Toxicity, mechanisms pharmacodynamics

Special tools are needed to study those underlying processes, and a significant fraction of scientists in the toxicology community are involved in such research. Sometimes the phrase mechanism of toxic action is used to describe these various underlying processes, although it is often used to describe only the pharmacodynamic piece of the picture. It is extraordinarily difficult to uncover all relevant mechanistic processes, but significant pieces of the puzzle of toxicity are known for many substances. 

Knowledge of which mechanism of delayed toxicity is operating in specific cases cannot usually be gained from the animal test or from epidemiology studies additional studies of ADME, and of pharmacodynamic interactions of the chemical with cellular components, are necessary to understand mechanisms of delayed toxicity. Some mechanisms are discussed in the following to illustrate the value of this kind of study. 

The effectiveness of drug targeting should be evaluated by taking into account not only pharmacokinetic aspects, but also the pharmacodynamic aspects. The latter include the concentration-effect relationship in the target tissue and at the sites where toxicity may occur [7,12]. The therapeutic effect of the drug and its toxic effect may be different with regard to their mechanisms, and hence their concentration-effect relationship may also be different, both qualitatively (different PD models) and quantitatively (different model parameters). 

The effects of a chemical in a tissue frequently depend on the chemical s interaction with cell surface or cytoplasmic receptors. In some cases, a chemical interacts directly with the cell membrane and alters its permeability. The pharmacodynamic actions of drugs are usually mediated by interactions with a receptor, and a drug often competes with endogenous ligands of a receptor. The toxicity of environmental chemicals can also depend on and be mediated by interactions with receptors. In some cases, the responses are different for chemical exposures at different fetal stages of development, and it is possible to explain the different responses by the chronology of the development of fetal receptor systems. The fetus may develop receptor systems for a compound before it develops the ability to metabolize that compound thus, a low level of an active chemical can have greater and more persistent effects in the fetus than in the mother, whose metabolism limits the duration and extent of the effect. This is one mechanism for selective developmental toxicity of chemicals. 

Artemisinin compounds clear parasites from the blood more rapidly than any other antimalarial agent, by a unique pharmacodynamic action. They are concentrated in parasitized erythrocytes, and structure-activity relations (see Chapter 2) suggest that their endoperoxide bridge is essential for the antimalarial effect. A critical step in the mechanism of action seems to be a hemin-catalyzed reduction of the peroxide moiety, which results in free radicals and reactive aldehydes that subsequently kill the malaria parasites. The hemin-rich internal environment of the parasites is assumed to be responsible for the selective toxicity of artemisinin toward these organisms. 

The UEL for reproductive and developmental toxicity is derived by applying uncertainty factors to the NOAEL, LOAEL, or BMDL. To calculate the UEL, the selected UF is divided into the NOAEL, LOAEL, or BMDL for the critical effect in the most appropriate or sensitive mammalian species. This approach is similar to the one used to derive the acute and chronic reference doses (RfD) or Acceptable Daily Intake (ADI) except that it is specific for reproductive and developmental effects and is derived specifically for the exposure duration of concern in the human. The evaluative process uses the UEL both to avoid the connotation that it is the RfD or reference concentration (RfC) value derived by EPA or the ADI derived for food additives by the Food and Drug Administration, both of which consider all types of noncancer toxicity data. Other approaches for more quantitative dose-response evaluations can be used when sufficient data are available. When more extensive data are available (for example, on pharmacokinetics, mechanisms, or biological markers of exposure and effect), one might use more sophisticated quantitative modeling approaches (e.g., a physiologically based pharmacokinetic or pharmacodynamic model) to estimate low levels of risk. Unfortunately, the data sets required for such modeling are rare. 

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