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Ingested arsenic and internal cancer: A historical cohort study followed for 33 years
Abstract
A historical cohort study was conducted to investigate the long-term effect of exposure to ingested arsenic. The 454 residents who had been identified in a list made in 1959 were followed until 1992. They lived in an arsenic-polluted area, called Namiki-cho, Nakajo-machi, in Niigata Prefecture, Japan, and used well water containing inorganic arsenic. The exposure period was estimated to be about 5 years (1955-1959). Death certificates for the people who died between 1959 and 1992 were examined, and a total of 113 of the 454 residents were estimated to have drunk well water containing a high dose of arsenic (> or = 1 ppm). The standardized mortality rate ratios of these 113 residents were 15.69 for lung cancer (observed/expected = 8/0.51; 95% confidence interval (CI) 7.38-31.02) and 31.18 for urinary tract cancer (observed/expected = 3/0.10; 95% CI 8.62-91.75). Cox's proportional hazard analyses demonstrated that the hazard ratios of the highest exposure level group (> or = 1 ppm) versus the background exposure level group (0.001 ppm) were 1.74 (95% CI 1.10-2.74) for all deaths and 4.82 (95% CI 2.09-11.14) for all cancers. The analysis according to the skin signs of chronic arsenicism in 1959 showed that they were useful risk indicators for subsequent cancer development. In the development of lung cancer, there was evidence of synergism between arsenic intake and smoking habit.
... Much of evidence related to the carcinogenetic association between As in drinking water and lung cancer is from Asia and South America, where drinking water contains high concentrations (concentrations ≥150 μg/L) of As (Chen et al., 1985;Hopenhayn-Rich et al., 1998;Smith et al., 1998;Tsuda et al., 1995). Findings from epidemiological studies and systematic reviews examining the dose-response relationship between lung cancer and lower concentrations of As in drinking water are inconclusive. ...
... Fifteen studies met the inclusion criteria for the meta-analysis: six studies reporting incidence and nine studies reporting mortality from lung cancer. Study locales included -Taiwan (8 studies) (Chen et al., 2004;Chen et al., 1988a;Chiou et al., 1995;Yang et al., 2013;Chung et al., 2013;Morales et al., 2000;Su et al., 2011;Tsai et al., 1999), Chile (4 studies) (Ferreccio et al., 2000;Steinmaus et al., 2013;Steinmaus et al., 2014a;Roh et al., 2018), USA (1 study) (Ferdosi et al., 2016), Argentina (1 study) (Hopenhayn-Rich et al., 1998) and Japan (1 study) (Tsuda et al., 1995). ...
... The remaining 25 studies controlled for smoking either by direct adjustment, stratification or by including socioeconomic status as a proxy variable for tobacco smoking (Chen et al., 2010;D'Ippoliti et al., 2015;Chen et al., 2004;Chiou et al., 1995;Yang et al., 2013;Chung et al., 2013;Ferreccio et al., 2000;Steinmaus et al., 2013;Steinmaus et al., 2014a;Mendez Jr. et al., 2017;Chen et al., 1986;Mostafa et al., 2008;Heck et al., 2009;Steinmaus et al., 2010;Dauphine et al., 2013;Ferreccio et al., 2013;Melak et al., 2014;Steinmaus et al., 2014b;Baastrup et al., 2008;Garcia-Esquinas et al., 2013;Hsu et al., 2013;Argos et al., 2014;Wu et al., 2016;Hsu et al., 2017;Nuvolone et al., 2023). Among the 15 studies included in the meta-analysis (Hopenhayn-Rich et al., 1998;Tsuda et al., 1995;Chen et al., 2004;Chen et al., 1988a;Chiou et al., 1995;Yang et al., 2013;Chung et al., 2013;Morales et al., 2000;Su et al., 2011;Tsai et al., 1999;Ferreccio et al., 2000;Steinmaus et al., 2013;Steinmaus et al., 2014a;Roh et al., 2018;Ferdosi et al., 2016), eight (six ecological and two cohort) studies did not account for tobacco smoking (Hopenhayn-Rich et al., 1998;Tsuda et al., 1995;Chen et al., 1988a;Morales et al., 2000;Su et al., 2011;Tsai et al., 1999;Roh et al., 2018;Ferdosi et al., 2016). Although the remaining studies accounted for tobacco smoking, more than half of these did not control for other important covariates, including socioeconomic status or other diseaserelated characteristics (e.g., body mass index, family history of cancer, or comorbidities) (Chiou et al., 1995;Yang et al., 2013;Chung et al., 2013;Steinmaus et al., 2014a). ...
... De nombreuses études épidémiologiques cas-témoins et de cohortes indiquent un excès de risque de cancer de l'arbre urinaire dans les populations consommant une eau contaminée par l'arsenic [28,140]. Ces études ont été conduites par de multiples équipes et dans plusieurs pays : à Taïwan [140], en Argentine [140,267], au Chili [140,264], au Japon [268] et aux USA [269]. ...
... Plusieurs études épidémiologiques écologiques et castémoins conduites à Taïwan [140] en Argentine [276], au Chili [277] et au Japon [268], indiquent un excès de risque de mortalité par cancer hépatique (tous types confondus) dans des populations consommant des eaux contaminées par l'arsenic. La plupart d'entre elles indiquent une augmentation du risque avec la concentration d'arsenic dans l'eau, ce qui est fortement en faveur d'un lien causal. ...
... En 2004, l'OEHHA a caractérisé les relations dose-réponse pour les risques de cancer bronchopulmonaire et des voies urinaires associés à la consommation d'eau contaminée par de l'arsenic [6], à partir d'études épidémiologiques conduites à Taïwan [291,292], en Argentine [276], au Chili [293,294] et au Japon [268]. L'excès de risque unitaire observé était de 2,7 × 10 −4 par g/L d'arsenic dans l'eau. ...
Contexte et objectifs
À la demande de la direction générale de la santé (DGS), la HAS et la STC ont coordonné l’élaboration d’une recommandation de bonne pratique à l’intention des professionnels de santé, pour le dépistage, la prise en charge et le suivi des populations résidant sur des sites et sols pollués ou à risque de pollution par l’arsenic inorganique (Asi).
Résultats et principales recommandations
Les principales sources d’exposition de la population générale à l’Asi sont alimentaires et constituées par l’eau et les céréales, en particulier le riz. Ce bruit de fond est assez important, avec des prises moyennes de 0,2 à 0,4 μg/kg pc/j et des 95es percentiles compris entre 0,5 et 0,8 μg/kg/j, selon les tranches d’âge ; les enfants âgés de 7 à 12 mois sont la fraction la plus exposée du fait de l’alimentation. Dans les sites dont le sol est pollué par l’Asi, le principal mode de contamination est l’ingestion de poussières et de terre ; les enfants de moins de 7 ans, en particulier, ceux âgés de 6 mois à 4 ans sont la fraction de la population la plus exposée ; des surexpositions sont également prévisibles chez les individus plus âgés mais géophages ou onychophages et à un moindre degré chez les consommateurs habituels de légumes produits localement (en particulier, les légumes-feuilles) ou d’eau locale (hors celle du réseau public). La bioaccessibilité (fraction dissoute dans le tube digestif et disponible pour y être absorbée) de l’Asi des sols et le risque de surexposition associé sont très variables. Les effets sur la santé de l’exposition chronique à l’Asi sont nombreux et divers. Les effets critiques (ceux qui surviennent pour les expositions les plus faibles) sont : pour les effets à seuil de dose des anomalies de la pigmentation et de la kératinisation de la peau ; pour les effets sans seuil de dose, des carcinomes cutanés baso-cellulaires et épidermoïdes en cas d’exposition par voie orale et des cancers broncho-pulmonaires pour la voie respiratoire. Les valeurs toxicologiques de référence (VTR) retenues par le groupe de travail sont : 0,3 μg/kg pc/j pour les effets à seuil de dose, toutes voies confondues et pour les effets sans seuil, des excès de risque unitaire (ERU) de respectivement, 1,5.10⁻³ par μg/kg pc/j par voie orale et 3,3.10⁻³ par μg/m³, par voie respiratoire. L’indicateur biologique d’exposition (IBE) de référence pour l’Asi est la somme des concentrations urinaires de l’Asi, de l’acide méthylarsonique (MMA) et de l’acide diméthylarsinique (DMA). Cette somme (ΣAs) est un bon indicateur de l’exposition récente (des derniers jours) à l’Asi. Les produits de la mer (animaux ou végétaux) contenant du DMA, ils ne doivent pas être consommés dans les 3 jours précédant le prélèvement urinaire qui doit être réalisé dans des conditions propres à prévenir toute contamination externe. Dans la population générale résidant en France et en l’absence d’exposition à une source spécifique d’Asi, ΣAs est généralement inférieure à 10 μg/g créatinine et 11 μg/L. Cependant, on manque de données chez les individus de moins de 18 ans, en particulier chez les moins de 6 ans. Le seuil de 25 mg/kg de poussière ou de terre constitue la limite supérieure de la concentration d’Asi dans les sols dits « ordinaires » dans le référentiel de l’INRA utilisé par la Méthodologie nationale de gestion des sites et sols pollués. Les évaluations réalisées par le groupe de travail ont montré que, à ce niveau, lorsque la bioaccessibilité de l’Asi était de 100 %, le risque de surexposition des enfants de 6 mois à 4 ans et des individus plus âgés géophages ou onychophages était élevé. Il est donc recommandé de rechercher une surexposition à l’Asi, lorsque la concentration de sa fraction bioaccessible dans le sol est > 25 mg/kg. Les populations cibles du dépistage des surexpositions sont alors : les enfants âgés de 6 mois à 4 ans ; les femmes enceintes ou envisageant de débuter une grossesse, si elles sont géophages ou onychophages ou si elles consomment des légumes produits localement, de l’eau extraite localement (hors l’eau du réseau public), si elles jardinent ou ont des activités de loisir exposant aux poussières de sol ; les individus de tous âges avec pica, géophagie ou onychophagie. L’outil du dépistage est ΣAs et les valeurs limites sont de 10 μg/g créatinine chez les personnes de plus de 12 ans, 10 μg/g créatinine + 11 μg/L chez les autres. Dans les sites pollués par l’Asi, il est recommandé de constituer une base de données rassemblant et conservant tous les résultats des évaluations biométrologiques des expositions : pour la traçabilité de ces dernières, à l’usage des intéressés, de leurs familles et des professionnels de santé concernés ; également, pour des analyses périodiques, guidant les actions de prévention et évaluant leur efficacité. Il n’est recommandé de rechercher des complications de l’exposition à l’Asi, sur un site pollué que lorsque le dépistage a montré des cas de surexposition (voir ci-dessus). La population-cible de cette recherche de complications n’est pas la même que celle visée par la recherche de surexpositions. Les complications sont surtout attendues chez les individus surexposés depuis longtemps. Il est recommandé de ne les rechercher que chez les personnes dont l’exposition (séjour sur un site dont l’Asi bioaccessible des sols est > 25 mg/kg) cumulée est d’au moins 5 ans et dont l’exposition a débuté avant l’âge de 4 ans et/ou qui ont une durée cumulée d’au moins un an de consommation habituelle de légumes produits localement ou d’eau locale (hors celle du réseau public) et/ou qui ont ou ont eu sur le site un pica, une géophagie ou une onychophagie. Les effets sur la santé à rechercher sont, en première intention, des troubles de la pigmentation et de la kératinisation cutanée, associés ou non à des carcinomes de la peau. Les autres effets possibles de l’exposition à l’Asi ne nécessitent d’être recherchés que si des signes cutanés sont présents. Les médecins locaux doivent recevoir une formation spécifique sur les complications possibles de l’exposition à l’Asi, les caractéristiques des personnes à risque et les modalités du diagnostic. La collaboration avec les spécialistes hospitalo-universitaires loco-régionaux est indispensable pour ces formations et la confirmation des diagnostics. En cas de dépassement du ou des seuils biométrologiques de référence, la personne concernée ou son entourage adulte doit être informée des causes probables de ce dépassement et des mesures à prendre pour prévenir d’autres contaminations. L’efficacité de ces mesures préventives est vérifiée par un nouveau dosage urinaire 1 à 3 mois plus tard (dans les 2 mois, s’il s’agit d’une femme enceinte). Même en l’absence de dépassement des valeurs seuils, une surveillance biométrologique est indiquée chez les individus à risque résidant sur un site ou l’Asi bioaccessible des sols est > 25 mg/kg : elle est semestrielle chez les enfants de 6 mois à 4 ans, annuelle chez ceux de 5 et 6 ans, au moins semestrielle chez les géophages, onychophages ou consommateurs habituels de légumes produits localement. De même une surveillance clinique (recherche de complications cutanées : voir ci-dessus) au moins annuelle est indiquée chez les personnes dont l’exposition cumulée est d’au moins 5 ans et dont l’exposition a débuté avant l’âge de 4 ans et/ou qui ont une durée cumulée d’au moins un an de consommation habituelle de légumes produits localement ou d’eau locale (hors celle du réseau public) et/ou qui ont ou ont eu sur le site un pica, une géophagie ou une onychophagie et/ou qui ont des antécédents personnels de dépassement des seuils biométrologiques.
... De nombreuses études épidémiologiques cas-témoins et de cohortes indiquent un excès de risque de cancer de l'arbre urinaire dans les populations consommant une eau contaminée par l'arsenic [28,140]. Ces études ont été conduites par de multiples équipes et dans plusieurs pays : à Taïwan [140], en Argentine [140,267], au Chili [140,264], au Japon [268] et aux USA [269]. ...
... Malgré l'absence d'étude épidémiologique publiée, la fréquence de l'association de cette tumeur rare avec une exposition à l'arsenic dans les cas publiés est en faveur d'un lien causal. Plusieurs études épidémiologiques écologiques et castémoins conduites à Taïwan [140] en Argentine [276], au Chili [277] et au Japon [268], indiquent un excès de risque de mortalité par cancer hépatique (tous types confondus) dans des populations consommant des eaux contaminées par l'arsenic. La plupart d'entre elles indiquent une augmentation du risque avec la concentration d'arsenic dans l'eau, ce qui est fortement en faveur d'un lien causal. ...
... En 2004, l'OEHHA a caractérisé les relations dose-réponse pour les risques de cancer bronchopulmonaire et des voies urinaires associés à la consommation d'eau contaminée par de l'arsenic [6], à partir d'études épidémiologiques conduites à Taïwan [291,292], en Argentine [276], au Chili [293,294] et au Japon [268]. L'excès de risque unitaire observé était de 2,7 × 10 −4 par g/L d'arsenic dans l'eau. ...
Résumé
Contexte et objectifs
À la demande de la Direction générale de la santé, la Haute Autorité de santé, en partenariat avec la Société de toxicologie clinique, a élaboré des recommandations pour le dépistage des surexpositions environnementales à l’arsenic inorganique (Asi) et la prise en charge des populations concernées. Nous rapportons l’étape préalable à la production de ces recommandations qui a consisté à caractériser les effets possibles sur la santé de l’Asi et les valeurs toxicologiques de référence propres (VTR) à assurer la protection de la santé de la population.
Méthode
En première intention, les monographies publiées par des agences sanitaires nationales ou internationales au cours des trois dernières décennies ont été examinées. Cette analyse a été complétée par une recherche bibliographique conduite dans Medline et Scopus, ciblée sur les publications postérieures au 1er janvier 2016, année de publication de la plus récente des évaluations publiées antérieurement.
Résultats
L’exposition répétée à l’arsenic inorganique peut être à l’origine de multiples effets sanitaires. En raison de leur apparition aux doses les plus faibles et de leurs relations dose–réponse les mieux caractérisées, les effets cutanés non cancérogènes (troubles de la pigmentation et de la kératinisation) ont été retenus comme effets critiques à seuil, avec une VTR de 0,3 μg/kg pc/j. Les effets cancérogènes critiques sont les carcinomes cutanés pour la voie orale, avec un excès de risque unitaire vie entière de 1,5 × 10⁻³ par μg/kg pc/j et les cancers bronchopulmonaires pour la voie respiratoire avec un excès de risque unitaire vie entière de 3,3 × 10⁻³ par μg/m³.
Discussion
Les principales sources d’exposition à l’arsenic inorganique de la population générale sont alimentaires (eau et céréales, en particulier riz). En France, les dernières évaluations de l’exposition alimentaire de la population indiquent que le 95e percentile est de 0,46–0,51 μg/kg pc/j chez les adultes et de 0,61–0,77 μg/kg pc/j chez les enfants de 7–12 mois (les plus fortement exposés). Ces niveaux dépassent la VTR recommandée pour la protection contre les effets à seuil et correspondent à un risque de cancer cutané de 6,9 × 10⁻⁴ à 1,2 × 10⁻³, pour une exposition vie entière. Cela implique de maintenir les autres sources d’exposition à l’Asi à des niveaux aussi faibles que possible.
... Among these, 103 potentially eligible records were chosen for abstract screening and 56 studies were excluded because they were reviews, occupational studies, animal studies, or cellular studies. After full-text screening the remaining 47 articles, 15 studies 8,9,12,[19][20][21][22][23][24][25][26][27][28][29][30] involving a total of 218 481 participants met the inclusion criteria ( Fig. 1). Table 1 shows the characteristics for each of the included studies. ...
... Table 1 shows the characteristics for each of the included studies. The publication year of the 15 included studies ranged from 1995 to 2015, including 6 from South America (five studies in Chile 11,20,23,29,30 and one study in Argentina 25 ), 4 from Asia (2 studies in Taiwan, 19,24 one study in Bangladesh, 22 and one study in Japan 20 ), 3 from the US, 23,26,28 and 2 from European countries (Denmark 8 and Italy 9 ). These consist of nine case-control studies 12,[21][22][23][25][26][27]29,30 and six cohort studies. ...
... These consist of nine case-control studies 12,[21][22][23][25][26][27]29,30 and six cohort studies. 8,9,19,20,24,28 The nine case-control studies were incidence studies with adjusted odds ratios as the measure of the association. Three of the six included cohort studies were incidence studies with adjusted incidence rate ratio as the measure of association. ...
Background: High dose arsenic in drinking water (≥100μg/L) is known to induce lung cancer, but lung cancer risks at low to moderate arsenic levels and its dose-response relationship remains inconclusive. Methods: We conducted a systematic review of cohort and case-control studies that quantitatively reported the association between arsenic concentrations in drinking water and lung cancer risks by searching PubMed database till June 14, 2018. Pooled relative risks (RRs) of lung cancer expose to full range (10 μg/L -1000 μg/L) and low to moderate range (<100μg/L) of water arsenic concentrations were calculated using random-effects models. A dose-response meta-analysis was performed to estimate the pooled associations between restricted cubic splines of log-transformed water arsenic and the lung cancer risks. Results: Fifteen studies (9 case-control and 6 cohort studies) involved a total of 218,481 participants met inclusion criteria. Meta-analysis identified significant increased risks of lung cancer exposed to both full range (RR=1.21; 95% confidence interval [CI] =1.05-1.37; heterogeneity I2= 54.3%) and low to moderate range (RR=1.18; 95%CI=1.00-1.35; I2= 56.3%) of water arsenic. In dose-response meta-analysis of eight case-control studies, we found no evidence of non-linearity; although statistical power was limited. The corresponding pooled RRs and their 95%CIs for exposure to 10 μg/L, 50 μg/L, and 100 μg/L water arsenic were 1.02 (1.00-1.03), 1.10 (1.04-1.15), and 1.20 (1.08-1.32), respectively. Conclusion: We provided evidence on the association between increased lung cancer risks and inorganic arsenic in drinking water across low-moderate to high levels. Minimizing arsenic levels in drinking water may be of public health importance.
... 33 Σημαντικές επιδημιολογικές μελέτες σχετικά με τον καρκίνο και την έκθεση στο αρσενικό μέσω του πόσιμου νερού είναι κυρίως οικολογικές μελέτες και λιγότερο μελέτες ασθενών-μαρτύρων και κοόρτης. Πολλές συστηματικές μελέτες έχουν διεξαχθεί σε διάφορα μέρη του κόσμου (Ταϊβάν, Ιαπωνία, Αργεντινή, Χιλή, Μεξικό, ΗΠΑ, Ευρώπη, Αυστραλία) αναφορικά με την έκθεση στο αρσενικό μέσω του πόσιμου νερού και τον αυξημένο κίνδυνο ανάπτυξης καρκίνου της ουροδόχου κύστης και των νεφρών, 34-55 του ήπατος, [34][35][36][37]40,[42][43][44][45]48,[51][52][53]56 του πνεύμονα, [34][35][36][37]40,[42][43][44][45]48,49,[51][52][53]56,57 και του δέρματος. 7,[34][35][36][37]39,40,42,43,48,[58][59][60][61][62][63][64][65][66][67][68][69] Ειδικότερα, σχετικά με τον καρκίνο του ήπατος τα τελευταία 11 χρό-νια έχουν διεξαχθεί σειρά επιδημιολογικών μελετών. ...
... 33 Σημαντικές επιδημιολογικές μελέτες σχετικά με τον καρκίνο και την έκθεση στο αρσενικό μέσω του πόσιμου νερού είναι κυρίως οικολογικές μελέτες και λιγότερο μελέτες ασθενών-μαρτύρων και κοόρτης. Πολλές συστηματικές μελέτες έχουν διεξαχθεί σε διάφορα μέρη του κόσμου (Ταϊβάν, Ιαπωνία, Αργεντινή, Χιλή, Μεξικό, ΗΠΑ, Ευρώπη, Αυστραλία) αναφορικά με την έκθεση στο αρσενικό μέσω του πόσιμου νερού και τον αυξημένο κίνδυνο ανάπτυξης καρκίνου της ουροδόχου κύστης και των νεφρών, 34-55 του ήπατος, [34][35][36][37]40,[42][43][44][45]48,[51][52][53]56 του πνεύμονα, [34][35][36][37]40,[42][43][44][45]48,49,[51][52][53]56,57 και του δέρματος. 7,[34][35][36][37]39,40,42,43,48,[58][59][60][61][62][63][64][65][66][67][68][69] Ειδικότερα, σχετικά με τον καρκίνο του ήπατος τα τελευταία 11 χρό-νια έχουν διεξαχθεί σειρά επιδημιολογικών μελετών. ...
... Σχετικές μελέτες που δημοσιεύτηκαν πριν το 2000 δεν συμπεριλήφθησαν στην παρούσα ανάλυση όπως ορίστηκε αρχικά από τα κριτήρια αποδοχής των μελετών. 34,36,37,40,42,44,45,48,49,[51][52][53][88][89][90][91][92][93][94][95] Το ζήτημα της συσχέτισης της έκθεσης στο αρσενικό μέσω του πόσιμου νερού και τον καρκίνο του ήπατος απασχολεί την επιστημονική κοινότητα έντονα τα τελευταία χρόνια. 96 ...
... In Japan, a historical cohort study was conducted in an arsenic-polluted area in which well water was polluted by liquid waste containing inorganic arsenic from a dye factory [72]. Results showed a significant increase in mortality for lung and urinary tract cancer among residents who drank well water containing a high concentration of arsenic (≥ 1 ppm). ...
... On the other hand, a positive association was found for never smokers but a test for interaction was not statistically significant among women. This observed interaction among men is consistent with studies characterized by a high level of arsenic exposure [72,77,78]. On the other hand, the reason for the discrepant results between men and women is less clear, although possible explanations include the small number of smokers and relatively low validity of estimated arsenic intake from the FFQ among women. ...
Exposure to certain chemicals in the environment may contribute to the risk of developing cancer. Although cancer risk from environmental chemical exposure among general populations is considered low compared to that in occupational settings, many people may nevertheless be chronically exposed to relatively low levels of environmental chemicals which vary by such various factors as residential area, lifestyle, and dietary habits. It is therefore necessary to assess population-specific exposure levels and examine their association with cancer risk. Here, we reviewed epidemiological evidence on cancer risk and exposure to dichlorodiphenyltrichloroethane (DDT), hexachlorocyclohexane (HCH), polychlorinated biphenyls (PCBs), per- and polyfluoroalkyl substances (PFASs), cadmium, arsenic, and acrylamide. Japanese are widely exposed to these chemicals, mainly through the diet, and an association with increased cancer risk is suspected. Epidemiological evidence from Japanese studies to date does not support a positive association between blood concentrations of DDT, HCH, PCBs, and PFASs and risk of breast or prostate cancer. We established assessment methods for dietary intake of cadmium, arsenic, and acrylamide using a food frequency questionnaire. Overall, dietary intakes of cadmium, arsenic, and acrylamide were not significantly associated with increased risk of total cancer and major cancer sites in the Japan Public Health Center-based Prospective Study. However, statistically significant positive associations were observed between dietary cadmium intake and risk of estrogen receptor-positive breast cancer among postmenopausal women, and dietary arsenic intake and risk of lung cancer among male smokers. In addition, studies using biomarkers as exposure assessment revealed statistically significant positive associations between urinary cadmium concentration and risk of breast cancer, and between ratio of hemoglobin adducts of acrylamide and glycidamide and risk of breast cancer. Epidemiological studies of general populations in Japan are limited and further evidence is required. In particular, studies of the association of organochlorine and organofluorine compounds with risk of cancer sites other than breast and prostate cancer are warranted, as are large prospective studies of the association between biomarkers of exposure and risk of cancer.
... Ogawa et al. Tsuda et al. (1992Tsuda et al. ( , 1995 conducted a series of studies on the short-term effects of elements La, Y and Eu on rats fed with hydrated chloride. By comparing the responses of these three REEs with different oral doses of 0, 40, 200 and 1000 mg kg −1 for 28 successive days, results indicated that the biological effects of Y were very similar to those of La except for the accumulating patterns and volumes, while Eu showed an obvious irritation effect as hyperkeratosis of the forestomach and eosinocyte infiltration of stomach submucosa were found in both males and females receiving a dose of 1000 mg kg −1 EuCl 3 -6H 2 O (Tsuda et al., 1992(Tsuda et al., , 1995. ...
... Tsuda et al. (1992Tsuda et al. ( , 1995 conducted a series of studies on the short-term effects of elements La, Y and Eu on rats fed with hydrated chloride. By comparing the responses of these three REEs with different oral doses of 0, 40, 200 and 1000 mg kg −1 for 28 successive days, results indicated that the biological effects of Y were very similar to those of La except for the accumulating patterns and volumes, while Eu showed an obvious irritation effect as hyperkeratosis of the forestomach and eosinocyte infiltration of stomach submucosa were found in both males and females receiving a dose of 1000 mg kg −1 EuCl 3 -6H 2 O (Tsuda et al., 1992(Tsuda et al., , 1995. ...
... Ogawa et al. Tsuda et al. (1992Tsuda et al. ( , 1995 conducted a series of studies on the short-term effects of elements La, Y and Eu on rats fed with hydrated chloride. By comparing the responses of these three REEs with different oral doses of 0, 40, 200 and 1000 mg kg −1 for 28 successive days, results indicated that the biological effects of Y were very similar to those of La except for the accumulating patterns and volumes, while Eu showed an obvious irritation effect as hyperkeratosis of the forestomach and eosinocyte infiltration of stomach submucosa were found in both males and females receiving a dose of 1000 mg kg −1 EuCl 3 -6H 2 O (Tsuda et al., 1992(Tsuda et al., , 1995. ...
... Tsuda et al. (1992Tsuda et al. ( , 1995 conducted a series of studies on the short-term effects of elements La, Y and Eu on rats fed with hydrated chloride. By comparing the responses of these three REEs with different oral doses of 0, 40, 200 and 1000 mg kg −1 for 28 successive days, results indicated that the biological effects of Y were very similar to those of La except for the accumulating patterns and volumes, while Eu showed an obvious irritation effect as hyperkeratosis of the forestomach and eosinocyte infiltration of stomach submucosa were found in both males and females receiving a dose of 1000 mg kg −1 EuCl 3 -6H 2 O (Tsuda et al., 1992(Tsuda et al., , 1995. ...
Biomaterials in the form of implants (sutures, bone plates, joint replacements, etc.) and medical devices (pacemakers, artificial hearts, blood tubes, etc.) are widely used to replace and/or restore the function of traumatized or degenerated tissues or organs, and thus improve the quality of life of the patients. The first and foremost requirement for the choice of the biomaterial is its acceptability by the human body. To ensure its long-term usage in the body without any rejection, it is essential for the biomaterial to possess certain significant properties. The most common classes of materials used for biomedical applications are metals, polymers, ceramics and composites. These four classes are either used alone or in combination in most of the implantation devices that are available today. This article focuses on the biocompatibility of various metal matrix composites used for biomedical applications.
... Oral exposures of experimental animals to iAs alone have generally failed to elicit a cancer response unless the exposure includes the early developmental period [92]. In contrast, there is abundant epidemiological evidence of arsenic carcinogenicity to human populations, including cases where the exposure did not include early life [96]. Reviews of the epidemiological evidence for the toxicity and carcinogenicity of arsenic are provided elsewhere in this text. ...
... Cancer incidence has been reported to be significantly higher among those with Blackfoot disease after adjustment for iAs exposure [25]. Arsenic-induced skin lesions also appear to be a predictor of higher cancer risk [35,96]. However, data available to date indicate that it is unlikely that any of the noncancer effects of iAs, such as skin keratoses, are precursors to neoplastic lesions. ...
This chapter describes the variety of factors that must be considered in order to derive a biologically sound risk assessment for arsenic, including both cancer and noncancer endpoints. A risk assessment for inorganic arsenic (iAs) should include explicit consideration of the underlying biological processes, and integrate and quantify the dose of the active arsenic species to the target tissue with an evaluation of the dose-response for those cellular interactions that are thought to enhance tumor formation. Thus far, the available pharmacokinetic and mechanistic information for arsenic has had little impact on quantitative cancer risk assessments for iAs, which uniformly followed default guidelines rather than relying on chemical-specific mechanistic data. Biologically motivated risk analysis must take into account the metabolism and disposition of iAs and the toxicity of its trivalent metabolites. The chapter focuses on the small number of epidemiological studies that provide insights into the possible dose-response for arsenic carcinogenicity.
... Human exposure to arsenic through contaminated water, soil, air, and foods results in various adverse health effects. 2,3,4,5 Epidemiological studies have revealed that arsenic exposure is closely associated with the occurrence of multiple diseases, such as neurological, immune, reproductive, and cardiovascular disorders, in addition to diabetes mellitus and various cancers. 6,7,8,9,10 The liver is a major metabolic organ and plays a critical role in detoxification in the body. ...
Arsenic, a widely existing environmental contaminant, is recognized to be toxic to multiple organs. Exposure to arsenic results in liver damage via excessive production of reactive oxidative species (ROS). PIN1 regulates the levels of ROS. N-acetyl-L-cysteine (NAC) is an ROS scavenger that protects the hepatic functions. Whether PIN1 plays a regulatory role in NAC-mediated antagonism against arsenic hepatotoxicity remains largely unknown. In our study, the protective effects of NAC against arsenic (NaAsO2)-induced hepatotoxicity were evaluated in vitro and in vivo. Arsenic exposure induced cytotoxicity by increasing the intracellular ROS production, impairing mitochondrial function and inducing apoptosis in L02 hepatocytes. Overexpression of PIN1 markedly protected against arsenic cytotoxicity, decreased ROS levels, and mitigated mitochondrial dysfunction and apoptosis in L02 cells. However, loss of PIN1 further aggravated arsenic-induced cytotoxicity and abolished the protective effects of NAC in L02 cells. An in vivo study showed that pretreatment with NAC rescued arsenic-induced liver injury by restoring liver function and suppressing hepatic oxidative stress. Overexpression of PIN1 in mice transfected with AAV-Pin1 relieved arsenic-induced liver dysfunction and hepatic oxidative stress. Taken together, our study identified PIN1 as a novel intervention target for antagonizing arsenic-induced hepatotoxicity, highlighting a new pharmacological mechanism of NAC targeting PIN1 in antagonism against arsenic toxicity.
... The IARC contemplates there is enough indication for arsenic to increase the danger of urinary bladder cancer in individuals (Humans, 2004). A significant number of persons with cancer mortality were observed, mainly because of the exposure to an enormously high concentration of arsenic; this has been reported in Japan (Tsuda et al., 1995) and Chile (Marshall et al., 2007). Reports approve that the connotation between the contact to iAs in consumption water and the bladder cancer is initiated only after exposure to iAs levels bigger than 100 μg/L. ...
... The goal of the present study was to identify differentially expressed genes in arsenic exposed humans and determine if a molecular signature could be developed that would stratify and predict the risk of urothelial cancer for those with known exposure to arsenic. Urothelial cancer, which is the most common type of bladder cancer, was chosen as an initial proof of principle since epidemiological, and other evidence is strong for the link between arsenic and the development of urothelial cancer, and there are publicly available databases for data mining [7,[20][21][22][23][24]. A theme of such studies shows a strong association at more extreme levels (>150 μg/L) whereas there is uncertainty of health effects that may develop below this threshold. ...
The IARC classified arsenic (As) as “carcinogenic to humans.” Despite the health consequences of arsenic exposure, there is no molecular signature available yet that can predict when exposure may lead to the development of disease. To understand the molecular processes underlying arsenic exposure and the risk of disease development, this study investigated the functional relationship between high arsenic exposure and disease risk using gene expression derived from human exposure. In this study, a three step analysis was employed: (1) the gene expression profiles obtained from two diverse arsenic-exposed Asian populations were utilized to identify differentially expressed genes associated with arsenic exposure in human subjects, (2) the gene expression profiles induced by arsenic exposure in four different myeloma cancer cell lines were used to define common genes and pathways altered by arsenic exposure, and (3) the genetic profiles of two publicly available human bladder cancer studies were used to test the significance of the common association of genes, identified in step 1 and step 2, to develop and validate a predictive model of primary bladder cancer risk associated with arsenic exposure. Our analysis shows that arsenic exposure to humans is mainly associated with organismal injury and abnormalities, immunological disease, inflammatory disease, gastrointestinal disease, and increased rates of a wide variety of cancers. In addition, arsenic exerts its toxicity by generating reactive oxygen species (ROS) and increasing ROS production causing the imbalance that leads to cell and tissue damage (oxidative stress). Oxidative stress activates inflammatory pathways leading to transformation of a normal cell to tumor cell specifically; there is significant evidence of the advancing changes in oxidative/nitrative stress during the progression of bladder cancer. Therefore, we examined the relation of differentially expressed genes due to exposure of arsenic in human and bladder cancer and developed a bladder cancer risk prediction model. In this study, integrin-linked kinase (ILK) was one of the most significant pathways identified between both arsenic exposed population which plays a key role in eliciting a protective response to oxidative damage in epidermal cells. On the other hand, several studies showed that arsenic trioxide (ATO) is useful for anticancer therapy although the mechanisms underlying its paradoxical effects are still not well understood. ATO has shown remarkable efficacy for the treatment of multiple myeloma; therefore, it will be helpful to understand the underlying cancer biology by which ATO exerts its inhibitory effect on the myeloma cells. Our study found that MAPK is one of the most active network between arsenic gene and ATO cell line which is involved in indicative of oxidative/nitrosative damage and well associated with the development of bladder cancer. The study identified a unique set of 147 genes associated with arsenic exposure and linked to molecular mechanisms of cancer. The risk prediction model shows the highest prediction ability for recurrent bladder tumors based on a very small subset (NKIRAS2, AKTIP, and HLA-DQA1) of the 147 genes resulting in AUC of 0.94 (95% CI: 0.744-0.995) and 0.75 (95% CI: 0.343-0.933) on training and validation data, respectively.
1. Introduction
Arsenic (As) is a ubiquitous element in the environment, ranked the 20th most abundant element on earth. The toxic impact of arsenic on human health has been documented in numerous studies leading to arsenic identification as a known carcinogen by the International Agency Research on Carcinogens (IARC), the National Toxicity Program (NTP), and the United States Environmental Protection Agency (EPA) [1, 2]. In addition to cancer, long-term exposure to arsenic has been associated with developmental effects, cardiovascular disease, neurotoxicity, and diabetes (WHO, https://www.who.int/news-room/fact-sheets/detail/As). Typically, arsenic would only be found in background levels in soil and groundwater. However, high levels of arsenic accumulate in these medians from anthropogenic activities such as indiscriminate waste disposal from mining, milling, and smelting of ores [3], raw and spent oil shale [4], and coal fly ash amendments [5]. The usage pattern in the 1960s for arsenic compounds in the United States was 77% pesticides, 18% as glass, and 4% industrial chemicals. The past use of arsenic as a pesticide in agriculture is exemplified by New Jersey, where between 1900 and 1960, it is estimated that approximately 15 million pounds of arsenic were applied to New Jersey soils alone [6]. Leaching of arsenic from soils into the water supply has now resulted in the significant contamination of drinking water in many areas of the United States and the world. This past usage of arsenic in anthropogenic activities has now resulted in exposure to arsenic being a global public health problem [7–9]. This is illustrated by the fact that over 120 million people are affected by arsenic exposure, many of which reside in Bangladesh and India [8, 10]. A recent study has modeled the role of atmospheric exposure to arsenic as being additive to overall exposure levels [11]. Despite the health consequences of arsenic exposure, there is no molecular signature that might predict the risk of developing cancer or other diseases following exposure to arsenic.
On the other hand, the use of arsenicals as therapeutic agents in medicine is very well known dating back more than 2400 years to ancient Greece and Rome [12]. In the 19th century, potassium arsenite was used to treat different types of disease [13] including diabetes, psoriasis, syphilis, skin ulcers, and joint diseases. More recently, phase I/II trials have been conducted in heavily pretreated patients with relapsed or refractory multiple myeloma shows arsenic trioxide (ATO) is the most active, single agent in acute promyelocytic leukemia (multiple myeloma: types of blood cancers) [14]. Another study suggested that ATO can be used as an effective alternative therapeutic for the treatment of retinoblastoma which is the most common intraocular cancer in children [15]. The study shows an antitumor activity of arsenic which mainly targets multiple pathways in malignant cells, resulting in the promotion of differentiation or in the induction of apoptosis, which would be very helpful to understand the molecular mechanism of arsenic-exposed cancer biology as a reverse engineering approach.
Biomarkers are classified based on exposure, effect, and susceptibility [16]. For arsenic, biomarkers of exposure have received the greatest attention and success in defining individual exposures [17]. Human susceptibility to arsenic, especially as it applies to predicting disease states, is probably the least studied area of biomarkers. A few biomarkers of interest attracting study include clastogenicity in peripheral lymphocytes, micronuclei in oral mucosa and bladder cells, and induction of heme oxygenase [16, 18, 19]. The goal of the present study was to identify differentially expressed genes in arsenic exposed humans and determine if a molecular signature could be developed that would stratify and predict the risk of urothelial cancer for those with known exposure to arsenic. Urothelial cancer, which is the most common type of bladder cancer, was chosen as an initial proof of principle since epidemiological, and other evidence is strong for the link between arsenic and the development of urothelial cancer, and there are publicly available databases for data mining [7, 20–24]. A theme of such studies shows a strong association at more extreme levels (>150 μg/L) whereas there is uncertainty of health effects that may develop below this threshold. Suggested mechanisms for arsenic carcinogenesis include oxidative damage, epigenetic effects, and interference with DNA repair. In addition, the development of bladder cancer is known to have a strong association with environmental exposures from mentioned anthropogenic activities [25]. Overproduction of reactive oxygen species (ROS) due to arsenic exposure primarily follows direct toxicity or the metabolic processes of arsenic products. Inhibiting succinic dehydrogenase activity in mitochondrial complexes I and III in electron transport chain produces superoxide radical anion, while monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) will form radicals in the cell and specifically the endoplasmic reticulum [26, 27]. Since inorganic arsenic compounds tend to be more toxic than organic, ATO is of interest for its global concern along with its involvement in oxidative and nitrosative stress properties. Translational damage from reactive species can regulate MAPK family or induce extended states of inflammation, genetic, and epigenetic mechanisms such as these are indicative of oxidative/nitrosative damage and well associated with the development of bladder cancer [28–30]. ILK signaling and neuroinflammation signaling pathway were the most frequent pathways affected by the exposure of arsenic, and both of them are highly associated with oxidative stress. Oxidative stress and neuroinflammation could potentiate each other to promote progression of mental disorders [31], whereas ILK plays a complex roles in the modulation of oxidant species production [32].
The strategy used in the present study involved three steps. The first step was a blood cell gene expression analysis of two diverse human populations with known levels of exposure to arsenic. One population was stratified to low and high exposure, and the second population to low, medium, and high exposure with correlation to human global gene expression. After identifying statistically significant genes unique to the mentioned test conditions, we found that cancer was the most significant disease and lipid metabolism (which is considered as a major metabolic pathway involved in the progression of cancer) was most significant molecular and cellular functions associated with genes differentially expressed due to different levels of arsenic. Therefore, the next stage was to compare it with data from four independent myeloma cell lines that had been treated with As trioxide (ATO) to understand the molecular mechanism of cancer. Many of the genes that were up- and downregulated due to arsenic exposure are associated with cancer biology. There gene lists were then subjected to enrichment analysis to identify statistically significant pathways and further scrutinized for functional relevance. The third step was to develop a model by examining the ability of the most significant genes to predict the progression and possible development of bladder cancer using publicly available patient biopsy samples. Using this approach, we developed a robust regression model of three significant probes and corresponding gene results with AUC of 0.94 (95% CI: 0.744-0.995) and 0.75 AUC (95% CI: 0.343-0.933) on the training and validation data, respectively. The most significant pathway identified is integrin-linked kinase (ILK) which plays a key role in eliciting a protective response to oxidative damage in epidermal cells [32].
2. Materials and Methods
2.1. Data
Two publicly available gene expression datasets of previously conducted experiments were accessed from two independent populations. The set from Bangladesh (Gene Expression Omnibus GEO ID: GSE57711) had 29 individuals; 16 were males, and 13 were females. The second dataset was from Pakistan (GSE110852 ID) and had 57 individuals composed of 31 males and 26 females. In this report, the set from Bangladesh is denoted as Data1 and that from Pakistan is Data2 and remains unchanged from their original, respective studies. Data1 samples were part of a clinical trial in June 2011 [33]. For these samples, “low” exposure levels correlate to a range of 50-200 μg/L, whereas “high” levels correlate to a range from 232 to 1000 μg/L (there were no samples collected from patients exposed in the range of 201-231 μg/L). Data2 samples were from two main districts of rural Pakistan, Lahore, and Kasur. The study is aimed at investigating the blood transcriptome profile among the exposed samples to correlate gene expression to exposure levels of As [34]. Urine sampling was used to define levels of arsenic exposure, with “low” being 0-50 μg/g creatinine, “medium” as 51-100 μg/g creatinine, and “high” as >101 μg/g creatinine. The general characteristics of both data sets are detailed in Table 1. The results from 4 multiple myeloma cell lines treated with ATO were obtained from the GEO database, series GSE14519 [35]. These cell lines U266, MM1S, KMS11, and 8226S were exposed to ATO for 6 hr, 28 hr, and 48 hr before analysis. Gene expression profiling was used to determine differences in cell line response to ATO. This study was used as a reference point in the present study since it documents the effects of arsenic compounds on gene expression at different exposure levels.
Total samples
Gender
Low exposure
Medium exposure
High exposure
Males
Females
Data1
Water As 50–200 (μg/L)
—
Water As 232–1000 (μg/L)
GSE57711
29
16
13
15
—
14
Data2
Water As (μg/L)
Water As (μg/L)
Water As (μg/L)
GSE110852
57
31
26
18
19
20
... The IARC contemplates there is enough indication for arsenic to increase the danger of urinary bladder cancer in individuals (Humans, 2004). A significant number of persons with cancer mortality were observed, mainly because of the exposure to an enormously high concentration of arsenic; this has been reported in Japan (Tsuda et al., 1995) and Chile (Marshall et al., 2007). Reports approve that the connotation between the contact to iAs in consumption water and the bladder cancer is initiated only after exposure to iAs levels bigger than 100 μg/L. ...
Freshwater demand will rise in the next couple of decades, with an increase in worldwide population growth and industrial development. The development activities, on one side, have increased the freshwater demand. However, the ground water has been degraded. Among the various organic and inorganic contaminants, arsenic is one of the most toxic elements. Arsenic contamination in ground waters is a major issue worldwide, especially in South and Southeast Asia. Various methods have been applied to provide a remedy to arsenic contamination, including adsorption, ion exchange, oxidation, coagulation-precipitation and filtration, and membrane filtration. Out of these methods, adsorption of As(III)/As(V) using nanomaterials and biopolymers has been used on a wide scale. The present review focuses on recently used nanomaterials and biopolymer composites for As(III)/As(V) sorptive removal. As(III)/As(V) adsorption mechanisms have been explored for various sorbents. The impacts of environmental factors such as pH and co-existing ions on As(III)/As(V) removal, have been discussed. Comparison of various nanosorbents and biopolymer composites for As(III)/As(V) adsorption and regeneration of exhausted materials has been included. Overall, this review will be useful to understand the sorption mechanisms involved in As(III)/As(V) removal by nanomaterials and biopolymer composites and their comparative sorption performances.
... Arsenic is an environmental pollutant and a carcinogen that has been reported to contaminate groundwater in many parts of the World, including Nigeria [1][2][3][4][5][6][7]. Several studies have linked arsenic exposures from contaminated drinking water to carcinogenesis among inhabitants of different countries [8][9][10][11][12]. Exposure to arsenic has also been reported to culminate in renal injury which may lead to the development of tubulointerstitial nephritis and acute tubular necrosis [13]. ...
Arsenic has been reported to contaminate groundwater and agricultural soil in different parts of the World. The effect of ethanol leaf extract of Irvingia gabonensis (ELEIG) against sodium arsenite (SA)-induced renal toxicity was investigated in this study. Wistar albino rats of weights between 100 and 161 g were assigned to eleven (11) groups of five (5) animals each. Group 1 (control) was given feed and water ad libitum. Group 2 was exposed to SA at a dose of 4.1 mg/kg body weight (kgbw) for two weeks. Groups 3-11 were treated with ELEIG with or without SA. Treatment was done orally and lasted for 14 days. Serum concentrations of urea, creatinine, sodium ion (Na +), potassium ion (K +), bicarbonate (HCO 3-) and chloride ion (Cl-) as well as histological assessment of kidney tissues were used to assess kidney function. Results show that SA caused significant (p˂0.05) increases in serum concentrations of all assayed parameters as well as acute tubular necrosis, vascular lesions of ulceration and stenosis. Treatment with ELEIG both simultaneously and 2 weeks after SA exposure reversed the deleterious effects of SA. Administration of the extract alone at various doses also produced similar results with those of the normal control. It may therefore be concluded that ELEIG possesses potent medicinal properties against SA-induced renal toxicity in Wistar rats.
... These co-contaminants include heavy metals such as arsenic (Anwar-Mohamed et al., 2009). Several epidemiological studies have reported significantly high incidence of lung cancer among cigarette smokers who are concurrently exposed to arsenic (Chen et al., 2004;Ferreccio et al., 2000;Hertz-Picciotto and Smith, 1993;Hertz-Picciotto et al., 1992;Järup and Pershagen, 1991;Pershagen et al., 1981;Tsuda et al., 1995). Studies on animals have also revealed that tumorigenic potential of B[a]P in the respiratory tract can be significantly enhanced by arsenic co-exposure (Ishinishi et al., 1977;Pershagen et al., 1984). ...
Arsenic is well-recognized as one of the most hazardous elements which is characterized by its omnipresence throughout the environment in various chemical forms. From the simple inorganic arsenite (iAsIII) and arsenate (iAsV) molecules, a multitude of more complex organic species are biologically produced through a process of metabolic transformation with biomethylation being the core of this process. Because of their differential toxicity, speciation of arsenic-based compounds is necessary for assessing health risks posed by exposure to individual species or co-exposure to several species. In this regard, exposure assessment is another pivotal factor that includes identification of the potential sources as well as routes of exposure. Identification of arsenic impact on different physiological organ systems, through understanding its behavior in the human body that leads to homeostatic derangements, is the key for developing strategies to mitigate its toxicity. Metabolic machinery is one of the sophisticated body systems targeted by arsenic. The prominent role of cytochrome P450 enzymes (CYPs) in the metabolism of both endobiotics and xenobiotics necessitates paying a great deal of attention to the possible effects of arsenic compounds on this superfamily of enzymes. Here we highlight the toxicologically relevant arsenic species with a detailed description of the different environmental sources as well as the possible routes of human exposure to these species. We also summarize the reported findings of experimental investigations evaluating the influence of various arsenicals on different members of CYP superfamily using human-based models.
... Continuous exposure of humans to arsenic through long term ingestion of contaminated water and its attendant health problem has been reported [1]. Epidemiological studies conducted in Taiwa [2], Chile [3] and Japan [4] indicated a connection between arsenic exposures from contaminated drinking water among the inhabitants. Arsenic is a well-known human carcinogen, which potentially affects ~160 million people worldwide via exposure to unsafe levels in drinking water [5]. ...
Ingestion of arsenic, a known contaminant in drinking water causes cancer at multiple tissues and there is no cure. Consumption of arsenic contaminated water has been implicated metalloid-induced carcinogenesis. Research is therefore directed at chemoprevention using medicinal herbs for the management of arsenicosis. In this study hepatoprotective activity of ethanolic extract of Annona muricata (AM) leaves was assessed against sodium arsenite (SA) induced hepatic injury in albino rats. The animals were pre-treated with either 250 or 500mg/kg body weight of rat before exposure to SA. SA was dissolved in distilled water and administered at a dose of 5 mg/kg body weight on the 7th, 14th and 21st day of the experiment. SA was observed to induce a significant increase (p < 0.05) in serum aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase activities (ALP). However, pretreatments of rats with various doses of AM significantly (P<0.005) reduced serum enzyme levels to near normal against SA treated rats. Furthermore, histopathological observations revealed that treatment with AM extract protected the animals from SA induced liver damage. The results indicated that the leaves of Annona muricata possess hepatoprotective activity on SA induced hepatic injury in rats.
... Exposure to inorganic arsenic has been documented as an etiological factor of all-cause mortality in humans [1]. Cancers of the skin and other internal organ cancers, including lung, liver, bladder, and kidney, were associated with inorganic arsenic exposure [2,3]. Recently, studies from Bangladesh have also demonstrated the association between inorganic arsenic exposure and the development of various cancers [4,5] Therefore, the WHO and the US EPA has adopted a new standard for arsenic in drinking water of 0.01 mg/l or 10 parts per billion (ppb), replacing the old standard of 50 ppb [6,7]. ...
Background
Chronic exposure to inorganic arsenic results in many cancers in susceptible persons. The metabolism of inorganic arsenic and genomic susceptibility are thought to be associated with cancer occurrence.
Material and methods
This study aims to examine the interaction of genomic susceptibility markers and urinary methylation capacity indicators involved in inorganic arsenic metabolism with all-cancer occurrence. This study conducted a follow-up on 96 residents to determine their urinary inorganic arsenic metabolites and genomic assay from an arseniasis area. Among them, 24 cancer developed. Multivariable Cox proportional hazards model was used to determine and estimate the candidate independent variables for cancer development.
Results
The residents with high inorganic arsenic exposure, high primary methylation index (PMI; MMA/InAs) (but lower secondary methylation index (SMI)), and non-heterogeneity type of genomic markers, including GSTO1, AS3MT, and MPO, tend to develop cancers. Subjects with higher PMI are at higher risk of developing cancers (HR = 1.66; 95% CI = 1.30–2.12). Cancer occurrence was greater among the CC type of GSTO1 (HR = 3.33; 95% CI = 1.11–10.00), CC type of AS3MT (HR = 19.21; 95% CI = 1.16–318.80), and AA type of MPO (HR = 13.40; 95% CI = 1.26–142.40). After adjusting confounders, a mutually moderating effect was revealed between genomic markers and methylation capacity on cancer occurrence.
Conclusions
This study found the hypermethylation responses to inorganic arsenic exposure and an array of genomic markers may increase the susceptibility of a wide range of organ cancers. The findings indicated a high-risk arsenic-exposed population to develop cancers. The phenotype of arsenic metabolism and genomic polymorphism suggested a potential preventive strategy for arsenic carcinogenesis.
... Chronic arsenic poisoning has become a worldwide public health issue. The major source of arsenic exposure is drinking water containing high amounts of inorganic arsenic. 2 Previous studies have suggested that chronic arsenic exposure is related to skin, lung, bladder, kidney, and liver cancer, [3][4][5][6][7][8][9][10][11][12][13] hyperkeratosis, ischemic heart disease, cerebrovascular disease, type 2 diabetes, and peripheral neuropathy. [14][15][16][17] Acute arsenic poisoning in suicidal and homicidal attempts or by accidental ingestion is relatively rare. ...
In 1955, an outbreak of arsenic poisoning caused by the ingestion of arsenic-contaminated Morinaga Dry Milk occurred in western Japan. This study aimed to assess the mortality and cancer incidence risk among Japanese individuals who were poisoned during this time as infants. A total of 6,223 survivors (mean age at enrollment, 27.5 years) who had ingested contaminated milk when they were aged ≤2 years participated in this study. Follow-up was conducted from 1982 to 2018 (mean follow-up duration, 30.3 years). Standardized mortality ratio (SMR) and standardized incidence ratio (SIR) were used to compare mortality and cancer incidence rates of subjects with the respective Japanese population rates, and 95% confidence intervals (95% CIs) of the SMR and SIR were also calculated. A total of 561 deaths and 524 new cancer cases were observed. A statistically significant increase in mortality rate was observed for all causes (SMR, 1.15; 1.01-1.19), nervous system disease (2.83, 1.62-4.19), respiratory disease (2.02, 1.37-2.62), genitourinary system disease (2.25, 1.10-3.73), and traffic accident (2.03, 1.14-3.04). In contrast, a significant decrease in cancer incidence rate was observed for all cancers (SIR, 0.96; 0.84-0.99), stomach cancer (0.77, 0.57-0.92), colon cancer (0.63, 0.41-0.85), rectum cancer (0.69, 0.43-0.95), and breast cancer (0.72, 0.52-0.89). Liver cancer showed a high mortality rate (SMR, 1.68; 1.06-2.31). In this study, we revealed overall and cause-specific mortality and cancer incidence risk among survivors who ingested arsenic-contaminated dry milk in infants after the long-term follow-up.
... Environmental exposure to arsenite (As 3+ ) has a strong association with the development of human UC. The increased risk of UC correlates to the same endemic areas of the world where populations have been identified with arsenic-induced skin cancer [10][11][12][13][14][15]. We have developed a cell culture model of arsenic-induced urothelial cancer by exposing the immortalized non-tumorigenic urothelial cell line UROtsa to arsenite. ...
Environmental exposure to arsenite (As³⁺) has a strong association with the development of human urothelial cancer (UC) and is the 5th most common cancer in men and the 12th most common cancer in women. Muscle invasive urothelial cancer (MIUC) are grouped into basal or luminal molecular subtypes based on their gene expression profile. The basal subtype is more aggressive and can be associated with squamous differentiation, characterized by high expression of keratins (KRT1, 5, 6, 14, and 16) and epidermal growth factor receptor (EGFR) within the tumors. The luminal subtype is less aggressive and is predominately characterized by elevated gene expression of peroxisome proliferator-activated receptor- gamma (PPARγ) and forkhead box protein A1 (FOXA1). We have previously shown that As³⁺-transformed urothelial cells (As-T) exhibit a basal subtype of UC expressing genes associated with squamous differentiation. We hypothesized that the molecular subtype of the As-T cells could be altered by inducing the expression of PPARγ and/or inhibiting the proliferation of the cells. Non-transformed and As-T cells were treated with Troglitazone (TG, PPARG agonist, 10 μM), PD153035 (PD, an EGFR inhibitor, 1 μM) or a combination of TG and PD for 3 days. The results obtained demonstrate that treatment of the As-T cells with TG upregulated the expression of PPARγ and FOXA1 whereas treatment with PD decreased the expression of some of the basal keratins. However, a combined treatment of TG and PD resulted in a consistent decrease of several proteins associated with the basal subtype of bladder cancers (KRT1, KRT14, KRT16, P63, and TFAP2A). Our data suggests that activation of PPARγ while inhibiting cell proliferation facilitates the regulation of genes involved in maintaining the luminal subtype of UC. In vivo animal studies are needed to address the efficacy of using PPARγ agonists and/or proliferation inhibitors to reduce tumor grade/stage of MIUC.
... Environmental exposure to arsenite (As 3+ ) has a strong association with the development of human UC. The increased risk of UC correlates to the same endemic areas of the world where populations have been identified with arsenic-induced skin cancer [10][11][12][13][14][15]. We have developed a cell culture model of arsenic-induced urothelial cancer by exposing the immortalized non-tumorigenic urothelial cell line UROtsa to arsenite. ...
... Arsenic exposure in many parts of the World occurs via the consumption of arsenic-contaminated drinking water and food and it causes noxious effects in vivo. There is a link between consumption of arsenic-contaminated drinking water and cancer development among residents of various countries [8][9][10][11][12]. Chronic or prolonged inflammation is associated with severe detrimental health effects such as cancer [13,14]. ...
Aim: To investigate the effect of ethanol leaf extract of Irvingia gabonensis (ELEIG) on sodium arsenite (SA)-induced hepatic pro-inflammatory cytokines and haematological derangements in Wistar rats. Study Design: Fifty five Wistar rats weighing between 100 g and 161 g were randomly distributed to eleven (11) groups (n=5). Group 1 (control) had feed and water only. Group 2 received SA at a dose of 4.1 mg/kg body weight (kgbw) for 14 days. Groups 3-11 received ELEIG with or without SA. Place and Duration Methodology: Treatment was done orally for 14 days. Immunological markers: tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-4 (IL-4), interleukin-10 (IL-10), and haematological indices: red blood cell (RBC) count, haemoglobin (HB) concentration, packed cell volume (PCV), mean cell haemoglobin (MCH), mean cell haemoglobin concentration (MCHC), mean corpuscular volume (MCV), white blood cell (WBC) count and its differentials and platelet (PLT) count were used to determine the immunomodulatory and haematological effects of the extract. Results: Intoxication with SA caused significant (p ˂ 0.05) increases in hepatic TNF-α, IL-1β, and IL-4 levels and a significant decrease in hepatic IL-10 level, relative to control. The SA treatment also caused significant (p ˂ 0.05) decreases in RBC, HB, PCV MCH, MCHC, MCV, PLT and monocyte counts as well as significant (p ˂ 0.05) increases in WBC, lymphocyte, basophil, eosinophil and neutrophil counts, relative to control. However, post-treatment and concomitant treatment with ELEIG ameliorated the noxious effect of SA. In addition, ELEIG alone at various doses produced results with most of the assayed parameters having values comparable with those control. Conclusion: These results indicate that ELEIG mitigates SA-induced inflammation and haematological perturbations in Wistar rats.
... Moreover, inorganic As is a potent human carcinogen which was recognised as a cause of skin, bladder, kidney, and lung cancer (IARC International Agency for Research on Cancer, 2004). Tsuda et al. (1995) *Not specified. ...
Concern about health effect of Potentially Toxic Elements (PTEs) has led to an increasing global attention about their concentration levels in the environment. Soil geochemistry has been widely used as a tool for environment monitoring. This study investigates topsoil geochemistry of Campania region (Southern Italy) and (i) allows a reliable overview of the PTEs (As, Be, Cd, Co, Cr, Cu, Hg, Ni, Pb, Sb, Se, Sn, Tl, V and Zn) concentration in soils, (ii) enable the investigation of the main factors governing PTEs geochemical variation on a regional scale.. Over 7300 topsoil samples were collected from the survey area, which occupies an area of about 13.600 km². Samples were analyzed for pseudo-total content of 53 elements (major and trace elements) by ICP-MS after aqua regia digestion. Data analysis was performed taking into account both raw data and their compositional nature as a tool for the PTEs environmental evaluation and origin investigation.
As, Be, Cu, Pb, Sn, Tl, V and Zn in soils of Campania region show higher median concentration levels than Italian and European ones. All PTEs are characterized by exceeding of the residential/ recreational intervention limit (CSCA) set by Italian legislation. The variation structure of compositional data had been visualized using compositional (clr) biplots and displaying the individual sample observations according to their parent rock. Clr-biplot analysis allowed us to recognize geochemical processes controlling most of soil chemical signatures. Multivariate analysis has been performed and three proncipal components were determined. PC1 is controlled by enrichment of elements deriving from dominant parent rocks of the area (siliciclastics and volcanoclastics). On the other hand, PC1 reveals the presence of an elemental association dominated by Na, K, U, Th, Zr, Ti, Tl and Be (clr variables), which are pathfinder element of soils developed from volcanic parent material. The second (PC2) component well discriminates the geochemical mobility of the elements in soils. The third (PC3) component reveal the presence of an anthropogenic association (Hg, Sb, Pb, Sn, Au, Ag) which depict a marginal contribution in soil geochemistry of the study area. The generation of clr-biplot helped us in a deeper interpretation of single element spatial distribution patterns. As, Be, Sn, Tl and V spatial distribution shows dominance in soil developed from volcanic products of the main volcanic complexes. Our study showed that element such as Be, Sn and Tl naturally exceed the contamination thresholds in almost the entire territory, due to a quite elevated background concentration values. Hence, Campania region con not be considered entirely contaminated (at this scale) by such elements. Co, Cd, Cr and Ni are more abundant where siliciclastic parent rocks occur.
... Oral exposures of experimental animals to iAs alone generally failed to elicit a cancer response unless the exposure included the early developmental period (Tokar et al. 2011). In contrast, there is abundant epidemiological evidence of iAs carcinogenicity in multiple tissuesincluding lung, bladder, liver, and skinin human populations exposed to high (greater than 100 ppb) concentrations of iAs in drinking water (Gentry et al. 2014a;Lynch et al. 2017;NRC 2013), including cases where the exposure did not include early life (Tsuda et al. 1995;Tsai, Wang, and Ko 1998;Yang et al., 2008). In vitro, arsenite is clastogenic, producing chromosomal aberrations (CA), but does not produce point mutations at single gene loci (Clewell et al. 1999). ...
The aim of this study was to establish a process for deriving a chemical-specific mode of action (MOA) from chemical-agnostic adverse outcome pathway (AOPs), using inorganic arsenic (iAs) as a case study. The AOP developed for this case study are related to disruption of cellular signaling by chemicals that strongly bind to vicinal dithiols in cellular proteins, leading to disruption of inflammatory and oxidative stress signaling along with inhibition of the DNA damage responses. The proposed MOA for iAs incorporates this AOP, overlaid on a background of increasing oxidative stress and/or co-exposure to mutagenic chemicals or radiation. The most challenging aspect of developing a MOA from AOP is the incorporation of metabolism and dose-response, neither of which may be considered in the development of an AOP. The cellular responses to relatively low concentrations (below 100 parts per billion) of iAs in drinking water appear to be secondary to binding of trivalent arsenite and its trivalent metabolite, monomethyl arsenous acid to key cellular vicinal dithiols in target tissues, resulting in a co-carcinogenic MOA. The proposed AOP may also be applied to non-cancer endpoints, enabling an integrated approach to conducting a risk assessment for iAs.
... It seems however that bladder cancer related to as exposure is more aggressive and appears earlier in life (24). In the present study, we could not adjust the incidence for sex and age, and therefore could not evaluate any correlation. ...
In approximately 50% of cases of bladder carcinoma, an associated predisposing factor can be established. The main factors are exposure to tobacco, arsenic (As) ore and aromatic compounds. Arsenic is a metalloid with a low average concentration in the earth's crust, and one of the most dangerous substances for human health. The present study aims to evaluate the incidence of hospitalization and mortality from bladder neoplasia and its possible association with As concentration in water and soil in two of the most critical regions of Brazil: the states of São Paulo and Minas Gerais. We have investigated bladder cancer hospitalization and mortality in the states of São Paulo and Minas Gerais during 2010-2014. Water and soil samples were analyzed and As concentrations were established. Data were obtained through the Department of Informatics of the Brazilian Unified Health System. Correlation was made with water samples from São Paulo and with data on soil analysis from Minas Gerais. The results revealed no direct association in the distinctive municipalities. Areas with high environmental As concentration had a low bladder cancer rate, while areas with normal as levels had similar cancer rates. The quantitative variables did not present a normal distribution (p < 0.05). In conclusion, we did not observe a correlation between as concentration in water or soil and bladder cancer's hospitalization and mortality rates in the states of São Paulo and Minas Gerais.
... Exposure to arsenic causes both chronic and acute toxicity and is also evaluated as a human carcinogen [6,7]. The chronic exposure to arsenic causes various types of carcinogenic and non-carcinogenic health effects such as cancer of skin and internal organs, diabetes mellitus, hypertension, and respiratory conditions [8,9]. ...
Objective: The present study investigated the antigenotoxic effect of Zingiber officinale (Ginger) on arsenic-induced genotoxic effects in chromosome structure of Swiss albino mice.Methods: Albino mice were divided into four groups: Group I was kept as control, Group II was administrated an oral dose of arsenic trioxide 5 mg/kg bw for 15 days, Group III was given an oral dose of arsenic trioxide 5 mg/kg bw followed by 20 mg/kg bw of ginger orally, and Group IV was administered with 20 mg/kg bw of ginger orally for 15 days and kept as positive control. The autopsies were done from all the groups on 15-day post-treatment, and bone marrow was removed for chromosomal study and for calculating the frequency of micronuclei (MN).Results: It is concluded from this study that long-term arsenic exposure causes chromosomal anomalies, for example, breaks, gaps, rings, stretching, and stickiness which leads to the fragmentation of chromosomes and increases the frequency of MN.Conclusion: The administration of ginger showed modulatory effects against arsenic-induced genotoxicity.
... Потребление с водой мышьяка 10 мкг x кг -1 x день -1 в Тайване увеличивало риск рака мочевого пузыря [39]. Этот увеличенный риск был подтвержден в работах из Японии [40], Аргентины [41] и Чили [42]. В настоящее время, однако, неизвестно, являются ли органические разновидности мышьяка канцерогенами для людей. ...
Given are the data on the behavior of arsenic and its varieties in the marine environment, including sources, chemical structures and properties, toxicity and transformation. The levels of arsenic concentration in water, biota and bottom sediments are considered. The distribution of arsenic in marine environment connected with its adsorption and desorption in bottom sediments and bioaccumulation is described. Special attention has been paid at the analysis of arsenic and its forms in marine samples and potential impact on human health.
... "Black Foot Disease" in the southwest coast of Taiwan, "Bell Ville Disease" in Córdoba Province of Argentina, and "Kai Dam" in Thailand are well-documented cases of health disorders due to groundwater arsenic poisoning. It is evident from Taiwan and Chile that skin cancers can appear after latency of about 10 years, while internal cancers, particularly bladder and lung, can appear after a latency of 30 years at a concentration of 50 µg/L of arsenic (Brown and Chen, 1995;Tsuda et al., 1995). Chronic exposure to elevated levels of arsenic is associated with substantial increased risk of a wide array of diseases including skin manifestations (Sarma, 2016); cancers of the lung (Sherwood and Lantz, 2016), bladder (Medeiros and Gandolfi, 2016), liver (Lin et al., 2013), skin (Fraser, 2012), and kidney (Hsu et al., 2013); neurological (Fee, 2016); diabetes (Kuo et al., 2015); and cardiovascular (Barchowsky and States, 2016) diseases. ...
... About 200 million people worldwide are exposed to As levels in water exceeding the World Health Organization (WHO)-recommended limit of 10 µg/L (George et al., 2014). Exposure to As is related to adverse health outcomes, including skin lesions, cardiovascular diseases, as well as cancer (Chen et al., 1996;Hopenhayn-Rich et al., 1998;Tondel et al., 1999;Tseng et al., 2003;Tsuda et al., 1995;Yoshida et al., 2004;IARC, 1987). Among children, exposure to As is associated with deficits in intelligence quotient (IQ), cognitive development, and neurobehavioral function, although the evidence has been inconsistent (Calderon et al., 2001;Nahar et al., 2014;Rosado et al., 2007;Tsai et al., 2003;Wang et al., 2007;Hamadani et al., 2011;Wasserman et al., 2007Wasserman et al., , 2004Wasserman et al., , 2011. ...
Background:
Few studies have evaluated the association between low-level arsenic (As) exposure and cognitive performance among children.
Objectives:
In this cross-sectional study, we assessed the association between low-level As exposure and cognitive performance among 5-8 year-old children in Montevideo, and tested effect modification by As methylation capacity and children's dietary folate intake.
Methods:
We measured total urinary As (UAs) concentrations and the proportion of monomethylarsonic acid (MMA) in the urine of 328 children. Seven subtests of the standardized Woodcock-Muñoz cognitive battery were used to assess cognitive performance, from which, the general intellectual abilities (GIA) score was derived. Total folate intake was estimated from two 24-h dietary recalls. Linear regression analyses were performed. Effect modification was assessed by stratifying at the median %MMA value and tertiles of total folate intake calculated as micrograms (µg) of dietary folate equivalents (dfe).
Results:
The median UAs was 11.9 µg/l (range = 1.4-93.9), mean folate intake was 337.4 (SD = 123.3) µg dfe, and median %MMA was 9.42 (range = 2.6-24.8). There was no association between UAs and cognitive abilities, and no consistent effect modification by %MMA. UAs was associated inversely with concept formation, and positively with cognitive efficiency and numbers reversed subtest in the lowest folate intake tertile; UAs was also positively associated with sound integration in the second tertile and concept formation in the highest tertile of folate intake. There was no consistent pattern of effect modification by %MMA or folate intake.
Conclusion:
There was no association between low-level As exposure and general cognitive abilities.
... The American Conference of Governmental Hygienists recommend a Biological Exposure Index (BEI) level of 35 µM for total urine arsenic [7]. Arsenic has been classified as a strong carcinogen [8], and is estimated to contribute to as much as 21.4% of all causes of mortality in highly exposed regions of the world [9]. Chronic exposure to arsenic has been associated with elevated risk of cardiovascular disease (CVD) endpoints including ischemic heart disease incidence and mortality in several American Indian populations with water sources measured up to 21 ppb arsenic [10] and among populations in Bangladesh, over half of which consume ground water that substantially exceeds 50 ppb arsenic [9]. ...
Arsenic methylation capacity is associated with metabolic syndrome and its components among highly exposed populations. However, this association has not been investigated in low to moderately exposed populations. Therefore, we investigated arsenic methylation capacity in relation to the clinical diagnosis of metabolic syndrome in a low arsenic exposure population. Additionally, we compared arsenic methylation patterns present in our sample to those of more highly exposed populations. Using logistic regression models adjusted for relevant biological and lifestyle covariates, we report no association between increased arsenic methylation and metabolic syndrome in a population in which arsenic is regulated at 10 ppb in drinking water. However, we cannot rule out the possibility of a positive association between arsenic methylation and metabolic syndrome in a subsample of women with normal body mass index (BMI). To our knowledge this is the first investigation of arsenic methylation capacity with respect to metabolic syndrome in a low exposure population. We also report that methylation patterns in our sample are similar to those found in highly exposed populations. Additionally, we report that gender and BMI significantly modify the effect of arsenic methylation on metabolic syndrome. Future studies should evaluate the effectiveness of arsenic policy enforcement on subclinical biomarkers of cardiovascular disease.
... Arsenic is a potent cardiovascular toxicant; epidemiological evidence has linked arsenic exposure to ischemic heart disease, cerebrovascular disease, atherosclerosis, and hypertension in exposed human populations [2][3][4]. Arsenic has been characterized as a strong carcinogen [5]. Arsenic-induced reactive oxygen species (ROS) cause genetic mutations and cancer by promoting DNA damage, activating oncogenic kinases, and activating lipids and proteins that inactivate DNA repair mechanisms [6,7]. ...
Arsenic is a potent cardiovascular toxin associated with numerous biomarkers of cardiovascular diseases in exposed human populations. Arsenic is also a carcinogen, yet, arsenic trioxide is used as a therapeutic agent in the treatment of acute promyelotic leukemia (APL). The therapeutic use of arsenic is limited due to its severe cardiovascular side effects. Many of the toxic effects of arsenic are mediated by mitochondrial dysfunction and related to arsenic’s effect on oxidative stress. Therefore, we investigated the effectiveness of antioxidants against arsenic induced cardiovascular dysfunction. A growing body of evidence suggests that antioxidant phytonutrients may ameliorate the toxic effects of arsenic on mitochondria by scavenging free radicals. This review identifies 21 antioxidants that can effectively reverse mitochondrial dysfunction and oxidative stress in cardiovascular cells and tissues. In addition, we propose that antioxidants have the potential to improve the cardiovascular health of millions of people chronically exposed to elevated arsenic concentrations through contaminated water supplies or used to treat certain types of leukemias. Importantly, we identify conceptual gaps in research and development of new mito-protective antioxidants and suggest avenues for future research to improve bioavailability of antioxidants and distribution to target tissues in order reduce arsenic-induced cardiovascular toxicity on a real-world context.
... Although little is known about the latency period between exposure to arsenic and the risk of many arsenic-associated noncancer diseases, a few earlier studies in Taiwan and Japan and our own studies in Chile are consistent in suggesting that internal cancers associated with arsenic ingestion have substantial latency periods, frequently in excess of 20 years from the beginning of exposure (8)(9)(10)(11)(12)(13). The knowledge of latency effects is an important factor in assessing the public health implications of arsenic exposure. ...
Background:
Region II in northern Chile (population 442 570) experienced a sudden major increase in arsenic water concentrations in 1958 in the main city of Antofagasta, followed by a major reduction in exposure when an arsenic removal plant was installed in 1970. It provides a unique opportunity to study latency effects of exposure to arsenic, and this is the first study with mortality data up to 40 years after exposure reduction.
Methods:
We previously identified high mortality rates in Region II up to the year 2000. Here we present rate ratios (RRs) for Region II compared with all the rest of Chile from 2001 to 2010, and with unexposed Region V (population 1 539 852) for all years from 1950 to 2010. All statistical tests were one-sided.
Results:
From 2001 to 2010, comparing Region II with the rest of Chile, lung and bladder mortality were still greatly elevated (RR = 3.38, 95% confidence interval [CI] = 3.19 to 3.58, P < .001 for lung cancer in men; RR = 2.41, 95% CI = 2.20 to 2.64, P < .001 for lung cancer in women; RR = 4.79, 95% CI = 4.20 to 5.46, P < .001 for bladder cancer in men; RR = 6.43, 95% CI = 5.49 to 7.54, P < .001 for bladder cancer in women). Kidney cancer mortality was also elevated (RR = 1.75, 95% CI = 1.49 to 2.05, P < .001 for men; RR = 2.09, 95% CI = 1.69 to 2.57, P < .001 for women). Earlier short latency acute myocardial infarction mortality increases had subsided.
Conclusions:
Lung, bladder, and kidney cancer mortality due to arsenic exposure have very long latencies, with increased risks manifesting 40 years after exposure reduction. Our findings suggest that arsenic in drinking water may involve one of the longest cancer latencies for a human carcinogen.
... Nonetheless, Moselle wine growers with exposure to arsenical pesticides through drinking alcoholic beverages and spraying pesticides were found to have an excess risk of lung cancer (22). In addition, studies in Japan (12,23), Chile (24), Argentina (25), and China (26) on populations exposed to arsenic through drinking water have also found an association between exposure to arsenic in drinking water and lung cancer. Overall, there is adequate evidence to argue that arsenic ingestion may cause lung cancer. ...
Background: Arsenic is a well-documented human carcinogen, and studies on urinary and skin cancers have shown that the carcinogenicity of ingested arsenic has cell-type specificity. To evaluate whether this is also true for lung cancers, we conducted a study on 243 townships in Taiwan.
Methods: The arsenic levels were assessed using measurement reports from a previous survey, and the incidence of lung cancer was assessed using the data gathered by the National Cancer Registry Program. We analyzed data by regression models with multiple variables to describe exposure levels; each variable denoted the proportion of people in a specific exposure category in each township. An urbanization index and variables denoting the distribution of age in each township were also included in the model to adjust for effects of urbanization and age.
Results: Among the three major cell types of lung cancer, squamous cell carcinoma appeared to be associated with arsenic level in drinking water, and the association was more prominent at exposure level above 0.64 mg/L in both men and women. A 1% increase in the proportion of wells in this category was associated with an increase of 0.27 per 100,000 per year in the incidence of squamous cell lung cancer in men and 0.13 per 100,000 per year in women. Adenocarcinoma and small cell carcinoma were not associated with arsenic level in drinking water.
Conclusions: The results suggested that the carcinogenicity of arsenic on lungs is cell-type specific, which is compatible with observations on urinary and skin cancers. Whereas data in the literature were limited, the association between adenocarcinoma and arsenic exposures through inhalation appeared to be stronger than that of squamous cell carcinoma. Therefore, different exposure routes may give rise to different mechanisms in the carcinogenicity of arsenic.
... Residents of Japan's Niigata Prefecture lived in an arsenic-polluted area and used well water containing inorganic arsenic. A Japanese historical cohort study [53] investigated the long-term effect of high exposure to ingested arsenic (≥ 1000 ppb). From 1949 until 1952, 454 residents who used well water containing inorganic arsenic were followed. ...
Through contaminated diet, water, and other forms of environmental exposure, arsenic affects human health. There are many U.S. and worldwide "hot spots" where the arsenic level in public water exceeds the maximum exposure limit. The biological effects of chronic arsenic exposure include generation of reactive oxygen species (ROS), leading to oxidative stress and DNA damage, epigenetic DNA modification, induction of genomic instability, and inflammation and immunomodulation, all of which can initiate carcinogenesis. High arsenic exposure is epidemiologically associated with skin, lung, bladder, liver, kidney and pancreatic cancer, and cardiovascular, neuronal, and other diseases. This review briefly summarizes the biological effects of arsenic exposure and epidemiological cancer studies worldwide, and provides an overview for emerging rodent-based studies of reagents that can ameliorate the effects of arsenic exposure in vivo. These reagents may be translated to human populations for disease prevention. We propose the importance of developing a biomarker-based precision prevention approach for the health issues associated with arsenic exposure that affects millions of people worldwide.
... Several studies have revealed an elevated cancer risk for populations exposed to varying amounts of iAs from industrial emissions [4,[21][22][23]. In addition, an association between various cancers and contaminated drinking water [21] has been observed in cohorts from a variety of regions around the world including Taiwan [24], Japan [25], USA [26], and parts of South America [27,28]. Recent reports from the United Nations International Children's Emergency Fund (UNICEF) indicate that over 140 million people across more than 70 countries are exposed to iAs in their drinking water [29]. ...
Purpose of Review
The goal of this review is to delineate the following: (1) the primary means of inorganic arsenic (iAs) exposure for human populations, (2) the adverse public health outcomes associated with chronic iAs exposure, (3) the pathophysiological connection between arsenic and type 2 diabetes (T2D), and (4) the incipient evidence for microRNAs as candidate mechanistic links between iAs exposure and T2D.
Recent Findings
Exposure to iAs in animal models has been associated with the dysfunction of several different cell types and tissues, including liver and pancreatic islets. Many microRNAs that have been identified as responsive to iAs exposure under in vitro and/or in vivo conditions have also been shown in independent studies to regulate processes that underlie T2D etiology, such as glucose-stimulated insulin secretion from pancreatic beta cells.
Summary
Defects in insulin secretion could be, in part, associated with aberrant microRNA expression and activity. Additional in vivo studies need to be performed with standardized concentrations and durations of arsenic exposure in order to evaluate rigorously microRNAs as molecular drivers of iAs-associated diabetes.
... Chronic exposure to arsenic is associated, in a dose-related fashion, with an increased risk of bladder cancer [25, [45][46][47][48][49][50][51][52]. Arsenic also has been associated with an excess risk of cancers of the kidney [25, [53][54][55]. ...
A large number of environmental chemicals are potentially toxic to the kidneys. History of past and current exposures to lead, mercury, arsenic, cadmium, uranium, melamine, ochratoxins, pesticides and aristolochic acid should be considered in the differential diagnosis of renal injuries. Children may be exposed to these chemicals in water, milk, infant formula, and food. These chemicals may be in toys and inexpensive jewelry, consumer products, household pesticides, and Chinese traditional medicines. This chapter provides information about some of the chemicals that pediatricians should consider when a child presents with renal injury of unknown etiology. In order to determine the possibility of exposure to nephrotoxic chemicals, the clinician must perform a careful environmental history as part of the complete history and physical examination.
... Nude mice (n = 3 per group) were treated with vehicle or sodium arsenic (0.5 or 5 ppm) via drinking water for six months. The 0.5 ppm concentration is consistent with environmentally relevant arsenic exposure associated with carcinogenesis in humans, including skin carcinogenesis [39][40][41]. A does of 5 ppm represents a higher dose of relevant arsenic exposure in humans and was used to verify the effect of arsenic in a dose-response manner compared to 0.5 ppm [42]. ...
Exposure to inorganic arsenic in contaminated drinking water poses an environmental public health threat for hundreds of millions of people in the US and around the world. Arsenic is a known carcinogen for skin cancer. However, the mechanism by which arsenic induces skin cancer remains poorly understood. Here, we have shown that arsenic induces p62 expression in an autophagy-independent manner in human HaCaT keratinocytes. In mouse skin, chronic arsenic exposure through drinking water increases p62 protein levels in the epidermis. Nrf2 is required for basal and arsenic-induced p62 up-regulation. p62 knockdown reduces arsenic-induced Nrf2 activity, and induces sustained p21 up-regulation. p62 induction is associated with increased proliferation in mouse epidermis. p62 knockdown had little effect on arsenic-induced apoptosis, while it decreased cell proliferation following arsenic treatment. Our findings indicate that arsenic induces p62 expression to regulate the Nrf2 pathway in human keratinocytes and suggest that targeting p62 may help prevent arsenic-induced skin cancer.
... Exposure to inorganic arsenic (InAs) is considered an etiologic factor for mortality of cancers and vascular diseases in humans (1). Cancers of skin and other internal organs, including lung, liver, bladder, and kidney, are associated with InAs exposure (2,3). Recent studies from Bangladesh have demonstrated an association between InAs exposure and the onset of lung and other internal organ cancers (4,5). ...
Background: Exposure to inorganic arsenic (InAs) has been documented as a risk factor for lung cancer. This study examined the association between InAs exposure, its metabolism, and lung cancer occurrence.
Methods: We followed 1,300 residents from an arseniasis area in Taiwan, determined urinary InAs metabolites, and identified 39 lung cancer cases. Cox proportional hazards model was performed.
Results: The results demonstrated that participants with either the primary methylation index [monomethylarsonic acid (MMA)/InAs] or the secondary methylation index [dimethylarsenic acid (DMA)/MMA] lower than their respective median values were at a higher risk of lung cancer (HRs from 3.41 to 4.66) than those with high methylation capacity. The incidence density of lung cancer increased from 79.9/100,000 (year⁻¹) to 467.4/100,000 (year⁻¹) for residents with low methylation capacity and from 0 to 158.5/100,000 (year⁻¹) for residents with high methylation capacity when the arsenic exposure dose increased from 2 to 10 ppb to ≥200 ppb, respectively. The analyses revealed a dose–response relationship between lung cancer occurrence and increasing arsenic concentrations in drinking water as well as cumulative arsenic exposure (monotonic trend test; P < 0.05 and P < 0.05, respectively) among the residents with low methylation capacity. The relationship between arsenic exposure and lung cancer among high methylators was not statistically significant.
Conclusions: Hypomethylation responses to InAs exposure may dose dependently increase lung cancer occurrence.
Impact: The high-risk characteristics observed among those exposed should be considered in future preventive medicine and research on arsenic carcinogenesis.
Arsenic is an environmental toxicant that significantly enhances the risk of developing disease, including several cancers. While the epidemiological evidence supporting increased cancer risk due to chronic arsenic exposure is strong, therapies tailored to treat exposed populations are lacking. This can be accredited in large part to the chronic nature and pleiotropic pathological effects associated with prolonged arsenic exposure. Despite this fact, several putative mediators of arsenic promotion of cancer have been identified. Among these, the critical transcription factor NRF2 has been shown to be a key mediator of arsenic's pro-carcinogenic effects. Importantly, the dependence of arsenic-transformed cancer cells on NRF2 upregulation exposes a targetable liability that could be utilized to treat arsenic-promoted cancers. In this chapter, we briefly introduce the “light” vs “dark” side of the NRF2 pathway. We then give a brief overview of arsenic metabolism, and discuss the epidemiological and experimental evidence that support arsenic promotion of different cancers, with a specific emphasis on mechanisms mediated by chronic, non-canonical activation of NRF2 (i.e., the “dark” side). Finally, we briefly highlight how the non-canonical NRF2 pathway plays a role in other arsenic-promoted diseases, as well as research directions that warrant further investigation.
There is a strong association between arsenic exposure and lung cancer development, however, the mechanism by which arsenic exposure leads to carcinogenesis is not clear. In our previous study, we observed that when BEAS-2B cells are chronically exposed to arsenic, there is an increase in secreted TGFα, as well as an increase in EGFR expression and activity. Further, these changes were broadly accompanied with an increase in cell migration. The overarching goal of this study was to acquire finer resolution of the arsenic-dependent changes in cell migration, as well as to understand the role of increased EGFR expression and activity levels in the underlying mechanisms of cell migration. To do this, we used a combination of biochemical and single cell assays, and observed chronic arsenic treatment enhancing cell migration by increasing cell speed, cell persistence and cell protrusion length. All three parameters were further increased by the addition of TGFα, indicating EGFR activity is sufficient to enhance those aspects of cell migration. In contrast, EGFR activity was necessary for the increase in cell speed, as it was reversed with an EGFR inhibitor, AG1478, but was not necessary to enhance persistence and protrusion length. From these data, we were able to isolate both EGFR-dependent and –independent features of cell migration that were enhanced by chronic arsenic exposure.
Chronic arsenic exposure via drinking water is associated with diabetes in human pop-ulations throughout the world. Arsenic is believed to exert its diabetogenic effects via multiple mechanisms, including alterations to insulin secretion and insulin sensitivity. In the past, acute arsenicosis has been thought to be partially treatable with selenium supplementation, though a potential interaction between selenium and arsenic had not been evaluated under longer-term exposure models. The purpose of the present study was to explore whether selenium status may augment arsenic’s effects during chronic arsenic exposure. To test this possibility, mice were exposed to arsenic in their drinking water and provided ad libitum access to either a diet replete with selenium (Control) or deficient in selenium (SelD). Arsenic significantly improved glucose tolerance and decreased insulin secretion and β-cell function in vivo. Dietary selenium deficiency resulted in similar effects on glucose tolerance and insulin secretion, with significant interactions between arsenic and dietary conditions in select insulin-related parameters. The findings of this study highlight the complexity of arsenic’s metabolic effects and suggest that selenium deficiency may interact with arsenic exposure on β-cell-related physiological parameters.
Arsenic in private drinking water wells is a significant problem across much of eastern Wisconsin, USA. The release mechanism and stratigraphic distribution of sulfide and iron (hydr)oxide sources of arsenic in bedrock aquifers are well understood for northeastern Wisconsin. However, recent geologic mapping has identified numerous small bedrock folds to the south, and the impact of these geologic structures on local groundwater flow and well contamination has been little studied. This paper examines the hydrologic and structural effects of the Beaver Dam anticline, southeast Wisconsin, on arsenic in groundwater in the region. Multivariate logistic regression shows wells near the Beaver Dam anticline are statistically more likely to detect arsenic in groundwater compared to wells farther away. Structural and hydrologic changes related to folding are interpreted to be the cause. Core drilled near the fold axis is heavily fractured, and many fractures are filled with sulfides. Elevated hydraulic conductivity estimates are also recorded near the fold axis, which may reflect a higher concentration of vertical fractures. These structural and hydrologic changes may have led to systematic changes in the distribution and concentration of arsenic-bearing mineral hosts, resulting in the observed detection pattern. For areas with similar underlying geology, this approach may improve prediction of arsenic risk down to the local level.
More than 2.5 billion people on the globe rely on groundwater for drinking and providing high-quality drinking water has become one of the major challenges of human society. Although groundwater is considered as safe, high concentrations of heavy metals like arsenic (As) can pose potential human health concerns and hazards. In this paper, we present an overview of the current scenario of arsenic contamination of groundwater in various countries across the globe with an emphasis on the Indian Peninsula. With several newly affected regions reported during the last decade, a significant increase has been observed in the global scenario of arsenic contamination. It is estimated that nearly 108 countries are affected by arsenic contamination in groundwater (with concentration beyond maximum permissible limit of 10 ppb recommended by the World Health Organization. The highest among these are from Asia (32) and Europe (31), followed by regions like Africa (20), North America (11), South America (9) and Australia (4). More than 230 million people worldwide, which include 180 million from Asia, are at risk of arsenic poisoning. Southeast Asian countries, Bangladesh, India, Pakistan, China, Nepal, Vietnam, Burma, Thailand and Cambodia, are the most affected. In India, 20 states and 4 Union Territories have so far been affected by arsenic contamination in groundwater. An attempt to evaluate the correlation between arsenic poisoning and aquifer type shows that the groundwater extracted from unconsolidated sedimentary aquifers, particularly those which are located within the younger orogenic belts of the world, are the worst affected. More than 90% of arsenic pollution is inferred to be geogenic. We infer that alluvial sediments are the major source for arsenic contamination in groundwater and we postulate a strong relation with plate tectonic processes, mountain building, erosion and sedimentation. Prolonged consumption of arsenic-contaminated groundwater results in severe health issues like skin, lung, kidney and bladder cancer; coronary heart disease; bronchiectasis; hyperkeratosis and arsenicosis. Since the major source of arsenic in groundwater is of geogenic origin, the extend of pollution is complexly linked with aquifer geometry and aquifer properties of a region. Therefore, remedial measures are to be designed based on the source mineral, climatological and hydrogeological scenario of the affected region. The corrective measures available include removing arsenic from groundwater using filters, exploring deeper or alternative aquifers, treatment of the aquifer itself, dilution method by artificial recharge to groundwater, conjunctive use, and installation of nano-filter, among other procedures. The vast majority of people affected by arsenic contamination in the Asian countries are the poor who live in rural areas and are not aware of the arsenic poisoning and treatment protocols. Therefore, creating awareness and providing proper medical care to these people remain as a great challenge. Very few policy actions have been taken at international level over the past decade to reduce arsenic contamination in drinking water, with the goal of preventing toxic impacts on human health. We recommend that that United Nations Environment Programme (UNEP) and WHO should take stock of the global arsenic poisoning situation and launch a global drive to create awareness among people/medical professionals/health workers/administrators on this global concern.
The impacts of acute arsenic exposure (i.e. vomiting, diarrhea, and renal failure) are distinct from those brought about by sustained, low level exposure from environmental sources or drinking of contaminated well water. Chronic arsenic exposure is a risk factor for the development of pulmonary diseases, including lung cancer. How arsenic exposure leads to pulmonary disease is not fully understood. Both acute versus chronic arsenic exposure increase EGFR expression, but do so via distinct molecular mechanisms. BEAS-2B cells were exposed to either acute sodium arsenite (5 μM for 24 h) or chronic sodium arsenite (100 nM for 24 weeks). Cells treated with acute arsenic exhibited a decrease in viability, changes in morphology, and increased mRNA level of BTC. In contrast, during 24 weeks of arsenic exposure, the cells had increased EGFR expression and activity, and increased mRNA and protein levels of TGFα. Further, chronic arsenic treatment caused an increase in cell migration in the absence of exogenous ligand. Elevated TGFα and EGFR expression are features of many non-small cell lung cancers. We propose that lung epithelial cells chronically exposed to low level arsenic increases EGFR signaling via TGFα production to enhance ligand-independent cell migration.
This study is the first attempt to evaluate occurrence, distribution and potential health impacts of As at a national scale in Italy. In various environmental matrices, As geochemical distribution was investigated and carcinogenic and non-carcinogenic risks were assessed with respect to different exposure routes and age groups. Both deterministic and probabilistic methods were used to determine the health risks. Geochemical mapping at a subcontinental scale provided a useful tool to spatially represent As concentration and the critical areas posing a health threat to inhabitants. The results show that significant As concentrations in tap water and soil (up to 27.20 μg/l and 62.20 mg/kg, respectively) are mainly governed by geological features. In the central parts of Italy, where alkaline volcanic materials and consequently high levels of As occur, the residents are prone to
health issues. Daily exposure to As in tap water is unparalleled playing an important role in the potential cancer and non-cancer risks. The Incremental Lifetime Cancer Risk for skin cancer and also lung and bladder cancer associated with tap water ingestion interestingly shows that (i) almost 80% of the computed values fall above the
internationally accepted benchmark value of 1 × 10−5; (ii) majority of the data exceed the acceptable risk proposed by most jurisdictions, such as that of Italian law (1 × 10−6). Further, geographical variation of health risk highlights high carcinogenic and non-carcinogenic risk associated with water ingestion for those living in the northern Alps (including the city of Trento) and the central and southern Italy (including the capital Rome and the cities of Napoli and Catanzaro). According to the results, application of the probabilistic method which
considers variability and uncertainty is preferred to the deterministic approach for risk assessment. The sensitivity analysis showed that As concentration in drinking water and exposure duration are the factors with the greatest impact on the outcome of risk assessment (for all age groups). The results of the current study may be a good starting point for authorities to urgently decide about the needed policy actions in order to prevent the adverse health effects and to reduce the human health risk due to As exposure.
Arsenic affects hundreds of millions of people around the world, with majority of the arsenic-affected populations living in Southeast Asia. Recent reports estimated that population exposed to water arsenic at concentrations higher than the World Health Organization guideline level of 10 μg/L or higher than 50 μg/L included 70–80 million people living in India, 28–60 million in Bangladesh, 47–60 million in Pakistan, about 10 million in Vietnam, 2–5 million in China, more than 3 million in Nepal, about 3.4 million in Myanmar, and 0.32–2.4 million in Cambodia. The sum of the arsenic-affected populations from these areas ranged from 150 million to 240 million. Chronic exposure to high concentrations of arsenic from drinking water is associated with increased risk of various adverse health effects, such as cancers, cardiovascular disease, diabetes, and neurological effects. Continued research and mitigation actions are required to protect public health from arsenic-induced diseases.
Arsenic is a naturally occurring element, found in soil, some groundwaters, and food. Throughout the world, including Taiwan, India, Mongolia, and Bangladesh, human populations are exposed to high levels of arsenic in drinking water. Short-term exposures to large doses of arsenic can cause health effects such as encephalopathy, peripheral neuropathy, and death. Long-term human exposure to high levels of arsenic causes a variety of noncancer health effects (including pigmentation changes, hyperkeratosis, and vascular effects) and also cancer (including skin, bladder, and lung cancer). However, consistent health effects have been observed only in populations outside the United States exposed to relatively high concentrations of arsenic in drinking water, often in populations suffering from nutritional deficiencies that may increase susceptibility. To standardize quantitative risk assessments for arsenic, US regulatory agencies have developed arsenic-specific toxicity factors (reference doses for noncancer effects, and cancer slope factors for cancer), based primarily on Taiwanese populations exposed to high levels of arsenic in drinking water. These analyses contain conservative elements; what is particularly important is that there is convincing human and mechanistic data to support a nonlinear dose–response relationship for arsenic. Overall, the arsenic cancer slope factor is likely to overestimate cancer risk at low levels of exposure.
Background:
Elevated body mass index (BMI) and arsenic are both associated with cancer and with non-malignant lung disease. Using a unique exposure situation in Northern Chile with data on lifetime arsenic exposure, we previously identified the first evidence of an interaction between arsenic and BMI for the development of lung cancer.
Objectives:
We examined whether there was an interaction between arsenic and BMI for the development of non-malignant lung disease.
Methods:
Data on lifetime arsenic exposure, respiratory symptoms, spirometry, BMI, and smoking were collected from 751 participants from cities in Northern Chile with varying levels of arsenic water concentrations. Spirometry values and respiratory symptoms were compared across subjects in different categories of arsenic exposure and BMI.
Results:
Adults with both a BMI above the 90th percentile (>33.9kg/m(2)) and arsenic water concentrations ≥11µg/L exhibited high odds ratios (ORs) for cough (OR = 10.7, 95% confidence interval (CI): 3.03, 50.1), shortness of breath (OR = 14.2, 95% CI: 4.79, 52.4), wheeze (OR = 14.4, 95% CI: 4.80, 53.7), and the combined presence of any respiratory symptom (OR = 9.82, 95% CI: 4.22, 24.5). In subjects with lower BMIs, respiratory symptom ORs for arsenic water concentrations ≥11µg/L were markedly lower. In never-smokers, reductions in forced vital capacity associated with arsenic increased as BMI increased. Analysis of the FEV1/FVC ratio in never-smokers significantly increased as BMI and arsenic concentrations increased. Similar trends were not observed for FEV1 alone or in ever-smokers.
Conclusions:
This study provides preliminary evidence that BMI may increase the risk for arsenic-related non-malignant respiratory disease.
Urothelial cancers have an environmental etiological component, and previous studies from our laboratory have shown that arsenite (As+ 3) can cause the malignant transformation of the immortalized urothelial cells (UROtsa), leading to the expression of keratin 6 (KRT6). The expression of KRT6 in the parent UROtsa cells can be induced by the addition of epidermal growth factor (EGF). Tumors formed by these transformed cells have focal areas of squamous differentiation that express KRT6. The goal of this study was to investigate the mechanism involved in the upregulation of KRT6 in urothelial cancers and to validate that the As+ 3-transformed UROtsa cells are a model of urothelial cancer. The results obtained showed that the parent and the As+ 3-transformed UROtsa cells express EGFR which is phosphorylated with the addition of epidermal growth factor (EGF) resulting in an increased expression of KRT6. Inhibition of the extracellular-signal regulated kinases (ERK1/2) pathway by the addition of the mitogen-activated protein kinase kinase 1 (MEK1) and MEK2 kinase inhibitor U0126 resulted in a decrease in the phosphorylation of ERK1/2 and a reduced expression of KRT6. Immuno-histochemical analysis of the tumors generated by the As+ 3-transformed isolates expressed EGFR and tumors formed by two of the transformed isolates expressed the phosphorylated form of EGFR. These results show that the expression of KRT6 is regulated at least in part by the ERK1/2 pathway and that the As+ 3-transformed human urothelial cells have the potential to serve as a valid model to study urothelial carcinomas.
Epidemiological studies have established an association between arsenic exposure and the development of bladder cancer. Studies in arsenic-endemic areas such Taiwan, Chile, and Argentina have led the International Agency for Research on Cancer (IARC) to list arsenic as an environmental contaminant and human carcinogen. Genetic polymorphisms in arsenic biotransformation enzymes provide individuals with varying degrees of susceptibility to arsenic exposure or development of cancer. To determine the biological effects of and mechanisms involved with arsenic exposure in humans, in vivo and in vitro models have been developed. With in vitro models such as the human urothelial cells (HUC) line, UROtsa, researchers have found that arsenical toxicity can vary with oxidation state and methylation, arsenic impacts the intracellular signaling of bladder cells by promoting proliferation and growth, arsenic can change the redox state of the cells, and arsenical interactions lead to alterations in normal gene expression patterns with concomitant epigenetic changes.
Chronic low dose inorganic arsenic exposure causes cells to take on an epithelial-to-mesenchymal phenotype, which is a crucial process in carcinogenesis. Inorganic arsenic is not a mutagen and thus epigenetic alterations have been implicated in this process. Indeed, during the epithelial-to-mesenchymal transition, morphologic changes to cells correlate with changes in chromatin structure and gene expression, ultimately driving this process. However, studies on the effects of inorganic arsenic exposure/withdrawal on the epithelial-to-mesenchymal transition and the impact of epigenetic alterations in this process are limited. In this study we used high-resolution microarray analysis to measure the changes in DNA methylation in cells undergoing inorganic arsenic-induced epithelial-to-mesenchymal transition, and on the reversal of this process, after removal of the inorganic arsenic exposure. We found that cells exposed to chronic, low-dose inorganic arsenic exposure showed 30,530 sites were differentially methylated, and with inorganic arsenic withdrawal several differential methylated sites were reversed, albeit not completely. Furthermore, these changes in DNA methylation mainly correlated with changes in gene expression at most sites tested but not at all. This study suggests that DNA methylation changes on gene expression are not clear-cut and provide a platform to begin to uncover the relationship between DNA methylation and gene expression, specifically within the context of inorganic arsenic treatment.
Since 1955, a number of outbreaks of arsenic poisoning have occurred throughout Japan among industrial workers and the general population. The sources and types of exposure differ according to the incident, and the victims vary in sex and age. These incidents include arsenic poisoning in milk, soy sauce, and well water, pollution originating from the Toroku Mine on the island of Kyushu, the Matsuo Mine in Shimane Prefecture and Saganoseki Smelter on Kyushu. The type, routes, and dose of exposure as well as major symptoms are given. The clinical signs and symptoms are discussed in relation to the various types of exposure which occurred in these incidents. Dose-response relationships will be considered where data are available.