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A Broad View of Arsenic

Center of Excellence for Poultry Science, University of Arkansas, Fayetteville 72701

¹ Corresponding author: ftjones{at}uark.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION BACKGROUND ARSENIC AND MINING ARSENIC IN WATER, AIR,... ARSENIC IN PLANTS ARSENIC IN FOODS A SHORT GLOBAL PERSPECTIVE... HUMAN TOXICITY-BRIEFLY TOXICITY MECHANISMS ARSINE GAS ARSENIC USES A BRIEF HISTORY OF... USE OF ARSENICALS AS... RESIDUES ARSENICAL USE AND ENVIRONMENT... REFERENCES

 
In the mind of the general public, the words "arsenic" and "poison" have become almost synonymous. Yet, As is a natural metallic element found in low concentrations in virtually every part of the environment, including foods. Mining and smelting activities are closely associated with As, and the largest occurrence of As contamination in the United States is near the gold mines of northern Nevada. Inhabitants of Bangladesh and surrounding areas have been exposed to water that is naturally and heavily contaminated with As, causing what the World Health Organization has described as the worst mass poisoning in history. Although readily absorbed by humans, most inorganic As (>90%) is rapidly cleared from the blood with a half-life of 1 to 2 h, and 40 to 70% of the As intake is absorbed, metabolized, and excreted within 48 h. Arsenic does not appreciably bioaccumulate, nor does it biomagnify in the food chain. The United States has for some time purchased more As than any other country in the world, but As usage is waning, and further reductions appear likely. Arsenic is used in a wide variety of industrial applications, from computers to fireworks. All feed additives used in US poultry feeds must meet the strict requirements of the US Food and Drug Administration Center for Veterinary Medicine (Rockville, MD) before use. Although some public health investigators have identified poultry products as a potentially significant source of total As exposure for Americans, studies consistently demonstrate that <1% of samples tested are above the 0.5 ppm limit established by the US Food and Drug Administration Center for Veterinary Medicine. Although laboratory studies have demonstrated the possibility that As in poultry litter could pollute ground waters, million of tons of litter have been applied to the land, and no link has been established between litter application and As contamination of ground water. Yet, the fact that <2% of the United States population is involved in production agriculture and the overtones associated with the word "arsenic" could mean the matter becomes a perception issue.

Key Words: arsenic • poison • toxicity

	INTRODUCTION

TOP ABSTRACT INTRODUCTION BACKGROUND ARSENIC AND MINING ARSENIC IN WATER, AIR,... ARSENIC IN PLANTS ARSENIC IN FOODS A SHORT GLOBAL PERSPECTIVE... HUMAN TOXICITY-BRIEFLY TOXICITY MECHANISMS ARSINE GAS ARSENIC USES A BRIEF HISTORY OF... USE OF ARSENICALS AS... RESIDUES ARSENICAL USE AND ENVIRONMENT... REFERENCES

 
Among the general public, the word "arsenic" has become almost synonymous with the word "poison" (Shakhashiri, 2000). This reputation was apparently gained via several circa 1900 poisonings as well as the play and 1944 movie titled "Arsenic and Old Lace." Yet several other chemicals (i.e., Se) were later identified in the 1900 poisoning incidents, and the symptoms of the victims in "Arsenic and Old Lace" suggest that cyanide or strychnine was primarily responsible for the fatalities (Lykknes and Kvittingen, 2003; PDR Health, 2004). Indeed, Haas (2004) has suggested that As has a fairly low toxicity in comparison with some of the other metals. Furthermore, As deprivation has been associated with impaired growth and abnormal reproduction in rats, hamsters, chicks, goats, and miniature pigs (National Academy of Sciences, 2001). In addition, there appears to be some evidence that As is an essential element involved in Met metabolism in humans (Uthus, 2003)

Nonetheless, lawsuits have been filed alleging environmental pollution and human health effects associated with As containing additives in poultry feeds (Leonard, 2004; Tyree, 2006). Arsenic has been identified as a road-block to potential animal waste management solutions (Nachman et al., 2005). Public health workers have expressed concern about the As content of chicken meat (Lasky et al., 2004). Thus, this review is intended to outline the facts surrounding the use of As in poultry feed additives.

	BACKGROUND

TOP ABSTRACT INTRODUCTION BACKGROUND ARSENIC AND MINING ARSENIC IN WATER, AIR,... ARSENIC IN PLANTS ARSENIC IN FOODS A SHORT GLOBAL PERSPECTIVE... HUMAN TOXICITY-BRIEFLY TOXICITY MECHANISMS ARSINE GAS ARSENIC USES A BRIEF HISTORY OF... USE OF ARSENICALS AS... RESIDUES ARSENICAL USE AND ENVIRONMENT... REFERENCES

 
Arsenic is a metallic element that occurs naturally in the earth’s surface at 1.5 to 2 ppm, mostly in inorganic form (National Academy of Sciences, 1977). However, As is not distributed uniformly throughout the world. Inorganic As can exist in 4 valence states (–3, 0, +3, and +5), depending upon environmental conditions. In oxidizing conditions As will usually exist as compounds of H₃AsO₄ called arsenates (+5), whereas in mildly reducing conditions, As is generally present as H₃AsO₃ compounds called arsenites (+3; Duker et al., 2004). In moderate reducing conditions, As often combines with S and Fe to form As sulfides or FeAsS, which are virtually insoluble in water and immobilized in the environment. In strongly reducing environments, elemental As (0) or H₃As [–3] can exist, but such conditions are rare (World Health Organization, 2001a; Magalhaes, 2002).

	ARSENIC AND MINING

TOP ABSTRACT INTRODUCTION BACKGROUND ARSENIC AND MINING ARSENIC IN WATER, AIR,... ARSENIC IN PLANTS ARSENIC IN FOODS A SHORT GLOBAL PERSPECTIVE... HUMAN TOXICITY-BRIEFLY TOXICITY MECHANISMS ARSINE GAS ARSENIC USES A BRIEF HISTORY OF... USE OF ARSENICALS AS... RESIDUES ARSENICAL USE AND ENVIRONMENT... REFERENCES

 
Arsenic generally exists in low concentrations in many rock types but is frequently associated with metal ore deposits (e.g., Au, Ag, Cu, and Fe). Because of this association with ore and the stability of As in forms like AsFeS, As was used as a "pathfinder element" that indicated to miners that significant metal ore deposits were near (Bowell and Parshley, 2001). Although most As compounds have no smell or taste, heat can cause As to sublimate to a gas with a distinctive garlic odor. Miners once recognized As in rock (and ore deposits) by the pungent odor released when rocks were struck by hammers or picks (Hamilton, 2005). Indeed, a circa 1900 account of a mine in Sweden reported recovering the following materials from a ton of ore: 1 oz (28.3 g) of Au, 2 oz (56.7 g) of Ag, 20 lb (9071.8 g) of Cu, and 180 lb (81646.6 g) of As (Calvert, 2004). Furthermore, the largest occurrence of As in the United States is near Au mines in northern Nevada (Bowell and Parshley, 2001).

Although As in AsFeS is virtually immobile in the environment, the blasting and tunneling associated with mining creates fractures in the rock, exposing these compounds to an oxidizing environment. This exposure to oxidation converts AsFeS to water-soluble As compounds, perhaps by the following equation 4FeAsS + 3O₂ + 6H₂O 4Fe⁺² + 4AsO₄^–3 + 12 H⁺ (Duker et al., 2004). Additionally, aerobic bacterial contaminants likely metabolize other As compounds, further increasing the concentration of water-soluble As compounds (Islam et al., 2004).

Although ores are now processed using cleaner, more efficient wet extraction methods, smelting (or heating) was once the primary extraction method (Lugaski, 1997). Because heating liberated As, most of the mineral was either released into the atmosphere or collected on the inside of the smokestack (Hamilton, 2005). The last US smelting operation closed in 1985, because they could not meet the environmental regulations (Loebenstein, 1994).

	ARSENIC IN WATER, AIR, AND SOIL

TOP ABSTRACT INTRODUCTION BACKGROUND ARSENIC AND MINING ARSENIC IN WATER, AIR,... ARSENIC IN PLANTS ARSENIC IN FOODS A SHORT GLOBAL PERSPECTIVE... HUMAN TOXICITY-BRIEFLY TOXICITY MECHANISMS ARSINE GAS ARSENIC USES A BRIEF HISTORY OF... USE OF ARSENICALS AS... RESIDUES ARSENICAL USE AND ENVIRONMENT... REFERENCES

 
Because surface and ground waters are often in contact with ores or tailings, waters near former mining or smelting sites often contain elevated As levels. Figure 1 outlines the affect of pH and oxidation reduction potential on As chemistry (Ferguson and Gavis, 1972). Arsenic can also occur naturally in geothermal springs such as Yellowstone National Park (WY), where As concentrations often exceed 1.00 ppm (1,000 ppb; Shakhashiri, 2000). However, not all geothermal springs are contaminated with As. The concentration of naturally occurring As in ground water varies with climate and geology (Welch et al., 2000).

View larger version (14K): [in this window] [in a new window]   Figure 1. Behavior of As at various oxidation-reduction- (Eh) pH combinations. ORP = oxidation reduction potential; AsO4 = arsenate compounds; AsO3 = arsenite compounds; AsS2 = arsenic disulfide compounds; As = elemental arsenic; and AsH3 = arsine. Adapted from Ferguson and Gavis (1972).

The As content of soils averages 5 to 6 ppm, but ranges from 0.2 to 40 ppm. Most naturally occurring As has been transported in particulate form from weathered rocks (National Toxicology Program, 2005). However, near smelting operations and around older orchards where arsenical pesticides were used, soil levels of 100 to 2,500 ppm As have been found (World Health Organization, 2000). Although it is estimated that about 80% of the total amount of anthropogenic (or man-made) As released into the environment resides in soil, most As compounds remain in particulate form and adsorb to soil particles being transported via leaching only short distances in the soil (US EPA, 1998; World Health Organization, 2001b). The As adsorption capacity of the soil is positively correlated with the free Fe oxide, MgO, Al₂O₃, and clay content of the soil. Many common microbial genera (Bacillus, Clostridium, Alcaligenes, and Citrobacter) have been shown to convert As compounds to arsine or methylarsine gases, reducing the amount of arsine present in soils (Cheng and Focht, 1979; Oremland and Stolz, 2003).

	ARSENIC IN PLANTS

TOP ABSTRACT INTRODUCTION BACKGROUND ARSENIC AND MINING ARSENIC IN WATER, AIR,... ARSENIC IN PLANTS ARSENIC IN FOODS A SHORT GLOBAL PERSPECTIVE... HUMAN TOXICITY-BRIEFLY TOXICITY MECHANISMS ARSINE GAS ARSENIC USES A BRIEF HISTORY OF... USE OF ARSENICALS AS... RESIDUES ARSENICAL USE AND ENVIRONMENT... REFERENCES

 
It has been known for decades that soils with elevated As levels (i.e., 20 ppm) produce plants with increased As levels (Williams and Whetstone, 1940). However, it should be recognized that many of these studies were conducted with soils containing >500 ppm, whereas most soils contain 10 ppm As (Warren and Alloway, 2003; Warren et al., 2003). In addition, concentrations of As may be 10 to 1000 times greater in soil than in plants growing on that soil. Moreover, the distribution of As among various plant parts is highly variable, with seeds and fruits having lower As concentration than leaves, stems, or roots. Roots and tubers generally have the highest As concentrations, with the skin having higher concentrations than the inner flesh (Peryea, 2001). The edible portions of vegetables seldom accumulate high concentrations of As, because most plants will be killed or severely stunted long before the As concentration in their tissues reaches concentrations that pose a health risk (Ontario Ministry of the Environment, 2001). A recent survey of As levels in vegetables grown in Bangladesh offered for sale in the United Kingdom found a mean level of 0.0545 ppm (54.5 ppb) and a range of concentrations of 0.005 to 0.54 ppm (5 to 540 ppb) As. Although Bangladesh-grown vegetables were 2- to 3-fold higher in As content than UK-grown vegetables, the concentrations found were far lower than the 1 ppm regulatory limit established for the United Kingdom (Al Rmalli et al., 2005). Indeed, a recent study of heavy metals and dioxin in commercial fertilizers, crop lands, and vegetables found that leaf tissues contained 0.1 ppm dry weight and concluded that crops do not take up significant amounts of As (California Department of Food and Agriculture, 2004). Woodbury (2005) concluded while working with municipal solid wastes that As is not readily taken up by plants and thus is unlikely to pose a problem. However, it should be recognized that the As content found in plants will also depend on soil conditions.

With equivalent soil As concentrations, plants grown on sands or sandy loam soil usually have higher total As contents than those grown on heavier-textured soils. Plants generally absorb the least amount of soil As at neutral soil pH and increasing soil organic matter by adding compost, manures, or other organic soil amendments has been found to reduce plant uptake of soil As. The addition of lime to soils tends to immobilize As (Moon et al., 2004). However, adding phosphate amendments to high-As soils has been found to increase plant uptake of soil As (Peryea, 2001). This phenomenon could be because of the chemical similarity between P and As, which are in the same column of the periodic table, 1 row apart.

Arsenic, like other naturally occurring minerals (including P) tends to cycle in the environment (Figure 2). This cycling insures that humans are always and unavoidably exposed to As (Roy and Saha, 2002). Indeed, As is present in all living organisms, and every organism from Escherichia coli to man has developed detoxification pathways (National Academy of Sciences, 1977; Rosen, 2002).

View larger version (43K): [in this window] [in a new window]   Figure 2. Natural cycling of As. Reprinted with permission from Arsenic: Medical and Biological Effects of Environmental Pollutants (National Academy of Sciences, 1997, Natl. Acad. Press, Washington, DC).

	ARSENIC IN FOODS

TOP ABSTRACT INTRODUCTION BACKGROUND ARSENIC AND MINING ARSENIC IN WATER, AIR,... ARSENIC IN PLANTS ARSENIC IN FOODS A SHORT GLOBAL PERSPECTIVE... HUMAN TOXICITY-BRIEFLY TOXICITY MECHANISMS ARSINE GAS ARSENIC USES A BRIEF HISTORY OF... USE OF ARSENICALS AS... RESIDUES ARSENICAL USE AND ENVIRONMENT... REFERENCES

	A SHORT GLOBAL PERSPECTIVE ON ARSENIC

TOP ABSTRACT INTRODUCTION BACKGROUND ARSENIC AND MINING ARSENIC IN WATER, AIR,... ARSENIC IN PLANTS ARSENIC IN FOODS A SHORT GLOBAL PERSPECTIVE... HUMAN TOXICITY-BRIEFLY TOXICITY MECHANISMS ARSINE GAS ARSENIC USES A BRIEF HISTORY OF... USE OF ARSENICALS AS... RESIDUES ARSENICAL USE AND ENVIRONMENT... REFERENCES

In 1960, Bangladesh, one of the poorest, most densely populated countries in the world, the consumption of surface water contaminated with water borne pathogens such as cholera and dysentery contributed to an infant mortality rate of 247 per 1,000 live births. In 1971, international agencies collaborated with private interests and began addressing the problem of surface water contamination by installing tubewells. Tubewells are 2-in (5.08 cm) metal pipes with an attached hand pump that are drilled over 50 m to access aquifers. Despite warnings from some local people that they were pumping "devil’s water," an estimated 4 million tubewells were installed over the next 20 yr, and the infant mortality rate decreased to 112 deaths per 1,000 births in 1996, fostering the belief that the tubewell program was incredibly successful (Pearce, 2001; Chaudhuri, 2004). However, later surveys indicated that 8, 35, and 58% of the water tested contained As levels >0.3, 0.05, and 0.01 ppm (300, 50, and 10 ppb), respectively. Human mortalities of 20,000 annually occur in Bangladesh as a result of As poisoning, and an estimated 50 million people are at risk for severe health consequences (Pearce, 2001; Chaudhuri, 2004). The World Health Organization labeled the situation "the worst mass poisoning in history" (Mead, 2005, p. A382).

Health data collected from Bangladesh and other locations where people consumed water with elevated As concentrations have been used to project the risks associated with the consumption of water containing very low concentrations of As (Pearce, 2001). Yet, epidemiologists have recently warned "The low-dose extrapolations used for risk assessment purposes may be subject to error in part because they are based more on ecologic data than on individual measures of exposure" (Mead, 2005, p. A383). It should be noted that an estimated 5% of the water sources in the United States exceed the 0.01 ppm (10 ppb) As standard established by the EPA in January of 2006 (US EPA, 2006). Indeed, people in certain areas of the West, Midwest, Southwest, and Northeast United States drink well water with As levels ranging from 50 to 90 ppb and, to date, no statistically significant relationships have been found between As exposure and cancer in these areas (Mead, 2005). Further, the in situ toxicity of As compounds is a thorny issue, because environmental conditions and the metabolism of various living organisms can rapidly change the chemical state of As compounds (Kumaresan and Riyazuddin, 2001). To further confound matters, there is a lack of adequate animal models in the investigation of As toxicity (Cohen et al., 2006).

	HUMAN TOXICITY–BRIEFLY

TOP ABSTRACT INTRODUCTION BACKGROUND ARSENIC AND MINING ARSENIC IN WATER, AIR,... ARSENIC IN PLANTS ARSENIC IN FOODS A SHORT GLOBAL PERSPECTIVE... HUMAN TOXICITY-BRIEFLY TOXICITY MECHANISMS ARSINE GAS ARSENIC USES A BRIEF HISTORY OF... USE OF ARSENICALS AS... RESIDUES ARSENICAL USE AND ENVIRONMENT... REFERENCES

 
In everyday life, the toxicity of a given As compound will depend on chemical factors such as valence, solubility, and the presence of other impurities, physical factors [i.e., form (gas, solution, or powder) and particle size], the route of exposure, and the age, gender, exercise level, health status, and genetics of the animal involved (Gochfeld, 1997; Agency for Toxic Substances and Disease Registry, 2000). In addition, some investigators have theorized that As at different doses may act by different mechanisms, perhaps producing different patterns of disease. Others have speculated that the toxic affects of As are nonlinear, with extremely low levels of As exposure posing no excess risk (Mead, 2005; Cohen et al., 2006).

Food and drinking water together usually account for 99% of the total human intake of As (Ontario Ministry of the Environment, 2001). In humans, 60 to 90% of ingested, soluble As is quickly absorbed from the gastrointestinal tract. Although precise estimates of As absorption via inhalation have not been precisely determined, absorption rates via inhalation would appear to be similar to gastrointestinal tract values. Dermal absorption of As is generally considered to be negligible except in rare occupational accidents in which H₃AsO₄ was splashed on worker’s skin, causing skin damage (Agency for Toxic Substances and Disease Registry, 2000).

Following absorption, the majority of inorganic As (>90%) is rapidly cleared from the blood with a half-life of 1 to 2 h (Cohen et al., 2006). Although some As compounds are converted in testes, kidney, and lung tissue, the liver is the primary site of As metabolism in mammals. In humans, 40 to 70% of As exposure is absorbed, metabolized, and excreted within 48 h (Cohen et al., 2006). Although As is eliminated from the body primarily through the kidneys, other less important routes of elimination include feces, sweat, skin desquamation, and incorporation into hair and nails (Agency for Toxic Substances and Disease Registry, 2000). Arsenic does not appreciably bioaccumulate in the body over time nor does it biomagnify in the food chain (Hamilton, 2005).

Unless followed by immediate, aggressive treatment, the oral consumption of 70 to 180 mg of As₂O₃ in humans is generally fatal in <1 h (New Hampshire Department of Environmental Services, 2004). When humans or animals are exposed to subfatal As doses, the time frame for the appearance of symptoms (i.e., vomiting, abdominal pain, and diarrhea) depends on the dose involved, the route of exposure, and the health of the subject (Agency for Toxic Substances and Disease Registry, 2000). In chronic long-term exposures, sensitive individuals begin to display characteristic signs of As toxicity at oral intakes of around 20 µg/kg per day of BW, but some humans can ingest over 150 µg/kg per day without any apparent ill-effects (Ontario Ministry of the Environment, 2001). The first symptoms of chronic long-term exposure to low levels of As (arsenicosis) are skin discolorations, chronic indigestion, and stomach cramps. Longer-term effects include skin, lung, kidney, and liver cancer as well as gangrene-like sores. However, the internal cancers may not appear for 20 or 30 yr after exposure (Flynn, 1998). Chronic As exposure has also been linked to a host of other symptoms, and few established medical protocols exist for treatment (World Health Organization, 2001a). To further complicate matters, the symptoms of chronic exposure differ among individuals, population groups, and geographic areas, resulting in the conclusion that there is no universal definition of the symptoms caused by chronic As exposure (Sharpe, 2003). Furthermore, some persons, the so-called "arsenic eaters" of the mountains of southern Austria, have found that As has an invigorating or refreshing (tonic) effect and have built up a tolerance for it so that they can ingest each day an amount that would normally be a fatal dose. A similar tolerance has been documented in laboratory animals (Smith, 2002). This tolerance, however, does not protect them against the same amount of As administered hypodermically (Hamilton, 2005).

	TOXICITY MECHANISMS

TOP ABSTRACT INTRODUCTION BACKGROUND ARSENIC AND MINING ARSENIC IN WATER, AIR,... ARSENIC IN PLANTS ARSENIC IN FOODS A SHORT GLOBAL PERSPECTIVE... HUMAN TOXICITY-BRIEFLY TOXICITY MECHANISMS ARSINE GAS ARSENIC USES A BRIEF HISTORY OF... USE OF ARSENICALS AS... RESIDUES ARSENICAL USE AND ENVIRONMENT... REFERENCES

 
Many heavy metals (including As, Cd, Pb, and Hg) have affinity for sulfhydryl bonds and can alter protein structure, leading to disruptions of metabolic processes (Gochfeld, 1997). The binding with sulfhydryl groups by arsenite compounds has the potential to influence a wide range of metabolic activities including cellular glucose uptake, gluconeogenesis, fatty acid oxidation, and production of glutathione. This broad metabolic toxicity can produce confusing symptoms (Young, 2000). For instance, As poisoning can produce thiamine deficiency symptoms in humans, because it prevents the transformation of thiamine into acetyl-coenzyme A and succinyl-coenzyme A (Dyro, 2005). However, it should be noted that the binding of As with sulfhydryl bonds is often reversible (Young, 2000).

The chemical similarity between phosphate compounds and arsenate compounds allows As to substitute in vital compounds or reactions. Although the similarity in these compounds could affect many crucial compounds, potential interactions with genetic materials could have long-term consequences. Yet, Mead (2005) observed that As does not directly interact with DNA. Instead, the effects of As occur through indirect alteration of gene expression via disruption of DNA methylation, inhibition of DNA repair, oxidative stress, or altered modulation of signal transduction pathways. Thus, toxicity of arsenate compounds (particularly at low doses) is apparently dependent on exposure to other toxic cofactors such as exposure to tobacco smoke, malnutrition, ultraviolet light exposure, Se deficiency, reduced animal protein intake, marginal Ca status, and folate deficiency (Gamble et al., 2005; Cohen et al., 2006).

Although a discussion of the toxicology of every As compound is beyond the scope of this review, a few basic principles should be mentioned. Arsenite compounds are often several-fold more toxic than the arsenate compounds. Although the affinity of arsenite compounds for disulfide bonds undoubtedly accounts for much of this difference in toxicity, the water solubility of a given compound might also contribute. Although not always true, there would appear to be a positive correlation between water solubility and toxicity of As compounds (Magalhaes, 2002). In addition, organic As compounds are considered less toxic than inorganic forms. Indeed, certain organic compounds (e.g., arsenobetaine) are considered by many to be virtually nontoxic (Environment Agency, 2002). In contrast, AsH₃ gas is the most toxic As compound known, warranting further discussion.

	ARSINE GAS

TOP ABSTRACT INTRODUCTION BACKGROUND ARSENIC AND MINING ARSENIC IN WATER, AIR,... ARSENIC IN PLANTS ARSENIC IN FOODS A SHORT GLOBAL PERSPECTIVE... HUMAN TOXICITY-BRIEFLY TOXICITY MECHANISMS ARSINE GAS ARSENIC USES A BRIEF HISTORY OF... USE OF ARSENICALS AS... RESIDUES ARSENICAL USE AND ENVIRONMENT... REFERENCES

 
Arsine, the simplest and most toxic compound of As, is formed when inorganic As compounds are exposed to strong reducing conditions (National Occupational Health and Safety Commission, 1989). Arsine can also be formed by the reaction of As impurities in commercial acids stored in metal tanks (US EPA, 1998). Arsine gas is colorless, heavier than air, nonirritating, but highly poisonous. Arsine has a mild garlic odor, but this odor does not provide a reliable warning (National Occupational Health and Safety Commission, 1989). Arsine is unstable in the presence of heat and can be readily oxidized by O or air, producing As₂O₃ and water as end products. However, the reaction of H with O is volatile, making the danger of explosion very real when AsH₃ reacts with O (Wikipedia, 2006). Arsine and its methylated forms may also be produced if As-rich ores are treated with strong oxidizers or are degraded by microbial metabolic activities. Both pure AsH₃ and its methylated forms (mono-, di-, and trimethylarsine) are produced by microorganisms (Oremland and Stolz, 2003).

	ARSENIC USES

TOP ABSTRACT INTRODUCTION BACKGROUND ARSENIC AND MINING ARSENIC IN WATER, AIR,... ARSENIC IN PLANTS ARSENIC IN FOODS A SHORT GLOBAL PERSPECTIVE... HUMAN TOXICITY-BRIEFLY TOXICITY MECHANISMS ARSINE GAS ARSENIC USES A BRIEF HISTORY OF... USE OF ARSENICALS AS... RESIDUES ARSENICAL USE AND ENVIRONMENT... REFERENCES

 
In 1909, the first synthetic chemotherapeutic agent (Salvarsan) was released by the Nobel Prize-winning German pharmacologist Paul Ehrlich. Although inconvenient, Salvarsan ("salvation by arsenic") was the first effective treatment of syphilis (Yarnell, 1983; Van den Enden, 1999). Other researchers developed As compounds against parasites causing yaws, relapsing fever (which is similar to Lyme disease), trichomonal vaginitis, trypanosomiasis (African sleeping sickness), and amebic dysentery (National Academy of Sciences, 1977). Until recently, As compounds were used in developing countries around the world as treatments for a variety of diseases (Roy and Saha, 2002). In point of fact, an As compounds is still in common use in human medicine against trypanosomiasis, but this drug is not available in the United States or Canada (Drugs.com, 2006). In 2000, the US Food and Drug Administration approved the use of As₂O₃ for treatment of relapsed or refractory acute promyelocytic leukemia (Antman, 2001). It should also be noted that even after As compounds were phased out of use in human medicine, some were later reintroduced as feed additives (Yarnell, 1983).

Lead, Ca, and Cu As compounds were very effective insecticides for many years. Nearly all of these early insecticides were virtually insoluble in water, otherwise a good rain would have washed them off, making them ineffective (Calvert, 2004). Although arsenical usage is curtailed in the United States, the EPA registration of many organic and inorganic As compounds as herbicides, defoliants, fungicides, rodenticides, and insecticides remains intact (Orme and Kegley, 2006). Arsenic is also used to remove impurities (particularly Fe) so that clear glass is produced, to make rounder lead shot, to harden and increase the durability of plates and posts in lead acid batteries, to produce color in fireworks, to act as an alloy in the bronzing process, to act as an alloy with Ga in integrated circuits and in laser materials to convert electricity directly into coherent light (Ishiguro, 1992). Table 3 lists some inorganic As compounds in common industrial use.

	A BRIEF HISTORY OF US ARSENIC PRODUCTION AND USE

TOP ABSTRACT INTRODUCTION BACKGROUND ARSENIC AND MINING ARSENIC IN WATER, AIR,... ARSENIC IN PLANTS ARSENIC IN FOODS A SHORT GLOBAL PERSPECTIVE... HUMAN TOXICITY-BRIEFLY TOXICITY MECHANISMS ARSINE GAS ARSENIC USES A BRIEF HISTORY OF... USE OF ARSENICALS AS... RESIDUES ARSENICAL USE AND ENVIRONMENT... REFERENCES

	USE OF ARSENICALS AS FEED ADDITIVES

TOP ABSTRACT INTRODUCTION BACKGROUND ARSENIC AND MINING ARSENIC IN WATER, AIR,... ARSENIC IN PLANTS ARSENIC IN FOODS A SHORT GLOBAL PERSPECTIVE... HUMAN TOXICITY-BRIEFLY TOXICITY MECHANISMS ARSINE GAS ARSENIC USES A BRIEF HISTORY OF... USE OF ARSENICALS AS... RESIDUES ARSENICAL USE AND ENVIRONMENT... REFERENCES

 
Although the use of arsenical feed additives was prohibited in Europe in 1998, the arsenical feed additives presently approved for use in United States poultry feeds are listed in Table 4 along with their approved usage levels and indications for use (Nachman et al., 2005). Arsanilic acid is infrequently used in poultry feeds, and nitrosone is used only for the treatment or prevention of blackhead. However, Chapman and Johnson (2002) estimated that from 1995 to 2000, roxarsone was used in 69.8 and 73.9% of the broiler starter and broiler grower feeds in the United States. Roxarsone is approved for use in broilers and results in increased growth rates, improved feed utilization, and enhanced pigmentation. Because roxarsone has been shown to be an effective potentiator against intestinal parasites, particularly coccidiosis, the improved intestinal health is the apparent reason for improved growth and feed utilization (Alpharma, 1999). In addition, recent field experience has revealed that roxarsone may be effective at suppressing Salmonella and possibly other enteric organisms that can cause food safety hazards for consumers.

1. Efficacy (the material must be demonstrated to work as intended).
   
2. Safety (the material must be demonstrated safe for the intended animal).
   
3. Adequate manufacture (the company must demonstrate that they can manufacture the drug in the necessary form, dose, and purity required).
   
4. Environmental safety (the company must demonstrate that the material is not environmentally hazardous).
   

If the material is intended for use in food animals, companies must present data in an additional (fifth) area:

1. Human safety (drugs used in food animals must demonstrate human food safety).
   

Once the FDA-CVM has accepted the necessary data, the agency establishes a safe residue level for the drug and, where necessary, establishes withdrawal times. The agency then imposes strict labeling requirements that delineate usage directions, approved species, dosage, duration, and withdrawal periods before harvest of meat, milk, or eggs (Animal Health Institute, 2002). The safe residue level for As in poultry meat is 0.5 ppm in muscle tissue and 2 ppm in liver (US Food and Drug Administration, 1997). Hutchinson and Leffingwell (1998) observed that because the FDA-CVM requires extensive efficacy and safety testing for drugs, the probability of adverse effects from use of these drugs is very small.

Roxarsone is not allowed in layer feeds but is approved at 22.7 to 45.4 g/ton (25 to 50 ppm) in broiler feeds, with a required 5-d withdrawal period before slaughter [Miller Publishing Company (2005)]. Because roxarsone is 28.5% As, the addition of 50 ppm roxarsone would add (0.285 x 50) 14.25 ppm As to feeds. This means that over the duration of their lives, birds are exposed to considerably more As than the 0.5 ppm tolerance limit established by the FDA. However, most As passes through the bird unchanged and remains in the litter (Garbarino et al., 2003).

	RESIDUES

TOP ABSTRACT INTRODUCTION BACKGROUND ARSENIC AND MINING ARSENIC IN WATER, AIR,... ARSENIC IN PLANTS ARSENIC IN FOODS A SHORT GLOBAL PERSPECTIVE... HUMAN TOXICITY-BRIEFLY TOXICITY MECHANISMS ARSINE GAS ARSENIC USES A BRIEF HISTORY OF... USE OF ARSENICALS AS... RESIDUES ARSENICAL USE AND ENVIRONMENT... REFERENCES

 
Morrision (1969) tested the liver, muscle, skin, and kidneys of broilers fed roxarsone and subjected to a 5-d withdrawal period and found 0.39, <0.10, <0.10, and 0.13 ppm, respectively. The data in Figure 3 provide an overview of As residues in poultry meat and liver before, during, and after the feed withdrawal period. These data indicate that if provided concentrations are correct in feeds and the withdrawal period is observed, residues above FDA-CVM violative levels should not occur. Lasky et al. (2004) examined trends in 3,611 mostly liver samples collected by the United States Department of Agriculture Food Safety and Inspection Service from 1989 to 2000. The authors used published data to estimate As concentrations in muscle tissues. About 0.3% of the broiler samples tested contained violative residues, but 69% contained measurable As residues that were below violative levels. Even at the highest projected human consumption patterns, these researchers found that residues were below maximum recommended As levels established by the WHO. However, the researchers expressed concern that As residues were higher than previously thought and were apparently increasing; no reason was offered for these trends.

View larger version (17K): [in this window] [in a new window]   Figure 3. Arsenic residues in chicken muscle and liver. Adapted from Alpharma (1999).

Silbergeld (2004) commented on the Lasky et al. (2004) study via a letter to the editor of the journal (Environmental Health Perspectives) stating that the true risks associated with As exposure were probably underestimated. Silbergeld also did a press release, which was subsequently propagated by the media (O’Brien, 2004). However, as other scientists later examined Silbergeld’s conclusions, a calculation error was discovered whereby the As concentration was overestimated by 7000% (Bernard, 2005). Although Silbergeld acknowledged the calculation error in a follow-up letter to the journal editor, subsequent press releases were apparently not done (Silbergeld, 2005).

In addition, a small As residue survey recently surfaced which reported on results involving a total of 151 samples of ready-to-cook chicken representing 14 brands and 5 different products (Wallinga, 2006). The survey also included 90 fast-food chicken product samples representing 12 different restaurants and 4 different products. The author reportedly collected samples in 2 locations within the United States, offered few details with respect to sampling or laboratory methodology, reported results in parts per billion, and produced a press release rather than a peer review manuscript. These data are summarized in Tables 5 and 6 in parts per million. Interestingly, average As results reported by Wallinga (2006) for conventionally raised birds were lower than those reported by Lasky et al. (2004).

	ARSENICAL USE AND ENVIRONMENT POLLUTION

TOP ABSTRACT INTRODUCTION BACKGROUND ARSENIC AND MINING ARSENIC IN WATER, AIR,... ARSENIC IN PLANTS ARSENIC IN FOODS A SHORT GLOBAL PERSPECTIVE... HUMAN TOXICITY-BRIEFLY TOXICITY MECHANISMS ARSINE GAS ARSENIC USES A BRIEF HISTORY OF... USE OF ARSENICALS AS... RESIDUES ARSENICAL USE AND ENVIRONMENT... REFERENCES

Morrison (1969) reported that 26 to 88% of the As in litter was in the form of roxarsone. However, later compound speciation has indicated roxarsone subsequently degrades to mostly inorganic As compounds (Jackson et al., 2003). Laboratory experiments indicated that when litter moisture was increased to 50% and the mixture was incubated at 40°C for 30 d, arsenate compounds became the dominant. Increasing the amount of water added increased the roxarsone degradation rate, whereas the addition of azide decreased rates and autoclaving eliminated activity (Garbarino et al., 2003). Clearly these results suggest that microbial activity was responsible for the degradation of roxarsone in litter to inorganic As compounds. Because degradation of As compounds likely involves many microbial species with widely varying metabolic activity, a complete understanding of these processes would likely be a complex affair. Nonetheless, Figure 4 contains a simplified outline of how these processes could occur.

View larger version (14K): [in this window] [in a new window]   Figure 4. A simplified outline of major As reactions in the environment. MMA = monomethylarsonic acid; DMA = dimethylarsonic acid. Adapted from Roy and Saha (2002).

Morrison (1969) also reported that soil and ground water were unaffected by treatment of the soil with poultry litter containing roxarsone. Although laboratory experiments have indicated that the As in the poultry litter is easily mobilized by water, its leach rate from amended soils appears to be slow (Rutherford et al., 2003). Other laboratory researchers have suggested that As in litter has probably been transported via leaching, surface run-off, or surface erosion or uptake by agricultural crops, but that there is no evidence of significant accumulation in agricultural crops (e.g., corn) harvested from litter amended soils (Arai et al., 2003). However, in spite of these suggestions, the US Geological Survey and other research units have been unable to tie the application of poultry litter to As in drinking water (Arai et al., 2003; Rutherford et al., 2003; Christen, 2006). Indeed, As concentrations in waters within soils are generally very low, probably as a result of chelation, cation exchange, adsorption, and mineralization processes occurring in soils (Magalhaes, 2002).

Moreover, the few studies of inorganic As pesticides suggest that As contamination of ground water is rare. In some areas, high As concentrations in water coincide with agricultural use, but these concentrations do not appear to be a result of agricultural use (Welch et al., 2000). For example, elevated levels of As were found in certain New Hampshire wells (Blume and Renshaw, 2004). Because orchards that heavily used PbHAsO₄ operated in the area some 50 to 70 yr prior, these pesticides were assumed to be the contamination source. However, Renshaw et al. (2006) found that although the PbHAsO₄ had degraded, As and lead levels were primarily adsorbed to fine silt, amorphous oxides, and organic matter, and little vertical redistribution of As occurred, with the top 10 cm of soil containing the highest concentration. However, tillage and erosion had allowed horizontal redistribution of some As and Pb. Kimber et al. (2002) found a similar result in soil around cattle dip sites, where arsenicals had been used 50 yr before control ticks.

Although questions have been raised about the environmental fate of arsenicals in poultry litter, the leaching rate of As from litter into soils is slow and appears to be highly dependent on the soil structure and chemistry (Rutherford et al., 2003). Indeed, earlier studies had already demonstrated that the use of As-containing feed additives pose no threat to soil or crops (Morrison, 1969). Furthermore, from 1955 to 2005 the broiler industry produced an estimated 230 billion broilers, weighing slightly over 1 trillion pounds. This resulted in a projected total litter production of 304 million tons during the same period. Assuming that all of the litter contained As-containing feed additives, and 95% was land-applied, an estimated total of 289 million tons of litter was land-applied between 1955 and 2005 (Fulhage, 1993; National Chicken Council, 2006). Such applications of litter have resulted in a great improvement in soil conditions in many locations. Yet, according to the US Geologic Survey, As concentrations in ground water (Figure 5) near major broiler production are generally among the lowest found in the United States (Ryker, 2001).

View larger version (54K): [in this window] [in a new window]   Figure 5. Arsenic in drinking water. Reprinted from Ryker (2001).

Received for publication July 24, 2006. Accepted for publication September 11, 2006.

	REFERENCES

TOP ABSTRACT INTRODUCTION BACKGROUND ARSENIC AND MINING ARSENIC IN WATER, AIR,... ARSENIC IN PLANTS ARSENIC IN FOODS A SHORT GLOBAL PERSPECTIVE... HUMAN TOXICITY-BRIEFLY TOXICITY MECHANISMS ARSINE GAS ARSENIC USES A BRIEF HISTORY OF... USE OF ARSENICALS AS... RESIDUES ARSENICAL USE AND ENVIRONMENT... REFERENCES

 
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