Human toxicity predictions development

Cytotoxicity Evaluated for confounding interpretation of in vitro efficacy assays, for predicting potential for human toxicity especially in liver but also if warranted by other safety assessments in bone marrow, kidney, neurons, immu-nocytes and so on. Also used for developing understanding of biochemical mechanisms of toxicity. HCA has been repeatedly demonstrated to be an effective tool in predictive toxicology. May also be used for certain translational safety biomarkers of toxicity [37]... 

As the use of metabonomics advances, there are several challenges facing scientists using this tool that must be addressed in order to make it more mainstream and more relevant to predicting toxicity, and useful for hazard identification, human risk assessment and clinical medicine. First, advancing the use of metabonomics to identify mechanisms of toxicity is essential, and such efforts should help to increase the overall usefulness, validity, and relevance of toxicity prediction and biomarker development. Second, the use of metabonomic evaluations in the course of chronic toxicity rather than the heretofore emphasis on acute studies will help to establish its place in following the... 

The most successful application of structure-based predictive modeling in the future may be to specific endpoints. As described in Chapter 8 the prediction of something as broad as carcinogenicity is very difficult. If one isolates individual effects and endpoints within this category, then more success will ensue. Such an approach is likely to require the development of tiered strategies for toxicity prediction. It will also allow for the integration of test data from other assays, and where possible, human knowledge. 

Computers are now used in the design and development of new chemicals, and their employment in toxicity prediction could lead to improved products that present a reduced hazard to humans. Although computers are useful for performing routine calculations, they do not usually possess insight or rationalization. Therefore, they should represent only one of a number of test procedures used to formulate a full safety evaluation in a given chemical. Where they are used, their results should be interpreted by a panel of expert toxicologists capable of providing an overall view of the likely toxic risk in the human environment. 

MEANING AND VALUE OF PREDICTING HUMAN TOXICITY IN PHARMACEUTICAL DEVELOPMENT... 

ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) prediction has two separate, but coincident aims. Some assays, used in early preclinical development, are aimed at gaining insights into the likely performance of a compound in a later-stage preclinical assay. Ultimately, though, assays are aimed at gaining a strong indication of how a compound will react once it is in a human metabolic environment. 

As a practical development and promotion of the computatiorral toxicity prediction for the risk assessment of chemicals in industry, the Eitropean Corrrmimity has adopted a special law— Registratiorr, Evaliratiorr, Authorization and Restriction of Chemicals (REACH). REACH provides the basis for a regular use of quantitative/ qiralitative analysis of stractrrre—activity (Qrtantitative Stractme-Activity Relatiortships—(Q)SAR analysis) in the Emopean Commimity. The aim of REACH is to improve the protection of hitmans and the environment through the better and earlier identification of the toxic properties of compounds [5]. The effect of 60,000 compounds on humans and the environment, which are produced in the EU in amoimts of more than 1 ton per year, will be evaluated by REACH. Examples of QSAR practice in REACH are given in the following review [6, 7]. 

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