Mechanism-based toxicity studies

Mechanism-based toxicity studies for drug development... 

The physiological similarity and phylogenetic proximity of nonhuman primates to humans are often cited as rationale for primate selection for safety studies especially when mechanisms of toxicity or pharmacologic action are expected to be closely related to potential physiological reactions in humans. Likewise, species selection is often based on the demonstration of pharmacologic activity of the test article. Many biopharmaceuticals do not exhibit their intended activity in nonprimate species, whereas small molecules may have activity across all species. 

In chapter 3 one of these specific mechanism-based in vitro toxicity tests was studied in more detail. 

The enormous cost of multiple-species, multiple-dose, lifetime evaluations of chronic effects has already made the task of carrying out hazard assessments of all chemicals in commercial use impossible. At the same time, quantitative structure activity relationship (QSAR) studies are not yet predictive enough to indicate which chemicals should be so tested and which chemicals need not be tested. In exposure assessment, continued development of analytical methods will permit ever more sensitive and selective determinations of toxicants in food and the environment, as well as the effects of chemical mixtures and the potential for interactions that affect the ultimate expression of toxicity. Developments in QSARs, in short-term tests based on the expected mechanism of toxic action and simplification of chronic testing procedures, will all be necessary if the chemicals to which the public and the environment are exposed are to be assessed adequately for their potential to cause harm. 

From studies of human populations exposed to certain chemicals, available data are sufficient to characterize the dose-incidence relationships for some types of cancer at high dose levels. However, as in the case of ionizing radiation, the data are not sufficient to define the dose-incidence relationships precisely for any form of cancer over a wide range of doses and dose rates. Therefore, the probability of cancer induction that may be associated with low doses of chemicals that would be of primary concern in protection of public health can be estimated only by interpolation and extrapolation of data at higher doses and dose rates, based on assumptions about the dose-incidence relationships and mechanisms of toxicity. For the few chemicals for which incidence data are available over a range of doses, the dose-incidence relationship is not inconsistent with linearity, but this result does not constitute proof of linearity. 

Action level for dioxin and dioxin-like compounds in soil. Action levels are concentrations of chemicals at which consideration of action to interdict exposure occurs 1 ppb TCDD in residential soil was identified by Kimbrough et al. (1984) as a "level of concern" and recommended as "a reasonable level to begin consideration of action to limit exposure." The conclusions of Kimbrough et al. (1984) were derived in part from an evaluation of the carcinogenic potential of TCDD, based on a 2-year oral chronic toxicity and oncogenicity study in rats (Kociba et al. 1978). With the advancement of knowledge about dioxin-like chemicals and their assumed common mechanism of toxicity, the TEQs were introduced into the risk assessment process. Since then, 1 ppb of total dioxins (expressed as TEQs) in soil has been used as an action level by ATSDR. 

When assessing manifestations of toxicity, evaluators might base their conclusions about relevance on the mechanism that produces a toxicological effect however, a basic default assumption is that any manifestation of reproductive or developmental toxicity is relevant to humans unless the mechanism by which it occurs is impossible in humans. For example, if a toxic effect occurs in animals through an inhibition of folic acid synthesis, that effect would not be considered relevant for humans because humans do not synthesize folic acid. It is unusual, however, to have such detailed knowledge about mechanisms of toxicity from experimental animal studies. 

Finally, ASKA mice should provide crucial information regarding the therapeutic index. ASKA-based in-vivo studies will be able to establish mechanism and target-based efficacy and toxicity for most protein kinases. Such information should prove useful in the preclinical testing of development candidates, because it will allow distinction between mechanism (target)-based and compound (off-target)-based toxicities [35], At this point, we would like to challenge the scientific community and express our interest in the development of p38-ASKA mice, to either promote or discourage the numerous clinical trials of p38 for various indications and to clarify the associated liver toxicity upon treatment of patients with p38 inhibitors. 

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