Arsenic metabolism differs between child and adult patients during acute arsenic poisoning.

Epidemiological studies on chronic arsenic poisoning have clarified the relationship between various adverse effects and methylation efficiency or methylation capacity. However, no study has similarly investigated such effects on patients with acute arsenic poisoning. In the present work, we studied 61 patients with acute oral arsenic poisoning occurring after consumption of an arsenic trioxide-laced meal (curry soup). The cohort included children (defined as under 15 year old [y/o], n = 22) and adults (over 16 y/o, n = 39) whose urinary arsenic profiles were analyzed. None of these patients had received treatment with chelating agents. The estimated median (IQR) arsenic intake was 64.5 mg (48.3-80.5 mg) in children and 76.0 mg (56.0-91.0 mg) in adults, and these values were not significantly different. Symptoms of poisoning in children improved approximately 1 week after hospitalization. However, the symptoms in most adults deteriorated with severe signs of arsenic poisoning. Urinary arsenic profiles of all the patients were analyzed to obtain the following information: % monomethylarsonic acid (MMA), % dimethylarsinic acid (DMA), second methylation ratio (DMA/MMA), and secondary methylation index (SMI, DMA/MMA + DMA). The levels of these parameters may help identify patients at risk for worsening symptoms. %MMA, an indicator of incomplete methylation, increased more in adults, who experienced more severe symptom progression, compared with children. In contrast, %DMA, which indicates more complete and efficient methylation, increased particularly in children with mild symptoms. Overall the present results indicate that children possess an excellent capacity for methylation (second methylation ratio) of arsenic to DMA and therefore, experience relatively less severe progression of symptomology during acute arsenic poisoning.

Associations between and risks of trace elements related to skin and liver damage induced by arsenic from coal burning.

Long-term exposure to high levels of arsenic has been documented to induce skin and liver damage, affecting hundreds of millions of people. While arsenic-induced skin and liver damage and trace element alterations have been studied, their correlations and risks have not been explained. Based on the above premise, this study included a total of 172 subjects from a coal-burning arsenic poisoning area. The levels of 18 trace elements in hair and six liver function indices in serum were detected, and the associations between and risks of trace elements related to skin and liver damage were analyzed. Finally, the receiver operating characteristic (ROC) curve and areas under the curve (AUC) were used to analyze the diagnostic values of certain trace elements for arsenic-induced skin and liver damage. The results found that a decrease in Se was a risk factor for arsenic-induced skin and liver damage (OR = 8.33 and 1.92, respectively). Furthermore, increases in Al and V were risk factors for arsenic-induced skin damage (OR = 1.05) and liver damage (OR = 13.16), respectively. In addition, the results found that Se and Al possessed certain diagnostic values for arsenic-induced skin damage (AUC = 0.93, 0.80), that Se possessed a diagnostic value for liver damage (AUC = 0.93), and that the combination of Se and Al increased the diagnostic value for skin damage (AUC = 0.96). This study provides an important research basis for further understanding the reasons for arsenic-induced skin and liver damage, for screening and identifying candidate diagnostic biomarkers, and for improving prevention and control strategies for arsenism.

Progress in the prevention and control of water-borne arsenicosis in China.

In this report, we provided an overview of the prevalence, control, and prevention of water-borne arsenicosis in China during 2001-2016. Random sampling was continuously performed during 2001-2010 to find villages having high levels of arsenic (>50 µg/L) in drinking water. The high-arsenic-exposure villages with more geographically dispersed water supplies were subsequently analyzed for characteristics of arsenic distribution, and villages with relatively large populations were investigated for arsenicosis. The results showed that among 32,673,677 inhabitants in 36,820 villages, 1,894,587 inhabitants in 2,476 villages were at risk of high arsenic exposure. Among the 33,318 drinking water sources surveyed in 625 high-arsenic-exposure villages, 9,807 drinking water sources that contained high levels of arsenic (>50 µg/L) were identified. The overall prevalence rate of arsenicosis was 1.93%. Further, some representative villages were chosen to monitor arsenicosis annually, showing that the prevalence rate of arsenicosis was lower in villages with arsenic-safe water supplies than in villages without arsenic-safe water supplies. To the best of our knowledge, this report provides the most comprehensive assessment of the distribution of high arsenic exposure and arsenicosis in China until now.

Health effects inflicted by chronic low-level arsenic contamination in groundwater: A global public health challenge.

Groundwater arsenic (As) contamination is a global public health concern. The high level of As exposure (100-1000 µg/L or even higher) through groundwater has been frequently associated with serious public health hazards, e.g., skin disorders, cardiovascular diseases, respiratory problems, complications of gastrointestinal tract, liver and splenic ailments, kidney and bladder disorders, reproductive failure, neurotoxicity and cancer. However, reviews on low-level As exposure and the imperative health effects are far less documented. The World Health Organization (WHO) and the United States Environmental Protection Agency (USEPA) has set the permissible standard of As in drinking water at 10 µg/L. Considering the WHO and USEPA guidelines, most of the developed countries have established standards at or below this guideline. Worldwide many countries including India have millions of aquifers with low-level As contamination (≤50 µg/L). The exposed population of these areas might not show any As-related skin lesions (hallmark of As toxicity particularly in a population consuming As contaminated groundwater >300 µg/L) but might be subclinically affected. This review has attempted to encompass the wide range of health effects associated with chronic low-level As exposure ≤50 µg/L and the probable mechanisms that might provide a better insight regarding the underlying cause of these clinical manifestations. Therefore, there is an urgent need to create mass awareness about the health effects of chronic low-level As exposure and planning of proper mitigation strategies.

Clinicopathological Correlates: Chronic Arsenic Toxicity Causing Bilateral Symmetric Progressive Optic Neuropathy.

A 70 year-old man presented with insidiously progressing central visual acuity loss in both eyes over several years. Objectively the only abnormality identified on the exam was questionable granularity in the fovea in each eye. Extensive work up which included neuro-imaging, screening blood work for toxic and nutritional causes of optic neuropathy as well as electroretinogram and fluorescein angiography to rule out subtle maculopathy was all unrevealing. When vision continued to deteriorate over the next several years investigations were repeated and again did not yield any positive results. Levels of heavy metals were then obtained after further progression of visual loss, revealing very high levels of arsenic. Subsequent investigations revealed that patient has been spending almost every weekend for the past 28 years alone at a remote country cottage where the sole supply of water was from the local well. He also recalled that 1.5 months after purchasing the cottage he developed hemorrhagic colitis requiring partial colectomy. The specimen from colectomy was located and total reflection x-ray fluorescence testing performed in a specialized lab revealed greatly increased level of arsenic particle in the colonic biopsy from 28 years ago. This case is a reminder that heavy metal toxicity should be considered in a differential diagnosis of patients with bilateral symmetric optic neuropathy.

Chronic arsenic intoxication diagnostic score (CAsIDS).

Arsenic and its compounds are well-established, potent, environmentally widespread and persistent toxicants with metabolic, genotoxic, mutagenic, teratogenic, epigenetic and carcinogenic effects. Arsenic occurs naturally in the Earth's crust, but anthropogenic arsenic emissions have surmounted the emissions from important natural sources such as volcanism. Inorganic arsenicals exhibit acute and chronic toxicities in virtually all cell types and tissues, and hence arsenic intoxication affects multiple systems. Whereas acute arsenic intoxication is rare and relatively easy to diagnose, chronic arsenic intoxication (CAsI) is common but goes often misdiagnosed. Based on a review of the literature as well as our own clinical experience, we propose a chronic arsenic intoxication diagnostic score (CAsIDS). A distinctive feature of CAsIDS is the use of bone arsenic load as an essential criterion for the individual risk assessment of chronic arsenic intoxication, combined with a systemic clinical assessment. We present clinical examples where CAsIDS is applied for the diagnosis of CAsI, review the main topics of the toxicity of arsenic in different cell and organ systems and discuss the therapy and prevention of disease caused or aggravated by chronic arsenic intoxication. CAsIDS can help physicians establish the diagnosis of CAsI and associated conditions.

DNA methylation of extracellular matrix remodeling genes in children exposed to arsenic.

Several novel mechanistic findings regarding to arsenic's pathogenesis has been reported and some of them suggest that the etiology of some arsenic induced diseases are due in part to heritable changes to the genome via epigenetic processes such as DNA methylation, histone maintenance, and mRNA expression. Recently, we reported that arsenic exposure during in utero and early life was associated with impairment in the lung function and abnormal receptor for advanced glycation endproducts (RAGE), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) sputum levels. Based on our results and the reported arsenic impacts on DNA methylation, we designed this study in our cohort of children exposed in utero and early childhood to arsenic with the aim to associate DNA methylation of MMP9, TIMP1 and RAGE genes with its protein sputum levels and with urinary and toenail arsenic levels. The results disclosed hypermethylation in MMP9 promotor region in the most exposed children; and an increase in the RAGE sputum levels among children with the mid methylation level; there were also positive associations between MMP9 DNA methylation with arsenic toenail concentrations; RAGE DNA methylation with iAs, and %DMA; and finally between TIMP1 DNA methylation with the first arsenic methylation. A negative correlation between MMP9 sputum levels with its DNA methylation was registered. In conclusion, arsenic levels were positive associated with the DNA methylation of extracellular matrix remodeling genes;, which in turn could modifies the biological process in which they are involved causing or predisposing to lung diseases.

Specific histone modification responds to arsenic-induced oxidative stress.

To explore whether specific histone modifications are associated with arsenic-induced oxidative damage, we recruited 138 arsenic-exposed and arsenicosis subjects from Jiaole Village, Xinren County of Guizhou province, China where the residents were exposed to arsenic from indoor coal burning. 77 villagers from Shang Batian Village that were not exposed to high arsenic coal served as the control group. The concentrations of urine and hair arsenic in the arsenic-exposure group were 2.4-fold and 2.1-fold (all P<0.001) higher, respectively, than those of the control group. Global histone modifications in human peripheral lymphocytes (PBLCs) were examined by ELISA. The results showed that altered global levels of H3K18ac, H3K9me2, and H3K36me3 correlated with both urinary and hair-arsenic levels of the subjects. Notably, H3K36me3 and H3K18ac modifications were associated with urinary 8-OHdG (H3K36me3: ß=0.16; P=0.042, H3K18ac: ß=-0.24; P=0.001). We also found that the modifications of H3K18ac and H3K36me3 were enriched in the promoters of oxidative stress response (OSR) genes in human embryonic kidney (HEK) cells and HaCaT cells, providing evidence that H3K18ac and H3K36me3 modifications mediate transcriptional regulation of OSR genes in response to NaAsO2 treatment. Particularly, we found that reduced H3K18ac modification correlated with suppressed expression of OSR genes in HEK cells with long term arsenic treatment and in PBLCs of all the subjects. Taken together, we reveal a critical role for specific histone modification in response to arsenic-induced oxidative damage.

Mississippi Perspective: Dermatologic Manifestations of Arsenic Poisoning.

A Mississippi perspective on arsenic poisoning is largely related to thousands of asthma patients cared for by one physician, Elmer D. Gay, MD, in the 1950s. The general medical uses of arsenic and its specific use in intractable asthma are reviewed along with the dermatologic manifestations of arsenic poisoning.

Distribution and chemical speciation of arsenic in ancient human hair using synchrotron radiation.

Pre-Columbian populations that inhabited the Tarapacá mid river valley in the Atacama Desert in Chile during the Middle Horizon and Late Intermediate Period (AD 500-1450) show patterns of chronic poisoning due to exposure to geogenic arsenic. Exposure of these people to arsenic was assessed using synchrotron-based elemental X-ray fluorescence mapping, X-ray absorption spectroscopy, X-ray diffraction and Fourier transform infrared spectromicroscopy measurements on ancient human hair. These combined techniques of high sensitivity and specificity enabled the discrimination between endogenous and exogenous processes that has been an analytical challenge for archeological studies and criminal investigations in which hair is used as a proxy of premortem metabolism. The high concentration of arsenic mainly in the form of inorganic As(III) and As(V) detected in the hair suggests chronic arsenicism through ingestion of As-polluted water rather than external contamination by the deposition of heavy metals due to metallophilic soil microbes or diffusion of arsenic from the soil. A decrease in arsenic concentration from the proximal to the distal end of the hair shaft analyzed may indicate a change in the diet due to mobility, though chemical or microbiologically induced processes during burial cannot be entirely ruled out.

Arsenic Poisoning-Induced Sensorineural Hearing Loss: A Case Report.

Arsenic is frequently used in alternative medicine, and it is critical to promptly identify and treat suspected arsenic toxicity in patients. In a case study, a female patient presented with several symptoms, including nausea, vomiting, bilateral tinnitus, hearing loss, vertigo, and other associated complaints. After admission, the patient showed lethargy, and topical application of Chinese herbal medicine was found on her left breast, along with visible pigmentation on her torso. Examination revealed severe bilateral sensorineural deafness, liver and kidney injury, and pancytopenia. Due to the presence of broken skin, toxicological analysis detected elevated levels of arsenic in both blood (113 ng/mL) and urine (865.4 ng/mL). The patient was diagnosed with arsenic poisoning and received symptomatic treatment, including detoxification. Unfortunately, the patient died due to long-term exposure to arsenic. Therefore, early identification of the etiology is crucial for managing cases of arsenic poisoning.

The evolving use of arsenic in pharmacotherapy of malignant disease.

For more than 2,000 years, arsenic and its derivatives have shown medical utility. Owing to the toxicities and potential carcinogenicity of arsenicals, their popularity has fluctuated. The exact mechanism of action of therapeutic arsenic is not well characterized but likely to involve apoptosis, generation of reactive oxygen species, inhibition of intracellular transduction pathways, and cell functions. Arsenic trioxide has received approval for use in patients with relapsed acute promyelocytic leukemia for remission induction. Arsenic has additionally shown activity in a range of solid tumors, myelodysplastic syndrome, multiple myeloma, and in autoimmune diseases. The following is a review of the history of arsenic, its cellular metabolism, pharmacology, genetic basis of disposition, associated toxicities, and clinical efficacy.

Human urothelial micronucleus assay to assess genotoxic recovery by reduction of arsenic in drinking water: a cohort study in West Bengal, India.

Chronic exposure to arsenic through drinking water affects nearly 26 million individuals in West Bengal, India. Cytogenetic biomarkers like urothelial micronucleus (MN) are extensively used to monitor arsenic exposed population. In 2004-2005, 145 arsenic exposed individuals and 60 unexposed controls were surveyed of which 128 exposed individuals and 54 unexposed controls could be followed up in 2010-2011. In 2004-2005, the extent of arsenic content in the drinking water was 348.23 ± 102.67 µg/L, which was significantly lowered to 5.60 ± 10.83 µg/L in 2010-2011. Comparing the data obtained between 2004-2005 and 2010-2011, there was a significant decline in the MN frequency, when assayed in 2010-2011 compared to 2004-2005. Hence, we infer that urothelial MN can be utilized as a good biomarker in detecting remedial effects from toxicity of the low dose of arsenic through drinking water.

Nanoinspired Biocompatible Chemosensors: Progress toward Efficient Prognosis of Arsenic Poisoning.

Diagnosing heavy metals poisoning in human beings is of paramount importance. In this work, we present the design of a biocompatible FexNi(1-x)O hierarchical nanostructure-based sensor for ultraselective detection of arsenate (As(V)) ions in biological environments (e.g., body fluids, blood plasma, etc.). A novel iron doping technique was employed to fabricate the nanostructures rich with Fe cores to induce ultraselectivity toward arsenates. These nanostructures were used as dispersed markers and thin films deposited on Si/SiO2 substrates to support in vivo and in vitro detection of As(V) ions. The device demonstrated excellent sensitivity with a maximum response of 64.7% (for 1000 ppm As(V) ions) with a limit of detection of 1 ppb in blood plasma. The sensor's response time (τr) was 5 s with 95.48% recovery with a maximum error of ±0.549% after three washes. The device showed excellent response stability for 63 days with a maximum error of ±1.27%. The sensor devices were highly reproducible, with a maximum variation of ±0.6% in response for a batch of four devices. Due to Fe doping, the nanostructures in suspension demonstrated as arsenate markers with excellent cytocompatibility (with dosage up to 1 mg/mL) for human umbilical vein endothelial cells and 3T3 fibroblasts (LDH < 120 and cell viability ∼80%) till 48 h of incubation. The sensing mechanism suggested that the nanostructures not only detect arsenates but also prevent their substantial reduction to arsenites under anoxic environments. Thus, the sensors may show considerable progress toward early arsenate detection in living systems.

Exposure to arsenic in drinking water is associated with increased prevalence of diabetes: a cross-sectional study in the Zimapán and Lagunera regions in Mexico.

BACKGROUND: Human exposures to inorganic arsenic (iAs) have been linked to an increased risk of diabetes mellitus. Recent laboratory studies showed that methylated trivalent metabolites of iAs may play key roles in the diabetogenic effects of iAs. Our study examined associations between chronic exposure to iAs in drinking water, metabolism of iAs, and prevalence of diabetes in arsenicosis-endemic areas of Mexico. METHODS: We used fasting blood glucose (FBG), fasting plasma insulin (FPI), oral glucose tolerance test (OGTT), glycated hemoglobin (HbA1c), and insulin resistance (HOMA-IR) to characterize diabetic individuals. Arsenic levels in drinking water and urine were determined to estimate exposure to iAs. Urinary concentrations of iAs and its trivalent and pentavalent methylated metabolites were measured to assess iAs metabolism. Associations between diabetes and iAs exposure or urinary metabolites of iAs were estimated by logistic regression with adjustment for age, sex, hypertension and obesity. RESULTS: The prevalence of diabetes was positively associated with iAs in drinking water (OR 1.13 per 10 ppb, p < 0.01) and with the concentration of dimethylarsinite (DMAsIII) in urine (OR 1.24 per inter-quartile range, p = 0.05). Notably, FPI and HOMA-IR were negatively associated with iAs exposure (ß -2.08 and -1.64, respectively, p < 0.01), suggesting that the mechanisms of iAs-induced diabetes differ from those underlying type-2 diabetes, which is typically characterized by insulin resistance. CONCLUSIONS: Our study confirms a previously reported, but frequently questioned, association between exposure to iAs and diabetes, and is the first to link the risk of diabetes to the production of one of the most toxic metabolites of iAs, DMAsIII.

[Arsine: an unknown industrial chemical toxic]. / L'arsine : un toxique chimique industriel peu connu.

Arsines family includes many compounds with various toxicities. Arsenic trihydride or arsine is the most toxic form of arsenic. Powerful haemolytic gas, it has never been used as a chemical weapon because its toxicity is not immediate and it is non persistent. However, cases of industrial poisoning with arsine are still identified in spite of a strict regulation at work. It is also identified as a potential toxic of chemical terrorism. This agent, of which the mechanism of action is still not well defined, is badly recognized because of intoxications rarity. However, fast detection means are available. Health professionals and especially those who are involved in piratox plan need to learn to recognize arsine intoxication (hematuria, oliguria, haemolytic anemia) in order to provide early, specific treatment and avoid damages.

High nuclear expression of HIF1α, synergizing with inactivation of LIMD1 and VHL, portray worst prognosis among the bladder cancer patients: association with arsenic prevalence.

PURPOSE: Our study was aimed to understand the importance of LIMD1-VHL-HIF1α pathway in development of bladder carcinoma (BlCa) in association with arsenic prevalence. METHODS: At first, the mRNA expression pattern of the genes of this pathway (LIMD1, VHL and HIF1α) was checked in GEO datasets and in our samples. Next, genetic and epigenetic profiling of LIMD1 and VHL was done in our sample pool, validated in T24 BlCa cell line. The results were next correlated with various clinico-pathological parameters. RESULTS: Differential under-expression of LIMD1 and VHL genes was found in muscle-invasive BlCa (MIBC) in comparison to non-muscle-invasive BlCa (NMIBC). However, HIF1α protein, but mRNA, was found to be overexpressed among the MIBC samples; depicting the probability of HIF1α protein stabilization. Analysis of genetic and epigenetic profiles of LIMD1 and VHL exposed a frequent promoter methylation of LIMD1 gene in MIBC samples. Further, in-depth look into the results unveiled that the high nuclear expression of HIF1α was significantly correlated with genetic alterations of LIMD1, alone or in combination with VHL. Moreover, treating the T24 cells with a de-methylating agent (5-aza-2'-deoxycytidine) re-expressed the methylated LIMD1 and VHL genes, which in turn, reduced the HIF1α protein level significantly. Additionally, patients with high arsenic content (> 112 ng/g, AsH) seemed to have recurrent promoter methylation in LIMD1, as well as co-methylation/alteration of LIMD1 and VHL gene. Lastly, high nuclear expression of HIF1α in association with co-alteration of VHL and LIMD1 showed the worst overall survival (OS) among the patients. CONCLUSION: To conclude, MIBC samples portrayed higher alterations in VHL and LIMD1, thereby, stabilizing HIF1α protein and lowering the OS of patients.