By Curtis D. Klaassen
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Additional resources for Casarett and Doull's toxicology: the basic science of poisons Sixth Edition
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. The effects of two chemicals given simultaneously produce a response that may simply be additive of their individual responses or may be greater or less than that expected by addition of their individual responses. The study of these interactions often leads to a better understanding of the mechanism of toxicity of the chemicals involved.
Similarly, an index of comparative toxicity is obtained by the ratio of doses of two different materials to produce an identical response or the ratio of doses of the same material necessary to yield different toxic effects. The most commonly used index of effect, whether beneficial or toxic, is the median dose—that is, the dose required to result in a response in 50 percent of a population (or to produce 50 percent of a maximal response). The therapeutic index of a drug is an approximate statement about the relative safety of a drug expressed as the ratio of the lethal or toxic dose to the therapeutic dose: TI ϭ LD50/ED50 From Fig.
Interestingly, rats do possess the gene for a form of glutathione S-transferase with high catalytic activity toward aflatoxin epoxide (rGSTA5-5) that is inducible by certain dietary antioxidants and drugs. Thus, dietary treatment can dramatically change the sensitivity of a species to a carcinogen. Other examples in which large species differences in response to carcinogens have been observed include the development of renal tumors from 2,3,5-trimethylpentane and d-limonene in male rats (Lehman-McKeeman and Caudill, 1992), the production of liver tumors from “peroxisomal proliferators” such as the antilipidemic drug clofibrate and the common solvent trichloroethylene (Roberts, 1999), and the induction of nasal carcinomas in rats after inhalation exposure to formaldehyde (Monticello and Morgan, 1997).