Arsenic

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26 Arsenic Tam Garland

INTRODUCTION

PHARMACOKINETICS/ TOXICOKINETICS

The ubiquitous element arsenic (As) is a non-metal or metalloid in group V of the period chart. Frequently it is referred to as arsenic metal and is classified for many toxicological purposes as a metal. It exists in several forms and has a long history of various uses. It has been used in preparations from insecticides for animal to wood preservatives, herbicides and even has some medicinal uses. It is responsible for many poisonings in people and animals, both large and small.

Different toxic disease syndromes are caused by the different forms of arsenic. Inorganic arsenicals and trivalent organics cause a disease syndromes characterized by an effect on the gastrointestinal (GI) tract and the capillaries. In extremely low doses it is possible the body will develop a tolerance to the arsenic. Pentavalent organic arsenicals produce a neurological syndrome. There are many factors influencing the absorption of arsenicals. Among those variables are the form of the metal, the particle size, the purity, the solubility, the species affected, and the physical condition of the animal exposed. Susceptibility to inorganic arsenicals varies among species, being highest in humans, followed by dogs, rats, and mice (Harrison et al., 1958; Hays, 1982). So clearly there are many variable affecting the absorption and toxicity of this metal, which increases the difficulty of making accurate predictions of lethal amounts. Pentavalent organic arsenicals are better absorbed than are the trivalent arsenicals, especially through the GI tract. Small amounts of either form may be absorbed via the intact skin, but it usually remains locally within the skin. However, absorption is limited by the size of the arsenical particle size. If the particle size is too large, it is not absorbed. Hence, a more toxic arsenical that is not absorbed because of large particle size may effectively be less toxic. Once arsenicals are absorbed, the distribution is through the blood to all the organs of the body. Arsenic accumulates in the liver and is slowly distributed to the

BACKGROUND Arsenic is a ubiquitous element with several different forms. The form may determine the toxicity. The prevalent valences are the ⫹3 and the ⫹5 forms. Arsenic is found in both organic and inorganic forms with valet numbers ranging from ⫹3 to ⫹5. As⫹3 or arsenite is more toxic than arsenate or As⫹5. The toxicity of arsenic is determined by its form. It is found as different ores and rocks being mined, then smelted resulting in elemental arsenic and arsenic trioxide. In the environment, arsenic usually exists as the pentavalent form and soil microorganisms may methylate it. Since it is a ubiquitous in many forms it is not likely that complete avoidance is possible. Arsenic has a long and varied history of its sources and uses. A partial list is available in Table 26.1. Veterinary Toxicology, Edited by Ramesh C. Gupta ISBN: 978-0-12-370467-2

Copyright © 2007, Elsevier Inc. All rights reserved.

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MECHANISM OF ACTION

TABLE 26.1

Sources and uses of arsenic

Sources

Valence/form

Uses

Commercial uses and products

Inorganic arsenic trioxide (⫹3)

Insecticide, cattle dip (0.18%)

Inorganic sodium arsenite (⫹3) Inorganic copper acetoarsenite (⫹3) Inorganic arsenic trioxide (⫹3) Inorganic sodium arsenate (⫹5) Inorganic chromated copper arsenate (⫹5) Inorganic lead arsenate (⫹5) Organic pentavalent (⫹5)

Defoliant (highly toxic) Paris green – insecticide (emerald green) Smelters Herbicide Wood preservative Insecticide and medicinal Monosodium methylarsenate (MSMA) and disodium methylarsenate (DSMA) (highly toxic to cattle) Ant bait Leaded gasoline Ant baits

Natural sources Medicinals

Ores, minerals, volcanoes Ground water and soil Potassium arsenite (⫹3) Organic trivalent arsenical Organic pentavalent arsenical Organic trivalent arsenical Organic pentavalent arsenical

other tissues. The spleen, kidneys, and lungs are able to accumulate large amounts of arsenic. Arsenic has been shown to cross into the placenta barrier, particularly in monkeys, hamsters, and gerbils. Chronic doses are stored in the bone, the skin, and other keratinized tissues, such as skin, hair, hooves, and nails (Agency for Toxic Substances and Disease Registry, 1990). The biotransformation of the arsenicals is poorly understood. There is some conversion from the ⫹5 state to the ⫹3 state, but the redox equilibrium favors the ⫹3. Methylation occurs by microorganism in the soil, but inorganic arsenicals are also methylated in vivo. The in vivo process may aid in the detoxification process. The kidneys may reduce a small amount of pentavalent arsenic to the more toxic trivalent form. Arsenicals are excreted through many processes. In most species, between 40% and 70% of the absorbed amount of pentavalent arsenicals are excreted through the urine within 48 h (Vahter, 1983). It may also be excreted in much smaller quantities through the sweat. Trivalent forms of arsenic are excreted more slowly and through the bile into the fees.

MECHANISM OF ACTION Arsenite (⫹3) react with sulfhydryl groups (—SH) of proteins and inhibits the enzymes by blocking the active

Fowler’s solution tonic/conditioner Thiacetarsamide – heartworm treatment in dogs Tryparsamide – trypanosomiasis – old Melarsoprol – trypanocidal Arsenicals feed additives (arsanilic acid, sodium arsanilate, 3-nitro, 4-hydroxyphenylarsonic acid)

groups. The arsenite inhibits alpha-keto oxidases which contain dithiol groups and are involved in oxidation of pyruvate. Lipoic acid, an essential co-enzyme for pyruvic acid oxidase and alpha-oxyglutaric acid oxidase are inhibited by the arsenite. These play an essential role in the tricarboxylic acid cycle. Actively dividing cells that have a high oxidative energy requirement are most susceptible to the effects of arsenicals. Arsenites induce vasodilation and can cause capillary damage. The cellular integrity of the capillary is affected by an unknown mechanism. Evidence of vascular instability is seen by the presence of congestion, edema, and hemorrhage in most of the visceral organs of animal with acute poisoning. This same mechanism of action occurs with inorganic arsenicals and with organic trivalent arsenicals, and they may be considered as “vascular poisons” (Hann and McHugo, 1960; Agency for Toxic Substances and Disease Registry, 1990; Jubb and Huxtable, 1993). Arsenates (⫹5) are a little different. They are uncouplers of oxidative phosphorylation. The inorganic pentavalents may substitute of phosphate in this reaction. The result is an increase in body temperature. Organic pentavalents have an unknown mechanism of action. There is some thought that they may interfere with vitamins B6 and B1, which may allow for the demyelination and subsequent axonal degeneration that occurs. Although arsenicals have been classified as carcinogens in people, this has not been the case in animals. Experimentally there have attempts to document arsenic-related

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26. ARSENIC

cancer in animals but the experiments have been unsuccessful (Agency for Toxic Substances and Disease Registry, 1990; Chan and Huff, 1997).

TOXICITY Inorganic arsenicals are up to 10 times more toxic than pentavalent arsenicals. The order of toxicity from greatest to least follows this schematic: inorganic As⫹3 (arsenite) ⬎ inorganic As⫹5 (arsenate) ⬎ trivalent organics ⬎ pentavalent organics (I As⫹3 ⬎ I As⫹5 ⬎ O As⫹3 ⬎ O As⫹5). In other metal toxicities, the organics are more toxic but with arsenicals the inorganics are the more toxic. Toxicity is also influenced by many factors, including particle size. The more finely ground, the more surface area there is for reactions. Solutions, such as dips and defoliants are the most dangerous. However the causes of the poisonings are varied. Debilitated animals are more sensitive. Since arsenic is not biodegradable, the soil and the old corrals around old dipping vats are still a source for arsenic poisoning. The area around smelters are also a source of poisoning, similar to that of dipping vats. Human mistakes and carelessness are the largest contributing factors to toxic events. For example, feeding a product known as gin trash instead of cotton seed hulls has resulted in acts numerous animals being poisoned. Clinical sings caused by either inorganic or trivalent aliphatic arsenicals are similar. Peracute toxicities often result in sudden death within minutes to a few hours, if the dose is high, of dissolved arsenic ingestion. Acute poisonings have more clinical signs: abdominal pain or colic, vomiting, a staggering gait and weakness, clear incoordination, rapid weak pulse and shock, diarrhea, followed collapse, and death. If the acute poisoning is through dermal contact, then the arsenic will also be systemic. The skin will have blisters, edema, and may be cracked and bleeding, leaving the skin susceptible for secondary infection (National Academy of Science, 1977; Evinger and Blakemaore, 1984) Those receiving a lower dose over a period of time may have subacute poisonings will likely live several days, developing depression and anorexia. Movements may be difficult, stiff, and incoordinated. Diarrhea is dark and possibly hemorrhagic and very fluid. Hematuria may be present, or the urine may contain protein and casts (National Academy of Science, 1977; Osweiler et al., 1985). However, those suffering chronic poisoning are easily fatigued and have dyspnea when they are moved. These animals display intense thirst and have a rough dry hair coat as well as dry, brick-red mucous membranes. Cattle are described as having enlarged joints. Clinical signs of phenylarsenic poisoning occur within 3 days of a high dose or after chronic exposure. Most

noticeable are the neurological signs. The animal is generally bright and alert but uncoordinated. The animal may or may not be blind, and these animals may have erythema in the skin. Some of the neurological damage may be reversible unless the nerves are damaged. Lesions are often dependent upon the dose and survival times. There may be no lesions at all in animals that die from peracute poisoning. However, even these animals have some GI irritation. With the exception of peracute deaths, most of the other animals that die from some form of arsenic poisoning may have excess fluid in the GI tract. In cattle there is hyperemia of the abomasum and this may be the only finding. If there are other lesions in cattle, it is often necrosis of the rumen mucosal epithelium. Ruminants have gelatinous serosal edema in the rumen, reticulum, omasum, and abomasum. The GI tract may have indication of irritation and be hemorrhagic. Lesions are indicative of capillary damage and the liver is usually soft and yellow. The phenylarsonics (⫹5) are used in feed additives and lesions would be expected to be associated with overdoses in the feed mixture. A “downer pig” may have severe abrasions with muscle atrophy. Microscopic lesions indicate there is demyelination in the optic nerve and the posterior cord.

TREATMENT A diagnosis of arsenic poisoning is important and is based upon clinical history and signs. If more than one animal is involved, then lesions may also be important. Diagnostic arsenic levels in the kidney and liver are usually more than 8–10 parts per million (ppm), unless several days have lapsed since exposure, in which case it would likely be 2–4 ppm. Diagnostic levels of arsenic in the urine and feces are greater between 10 and 20 ppm. Arsenic should not be found in phenylarsonic acid intoxications. Arsenic can poison to large and small animals. If small animals are not showing clinical signs then evacuation of the stomach followed by lavage with 1% of sodium bicarbonate solution is recommended treatment. As a general rule early treatment, within 4 h of exposure is best. In carnivorous small animals, emetics followed by gastric lavage is the best treatment. The lavage may be milk and egg whites or with 1–5 g of sodium thiosulfate. In herbivores treatment within 4 h of exposure is also best. A large saline purgative is effective, demulcents, 20–30 g of sodium thiosulfate orally followed by a 10% solution 3 times a day for the next several days. Regardless of the carnivore or herbivore if treatment is more than 4 h after exposure, then dimercaprol (British anti-Lewisite, BAL) is recommended at 1.5–5 mg/kg,

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REFERENCES

intramuscularly, 2–4 times a day for 10 days or until recovery should be administered. Additionally, sodium thiosulfate at 30–40 mg/kg administered intravenously 2–4 times daily until recovery, which if recovery occurs will be within 2–4 days. If the diagnosis is a phenylarsenic compound, there is no effective treatment for nerve damage caused by these compounds. BAL is not effective for these intoxications.

CONCLUSION Determining the diagnosis early and initiating treatment early will determine the prognosis. Acutely poisoned animals have a poor prognosis without early intervention. Understanding the differentials is important to institute the appropriate treatment for the appropriate condition. Arsenic produces signs of severe gastroenteritis, similar to those of pancreatitis, viral or bacterial gastroenteritis, irritating plants, caustic agents, and zinc phosphide poisoning. Likewise, other heavy metals will produce similar clinical signs. However, poisoning with phenylarsonics, used most frequently in feed additives, have a high morbidity rate but are associated with a low mortality rate. Recovery generally requires 2–4 weeks.

REFERENCES Agency for Toxic Substances and Disease Registry (ATSDR) (1990) Arsenic Toxicity, Case Studies in Environmental Medicine. US Department of Health and Human Services, Washington, DC. Chan PC, Huff J (1997) Arsenic carcinogenesis in animals and in humans: mechanistic, experimental, and epidemiological evidence. Environ Carcino Ecotox Rev 15(2): 83–122. Evinger JF, Blakemaore JC (1984) Dermititis in a dog associated with exposure to an arsenic compound. J Am Vet Med Assoc 184: 1281–2. Hann C, McHugo PB (1960) Studies on the capillary and cardiovascular actions of intravenous sodium arsenate and arsenite. Toxicol Appl Pharmacol 2: 674–82. Harrison WE, Packman EW, Abbott DD (1958) Acute oral toxicity and chemical and physical properties of arsenic trioxides. AMA Arch Ind Health 17: 118–23. Hays WJ (1982) Pesticides Studied in Man. Williams and Wilkins, Baltimore, MD. Jubb KVF, Huxtable CR (1993) The nervous system. In Pathology of Domestic Animals, 4th edn, vol. 1, Jubb KVF, Kennedy PC, Palmer N (eds). Academic Press, New York. National Academy of Science (NAS) (1977) Arsenic. National Academy of Science, Washington, DC. Osweiler GD, Carson TL, Buck WB, Van Gelder GA (1985) Clinical and Diagnostic Veterinary Toxicology. Kendall/Hunt, Dubuque, IA. Vahter M (1983) Metabolism of arsenic. In Biological and Environmental Effects of Arsenic, Fowler BA (ed.). Elsevier, New York.