Arsenic-induced neurotoxicity in patients with acute promyelocytic leukaemia.

Arsenic trioxide is an essential component of therapy for acute promyelocytic leukaemia (APL) and is currently dosed on actual body weight with no upper limit. Arsenic-induced neurotoxicity is a well-recognised complication; however, there is uncertainty about its relationship to arsenic dose and obesity. We conducted a large multicentre retrospective study of 487 patients with APL treated with arsenic-based therapy across 23 sites in Australia from 2008 to 2023. The primary outcome was incidence of neurotoxicity, and secondary outcomes included relationship of neurotoxicity to obesity and cumulative arsenic dose. Any-grade neurotoxicity occurred in 113 (23%) patients, predominantly peripheral neuropathy (91%). Most events were grade 1-2 severity (85%), with grade 3 events in 12% and grade 4-5 in 3%. The incidence of neurotoxicity increased with BMI (non-obese: 16%, obesity class I: 25%, obesity class II-III: 41%; p < 0.001). On univariable analysis, obesity class I (OR 1.81, p = 0.036), obesity class II-III (OR 3.93, p < 0.001), weight >100 kg (OR 2.72, p < 0.001), daily arsenic trioxide dose >15 mg (OR 5.05, p < 0.001) and cumulative induction dose >500 mg (OR 3.95, p < 0.001) were all significantly associated with neurotoxicity. Obesity class II-III and induction dose >500 mg remained significant on multivariable analysis. Our study highlights the strong association between BMI, arsenic trioxide dose and neurotoxicity. Pre-emptive dose reductions should be considered for obese patients receiving high doses of arsenic.

Effect of arsenic on the risk of gestational diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND: Gestational diabetes mellitus (GDM) is a complication of pregnancy associated with numerous adverse outcomes. There may be a potential link between GDM and arsenic (As) exposure, but this hypothesis remains controversial. This meta-analysis summarizes the latest studies evaluating the association between As and GDM. METHODS: A comprehensive search of the PubMed, Embase, and Scopus databases up to September 2023 was performed. The pooled estimates with 95% CIs were presented using forest plots. Estimates were calculated with random effects models, and subgroup and sensitivity analyses were conducted to address heterogeneity. RESULTS: A total of 13 eligible studies involving 2575 patients with GDM were included in this meta-analysis. The results showed that women exposed to As had a significantly increased risk of GDM (OR 1.47, 95% CI: 1.11 to 1.95, P = 0.007). Subgroup analyses suggested that the heterogeneity might be attributed to the years of publication. In addition, sensitivity analysis confirmed the robust and reliable results. CONCLUSIONS: This analysis suggested that women exposed to As have a greater risk of GDM. However, the significant heterogeneity across studies requires careful interpretation. REGISTRATION: The PROSPERO registration ID is CRD42023461820.

The role and mechanism of miR-425-3p regulating neuronal pyroptosis -mediated inorganic arsenic-induced generalized anxiety disorder.

Pyroptosis plays a critical role in the pathogenesis of mental disorders. However, its specific role and mechanism in arsenic (As)-induced generalized anxiety disorder (GAD) remain elusive. We utilized the data from CtdBbase, Phenopedia and DisGeNet to analyze genes that interact with arsenic poisoning and GAD. Subsequently KEGG and GO enrichment analysis were conducted to preliminatively predict the mechanism of inorganic arsenic-induced GAD. Male Wistar rats were administered water containing NaAsO2 (50, 100 µg/L) to evaluate GAD-like behavior through open field test and elevated plus maze. The expression of differential miRNAs including miR-425-3p, and pyroptosis in the prefrontal cortex of rats were detected. Furthermore, SKNSH cells were stimulated with NaAsO2 to examine the molecular changes, and then miR-425-3p mimic was transfected into SKNSH cells to detect pyroptosis in order to verify the function of miR-425-3p. Inorganic arsenic was confirmed to induce GAD-like behavior in rats, characterized by decreased locomotor activity and exploratory activities. Rats with inorganic arsenic-induced GAD exhibited reduced miR-425-3p expression levels in the prefrontal cortex and increased expression of pyroptosis-related proteins, including NF-κB, NLRP3, Caspase-1, GSDMD, IL-1ß, and IL-18. Treating with different concentrations of NaAsO2 showed that inorganic arsenic exposure downregulates miR-425-3p expression in SKNSH cells and upregulates the expression levels of pyroptosis-related proteins. Dual-luciferase reporter gene experiments demonstrated that miR-425-3p targets the NFKB1. Overexpressing miR-425-3p reversed the inorganic arsenic-induced pyroptosis in SKNSH cells by inhibiting the expression of NF-κB, NLRP3, Caspase-1, GSDMD, IL-1ß, and IL-18. Our findings suggest that inorganic arsenic exposure may induce GAD-like behavior in rats by downregulating miR-425-3p in prefrontal cortex, which targets NF-κB and regulates pyroptosis in neuronal cells.

Copper, Iron, Cadmium, and Arsenic, All Generated in the Universe: Elucidating Their Environmental Impact Risk on Human Health Including Clinical Liver Injury.

Humans are continuously exposed to various heavy metals including copper, iron, cadmium, and arsenic, which were specifically selected for the current analysis because they are among the most frequently encountered environmental mankind and industrial pollutants potentially causing human health hazards and liver injury. So far, these issues were poorly assessed and remained a matter of debate, also due to inconsistent results. The aim of the actual report is to thoroughly analyze the positive as well as negative effects of these four heavy metals on human health. Copper and iron are correctly viewed as pollutant elements essential for maintaining human health because they are part of important enzymes and metabolic pathways. Healthy individuals are prepared through various genetically based mechanisms to maintain cellular copper and iron homeostasis, thereby circumventing or reducing hazardous liver and organ injury due to excessive amounts of these metals continuously entering the human body. In a few humans with gene aberration, however, liver and organ injury may develop because excessively accumulated copper can lead to Wilson disease and substantial iron deposition to hemochromatosis. At the molecular level, toxicities of some heavy metals are traced back to the Haber Weiss and Fenton reactions involving reactive oxygen species formed in the course of oxidative stress. On the other hand, cellular homeostasis for cadmium and arsenic cannot be provided, causing their life-long excessive deposition in the liver and other organs. Consequently, cadmium and arsenic represent health hazards leading to higher disability-adjusted life years and increased mortality rates due to cancer and non-cancer diseases. For unknown reasons, however, liver injury in humans exposed to cadmium and arsenic is rarely observed. In sum, copper and iron are good for the human health of most individuals except for those with Wilson disease or hemochromatosis at risk of liver injury through radical formation, while cadmium and arsenic lack any beneficial effects but rather are potentially hazardous to human health with a focus on increased disability potential and risk for cancer. Primary efforts should focus on reducing the industrial emission of hazardous heavy metals.

Toxic Metals and Subclinical Atherosclerosis in Carotid, Femoral, and Coronary Vascular Territories: The Aragon Workers Health Study.

OBJECTIVE: Studies evaluating the association of metals with subclinical atherosclerosis are mostly limited to carotid arteries. We assessed individual and joint associations of nonessential metals exposure with subclinical atherosclerosis in 3 vascular territories. Approach and Results: One thousand eight hundred seventy-three Aragon Workers Health Study participants had urinary determinations of inorganic arsenic species, barium, cadmium, chromium, antimony, titanium, uranium, vanadium, and tungsten. Plaque presence in carotid and femoral arteries was determined by ultrasound. Coronary Agatston calcium score ≥1 was determined by computed tomography scan. Median arsenic, barium, cadmium, chromium, antimony, titanium, uranium, vanadium, and tungsten levels were 1.83, 1.98, 0.27, 1.18, 0.05, 9.8, 0.03, 0.66, and 0.23 µg/g creatinine, respectively. The adjusted odds ratio (95% CI) for subclinical atherosclerosis presence in at least one territory was 1.25 (1.03-1.51) for arsenic, 1.67 (1.22-2.29) for cadmium, and 1.26 (1.04-1.52) for titanium. These associations were driven by arsenic and cadmium in carotid, cadmium and titanium in femoral, and titanium in coronary territories and mostly remained after additional adjustment for the other relevant metals. Titanium, cadmium, and antimony also showed positive associations with alternative definitions of increased coronary calcium. Bayesian Kernel Machine Regression analysis simultaneously evaluating metal associations suggested an interaction between arsenic and the joint cadmium-titanium exposure. CONCLUSIONS: Our results support arsenic and cadmium and identify titanium and potentially antimony as atherosclerosis risk factors. Exposure reduction and mitigation interventions of these metals may decrease cardiovascular risk in individuals without clinical disease.

Arsenic and other metals as phenotype driving electrophiles in carcinogenesis.

There are several sources of heavy metal exposures whether occupational or environmental. These are connected both with the existence of natural reservoirs of metal toxicants or human activity such as mining, welding and construction. In general, exposure to heavy metals, such as cadmium (Cd), mercury (Hg), nickel (Ni), lead (Pb) and metalloids, such as arsenic (As), has been associated with diseases including neurodegenerative diseases, diabetes and cancer. Common to these diseases is the loss of cellular physiologic performance and phenotype required for proper function. On the metal side, electrophilic behavior that disrupts the electronic (or redox) state of cells is a common feature. This suggests that there may be a connection between changes to the redox equilibrium of cells caused by environmental exposures to heavy metals and the pathogenic effects of such exposures. In this mini-review, we will focus on two environmental contaminants cadmium (a metal) and arsenic (a metalloid) and explore their interactions with living organisms from the perspective of their electrophilic chemical reactivity that underlies both their potential as carcinogens and as drivers of more aggressive tumor phenotypes.

Arsenic-induced epigenetic changes in cancer development.

Arsenic is a ubiquitous metalloid whose high levels of toxicity pose major health concerns to millions of people worldwide by increasing susceptibility to various cancers and non-cancer illnesses. Since arsenic is not a mutagen, the mechanism by which it causes changes in gene expression and disease pathogenesis is not clear. One possible mechanism is through generation of reactive oxygen species. Another equally important mechanism still very much in its infancy is epigenetic dysregulation. In this review, we discuss recent discoveries underlying arsenic-induced epigenetic changes in cancer development. Importantly, we highlight the proposed mechanisms targeted by arsenic to drive oncogenic gene expression.

Connections between endoplasmic reticulum stress-associated unfolded protein response, mitochondria, and autophagy in arsenic-induced carcinogenesis.

Arsenic exposure in contaminated drinking water is a global health issue, as more than 200 million people are affected globally. Arsenic has been known to cause skin, liver, lung, bladder and prostate cancers. Accordingly, it has been categorized as a group I human carcinogen by the International Agency for Research on Cancer (IARC). Various natural and anthropogenic activities lead to the release of arsenic in the environment, contaminating air, water and food sources. Traditionally, genetic mutations have been the center of cancer research. However, emerging studies have now focused on the importance of epigenetics, metabolism and endoplasmic reticulum (ER) stress in cancer. Arsenic is highly capable of inducing stress in the cells via the generation of free radicals causing oxidative stress, epigenetic and genetic alterations, mitochondrial dysfunction, activation of intracellular signaling pathways, and impairment of autophagy and DNA repair systems. The cancer cells are able to utilize the unfolded protein response (UPR) to overcome these internal stresses in various stages of arsenic-induced carcinogenesis, from cancer growth to immune responses. The UPR is an evolutionarily conserved stress response that has both survival and apoptotic outcomes. PERK, IRE1α and ATF6α are the three ER stress sensors that are activated to maintain cellular proteostasis, which can also promote apoptosis on prolonged ER stress. The dual nature of UPR in different cancer types and stages is a challenge for researchers. We must investigate the role and the connections among ER stress-associated UPR, mitochondrial dysfunction and autophagy in arsenic malignancies to identify key targets for cancer prevention and therapeutics.

Mechanisms of the synergistic lung tumorigenic effect of arsenic and benzo(a)pyrene combined- exposure.

Humans are often exposed to mixtures of environmental pollutants especially environmental chemical carcinogens, representing a significant environmental health issue. However, our understanding on the carcinogenic effects and mechanisms of environmental carcinogen mixture exposures is limited and mostly relies on the findings from studying individual chemical carcinogens. Both arsenic and benzo(a)pyrene (BaP) are among the most common environmental carcinogens causing lung cancer and other types of cancer in humans. Millions of people are exposed to arsenic via consuming arsenic-contaminated drinking water and even more people are exposed to BaP via cigarette smoking and consuming BaP-contaminated food. Thus arsenic and BaP combined-exposure in humans is common. Previous epidemiology studies indicated that arsenic-exposed people who were cigarette smokers had significantly higher lung cancer risk than those who were non-smokers. Since BaP is one of the major carcinogens in cigarette smoke, it has been speculated that arsenic and BaP combined-exposure may play important roles in the increased lung cancer risk observed in arsenic-exposed cigarette smokers. In this review, we summarize important findings and inconsistencies about the co-carcinogenic effects and underlying mechanisms of arsenic and BaP combined-exposure and propose new areas for future studies. A clear understanding on the mechanism of co-carcinogenic effects of arsenic and BaP combined exposure may identify novel targets to more efficiently treat and prevent lung cancer resulting from arsenic and BaP combined-exposure.

The role of autophagy in metal-induced urogenital carcinogenesis.

Environmental and/or occupational exposure to metals such as Arsenic (As), Cadmium (Cd), and Chromium (Cr) have been shown to induce carcinogenesis in various organs, including the urogenital system. However, the mechanisms responsible for metal-induced carcinogenesis remain elusive. We and others have shown that metals are potent inducers of autophagy, which has been suggested to be an adaptive stress response to allow metal-exposed cells to survive in hostile environments. Albeit few, recent experimental studies have shown that As and Cd promote tumorigenesis via autophagy and that inhibition of autophagic signaling suppressed metal-induced carcinogenesis. In light of the newly emerging role of autophagic involvement in metal-induced carcinogenesis, the present review focuses explicitly on the mechanistic role of autophagy and potential signaling pathways involved in As-, Cd-, and Cr-induced urogenital carcinogenesis.

Arsenic co-carcinogenesis: Inhibition of DNA repair and interaction with zinc finger proteins.

Arsenic is widely present in the environment and is associated with various population health risks including cancers. Arsenic exposure at environmentally relevant levels enhances the mutagenic effect of other carcinogens such as ultraviolet radiation. Investigation on the molecular mechanisms could inform the prevention and intervention strategies of arsenic carcinogenesis and co-carcinogenesis. Arsenic inhibition of DNA repair has been demonstrated to be an important mechanism, and certain DNA repair proteins have been identified to be extremely sensitive to arsenic exposure. This review will summarize the recent advances in understanding the mechanisms of arsenic carcinogenesis and co-carcinogenesis, including DNA damage induction and ROS generation, particularly how arsenic inhibits DNA repair through an integrated molecular mechanism which includes its interactions with sensitive zinc finger DNA repair proteins.

Cooperation between NRF2-mediated transcription and MDIG-dependent epigenetic modifications in arsenic-induced carcinogenesis and cancer stem cells.

Environmental exposure to arsenic, a well-established carcinogen linked to a number of human cancers, is a public health concern in many areas of the world. Despite extensive studies on the molecular mechanisms of arsenic-induced carcinogenesis, how initial cellular responses, such as activation of stress kinases and the generation of reactive oxygen species, converge to affect the transcriptional and/or epigenetic reprogramming required for the malignant transformation of normal cells or normal stem cells remains to be elucidated. In this review, we discuss some recent discoveries showing how the transcription factor NRF2 and an epigenetic regulator, MDIG, contribute to the arsenic-induced generation of cancer stem-like cells (CSCs) as determined by applying CRISPR-Cas9 gene editing and chromosome immunoprecipitation followed by DNA sequencing (ChIP-seq).

Quercetin attenuates the proliferation of arsenic-related lung cancer cells via a caspase-dependent DNA damage signaling.

Exposure to arsenic (As) mainly through contaminated drinking water enhances the lung tumor progression, invasion, and metastasis. The carcinogenic effect of As is due to the generation of reactive oxygen species (ROS) and DNA damage, and interference with DNA repair machinery. Herein, we investigated the potential therapeutic function of quercetin on As-treated lung cancer cells. Quercetin is a natural product with antioxidative, anti-inflammatory, and antiproliferative properties. We showed that quercetin induced cell death in the As-exposed lung cancer cells in a dose-dependent manner. Quercetin was able to significantly inhibit the proliferation of the As-treated cells over a period of 5 weeks. In addition, quercetin induced ROS-mediated DNA double-strand breaks in the As-treated lung cancer cells. We also showed that ROS generation induced by quercetin activated caspase-3 to a sufficient level to induce DNA damage but insufficient to induce death in As-treated lung cancer cells. Moreover, transient activation of caspase-2 was detected in quercetin- and As-cotreated cells. The flow cytometry-based cell cycle analysis showed that the antiproliferative function of quercetin was mediated by S-phase cell cycle arrest, which was associated with upregulation of the Ataxia Telangiectasia-mutated (ATM), but not ATM and RAD3-related. In conclusion, quercetin synergized the As-driven ROS generation and DNA damage, and induced the S-phase arrest, thus inhibiting the proliferation of As-exposed lung cancer cells. This data suggested that quercetin is an alternative reagent to chemo-drugs to prevent the growth of As-exposed lung cancer cells.

Arsenic induces bronchial epithelial carcinogenesis with mitochondrial dysfunction through AKAP95-mediated cell cycle alterations.

Arsenic is a widely existing pollutant in the environment, but the mechanism of occurrence and development of lung cancer by long-term arsenic exposure needs to be elucidated further. How the high and low doses of arsenic induce human bronchial epithelial cell transformation is yet to be elucidated. In the present study, human bronchial epithelial cells were exposed to varying high-dose sodium arsenite (NaAsO2) for the short-term or treated with low dose for long-term. The data showed that both short- and long-term treatment promoted G1/S transition of Beas-2B cells, inducing a significant increase in the expression of AKAP95, cyclin D1, cyclin D2, and cyclin E1. However, silencing AKAP95 by treating cells with siAKAP95 exerted a protective function that inhibited G1/S transition, suggesting a regulatory mechanism of AKAP95 on the cell cycle during cell malignant transformation induced by NaAsO2. In addition, mitochondrial dysfunctions occurred during NaAsO2 exposure. Beas-2B cells exposed to low-dose NaAsO2 for long-term were subcultured for 20 generations, and the exposure time was positively proportional to the growth and migration rate of the cells. The exposed cells were used in a tumor-bearing transplantation experiment (mice), and the results showed that the longer the exposure time, the faster the tumor volume growth rate of As-Beas-2B cells. Tumor tissues were excised for hematoxylin-eosin staining, which showed altered cell morphology and increased volume.

Arsenic activates STAT3 signaling during the transformation of the human bronchial epithelial cells.

Arsenic (As3+), a metalloid abundant in environment, is classified as a group I carcinogen associated with several common human cancers, including cancers in lung, skin, bladder, liver, and prostate (Wei et al., 2019). The mechanisms of As3+-induced carcinogenesis had been extensively studied, and different mechanisms might be involved in different types of cancer (Wei et al., 2019). Recent studies showed that exposure to a high dose of arsenic is able to induce lung cancer. Meanwhile, prolonged exposure to a low concentration of arsenic can increase the risk of lung cancer also (Liao et al., 2009; Fernández et al., 2012). Emerging evidence indicated that prolonged exposure to arsenic promotes malignant transformation and some of the transformed cells have cancer-stem-like properties (Ngalame et al., 2014). In the present report, we revealed that exposure to As3+ for short time period inhibited tyrosine-705 phosphorylation of signal transducer and activator of transcription 3 (pSTAT3Y705) and induced Src homology region 2 domain-containing phosphatase-1 (SHP-1) in bronchial epithelial cell line, BEAS-2B. In addition, we found that long term exposure of the cells to As3+ activates phosphorylation of STAT3 at serine 727 (pSTAT3S727) as well as pSTAT3Y705. Moreover, As3+ is able to induce the expression of miRNA-21 (miR-21) and decrease the expression of PDCD4. Taken together, our data suggest that activation of STAT3 and induction of miR-21 are important contributing factors to the reduced expression of PDCD4, which may play significant role in As3+-induced transformation of BEAS-2B cells.

Health risk assessment for human exposure to mercury species and arsenic via consumption of local food in a gold mining area in Colombia.

The risk to human health from exposure to certain pollutants through the consumption of fruits, tubers, and fish were evaluated in a settlement located in a Colombian area highly impacted by gold mining activities. The concentrations of mercury (Hg) and arsenic (As) in edible food tissues and methylmercury (MeHg) in fish were determined for risk assessment. A questionnaire-based dietary survey was answered by 178 residents of three population groups: children (CHD), women of childbearing age (WCBA), and the rest of the population (RP). The estimated weekly intake (EWI) of MeHg presented values of 1.9 and 2.4 times higher than the provisional tolerable weekly intake (1.6 µg/kg BW/week) recommended by the FAO/WHO for CH and WCBA, respectively. The results of the HQ values of As and Hg for different food were above the safety level (HQ < 1) for most of the groups. For Hg, the highest HQ values correspond to fish, whereas for As in most of the food, but specially in fruits. The total target hazard quotients (HI) were higher than 1, in all the groups (except for CHD that consume tubers) indicating potential non-carcinogenic health risks. The values of carcinogenic risk (CR) for As through exposure to food ranged from 1.2·10-4 to 7.7·10-4, well above than the safety level of US EPA risk (10-4-10-6), suggesting the probability of carcinogenic risk for the entire population via ingestion. Therefore, safety control mechanisms and environmental education strategies should be applied to address food intake, associated with good agricultural practices to provide solutions to protect the health of the residents in areas affected by gold mining activities.

Urinary Metals, Arsenic, and Polycyclic Aromatic Hydrocarbon Exposure and Risk of Self-reported Emphysema in the US Adult Population.

PURPOSE: Metal and chemical exposure can cause acute and chronic respiratory diseases in humans. The purpose of this analysis was to analyze 14 types of urinary metals including mercury, uranium, tin, lead, antimony, barium, cadmium, cobalt, cesium, molybdenum, manganese, strontium, thallium, tungsten, six types of speciated arsenic, total arsenic and seven forms of polycyclic aromatic hydrocarbons (PAHs), and the link with self-reported emphysema in the US adult population. METHODS: A cross-sectional analysis using the 2011-2012, 2013-2014 and 2015-2016 National Health and Nutrition Examination Survey datasets was conducted. A specialized weighted complex survey design analysis package was used in analyzing the data. Multivariate logistic regression models were used to assess the association between urinary metals, arsenic, and PAHs and self-reported emphysema among all participants and among non-smokers only. Models were adjusted for lifestyle and demographic factors. RESULTS: A total of 4,181 adults were analyzed. 1-Hydroxynaphthalene, 2-hydroxynaphthalene, 3-hydroxyfluorene, 2-hydroxyfluorene, 1-hydroxypyrene, and 2 & 3-hydroxyphenanthrene were positively associated with self-reported emphysema. Positive associations were also observed in cadmium and cesium with self-reported emphysema. Among non-smokers, quantiles among 2-hydroxynaphthalene, arsenocholine, total urinary arsenic, cesium, and tin were associated with increased odds of self-reported emphysema. Quantiles among 1-hydroxyphenanthrene, cadmium, manganese, lead, antimony, thallium, and tungsten were associated with an inverse relationship with self-reported emphysema in non-smokers. CONCLUSION: The study determined that six types of urinary PAHs, cadmium, and cesium are positively associated with self-reported emphysema. Certain quantiles of 2-hydroxynaphthalene, arsenocholine, total urinary arsenic, cesium, and tin are positively associated with self-reported emphysema among non-smokers.

The simpler, the better: oral arsenic for acute promyelocytic leukemia.

Arsenic trioxide and all-trans retinoic acid have become the frontline treatments for patients with acute promyelocytic leukemia (APL). Despite the long wait for an oral arsenic drug, a commercially available agent, realgar-indigo naturalis formula (RIF), was not launched in China until 2009. Since then, over 5000 APL patients have been treated with oral RIF in China. Oral arsenic not only shows a clinical efficacy comparable to that of IV formulations but also displays a better safety profile, improved quality of life, and lower medical costs for patients. The promising results promote incorporating an outpatient postremission therapy model into clinical practice for both low-risk and high-risk APL patients in China. In this review, we discuss the evolution of oral arsenic RIF in the treatment of APL, with a special focus on how to address the related complications during induction therapy.

Multibiomarker approach to assess the magnitude of occupational exposure and effects induced by a mixture of metals.

Metals and metalloids including lead (Pb), arsenic (As) and manganese (Mn) can occur as mixtures in occupational contexts, such as mines. These chemicals are all known to be neurotoxic and provoke changes in heme metabolism also known to induce neurotoxicity. The objective of this work was to propose a multi-biomarker (BM) methodology to screen subjects exposed to the mixture of Pb, As and Mn and assess the severity of their exposure/effects, in an individual basis. The urinary levels of the metals, dela-aminolevulinic acid (ALA) and porphyrins were determined in Portuguese miners and in a control group. The combination of Pb and As urinary levels had the highest capability to identify subjects occupationally exposed to this mixture in mines, as evaluated through Receiver Operating Characteristic (ROC) (A = 98.2%; p < 0.05), allowing that 94.2% of 86 studied subjects were properly identified and the generation of an equation indicating the odd of a subject be considered as exposed to the metal mixture. The combination of urinary ALA and porphyrins revealed to be best one to be applied in the assessment of subjects with high, intermediate, and low magnitudes of exposure/effects, with 95.7% of 46 miners classified correctly according to their severity sub-group and allowing to generate equations, which can be applied in new subjects. The proposed methodology showed a satisfactory performance, evaluating in an integrated manner the magnitude of exposure/effects of the exposed workers, may contributing to improve the control of their health.

T helper 2-driven immune dysfunction in chronic arsenic-exposed individuals and its link to the features of allergic asthma.

Limited information is available regarding the effects of arsenic exposure on immune function. We have recently reported that chronic exposure to As was associated asthma, as determined by spirometry and respiratory symptoms. Because T helper 2 (Th2)-driven immune responses are implicated in the pathogenesis of allergic diseases, including asthma, we studied the associations of serum Th1 and Th2 mediators with the As exposure markers and the features of asthma among individuals exposed to As. A total of 553 blood samples were selected from the same study subjects recruited in our previous asthma study. Serum levels of Th1 and Th2 cytokines were analyzed by immunoassay. Subjects' arsenic exposure levels (drinking water, hair and nail arsenic concentrations) were determined by inductively coupled plasma mass spectroscopy. Arsenic exposure levels of the subjects showed significant positive associations with serum Th2-mediators- interleukin (IL)-4, IL-5, IL-13, and eotaxin without any significant changes in Th1 mediators- interferon-γ and tumor necrosis factor-α. The ratios of Th2 to Th1 mediators were significantly increased with increasing exposure to As. Notably, most of the Th2 mediators were positively associated with serum levels of total immunoglobulin E and eotaxin. The serum levels of Th2 mediators were significantly higher in the subjects with asthma than those without asthma. The results of our study suggest that the exacerbated Th2-driven immune responses are involved in the increased susceptibility to allergic asthma among individuals chronically exposed to As.