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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 arsenobetaine, as well as arsenic chemical weapons such as lewisite, diphenylchloroarsin, and diphenylcyanoarsine.
Department of Preventive Medicine, St. Marianna University School of Medicine, Kawasaki, Japan
Takahiko Yoshida
Department of Social Medicine, Asahikawa Medical University, Asahikawa, Japan
Ayako Takata
Department of Preventive Medicine, St. Marianna University School of Medicine, Kawasaki, Japan
*Address all correspondence to: hyama@marianna-u.ac.jp
1. Introduction
As a result of naturally occurring inorganic arsenic (iAs) leached into aquifers and polluted drinking water, large-scale chronic arsenic poisoning in various areas of the worldwide occurred and has not ended even today. As the source of iAs contamination cannot be fundamentally removed, chronic arsenic poisoning is difficult to eradicate. The adverse health effects of arsenic exposures observed on the general population from the fetus through maternal placenta to the elderly comprise lifestyle disorders and cognitive dysfunctions in addition to the conventional poisoning symptoms such as skin lesions and malignancy. The health effects of iAs exposure are expected to be strongly associated with a reduction in arsenic methylation capacity (AMC) [1, 2]. In general, various confounding factors can affect the AMC results obtained from urinary samples. Valid supportive information on this issue is based on the occurrence of acute arsenic poisoning in 61 patients [3]; however, it virtually included no confounding effect and was able to serve as a reference value in the AMC evaluation in chronic arsenic poisoning. The results of a survey of 6223 survivors at the time of 65 years of follow-up among the 12,131 subjects exposed to arsenic sub-acutely in infancy [4] provide important data in predicting effects on the future health outcomes of chronic arsenic exposure, especially on carcinogenesis and the cognitive impairment resulting from the damage to the brain and central nervous system.
Conventionally, the complications of arsenic exposure are attributed only to iAs. The seafood for daily consumption contains arsenolipids (AsLipids) with an estimated stronger toxicity than iAs [5, 6]. Accordingly, the European Food Safety Agency (EFSA) is preparing a legal regulation focusing on AsLipids ingested via seafood [7]. On the other hand, arsenic chemical weapons, largely produced during World War II, have been causing environmental contamination due to abandoned phenylarsenic chemical warfare agents in the Baltic Sea [8, 9, 10], Germany [11], China [12, 13, 14], and Japan [15]. The degradation product of phenylarsenic chemical warfare agents is diphenylarsinic acid (DPAA). In Japan, poisoning by DPAA has been confirmed in 157 patients [15]. The target organ of this DPAA is the brain, where it can infiltrate the blood-brain barrier (BBB) and cause cerebral central nervous system damage.
This review aims to outline the differences in health effects of acute, subacute, and chronic arsenic poisoning based on the results of the AMC. In addition, it presents the adverse effects of AsLipids and phenylarsenic chemical warfare agents, which are likely to be more toxic than iAs.
2. Factors affecting the occurrence and the symptoms of acute arsenic poisoning
2.1 Crystallized and dissolved arsenic trioxide (ATO)
Arsenic compounds have long been used in many countries for intentional suicide and homicide. The background of their utilization is related to their physical properties of being tasteless, odorless, and non-irritating. Powdered arsenic trioxide (ATO) has been used in many cases of suicide (Table 1) [16, 17, 18, 19, 20] and by some medical personnel with access to ATO [17]. Factors such as the arsenic dose ingested, the form of ATO (crystals or solution), and time to life-saving treatment play a key role in the development of acute arsenic poisoning. It should be noted that in case reports of acute arsenic poisoning, most references to ATO intake are in terms of the swallowed weight (g) rather than the actual amount absorbed into the body. ATO crystals do not rapidly dissolve in water, predicting their gradual dissolution in the gastrointestinal tract; this slow dissolution rate provides an opportunity for emergency treatment, such as washing the stomach and the intestines, and adsorption and removing ATO with activated carbon. As ATO is a metalloid with metallic properties, an abdominal X-ray of the patient should show a white shadow on the wall of the gastrointestinal tract [16, 19, 20], indicating the ingestion status. A critically ill patient who ingested a large amount of ATO (54 g) was successfully saved by surgically removing the ATO through an incision in the stomach [19]. In other words, in acute arsenic poisoning caused by crystalline ATO, the removal of ATO residues from the gastrointestinal tract has been shown to be extremely important for the patient’s survival.
An acute arsenic poisoning of 61 people, including children (n = 22) and adults (n = 39), in Wakayama, Japan, was caused by the intentional addition of industrial ATO to hot curry soup. Later investigations revealed that most of the ATO was dissolved (with small amounts of crystals) in the residual heat of the curry soup. The estimated arsenic intake amount (body absorption) was calculated using the arsenic in the patient’s urine. The arsenic doses in children and adults were 67.4 ± 29.5 mg and 78.3 ± 38.7 mg, respectively. Information on the lethal dose in humans is scarce; however, it is nearly 300 mg [21]. Four people (aged 10, 16, 53, and 64 years) died by approximately 12 h after ingesting ATO. Dissolved ATO is presumed to be absorbed faster and at a higher rate in the gastrointestinal tract than crystallized ATO. Adults with severe symptoms have taken 100–200 mg of ATO. In contrast, even when the ingested arsenic dose exceeded 100 mg, the children had mild symptoms and were discharged from the hospital after about 1 week. The differences in symptoms between children and adults are discussed in later chapters (see 2.3).
In all patients, the ingestion of dissolved ATO caused severe nausea and vomiting within approximately 5 min [3]. Gastrointestinal symptoms were observed even at the minimum body arsenic dose of 22 mg (1-year-old infant). Afterward, watery diarrhea developed in approximately 30% of the patients. Laboratory values showed an initial increase in white blood cell count, followed by a rapid decrease to reach a minimum on days 3–6. The liver dysfunction (abnormal increase of GOT and GPT) peaked at about 1 week and then slowly recovered. The prolongation of the Q–T interval was characteristic of the electrocardiogram and was also observed in children. In adults with severe disease, erythematous macule, without pain or itching, was found as skin lesions on the abdomen, armpits, and neck [22]. In addition, peripheral neuropathy (paresthesia and motor paralysis) was observed [23]. Patients showed white shadows on the wall of their gastrointestinal tract on the abdominal X-ray, consistent with the observations on the reported victims who ingested crystalline ATO [16, 19, 20]. Therefore, the symptoms of acute arsenic poisoning by dissolved ATO tend to develop quickly and severely ill, especially in adults.
2.2 Effects of chelating agent treatment
British Anti-Lewisite (BAL), initially developed against the arsenic chemical weapon-lewisite, was subsequently used to treat acute iAs poisoning. However, BAL has disadvantages, such as severe pain with muscle injection. The use of chelating agents in acute arsenic poisoning is to promote urinary excretion by binding iAsIII to SH groups. To achieve a high rate of this pharmacological reaction, iAsIII should be not oxidized or methylated to monomethylarsonic acid (MMA) or dimethylarsinic acid (DMA), and the chelating agent must be used as soon as possible after ATO ingestion. This mechanism of action is common to BAL, 2,3-dimercapto-1-propanesulfonic acid (DMPA) and 2, 3-dimercaptosuccinic acid (DMSA) [24, 25]. DMPA tends to be used orally or intramuscularly, depending on the patient’s symptoms [20].
On the other hand, DMPA or DMSA as a treatment for chronic arsenic poisoning due to iAs exposure has been tested in India and Bangladesh without efficacy [24, 25]. However, studies are still ongoing for the development of an effective therapeutic drug for chronic arsenic poisoning.
2.3 Differences in symptoms between children and adults: evaluation by AMC
Epidemiological studies of chronic arsenic poisoning have been attempted to elucidate the relationship between health effects and AMC. In summary, the studies suggested that any decrease in the metabolic efficiency of methylation to iAs can lead to health deterioration. The indicators of an AMC decrease are an increase in %MMA and a decrease in the second methylation ratio (DMA/MMA) or the secondary methylation index (SMI; DMA/MMA + DMA). Recent reports indicate a trend toward higher rates of AMC in children compared to adults [26, 27, 28]. Chronic arsenic poisoning occurs more often in economically developing countries, and the situation of poisoning has been related to the environment, diet, and hygienic conditions in which the subjects live. There are various confounding factors in the urinary arsenic results obtained from subjects, especially the influence of nutrients [29, 30].
To our knowledge, there are no studies evaluating AMC in patients with acute arsenic poisoning, including ATO. The 61 patients with acute arsenic poisoning cases presented in this review did not have the opportunity for emergency treatment with chelating agents [3]. Therefore, their urinary arsenic results reflected only the observed results without confounding factors such as nutrients and arsenic species in the diet, which are usually noted in epidemiological studies of chronic arsenic poisoning. Although the estimated arsenic intake amount of ATO was similar among the patients (see section 2.1), the symptoms were milder in children and, conversely, more significant in adults [3]. The characteristics of AMC in children and adults are shown in Figure 1. Children had lower %MMA and higher second methylation ratio or SMI. In adults with severe symptoms, we observed a significant trend toward increased %MMA and decreased second methylation ratio or SMI. In acute and chronic arsenic poisoning [27], the data available to elucidate the cause of high AMC in younger children are limited. The mechanism that is currently receiving the most attention is its association with one-carbon metabolism (OCM). OCM is a biochemical pathway that provides methyl donor group S-adenosylmethionine (SAM) to methylate arsenic. It has been estimated that OCM is activated in younger children and degrades with age; there are several interesting reviews that have evaluated the link between OCM and arsenic methylation [1, 29, 31].
Figure 1.
Characteristics of arsenic methylation capacity (AMC) in children and adults with acute arsenic poisoning. Children are under 16 years old and adults are over 16 years old. Monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), S-adenosylmethionine (SAM), reduced glutathione (GSH). First methylation ratio (MMA/inorganic arsenic (iAs)), second methylation ratio (DMA/MMA). Methylation efficiency was assessed by determining the relative amounts of total arsenic in urinary (%iAs, %MMA, and %DMA).
AMC findings from children and adults with acute arsenic poisoning may serve as a valid guideline for evaluating AMC in patients with chronic arsenic poisoning and those exposed to high concentrations of iAs.
3. After-effects of subacute arsenic poisoning in infants after 55–65 years
Subacute arsenic poisoning occurs under conditions of continuous intake of approximately 1/100th of the lethal dose of acute arsenic poisoning over several months. In 1955, out of 12,131 infants who developed subacute arsenic poisoning after ingesting the powdered Morinaga Milk contaminated with iAs (arsenate, iAsV), 130 died. The contaminated milk was consumed on an average of 3 months with an estimated daily arsenic intake of 1.3–3.6 mg, leading to a total accumulation of 90–140 mg. The major initial symptoms were fever, vomiting, diarrhea, abdominal distension, hepatomegaly, cough, nasal discharge, conjunctivitis, and melanoderma. Nevertheless, the neurological indices might not have been properly identified due to the age of the patients who were infants. The confirmed laboratory results comprised anemia, electrocardiographic abnormalities, and a radiographic band-like shadow of the epiphysis of the long bone [4, 32].
The acute arsenic poisoning patients in Wakayama included four 1-year-old infants (mean ATO intake; 44 (22–65) mg) with mild symptoms [3]. In contrast, 130 infants of the same age died from subacute arsenic poisoning [4]. To date, this question has not been resolved, but we can speculate on possible interpretations on the basis of differences in AMC affected by exposure situation of iAs. The continual ingestion of iAs is assumed to accelerate the deterioration of physical condition. The iAs methylation requires the supply of the methyl group donor SAM and reduced glutathione (GSH) by the OCM pathway. If deteriorating physical conditions persist, the supply of SAM decreases due to the reduced function of the OCM [1, 29, 31]. It is assumed that the deterioration of physical conditions led to the depletion of SAM and GSH due to the inability of the nutritional supply to function, and as a result, the detoxification mechanism of iAs was blocked, leading to severe illness and even death.
Results of a subsequent follow-up survey in the 15th year showed a delayed growth, intellectual disability, central nervous system disorders such as epilepsy and hearing loss, and skin conditions such as melanoderma and keratosis [32]. Another survey in the 55th year demonstrated carcinogenesis and cognitive dysfunctions, with a significantly higher risk of mortality from neurological diseases compared to the general population [33]. Recently, the results of the 65th-year follow-up study were reported [4]. In total, 6223 survivors of the iAs poisoning were enrolled in a prospective cohort study from 1982 to 2018. Using standardized mortality rates (SMRs), the subjects’ mortality and cancer incidence rates were compared to their respective Japanese population rates and 95% confidence intervals (95% CI) were calculated. A statistically significant increase in mortality ratio was observed for all causes (SMR, 1.15; 1.01–1.19), nervous system disease (2.83, 1.62–4.19), respiratory disease (2.02, 1.37–2.62), genitourinary systems disease (2.25, 1.10–3.73). It should be noted that epilepsy and cerebral palsy mainly contributed to the high mortality rate caused by the central nervous system disease. Therefore, it is suggested that subacute arsenic poisoning in infancy may cause permanent damage to the central nervous system. Furthermore, liver cancer showed a high mortality rate (SMR, 1.68, 1.06–2.31), whereas that of bladder cancer increased; however, no significant difference was detected. These findings are consistent with the epidemiological studies in Chile [34, 35] that suggested a link between exposure to high levels of iAs during infancy and the risk of developing bladder and lung cancers at an older age. Consequently, we consider that the results of the subsequent follow-up surveys applied to the subacute arsenic poisoning survivors are a warning sign against the risk of human exposure to iAs when the BBB is still not functional, such as in infants and fetuses.
4. Past, present, and expected future health effects from exposure to environmental iAs
In the early twentieth century, chronic arsenic poisoning was first discovered in Argentina, followed by large epidemics in Chile and Taiwan. Then, starting in the late 1970s, it was detected in India, Bangladesh, and China among Asian countries. Chronic arsenic poisoning occurred by consuming the provided drinking water without previous testing for the presence of toxic substances. Particularly well water triggered the outbreaks of serious poisoning. Because chronic arsenic poisoning is caused by naturally existing iAs and the source cannot be eliminated, the potential occurrence of epidemic to be continue in the future [32].
4.1 iAs exposure and skin lesions
Chronic arsenic poisoning generally develops from drinking well water contaminated with iAsIII or iAsV (approximately 50 μg/L) over a period of more than several years. However, even low concentrations (5–10 μg/L) have been associated with the development of skin lesions [36]. The most prominent symptom of chronic arsenic poisoning is skin lesions, characterized by hyperkeratosis of the palms and soles and hyperpigmentation and depigmentation (raindrops) particularly pronounced on the abdomen and trunk. Hyperkeratosis is painful and can affect daily routine activities and reduce the quality of life.
The iAs exposure dose is the primary factor in the development of skin lesions. Another possible factor suggested factor is the decrease in AMC, which raises %MMA and decreases SMI [2]. This factor is more significant in males compared with females. On the other hand, skin lesions in children are significantly milder than in adults, suggesting that AMC in children is higher than in adults [27]. This is consistent with the acute arsenic poisoning case, in which children had milder symptoms than adults [3]. The mechanism between the decrease in AMC and skin lesions has not been clearly elucidated, but the genetic polymorphism of methylation has been explored [37, 38].
4.1.1 AMC determined from blood arsenic and evaluation of skin lesions
For unknown reasons, epidemiological studies of chronic arsenic poisoning have not reported the profile of arsenic species in the blood. The difficulty in analyzing arsenic in blood by chemical form (its species) may be one of the reasons for the lack of reports. In 1999, we measured the urinary and blood arsenic in a small sample (n = 78) in Gangfangying village, Inner Mongolia, China, without publishing the results. In this review, we reanalyzed the relationship between the index of AMC determined from blood arsenic and skin lesions.
The determination of the chemical form of arsenic in blood is similar to the method of urine analysis [39].
Of the 78 subjects [14 children (7–17 years) and 64 adults (21–70 years)], 38 had skin lesions (dyspigmentation and hyperkeratosis). Table 2 shows the comparison of compares the urinary and blood arsenic concentrations and the index values of AMC (iAs, MMA, and DMA) in the subjects grouped by the presence and absence of skin lesions. Arsenic levels in urine and blood were significantly higher in the group with skin lesions (p < 0.001). However, urinary arsenic profile did not show any statistically significant difference in the AMC index, unlike blood arsenic profile (p < 0.001) (Table 2). In general, urinary arsenic is known to vary due to confounding factors. The urinary arsenic levels of the 78 subjects showed four cases of outliers for iAs, three for MMA, and another three for DMA, but no outliers for blood arsenic (results not shown in table). Tamayo et al. [40] noted that arsenic in blood has fewer outliers than arsenic in urine. The fact that AMC calculated based on blood arsenic is superior to that based on urinary arsenic in evaluation of the AMC of individual subjects is due to the result of the relatively stable of blood arsenic concentration.
Comparison of urinary and blood arsenic concentrations and AMC in 78 residents of Gangfangying village, China.
μg/l years. Urine, U; blood, B. Values are median (IQR). IMD, inorganic arsenic (iAs) + methylarsonic acid (MMA) + dimethylarsinic acid (DMA). First methylation ratio (MMA/iAs), second methylation ratio (DMA/MMA). Primary methylation index (PMI, MMA + DMA/IMD), secondary methylation index (SMI, DMA/MMA + DMA).
Mann-Whitney’s U test was used for continuous variables, and Chi-square test was used for categorical variables to compare two groups.
Table 3 shows the adjusted odds ratios (OR) for age and sex for each of the variables listed in Table 2. In the AMC determined from of blood, %MMA showed a significant association with the risk of developing skin lesions (OR = 1.12, 95%CI: 1.06–1.19, p < 0.001). AMC determined from blood arsenic profiles was validated in a small group of subjects; however, more studies reaching various research areas are needed.
OR and 95% CI for skin lesions by variable factors using arsenic methylation capacity calculated based on arsenic species in urine or blood.
μg/l years.
Adjusted for age and sex. OR, odds ratio; CI, confidence interval.
4.1.2 Improvement of skin lesions by reducing iAs exposure
We investigated through a one-year observation study whether the confirmed skin lesions of the 38 subjects could be ameliorated by reducing iAs doses from well water by changing water source. The average arsenic concentration in well water during iAs exposure was 0.13 ± 0.20 mg/l, while the one used for exposure reduction was 0.037 mg/l. The urinary IMD (iAs + MMA + DMA) concentration during iAs exposure was median (IQR) 200 (53.5–398) μg/g cr., while the IMD level at 1-year was median (IQR) 50.4 (33.3–83.0) μg/g cr. Dyspigmentation and hyperkeratosis changes are shown in Figure 2, where relative but insufficient improvement was observed. The AMC index determined from urinary arsenic in all 38 subjects did not significantly change. 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].
Figure 2.
Improvement of skin lesions by reducing iAs exposure for 1 year. Dyspigmentation at top, and hyperkeratosis at bottom.
A study in Bangladesh suggested that reducing iAs exposure from well water (from >50 μg/l to <50 μg/l) over a 2-year period not only increased the recovery rate of skin lesions, but also reduced the severity of skin lesions in patients over time [42]. A study in Inner Mongolia, China, tested whether skin lesions improved by reducing the arsenic concentrations in the well water from >200 μg/l (2004) to <5 μg/l (2017). The 119 subjects were compared for skin symptoms (hyperkeratosis), urinary arsenic levels, and AMC indices in 2004 and 2017. As a result, 25 subjects (21%) showed improvement of skin symptoms. However, recovery of skin symptoms showed an association between %iAs and %DMA, no association between %MMA due to its wide variable value [43]. Reduction of iAs exposure from drinking water may not be sufficient for improvement of hyperkeratosis.
4.2 iAs exposure and carcinogenesis
IARC has identified iAs as a Group 1 carcinogen that causes skin, lung, bladder, and liver cancers [44]. The latent period of arsenic carcinogenesis is generally estimated at 30–50 years. The data on carcinogenesis in patients with chronic arsenic poisoning recognize a trend toward reporting from countries with a relatively long history of iAs exposure. Evidence between iAs exposure and carcinogenesis has been reported from Taiwan for skin [45, 46, 47] and bladder cancers [48], and from Chile [49] and Argentina [50] for lung cancers. Previous reports have suggested a relationship between decreased AMC and carcinogenesis. Epidemiological studies in Chile [34, 35] have reported that exposure to high levels of iAs in infancy increased the risk of developing bladder and lung cancer in older age. Since the iAs exposure level in Asian countries had increased around 1980, a peak of carcinogenesis is expected around 2010–2030 if the incubation period for carcinogenesis is correct. Recently, reports of bladder cancer due to iAs exposure have increased [35, 48, 49]. On the other hand, some reports predicted a relatively low incidence of skin cancer in China [51].
Strangely, little progress has been made in elucidating the mechanism of arsenic carcinogenesis. Because the accumulation of knowledge that arsenic has none or weakly mutagenic property, researchers shifted their focus on the mechanisms involving epigenetic dysregulation in the carcinogenicity arsenic [52, 53].
4.3 iAs exposure and cognitive dysfunction
A growing number of studies on iAs exposure and health effects have focused on the cognitive abilities. A prospective study of subacute arsenic poisoning in infants led to find the cognitive dysfunction manifested in the elderly as a sequela of cerebral and central nervous system damage [4]. The outcomes are important as predictive data for cognitive dysfunction in chronic arsenic poisoning.
Studies in Bangladesh [54, 55], Taiwan [56], Mexico [57], Spain [58], and United States [59] confirmed cognitive abilities in children. Taiwanese studies reported that a lower AMC can lead to cognitive development [56]. The WHO (2018) raised the alarm about cognitive abilities from iAs exposure during fetal and infancy stages [60]. Recently, it has become known that rice accumulates arsenic in the soil at a high rate during cultivation. Since rice is a staple food in most Asian countries (which account for approximately 50% of the world’s population), it is likely that the discussion of the sources of iAs exposure would revolve around rice, rather than drinking water. In this regard, EFSA discusses the need for the legal regulation of iAs intake from rice and processed rice products for infants and children [61].
Although the effects on cognitive abilities have been studied mainly in children, an association between iAs exposure and cognitive dysfunction in adults has been suggested [62, 63, 64]. However, there is insufficient information on the mechanism of cognitive dysfunction, whether it is due to the exposure in infancy which was manifested in older age [4] or to direct exposure in adults. iAs exposure started to be among the stated causes of cognitive dysfunction.
4.4 iAs exposure and cardiovascular disease (CVD) and diabetes
Exposure to high concentrations of iAs has been associated with CVD. The relationship between iAs exposure and CVD has been attributed to carotid atherosclerosis [65, 66], with an increase in %MMA, suggesting an association with a decrease in AMC. Nevertheless, no significant association between hypertension and a decreased AMC has been observed. We were the first to discover that peripheral vascular damage in iAs-exposed humans is induced by nitric oxide (NO), an oxidative stress [67].
Exposure to high concentrations of iAs has been suggested to be associated with diabetes [68, 69]. However, the relationship between AMC and diabetes at low iAs exposures has been studied, but no clear association has been found. The relationship between iAs intake (mainly from rice) and lifestyle-related diseases (non-communicable diseases, NCDs) is expected to be the subject of much debate among most people living in non-arsenic-contaminated environments.
5. Health effects of organic arsenic compounds ingested from seafood and seaweeds
The demand for seafood is increasing internationally as the dietary intake of omega-3 fatty acids, mainly found in seafood, has been highly recommended for the prevention of NCDs. On the other hand, arsenolipids, arsenobetaine, and arsenosugars are found in fish and shellfish, and varying toxicity has been observed (Figure 3). In 2022, the EFSA started to adopt legal regulations for the dietary intake of AsLipids in fish and shellfish [7].
Figure 3.
Chemical structure of arsenolipids, arsenosugars, and arsenobetaine. Typical arsenolipids are known as arsenic-containing hydrocarbons (AsHCs) and arsenic-containing fatty acids (AsFAs). The major metabolite of arsenolipids and arsenosugars is DMA.
5.1 Arsenolipids (AsLipids)
Many types of AsLipids have been detected in marine organisms, among which four were identified, including arsenic-containing hydrocarbons (AsHCs), arsenic-containing fatty acids (AsFAs), arsenic-containing phospholipids, and arsenic-containing phosphatidyl-cholines. Of these, the first two are noted in this study [5, 6, 70].
One of the major adverse health effects of AsLipids concerns brain function. An experimental validation suggests that AsHCs can penetrate the BBB and migrate to the brain tissues. An in vitro model of the blood–cerebrospinal fluid barrier composed of porcine choroid plexus epithelial cells showed that AsHCs were 1.5-fold more potent than arsenite (iAsIII) in disrupting the barrier function. Consequently, it is suggested that being exposed to high levels of certain AsLipids may be harmful to the central nervous system [71]. In addition, AsHCs have been shown to accumulate in brain tissues when applied to drosophila [72]. The toxicity of AsHCs in brain cells has been shown to be 5–19 times greater than that of iAsIII when applied to human neuronal astrocytes [73]. In contrast, AsFAs tend to be less permeable to the BBB and less neurotoxic than AsHCs [74].
To our knowledge, there is insufficient information to evaluate the effects of AsLipids on the human brain. After 24 h of salmon ingestion containing AsHCs, approximately 3% was detected in breast milk [75], which could cross the BBB and migrate to the infant’s brain tissue. Alternatively, the strong brain cytotoxicity of AsHCs is also predicted to cause brain dysfunction.
Detailed studies on the biotransformation of AsLipids in animal studies are deemed difficult to conduct, due to the required large sample size. To search for AsLipid metabolites, the urinary arsenic was measured in two volunteers who took a single oral dose of test material prepared from cod liver oil. The major metabolites of AsLipids were DMA and small amounts of thio-dimethylarsenobutanoic acid (DMAB), oxo-DMAB, thio-dimethylarsenopropanoic acid (DMAPr), and oxo-DMAPr [76].
Studies predicting the daily intake of AsLipids are difficult and limited. However, a market basket survey estimated the daily intake of AsLipids from 152 food items, including seafood and algae. AsHCs and AsFAs were 4200 and 2100 ng As/person/day, respectively, as solely detected in seafood and algae [77]. Notably, AsLipid concentrations were measured in 18 samples of the purchased seafood, and AsHC values were 83 ± 73 ng As/g fresh-weight; this study revealed that consumed seafood contain toxic AsHC [78]. Seafood is commonly cooked by boiling or baking. The chemical structure of AsLipids, when heated in a microwave oven, was reported unchanged [79]. Therefore, toxic AsLipids are absorbed without loss due to cooking.
5.2 Arsenobetaine (AsB)
AsB in seawater is produced by the methylation of iAs by phytoplankton and zooplankton and is concentrated in fish or shellfish through the food chain. In mammals, AsB is not synthesized in the body; thus, it is entirely derived from seafood and is rapidly excreted in the urine, as verified in human [80] and animal [81, 82] studies. Its half lethal dose (LD50) is 10 g/kg, and AsB has been shown to be the least toxic of the arsenic compounds [5, 6].
5.3 Arsenosugars (AsSugars)
The structure of AsSugars was first elucidated from brown kelp (Ecklonia radiata) by Edmonds and Francesconi in 1981 [83]. It is presumed that AsSugars in seaweeds are originally biosynthesized by the direct absorption of iAs from seawater. Seaweed and kelp showed to contain large amounts of AsSugar-Gly and AsSugar-SO3, which are not degraded into iAs when treated with heat or stomach acid [6]. The metabolites of AsSugars, validated in humans, were DMA, thio-dimethylarsinoylacetate, thio-dimethylarsinoylethanol, and thio-dimethyl arsenate [84]. The last two seem to be the most toxic, and their cytotoxicity is suggested to be similar to that of iAsIII [85]. The major metabolite of AsSugars in human urine is DMA, which is less toxic than iAs. Further monitoring is needed due to the limited knowledge of the metabolism and toxicity of AsSugars.
6. Abandoned arsenic chemical weapons and health effects
Chemical weapons (CW) were produced in large amounts by the countries that participated in World Wars I and II. In 1997, the Chemical Weapons Convention was signed by the international community, which now includes 192 countries. The Organization for the Prohibition of Chemical Weapons (OPCW, Hague, the Netherlands) oversees and operates the disposal of CW [86]. OPCW defines CW as any chemical substance used to intentionally cause death or harm by its toxicity. The most potent chemical warfare agents include the blister agents: sulfur or nitrogen mustards (yperite), and lewisite; the riot control (vomiting) agents: diphenylchloroarsine (DA, Clark I), diphenylcyanoarsine (DC, Clark II), and adamsite; the blood agents: hydrogen cyanide and arsine; the asphyxiants: chlorine and phosgene; and the nerve agents: sarin, soman, tabun, VX, and Novichok. The main arsenic CW (Figure 4) produced in World War II were the blister and the vomiting agents, which have been largely produced in Japan, Germany, the Soviet Union, and the United States [87].
Figure 4.
Chemical structure of arsenic chemical weapons. The degradation products of diphenylchloroarsin (DA, Clark I) and diphenylcyanoarsine (DC, Clark II) are diphenylarsinic acid (DPAA).
There are two types of CW: stockpile (available) and non-stockpile (abandoned). So far, the largest stockpiles have been held by the United States and Russia, both of which have approximately 30,000–40,000 tons. The United States declared that most of its stockpiled CW have been completely destroyed [87]; however, information about the destruction process in Russia is still not credible. The international community has major concerns related to the non-signatory countries that still possess CW, in addition to the fears of CW possession and use by terrorist organizations. After World War II, many countries dumped their CW in the sea as a cheap disposal method [87]. Approximately 50,000 tons of arsenic CW (including Clarks I and II and adamsite) are estimated to be left in the Baltic Sea [8], which has resulted in phenylarsenic chemical contamination of some seafood [8, 9, 10]. The former Japanese military buried large quantities of arsenic CW in various parts of China during its defeat in World War II. In particular, iAs and phenylarsenic chemical warfare agents derived from arsenic CW have been recently detected in agricultural soil in Jilin Province [12, 13, 14]. Alternatively, the arsenic contamination persists in Germany at the sites of the facilities where arsenic CW filling operations were conducted [11]. After more than 75 years of arsenic CW abandonment, the derived risk of health effects from arsenic still exists in soils and the seabed. Therefore, the international community is invited to recognize the current situation and take action accordingly.
6.1 Lewisite
The blister agents include mustard and lewisite. The former freezes in cold climates (≤ − 20°C) and loses its function as a weapon, while the latter, to which arsenic is added, does not freeze and is used in cold climates. Therefore, lewisite was manufactured in larger amounts by the former Japanese Army and the Soviet Union than in any other country. In 2003, 44 people at a construction site in Heilongjiang Province in China, suffered from severe skin damage due to exposure to containers filled with arsenical CWs (lewisite + mustard), believed to have been abandoned by the former Japanese army [88]. Consequently, this incident implies that the arsenic-containing CW, lewisite, has not been completely and safely removed from the environment.
Exposure to lewisite can cause rapid hydrolysis in the epidermis, resulting in severe skin blistering and inflammation, after which the arsenic is absorbed through the dermis [89]. The eyes are sensitive to lewisite exposure, which can cause edema, blepharospasm, and blindness [90]. Lewisite is absorbed transdermally and distributed throughout the body, causing multiple organ damage in the lungs [91] and kidneys [92], and increasing the likelihood of mortality. On the other hand, little is known about the sequelae following lewisite and mustard exposure. A > 10-year follow-up study on the 44 victims exposed at construction work sites revealed mental and cognitive dysfunctions as new arising health problems [88].
6.2 Diphenylchloroarsine (DA) and diphenylcyanoarsine (DC)
Arsenic CWs that are known as vomiting agents, include DA, DC, and adamsite (Figure 4) and were aimed to be used for disturbing combat abilities of the soldiers rather than for killing or wounding them. Exposure to DA or DC can cause a strong sneeze, nausea, and instant vomiting. However, their detailed toxic effect is still unclear. Diphenylarsinic acid (DPAA) is the raw material for the production of DA and DC and, conversely, their degrading substance in the human body. In 2003, poisoning from contaminated well water in Kamisu, Japan, was caused by DPAA that had been buried underground. The residents used this water for cooking and bathing, while some others used it to prepare infant formula. Ishii et al. (2004) reported that in 2000, the first victim was a junior high school student who had cerebellar ataxia, tremors, and myoclonus [15]. Subsequently, a population health survey led by medical professionals revealed the presence of a total of 157 victims in the surrounding area. Before this incident, there was no toxicological data on DPAA. DPAA can pass through the BBB in trace amounts and target the cerebellum, causing disruption of the glutamatergic system [93, 94]. A summary document published by the Japanese Ministry of the Environment [95] revealed that DPAA is mainly absorbed in the gastrointestinal tract, while a mere amount is absorbed through the skin. Additionally, DPAA is not metabolized in the body and is mainly excreted in the urine. The relative toxicity of DPAA deduced from cytotoxicity studies is 1/100th compared with ATO.
So far, information on DA and DC has been limited to their acute toxicity as vomiting agents, damaging the mucous membranes of the eyes and nasal passages. We did not envision a situation where DA and DC would be decomposed to product DPAA, which would then be ingested via drinking water. However, DPAA and related substances have been found to contaminate fish, shellfish, and soil [8, 9, 10, 11, 12, 13, 14]. The clinical findings in DPAA poisoning patients [15] and animal studies [93, 94, 95] are consistent with the brain being the target organ. Toxicological information on DPAA suggests that it may be the most dangerous of the arsenic compounds. In the future, the factual extent of contamination in seafood, agricultural products, and drinking water needs to be further investigated.
The AMC index determined from non-confounding urinary arsenic in patients with acute arsenic poisoning is expected to contribute to research investigations of chronic arsenic poisoning. The effects of acute and chronic arsenic poisoning on health are associated with decreased AMC. Children and adult females tend to have higher levels of AMC than adult males. However, iAs exposure in infancy increases cancer and cognitive dysfunction in old age. Furthermore, AsLipids ingested from seafood penetrate the BBB and accumulate in the brain, resulting in toxicity. DPAA, a degradant of DA and DC used in vomiting agents among the arsenic CWs used in World War II, is overlooked by the international community as a cause of cerebellar disorders. In the past, the effects of arsenic on health have been mostly concerned with carcinogenesis. However, the target organ for iAs, AsLipids, and DPAA is mainly the brain; therefore, a deeper understanding of brain dysfunction is needed. Scientific evidence has begun to confirm that exposure to iAs during infancy and conception (fetus) exacerbates carcinogenesis and cognitive dysfunction in old age.
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Written By
Hiroshi Yamauchi, Takahiko Yoshida and Ayako Takata
Submitted: 20 March 2023Reviewed: 23 March 2023Published: 10 May 2023
Open access peer-reviewed chapter
