessons learned from the studies done on chronic As exposure in Taiwan.

Figure 1.

The worldwide distribution of arsenic (As) exposure from drinking water. As much as 100 million people may be exposed to As‐containing drinking water. 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 (in red circle). Taiwan has more than 50 years of research experiences on adverse health effects resulting from chronic As exposure. (Modified from Garelick and Jones [9]). For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.

As exposure by means of groundwater in Taiwan

The native residents in certain areas located at the southwest coast of Taiwan have been using artesian well water containing high concentrations of As since the early 1900s [12]. In these endemic areas, the high As‐containing water was not only used for drinking, but also for washing and agricultural/fishery purpose. Therefore, the agricultural and fishery products from these areas have also been reported to contain high levels of As [13]. Furthermore, the soil samples obtained from these areas also contained elevated As levels. Therefore, it was estimated that during the 1950s, the daily As ingestion by the residents living in these endemic areas might be as high as 1 mg [14]. Series of epidemiologic studies have been performed to document the adverse health effects inflicted by chronic As exposure on these inhabitants.

Adverse health effects related to chronic As exposure

One of the adverse conditions related to chronic As exposure bared on earlier reports in Taiwan is the infamous blackfoot disease. Because blackfoot disease is unique to the As endemic areas in Taiwan, the contribution of As in the pathogenetic process of this disease remains to be determined. Patients with this blackfoot experienced symptoms starting with numbness or coldness of the extremities that progressed to intermittent claudication and ultimately resulted in black discoloration, ulceration, and gangrene [15]. The pathomechanisms resulting in blackfoot disease are not clear, but high concentrations of As and/or humic substances ingestion in addition to individual susceptibility to produce anti‐endothelial cell antibody are believed to play important roles [16]. Subsequently, the population of the blackfoot disease endemic area were shown to have significantly elevated incidences of skin cancers (1.06 of 1,000) and the age–sex adjusted odds ratios of developing bladder, lung, and liver cancers for those who had used artesian well water for 40 or more years were 3.90, 3.39, 2.67, respectively, as compared with those who had never drank from the artesian well [[5], [17]]. Additional studies revealed that the years of artesian well water used and the well water As levels had dose‐response relationships with the occurrences of internal cancers. More specifically, it was shown that the age‐adjusted mortality per 100,000 person‐years for every 0.1 ppm increase in As level of well water was 6.8 and 2.0, 5.3 and 5.3, 0.9 and 1.0, 3.9 and 4.2, and 1.1 and 1.7, respectively, in males and females for cancers of the liver, lung, skin, bladder and kidney [[18], [19]]. These results corroborated with studies from different parts of the world including certain areas in Argentina, India, and Japan, where high As levels in drinking water were associated with increased bladder and lung cancers [[20], [21], [22]]. Other than the increased cancer risks, residents of As endemic areas also demonstrated elevated prevalence of non‐cancer risks. Theoretically, As can cause increased lipid peroxidation, which is related to the development of many chronic diseases [23]. In fact, it was found that the residents of the As endemic areas showed greater mortality rates in terms of diabetes mellitus, ischemic heart disease, bronchitis, liver cirrhosis, nephropathy, and cerebrovascular diseases [24]. Therefore, it is likely that the chronic exposure to high levels of As has a global adverse effect on human health. At present, no specific preventive treatment is available for the population who had already been exposed to drinking water containing high levels of As. In Taiwan, the government had recognized the problem with drinking water obtained from the artesian well in the blackfoot endemic areas and started to replace ground water with tap‐water supply since the mid 1950s. This water source replacement program has significantly decreased the mortality incidence of As‐related cancers reported from blackfoot endemic communities [25].

Detection of individual As exposure

To clarify the mechanisms involved in As‐related adverse health effects, it is important to evaluate the dose‐response relationship between As exposure and the occurrences of associated illness at individual levels. Most of the earlier studies investigating this issue used ecological correlations on the associations between As exposure and adverse health effects at township or village levels, which provided insightful results for epidemiologic purposes [[19], [26]]. The individual susceptibility to different concentrations of As, however, remains unclear with this simple and convenient approach. In other words, it is not possible to accurately identify which individual among the high As‐exposed group will develop certain adverse health conditions. Therefore, to establish an unequivocal dose‐response relationship for every individual exposed to chronic As ingestion, it is important to trace the As exposure at personal levels. To accomplish this task, understanding of As metabolism in human body is crucial. Accordingly, after entering the human body, inorganic As was distributed mostly to liver, kidneys, spleen, lungs, intestines, and skin [[27], [28], [29]]. Subsequently, As^V is reduced to As^III and methylated to monomethylarsonous acid and dimethylarsinic acid, which are less toxic as compared with inorganic As. Therefore, methylation of inorganic As in liver is considered an important detoxication process for the human body. Other factors that play an important role in As methylation capacity include dose, routes and forms of As exposure, life style, and genetic polymorphism [30]. The metabolic pathway of As in human body is shown in Fig. 2. The most common method for documentation of individual As exposure is through urine sample analysis. However, as the urinary levels of inorganic As metabolites reflected only the recent exposure, it is difficult to assess how cumulative As levels in the human body contribute to the occurrences of adverse health effects associated with previous As exposure. Other samples used for estimation of As exposure include toenails, hair, and blood, but none of these markers evaluate As methylation. Furthermore, the water source replacement by the authorities to prevent further public health hazards induced by As‐containing drinking water also made mechanistic retrospective studies difficult if the assay for documenting cumulative As exposure remains elusive.

Figure 2.

The metabolic pathway of arsenic in human body. It should be noted that the samples used for estimation of arsenic exposure include urine, nails, hair, and blood. At present, only relatively recent exposures can be documented. As^III: trivalent arsenite, As^V = pentavalent arsenate, DMA = dimethylarsinic acid, MMA = methylated to monomethylarsonous acid.

Evaluation of individual susceptibility

As mentioned previously, the ground water from different parts of the world has been documented to contain high levels of As. Nevertheless, studies on the population from different parts of the world exposed to drinking water with comparable As levels showed varying individual susceptibilities to As‐related adverse health effects. Studies have been shown that life style factors, including smoking habits and nutritional status, also contributed to the occurrences of As‐related adverse health events [[31], [32]]. Furthermore, among the population exposed to high As levels, only a minor percentage developed hallmark skin lesions associated with chronic As ingestion. It has been observed that the impact of high As exposure on human health varies remarkably between individuals exposed to similar levels of As [[33], [34], [35], [36], [37]]. Therefore, the genomic variation among the exposed population may provide a reasonable explanation accounting for the differential susceptibility between individuals. In fact, many studies from different parts of the world (including Taiwan) have focused on associations between human As toxicity and genetic polymorphisms in terms of cellular detoxification enzymes, tumor suppressor proteins, and DNA repair pathway but failed to provide a consensus data [37]. It was proposed that population differences (ethnic background) must be considered and larger sample sizes must be recruited to generate a viable hypothesis concerning chronic As toxicity through the toxicogenomic approach just described.

On the horizon

In Taiwan, the studies focusing on health effect resulting from chronic As exposure have been ongoing for more than half a century. Our experiences on As‐related health problems can serve as a paradigm for managing this emerging global threat now occurring at earlier stages in different parts of the world. For instance, it was revealed that the pre‐cancerous skin lesions started to develop within 10 years, invasive skin cancer after 20–30 years, and pulmonary cancer after 30 years after suspect As exposure [7]. Therefore, As‐induced skin lesions may be considered as a long‐term biomarker of As exposure [38]. Furthermore, because of the adverse health effects associated with chronic As exposure occurred in a sequential manner, from pre‐cancerous lesions to malignant neoplasms, proper preventive measures should be implanted when the “warning signals” (i.e. characteristic As‐related skin lesions) start to appear. The experiences gained in Taiwan indicated that water source replacement can successfully lead to reducing the mortality associated chronic As exposure [25]. However, there are still many important and unanswered questions. Because the pathomechanisms for different As‐associated adverse health effects remained unclear, effective and validated chemopreventive strategies have yet to evolve. This situation is frequently encountered in the environmental medicine and health research where the exposure, individual susceptibility, disease outcome, exposure assessment, and disease management intertwine in a complicated and sophisticated manner (Fig. 3). With the advent of OMIC technologies, new breakthroughs may be on the horizon. The OMICS field ranges from genomics to proteomics and metabolomics. These validated technologies will allow for functional evaluation of the phenotype (proteomics and metabolomics) in addition to more conventional genetic variants. The present aim is to integrate these new technologies into our studies focusing on health effects resulting from chronic As exposure in Taiwan. Moreover, since previous experiences through toxicogenomic approach have already emphasized the importance of large sample size and standardized methods for evaluation and documentation regarding the levels of As exposure, a large‐scale international collaborative work is required to gain path‐breaking insights on adverse effects of As on human health. Although some may argue that the water source replacement is the panacea for chronic As exposure from drinking water, more than 50 years of research experiences on As in Taiwan may serve as a paradigm to elucidate other important environmental health issues around the globe.

Figure 3.

The intertwined interactions of chronic arsenic exposure, individual susceptibility, disease outcome, exposure assessment, and disease management exemplified the complicated situation frequently encountered in environmental medicine and health research. Interactions between environmental exposure and the individual susceptibility represent the core of the environment‐related health issue. To understand the pathogenesis of disease outcome resulting from the core, it is important to accurately assess and document the levels of environmental exposure. Clarification of the pathomechanisms involved in disease evolution will lead to better strategies for managing the complex problems involved in environmental health issues.