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5 10 20 50 100 400 800 2000 Dose (mg/kg)

Figure 1. A typical sigmoid form of the dose-response relationship. Dosage is most often expressed as mg/kg and plotted on a log scale.

5 10 20 50 100 400 800 2000 Dose (mg/kg)

Figure 1. A typical sigmoid form of the dose-response relationship. Dosage is most often expressed as mg/kg and plotted on a log scale.

Toxicant Toxicant

Toxicant Toxicant

Figure 2. The three phases of toxicant action: the exposure phase, the toxico-kinetic phase, and the toxodynamic phase.

Exposure Toxicokinetic Toxodynamic phase phase phase

Figure 2. The three phases of toxicant action: the exposure phase, the toxico-kinetic phase, and the toxodynamic phase.

posure phase, the toxicant may undergo chemical alteration to compounds that may be more or less toxic than the parent compound. For example, hydrolysis of esters can take place in the gastrointestinal tract through the action of intestinal microflora. In this connection, azo compounds can be reduced to the more toxic aromatic amines.

The toxicokinetic phase includes all the processes involved in the relationship between the effective dose of a toxicant and the concentration present at the various body fluid compartments and the target tissue. During the toxicokinetic phase, two types of processes play an important role:

1. Distribution processes that involve absorption, distribution to the organs, and excretion. Toxicants are transported and then may bind to protein carriers or tissue components. The principles of pharmacokinetics apply to this distribution process of toxicants.

2. Biotransformation of toxicants. This usually involves the bioactivation of the toxic agent. This metabolic biotransformation is accompanied by changes in chemical properties such as hydrophilicity and lipo-philicity, which in turn affect their distribution in the organisms, the binding to macromolecules (such as proteins and DNA), and excretion.

Metabolism of toxicants mainly occurs in the liver but may also occur in other tissues, such as the lung, kidney, skin, and gonads. Through enzymatic biotransformation processes, the lipophilic compounds are converted to more water-soluble metabolites. Two types of enzymatic reactions are involved in toxicant metabolism: phase I reactions, which involve oxidation, reduction, and hydrolysis; and phase II reactions, which consist of conjugation reactions. Phase I reactions generally convert compounds to derivatives that are more water soluble than the parent molecule. The reactions occur mainly via two oxidative enzyme systems, the cytochrome P-450 system (the mixed-function oxygenase) and the mixed-function amine oxidase. More important than these particular conversions is that these two systems also add or expose functional groups such as —OH, —SH, —NH2, and —COOH, which promote the compound's covalent conjugation with endogenous moieties such as glucuronic acid, sulfate, and amino acids through the actions of phase II reaction enzymes. These conjugated secondary metabolites possess increased water solubility and significant ionization properties at physiologic pH that in turn facilitate their secretion or transfer across hepatic, renal, and intestinal membranes.

The toxodynamic phase comprises the action of the toxicant molecules on the specific sites of action and the expression of the observed toxic effect. The target organ on which the toxicant acts and the effector organ in which the effect is induced, or on which the effect is observed, need not be identical. The concentration of the active toxicant metabolite reached in the target determines to what degree a biological action will be elicited. The toxic effect observed in the biological system can be the result of interference with the normal function of the enzyme systems; blockade of the oxygen transport by hemoglobin; interference with the general functions of the cell; interference with DNA, RNA, and protein synthesis; hypersensitivity reactions; and direct chemical irritation of tissues.

Many carcinogens undergo enzymatic activation to reactive ultimate carcinogens that are electrophilic and are capable of covalent interaction with cellular macromolecules, including DNA. In addition to these secondary carcinogens, there are also primary carcinogens that are reactive and do not require metabolic activation. If the damaged DNA is not repaired, the genome lesions are expressed in replicated cells that later will transform into abnormal cells. For a review of carcinogen metabolism, DNA adduct formation, and DNA repair, see reference 5. These abnormally altered or initiated cells may be removed through the process of programmed cell death (apoptosis) or may undergo proliferation to form preneoplastic lesions. The growth and progression of preneoplastic lesions into a neoplasm or cancer depends on the presence of promoting or inhibiting compounds or conditions in the animal's environment. For many types of cancers, dietary factors have been shown to play a major role in the promotion or inhibition of tumor development. For detailed discussions on carcinogenesis mechanisms, refer to References 5 and 6. The role of dietary factors in cancer development was summarized in Reference 7.

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