Toxicology is the study of the adverse effects of substances on living organisms. It is a multidisciplinary field of study dealing with the detection, occurrence, properties, effects, and regulations of toxic compounds. It therefore involves an understanding of chemical reactions as well as biological mechanisms of toxic actions.
A toxicological study usually consists of four elements:
(2) a chemical agent capable of causing a deleterious response; (2) a biological system with which the chemical agent may interact to produce the deleterious response;
(3) a means by which the chemical agent and the biological system are permitted to interact; and (4) a response that can be used to quantitate the deleterious effect on the biological system.
Two aspects of interaction between substances and living organisms are of importance: the influence of the substances on the living organism and the influences of the organism on the substances. The chemical agent capable of causing a deleterious effect in the organism is defined as a poison or toxicant. A toxicant will exert toxicity, which is defined as the capacity to produce toxic injury to cells or tissues, only at appropriate conditions when the biological system is exposed to a certain dose of the toxicant. In effect, Paraceisus (1493-1541) noted, "All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy." Thus, as a rule, a substance is a toxicant only in toxic doses; virtually any substance, even pure water or sugar, is poisonous when taken in great excess. The capability to detect subtoxic levels of toxicants in biological system, such as in the plasma or urine, is of particular importance because, once known, further exposure can be avoided. In toxicology, exposure is the total amount of toxicants received by the biological system of interest. It can be expressed as the product of concentration and duration. A chemical agent does not produce toxic effects in a biological system unless that agent or its biotransformation products reach appropriate sites in the body at a concentration and for a length of time sufficient to produce the toxic manifestation.
The route or site of exposure affects the toxicity of a chemical agent to the biological system. In food toxicology, the route of exposure is through the gastrointestinal tract (ingestion). The duration of animal exposure to toxicants is usually divided into four categories: acute, subacute, subchronic, and chronic. Acute exposure is defined as exposure to a toxic chemical for less than 24 hours. Although acute exposure usually refers to a single administration, repeated exposures may be given within a 24-hour period for some slightly toxic or practically nontoxic chemicals. Subacute exposure refers to repeated exposure to a toxic chemical for 1 month or less; subchronic exposure, to repeated exposure for 1 to 3 months; and chronic exposure, to repeated exposure for more than 3 months.
The LD50 of a compound is commonly reported as a measure of the toxicity of that compound. The LD50 can be defined as the dose of a compound that causes 50% mortality in a population. However, limitations of the LD50 as a measure of toxicity are often not recognized. The LD60 is an indicator of acute toxicity, using death as the end point, and therefore is not indicative of the effect of the compound under low dose or long-term exposure, which is usually the case for food toxicants. Chronic toxicity studies are needed to establish the effects of long-term or repeated administration of a compound. Chronic toxicity studies are used to determine the no observed effect level (NOEL) or no observed adverse effect level (NOAEL). From these studies, the reference dose (RfD) can be established. The RfD is defined as the maximum dose (mg/kg body weight) of an agent that is assumed to be without an adverse noncancer health impact on the human population (1).
The biological systems used for toxicity testing can be whole animals, including humans, dogs, and rodents, or they can be tissues or organs in culture, cell cultures, cellfree systems, eukaryotes (such as yeast and Aspergillus) and prokaryotes (such as Salmonella typhimurium and Escherichia coli), and plants. The age, sex, strain, and nutritional and disease status of the animal species all affect the outcome of the toxic effect. The use of enzyme inducers or inhibitors to modulate drug metabolism enzyme systems also affects animal susceptibility and toxicity to environmental chemicals. Whole animals are used to determine LD50 and organ target toxicity. They are also used to assess whether a compound is carcinogenic (ie, capable of inducing cancers) or teratogenic (ie, capable of inducing defects in the developing embryo). Insects are used in conjunction with pesticide development and for the detection of environmental mutagens (ie, causing a change in the DNA). Eukaryotes and prokaryotes are now widely used for the determination of mutagenic and carcinogenic potencies of environmental toxicants, drug impurities, and compounds present in foods. Currently, there is a trend in toxicology to use cell cultures as an alternative model sys tem to animals. In this case, the TC50 (the toxic concentration that will induce poisonous effects to 50% of the cell population) is used to indicate the potential toxicity of the test compound. Cell-free systems are used to study the biochemical mechanism of toxicity.
Thus, the occurrence of a toxic response is dependent on the chemical and physical properties of the agent, the duration of exposure, and the susceptibility of the biological system or subject.
The single-most important factor that determines the potential harmfulness of a toxicant is the relationship between the concentration of the toxic agent and the effect produced in the biological system. This is referred to as the dose-response relationship. Toxic responses will not occur unless the chemical interacts with the target site(s). The degree of the response is related to the concentration of the agent at the reactive site, which in turn is related to the dose administered. In addition, the toxic response should be quantifiable.
A graphic expression of the typical dose-response relationship is shown in Figure 1. A sigmoidal response curve is obtained when the dosage is plotted on a logarithmic scale. The response may be applied to an individual, a system, or a fraction of a population; it ranges from 0 to 100%. The lowest dose of any toxicant that evokes a stated all-or-none response is called the threshold dose. Below this dose, there is no response. It is through the use of this dose-response relationship that the toxicologist is able to obtain the LD50 of a toxicant if mortality is used as an end point. See Reference 2 for a discussion of dose-response and LD50.
After administration to a test animal, toxicants usually undergo a series of complex processes, including absorption, distribution, metabolism, and excretion, before they exert their toxic effects (Fig. 2). An overview of these processes can be found in References 3 and 4. During the ex-
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