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PubMed2007

Arsenic: signal transduction, transcription factor, and biotransformation involved in cellular response and toxicity.

Arsenic is a naturally occurring metalloid that causes oxidative stress. Exposure of humans, experimental animals, and cultured cells to arsenic results in a variety of diverse health effects, dysfunction of critical enzymes, and cell damage. In this context, one area of arsenic study has been the role of its metabolism. Like organic chemicals, arsenic undergoes reduction, methylation, and glutathione conjugation to yield polar metabolites that are substrates for transporters. These events suggest that transcription factor(s) controlling the upregulation of antioxidant proteins, Phase II xenobiotic-metabolizing enzymes, and Phase III transporters should affect arsenic-mediated oxidative stress and the steady-state level of arsenic in the cells. In this review, we summarize recent progress in arsenic toxicity in terms of disrupted signal transduction cascades, the transcription factors involved, and arsenic biotransformation, including a novel pathway.

Animals↗
PubMed1996

Dose-response relationship between ischemic heart disease mortality and long-term arsenic exposure.

The cardiovascular effects of inorganic arsenic have been documented, but the dose-response relationship between ischemic heart disease (ISHD) and long-term arsenic exposure remains to be elucidated. Mortality rates from ISHD among residents in 60 villages of the area in Taiwan with endemic arseniasis from 1973 through 1986 were analyzed to examine their association with arsenic concentration in drinking water. Based on 1 355 915 person-years and 217 ISHD deaths, the cumulative ISHD mortalities from birth to age 79 years were 3.4%, 3.5%, 4.7%, and 6.6%, respectively, for residents who lived in villages in which the median arsenic concentrations in drinking water were <0.1, 0.1 to 0.34, 0.35 to 0.59, and > or = 0.6 mg/L. A cohort of 263 patients affected with blackfoot disease (BFD), a unique arsenic-related peripheral vascular disease, and 2293 non-BFD residents in the endemic area of arseniasis were recruited and followed up for an average period of 5.0 years. There was a monotonous biological gradient relationship between cumulative arsenic exposure through drinking artesian well water and ISHD mortality. The relative risks were 2.5, 4.0 and 6.5, respectively, for those who had a cumulative arsenic exposure of 0.1 to 9.9, 10.0 to 19.9, and > or = 20.0 mg/L-years compared with those without the arsenic exposure after adjustment for age, sex, cigarette smoking, body mass index, serum cholesterol and triglyceride levels, and disease status for hypertension and diabetes through proportional-hazards regression analysis. BFD patients were found to have a significantly higher ISHD mortality that non-BFD residents, showing a multivariate-adjusted relative risk of 2.5 (95% CI, 1.1 to 5.4).

Adolescent↗
PubMed1997

Are we ready to replace dimercaprol (BAL) as an arsenic antidote?

1 Dimercaprol (BAL), 2,3-dimercaptopropanesulphonate sodium (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) are effective arsenic antidotes, but the question which one is preferable for optimal therapy of arsenic poisoning is still open to discussion. Major drawbacks of BAL include (a) its low therapeutic index, (b) its tendency to redistribute arsenic to brain and testes, for example, (c) the need for (painful) intramuscular injection and (d) its unpleasant odour. 2 The newer antidotes DMPS and DMSA feature low toxicity and high therapeutic index. They can be given orally or intravenously due to their high water solubility. While these advantages make it likely that DMPS and DMSA will replace BAL for the treatment of chronic arsenic poisoning, acute intoxication-especially with lipophilic organoarsenicals-may pose a problem for the hydrophilic antidotes, because their ionic nature can adversely affect intracellular availability. 3 This article focuses on aspects dealing with the power of BAL, DMPS, and DMSA to mobilize tissue-bound arsenic in various experimental models, such as monolayers of MDCK (= Madin-Darby canine kidney) cells from dog kidney, isolated perfused liver from guinea-pigs, and perfused jejunal segments from rat small intestine. 4 The results show that hydrophilic DMPS and DMSA may fail to rapidly and completely remove arsenic that has escaped from the extracellular space across tight epithelial barriers. However, owing to their low toxicity, which allows larger doses to be applied, and the potential modification of their pharmacokinetics by means of inert oral anion-exchange resins, DMPS and DMSA may advantageously replace BAL whenever intervention time is not critical. With severe intoxication by organic arsenicals, when the point-of-no-return is a limiting factor, BAL may still have a place as an arsenic antidote.

Animals↗
PubMed2005

Percutaneous absorption of arsenic from environmental media.

Current knowledge of percutaneous absorption of arsenic is based on studies of rhesus monkeys using soluble arsenic in aqueous solution, and soluble arsenic mixed with soil (Wester et al., 1993). These studies produced mean dermal absorption rates in the range of 2.0-6.4% of the applied dose. Subsequently, questions arose as to whether these results represent arsenic absorption from environmental media. Factors such as chemical interactions, the presence of other metals, and the effects of weathering on environmental media all can affect the nature of arsenic and its potential for percutaneous absorption. Therefore, research specific to more relevant matrices is important. The focus of this effort is to outline study design considerations, including particle size, application rates, means of ensuring skin contact and appropriate statistical evaluation of the data. Appropriate reference groups are also important. The potential for background exposure to arsenic in the diet possibly obscuring a signal from a dermally applied dose of arsenic will also be addressed. We conclude that there are likely to be many site- or sample-specific factors that will control the absorption of arsenic, and matrix-specific analyses may be required to understand the degree of percutaneous absorption.

Administration, Topical↗
PubMed2000

Arsenic-induced skin lesions among Atacameño people in Northern Chile despite good nutrition and centuries of exposure.

It has been suggested that the indigenous Atacameño people in Northern Chile might be protected from the health effects of arsenic in drinking water because of many centuries of exposure. Here we report on the first intensive investigation of arsenic-induced skin lesions in this population. We selected 11 families (44 participants) from the village of Chiu Chiu, which is supplied with water containing between 750 and 800 microg/L inorganic arsenic. For comparison, 8 families (31 participants) were also selected from a village where the water contains approximately 10 microg/L inorganic arsenic. After being transported to the nearest city for blind assessment, participants were examined by four physicians with experience in studying arsenic-induced lesions. Four of the six men from the exposed village, who had been drinking the contaminated water for more than 20 years, were diagnosed with skin lesions due to arsenic, but none of the women had definite lesions. A 13-year-old girl had definite skin pigmentation changes due to arsenic, and a 19-year-old boy had both pigmentation changes and keratoses on the palms of his hands and the soles of his feet. Family interviews identified a wide range of fruits and vegetables consumed daily by the affected participants, as well as the weekly intake of red meat and chicken. However, the prevalence of skin lesions among men and children in the small population studied was similar to that reported with corresponding arsenic drinking water concentrations in both Taiwan and West Bengal, India--populations in which extensive malnutrition has been thought to increase susceptibility.

Adolescent↗
PubMed2002

The role of biomethylation in toxicity and carcinogenicity of arsenic: a research update.

Recent research of the metabolism and biological effects of arsenic has profoundly changed our understanding of the role of metabolism in modulation of toxicity and carcinogenicity of this metalloid. Historically, the enzymatic conversion of inorganic arsenic to mono- and dimethylated species has been considered a major mechanism for detoxification of inorganic arsenic. However, compelling experimental evidence obtained from several laboratories suggests that biomethylation, particularly the production of methylated metabolites that contain trivalent arsenic, is a process that activates arsenic as a toxin and a carcinogen. This article summarizes this evidence and provides new data on a) the toxicity of methylated trivalent arsenicals in mammalian cells, b) the effects of methylated trivalent arsenicals on gene transcription, and c) the mechanisms involved in arsenic methylation in animal and human tissues.

Animals↗
PubMed2005

Vascular dysfunction in patients with chronic arsenosis can be reversed by reduction of arsenic exposure.

Chronic arsenic exposure causes vascular diseases associated with systematic dysfunction of endogenous nitric oxide. Replacement of heavily arsenic-contaminated drinking water with low-arsenic water is a potential intervention strategy for arsenosis, although the reversibility of arsenic intoxication has not established. In the present study, we examined urinary excretion of cyclic guanosine 3 ,5 -monophosphate (cGMP), a second messenger of the vasoactive effects of nitric oxide, and signs and symptoms for peripheral vascular function in 54 arsenosis patients before and after they were supplied with low-arsenic drinking water in an endemic area of chronic arsenic poisoning in Inner Mongolia, China. The arsenosis patients showed a marked decrease in urinary excretion of cGMP (mean +/- SEM: male, 37.0 +/- 6.1; female, 37.2 +/- 5.4 nmol/mmol creatinine), and a 13-month period of consuming low-arsenic drinking water reversed this trend (male, 68.0 +/- 5.6; female, 70.6 +/- 3.0 nmol/mmol creatinine) and improved peripheral vascular response to cold stress. Our intervention study indicates that peripheral vascular disease in arsenosis patients can be reversed by exposure cessation and has important implications for the public health approach to arsenic exposure.

Adolescent↗
PubMed1992

Cancer risks from arsenic in drinking water.

Ingestion of arsenic, both from water supplies and medicinal preparations, is known to cause skin cancer. The evidence assessed here indicates that arsenic can also cause liver, lung, kidney, and bladder cancer and that the population cancer risks due to arsenic in U.S. water supplies may be comparable to those from environmental tobacco smoke and radon in homes. Large population studies in an area of Taiwan with high arsenic levels in well water (170-800 micrograms/L) were used to establish dose-response relationships between cancer risks and the concentration of inorganic arsenic naturally present in water supplies. It was estimated that at the current EPA standard of 50 micrograms/L, the lifetime risk of dying from cancer of the liver, lung, kidney, or bladder from drinking 1 L/day of water could be as high as 13 per 1000 persons. It has been estimated that more than 350,000 people in the United States may be supplied with water containing more than 50 micrograms/L arsenic, and more than 2.5 million people may be supplied with water with levels above 25 micrograms/L. For average arsenic levels and water consumption patterns in the United States, the risk estimate was around 1/1000. Although further research is needed to validate these findings, measures to reduce arsenic levels in water supplies should be considered.

Animals↗
PubMed2006

Effects of dietary arsenic levels on serum parameters and trace mineral retentions in growing and finishing pigs.

This experiment was conducted to investigate the effect of dietary arsenic (As) levels on growth performance, serum biochemistry, and the retention of iron, copper, and zinc in tissues of growing and finishing pigs. Ninety-six crossbred pigs were randomly allotted to four dietary treatments. The corn-soybean basal diets were supplemented with 0, 10, 20, and 30 mg As/kg. Arsenic trioxide was used as the arsenic source. The feeding experiment lasted for 78 d. The results showed that the high arsenic diet decreased average daily gain (ADG) (p<0.05) and increased feed gain ratio (F/G) (p<0.05). Arsenic intake significantly increased (p<0.05) serum gamma-gultamyltransferase (GGT), glutamic-pyruvic transaminase (GPT), and alkaline phosphatase (ALP) activities, and decreased (p<0.05) total protein, urea nitrogen, creatinine, and triglycerides. Glutamic-oxalacetic transaminase (GOT) activity, albumin, and cholesterol were not affected (p>0.05). Arsenic feeding elevated (p<0.05) liver and kidney copper concentration, but reduced (p<0.05) copper concentration in heart, bile, and lymphaden of intestine mesentery. There were increases in iron levels in liver, bile, spleen, thymus, and pancreas in pigs fed the high As diets (p<0.05), but iron contents in kidney, heart, and serum were decreased by the arsenic treatment (p<0.05). Zinc concentrations were increased (p<0.05) in liver, kidney, and thymus of pigs with arsenic treatment, but decreased (p<0.05) in bile and lymphaden of intestine mesentery. This study suggested that high dietary As levels could alter serum biochemical parameters and the retention of copper, iron, and zinc in the viscera of growing and finishing pigs.

Animal Feed↗
PubMed2001

History of the development of arsenic derivatives in cancer therapy.

Arsenic is a natural substance that has been used medicinally for over 2,400 years. In the 19th century, it was the mainstay of the materia medica. A solution of potassium arsenite (Fowler's solution) was used for a variety of systemic illnesses from the 18th until the 20th century. This multipurpose solution was also primary therapy for the treatment of chronic myelogenous leukemia until replaced by radiation and cytotoxic chemotherapy. The past 100 years have seen a precipitous decline in arsenic use and, by the mid-1990s, the only recognized indication was the treatment of trypanosomiasis. Much of this decline was due to concerns about the toxicity and potential carcinogenicity of chronic arsenic administration. The rebirth of arsenic therapy occurred in the 1970s when physicians in China began using arsenic trioxide as part of a treatment for acute promyelocytic leukemia (APL). Their accumulated experience showed that a stable solution of arsenic trioxide given by intravenous infusion was remarkably safe and effective both in patients with newly diagnosed APL leukemia and in those with refractory and relapsed APL. The mechanisms of action of arsenic derivatives in this disease and other malignancies are many and include induction of apoptosis, partial cytodifferentiation, inhibition of proliferation, and inhibition of angiogenesis. Molecular studies and ongoing clinical trials suggest that, as a chemotherapeutic agent, arsenic trioxide shows great promise in the treatment of malignant disease.

Antineoplastic Agents↗
PubMed2001

Analysis of a historical cohort of Chinese tin miners with arsenic, radon, cigarette smoke, and pipe smoke exposures using the biologically based two-stage clonal expansion model.

Hazelton, W. D., Luebeck, E. G., Heidenreich, W. F. and Moolgavkar, S. H. Analysis of a Historical Cohort of Chinese Tin Miners with Arsenic, Radon, Cigarette Smoke, and Pipe Smoke Exposures Using the Biologically Based Two-Stage Clonal Expansion Model. Radiat. Res. 156, 78-94 (2001).The two-stage clonal expansion model is used to analyze lung cancer mortality in a cohort of Yunnan tin miners based on individual histories with multiple exposures to arsenic, radon, cigarette smoke, and pipe smoke. Advances in methodology include the use of nested dose-response models for the parameters of the two-stage clonal expansion model, calculation of attributable risks for all exposure combinations, use of both a fixed lag and a gamma distribution to represent the time between generation of the first malignant cell and death from lung cancer, and scaling of biological parameters allowed by parameter identifiability. The cohort consists of 12,011 males working for the Yunnan Tin Corporation, with complete exposure records, who were initially surveyed in 1976 and followed through 1988. Tobacco and arsenic dominate the attributable risk for lung cancer. Of 842 lung cancer deaths, 21.4% are attributable to tobacco alone, 19.7% to a combination of tobacco and arsenic, 15.8% to arsenic alone, 11% to a combination of arsenic and radon, 9.2% to a combination of tobacco and radon, 8.7% to combination of arsenic, tobacco and radon, 5.5% to radon alone, and 8.7% to background. The models indicate that arsenic, radon and tobacco increase cell division, death and malignant conversion of initiated cells, but with significant differences in net cell proliferation rates in response to the different exposures. Smoking a bamboo water pipe or a Chinese long-stem pipe appears to confer less risk than cigarette use, given equivalent tobacco consumption.

Adolescent↗
PubMed2004

Arsenic speciation in tissues of the Mediterranean polychaete Sabella spallanzanii.

Arsenic toxicity is strictly related to its chemical form and marine organisms are known to accumulate this element mostly as organoarsenic nontoxic molecules. Contrasting with this general trend, the presence of moderately toxic to toxic arsenic compounds recently has been reported in some polychaete species, showing a completely different profile of represented chemical species. In this work the presence and distribution of arsenic were characterized in the Mediterranean polychaete Sabella spallanzanii, by analyzing total levels in different tissues and subcellular fractions and the occurrence of various arsenical compounds. Further investigations on arsenic accumulation in S. spallanzanii were based on the capability of this species to regenerate the branchial crown both in laboratory and field conditions. Though basal levels of arsenic in the thorax were similar to those already described for most polychaetes and invertebrate species, branchial crown revealed a remarkable accumulation of this element with concentrations higher than 1000 microg/g. Arsenic mainly was localized in a soluble form within the cytosol and dimethyl-arsinate (DMA) appeared the most represented chemical species. Experiments on bioaccumulation of arsenic in regenerating branchial crowns confirmed the environmental origin of this element and the time-dependent appearance of various As compounds suggested a methylation pathway more than a degradation process for the elevated content of DMA. The accumulation of this moderately toxic compound in the more vulnerable tissues of the polychaete might represent an antipredatory strategy, as indicated by some feeding trials where fish ate the thorax but rejected the branchial crowns.

Animals↗
PubMed2005

Design and development of low cost, simple, rapid and safe, modified field kits for the visual detection and determination of arsenic in drinking water samples.

Arsenic is naturally found in surface and ground waters and the inorganic forms of arsenic are the most toxic forms. The adverse health effects of arsenic may involve the respiratory, gastrointestinal, cardiovascular, nervous, and haematopoietic systems. Arsenic contamination in drinking water is a global problem widely seen in Bangladesh and West Bengal of the Indian sub continent. As there is a great demand for field test kits due to the anticipated reduction of the US EPA arsenic standard from 50ppb to 10ppb a field kit which offers rapid, simple and safe method for precise estimation of arsenic at 10ppb in drinking water samples is developed. Field methods, based on the mercuric-bromide-stain, consist of three different major parts, which are carried out stepwise. The first part of the procedure is to remove serious interference caused by hydrogen sulphide. In commercially available kits either the sulphide is oxidized to sulphate and the excess oxidizing reagent removed prior to the hydride generation step or, the hydrogen sulphide is filtered out by passing the gas stream through a filter impregnated with lead acetate during the hydride generation step. The present method employs cupric chloride in combination with ferric chloride or Fentonis reagent for the removal of hydrogen sulphide, which is rapid, simple and more efficient. Other interferences at this step of the analyses are normally not expected for drinking water analysis. In the second step, the generation of the arsine gas involves the classical way of using zinc metal and hydrochloric acid, which produce the enascenti hydrogen, which is the actual reducing agent. Hydrochloric acid can be replaced by sulfamic acid, which is solid and avoids a major disadvantage of having to handle a corrosive liquid in the field. The arsine gas produces a yellowish spot on the reagent paper. Depending on the arsenic content, either, Yellow n H (HgBr)2 As (10-50ppb), Brown n (HgBr)3 As (50-100ppb) or Black n Hg3 As2 (>100ppb) are formed which can be precisely estimated by visual comparison with standard color chart. The results obtained by field kits agree well with the data obtained through I.C.P.AES methods. The most important characteristic for field measurement is that analytical results can be obtained on the site where the sample is taken with high precision and can be conveniently utilized for monitoring arsenic rapidly in a highly contaminated large geographical area.

Arsenic↗
PubMed1981

Chromosome aberrations in cultured human lymphocytes exposed to trivalent and pentavalent arsenic.

Cultured human lymphocytes were exposed to trivalent (NaASO2) and pentavalent (Na2HAsO4) arsenic in concentrations comparable to the arsenic levels found in the urine of copper smelter workers. Significantly increased frequencies of chromosome aberrations (gaps, chromatid breaks, chromatid exchanges and chromosome breaks) were found after exposure to trivalent but not pentavalent arsenic. This effect was not found when nonstimulated (GO) lymphocytes were exposed to trivalent arsenic and then cultured. The rate of sister chromatid exchanges was also found to be increased after exposure to trivalent arsenic. Thus results suggest that trivalent arsenic is more genotoxic than pentavalent arsenic and that arsenic exerts its effect mainly during cell division.

Arsenates↗
PubMed1976

[Occupational chronic arsenical poisoning. On the cutaneous manifestations (author's transl)].

A physical examination with detailed dermatological examination was made on 28 Japanese male workers, 22 to 63 years old, who had been exposed to arsenic for one to 24 years, in processes manufacturing lead arsenate, calcium arsenate and so on to be used as insecticides. Many corn-like punctate keratoses were seen on the palms and soles of 7 workers. The histopathological features in 6 specimens of punctate keratoses of palms and other regions of 4 workers were hyperkeratosis, acanthosis and elongation of rete ridge, but no malignant changes, although there were mild disorderly arrangements in part of stratum malpighii. Multiple lesions of sharply demarcated dullred patch with scale were found on the trunk and extremities of 3 workers. These lesions histopathologically showed the typical feature of Bowen's disease. Characteristic bronze pigmentation on the trunk and extremities was seen in 6 workers, and 5 of these 6 workers showed tiny normal or depigmented skin (raindrops) throughout the involved areas. These corn-like punctate keratoses mainly on the palms and soles, multiple Bowen's disease and diffuse bronze pigmentation with raindrop areas of hypopigmentation on the trunk and extremities were manifest almost in the same individuals, and it was concluded that they were characteristic cutaneous symptoms of chronic arsenical poisoning. There was no correlation between the intensity of cutaneous manifestations and the term of exposure to arsenic. Cutaneous manifestations due to arsenic were generally recognized as follows: diffuse pigmentation appears at first in one to two years after exposure to arsenic, then punctate hyperkeratotic lesions appear mainly on the palms and soles, and Bowen's lesions occur after several years or more. The use of arsenic has been abandoned in this factory since January, 1971. Diffuse bronze pigmentation now seems to be considerably lightened, as long time has passed after exposure to arsenic. However, since punctate hyperkeratotic lesions on the palms, soles and others may, though rarely, undergo malignant transformations, new lesions of Bowen's disease may further occur and these lesions may develop to invasive squamous cell carcinoma, physical examinations of the workers exposed to arsenic should be continued and careful observation of them is necessary for the future.

Adult↗
PubMedDate not supplied

Hepatic manifestations in chronic arsenic toxicity.

OBJECTIVE: The hepatotoxic action of arsenic, when used as a therapeutic agent, has long been recognized. Data on liver involvement following chronic exposure to arsenic-contaminated water are scanty. We report the nature and degree of liver involvement on the basis of hospital-based and cohort follow-up studies in patients who consumed arsenic-contaminated drinking water for 1 to 15 years. METHODS: 248 patients with evidence of chronic arsenic toxicity underwent clinical and laboratory examinations including liver function tests and HBsAg status. Liver biopsy was done in 69 cases; in 29 patients, liver arsenic content was estimated by neutron activation analysis. A cohort follow up of 23 patients who took arsenic-free water for 2-12 years was also carried out. RESULTS: Hepatomegaly was present in 190 of 248 patients (76.6%). Noncirrhotic portal fibrosis (91.3%) was the predominant lesion in liver histology. The maximum arsenic content in liver was 6 mg/Kg (mean 1.46 [0.42], control value 0.16 [0.04]; p < 0.001); it was undetected in 6 of 29 samples studied. Cohort follow-up studies showed elevation of globulin in four cases and development of esophageal varices in one case. CONCLUSION: We report the largest number of patients with liver disease due to chronic arsenicosis from drinking arsenic-contaminated water. Noncirrhotic portal fibrosis is the predominant lesion in this population.

Adult↗
PubMed1999

Sample preparation and storage can change arsenic speciation in human urine.

BACKGROUND: Stability of chemical speciation during sample handling and storage is a prerequisite to obtaining reliable results of trace element speciation analysis. There is no comprehensive information on the stability of common arsenic species, such as inorganic arsenite [As(III)], arsenate [As(V)], monomethylarsonic acid, dimethylarsinic acid, and arsenobetaine, in human urine. METHODS: We compared the effects of the following storage conditions on the stability of these arsenic species: temperature (25, 4, and -20 degrees C), storage time (1, 2, 4, and 8 months), and the use of additives (HCl, sodium azide, benzoic acid, benzyltrimethylammonium chloride, and cetylpyridinium chloride). HPLC with both inductively coupled plasma mass spectrometry and hydride generation atomic fluorescence detection techniques were used for the speciation of arsenic. RESULTS: We found that all five of the arsenic species were stable for up to 2 months when urine samples were stored at 4 and -20 degrees C without any additives. For longer period of storage (4 and 8 months), the stability of arsenic species was dependent on urine matrices. Whereas the arsenic speciation in some urine samples was stable for the entire 8 months at both 4 and -20 degrees C, other urine samples stored under identical conditions showed substantial changes in the concentration of As(III), As(V), monomethylarsonic acid, and dimethylarsinic acid. The use of additives did not improve the stability of arsenic speciation in urine. The addition of 0.1 mol/L HCl (final concentration) to urine samples produced relative changes in inorganic As(III) and As(V) concentrations. CONCLUSIONS: Low temperature (4 and -20 degrees C) conditions are suitable for the storage of urine samples for up to 2 months. Untreated samples maintain their concentration of arsenic species, and additives have no particular benefit. Strong acidification is not appropriate for speciation analysis.

Arsenicals↗
PubMedDate not supplied

Oxidative stress in liver of mice exposed to arsenic-contaminated water.

BACKGROUND: Oxidative stress has been implicated in the initiation of hepatic damage caused by various agents. Not much data on oxidative stress in liver in chronic arsenic exposure are available in the literature. We therefore studied this aspect in a murine model. METHODS: BALB/c mice were given arsenic-contaminated (3.2 mg/L) or arsenic-free (< 0.01 mg/L, control) drinking water ad libitum. Batches of mice were sacrificed after 2 and 4 months, and blood samples and liver tissue were collected. Liver histology was examined and levels of hepatic reduced glutathione (GSH), malondialdehyde, and enzymes of the antioxidant defense system in the liver tissue were determined. Arsenic content in liver tissues obtained at 4 months was estimated. RESULTS: Two-month exposure to arsenic caused significant elevation of hepatic GSH (11.4 [0.8] micrograms/mg protein) compared to control mice (9.3 [0.4]; p < 0.01). Levels of enzymes related to GSH homeostasis were also elevated. At 4 months, hepatic GSH was significantly reduced (8.4 [0.5] micrograms/mg protein) when compared to control mice (9.3 [0.4]; p < 0.01). Arsenic content in the liver tissue after 4 months of exposure was significantly higher (0.40 [0.05] microgram/g) as compared to control mice (0.04 [0.04]; p < 0.01). CONCLUSION: The results suggest that the antioxidant defense system in the liver of mice is activated after exposure to arsenic for 2 months. However, prolonged exposure to arsenic probably causes overuse failure of this system, which might result in initiation of biochemical injury to the liver.

Animals↗