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General Characteristics of the Toxic Response

One could define a poison as any agent capable of producing a deleterious response in a biological system. Virtually every known chemical has the potential to produce injury or death if it is present in a sufficient amount. The LD50 is the dosage of chemicals needed to produce death in 50 percent of treated animals. However, it should be noted that measures of acute lethality such as LD50 may not accurately reflect the full spectrum of toxicity, or hazard, associated with exposure to a chemical. For example, some chemicals with low acute toxicity may have carcinogenic or teratogenic effects at doses that produce no evidence of acute toxicity.

Spectrum of Undesired Effects

The spectrum of undesired effects of chemicals is broad. In therapeutics, for example, each drug produces a number of effects, but usually only one effect is associated with the primary objective of the therapy; all the other effects are referred to as undesirable or side effects. However, some of these side effects may be desired for another therapeutic indication. Some side effects of drugs are always deleterious to the well-being of humans. These are referred to as the adverse, deleterious, or toxic effects of the drug.

Allergic Reactions
Chemical allergy is an immunologically mediated adverse reaction to a chemical resulting from previous sensitization to that chemical or to a structurally similar one. The term hypersensitivity, allergic reaction, and sensitization reaction are used to describe this situation. Once sensitization has occurred, allergic reactions may result from exposure to relatively very low doses of chemicals. However, for a given allergic individual, allergic reactions are dose-related. Sensitization reactions are sometimes very severe and may be fatal.

Most chemicals and their metabolic products are not sufficiently large to be recognized by the immune system as a foreign substance and thus must first combine with an endogenous protein to form an antigen. Such a molecule is called a hasten. The hapten-protein complex is then capable of eliciting the formation of antibodies. Subsequent exposure to the chemical results in an antigen-antibody interaction, which provokes the typical manifestations of allergy that range in severity from minor skin disturbance to fatal anaphylactic shock.

Idiosyncratic Reactions
Chemical idiosyncrasy refers to a genetically determined abnormal reactivity to a chemical. The response observed is usually qualitatively similar to that observed in all individuals but may take the form of extreme sensitivity to low doses or extreme insensitivity to high doses of the chemical. For example, individuals abnormally sensitive to nitrites readily oxidize the iron in hemoglobin to produce methemoglobin, which is incapable of transporting oxygen to tissues. Consequently, they may suffer from tissue hypoxia after exposure to doses of methemoglobin-producing chemicals that would be harmless to normal individuals.

Immediate versus Delayed Toxicity
Immediate toxic effects occur or develop rapidly after a single administration of a substance, whereas delayed toxic effects occur after the lapse of some time. Most substances produce immediate toxic effects. However, carcinogenic effects of chemicals usually have long latency periods, often 20 to 30 years after the initial exposure, before tumors are observed in humans.

Reversible versus Irreversible Toxic Effects
Some toxic effects of chemicals are reversible, and others are irreversible. If a chemical produces pathological injury to a tissue, the ability of that tissue to regenerate largely determines whether the effect is reversible or irreversible. For liver tissue, with its high regeneration ability, most injuries are reversible, whereas injury to the CNS is largely irreversible because its differentiated cells cannot be replaced. Carcinogenic and teratogenic effects of chemicals, once they occur, are usually considered irreversible toxic effects.

Local versus Systemic Toxicity
Another distinction between types of effects is made on the basis of the general site of action. Local effects occur at the site of first contact between the biological system and the toxicant. In contrast, systemic effects require absorption and distribution of a toxicant from its entry point to a distant site, at which deleterious effects are produced. Most substances, except for highly reactive materials, produce systemic effects. For some materials, both effects can be demonstrated.

Most chemicals that produce systemic toxicity usually elicit their major toxicity in only one or two organs, which are referred to as the target organs of toxicity of a particular chemical. The target organ of toxicity is often not the site of the highest concentration of the chemical.

Target organs in order of frequency of involvement in systemic toxicity are the CNS; the circulatory system; the blood and hematopoietic system; visceral organs such as the liver, kidney, and lung; and the skin. Muscle and bone are seldom target tissues for systemic effects.

Interaction of Chemicals

Chemical interactions can occur via various mechanisms, such as alterations in absorption, protein binding, and the biotransformation and excretion of one or both of the interacting toxicants. In addition to these modes of interaction, the response of the organism to combinations of toxicants may be increased or decreased because of toxicologic responses at the site of action.

An additive effect, most commonly observed when two chemicals are given together, occurs when the combined effect of two chemicals is equal to the sum of the effects of each agent given alone.

A synergistic effect occurs when the combined effects of two chemicals are much greater than the sum of the effects of each agent given alone.
Potentiation occurs when one substance does not have a toxic effect on a certain organ or system but when added to another chemical makes that chemical much more toxic. Isopropanol, for example, is not hepatotoxic, but when it is administered in addition to carbon tetrachloride, the hepatotoxicity of carbon tetrachloride is much greater than that when it is given alone.
Antagonism occurs when two chemicals administered together interfere with each other's actions or one interferes with the action of the other. There are four major types of antagonism: functional, chemical, dispositional, and receptor. Functional antagonism occurs when two chemicals counterbalance each other by producing opposite effects on the same physiologic function. Chemical antagonism or inactivation is simply a chemical reaction between two compounds that produces a less toxic product. Dispositional antagonism occurs when the absorption, biotransformation, distribution, or excretion of a chemical is altered so that the concentration and/or duration of the chemical at the target organ are diminished. Receptor antagonism occurs when two chemicals that bind to the same receptor produce less of an effect when given another together than the addition of their separate effects or when one chemical antagonizes the effect of the second chemical. Receptors antagonists are often termed blockers.

Characteristics of Exposure

Toxic effects in a biological system are not produced by a chemical agent unless that agent or its metabolic breakdown products 1)reach appropriate sites in the body 2)at a concentration and for 3)a length of time sufficient to produce a toxic manifestation.

Whether a toxic response occurs is dependent on the chemical and physical properties of the agent, the exposure situation, how the agent is metabolized by the system, and the overall susceptibility of the biological system or subject.

Route and Site of Exposure
The major routes (pathways) by which toxic agents gain access to the body are the gastrointestinal tract (ingestion), lung (inhalation), skin (topical, percutaneous, or dermal), and other parenteral routes. Toxic agents generally produce the greatest effect and the most rapid response when given directly into the bloodstream (the intravenous route). An approximate descending order of effectiveness for the other routes would be inhalation, intraperitoneal, subcutaneous, intramuscular, intradermal, oral, and dermal.

The "vehicle" (the material in which the chemical is dissolved) and other formulation factors can markedly alter absorption. In addition, the route of administration can influence the toxicity of agents. For example, an agent that acts on the CNS, but is efficiently detoxified in the liver, would be expected to be less toxic when given orally than when inhaled, because the oral route requires that nearly all of the dose pass through the liver before reaching the systemic circulation and then the CNS.

Duration and Frequency of Exposure
Toxicologists usually divide the exposure of experimental animals to chemicals into four categories: acute, subacute, sub chronic, and chronic.
Acute exposure is defined as exposure to a chemical for less than 24 h. While acute exposure usually refers to a single administration, repeated exposures may be given within a 24-h period for some slightly toxic or practically nontoxic chemicals. Acute exposure by inhalation refers to continuous exposure for less than 24 h, most frequently for 4 h.

Repeated exposure is divided into three categories: subacute, synchronic, and chronic. Subacute exposure refers to repeated exposure to a chemical for 1 month or less, subchronic for 1 to 3 months, and chronic for more than 3 months.

In human exposure situations, the frequency and duration of exposure are usually not as clearly defined as in controlled animal studies, but many of the same terms are used to describe general exposure situations. Thus, workplace or environmental exposures may be described as acute, sub chronic, or chronic.

For many agents, the toxic effects that follow a single exposure are quite different from those produced by repeated exposure. Acute exposure to agents that are rapidly absorbed is likely to produce immediate toxic effects but also can produce delayed toxicity that may or may not be similar to the toxic effects of chronic exposure. Conversely, chronic exposure to a toxic agent may produce some immediate (acute) effects after each administration in addition to the long-term, low-level, or chronic effects of the toxic substance.
The other time-related factor that is important in the temporal characterization of repeated exposures is the frequency of exposure. The relationship between elimination rate and frequency of exposure is shown in Figure 2-1. A chemical that produces severe effects with a single dose may have no effect if the same total dose is given in several intervals. For the chemical depicted by line B in Figure 2-1, in which the half-life for elimination is approximately equal to the dosing frequency, a theoretical toxic concentration of 2 U is not reached until the fourth dose, whereas that concentration is reached with only two doses for chemical A, which has an elimination rate much slower than the dosing interval. Conversely, for chemical C, where the elimination rate is much shorter than the dosing interval, a toxic concentration at the site of toxic effect will never be reached regardless of how many doses are administered. Of course, it is possible that residual cell or tissue damage occurs with each dose even though the chemical itself is not accumulating. The important consideration, then, is whether the interval between doses is sufficient to allow for complete repair of tissue damage.

Chronic toxic effects may occur, therefore, if the chemical accumulates in the biological system, if it produces irreversible toxic effects, or if there is insufficient time for the system to recover from the toxic damage within the exposure frequency interval.