Keywords

1.1 Introduction

Arsenic is one of the most well-known poisons in human history and was easy applied to murder by poisoning because of its physical properties, including being tasteless and odorless. Arsenic has been suggested to have been involved in the deaths of major historical figures such as Alexander the Great and Napoleon I. Although arsenic has been feared as a poison, it also has a long history of being used as a medicine. However, chronic arsenic poisoning developed as an adverse reaction to its use of medicinal arsenicals.

Among the various health problems associated with the exposure to arsenic in the twentieth century, development of cancer in copper smelters workers and those engaged in manufacturing of arsenic trioxide attracted early attention [1,2,3]. However, since the 1980s, chronic arsenic poisoning due to consumption of potable water naturally contaminated with inorganic arsenic (iAs) was also widely found in Asia, shifting the focus to environmentally caused chronic arsenic poisoning. The number of individuals excessively exposed to arsenic in Asia is speculated to be in the tens of millions. Serious health issues due to iAs exposure in Bangladesh, western India, and China have been detected, including skin cancer in some cases [4]. Furthermore, environmentally induced chronic arsenic poisoning occurred in Chile and Argentina as early as several decades before its occurrence in Asia. Indeed, an increasing number of lung and bladder cancer cases was already been confirmed in Argentina [5,6,7,8] and Chile [9,10,11] in association with arsenic exposure. The International Agency for Research on Cancer (IARC) has confirmed a causal relationship between the exposure to iAs and skin, lung, bladder, and liver cancers, for which the time of high-level iAs exposure was about 30 years [12]. In general, the total exposure time required from first exposure to tumor formation for human tumors associated with chemical insults is speculated to be approximately 30 years [12]. Given that 20–30 years on average have elapsed since the first exposures to high-level iAs in Asia, apart from in Taiwan, we consider it important to actively enhance the clinical diagnosis of cancer at sites typically associated with arsenic exposure in this geographic area as well as to conduct advanced studies using molecular biologic techniques to characterize the cancers as they are detected.

We expect that this book, titled Arsenic Contamination in Asia: Biological Effects and Preventive Measures, will aid in shedding light on the causes, consequences, and possible responses to this environmentally based chronic arsenic intoxication in Asia. We also hope the contents will help to stimulate important ideas for new study concepts and designs and define critical public health responses and possible administrative actions for this issue. We believe that, without exception, previous case studies on arsenic poisoning are helpful as references when clarifying current issues as well as issues that may arise in the future.

This chapter provides an outline of prior human arsenic poisoning cases arising from oral exposure. These cases are outlined here for the purpose of providing a historical perspective and to help in resolving current and future issues that will arise regarding arsenic poisoning.

1.2 Specific Historical Cases of Arsenic Poisoning

1.2.1 Arsenical Medicines

Arsenic compounds have a very long history of medicinal use worldwide. In Europe by the late 1700s, a major early medicinal arsenical had been introduced, namely, Fowler’s solution, which was a solution of potassium arsenite and was in frequent use (Fig. 1.1) for the treatment of cancer, infections, epilepsy, asthma, and skin diseases such as psoriasis and eczema. Generally, this solution was orally used by diluting it in water, and the oral arsenic intake is estimated to be approximately 9 mg/day in average pharmacological use [13, 14]. Coincidentally, this arsenic intake is similar to the daily dose of arsenic trioxide (10 mg/day) [15], which is a currently used, medically accepted medicinal arsenical drug which has proven highly efficacious in the treatment of acute myelocytic leukemia. An interesting point in the medical use of Fowler’s solution was that the daily consumed volume (and thus arsenic dose) was typically increased until the disease was completely cured. However, the medication would be stopped, at least temporarily, when eyelid swelling and/or severe gastrointestinal peristalsis occurred, which were considered to be limiting adverse reactions. Once these adverse reactions resolved, or at least diminished, therapy would again commence with a repeat of the same course of doses as from the onset of treatment. The long-term ingestion of Fowler’s solution was found to be associated with pigmentary degeneration of the trunk and palm and with footpad keratosis and squamous cell carcinoma on the hands and feet [13, 14]. Interestingly, these findings are strikingly similar to lesions seen in patients with chronic arsenic poisoning in Asia. Fowler’s solution was also used as a tonic, but demand for it gradually waned, and its use disappeared by the middle of the twentieth century.

Fig. 1.1
figure 1

Timing and historical causes of arsenic poisonings

Full size image

1.2.2 Beer Contaminated by Arsenic

In 1901, Reynolds reported over 500 patients with chronic arsenic poisoning due to oral exposure [16]. This arsenic poisoning developed in residents of the central and northern parts of the United Kingdom in 1900 (Fig. 1.1) and was caused by beer contaminated with arsenic (likely arsenic trioxide), which the patients unknowingly consumed for several months. A notable achievement by Reynolds is that he differentially diagnosed the symptoms of alcoholism from those of arsenic poisoning. The symptoms of arsenic poisoning observed in the patients were initially gastrointestinal, followed by catarrhal (mucosal inflammation), peripheral nervous system, and cutaneous symptoms, in that order. Reynolds reported that the cutaneous symptoms included raindrop pigmentation changes and subsequent palm and footpad keratosis. These clinical findings are similar to those of arsenic poisoning due to consumption of Fowler’s solution that was in common used in Europe and the United States from the eighteenth to mid-twentieth century. Thus, it is fascinating that the criterion for the diagnosis of arsenic poisoning was established over 100 years ago in the United Kingdom.

1.2.3 Dry Milk Contaminated with Arsenic

The Morinaga Milk arsenic poisoning incident that occurred in Japan in the 1950s could be the worst incident of poisoning from a food contaminated by arsenic in human history. However, this incident may not yet be correctly understood internationally because the situation and details of how the incident occurred have not been presented in English in the form of a report or a scientific research article.

In the Morinaga Milk arsenic poisoning incident in 1955, individuals from several cities in the western part of Japan, including Kyoto, Osaka, and Okayama, were affected (Fig. 1.1). The cause of the arsenic poisoning was the contamination of dry milk powder used for infants with iAs. Over 12,000 infants who ingested the iAs contaminated powdered milk after formulation developed subacute arsenic poisoning, and of these 130 died [17, 18]. The powdered milk contaminated with iAs was ingested on average for 3 months, and the estimated daily iAs intake per infant was 1.3–3.6 mg, which leads to an average total consumption of 90–140 mg of iAs. The primary initial symptoms presented as fever, vomiting, diarrhea, a sense of abdominal distension, hepatomegaly, cough, nasal discharge, conjunctivitis, and melanoderma. However, neurological manifestations likely would not have been easily identified because the patients were infants. Laboratory findings included anemia, decreased granulocyte count, electrocardiographic abnormalities, and a radiographic band-like shadow of the epiphysis of long bones. A foundation was formed for the long-term support and clinical care of these patients. Results of a survey of patients in the 15th year after the poisoning event identified delayed growth, intellectual disability, central nervous system disorders such as epilepsy, hearing loss, and skin disorders such as melanoderma and keratosis [19, 20]. A survey in the 50th year post-poisoning indicated increased incidence of cancer and dementia. Moreover, it was revealed that the survivors of the arsenic poisoning in their infancy had a significantly higher risk of death from a neurological disease than the general population [21, 22]. We consider that the results of these follow-up surveys of the survivors of the subacute arsenic poisoning in infancy are a warning of the risks of human exposure to iAs in early life and would likely include exposures to infants and fetuses (i.e., in utero) via pregnant women. That this early life “pulse” exposure to arsenic in humans can have such dire consequences, like cancer, dementia, and epilepsy, decades later in life indicates arsenic may have a special negative affinity for developing systems, including the developing nervous system.

1.3 Chronic Arsenic Poisoning Arising from the Exposure to iAs in Potable Water

Large-scale chronic arsenic poisoning arising from the long-term ingestion of potable water naturally contaminated by iAs seems to have been detected first in areas of Argentina, followed by sites in Taiwan, Chile, and other Asian countries.

1.3.1 Chronic Arsenic Poisoning in Argentina and Chile

Interestingly, it has been reported that arsenic contamination of drinking water in Argentina and Chile is linked to cancer risk, among other adverse health effects (Fig. 1.1).

In Argentina, the contamination of well water by iAs from the environment was reported in Cordoba Province since the 1910s, and patients with chronic arsenic poisoning from this area have been identified, although sporadically. In this vast country, because underground water is the only water source, the use of wells is common. The average arsenic (inorganic arsenic) concentration in groundwater of Cordoba Province is reported to have been 178 μg/L. When the standardized mortality ratio was compared between all of Argentina and just Cordoba Province on the basis of studies conducted mainly by the US researchers since the 1990s, significant increases in cancers of the lung and bladder, among other sites, were observed associated with the exposure to arsenic, though there was association observed for skin or liver cancers [5,6,7,8].

A well-known case of mass chronic arsenic poisoning occurred in Antofagasta in Chile, which is the world’s leading country for copper mining. In 1958, the source of tap water supplied to the residents of this city (with a population of approximately 300,000) was contaminated by mine drainage containing iAs. Because of the lack of an alternative water source due to the severe geographic conditions, this exposure to iAs continued until 1970 when water cleaning equipment was developed. In the 1970s, Chilean researchers reported the actual conditions of this chronic arsenic poisoning, in which the number of affected individuals was roughly estimated to be over 200,000. Subsequent studies, mainly by US researchers since the 1990s, revealed several relationships between exposure to iAs and causes of death. The cessation of iAs exposure significantly reduced mortality due to acute myocardial infarction. However, mortality due to lung and bladder cancers increased even after cessation of exposure. This indicates that the risk of cancer in individuals who have been exposed to chronically iAs is unlikely to decrease after cessation of exposure, at least at key sites [9,10,11].

1.3.2 Chronic Arsenic Poisoning in Asia

In the 1950s, chronic arsenic poisoning from iAs contamination in well water was discovered in the residents of southwest Taiwan (Fig. 1.1) [23, 24]. Some of these residents showed group of symptoms that formed a skin disorder in which the tips of the toes and fingers underwent a necrosis involving the microvasculature, leading to the diagnosis of would be called Blackfoot disease. However, Blackfoot disease has not been found in regions outside of Taiwan where chronic arsenic poisoning is endemic. Thus, Blackfoot disease has been suggested to be a pathological condition that is specific to Taiwan potentially because of how iAs interacts specifically with this local population or the possibility based in an interaction between iAs and local exposure to an ergot alkaloid [25, 26]. Its actual basis has never been definitively clarified. However, research in Taiwan has revealed a dose-response relationship between arsenic intake from well water and skin and bladder cancer. Because chronic arsenic poisoning by drinking water in this region was identified earlier than in other regions, it provided important foundational information for subsequent studies.

In the late 1970s, as the population increased in Asia, a switch in the use of surface water to groundwater was recommended as a measure to help prevent surface waterborne infections, and various international organizations supported the placement of pump-type wells on a wide scale to ensure the extensive availability of a clean water supply to local residents. However, a lack of a sufficient safety assessment of contaminants in well water, specifically iAs, subsequently led to the development of health issues. Thus, we must stress the importance of environmental risk assessments for researchers and administrators in the fields of environment science, public health, community medicine, and preventive medicine.

Hundreds of thousands of patients with chronic arsenic poisoning have been identified in Bangladesh [27, 28], western India [29, 30], China [31,32,33,34,35], and Nepal [36, 37] (Fig. 1.1). Moreover, although not showing signs of overt chronic arsenic poisoning, many more individuals from various countries have been identified that consume water contaminated by iAs at a level much higher than the WHO’s drinking water quality standard (10 μg/L), including Vietnam [38], Myanmar [39], and Cambodia [40], among others. However, the precise mechanism behind the contamination by iAs of groundwater that is tapped by wells remains unknown.

We propose a potential mechanism by which the iAs became available to intensively expose those in Bangladesh, western India, China, and Nepal that used groundwater for drinking. Accordingly, the actual source of iAs contamination in these regions, apart from China, was originally the presence of trace amounts of arsenic in the Himalayan mountains. Briefly, arsenic that seeped from the rocks in the Himalayas entered large rivers and then settled as sediments in the watersheds and estuaries of these rivers, which resulted in the exposure to iAs of individuals who sank wells into the sedimentary rock in search of underground water. On the other hand, in China, some of the underground water flowing through the rocks in the mountains where The Great Wall of China was constructed is contaminated by arsenic (Fig. 1.2). It is speculated that chronic arsenic poisoning developed there in individuals who consumed this contaminated well water. In any event, in the countries in which iAs contamination has been identified, various administrative procedures have been implemented to ensure compliance with the WHO’s drinking water quality standards. However, although wells with extremely high iAs contamination can be easily closed, the rapid population growth and heavy demand for inexpensive tap water in these developing countries make close all suspect wells an economically and technically difficult issue, and this severely hampers the complete avoidance of the use of well water contaminated with arsenic.

Fig. 1.2
figure 2

The potential mechanisms behind the contamination of underground water by iAs in Inner Mongolia and Shanxi Province in China. Chronic arsenic poisoning occurred in people who used groundwater contaminated with iAs. For groundwater, iAs-contaminated and nonpolluted waters are clearly distinguished and have complicated distribution. The average of iAs concentration in 303 well waters in Baotou City, Inner Mongolia was 133 ± 199 μg/L

Full size image

In the Araihazar District of Bangladesh [41, 42], the Health Effects of Arsenic Longitudinal Study (HEALS) has been promoted by the Columbia University. This study was implemented as a prospective cohort study including patients with chronic arsenic poisoning and those with a high risk of exposure to iAs. To date this study has been providing a variety of interesting findings and will no doubt continue to in the future.

This book introduces diverse information regarding the clinical findings and biological impact of chronic arsenic poisoning in its several chapters, mainly on the basis of the findings of the studies conducted in Bangladesh and China.

1.4 Summary

Arsenic poisoning has arisen from the oral ingestion of arsenic when used as a medicine and when found as a contaminant in food or potable water, among other sources. In the majority of cases, these poisonings are due to inorganic arsenicals. Findings that associate chronic oral iAs poisoning predominantly with skin lesions, including cancers, were originally made over 100 years ago and remain valid today. Considering that studies conducted in Argentina [5,6,7,8] and Chile [9,10,11] have now also identified that lung and bladder cancers are also associated with the long-term oral exposure to iAs, it is necessary to conduct screening tests for these cancers, in addition to skin cancer, in any future populations that arise.

In the recent years, the issues of how exposure to iAs in utero or in early life adversely impacts that generation as it matures have become apparent, and exposure during these key times in development can cause debilitating brain dysfunction as seen in studies of chronic arsenic poisoning in Asia [43,44,45,46]. Indeed, growth inhibition and severe central nervous system disorders were clearly identified as the aftereffects of infant subacute arsenic poisoning in infants in Japan [19,20,21,22]. This makes it apparent that the developing brain is highly sensitive to arsenic. Health issues arising from iAs exposure in Asia are an issue for which early resolution should not be expected. Moreover, in the regions contaminated by iAs, which include densely populated Asian countries, pregnant women and infants are readily exposed to iAs. Imagination and innovation are required to determine how the brain function of these most vulnerable humans can be preserved from the exposure to perhaps even low-level arsenic. Currently, the costs of social welfare and medical care for affected individuals are enormous when compared with the past and represent an increased burden on individuals, society, public health administrations, and governments.

In future studies on arsenic, the establishment of ways to prevent the health impact linked to arsenic exposure will likely be a critically important subject. To resolve such issues, there is an urgent need to develop environmental awareness but also remediation and purification technologies via collaboration across diverse fields like medicine, environment sciences, pharmacology, nutritional science, and engineering. Further, there is a need to elucidate the relationship between the exposure to arsenic and the host defense systems and their genetics as well as to develop drugs which help prevent, or at least mitigate, the chronic toxic manifestations of arsenic exposure. To this end, much more need to be elucidated with regard to molecular mechanisms of arsenic-induced diseases within specific target tissues or sites.