Hidroarsenicismo: mecanismos de acción asociados a la toxicidad del arsénico / Hydroarsenicism: Mechanisms of action related to arsenic toxicity

La exposición crónica al arsénico (As) inorgánico a través del agua de bebida da lugar al desarrollo de la enfermedad conocida como hidroarsenicismo. Esta enfermedad presenta sintomatología característica, sin embargo, para la mayoría de los efectos tóxicos que produce del As aún no se conoce en detalle el mecanismo de acción tóxica. Los mecanismos moleculares de acción del arsenito (unión a grupos sulfhidrilos) y del arseniato (sustitución del fosfato) están bien identificados, sin embargo, las consecuencias a nivel subcelular, celular, tisular y orgánico de esos mecanismos todavía presentan muchos huecos por llenar. A nivel subcelular y celular, la generación de especies reactivas de oxígeno (ERO) y de nitrógeno (ERN) son los mecanismos de acción tóxica del As más estudiados últimamente. Se los ha vinculado con la diferenciación y proliferación de queratinocitos, con la disfunción endotelial, con la resistencia a la insulina, con la inducción de peroxidación lipídica en hígado, de necrosis tubular renal y con cambios en la expresión del receptor estrogénico. Por último, la respuesta celular a proteínas no plegadas (como consecuencia del estrés del retículo endoplásmico) podría ser un mecanismo para explicar la afectación de la inmunidad humoral y la celular.

Chronic exposure to inorganic arsenic (As) through drinking water leads to the development of the disease known as hydroarsenicism. This disease presents characteristic symptomatology but the mechanisms underlying most of the toxic effects produced by As are not fully understand. The molecular mechanisms of action of arsenite (binding to sulfhydryl groups) and arsenate (phosphate substitution) are well identified, however, the consequences at the subcellular, cellular, tissue and organic levels of these mechanisms still have many gaps to fill. At the subcellular and cellular level, the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are the most studied mechanisms of toxic action. They have been linked to the differentiation and proliferation of keratinocytes, endothelial dysfunction, insulin resistance, induction of lipid peroxidation in the liver, renal tubular necrosis and changes in the expression of estrogen receptor. Finally, the cellular response to unfolded proteins (as a consequence of the stress of the endoplasmic reticulum) could be a mechanism to explain the affectation of humoral and cellular immunity.

Alteraciones bioquímicas en individuos expuestos al arsénico en el agua de bebida en Tucumán, Argentina / Biochemical alterations in individuals consuming high levels of arsenic in drinking water in Tucuman, Argentina

El objetivo de esta investigación fue evaluar los niveles del ácido siálico (S) y enzimas hepáticas en individuos que consumieron agua con arsénico (As) relacionándolos con la presencia ("I con H") o no de hepatomegalia ("I sin H"). Se incluyeron 200 individuos, 85 correspondieron al Grupo Control (GC), 32 "I con H" y 83 "I sin H" quienes habían consumido agua con niveles mayores a 0,01 mg/L. Se les tomó una muestra de sangre venosa y se les realizó el dosaje del S y de las enzimas alaninaninotransferasa (ALT), aspartatoaminotransferasa (AST), fosfatasa alcalina (FAL), gamma glutamil transferasa (GGT), bilirrubina directa (BD) y total (BT), lactato deshidrogenasa (LDH) y 5' nucleotidasa (5'Nu). En los individuos que consumieron agua contaminada se encontró un aumento de los niveles del S. En el grupo "I con H", la FAL, la GGT y la LDH se encontraron aumentadas. En el grupo "I sin H", la GGT y la LDH tuvieron niveles elevados. En los individuos expuestos al As, no se encontraron alteraciones en los otros parámetros bioquímicos estudiados y la prevalencia de hepatomegalia no fue significativa. Los cambios bioquímicos encontrados fueron compatibles con la presencia de un patrón colestásico. Estos datos muestran que la concentración del S sérico podría servir como un indicador de exposición al arsénico que podría ser utilizado en forma conjunta con otros marcadores.

The aim of this study was to investígate the relationship between the levels of serum sialic acid (S) and hepatic enzymes in individuáis who drink As contaminated water. Two hundred individuáis were selected: 85 were the control group, 32 presented hepatomegaly (I with H) and 83 did not present hepatomegaly (I without H) who had consumed drinking water containing As levels higher than O.Ol mg/L. Blood samples were collected for the determination of S and hepatic enzymes in serum: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (FAL), gamma glutamil transpeptidase (GGT), direct (BD) and total bilirrubin (BT), lactate deshydrogenase (LDH) and 5'nucleotldase (5'Nu). The populatlon exposed to As in drinking water presented high levels of S, FAL, GGT, LDH and GGT, LDH were increased in I with H and I without H respectively. No significant changes were observed in the other parameters studied. Prevalence of hepatomegaly was not significantly higher and the hepatic biochemical changes were related with the presence of cholestasis in As-exposed people. These data show that people with high As level intake would have an increased sialoprotein replacement which could be an marker with other one of the alterations caused by arsenic.

Hidroarsenisismo crónico regional endémico: un desafío diagnóstico y de prevención / Chronic endemic regional hydroarsenicism: a challenge for diagnosis and prevention

El arsénico (As) es un semi-metal, ampliamente distribuido en la naturaleza en aguas y suelos. La contaminación de los cursos de agua, tanto superficiales como profundos, constituye el principal problema ambiental generado por este elemento. La intoxicación con As se denomina hidroarsenicismo crónico regional endémico (HACRE). Su importancia de la intoxicación crónica con As en la infancia está dada por los conocidos efectos asociados a la exposición acumulada desde el período prenatal en bajas concentraciones. El HACRE se desarrolla progresivamente, comprometiendo diversos órganos y sistemas, principalmente la piel. Una de las complicaciones más importantes del HACRE es el desarrollo de neoplasias, principalmente tumores cutáneos. El HACRE es una enfermedad prevenible. La salud ambiental infantil representa un desafío del nuevo milenio y los profesionales de la salud cumplen un rol fundamental frente a las amenazas ambientales como las que presentala intoxicación crónica con arsenico.

Arsenic (As) is a semimetal that is widely distributed in nature, in water and soil. In Argentine, the contamination of both waterways and groundwater represents the main environmental problem caused by this element. Chronic As poisoning is known as Chronic endemic regional hydroarsenicism (C.E.R.HA.). Long-term exposure to low concentrations of the element from the prenatal period onward results in the well-known symptoms of chronic As poisoning. CERHA develops progressively, compromising different organs and systems, most importantly the skin. One of the most important complications of CERHA is de development of neoplasias, mainly skin tumors. Childhood environmental health is a challenge in the new millennium and health care professionals play a fundamental role in the protection against environmental hazards such as chronic arsenic poisoning.

Effect of drinking arsenic contaminated water in children.

OBJECTIVE: Chronic arsenic toxicity due to drinking of arsenic contaminated water is a major environmental health hazard throughout the world including India. Though lot of information is available on health effects due to chronic arsenic toxicity in adults, knowledge of such effect on children is scanty. A review of available literature has been made to highlight the problem in children. REVIEW METHODS: Scientific publication in journals, monograph, thesis and proceedings of conferences on arsenic in regard to epidemiological, clinical and psychometric studies were reviewed. RESULTS: Skin abnormalities including pigmentation change and keratosis are the diagnostic signs of chronic arsenic toxicity in adults. Incidence of skin manifestations vary between 1.9-37.1% in various arsenic exposed children populations in different regions of the world. Occurrence of chronic lung disease including pulmonary interstitial fibrosis was described in arsenic exposed children in Chile. Affection of intellectual function is also reported from Thailand, Bangladesh and India. CONCLUSION: Chronic arsenic toxicity due to drinking of arsenic contaminated water causes significant morbidity in children in different parts of the world.

Association of arsenic-contaminated drinking-water with prevalence of skin cancer in Wisconsin's Fox River Valley.

During July 2000-January 2002, the Wisconsin Division of Public Health conducted a study in 19 rural townships. A high percentage of private drinking-water wells in these townships contained traces of arsenic. Residents were asked to collect well-water samples and complete a questionnaire regarding residential history, consumption of drinking-water, and family health. In total, 2,233 household wells were tested, and 6,669 residents, aged less than one year to 100 years, provided information on water consumption and health. The well-water arsenic levels ranged from less than 1.0 to 3,100 microg/L. The median arsenic level was 2.0 microg/L. The arsenic levels were below the federal drinking-water standard of 10 microg/L in 80% of the wells, while 11% had an arsenic level of above 20 microg/L. Of residents aged over 35 years, those who had consumed arsenic-contaminated water for at least 10 years were significantly more likely to report a history of skin cancer than others. Tobacco use was also associated with higher rates of skin cancer and appeared to synergize the effect of arsenic on the development of skin cancer.

Arsenic exposure from drinking-water and carotid artery intima-medial thickness in healthy young adults in Bangladesh.

Epidemiological studies have linked high levels (>200 microg/L) of chronic exposure to arsenic in drinking-water with elevated risks of several vascular diseases. In this pilot study, the association between low-level arsenic exposure and carotid artery intimal-medial thickness (IMT) was evaluated among 66 healthy, normotensive, relatively young individuals (mean age 35 years) participating in the ongoing Health Effects of Arsenic Longitudinal Study in Bangladesh. Participants with a higher carotid IMT (>0.75 mm) in general had higher levels of past chronic exposure of arsenic than those with a lower carotid IMT (< or = 0.75 mm). Although the differences in average arsenic exposure between the two groups were not statistically significant, the findings suggest a possible association between low-level arsenic exposure from drinking-water and carotid atherosclerosis, warranting the need for larger studies.

Prevalence of arsenic-related skin lesions in 53 widely-scattered villages of Bangladesh: an ecological survey.

A survey was carried out to provide a representative assessment of prevalence and risk of arsenic-related skin lesions in relation to geographical distribution of arsenic in wells of rural Bangladesh as a necessary background for research into effects in pregnancy and cancer risks. A systematic random sample of 53 villages in four divisions of Bangladesh served by Gonoshasthaya Kendra was selected, and all women aged 18 years or more (n=16,740) were listed. Trained paramedics recorded the presence of skin thickening and nodules on the palms and soles, together with information on tubewell use. The prevalence was related to the mean concentration of arsenic for the district as indicated by data from the British Geological Survey and to the date the first well in the village was installed. Overall, the observed prevalence was 176 cases (1.3%) in 13,705 women examined, varying from 0% in 26 villages to 23% in one; lesions were observed more frequently on hands than on feet. The estimate doubled with concentrations of arsenic from 11 to < or =50 microg/L and increased more than 20 times at >50 microg/L. In the absence of further information, priority for control measures should be directed at areas where the average concentrations of arsenic are above 50 microg/L, especially in villages where skin lesions have been identified.

Levels of arsenic in drinking-water and cutaneous lesions in Inner Mongolia.

The most common health effects from drinking-water containing dissolved arsenic are skin abnormalities and lesions that are typically diagnosed as keratosis and pigment disorder. It was previously reported that the prevalence of cutaneous lesions was about 44% in arsenic-affected villages. However, there has been little research on the relationship between levels of arsenic in drinking-water and cutaneous lesions in Inner Mongolia. One study examined the association between the prevalence of keratosis and levels of arsenic exposure and the relationship between pigment disorder and levels of arsenic exposure among villagers aged 18 years or older in the arsenic-affected village of Hetao Plain in Inner Mongolia, PR China. The study included 227 participants who were affected by cutaneous lesions and 221 participants who were not affected by cutaneous lesions diagnosed in 1996 and 1998. Well-water drunk by the participants was collected to analyze arsenic content. Adjusting for age, sex, and smoking, logistic regression was applied to calculate the risks that arsenic in drinking-water will lead to cutaneous lesions. The results from the logistic regression showed that, with the increase of arsenic concentration in water, the risk of pigment disorder also increased (odds ratio [OR]=5.25, 95% confidence interval [CI] 1.32-83.24 for 50-199 microg/L; OR=10.97, 95% CI 1.50-79.95 for 200-499 [microg/L; OR=10.00, 95% CI 1.39-71.77 for > or = 500 microg/L (p=0.000), but the association between risk of keratosis and levels of arsenic was not significant (p=0.346). The findings suggest that keratosis is an early feature of arsenic poisoning, and the development of pigment disorder depends on higher doses of arsenic intake rather than keratosis. Further studies are needed to confirm that cutaneous lesions and other adverse health effects occur at low levels of arsenic exposure.

Electrocardiographic abnormalities among arsenic-exposed persons through groundwater in Bangladesh.

This study was carried out among arsenic-exposed and non-exposed people of Bangladesh to assess and compare their cardiac status based on electrocardiographic (ECG) findings. For the purpose of the study, participants were included in three groups: arsenic-exposed persons with arsenicosis (arsenicosis group), arsenic-exposed persons without arsenicosis (non-arsenicosis group), and persons not exposed to arsenic (non-exposed group). Each group included 50 respondents. In this study, no significant difference in heart rate, rhythm, axis, and pulse rate interval was detected among the arsenicosis, non-arsenicosis and non-exposed groups. A significant difference in corrected QT interval between the arsenicosis and the non-exposed group (p<0.05) was observed. On the contrary, no statistically significant difference in corrected QT interval between the non-arsenicosis and the non-exposed group was found. Abnormal QRS complex was found among 14%, 8%, and 2% of the arsenicosis, non-arsenicosis, and non-exposed groups respectively. ECG findings, indicative of left ventricular hypertrophy, ischaemic heart disease, and right bundle branch block, were high among the arsenicosis group. Overall, abnormal ECG findings were high (58%) among the respondents of the arsenicosis group and were highly significant (p<0.001). The findings revealed that there was a significant association between ECG abnormalities and arsenic exposure.

Arsenic in drinking-water and reproductive health outcomes: a study of participants in the Bangladesh Integrated Nutrition Programme.

This study examined 2,006 pregnant women chronically exposed to a range of naturally-occurring concentrations of arsenic in drinking-water in three upazilas in Bangladesh to find out relationships between arsenic exposure and selected reproductive health outcomes. While there was a small but statistically significant association between arsenic exposure and birth-defects (odds ratio=1.005, 95% confidence interval 1.001-1.010), other outcomes, such as stillbirth, low birth-weight, childhood stunting, and childhood under-weight, were not associated with arsenic exposure. It is possible that the association between arsenic exposure from drinking-water and birth-defects may be a statistical anomaly due to the small number of birth-defects observed. Future studies should look more closely at birth-defects, especially neural tube defects, to elucidate any potential health effects associated with arsenic exposure from drinking-water. Further, given the knowledge that serious health effects can result from chronic arsenic exposure, efforts to find alternatives of safe drinking-water for the population must continue.

Association between chronic exposure to arsenic and slow nerve conduction velocity among adolescents in Taiwan.

The association between chronic exposure to arsenic and peripheral neuropathy has been controversial in previous studies, which may be due to the influence of factors, such as age, gender, chronic diseases, occupational injuries, and arsenic exposure. To clarify the question of this association, a cross-sectional study was designed. In total, 130 junior high school students aged 12-14 years were included and examined for the motor and sensory nerve conduction velocity of peripheral nerves in their right-upper and lower limbs. Concentrations of arsenic in well-water and history of drinking well-water were retrieved from a baseline database created in 1991. After adjustment for gender and height, a significant odds ratio of 2.9 (95% confidence interval [CI] 1.1-7.5) was observed for the development of slow nerve conduction velocity of the sural sensory action potential (SAP) among the study subjects with a cumulative arsenic dosage of>100.0 mg. In addition, a borderline statistical significance with odds ratio of 7.8 (95% CI 1.001-69.5) for the development of slow nerve conduction velocity of sural SAP was also observed among the study subjects who drank well-water containing arsenic concentrations of >50.0 microg/L and with a cumulative arsenic dosage of >100.0 mg. The study found that chronic exposure to arsenic might induce peripheral neuropathy. It also found that the slowing of the nerve conduction velocity of sural SAP might be an early marker of chronic arsenic neuropathy.

Brainstem auditory evoked potentials (BAEPs) study in chronic arsenic poisoning patients.

OBJECTIVES: To explore the possible neurotoxicity of arsenic to auditory sensory pathways and evaluate roles of BAEPs in the detection of early brain damage resulting from arsenic exposure. DESIGN: Cross-sectional analytic study. MATERIAL AND METHOD: Twenty nine females with skin lesions consistent with arsenical dermatoses and 27 controls who met the inclusion criteria were investigatetd by Auditory Evoked Potentials (AEPs). Case findings resulted from a house-to-house survey in village 12, Ronphibun subdistrict and village 5, Saothong subdistrict, Nakhon Si Thammarat Province, southern Thailand in 1995. RESULTS: Differences between the arsenic-exposed population and the referent group regarding BAEP parameters, BAEP latencies and interpeak latencies were not found. CONCLUSION: Evidence of the abnormalities of the auditory sensory pathways was not found among female patients with arsenical dermtoses in Ronphibun. The role of BAEPs in the detection of brain damage resulting from arsenic exposure could not be demonstrated.

Pulmonary involvement in chronic arsenic poisoning from drinking contaminated ground-water.

OBJECTIVES: Chronic arsenic poisoning, due to ingestion of contaminated ground-water, is a major public health problem in West Bengal. It causes multiorgan damage. The present study attempts to objectively investigate the pulmonary involvement by examining the lung function. The nature of lung changes was also evaluated. MATERIAL AND METHODS: One hundred and seven subjects with (cases) and 52 subjects without (controls) chronic arsenic poisoning were examined by spirometry. Forced expiratory volume-I second (FEVI), forced vital capacity (FVC) and peak expiratory flow rate (PEFR) were measured. Bronchoalveolar lavage (BAL) was performed in five cases with and five cases without pulmonary involvement. RESULTS: Thirty three (30.8%) cases and four (7.6%) controls (p<0.01) had respiratory involvement. The pattern of involvement in cases was: obstructive- 20(68.9%) (including three (10%) with bronchiectasis), restrictive- 1(3.5%), mixed- 8(27.6%), malignancy- 4(12.1%) (adenocarcinoma-I, squamous cell- 2, undifferentiated- I). FEVI (69.7+/-25.9 [n=105] vs 83.7+/-15.19 [n=51], p=0.0005), FVC (77.4+/-22.7 [n=105] vs 85.6+/-18.23 [n=51], p=0.025), FEVI/FVC (73.6+/-13.38 [n=105] vs 79.1+/-18.65 [n=52], p=0.007) and PEFR (53.9+/-21.52 [n= 103] vs 67.3+/-18.36 [n=51], p=0.0002) (percent of predicted) were all reduced more in cases compared to controls. Worsening of these parameters correlated with increasing degree of arsenic toxicity. Markers of inflammation (macrophage, lactate dehydrogenase, nitric oxide) were apparently more in the BAL fluid of those with lung involvement than in those without, though the arsenic content did not differ significantly. CONCLUSION: Chronic arsenic poisoning causes pulmonary involvement, predominantly obstructive, the degree of which worsens with increasing degree of arsenic toxicity. Inflammation, rather than direct toxicity, appears to be the underlying mechanism.

Arsenic-related health problems among hospital patients in southern Bangladesh.

To assess the health effects of arsenic poisoning and to determine the relationship among duration and severity of skin lesions, exposure dose of arsenic, and nutritional status of people, 150 patients attending the Dermatology Outpatients Department of Sher-e-Bangla Medical College Hospital, Barisal, Bangladesh, were included in this cross-sectional study. The study was conducted during January-December 2000. Records of patients were collected prospectively using a pre-tested questionnaire, which included information on demography, sources of water for drinking and cooking, duration and amount of drinking-water obtained from shallow tubewells, clinical presentations, complications, and physical and laboratory findings. Water samples from tubewells currently being used by individual patients were examined. Nine percent of the patients were unaware that arsenic-contaminated water causes diseases. Due to lack of alternative water supplies, 25% of the subjects were still drinking water from contaminated tubewells. About 18% did not complain of any clinical symptoms, except that their skin lesions were ugly-looking, and 82% had moderate or severe skin lesions. Thirty-one percent of the water samples had arsenic concentrations 10-fold higher than the permissible limit of 0.05 mg/L in Bangladesh and 50-fold higher than the WHO guideline value of 0.01 mg/L. The mean arsenic concentration in water was significantly associated with the severity of disease. Body mass index correlated inversely (r = -0.298, p = 0.013) with the duration of disease after controlling for age. The findings suggest the need to enhance public awareness on negative health effects of arsenic poisoning in rural Bangladesh. From a public-health perspective, effective intervention strategies need to be developed to curb the exposure, strengthen rapid diagnostic facilities, establish effective treatment facilities in rural areas, and improve the nutritional status of people.

Desarsenicación del agua utilizando hidrogel activado de hidróxido de aluminio / Obtaining arsenic-free water using hydroxide of aluminum activated hydrogel

Estudios realizados en la provincia de Tucumán, otras provincias argentinas y algunos países latinoamericanos tales como Chile y México sobre el hidroarsenicismo crónico, demuestran la importancia sanitaria de contar con agua de bebida libre de arsénico ya que aún cuando este se encuentre en concentraciones muy bajas puede causar a largo plazo enfermedades neoplásicas malignas. Ultimamente la OMS ha propuesto normas más rigurosas para la concentración máxima admisible de arsénico en aguas para bebida humana reduciendo cinco veces el límite de 0,05 ppm, llevándolo a 0,01 ppm. El presente trabajo presenta un método para eliminar el arsénico del agua tratando en forma individual volúmenes reducidos de agua para bebida. Este método se aconseja aplicarlo en el caso de poblaciones dispersas de la zona rural que carecen de agua potable e infraestructura sanitaria y tienen acceso fácil a través de pozos de primera napa a fuentes de agua contaminada por arsénico. En este método la eliminación del arsénico se basa en un fenómeno de adsorción producido por un hidrogel activado de hidróxido de aluminio puro obtenido por síntesis química en el estado de crema gelatinosa que contiene un agregado de hipoclorito de calcio para producir además una desinfección del agua basado en las propiedades del cloro. El producto antiarsénico se aplica en dosis de 5 ml por litro de agua, el cual se dispersa en el interior de una botella conteniendo el agua contaminada agitando la misma y evitando arrastrar el sedimento y quedando lista para beber. El procedimiento no es solo capaz de remover el arsénico, sino también produce clarificación, desodorización y desinfección del agua dejándola con calidad de agua potable. El costo estimado por cada litro de agua tratada se calcula en U$S 0,08. La inocuidad del producto usado, basada en las propiedades del hidróxido de aluminio, está suficientemente comprobada por su amplia aplicación en la industria farmaceútica.