Toxicology modeling

For the present, the utilization of in vivo toxicological models is imperative for responsible risk assessment of new chemical entities. At the same time, the use of the many in vitro models currently available can serve as valuable adjuncts to these in vivo assessments, not only reducing the number of animals used in risk assessment, but providing unique information and possibilities for scientists involved in the drug discovery and development process. 

Many factors influence the outcomes of these studies, including the exact time of mating, species/strain used and local husbandry conditions. It is important to obtain sufficient numbers of offspring for analysis in these studies thus, the number of deaths caused by lethal mutation should be optimized to allow detection of both lethal and non-lethal effects. As with any toxicological model, careful control of parameters is required. However, this assay system is a useful model to examine inherited congenital malformations and tumours in the progeny of exposed males, and this kind of data could be useful for predicting effects in humans. 

BMD models are used to estimate human health guidance values for environmental substances. QSARs are used to provide data estimates for chemicals that lack adequate experimental documentation. The ATSDR uses two commercial computational toxicology models to make toxicity predictions based on QSARs. To increase confidence in the models predictions, ATSDR used the models similarity search features and established a minimum threshold similarity distance value of 0.25 to increase the probability that predicted toxicity values are close to nearest analog chemicals. 

Rosenkranz HS, Cunningham AR, Zhang YP, Claycamp HG, Macina OT, Sussman NB, Grant SG, Klopman G (1999) Development, characterization and application of predictive-toxicology models. SAR QSAR Environ Res 10 277-298... 

Overall, these computational toxicology models and many others developed at the US Food and Drug Administration, Center for Drug Evaluation and Research, Informatics and Computational Safety Analysis Staff (ICSAS) can predict with considerable precision the toxicological... 

Zhang, Z., Montiero-Riviere, N.A. (1997). Comparison of integ-rins in human skin, pig skin, and perfused skin an in vitro skin toxicology model. J. Appl. Toxicol. 17 247-53. 

Weber LW, Boll M, and Stampfl A (2003) Hepatotoxicity and mechanism of action of haloalkanes Carbon tetrachloride as a toxicological model. 33(2) 105-136. 

Agencies like the EPA commonly employ default assumptions in exposure, hazard assessment, and risk assessment assumptions. In most of these matters, the amount of available evidence is far less than that available for hormesis. Furthermore, our collective information confirms that among the available toxicological models, the hormetic one is the most predominant. 

In vitro Toxicological Models and Methods Commonly Used in Drug Discovery 23... 

IN VITRO TOXICOLOGICAL MODELS AND METHODS COMMONLY USED IN DRUG DISCOVERY... 

It must be stressed that the primary mechanism of many topical irritants (e.g., organic solvents, corrosives) is the impairment to the stratum corneum barrier properties discussed earlier. If the stratum corneum barrier is perturbed, a feedback response may be initiated whereby regeneration of the barrier occurs. This reaction is mediated by cytokines (especially TNF-a) originating locally within the epidermis. However, additional responses to these inflammatory mediators may in themselves launch an irritation response mediated by the keratinocytes. Thus, regardless of the initiating mechanism, the sequelae to many irritants is the same, making the definition of unique dermal computational toxicology models difficult. 

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