Sep. 02, 2024
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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.
Keywords:
arsenic, cancer, exposure
The word &#;arsenic&#; elicits a fearful response in most people. This is because arsenic has a long history of being a poison, both intentional and unintentional, to humans. However, most laymen do not know or understand that we are constantly exposed to arsenic because it is naturally present in the environment, is used in commercial products, and has medical applications. Although most typical environmental exposures to arsenic do not pose a health risk, several areas of the world contain arsenic from natural or anthropogenic sources at levels that create a toxicological concern. Many of these areas have been identified, and efforts are being made to either remediate these areas or limit access to them.
Arsenic is the number one substance in the most recent (ATSDR, a) Comprehensive, Environmental, Response, Compensation and Liability Act (CERCLA) Priority List of Hazardous Substances published by the Agency for Toxic Substances and Disease Registry (ATSDR). This list is comprised of substances found at hazardous waste sites on the National Priorities List. The substances are ranked on frequency or occurrence, toxicity, and potential for human exposure.
An understanding of the chemistry of arsenic is needed to appreciate the toxicology of this metalloid, which shares properties of metals and nonmetals. (A metal has luster, conducts heat and electricity, and is malleable and ductile. Elemental arsenic tends to be nonductile.) In the environment, arsenic is found in inorganic and organic forms and in different valence or oxidation states. The valence states of arsenic of environmental interest are the trivalent (III) and pentavalent (V) states. Elemental arsenic has a valence state of (0). Arsine and arsenides have a valence of (&#;III). In this review, we will be focused on the arsenicals in the trivalent and pentavalent states that are found in the environment and to which humans are exposed. A list of relevant environmental arsenicals is shown in . The structure of some of these arsenicals is shown in .
The most toxicologically potent arsenic compounds are in the trivalent oxidation state. This has to do with their reactivity with sulfur containing compounds and generation of reactive oxygen species (ROS). However, humans are exposed to both trivalent and pentavalent arsenicals. In this review, we will discuss in a historical context the exposure of these compounds, how we have learned that the metabolism of arsenic is a critical determinant of its toxic effects, and potential modes of action (MOA), animal carcinogenicity, and the epidemiology of this metalloid. highlights some of the historical aspects of arsenic over the past 250 years.
Arsenic is a naturally occurring element that an individual typically encounters every day in food, water, soil, and air. While understanding how environmental exposures may affect human health, especially at low levels, is currently an active area of research, humans have known on some level about the toxicity of arsenic for centuries.
In the Middle Ages, arsenic gained notoriety as an effective homicidal and suicidal agent, both because of the frequency of its use and because of its involvement in many high-profile murders. In fact, arsenic is often referred to as the &#;king of poisons&#; and the &#;poison of kings&#; because of its potency and the discreetness, by which it could be administered, particularly with the intent of removing members of the ruling class during the Middle Ages and Renaissance (Vahidnia et al., ). For example, it is well documented that arsenic was among the poisons used by the Medici and Borgia families to eradicate rivals (Cullen, ). Arsenic continued to enjoy its reputation as a high-profile poison and was implicated in several other prominent murder cases, most famously in the death of Napoleon Bonaparte in , which some conspiracy theorists claim was a political assassination (Cullen, ).
Up until the mid-s, arsenic remained a popular poison for several reasons. Arsenic was readily available and because it is odorless and tasteless, it was undetectable in food or beverages (Bartrip, ). The most visible symptoms of acute arsenic poisoning&#;nausea, vomiting, diarrhea, and abdominal pain&#;could be easily confused with other common diseases at the time (e.g., cholera and pneumonia) (ATSDR, b). Also, importantly, for a long time, there was no reliable analytical method for detecting, much less measuring, arsenic in tissue or other media, although early tests for arsenic were introduced in the mid-s. Interestingly, in the first trial ever recorded to present forensic evidence, a woman was sentenced to death because a white power recovered by a servant was &#;proven&#; to be arsenic, based on appearance, texture, behavior in water, and garlic-like odor when burned (Caudill, ; Cullen, ). The detection of arsenic took a leap forward in when James Marsh decided to investigate analytical methods to provide juries with more reliable evidence of &#;visible arsenic&#; (Cullen, ). His test method was first used in the trial of Marie LaFarge in France in , in which Mme. LaFarge was charged with poisoning her husband with arsenic-laden cakes (Cullen, ). Generally, the tests involved mixing the sample of interest with zinc and acid and heating the vessel with a flame, which would cause a silvery substance to accumulate on the glass vessel; this was considered diagnostic for arsenic in amounts as low as 0.02 mg (Marsh, ; Newton, ). Although this method would be considered primitive by today's standards, the Marsh test represented a turning point in arsenic analytics and the beginning of the end of undetected arsenic poisonings.
Although stories of murder by arsenic appeal to the morbid interests of the public, these murders provided important insights that advanced the knowledge of arsenic toxicology. For example, information on the acute effects of arsenic and the target organs involved was obtained by studying poisonings. Importantly, these cases also precipitated the development of analytical methods for different media, including biological samples, which eventually led to an increased understanding of metabolism of arsenic. Due to improved understanding of arsenic measurement, one cannot readily &#;get away with murder&#; by using arsenic anymore. Nonetheless, incidents do still occur. As recently as , arsenic poisoning made headlines when arsenic was detected in coffee served at a church meeting in Maine (Maine Rural Health, ; Zernike, ).
Arsenic&#;s use as a pigment (e.g., Paris Green or copper acetoarsenite) in the s was suspected as a major source of unintentional arsenic poisonings. Although the arsenic-based pigment was used in many consumer products (e.g., toys, candles, and fabric), its use in wallpaper was particularly linked to widespread sickness and death during this period (Scheindlin, ; Wood, ). Concerns associated with the use of wallpaper containing arsenic-based pigment were reported as early as , and the theory was eventually proposed that illnesses from wallpaper were related to the biotransformation of the arsenic compounds by mold to a toxic arsenic gas (Gosio gas) (Cullen and Bentley, ). This theory gained momentum, and in , Bartolomeo Gosio, an Italian physician, demonstrated that arsenic could be volatilized from arsenic-containing compounds, including Paris Green (Buck and Stedman, ; Cullen and Bentley, ). Although it became widely accepted at the time that arsenic gas from the wallpaper was responsible for the deaths and illnesses, this notion has been challenged recently by scientists who believe that there were insufficient quantities of the gas generated (now known to be trimethylarsine) to cause the reported effects; and possibly the mold, itself, was the responsible agent (Cullen and Bentley, ). Regardless of the toxicity of the wallpaper, the work conducted by Gosio and later by Frederick Challenger (in the late s), laid the groundwork for today&#;s understanding of arsenic metabolism, namely that the metabolism of arsenic involves sequential reduction and oxidative methylation steps (Cullen and Bentley, ).
Although arsenic use has been phased out of pigment products, it is still used in the production of glass and semiconductors (ATSDR, b).
The knowledge base of the exposure and toxicological effects of arsenic has expanded greatly, particularly in the past 10&#;20 years. We know that exposure to arsenic for most people is an everyday occurrence because it is a natural component of the environment. The exposure pathways of arsenic to most people are dietary and drinking water and these exposures occur at relatively low levels. However, there are areas of the world, such as India, Bangladesh, and others, where the levels of arsenic in drinking water are naturally excessive, which has led to toxic manifestations in these populations. The effects of arsenic in drinking water on the U.S. population are less clear, which may be due to a lower arsenic exposure than in other areas of the world such as Bangladesh. Data from Karagas et al. (, ) has suggested, especially among smokers, an increased risk of bladder and skin cancer is associated with toenail arsenic.
Other types of exposure can come from soil contaminated with arsenic, from its occupational use as a pesticide or a by-product of metal ore smelting, from its use as a chemotherapeutic agent, and what interests many people, but occurs rarely, as a homicidal agent. With increases in analytical technology, what most likely will occur is the discovery of presently unknown forms of arsenic (e.g., arsenolipids) that we are exposed to, particularly in our diet.
The metabolic pathway of arsenic is now more clearly but not exactly defined. The discovery of arsenic (+3 oxidation state) methyltransferase has been a major breakthrough, particularly with the findings that there are polymorphisms in this enzyme. Several of these polymorphisms are associated with the toxic effects that develop from exposure to arsenic. Experimental use of the As3mt knockout mouse in the investigation of the metabolism and toxicity of arsenic may provide new knowledge. Finally, elucidation of the pathway of formation of the thiolated arsenic metabolites (e.g., dimethyldithioarsinic acid), some of which are toxicologically potent in vitro, will aid in the understanding of the toxicology of arsenic.
We know that arsenic causes acute and chronic dose-dependent effects, in many organ systems. A major unknown is the mode of action for the toxic effects of arsenic. Certainly, metabolism of arsenic has a role in this effect. However, if one or several metabolites are the putative toxic species is not known. Many MOA have been studied including oxidative stress, genotoxicity, altered DNA methylation, and others. Several of these MOA may be interrelated. With the advent of the &#;omics&#; age, toxic pathways of arsenic may soon be elucidated. Other recent advances are the development of an animal (mouse) model for arsenic carcinogenicity following transplacental and whole-life exposure to arsenic and findings in mice that arsenic may impact stem cell population dynamics, which ultimately lead to transformed cells (Tokar et al., b). Also, there is important work in animal models that support a role for cytotoxicity and regenerative hyperplasia in the carcinogenic MOA for DMAsV.
More research is still needed to understand arsenic exposure, metabolism, effects, and MOA for cancer. Nevertheless, with recent findings and advances in technology, many of the unanswered questions regarding the toxicology of arsenic may soon be answered. This knowledge will lead to better protection of populations at risk from arsenic-related illnesses.
National Institute of Environmental Health Sciences (RO1ES;, P30Es to Y.C.); Intramural resources at U.S. EPA (to M.F.H. and D.J.T.).
We would like to thank Anna Engel of Gradient with assistance in researching the historical uses of arsenic. We also thank Drs Kirk Kitchin, Jane Ellen Simmons, and Erik Tokar for their helpful comments on an earlier version of this manuscript. Gradient, where B.D.B. and A.S.L. work, has conducted risk analyses for arsenic for a number of private and public sector clients. B.D.B. has been an expert in litigation matters involving arsenic. However, Gradient received no funding for preparation of this manuscript and the opinions are solely those of the author's.
Chemical Abstracts Service Registry Number: -42-1
NIOSH RTECS Number: CG
Chemical Formula: AsH 3
Arsine
Arsenic hydride
Arsenic trihydride
Arseniuretted hydrogen
Arsenous hydride
Hydrogen arsenide
The above information was obtained from the National Institute for Occupational Safety and Health&#;s computerized Registry of Toxic Effects of Chemical Substances (RTECS), and from the National Library of Medicine&#;s computerized chemical dictionary file CHEMLINE. Registered trademark information is not included in these files. Therefore, some of the above synonyms and identifiers may be trademarked but are not so indicated above.
The National Institute for Occupational Safety and Health (NIOSH) recommends that appropriate work practices be implemented to reduce the risk of worker exposure to arsine (AsH3) gas, There is a high potential for the generation of arsine gas when inorganic arsenic is exposed to nascent (freshly formed) hydrogen. This recommendation is based on several reports of worker exposure to arsine resulting in severe toxic effects or death. Most of the reported cases occurred when arsine was accidently generated during an industrial process. NIOSH would like to inform the occupational health community of some of the circumstances in which workers have been poisoned by arsine, with particular emphasis on the underlying mechanisms of generating the gas. We request that producers and distributors of arsenic and materials containing arsenic transmit information to their customers and employees, and that professional associations and unions inform their members.
Stibine (SbH3), another toxic gas, is formed when antimony is exposed to nascent hydrogen. In most situations where arsine can be formed stibine can also be formed if antimony is present. Therefore, similar work practices should be implemented to reduce the risk of worker exposure to stibine.
Identified in , arsine is a highly poisonous, colorless, nonirritating gas with a mild garlic odor. It is soluble in water, and slightly soluble in alcohol and alkalies. When nascent hydrogen is generated in the presence of arsenic, or when water reacts with a metallic arsenide, arsine evolves. Most cases of arsine poisoning have been associated with the use of acids and crude metals, one or both of which contained arsenic as an impurity. Ores contaminated with arsenic can liberate arsine when treated with acid.1 Arsine is commercially produced for use in organic synthesis, and the processing of solid state electronic components.
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In industrial settings arsine poisoning generally results from the accidental formation of arsine gas. Most reported cases of exposure to arsine have occurred during the smelting and refining of metals. However, there are many other situations where exposures to lethal concentrations of the gas have been reported including galvanizing, soldering, etching and lead plating operations. Arsine can be produced by fungi (especially in sewage) in the presence of arsenic. The renewed interest in coal as a source of energy causes concern for a possible increase in the number of exposures to arsine, because coal contains considerable quantities of arsenic. The processes for converting coal to gas and other by-products should include preventative measures aimed at reducing the chance of transformation of the arsenic impurities into arsine.1
The current Department of Labor, Occupational Safety and Health Administration (OSHA) standard for occupational exposure to arsine is 0.05 ppm (0.2 mg/cu m of air) as a time-weighted average in any 8-hour work shift of a 40-hour work week. The present OSHA standard for occupational exposure to stibine to 0.1 ppm (0.5 mg/cu m of air) in any 8-hour work shift of a 40-hour work week.2 The NIOSH Criteria Document on inorganic arsenic recommended that worker exposure to inorganic arsenic and to arsine be limited to 0.002 mg (2.0 µ) of arsenic/cu m of air as determined by a 15-minute sampling period. The document states that the short-term limit is intended to achieve the greatest practicable reduction in worker exposure while avoiding spurious sampling results which can be produced by natural background concentrations of inorganic arsenic.3 The NIOSH criteria document on antimony recommended the retention of the specific Federal limit for occupational exposure to antimony, without recommending a limit for stibine.4
The NIOSH National Occupational Hazard Survey (NOHS) estimates that approximately 900,000 workers are occupationally exposed to identified sources of arsenic for varying periods of time during the workday. This estimate is not, however, based on actual workplace environmental exposure measurements. However, arsenic is a widespread element, and therefore unidentified exposures can occur in unsuspected work situations. The NOHS estimate for occupational exposure to antimony is approximately l,7OO,OOO workers.5
The first case of arsine poisoning was reported in after a German chemist died from an exposure to arsine in his laboratory. From to , 247 cases of arsine poisoning were reported. From to an additional 207 cases were reported, of which 51 (25%) were fatal.1
Acute Arsine Toxicity &#; Arsine is the most acutely toxic form of arsenic and one of the major industrial causes of sudden extensive hemolysis (destruction of red blood cells). It has the ability to combine with hemoglobin within the red blood cell, causing destruction or severe swelling of the cell, rendering it nonfunctional.1 Inhalation of 250 ppm (800 mg/cu m) of arsine gas is instantly lethal. Exposures of 25-50 ppm (80-160 mg/cu m) for one-half hour are lethal, and 10 ppm (32 mg/cu m) is lethal after longer exposures. The Mean Lethal Dose (MLD) is unknown for man, but in small mammals it is about 0.5 mg/kg body weight.6
The characteristic features of acute arsine poisoning are abdominal paint bloody urine, and jaundice (yellow discoloration of the skin). Initial symptoms of arsine poisoning are headache, malaise, weakness, dizziness difficult breathing, abdominal pain, nausea, and vomiting, which are usually first noticed 2 to 24 hours after exposure. Bloody urine, light to dark red, is frequently noticed 4-6 hours after exposure to arsine and is often followed by jaundice 12-48 hours later. An unusual bronze discoloration of the skin can often be observed accompanying the jaundice. If the arsine exposure is severe, the products resulting from the breakdown of red blood cells and hemoglobin will clog the kidneys, causing a reduction in the amount of urine formed, sometimes to the point of complete blockage of urine formation. Other toxic effects of arsine include damage to the liver and heart, either by direct actions of arsine in the cells or due to the formation of arsenic.1,7
Chronic Arsine Toxicity &#; Most reported cases of arsine poisoning have been acute or sub-acute in nature, usually resulting from a single short exposure or from breathing the gas for a few hours. In one report of chronic arsine poisoning, it was noted that arsine in very small concentrations appeared to exert a cumulative, damaging effect. This was manifested by a progressive drop in the number of red blood cells and in the hemoglobin level. The exposed victims experienced shortness of breath on exertion, and a general feeling of weakness. However, in relation to the degree of blood destruction, the degree of known disability experienced by the victims of chronic arsine poisoning was less than expected.8
Chronic Arsenic Toxicity &#; Since inorganic arsenic is needed to generate arsine, prolonged exposures to low levels of arsine are likely to occur under conditions where workers are also exposed to inorganic arsenic. Once arsine is inhaled, it breaks down, releasing inorganic arsenic into the blood stream. The worker&#;s risk of arsenic poisoning is therefore increased by the combination of inorganic arsenic exposure and the breakdown of arsine. A number of signs and symptoms are associated with arsenic poisoning. When ingested arsenic compounds can cause nausea, vomiting and diarrhea within a few hours. Dermatitis may be observed after chronic ingestion but the typical signs include increased pigmentation, and thickening of the skin on the palms and soles of the feet. Changes in the heart&#;s performance as measured by the electrocardiogram (ECG) have been reported after chronic arsenic intoxication. Observed ECG changes regressed after arsenic exposure ceased. Decreased numbers of red and white blood were reported in cases of chronic intoxication but these changes also regressed after arsenic ingestion ended. Skin cancer has long been considered a consequence of arsenic exposure, however multiple cancers of the internal organs have also been reported.3
Case Reports &#; Most cases of arsine poisoning occur after the accidental generation of the gas in the workplace. During recent years of may incidents have involved a reaction between arsenic and aluminum, with the subsequent release of hydrogen in the presence of water to permit the formation of arsine gas.9 Tables 1, 2, and 3 list examples of accidental arsine poisoning reported in the literature.
TABLE 1. Examples of workers poisoned by arsine in smelting and refining operations.
TABLE 2. Examples of workers poisoned by arsine in enclosed spaces.
TABLE 3. Examples of workers poisoned by arsine in miscellaneous occupational settings.
Although the accidents illustrated in the above tables differ with respect to the surrounding circumstances, the basic reactions leading to arsine formation are similar. Arsine usually evolved when nascent hydrogen was generated in the presence of arsenical compounds or by the hydrolysis of a metallic arsenide in contact with water. Invariably, there was an acid medium where metal was present (e.g., dross residues galvanized implements, aluminum tanks or implements) thereby creating the key ingredients necessary for arsine formation.
A more recent area of concern involves the recycling of batteries. Lead alloys in car batteries contain antimony as a hardener, with arsenic and silver added to inhibit corrosion. In the production of &#;maintenance-free&#; batteries, calcium is added to the lead alloys as a hardening agent. During recycling, arsine can be released if scrap containing arsenic is melted down with the &#;maintenance-free&#; batteries containing calcium. When the scrap mixture is in the molten state, calcium arsenide is formed. As cooling occurs, the calcium arsenide floats to the surface as part of the dross, and in the presence of water, arsine evolves.20
Stibine (SbH3; hydrogen antimonide; antimony hydride; antimony trihydride)- Antimony (Sb) can be converted to stibine by a similar series of reactions required to convert arsenic to arsine. Stibine equals or surpasses arsine in toxicity, and causes a specific toxic action which closely resembles that of arsine.21 Although stibine is chemically similar to arsine, it is less stable. Probably because of this instability fewer cases of stibine poisoning have been reported.22 Stibine can evolve when certain alloys containing antimony (Sb) are treated with acid and subjected to electrolytic action, when certain antimony compounds are treated with steam, or whenever nascent hydrogen comes in contact with metallic antimony or with a soluble antimony compound.
When stibine enters the bloodstream, it reacts with the hemoglobin of red blood cells, leading to destruction of the cells.21 Stibine exerts a direct effect on the brain tissue cells, leading to various degrees of degeneration.23 Victims of stibine poisoning have experienced marked weakness headache, nausea, severe abdominal and lower back pain, and blood in the urine. These symptoms are similar to those caused by arsine toxicity.24
In light of the serious and accidental nature of exposure to arsine and/or stibine, NIOSH recommends that steps be taken to prevent exposure to these gases. Whenever the possibility exists for either gas being generated, such as when working with metals (crude, drosses, or implements made of metal) care should be taken to assure that arsenic and antimony do not react with any sources of fresh hydrogen. Similarly, when working with arsenical compounds care should always be taken to prevent the inadvertent generation of hydrogen gas in the presence of arsenicals. In all occupational settings where there is arsenic, workers should be informed of the possibility of arsine formation when there is nascent (freshly formed) hydrogen present. Likewise, workers exposed to antimony compounds should be informed of the possibility of exposure to stibine when freshly formed hydrogen is present.
Further research on the chronic and acute effects of exposure to arsine and stibine is needed. Although the acute toxicity of arsine in humans is fairly well defined, very little information is available on long term effects of exposure to arsine with simultaneous exposure to other arsenic compounds. In addition more research into methods of sampling for the presence of arsine and stibine in air is needed, for both monitoring and documentation purposes.
In the event arsine and/or stibine is generated, immediate steps should be taken to remove workers from the contaminated environment. In cases of exposure or when any symptoms are first observed prompt medical attention is imperative. Treatment of arsine poisoning should include: (a) immediate blood exchange transfusion to replace the destroyed red blood cells, and also to remove arsenic and the hemoglobin-arsine complex; (b) the administration of therapeutic amounts of dimercaprol (BAL); and (c) dialysis should be started if the patient has suffered kidney damage. Exchange transfusions lower blood arsenic levels, but dialysis, though it may be life-saving, does not remove arsenic from the patient. Therefore, efforts should be made to remove arsenic from the victim&#;s body.25 Other medical support measures should be utilized as indicated.
[signature]
Anthony Robbins, M.D.
Director
Current Intelligence Bulletin 32: Arsine (Arsenic Hydride) Poisining in the Workplace
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