Arsenic Exposure and Toxicology: A Historical Perspective

Abstract

The metalloid arsenic is a natural environmental contaminant to which humans are routinely exposed in food, water, air, and soil. Arsenic has a long history of use as a homicidal agent, but in the past 100 years arsenic, has been used as a pesticide, a chemotherapeutic agent and a constituent of consumer products. In some areas of the world, high levels of arsenic are naturally present in drinking water and are a toxicological concern. There are several structural forms and oxidation states of arsenic because it forms alloys with metals and covalent bonds with hydrogen, oxygen, carbon, and other elements. Environmentally relevant forms of arsenic are inorganic and organic existing in the trivalent or pentavalent state. Metabolism of arsenic, catalyzed by arsenic (+3 oxidation state) methyltransferase, is a sequential process of reduction from pentavalency to trivalency followed by oxidative methylation back to pentavalency. Trivalent arsenic is generally more toxicologically potent than pentavalent arsenic. Acute effects of arsenic range from gastrointestinal distress to death. Depending on the dose, chronic arsenic exposure may affect several major organ systems. A major concern of ingested arsenic is cancer, primarily of skin, bladder, and lung. The mode of action of arsenic for its disease endpoints is currently under study. Two key areas are the interaction of trivalent arsenicals with sulfur in proteins and the ability of arsenic to generate oxidative stress. With advances in technology and the recent development of animal models for arsenic carcinogenicity, understanding of the toxicology of arsenic will continue to improve.

Cardiovascular effects of arsenic: clinical and epidemiological findings

“…ROS are formed both in vivo and in vitro in the presence of As. They include superoxide anion, hydroxyl radical, hydrogen peroxide, reactive nitrogen species, and As-centered and As peroxyl radicals (Bao and Shi 2010b;Hughes et al 2011;Flora 2011). The mechanisms of ROS formation by As are not completely clear: they may be produced during oxidation of arsenite (III) to arsenate (V) during metabolization, by stimulation of the enzymes NADH or NADPH oxidase (Smith et al 2001), and NOX ), or by mobilization of free iron from ferritin (Shi et al 2004;Flora 2011;Jomova et al 2011).…”

“…Polymorphisms in the genes of enzymes involved in As metabolism, especially As methyltransferase, and in redox enzymes can modulate As toxicity and its CV effects (Vahter 2000;Hsueh et al 2005;States et al 2009;Hsieh et al 2011;Hughes et al 2011) Reduced synthesis of extracellular matrix and damage to vascular smooth muscle cells are other mechanisms that could promote atherosclerotic plaque formation and instability (Hays et al 2008;, while oxidation of lipids would make them more prone to be internalized in the vessel wall ). As appears to enhance platelet aggregation (Lee et al 2002), possibly by exposing phosphatidylserine (Bae et al 2009) though studies are conflicting (Lin et al 2010), and reduces endothelial fibrinolytic activity by reducing t-PA and increasing PAI-1 level and activity (Jiang et al 2002), and reduces synthesis of proteoglycans such as heparan sulfate (Fujiwara et al 2005).…”

“…Professional exposure is a concern for people working in mines, the wood industry, coal-fired power plants, ore smelting, battery assembly, and electronics. Intentional poisoning was considered a "perfect crime" in the past since As is odorless and tasteless and symptoms of acute intoxication are quite aspecific, but its use has become rare since As is now detectable in fluids and tissues (Hughes et al 2011). Contamination of drinking water is usually well-known in particular areas.…”

“…The most toxicologically potent As compounds are in the trivalent oxidation state. Organic arsenicals in the pentavalent oxidation state -such as those used as pesticides, even today -are much less toxic than inorganic ones, because unlike inorganic As they are not readily taken up by cells, and undergo limited metabolism (Cohen et al 2006;Hughes et al 2011); concern regarding these compounds is due to their progressive breakdown to inorganic As in the environment. As is ubiquitous; diet is the main source of total As for humans, but the organic compounds normally present in food, especially in fish and seafood, are considered non-toxic or of low toxicity.…”

“…Several modes of action, possibly interrelated, have been proposed: interaction with sulfur and binding to sulfhydryl groups on proteins and enzymes; substitution of arsenate for phosphate, since As and phosphorus both belong to group 15 of the periodic table and share physiochemical properties, cutting off ATP formation in particular; substitution for zinc in zinc fingers; genotoxic action, potentiating the mutagen action of other compounds but also inhibiting DNA enzymatic repair and altering DNA methylation; and alteration of cellular signal transduction (Hughes et al 2011;Flora 2011). The formation of reactive oxygen species (ROS), also occurring at concentrations that are not directly cytotoxic (Barchowsky et al 1996), could be the pathogenic mechanism for the observed CV effects.…”