# Case Study: Elemental Toxicity in Animals

A poison is any substance that when absorbed into the body of an organism will cause adverse or deleterious effects. Many elements and their resulting compounds are known toxins to animals, some of the most common and dangerous of which being As, Cu, Pb, Hg, and Se. The toxicity of a substance can be affected by various chemical properties, such as structure and solubility. Some poisons can be neutralized through administration of chelating agents.

### What Makes Something a Poison?

A poison is a substance that upon absorption into the body of an organism causes detrimental effects to the cells of that organism. While the exact mechanism of toxicity for most poisons is vastly unclear, it is believed that many poisons exert their negative effects by distressing the enzyme systems of the animal. Many toxins bind to specific enzymes and proteins necessary for cellular function and thus compete with other substances essential for the maintenance and continued function of cells. In this way, poisons can also have the effect of inducing mineral deficiencies. Additionally, many toxic substances appear to assist in the formation of the paramagnetic anion, superoxide (O2-), which is toxic itself and seems widely responsible for spontaneous cell death.

#### "The Dose Makes the Poison"

It is important to understand that quantity plays a critical role in the exhibited toxicity of a substance. Many elements that frequently cause lethal toxicity in animal populations also serve as essential elements in the regulation of vital biological processes within these organisms. For example, the element Selenium is considered an essential nutrient in the diet of most species of livestock. However, Selenium is also included as one of the elements most commonly responsible for poisoning in animals. Often times, the distinction between an element’s necessity as a micro-nutrient (a nutrient required only in trace amounts) and its threat as a destructive toxin varies by a relatively small amount.

### Chemical Properties Affecting Toxicity

#### Solubility

In general, the more soluble a substance is, the more toxic that substance will be. In order to be absorbed into the blood and lymph system of an animal, a substance must be either water or fat soluble. In this respect, the physical state of an element also determines the absorbability and, consequently, the toxicity of that substance. Elements in aqueous solution have a much faster and more efficient rate of absorption than those in solid form.

#### Structure/Form

Many toxins operate within an organism by “mimicking” other elements and taking their place in biological compounds. For this reason, the structure of the poison plays a major role in the acceptance of the feigning substance, as it must be very similar in structure to the element it will act as. Additionally, the distinct form of a substance can contribute to its toxicity within an animal. For example, of the three allotropes of the element Phosphorus, only white Phosphorus is toxic.

#### Oxidation State

The ability of the cations of transition metal elements to bind to protein, and thus exhibit a toxic effect within the animal, often increases with higher valences. In the case of the heavy metals, such as Pb, toxic effects are only seen when the element is present as an ion. In many instances, poisons absorbed into the body of an animal will undergo redox reactions that work to decrease the poison's level of toxicity. However, the characteristic of some elements to initiate redox reactions within the organism serves as the mechanism of toxicity for many substances.  For example, once in the body pentavalent arsenic (As5+) in the form of the arsenate ion can be reduced to trivalent arsenic (As3+) through a reaction with the peptide glutathione (GSH).  Unfortunately, the resulting arsenite is much more toxic than the original arsenate.

$$AsO_4^{3-} + 2GSH \longrightarrow AsO_3^{3-} + GSSG + H_2O$$

### Chemical Treatment

Treatment of a toxin usually consists of attempting to neutralize the substance and hence stop or slow its harmful effects. This often involves changing or compromising the structure of a poison.

#### Precipitation

Taking into account solubility’s effect on the toxicity of a substance, making it insoluble will reduce or eradicate the potential for poisoning. When toxins are believed to still be in the stomach of the animal, varying compounds can be given in an attempt to precipitate the poison before it can be absorbed into the body. Substances like magnesium sulfate and Tannic acid can be used to precipitate toxins such as lead and mercury to decrease absorption and facilitate elimination from the animal.  In the case of lead poisoning, an iodine compound can be administered, with the belief that dissociated iodide ions (I-) will form insoluble lead(II) iodide, and therefore impair toxic effects by decreasing the amount of toxin that is absorbed. The reaction (shown below) has a solubility product constant (Ksp) of 7.1 x 10-9, reflecting its low solubility.

$Pb^{2+} \; (aq) + 2I^- \; (aq) \longrightarrow PbI_2 \; (s)$

#### Chelation

The most notable method of chemical therapy is that of using a chelating agent to bind to the threatening substance, thereby interfering with its structure and rendering it harmless. As metals are commonly the cause of poisonings, polydentate ligands like the familiar EDTA can attach to toxic metal ions and form a nontoxic, stable ring compound that is then easily expelled from the body of the animal. Chelation using the hexadentate ligand EDTA is popular in dealing with lead poisoning.  Afflicted patients are fed the complex CaEDTA, and because EDTA has a higher affinity for the Pb2+ ion than it does for Ca2+, an exchange occurs following the reaction below.  The formation constant (Kf) for [Pb(EDTA)]2- is 2 x 1018, meaning that the reaction proceeds very strongly in the forward direction.

$$Pb^{2+} + [Ca(EDTA)]^{2-}\longrightarrow [Pb(EDTA)]^{2-} + Ca^{2+}$$

EDTA has a high affinity for lead, and thus is common as a treatment for lead poisoning.

### Toxic Elements

Many elements can be poisonous when ingested, inhaled, or allowed extended contact with the skin. However, the increased frequency of poisonings associated with the following elements elevates their potential in posing a particularly high risk to animal health when compared to others of the periodic table.

#### Arsenic

Arsenic (As) is well known as a poison. Once a common ingredient in rat and roach bait, arsenic poisoning was mainly a concern for dogs and cats that consumed the toxic bait or afflicted rodents, and cattle whose curiosity likewise led to their ingestion of the hazardous material.  Arsenic poisoning in animals is characterized by trembling, abdominal pain, seizures, difficulty with coordinated motion, and paralysis of the hind limbs. When absorbed, arsenic inactivates up to 200 enzymes and binds to essential proteins, wreaking havoc on proper cell function. Arsenite, formed through the reduction of an arsenic compound (described above), binds to the tripeptide antioxidant, glutathione, following the reaction below.  Glutathione protects cells from oxidative destruction due to attack by harmful free radicals, and its inhibition facilitates cell death and further DNA and protein damage.

$$AsO_3^{3-} + 3GSH \longrightarrow As(SG)_3 + 3OH^-$$

As the 20th most abundant element in the Earth's crust, arsenic can easily contaminate water supplies, and arsenic concentrated water is a serious threat in countries such as Bangladesh. However, the more common source of poisoning in animals is due to careless use of pesticides, rodenticides, herbicides, and even arsenical dips used directly on the animal to control parasites.

Cadmium (Cd) works by disrupting the normal state of a cell. Its similar structure to zinc and calcium allows it to interfere with the absorption of these elements, and it similarly inhibits copper and iron. Like most heavy metals, when absorbed into the body cadmium is stored in the liver and kidney of the animal. Cadmium is an accumulative poison, meaning that it builds up slowly over time in the bodies of exposed animals. Cadmium poisoning affects nearly all major organ systems and has noted reproductive effects, including decreased testes size and infertility. Additionally, because of this element's interference with the absorption of the mineral calcium, cadmium poisoning can also severely impact the healthy function of the bones. Though cadmium is extremely rare in the Earth's crust, pollution from industry processes has allowed this toxic metal access into soils and water supplies.

#### Copper

Copper (Cu) is an essential nutrient that is required in small amounts in the diets of animals for proper function. However, due to its widespread use in pesticides, herbicides, and in “foot-baths” to prevent and treat debilitating foot rot in hoofed animals, as well as its relative abundance in the Earth’s crust, copper remains a prominent poisonous substance to animals. Copper’s importance in the animal diet has also led to overdoses and poisoning due to incorrect and excessive use of supplemental copper in feed. Sheep are particularly sensitive to copper toxicity due to their inability to excrete the element from their liver. Copper exerts toxicity by binding to proteins and nucleic acids within cells, disrupting normal cellular function.  Copper's ability to shift between the +1 and +2 oxidation states within cells also allows it to participate in the Fenton reaction (below) to produce harmful free radicals, like the highly destructive hydroxyl radical. Symptoms include vomiting, salivation, greenish-blue feces (due to excreted copper), dark brown urine, severe abdominal pain, convulsions, jaundice, paralysis, and collapse.

$$Cu^+ + H_2O_2 \longrightarrow Cu^{2+} + \cdot{OH} + \colon{OH^-}$$

#### Fluorine

Fluorine (F) is the most electronegative and reactive element in the Periodic Table. As a result, fluorine is capable of forming complexes with many of the metals found in enzymes and in this way is able to exert its toxicity through enzymatic impairment. Fluorine also reacts with the calcium ion to form calcium fluoride, causing hypocalcemia by binding the calcium in the animal and thereby decreasing the amount available for other processes.

$$Ca^{2+}_{(aq)} + 2F^-_{(aq)} \longrightarrow CaF_{2 \; (s)}$$

Fluorine is a common addition to public water pathways because of its apparent benefit to dental health, though the effect of the element in both the human and animal diet is debated. The most common sources of fluorine toxicity are from grazing areas subjected to contamination from industrial plants, water high in fluoride, and improper use of feed supplements containing fluoride. As the 13th most abundant element in the Earth’s crust, excessive amounts of fluorine are also found naturally in soil. “Fluorosis,” or fluorine poisoning, is most prevalent in cattle, sheep, goats, and horses, and typical symptoms include salivation, a watery discharge from the eyes, vomiting, convulsions, hoof deformities, lameness, skeletal abnormalities, and lesions on the bones and teeth.  Fluorine is also used as an ingredient in rodenticides.

Lead (Pb) is one of the most frequent and dangerous sources of toxicity to animals. By mimicking the essential mineral calcium, lead is able to impair neurological function by interfering with the release of neurotransmitters within the brain. Lead also interferes with the biological processes of multiple enzymes, such as its inhibition of the production of heme, an important component of hemoglobin, by binding to the sulfhydryl group of proteins.

$$(protein-SH) + Pb^{2+} + (HS-protein) \longrightarrow (proteinS-Pb-Sprotein) + 2H^+$$

Common sources of lead toxicity include contaminated soils as a result of pollution from nearby industrial plants, corruption of water supplies due to the use of lead pipes, and licking or ingesting of lead paint, lead shot, wet-cell batteries, leaded gasoline, or lead sinkers. Once ingested, lead is stored in the bones, liver, and kidney of the animal.  Most often observed in cattle and horses, animals exhibiting effects of lead poisoning suffer muscular spasms, apparent blindness, hysteria, foaming at the mouth, abdominal pain, paralysis, abortion, convulsions, and can be seen wandering and circling erratically.

#### Mercury

Mercury (Hg) is a well known environmental toxin. Its presence in the oceans, and therefore in ocean fish, has had a disturbing effect on the public due to fear of biomagnification, or the progressive transfer of toxins up the food chain. The predominant natural source of mercury is volcanic activity, though sources of poisoning in animals more commonly arise from contamination of grazing areas as a result of careless use of pesticides and fungicides. Mercury inhibits over 50 enzymes in the body and has a severe corrosive effect on the internal digestive system of the animal, causing abdominal pain, diarrhea, bloody feces, tremors, blindness, deafness, convulsions, abnormal movement, and paralysis.

Figure showing threat of biomagnification of Mercury up the food chain. Figure used with permission from Wikipedia.

#### Selenium

Selenium (Se) is found in the same periodic group as sulfur and, having similar structure and properties, takes sulfur’s place in amino acid bonds. Selenium is an essential element, and insufficient amounts of selenium appear to have just as detrimental an effect on the health of the animal as when an excessive dose causes toxicity within the organism. In fact, the necessity of selenium in the diet can be observed close to home at the U.C. Davis Goat Barn, where all goats are administered selenium routinely to prevent deficiency and its consequences. Nevertheless, the danger of selenium poisoning has been understood for centuries, and was first described by the famous explorer, Marco Polo, who realized that the hooves of his livestock disintegrated upon the consumption of certain plants. Selenium toxicity typically originates from ingestion of plants containing elevated amounts of the element, and symptoms include circling, lameness, bloating, gastrointestinal distress, respiratory failure, a staggering gait, loss of mane and tail, poor coat, salivation, paralysis, impairment of vision, emaciation, and abnormal hoof growth.

### References

1. James, L., K. Panter, et al. (1989). "Selenium poisoning in livestock: a review and progress." SSSAJ Special Publication" Selenium in Agriculture and the Environment" 23: 123-131.
2. Ratnaike, R. (2003). "Acute and chronic arsenic toxicity." Postgraduate medical journal 79(933): 391.
3. Selby, L., A. Case, et al. (1977). "Epidemiology and toxicology of arsenic poisoning in domestic animals." Environmental Health Perspectives 19: 183.
4. Radeleff, R. (1970). Veterinary toxicology, Lea & Febiger.
5. Bartík, M. and A. Piskac Veterinary toxicology, Elsevier Scientific Pub. Co. Oxford. 1981.
6. Garner, R. J.(1961)-Veterinary Toxicology, 2nd ed.
7. National Research Council of the National Academies, . Mineral Tolerance of Animals. 2nd ed. 2005. 496. Print.

### Problems

1.       What are three chemical properties that affect the toxicity of a substance? (Highlight the green area)
Solubility, Structure/Form, Oxidation State
2.       True or False: Elements required in the diet of animals cannot be poisons.
False
3.       What three common poisons are also essential elements within the diet?
Copper, selenium, fluorine
4.       Poisonings from this element frequently occur due to animal exposure to paint, batteries, and sinkers containing the substance.