Arsenic Exposure and Toxicology: A Historical Perspective

Exposure to heavy metals is a common phenomenon due to their environmental pervasiveness. Metal intoxication particularly neurotoxicity, genotoxicity, or carcinogenicity is widely known. This review summarizes our current understanding about the mechanism by which metalloids or heavy metals (particularly arsenic, lead, cadmium and mercury) induce their toxic effects. The unifying factor in determining toxicity and carcinogenicity for all these metals is the generation of reactive oxygen and nitrogen species. The toxic manifestations of these metals are caused primarily due to imbalance between pro-oxidant and antioxidant homeostasis which is termed as oxidative stress. Besides these metals have high affinity for thiol groups containing enzymes and proteins, which are responsible for normal cellular defense mechanism. Long term exposure to these metals could lead to apoptosis. Signaling components affected by metals include growth factor receptors, G-proteins, MAP kinases and transcription factors. Chelation therapy with chelating agents like calcium disodium ethylenediamine tetra acetic acid (CaNa(2)EDTA), British Anti Lewisite (BAL), sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), meso 2,3-dimercaptosuccinic acid (DMSA) etc., is considered to be the best known treatment against metal poisoning. Despite many years of research we are still far away from effective treatment against toxicity caused due to exposure to heavy metals/metalloids. The treatment with these chelating agents is compromised with number of serious side-effects. Studies show that supplementation of antioxidants along-with a chelating agent prove to be a better treatment regimen than monotherapy with chelating agents. This review attempts a comprehensive account of recent developments in the research on heavy metal poisoning particularly the role of oxidative stress/free radicals in the toxic manifestation, an update about the recent strategies for the treatment with chelating agents and a possible beneficial role of antioxidants supplementation to achieve the optimum effects. We have selected only arsenic, lead, mercury and cadmium for this article keeping in view current concerns and literature available.

/pdf/heavy-metal-induced-oxidative-stress-its-possible-reversal-ktlielg4g8.pdf

Heavy metal induced oxidative stress & its possible reversal by chelation therapy.

Chelation therapy is the preferred medical treatment for reducing the toxic effects of metals. Chelating agents are capable of binding to toxic metal ions to form complex structures which are easily excreted from the body removing them from intracellular or extracellular spaces. 2,3-Dimercaprol has long been the mainstay of chelation therapy for lead or arsenic poisoning, however its serious side effects have led researchers to develop less toxic analogues. Hydrophilic chelators like meso-2,3-dimercaptosuccinic acid effectively promote renal metal excretion, but their ability to access intracellular metals is weak. Newer strategies to address these drawbacks like combination therapy (use of structurally different chelating agents) or co-administration of antioxidants have been reported recently. In this review we provide an update of the existing chelating agents and the various strategies available for the treatment of heavy metals and metalloid intoxications.

http://www.tracemin.com/fileadmin/uploads/pdf/en/Chelation_in_Metal_Intoxication.pdf

Chelation in Metal Intoxication

https://www.amjmed.com/article/0002-9343(56)90066-3/pdf

Penicillamine, a new oral therapy for Wilson's disease

Arsenic is a trace element found in the earth’s crust at an average concentration of ∼5 μg/g (ppm). Although its relative abundance in the earth’s crust is about 54th, arsenic can become concentrated in some parts of the world because of natural mineralization. Arsenic is a component of 245 minerals, associated most frequently with other metals such as copper, gold, lead, and zinc in sulfidic ores.1−3 When disturbed by natural processes, such as weathering, biological activity, and volcanic eruption, arsenic may be released into the environment. Anthropogenic activities, such as combustion of fossil fuels, mining, ore smelting, and well drilling, also mobilize and introduce arsenic into the environment.

Chronic exposure to arsenic from groundwater has been recognized to cause the largest environmental health disaster in the world, putting more than 100 million people at risk of cancer and other arsenic-related diseases.4,5 Because of its prevalence in the environment, potential for human exposure, and the magnitude and severity of health problems it causes, the United States Agency for Toxic Substances and Disease Registry (ATSDR) has ranked arsenic as No. 1 on its Priority List of Hazardous Substances for many years. The recent priority list, posted in 2011 (http://www.atsdr.cdc.gov/SPL/index.html), shows arsenic as No. 1, ahead of lead, mercury, and polychlorinated biphenyls (PCBs).

Epidemiological studies of populations exposed to high levels of arsenic due to ingestion from water, including those from Taiwan,6−8 Argentina,9,10 Chile,11,12 West Bengal, India,13,14 Bangladesh,15−17 and Inner Mongolia, China,18,19 have repeatedly shown strong associations between the exposure to high concentrations of arsenic and the prevalence of several cancers,20−23 most severely bladder, lung, and skin cancers. Arsenic is classified as a human carcinogen by the International Agency for Research on Cancer (IARC) and the U.S. Environmental Protection Agency (EPA). Chronic exposure to elevated concentrations of arsenic has also been associated with the increased risk of a number of noncancerous effects.24−27 Although the adverse health effects arising from exposure to arsenic have been well-recognized, the mechanism(s) of action responsible for the diverse range of health effects are complicated and poorly understood.26−30

It is believed that inorganic arsenate (HAsO42-), which is a molecular analogue of phosphate (HPO42-), can compete for phosphate anion transporters and replace phosphate in some biochemical reactions.28 For example, generation of adenosine-5′-triphosphate (ATP) during oxidative phosphorylation can be inhibited by the replacement of phosphate with arsenate. Depletion of ATP by arsenate has been observed in cellular systems.28 However, the replacement of phosphate in DNA by arsenic is not firmly established.31−35

The toxicity of trivalent arsenicals likely occurs through the interaction of trivalent arsenic species with sulfhydryl groups in proteins. Arsenic binding to a specific protein could alter the conformation and function of the protein as well as its recruitment of and interaction with other functional proteins. Therefore, there has been much emphasis on studies of arsenic binding to proteins, for the purpose of understanding arsenic toxicity and developing arsenic-based therapeutics.

This review summarizes various aspects of arsenic binding to proteins. It discusses the chemical basis and biological implications and consequences of arsenic binding to proteins. It also describes analytical techniques and the characterization of arsenic binding, including the binding affinity, kinetics, and speciation.

Arsenic binding to proteins.

IN the first fortnight of the War (1939) fundamental research was initiated in the Oxford Department of Biochemistry by Peters and carried out under his direction by a group of workers as an extra-mural research with the support of and for the Chemical Defence Research Department, Ministry of Supply; the object was to find antidotes for vesicants, both arsenical such as lewisite (CH.Cl: CH.As.Cl2) and also those of the mustard gas type. In this brief review, the main facts are given about the discovery of the antidote to lewisite known as BAL, owing to its medical importance; more detailed papers based upon the original reports are being prepared. An attempt is made to include the more relevant work from elsewhere and also to focus the main stages in this discovery, as this may prove useful in planning future work of this type.

British Anti-Lewisite (BAL)

/pdf/clinical-uses-of-2-3-dimercaptopropanol-bal-vi-the-treatment-133o48enun.pdf

Clinical uses of 2,3-dimercaptopropanol (bal). vi. the treatment of complications of arseno-therapy with bal (british anti-lewisite)

to the rays. I think that there are better methods of keeping bacteria out of wounds. The Americans have been using ultra-violet rays for air sterilization for many years., It is a standard equipment in many schools and hospitals. Wells calculates that it is equivalent to 500 turnovers of air per hour, compared with the 25 turnovers by the best ventilation. In groups of schools the incidence of susceptibility to measles in an epidemic was from 9 to 15.5% in irradiated schools, and 55.3%/0 and 51.8% in two unirradiated schools. Similar results have been found with chicken-pox. Experimentally, rabbits have been protected against air-borne tuberculosis. In my opinion ultra-violet light is the simplest and most efficient technique of this kind, and has no objectionable features if the eyes and skin are not irradiated. Respiratory disorders, from tuberculosis and pneumonia, through sinusitis to the common cold, are far the most frequent of the diseases of mankind, and they are spread mainly through the air. The common infectious and virus diseases of childhood cause a high mortality and lifelong respiratory tract disease, and the air is again the commonest vehicle. Air-borne sepsis and cross-infection are common, particularly in wartime. There is still a tendency to laugh away the protagonists of the control of air-borne infection as faddists I heard a gynaecologist quite recently become vastly humorous at the suggestion that a nurse with a cold was a menace. But there is far too much hospital-bred infection, and far too many " sterile" operations go wrong. I feel quite sure that the time will come when the methods of controlling air-borne sepsis discovered in Europe and developed in America will return fully fledged to roost in their parent country.

/pdf/british-anti-lewisite-1u3wbpqu73.pdf

L. A. Stocken

Papers

British Anti-Lewisite (BAL)

Clinical uses of 2,3-dimercaptopropanol (bal). vi. the treatment of complications of arseno-therapy with bal (british anti-lewisite)

British Anti-lewisite