Chronic Arsenic Toxicity Research Articles

Arsenic induced blood and brain oxidative stress and its response to some thiol chelators in rats

Chronic arsenic toxicity is a widespread problem, not only in India and Bangladesh but also in various other regions of the world. Exposure to arsenic may occur from natural or industrial sources. The treatment that is in use at present employs administration of thiol chelators, such as meso 2,3-dimercaptosuccinic acid (DMSA) and sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), which facilitate its excretion from the body. However, these chelating agents are compromised with number of limitations due to their lipophobic nature, particularly for their use in cases of chronic poisoning. During chronic exposure, arsenic gains access into the cell and it becomes mandatory for a drug to cross cell membrane to chelate intracellular arsenic. To address this problem, analogs of DMSA having lipophilic character, were examined against chronic arsenic poisoning in experimental animals. In the present study, therapeutic efficacy of meso 2,3-dimercaptosuccinic acid (DMSA), sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), monoisoamyl DMSA (MiADMSA) were compared in terms of reducing arsenic burden, as well as recovery in the altered biochemical variables particularly suggestive of oxidative stress. Adult male Wistar rats were given 100-ppm arsenic for 10 weeks followed by chelation therapy with the above chelating agents at a dose of 50 mg/Kg (orally) once daily for 5 consecutive days. Arsenic exposure resulted in marked elevation in reactive oxygen species (ROS) in blood, inhibition of ALAD activity and depletion of GSH. These changes were accompanied by significant decline in blood hemoglobin level. MiADMSA was the most effective chelator in reducing ROS in red blood cells, and in restoring blood ALAD compared to two other chelators. Brain superoxide dismutase (SOD) and glutathione peroxidase (GPx) decreased, while ROS and TBARS increased significantly following arsenic exposure. There was a significant increase in the activity of glutathione-S-transferase (GST) with a corresponding decline in its substrate i.e. glutathione. Among all the three chelators, MiADMSA showed maximum reduction in the level of ROS in brain. Additionally, administration of MiADMSA was most effective in counteracting arsenic induced inhibition in brain ALAD, SOD and GPx activity. Based on these results and in particular higher metal decorporation from blood and brain, we suggest MiADMSA to be a potential drug of choice for the treatment of chronic arsenic poisoning. However, further studies are required for the choice of appropriate dose, duration of treatment and possible effects on other major organs.

Arsenic-Induced Micronuclei Formation in Mammalian Cells and Its Counteraction by Tea

The Gangetic plain of West Bengal, India, has been engulfed by a disastrous environmental calamity of arsenic contamination of the ground water. Chronic arsenic toxicity caused by drinking arsenic-contaminated water has been one of the worst health hazards gradually affecting nine districts of West Bengal since the early 1980s. Over and above hyperpigmentation and keratosis,weakness, burning sensation of the eyes, swelling of the legs, liver fibrosis, chronic lung disease, gangrene of the toes, neuropathy, and skin cancer are other manifestations. Induction of cancer is frequently associated with DNA damage, changes in ploidy of cells, and non-random chromosome aberrations. Counteraction of these genotoxic and cytogenetic abnormalities with natural dietary polyphenols could be a useful strategy to combat arsenic-induced DNA damage and thereby cancer. A review of the literature showed that it is the antioxidant property of tea polyphenols that affords protection against various types of cancer. The present study was conducted to investigate whether the extracts of green tea and black tea (Darjeeling and Assam) as well as their polyphenols could ameliorate this arsenic-induced genotoxicity. The normal mammalian cell culture derived from male Chinese hamster lung fibroblast cells (V79) was used as the test system to assess the genotoxicity by micronucleus assay. The results showed that both green tea and black tea extracts have equal potential in modulating the arsenic-induced genotoxicity. This effect was perhaps induced by the constituent polyphenols present in green and black tea. In addition, the repair activity of the damaged cells was enhanced when treated with these tea extracts and their polyphenols. Thus, tea and its polyphenols may have a promising role in counteracting the devastating effects of arsenic.

Strategies for Safe and Effective Therapeutic Measures for Chronic Arsenic and Lead Poisoning

Exposure to toxic metals remains a widespread occupational and environmental problem in world. There have been a number of reports in the recent past suggesting an incidence of childhood lead poisoning and chronic arsenic poisoning due to contaminated drinking water in many areas of West Bengal in India and Bangladesh has become a national calamity. Low level metal exposure in humans is caused by air, food and water intake. Lead and arsenic generally interferes with a number of body functions such as the central nervous system (CNS), the haematopoietic system, liver and kidneys. Over the past few decades there has been growing awareness and concern that the toxic biochemical and functional effects are occurring at a lower level of metal exposure than those that produce overt clinical and pathological signs and symptoms. Despite many years of research, we are still far from an effective treatment of chronic plumbism and arsenicosis. Medical treatment of acute and chronic lead and arsenic toxicity is furnished by chelating agents. Chelating agents are organic compounds capable of linking together metal ions to form complex ring-like structures called chelates. They have been used clinically as antidotes for acute and chronic poisoning. 2, 3-dimercaprol (BAL) has long been the mainstay of chelation therapy for lead or arsenic poisoning. Meso 2, 3, -dimercaptosuccinic acid (DMSA) has been tried successfully in animals as well as in a few cases of human lead and arsenic poisoning. DMSA could be a safe and effective method for treating lead or arsenic poisoning, but one of the major disadvantages of chelation with DMSA has been its inability to remove lead from the intracellular sites because of its lipophobic nature. Further, it does not provide protection in terms of clinical/ biochemical recovery. A new trend in chelation therapy is to use combined treatment. This includes the use of structurally different chelators or a combination of an adjuvant and a chelator to provide better clinical/biochemical recovery in addition to lead mobilization. The present review article attempts to provide update information about the current strategies being adopted for a safe, effective and specific treatment for two major toxic metals or metalloid.

Murshidabad—One of the Nine Groundwater Arsenic-Affected Districts of West Bengal, India. Part II: Dermatological, Neurological, and Obstetric Findings

Introduction. To understand the severity of related health effects of chronic arsenic exposure in West Bengal, a detailed 3-year study was carried out in Murshidabad, one of the nine arsenic-affected districts in West Bengal. Methods. We screened 25,274 people from 139 arsenic-affected villages in Murshidabad to identify patients suffering from chronic arsenic toxicity for evidence of multisystemic features and collected biological samples such as head hair, nail, and spot urine from the patients along with the tubewell water they were consuming. Results. Out of 25,274 people screened, 4813 (19%) were registered with arsenical skin lesions. A case series involving arsenical skin lesions resulting in cancer and gangrene were noted during this study. Representative histopathological pictures of skin biopsy of different types of lesions were also presented. Out of 2595 children we examined for arsenical skin lesions, 122 (4%) were registered with arsenical skin lesions, melanosis with or without keratosis. Different clinical and electrophysiological neurological features were noticed among the arsenic-affected villagers. Both the arsenic content in the drinking water and duration of exposure may be responsible in increasing the susceptibility of pregnant women to spontaneous abortions, stillbirths, preterm births, low birth weights, and neonatal deaths. Some additional multisystemic features such as weakness and lethargy, chronic respiratory problems, gastrointestinal symptoms, and anemia were also recorded in the affected population. Discussion. The findings from this survey on different health effects of arsenic exposure were compared to those from previous studies carried out on arsenic-affected populations in India and Bangladesh as well as other affected countries. Conclusion. Multisystemic disorders, including dermal effects, neurological complications, and adverse obstetric outcomes, were observed to be associated with chronic arsenic exposure in the study population in Murshidabad, West Bengal. The magnitude of severity was related to the concentration of arsenic in water as well as duration of the exposure.

A Case of Bowen’s Disease and Small-Cell Lung Carcinoma: Long-Term Consequences of Chronic Arsenic Exposure in Chinese Traditional Medicine

Chronic arsenic toxicity occurs primarily through inadvertent ingestion of contaminated water and food or occupational exposure, but it can also occur through medicinal ingestion. This case features a 53-year-old lifetime nonsmoker with chronic asthma treated for 10 years in childhood with Chinese traditional medicine containing arsenic. The patient was diagnosed with Bowen’s disease and developed extensive-stage small-cell carcinoma of the lung 10 years and 47 years, respectively, after the onset of arsenic exposure. Although it has a long history as a medicinal agent, arsenic is a carcinogen associated with many malignancies including those of skin and lung. It is more commonly associated with non–small-cell lung cancer, but the temporal association with Bowen’s disease in the absence of other chemical or occupational exposure strongly points to a causal role for arsenic in this case of small-cell lung cancer. Individuals with documented arsenic-induced Bowen’s disease should be considered for more aggressive screening for long-term complications, especially the development of subsequent malignancies.

Implications of oxidative stress and hepatic cytokine (TNF-α and IL-6) response in the pathogenesis of hepatic collagenesis in chronic arsenic toxicity

Introduction: Noncirrhotic portal fibrosis has been reported to occur in humans due to prolonged intake of arsenic contaminated water. Further, oxystress and hepatic fibrosis have been demonstrated by us in chronic arsenic induced hepatic damage in murine model. Cytokines like tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) are suspected to play a role in hepatic collagenesis. The present study has been carried out to find out whether increased oxystress and cytokine response are associated with increased accumulation of collagen in the liver due to prolonged arsenic exposure and these follow a dose–response relationship. Methods: Male BALB/c mice were given orally 200 μl of water containing arsenic in a dose of 50, 100, and 150 μg/mouse/day for 6 days a week (experimental group) or arsenic-free water (<0.01 μg/l, control group) for 3, 6, 9 and 12 months. Hepatic glutathione (GSH), protein sulfhydryl (PSH), glutathione peroxidase (GPx), Catalase, lipid peroxidation (LPx), protein carbonyl (PC), interleukin (IL-6), tumor necrosis factor (TNF-α), arsenic and collagen content in the liver were estimated from sacrificed animals. Results: Significant increase of lipid peroxidation and protein oxidation in the liver associated with depletion of hepatic thiols (GSH, PSH), and antioxidant enzymes (GPx, Catalase) occurred in mice due to prolonged arsenic exposure in a dose-dependent manner. Significant elevation of hepatic collagen occurred at 9 and 12 months in all the groups associated with significant elevation of TNF-α and IL-6. However, arsenic level in the liver increased progressively from 3 months onwards. There was a positive correlation between the hepatic arsenic level and collagen content ( r = 0.8007), LPx ( r = 0.779) and IL-6 ( r = 0.7801). Further, there was a significant negative correlation between GSH and TNF-α ( r = −0.5336)) and LPx ( r = −0.644). Conclusion: Increasing dose and duration of arsenic exposure in mice cause progressive increase of oxystress and elevation of cytokines associated with increasing level of collagen in the liver.

Association of Clinical Complications with Nutritional Status and the Prevalence of Leukopenia among Arsenic Patients in Bangladesh

This study conducted in Bangladesh reports the relationship of clinical complications with nutritional status and the prevalence of leukopenia among arsenic exposed patients living in the rural villages. A total of 115 exposed individuals diagnosed as arsenicosis patients were randomly selected from four known arsenic endemic villages, and age-matched 120 unexposed subjects were enrolled in the study program. The duration of arsenic exposure in about 37% of the patients was at least 10 yrs, while the population mean and range were 7.6 +/- 5.2 yrs, and 1 - 25 yrs, respectively. The mean arsenic concentrations in the drinking water for the exposed and unexposed (control) population were 218.1 microg/L and 11.3 microg/L, respectively. The spot urine sample of the arsenicosis patients contained an average of 234.6 microg/L arsenic. Although very few patients showed elevated WBC count, 16% had leukopenia (below normal count), and the whole population had significantly low WBC count than the control subjects. Prevalences of neutropenia and lymphocytosis were observed in patients with chronic exposure to high levels of arsenic in water. The body mass index was found to be lower than 18.5, the cut-off point for malnutrition (underweight), in about 28% of the arsenicosis cases compared to 15% of the controls. The monthly income and total calorie consumption per day showed the patients were underprivileged than the controls. Arsenical symptoms and complications were more severe in the nutritionally vulnerable (underweight) patients than the overweight ones. Also, the incidences of leukopenia and anaemia were more common in the female patients who were underweight. The findings of this research demonstrate that the poor nutritional status of patients increases the complications of chronic arsenic toxicity; suggest the possibility of other sources of arsenic contamination different from drinking water in the study area; and establish a higher prevalence of leukopenia and lymphocytosis in arsenicosis patients.

Association between nutritional status and arsenicosis due to chronic arsenic exposure in Bangladesh

The role of nutritional factors in arsenic metabolism and toxicity is not clear. Provision of certain low protein diets resulted in decreased excretion of DMA and increased tissue retention of arsenic in experimental studies. This paper reports a prevalence comparison study conducted in Bangladesh to assess the nutritional status among the chronic arsenic exposed and unexposed population. 138 exposed individuals diagnosed as arsenicosis patients were selected from three known arsenic endemic villages of Bangladesh and age, sex matched 144 unexposed subjects were randomly selected from three arsenic free villages. The mean arsenic concentration in drinking water for the exposed and unexposed population was 641.15 and 13.5 μg L−1 respectively. Body Mass Index was found to be lower than 18.5, the cut off point for malnutrition, in 57 (41.31%) out of 138 exposed arsenicosis cases and 31 (21.53%) out of 144 unexposed individuals. The crude prevalence ratio (or risk) was 1.92 (95% CI = 1.33 – 2.78) for poor nutritional status among the arsenicosis cases compared to the unexposed population. The findings of this study add to the evidence that poor nutritional status may increase an individual's susceptibility to chronic arsenic toxicity, or alternatively that arsenicosis may contribute to poor nutritional status.

Water intake in an Asian population living in arsenic-contaminated area

Exposure evaluation is an indispensable step for the risk assessment of chronic arsenic toxicity. The amount of water intake, which consists of the base of exposure calculation, has been lacking for the arsenic-affected populations in the developing countries. Thus, the purposes of the present study were (1) to estimate the water intake in such population, and (2) to estimate the relative importance of water versus food as the source of arsenic exposure. Adult males and females ( n = 19 for each) were selected from two rural Bangladeshi communities that entirely depended on tubewells for their water supply. Their water intake was measured by two methods, a 24-h self-report and an interview with frequent visits. Results of the two methods generally agreed with each other in terms of correlation and the absolute intakes. Mean water intake obtained by the self-report method was found to be around 3 l/day with substantial individual variation (the maximum = 6 l/day), no sex difference, and a significant between-community difference. The calculation for total arsenic exposure demonstrated that there was no sex difference in arsenic exposure except when the exposure was mainly from food and thus relatively low. Although these results need to be further confirmed under various environmental settings, these results suggested that (1) the sex difference in the manifestation of arsenic toxicity previously observed in this area should be related with factors other than exposure level and that (2) the risks associated with low arsenic concentrations of groundwater should be carefully interpreted because food may be providing additional burden of arsenic.

Toxicokinetic and genomic analysis of chronic arsenic exposure in multidrug-resistance mdr1a/1b(-/-) double knockout mice.

Multidrug-resistance gene knockout mdr1a/1b(-/-) mice, which are deficient in P-glycoproteins, are more sensitive than wild-type (WT) mice to acute arsenic toxicity. This study assessed toxic manifestations of chronic oral arsenic in mdr1a/1b(-/-) mice, including oxidative stress and altered gene expression, and investigated altered toxicokinetics as a potential basis of enhanced arsenic toxicity. Thus, mdr1a/1b(-/-) and WT mice were exposed to sodium arsenite (0-80 ppm as arsenic) in the drinking water for 10 weeks at which time hepatic arsenic accumulation, lipid peroxidation (LPO), redox status and change in gene expression level were assessed. All mice survived the arsenic exposure, but body weight gain in the highest dose group was reduced in both mdr1a/1b(-/-) and WT mice. Arsenic induced pathological changes, elevated LPO levels and enhanced glutathione S-transferase (GST) activity, in the liver to a greater extent in mdr1a/1b(-/-) than in WT mice. Arsenic also decreased Cu/Zn superoxide dismutase activity in both mdr1a/1b(-/-) and WT mice. The expressions of certain genes, such as those encoding cell proliferation, GST, acute-phase proteins and metabolic enzymes, were modestly altered in arsenic-exposed mice. The expression of cyclin D1, a potential hepatic oncogene, was enhanced in arsenic-exposed mdr1a/1b(-/-) mice only. At the highest level of exposure, hepatic arsenic content was higher in mdr1a/1b(-/-) than in WT mice, suggesting that enhanced accumulation due to transport deficiency may, in part, account for the enhanced toxicity in these mice. In summary, this study shows that chronic arsenic toxicity, including liver pathology and oxidative stress, is enhanced in mdr1a/1b(-/-) mice, possibly due to enhanced accumulation of arsenic as a result of transport system deficiency.

Chronic arsenic poisoning in the rat: treatment with combined administration of succimers and an antioxidant

The influence of the coadministration of vitamin C or vitamin E on the efficacy of two thiol chelators, meso-2,3-dimercaptosuccinic acid (DMSA) or monoisoamyl DMSA, in counteracting chronic arsenic toxicity was investigated in rats. Vitamin C and vitamin E were only mildly effective when given alone or in combination with the above chelators in mobilizing arsenic from the target tissues. However, combined administration of vitamin C plus DMSA and vitamin E plus MiADMSA led to a more pronounced depletion of brain arsenic. The supplementation of vitamins was significantly effective in restoring inhibition of blood δ-aminolevulinic acid dehydratase (ALAD) oxidative stress in liver, kidneys, and brain as reflected by reduced levels of thiobarbituric acid reactive substance and oxidized and reduced glutathione levels. The results thus lead us to suggest that coadministration of vitamin E or vitamin C may be useful in the restoration of altered biochemical variables (particularly the effects on heme biosynthesis and oxidative injury) although it has only a limited role in depleting arsenic burden.

Chronic Arsenic Toxicity: Clinical Features, Epidemiology, and Treatment: Experience in West Bengal

Chronic arsenic toxicity due to drinking arsenic-contaminated water has been one of the worst environmental health hazards affecting eight districts of West Bengal since the early eighties. Detailed clinical examination and investigation of 248 such patients revealed protean clinical manifestations of such toxicity. Over and above hyperpigmentation and keratosis, weakness, anaemia, burning sensation of eyes, solid swelling of legs, liver fibrosis, chronic lung disease, gangrene of toes, neuropathy, and skin cancer are some of the other manifestations. A cross-sectional survey involving 7683 participants of all ages was conducted in an arsenic-affected region between 04 1995 and 03 1996. Out of a population of 7683 surveyed, 3467 and 4216 people consumed water containing As below and above 0.05 mg/L, respectively. Except pain abdomen the prevalence of all other clinical manifestations tested (e.g., pigmentation, keratosis, Hepatomegaly, weakness, nausea, lung disease and neuropathy) were found to be significantly higher in As exposed people (water As>0.05 mg/L) compared to control population (water As level<0.05 mg/L). The prevalence of pigmentation and keratosis, hepatomegaly, chronic respiratory disease and weakness rose significantly with increasing arsenic concentrations in drinking water. The respiratory effects were most pronounced in individuals with high arsenic water concentrations who also had skin lesion. Therapy with chelating agent DMSA was not found to be superior to placebo effect. However, therapy with DMPS caused significant improvement of clinical condition of chronic arsenicosis patients as evidenced by significant reduction of total clinical scores from 8.90 ± 2.84 to 3.27 ± 1.73; p<0.0001. Efficacy of specific chelation therapy for patients suffering from chronic As toxicity has further need to be fully substantiated. However, supportive treatment could help in reducing many symptoms of the patients. Treatment in hospital with good nutritious diet has been found to reduce symptom score in a subset of placebo treated patients in West Bengal during the course of DMSA and DMPS trial. People should be advised to stop drinking As contaminated water or exposure to As from any other source. The various clinical manifestations should be treated symptomatically.

Chronic toxicity of arsenic to the Great Salt Lake brine shrimp, Artemia franciscana

We determined the chronic toxicity of arsenic (sodium arsenate) to the Great Salt Lake brine shrimp, Artemia franciscana. Chronic toxicity was determined by measuring the adverse effects of arsenic on brine shrimp growth, survival, and reproduction under intermittent flow-through conditions. The study commenced with <24-h-old nauplii, continued through reproduction of the parental generation, and ended after 28 days of exposure. The concentrations tested were 4, 8, 15, 31, and 56 mg/L dissolved arsenic. The test was conducted using water from the Great Salt Lake, Utah as the dilution water. Adult survival was the most sensitive biological endpoint, with growth and reproduction somewhat less sensitive than survival. The no observed effect concentration (NOEC) for survival was 8 mg/L, and the lowest observed effect concentration (LOEC) was 15 mg/L dissolved arsenic. The LOEC for growth and reproduction was greater than the highest concentration tested, 56 mg/L. Based on survival, the final chronic value (geometric mean of the NOEC and LOEC) was 11 mg/L dissolved arsenic. The F 1 generation appeared to acclimate to the prior arsenic exposure of the parental generation and was significantly less sensitive than the parental generation. For example, survival for the F 1 generation through day 12 was 100% in 56 mg/L dissolved arsenic, compared to 26% for the parental generation. Growth of the F 1 generation was significantly less than that of the parental generation across all concentrations including the control, indicating a generational difference in brine shrimp growth rather than an arsenic effect. This study represents one of the few full life cycle toxicity tests conducted with brine shrimp.

Chromosomal aberrations and sister chromatid exchanges in individuals exposed to arsenic through drinking water in West Bengal, India

Arsenic contamination in groundwater has become a worldwide problem. Currently an unprecedented number of people in West Bengal, India and Bangladesh are exposed to the ubiquitous toxicant via drinking water in exposure levels far exceeding the maximum recommended limit laid down by WHO. This arsenic epidemic has devastated nine districts of West Bengal encompassing an area of 38,865 km 2 leading to various clinical manifestations of chronic arsenicosis. We conducted a human bio-monitoring study using chromosomal aberrations (CA) and sister chromatid exchanges (SCE) as end points to explore the cytogenetic effects of chronic arsenic toxicity in the population of North 24 Parganas, one of the arsenic affected districts in West Bengal. Study participants included 59 individuals residing in this district where the mean level (±S.E.) of arsenic in drinking water (μg/l) was 211.70±15.28. As age matched controls with similar socio-economic status we selected 36 healthy, asymptomatic individuals residing in two unaffected districts—Midnapur and Howrah where the mean arsenic content of water (μg/l) was 6.35±0.45. Exposure was assessed by standardized questionnaires and by detecting the levels of arsenic in drinking water, nails, hair and urine samples. In the exposed group the mean arsenic concentrations in nails (μg/g), hair (μg/g) and urine (μg/l) samples were 9.04±0.78, 5.63±0.38 and 140.52±8.82, respectively, which were significantly high ( P<0.01) compared to the corresponding control values of 0.44±0.03, 0.30±0.02 and 5.91±0.49, respectively. Elevated mean values ( P<0.01) of the percentage of aberrant cells (8.08%) and SCEs per cell (7.26) were also observed in the exposed individuals in comparison to controls (1.96% and 5.95, respectively). The enhanced rates of CAs and SCEs among the residents of North 24 Parganas are indicative of the cytogenetic damage due to long term exposure to arsenic through consumption of contaminated water.

Males in rural Bangladeshi communities are more susceptible to chronic arsenic poisoning than females: analyses based on urinary arsenic.

Spot urine samples were collected from the inhabitants of two rural communities in northwestern Bangladesh. We compared arsenic levels in the urine samples ([As](u); n = 346) with those in water from tube wells ([As](tw); range < 1-535 microg/L; n = 86) on an individual basis. The small variation of [As](u) within subjects and highly positive correlation with [As](tw) indicate that [As](u) is a useful indicator of exposure. Analyses of [As](u) showed that creatinine correction was necessary, that [As](u) only reflected recent exposure, and that there were substantial interindividual differences for a given [As](tw) level. To evaluate the toxic effects of arsenic exposure, we constructed a system for rating skin manifestations, which revealed distinct sex-related differences. Comparison of males and females in the same households confirmed that skin manifestations were more severe in the males, and in the males of one community a dose-response relationship between [As](u) and the degree of skin manifestation was evident. The results of this study indicate that [As](u) in spot urine samples can be used as an exposure indicator for As. They suggest that there might be sex-related, and perhaps community-related, differences in the relationship between [As](u) and skin manifestations, although several confounding factors, including sunlight exposure and smoking habits, might contribute to the observed sex difference. The existence of such differences should be further confirmed and examined in other populations to identify the subpopulations sensitive to chronic arsenic toxicity.

Chronic toxicity of arsenic in goats: clinicobiochemical changes, pathomorphology and tissue residues

Chronic inorganic arsenic toxicity was induced in goats by oral administration of one-fifth of the acute lethal dose 50 (ALD 50) of sodium arsenite (25 mg kg −1 body weight) packed in gelatin capsules and given daily for 12 weeks. Clinical signs of toxicity developed from 3 week post-exposure, consisting of gastrointestinal disturbances and renal insufficiency with 100% mortality in all animals. There were significant ( p<0.01) decreases in total serum protein and the albumin: globulin ratio, and increases in blood glucose and various enzymatic activities of treated animals. Toxicity also induced severe pathomorphological changes, indicative of haemorrhagic and degenerative and/or necrotic lesions in most organs. In addition, proliferative pneumonia in lungs, hyperplastic goitre in thyroid and chronic proliferative lesions in skin were observed. Liver contained the largest residues of arsenic, followed by intestine, kidneys, thyroid, abomasum, spleen, skin, lungs and lowest in brain. The intensity of pathomorphological changes was proportional to the accumulated amount of arsenic in tissues/organs.

Confounding variables in the environmental toxicology of arsenic

Arsenic is one of the most important global environmental toxicants. For example, in regions of West Bengal and Inner Mongolia, more than 100 000 persons are chronically exposed to well water often strongly contaminated with As. Unfortunately, a toxicologically safe risk assessment and standard setting, especially for long-term and low-dose exposures to arsenic, is not possible. One reason is that the key mechanism of arsenic’s tumorigenicity still is not elucidated. Experimental data indicate that either DNA repair inhibition or DNA methylation status alteration may be causal explanations. Moreover, when comparing epidemiological data, it cannot be ruled out that the susceptibility to arsenic’s carcinogenicity may be different between Mexican and Taiwanese people. Some other studies indicate that some Andean populations do not develop skin cancer after long-term exposure to As. It is not known yet how this resistance could be mediated. Finally, the situation is even more complicated when taking into consideration that there are several compounds suspected to modulate the chronic environmental toxicity of arsenic, variables that may either enhance or suppress the in vivo genotoxicity and carcinogenicity of the metalloid. Among them are nutritional factors like selenium and zinc as well as drinking water co-contaminants like antimony. Further, yet unidentified factors influencing the body burden and/or the excretion of arsenic are possibly prevailing: preliminary data from own human biomonitoring studies showed a peaking of As in urine samples of non-exposed people which was not caused by elevated exposure to As through seafood consumption. The relevance of these putative confounding variables cannot be finally evaluated yet. Further experimental as well as epidemiological studies are needed to answer these questions. This would help to conduct a toxicologically improved risk assessment, especially for low-dose and long-term exposures to arsenic.

Hepatic damage caused by chronic arsenic toxicity in experimental animals.

Noncirrhotic fibrosis of the liver is common in subjects chronically consuming ground water geologically contaminated with arsenic, but the mechanism of the hepatic fibrosis is not known. Because lipid peroxidation has been implicated in the development of several other forms of hepatic fibrosis, including iron and copper overload, we have explored the roles of oxidative stress and lipid peroxidation in the causation of hepatic fibrosis in a murine model of chronic arsenic toxicity. Male BALB/c mice were given drinking water contaminated with arsenic (3.2 mg/L) or arsenic-free (<0.01 mg/L, control) ad libitum. Mice were sacrificed at 3, 6, 9, 12, and 15 months for examination of hepatic histology and assays of hepatic reduced glutathione content, lipid peroxidation, enzymes of the antioxidant defense system, and membrane-bound sodium/potassium ATPase (Na+/K+ ATPase). After 12 months of arsenic feeding, the liver weights increased significantly as did serum aspartate aminotransferase and alanine aminotransferase. After 6 months of arsenic feeding, hepatic glutathione and the enzymes glucose-6-phosphate dehydrogenase and glutathione peroxidase were significantly lower than those of the control group. Hepatic catalase activity was significantly reduced at 9 months in the arsenic-fed group, while glutathione-S-transferase and glutathione reductase activities were also significantly reduced at 12 and 15 months. Plasma membrane Na+/K+ ATPase activity was reduced after 6 months while lipid peroxidation increased significantly after 6 months of arsenic feeding. Liver histology remained normal for the first 9 months, but showed fatty infiltration after 12 months of arsenic feeding. Histologic evidence of fibrosis was observed after 15 months. We have demonstrated hepatic fibrosis due to long-term arsenic toxicity in an animal model. Initial biochemical evidence of hepatic membrane damage, probably due to reduction of glutathione and antioxidant enzymes, may be seen by 6 months. Continued arsenic feeding resulted in fatty liver with serum aminotransferase and alanine aminotransferase elevated at 12 months and hepatic fibrosis at 15 months. The murine model is proposed as relevant to epidemic human toxicity in areas of arsenic contamination.

Acute and chronic arsenic toxicity should be monitored carefully

Acute and chronic arsenic toxicity should be monitored carefully

Acute and chronic arsenic poisoning associated with treatment of acute promyelocytic leukaemia

Seven relapsed and/or refractory acute promyelocytic leukaemia patients were treated by arsenic trioxide (As2O3). Four patients (4/7, 57%) achieved complete remission after one to three cycles of treatment and the most common acute side-effect was fluid retention (in six patients, 86%), including weight gains and pleuro-pericardial effusions. Evident polyneuropathy compatible with chronic arsenic toxicity was noted in two of the three patients who received As2O3 maintenance therapy and one of them had marked distal muscular atrophy. We suggest that As2O3 may be a useful salvage therapy for relapsed and refractory APL patients, but the acute or chronic arsenic toxicity should be carefully monitored.