Chapter 1 General Toxicological Principles

Toxicology is the study of poisons and their effects on living organisms. In veterinary medicine, this has come to mean an understanding of sources of poisons, circumstances of exposure, diagnosis of the type of poisoning, treatment, and application of management or educational strategies to prevent poisoning.^1–3 More so than many of the specialties in veterinary medicine, toxicology is based on the important principle of dose and response. That is, there is a graded and possibly predictable response based on increasing exposure to the toxicant. In the words of Philipus Aureolus Theophrastus Bombastus von Hohenheim-Paracelsus, a physician-alchemist of the sixteenth century, “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.”² Although alchemy has long since been abandoned, Paracelsus’ principle of what makes a poison is still true and relevant in the daily practice of nutrition, therapeutics, and toxicology. Today, with emphasis on synthetic drugs, natural or alternative therapies, and the rapidly growing field of nutraceuticals, there is increasing need to be aware of the dosage and response principle for both beneficial and detrimental effects in the daily practice of veterinary medicine. Many of the toxicants discussed in this book will provide examples of the point at which the dosage determines whether the agent is a nutrient, a remedy, or a poison.

Determinants of exposure that affect dosage may be more than simply the gross amount of material ingested or applied to the skin. Rather, the effective dosage at a susceptible receptor site determines the ultimate response. Thus species differences in metabolism, vehicle differences that promote skin penetration, specific drug or chemical interactions that potentiate response, and organ dysfunction that limits elimination can all influence the ultimate dosage.^2–4 Clinicians must consider all of these possibilities when working to diagnose a potential toxicosis or apply therapeutic agents to their patients.

Toxicology involves the knowledge of poisons, including their chemical properties, identification, and biologic effects, and the treatment of disease conditions caused by poisons. Toxicology shares many principles with pharmacology, including the dynamics of absorption, distribution, storage, metabolism, and elimination; mechanisms of action; principles of treatment; and dose-response relationships. Although some of these important principles will be mentioned, a full discussion of such factors is beyond the scope of this chapter.

Toxicology literature is best understood if some basic terminology is remembered. A poison or toxicant is usually considered any solid, liquid, or gas that when introduced into or applied to the body can interfere with homeostasis of the organism or life processes of its cells by its own inherent qualities, without acting mechanically and irrespective of temperature. The term toxin is used to describe poisons that originate from biological sources and are generally classified as biotoxins. Biotoxins are further classified according to origin as zootoxins (animal origin), bacterial toxins (which include endotoxins and exotoxins), phytotoxins (plant origin), and mycotoxins (fungal origin).^2–4

Poisons may be categorized as organic, inorganic, metallic, or biological. A further distinction is made by some between synthetic and natural agents. Synthetic agents may have been designed specifically as toxicants that may have a very broad or very narrow range of toxicity and/or may produce effects in very specific targets. Natural products used in nutrition, medicine, or commerce are sometimes believed to be less hazardous than synthetic products. However, natural products are not inherently more or less toxic than synthetic molecules. Indeed, some of the most toxic agents known (e.g., botulinum toxin, tetrodotoxin) are of natural origin. Knowledge of the chemical nature and specific effects of toxicants is the only certain way to assess hazard from exposure.

The terms toxic, toxicity, and toxicosis are often misunderstood or misused.^3,4 The word toxic is used to describe the effects of a toxicant (e.g., the “toxic” effects of organophosphate insecticides may be described as cholinesterase inhibition; vomiting, salivation, dyspnea, and diarrhea). However, toxicity is used to describe the quantitative amount or dosage of a poison that will produce a defined effect. For example, the acute lethal dosage to cats of ethylene glycol would be described as 2 to 5 mL/kg body weight. The toxic effects of ethylene glycol are acidosis and oxalate nephrosis. Finally the state of being poisoned by a toxicant, such as ethylene glycol, is toxicosis.

Mammalian and other vertebrate toxicities are usually expressed as the amount of toxicant per unit of body weight required to produce toxicosis. Dosage is the correct terminology for toxicity expressed as amount of toxicant per unit of body weight.^2–4 The commonly accepted dosage units for veterinary medicine are milligrams per kilogram (mg/kg) body weight. However, toxicity can also be expressed as moles or micromoles of agent per kilogram body weight. In some experimental studies, comparisons of large and small animals relate dosage to the body surface area, which is approximately equal to body weight.^2–4 The use of body surface area dosages is advocated by some as a more accurate way to account for very different body sizes in veterinary medicine. For clinical toxicology, the examples in Table 1-1 generally show that as animals increase in weight, the body surface area increases proportionally less, and this may affect the rate of metabolism, excretion, and receptor interaction with toxicants.³

Table 1-1 Comparison of Body Weight to Surface Area for Animals of Representative Sizes

For many toxicants, larger animals can be poisoned by relatively lower body weight dosages than can smaller mammals.⁴ However, other factors, such as species differences in metabolism or excretion or specific differences in receptor sites can alter this generalization. Dose is a term for the total amount of a drug or toxicant given to an individual organism. In veterinary medicine, the extreme ranges of body weight and surface area, even within some species, generally make the “dose” approach of little practical value.

A commonly used means to compare the toxicity of compounds with one another is the median lethal dosage, also known as the acute oral LD₅₀ in a standard animal, such as the laboratory rat. The LD₅₀ value is usually based on the effects of a single oral exposure with observation for several days after the chemical is administered to determine an end point for total deaths. The LD₅₀ is a standardized toxicity test that depends on a quantal (i.e., all-or-none) response to a range of regularly increasing dosages. In some cases a multiple-dosage LD₅₀ is used to show the acute effects (typically up to 7 days) produced by multiple dosages in the same animals. Increasing dosage levels are usually spaced at logarithmic or geometric intervals. When cumulative deaths are plotted on linear graph paper, the dose-response curve is sigmoid, and the most predictable value is usually around either side of the LD₅₀ (Figure 1-1).

Figure 1-1 Dose-response curve for a typical LD₅₀ study.

The end point of an LD₅₀ study is death, and the published LD₅₀ value says nothing about the severity of clinical signs observed in the surviving animals or the nature of the clinical effects.^2–4 Twenty or more animals may be used to arrive at a good estimate of the LD₅₀, which limits the use of LD₅₀ values in most animals of economic significance. In some species, such as birds and fish, the oral toxicity is often expressed on the basis of the concentration of the substance in the feed or water. The acute oral toxicity for birds is often expressed as the LC₅₀, meaning the milligrams of compound per kilogram of feed. For fish, the LC₅₀ refers to the concentration of toxicant in the water.

Other terms are used in the literature to define toxicity of compounds. The highest nontoxic dose (HNTD) is the largest dose that does not result in hematological, chemical, clinical, or pathological drug-induced alterations. The toxic dose low (TDL) is the lowest dose to produce drug-induced alterations; twice this dose will not be lethal. The toxic dose high (TDH) is the dose that will produce drug-induced alterations; administering twice this dose will cause death. The lethal dose (LD) is the lowest dose that causes toxicant-induced deaths in any animal during the period of observation. Various percentages can be attached to the LD value to indicate doses required to kill 1% (LD₁), 50% (LD₅₀), or 100% (LD₁₀₀) of the test animals. Another acronym occasionally used is MTD. It has been used to note the “maximum tolerated dose” in some situations or “minimal toxic dose.” Thus one should read such abbreviations carefully and look for the specific term defined.

Acute toxicity is a term usually reserved to mean the effects of a single dose or multiple doses measured during a 24-hour period. If toxic effects become apparent over a period of several days or weeks, the terms subacute or chronic toxicity may be used. Subacute may refer to any effects seen between 1 week and 1 month, whereas chronic often refers to effects produced by prolonged exposure of 3 months or longer. These definitions obviously leave a large gap between 30 days and 90 days. The term subchronic is sometimes used to define this time period, although others avoid the problem in semantics by stating the time period involved. For example, a study could refer to a 14-day toxicity trial with the toxic dosage being 5 mg/kg.

Duration of exposure can greatly affect the toxicity. The single-dose LD₅₀ of warfarin in dogs is approximately 50 mg/kg, whereas 5 mg/kg for 5 to 15 days may be lethal. In rats the single-dose LD₅₀ of warfarin is 1.6 mg/kg, whereas the 90-day LD₅₀ is only 0.077 mg/kg. On the other hand, rapidly inactivated or excreted compounds may have almost the same 90-day LD₅₀ as the single dose LD₅₀. For example, the single-dose LD₅₀ for caffeine in rats is 192 mg/kg and the 90-day LD₅₀ is slightly lower at 150 mg/kg. Conversely, animals may develop tolerance for a compound such that repeated exposure serves to increase the size of the dose required to produce lethality. The single-dose LD₅₀ of potassium cyanide in rats is 10 mg/kg, whereas rats given potassium cyanide for 90 days are able to tolerate a dosage of 250 mg/kg without mortality. The ratio of the acute to chronic LD₅₀ dosage is called the chronicity factor.³ Compounds that have strong cumulative effects have larger chronicity factors. In the foregoing examples the chronicity factors are as follows: warfarin, 20; caffeine, 1.3; and potassium cyanide, 0.04.

From a public health and diagnostic toxicology perspective, it is essential to know the exposure level that will not cause any adverse health effect. This level is usually referred to as the no observed adverse effect level (NOAEL).² It can also be thought of as the maximum nontoxic level. This is the amount that can be ingested without any deaths, illness, or pathophysiological alterations occurring in animals fed the toxicant for the stated period of time. Usually a NOAEL in laboratory animals is based on chronic exposures ranging from 90 days to 2 or more years, depending on the species. The no-effect level is the largest dosage that does not result in detrimental effects.

The concept of risk or hazard is important to clinical toxicology. Although toxicity defines the amount of a toxicant that produces specific effects at a known dosage, hazard or risk is the probability of poisoning under the conditions of expected exposure or usage. Compounds of high toxicity may still present low hazard or risk if animals are never exposed to the toxicant. For example, ethylene glycol antifreeze would be defined as low toxicity (2 to 5 mL/kg body weight), but because it is often readily available in homes, is voluntarily consumed by cats, and is difficult to reverse once clinical signs have developed, it is seen as a high-risk or high-hazard toxicant. Another way to define risk is to compare the ratio of the lowest toxic or lethal dosage (e.g., the LD₁) with the highest effective dosage, which could be defined as the ED₉₉. The ratio of LD₁/ED₉₉ is defined as the standard safety margin, and it is useful for comparing the relative risk of therapeutic drugs, insecticides, anthelmintics, and other agents applied to animals for their beneficial effects.^2,4

If all animals in an LD₅₀ study were the same, then the LD₅₀ would actually be a standard toxic dosage for all animals. However, at the same LD₅₀ dosage, not exactly 50% of animals will die each time. This biological variation can be due to many factors and is the reason that veterinary clinicians must exercise judgment about the response of animals to a given toxicant.

Even more variability is expected because of the differences in species, age, body size, route of exposure, inherent differences in metabolism, and pregnancy and lactation effects. Remember also that the slope of the LD₅₀ curve is important and is not revealed from the LD₅₀ value alone. An LD₅₀ with a very steep dose-response slope indicates a toxicant or drug has a very narrow margin between no effects and maximal lethal effects.^3,4 Although such compounds may be dangerous to use as therapeutics, they could be very effective pesticides because of lower probability of survival of target animals.

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