SOURCES

Arsenic (As) is a nonmetal or metalloid in group V of the Periodic Table, but is referred to as arsenic metal. It is rare to find elemental arsenic free in the natural environment. Arsenic combines with many elements besides oxygen and hydrogen, including sulfur, nickel, cobalt, copper, iron, aluminum, barium, bismuth, calcium, lead, magnesium, manganese, uranium, and zinc. Arsenic is ubiquitous and in one of its many forms can be found naturally in rocks, soils, water, and living organisms in concentrations of parts per million (ppm) or parts per billion.¹ Preponderant valences for arsenic are +3 and +5. Naturally occurring arsenic is usually pentavalent, and arsenic added to the environment is trivalent.² Activities of humans concentrate and redistribute arsenic in the environment. It is impossible for animals or humans to avoid exposure to natural sources of arsenic. It is questionable that complete avoidance would be a good thing even if it were possible. Animal studies show that trace amounts of dietary arsenic are beneficial.³ Because of arsenic’s ubiquitous nature, all food sources contain some arsenic.

Arsenic is present in all natural water supplies, but the concentrations vary greatly. Water arsenic usually comes from natural sources. Naturally high arsenic concentrations occur in water from hot springs, ground water in areas of thermal activity, ground water in areas with high arsenic content in rocks, and water with a high dissolved salt content. High arsenic levels in rivers and lakes are usually caused by human sources (e.g., mining).

Commercial use of arsenic has been declining since the 1960s. Chromated copper arsenate (CCA)-treated lumber is no longer available for residential use as of January 2004. A large percentage of commercial arsenic is used in wood preservation. According to the U.S. Department of Health and Human Services, potential sources of arsenic exposure include the following⁴:

TOXIC DOSE

This poem exposes the double-edged nature of arsenic. By 2000 bc arsenic trioxide, produced as a byproduct of copper smelting, was used as a medicine and a poison.⁶ Professional poisoners used arsenic extensively in the Middle Ages. In the nineteenth century, one third of the criminal poisonings in France were blamed on arsenic.⁶

In the 1700s and 1800s Fowler’s solution, a 1% solution of arsenic trioxide, was used extensively for diseases, such as psoriasis and bronchial asthma. The mild toxic side effects of gastrointestinal discomfort and pain were ignored. If the oral dose could not be tolerated, per rectum administration was used. If the treatment caused severe signs of vomiting and diarrhea, the dose was lowered.⁶

Factors affecting the toxicity of inorganic arsenic include purity, solubility, particle size, valence, the species exposed, and physical condition of the animal exposed. Toxicity increases as the purity and solubility increase, and the particle size decreases. Trivalent arsenicals are 4 to 10 times more toxic than pentavalent arsenicals. Susceptibility to inorganic arsenic varies among species and is highest in humans and then in dogs, rats, and mice, in that order.^7,8 Weak, debilitated, and dehydrated animals are more susceptible to arsenic toxicosis than are normal healthy animals.⁹ The lethal dose, because of the aforementioned factors, varies greatly; however, the lethal oral dose of sodium arsenite in most species falls within a range of 1 to 25 mg/kg of body weight. The cat is one of the more susceptible species, with the lethal dose being less than 5 mg/kg of sodium arsenite. Sodium arsenite is a highly toxic arsenical because it is inorganic, highly water soluble, and trivalent.

TOXICOKINETICS

Solutions of inorganic arsenicals are almost completely absorbed from the gastrointestinal tract. If the arsenical is relatively insoluble, it will have limited contact with the gastrointestinal mucosa and will not be extensively absorbed. Limited gastrointestinal absorption occurs if the particle size of a powdered arsenical is too large. Lack of absorption is why insoluble arsenical compounds or arsenicals consisting of coarse particles are less toxic than are highly soluble arsenicals. Topically applied inorganic arsenicals not only cause local skin damage, but also are absorbed and can cause systemic poisoning. Respiratory absorption depends on the chemical form of the inorganic arsenical inhaled.

After absorption, arsenic is transported in the blood to all organs of the body. Clearance of arsenic from the blood of most species follows a two- or three-phase exponential curve. The first phase is the largest (>90%). Arsenic is eliminated rapidly with a half-life of 1 to 2 hours. The second and third phases have estimated half-lives of 30 and 200 hours, respectively.

From the blood, arsenic accumulates to the greatest extent in the liver, spleen, kidney, lungs, and gastrointestinal tract. Clearance from these organs is rapid. Chronic residues are found in tissues that contain keratin, such as skin, hair, and nails.⁴ Placental transfer of arsenic has been shown in hamsters, mice, and monkeys.^10,11 Two to 3 days after a one-time exposure to inorganic arsenic, the concentration of arsenic in most organs falls off rapidly.

In most species, 40% to 70% of an absorbed dose of inorganic arsenic is excreted in the urine within 48 hours.¹² Urinary excretion rates of arsenic are affected by valence, degree of methylation, dose, route of exposure, and animal species.¹² Urinary arsenic is present as inorganic arsenic, methylarsonic acid, or cacodylic acid. The proposed detoxification of inorganic arsenic goes as follows: the pentavalent form is reduced to the trivalent form, then a methyl group is added to form methylarsonic acid, and a second methyl group is added to form dimethylarsinic acid. The more efficient the methylation process is, the more efficient the urinary excretion. Sweat, hair, milk, skin desquamation, and exhalation are arsenic elimination routes of low significance relative to urinary excretion. Limited amounts of systemic arsenic are eliminated in the feces.

MECHANISM OF TOXICITY

Trivalent arsenicals are 4 to 10 times more toxic than pentavalent arsenicals. Trivalent arsenicals interact with sulfhydryl groups of compounds in biological systems. In many cases this alters the activity of vital pathways and causes toxicosis. Although most documentation involves inactivation of enzymes, coenzymes and substrates can also be affected.¹³ Long lists have been compiled of enzymes susceptible to trivalent arsenic.^13,14

Pentavalent arsenicals are reduced to more toxic trivalent forms in vivo. However, pentavalent arsenic ion (arsenate) can also cause direct toxic effects. Squibb and Fowler¹³ have summarized the literature that shows that arsenate ion is isosteric and isoelectric with the phosphate ion. Therefore arsenate can substitute for phosphate in many important metabolic reactions. The arsenate esters formed undergo instantaneous spontaneous hydrolysis that is termed arsenolysis. This process interrupts metabolic pathways by spontaneous breakdown of crucial intermediates, such as glucose-6-arsenate. Also, cell energy stores can be depleted by the production of adenosine diphosphate arsenate instead of adenosine triphosphate, which spontaneously hydrolyzes, thereby producing no energy.^13,15

Many acute toxic effects of inorganic arsenicals are attributed to effects on the vascular system.^4,16,17 This conclusion is supported by the observed congestion, edema, and hemorrhage present in the visceral organs of animals with acute poisoning. This effect appears to be due to the relaxation and increased permeability of capillaries. Recent work in dogs with thiacetarsemide, a trivalent organic arsenical, shows a direct effect on arteries and the coagulation system.^18,19 Because trivalent organoarsenicals and inorganic arsenicals are considered to have the same mechanism of action, this finding supports the previous conclusion that inorganic arsenic is a “vascular poison.” It is clear that splanchnic capillary networks are affected by arsenic.¹⁷

Even though arsenic has been associated with multiple types of cancer in humans, attempts to produce cancer in experimental animals have been inconclusive.^4,20