Toxic metals such as arsenic, cadmium, lead, and mercury are ubiquitous, have no beneficial role in human homeostasis, and contribute to noncommunicable chronic diseases. While novel drug targets for chronic disease are eagerly sought, potentially helpful agents that aid in detoxification of toxic elements, chelators, have largely been restricted to overt acute poisoning. Chelation, that is multiple coordination bonds between organic molecules and metals, is very common in the body and at the heart of enzymes with a metal cofactor such as copper or zinc. Peptides glutathione and metallothionein chelate both essential and toxic elements as they are sequestered, transported, and excreted. Enhancing natural chelation detoxification pathways, as well as use of pharmaceutical chelators against heavy metals are reviewed. Historical adverse outcomes with chelators, lessons learned in the art of using them, and successes using chelation to ameliorate renal, cardiovascular, and neurological conditions highlight the need for renewed attention to simple, safe, inexpensive interventions that offer potential to stem the tide of debilitating, expensive chronic disease.

Chronic exposure to arsenic in drinking water is associated with skin lesions, neurological effects, hypertension and high risk of cancer. The treatment in use at present employs administration of thiol chelators, such as meso-2,3-dimercaptosuccinic acid (DMSA) which are compromised with number of limitations due to their lipophobic nature. To address this problem, therapeutic efficacy of monoisoamyl meso-2,3-dimercaptosuccinic acid (MiADMSA), an analog of DMSA having lipophilic character, was examined against chronic arsenic poisoning in rats. Adult male Wistar rats were orally exposed to arsenic (2mg sodium arsenite/kg body weight) for 10 weeks followed by treatment with MiADMSA (50mg/kg, orally, once daily for 5 consecutive days). As-exposed rats showed significant differences in behavioral functions (open field behavior, total locomotor activity, grip strength and exploratory behavior) and water maze learning. Further, the biochemical studies performed on three brain regions (cerebellum, cortex and hippocampus) also showed significant elevation in malondialdehyde (MDA) levels with a concomitant decrease in the oxidative stress marker enzymes Mn-superoxide dismutase (Mn-SOD), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione-S-transferase (GST). The alterations were more pronounced in cortex compared to cerebellum and hippocampus. The results showed that MiADMSA significantly reversed the As-induced alterations in behavior and biochemical variables suggestive of oxidative injury.

Charles Darwin's long-term illness has been the subject of much speculation. His numerous symptoms have led to conclusions that his illness was essentially psychogenic in nature. These diagnoses have never been fully convincing, however, particularly in regard to the proposed underlying psychological background causes of the illness. Similarly, two proposed somatic causes of illness, Chagas disease and arsenic poisoning, lack credibility and appear inconsistent with the lifetime history of the illness. Other physical explanations are simply too incomplete to explain the range of symptoms. Here, a very different sort of explanation will be offered. We now know that mitochondrial mutations producing impaired mitochondrial function may result in a wide range of differing symptoms, including symptoms thought to be primarily psychological. Examination of Darwin's maternal family history supports the contention that his illness was mitochondrial in nature; his mother and one maternal uncle had strange illnesses and the youngest maternal sibling died of an infirmity with symptoms characteristic of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome), a condition rooted in mitochondrial dysfunction. Darwin's own symptoms are described here and are in accord with the hypothesis that he had the mtDNA mutation commonly associated with the MELAS syndrome.

Arsenic (As) is a toxic metalloid existing widely in the environment, and chronic exposure to it through contaminated drinking water has become a global problem of public health. The present study focused on the protective effects of selenium on oxidative damage of chronic arsenic poisoning in rat liver. Rats were divided into four groups at random and given designed treatments for 20weeks. The oxidative damage of liver tissue was evaluated by lipid peroxidation and antioxidant enzymes. Oxidative stress related genes were detected to reflect the liver stress state at the molecular level. Compared to the control and Na2SeO3 groups, the MDA content in liver tissue was decreased and the activities of antioxidant enzymes were increased in the Na2SeO3 intervention group. The mRNA levels of SOD1, CAT, GPx and Txnrd1 were increased significantly (P<0.05) in the combined Na2SeO3+NaAsO2 treatment group. The expressions of HSP70 and HO-1 were significantly (P<0.05) increased in the NaAsO2 group and reduced in the combined treatment group. The results indicate that long-term intake of NaAsO2 causes oxidative damage in the rat liver, and Na2SeO3 protects liver cells by adjusting the expression of oxidative stress related genes to improve the activities of antioxidant enzymes.

ATF2 is a subfamily member of AP-1 and has an important role in cellular stress responses. ATF2 has been implicated in a transcriptional response leading to cell migration and malignant tumor progression. However, little is known about the effect of arsenic on expression of ATF2 and regulatory pathways in human urothelial cells. In this study, ATF2 expression was measured in NaAsO2-treated human uroepithelial cell line (SV-HUC-1) with 1, 2, 4, 8 and 10 μM concentrations in order to provide some basis data for the study on mechanism of bladder cancer induced by arsenic. We found that ATF2 expression levels at 2, 4, 8 and 10 μM arsenic-treated cells were significantly higher than those of control cells, and the strongest expression occurred in 4 μM NaAsO2-treated cells. Antioxidants (melatonin) and JNK or p38 inhibitors decreased significantly arsenic-induced ATF2 expression. Taken together, these data indicated that the increasing of ATF2 expression is mediated via oxidative stress induced by arsenic in SV-HUC-1 cells, and JNK or p38 rather than ERK is responsible for arsenic-induced ATF2 expression. ROS were also involved in arsenic induced the activation of JNK and p38 MAPK signaling pathway.

Metal poisonings through a mucocutaneous route are reported rarely in the literature.We report 2 cases of heavy metal intoxication from inappropriate use of Chinese mineral medicines confirmed by toxicologic investigations.A 51-year-old man developed perianal gangrene and a high fever after a 2-week anal use of hong-dan herbal mixtures for anal fistula. He presented gastrointestinal and constitutional symptoms, followed by skin rash, anemia, hair loss, peripheral neuropathy, and muscle atrophy. Elevated urine arsenic and mercury confirmed the heavy metal poisonings. The hong-dan mixture contained lead tetraoxide, arsenic, and mercury. He was treated with 2,3-dimercapto-1-propanesulfonic acid, with partial improvement, but peripheral neuropathy persists 4 years later. A 75-year-old man developed anorexia, weight loss, headache, dizziness, nausea, vomiting, constipation, weakness, and anemia after a 3-month use of an herbal patch for chronic leg ulcer. His blood lead concentration was 226 μg/dL, and the lead content of the herbal patch was 517 mg/g. Chelation with ethylene diamine tetraacetic acid and dimercaptosuccinic acid was followed by clinical recovery.These cases documented serious systemic poisoning after the short-term use of traditional Chinese medicines containing heavy metals in damaged or infected tissue.

Regional distribution of quantitative risk and hazard levels due to arsenic poisoning in some parts of Iran's Kurdistan province is considered. To investigate the potential risk and hazard level regarding arsenic-contaminated drinking water and further carcinogenic and non-carcinogenic effects on villagers, thirteen wells in rural areas of Qorveh County were considered for evaluation of arsenic concentration in water. Sampling campaign was performed in August 2010 and arsenic concentration was measured via the Silver Diethyldithiocarbamate method. The highest and lowest arsenic concentration are reported in Guilaklu and Qezeljakand villages with 420 and 67 mug/L, respectively. None of thirteen water samples met the maximum contaminant level issued by USEPA and Institute of Standards and Industrial Research of Iran (10 ppb). The highest arsenic concentration and consequently risk and hazard levels belong to villages situated alongside the eastern frontiers of the county. Existence of volcanic activities within the upper Miocene and Pleistocene in this part of the study area may be addressed as the main geopogenic source of arsenic pollution. Quantitative risk values are varying from 1.49E-03 in Qezeljakand to 8.92E-03 in Guilaklu and may be interpreted as very high when compared by similar studies in Iran. Regarding non-carcinogenic effects, all thirteen water samples are considered hazardous while all calculated chronic daily intakes are greater than arsenic reference dose. Such drinking water source has the potential to impose adverse carcinogenic and non-carcinogenic effects on villagers. Accordingly, an urgent decision must be made to substitute the current drinking water source with a safer one.

BACKGROUND:

In 2010 Médecins Sans Frontières discovered a lead poisoning outbreak linked to artisanal gold processing in northwestern Nigeria. The outbreak has killed ~400 young children and affected thousands more.

OBJECTIVES:

Undertake an interdisciplinary geological- and health-science assessment to clarify lead sources and exposure pathways, identify additional toxicants of concern and populations at risk, and examine potential for similar lead poisoning globally.

METHODS:

We applied diverse analytical methods to ore samples, soil and sweep samples from villages and family compounds, and plant foodstuff samples.

RESULTS:

Natural weathering of lead-rich gold ores before mining formed abundant, highly gastric-bioaccessible lead carbonates. The same fingerprint of lead minerals found in all sample types confirms ore processing caused extreme contamination, with up to 185,000 ppm lead in soils/sweep samples and up to 145 ppm lead in plant foodstuffs. Incidental ingestion of soils via hand-mouth transmission and of dusts cleared from the respiratory tract is the dominant exposure pathway. Consumption of water and foodstuffs contaminated by the processing are likely lesser but still significant exposure pathways. Although young children suffered the most immediate and severe consequences, results indicate older children, adult workers, pregnant women, and breastfed infants are also at risk for lead poisoning. Mercury, arsenic, manganese, antimony, and crystalline silica exposures pose additional health threats.

CONCLUSIONS:

Results inform ongoing efforts in Nigeria to assess lead contamination and poisoning, treat victims, mitigate exposures, and remediate contamination. Ore deposit geology, pre-mining weathering, and burgeoning artisanal mining may combine to cause similar lead poisoning disasters elsewhere globally.

Concerns for arsenic exposure are not limited to toxic waste sites and massive poisoning events. Chronic exposure continues to be a major public health problem worldwide, affecting hundreds of millions of persons.Objectives: We reviewed recent information on worldwide concerns for arsenic exposures and public health to heighten awareness of the current scope of arsenic exposure and health outcomes and the importance of reducing exposure, particularly during pregnancy and early life.We synthesized the large body of current research pertaining to arsenic exposure and health outcomes with an emphasis on recent publications.Locations of high arsenic exposure via drinking water span from Bangladesh, Chile, and Taiwan to the United States. The U.S. Environmental Protection Agency maximum contaminant level (MCL) in drinking water is 10 µg/L; however, concentrations of > 3,000 µg/L have been found in wells in the United States. In addition, exposure through diet is of growing concern. Knowledge of the scope of arsenic-associated health effects has broadened; arsenic leaves essentially no bodily system untouched. Arsenic is a known carcinogen associated with skin, lung, bladder, kidney, and liver cancer. Dermatological, developmental, neurological, respiratory, cardiovascular, immunological, and endocrine effects are also evident. Most remarkably, early-life exposure may be related to increased risks for several types of cancer and other diseases during adulthood.These data call for heightened awareness of arsenic-related pathologies in broader contexts than previously perceived. Testing foods and drinking water for arsenic, including individual private wells, should be a top priority to reduce exposure, particularly for pregnant women and children, given the potential for life-long effects of developmental exposure.

In order to evaluate the degree of arsenic (As) exposure and the factors influencing urinary As excretion and metabolism, 192 workers from a steel and iron smelting plant, with different type of work in production such as roller, steel smelting, iron smelting and metallic charge preparation, were recruited. Information about characteristics of each subject was obtained by questionnaire and inorganic As (iAs), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA) in urine were determined. The results showed that steel smelters had significantly higher concentrations of DMA and total As (TAs) than rollers and metallic charge preparation workers, and iron and steel smelters had a higher value of primary methylation index and lower proportion of the iAs (iAs%) than rollers and metallic charge preparation workers. In steel smelters, urinary As level exceeded the biological exposure index (BEI) limit for urinary As of 35 μg/l by 65.52%, and higher than metallic charge preparation workers (35.14%). The individuals consumed seafood in recent 3 days had a higher TAs than the individuals without seafood consumption. Multivariate logistic regression analysis showed that different jobs, taken Chinese medicine of bezoar and seafood consumption in recent 3 days were significantly associated with urinary TAs exceeded BEI limit value 35 μg/l. Our results suggest that workers in steel and iron smelting plant had a lower level of As exposure, and seafood consumption and taking Chinese medicine of bezoar also could increase the risk of urinary TAs exceeded BEI limit value.Journal of Exposure Science and Environmental Epidemiology advance online publication, 27 February 2013; doi:10.1038/jes.2013.2.