Computational toxicology modeling

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. 

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... 

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. 

Mekenyan OG, Dimitrov SD, Pavlov TS, Veith GD. A systematic approach to simulating metabolism in computational toxicology. I. The TIMES heuristic modelling framework. Curr Pharm Des 2004 10 1273-93. 

Keywords Alternatives to animal testing, Computational toxicology, In silico, In vitro, Predictive models, QSAR models, Regulation... 

The toxicological "facts" I have used goes beyond present validated knowledge and thus indicates directions that future work might take to produce the data that can actually be used in a computer fire model. 

Investigative toxicology Determine sequence and mechanisms of toxic action. Discover the genes, proteins, pathways involved. Develop new methods for assessing toxicity use computer-assisted modeling. 

The ATSDR use of QSAR and models to predict toxicity is well described by El-Masri et al. (2002). In 1998, the ATSDR established a computational toxicology laboratory and initiated efforts to use Physiologically Based PharmacoKinetic (PBPK) models, BenchMark Dose (BMD) models, and QSARs. PBPK models are used by the ATSDR to ... 

Reisfeld B, Mayeno AN, Lyons MA, Yang RSH. 2007. Physiologically-based pharmacokinetic and pharmacodynamic modeling, in computational toxicology. In Ekins S, editor, Risk assessment for pharmaceutical and environmental chemicals. Hoboken (NJ) John Wiley Sons, p 33-69. 

The computational toxicology software programs and models were obtained by FDA/CDER/ICSAS through cooperative research and development agreements with MDL Information Systems and Lhasa Ltd (Benz, 2007)... 

Computational toxicology is the application of mathematical and computer models for prediction of effect of toxic agents and understanding the mechanism. 

In this chapter we provide a historical perspective of the development of the field of computational toxicology. Beginning from the similarity-based grouping of elements into the periodic table, the chapter presents a chronology of developments from the simple observations of qualitative relations between structure and toxicity through LFER (linear free energy related) and QSAR (quantitative structure activity relationship) models, to the current... 

It must be stressed that both transdermal flux and Kp are not only chemical dependent but also tightly constrained by the membrane system studied as well as the experimental design of the study used to estimate it (neat compound, vehicle, length of experiment, etc.). The PC that is integral to Kp is the PC between the surface or applied vehicle and the stratum corneum lipids. Different vehicles will thus result in different PCs. Similarly skin from different species may result in different PC due to differences in the stratum corneum lipids and intercellular path lengths. From the computational toxicology perspective, this translates into quantitative models whose parameters are very dependent on experimental variables often not appreciated to be significant contributors to the process. 

This brief review illustrates that many experimental variables can effect the determination of Kp, an essential metric in any topical computation toxicology exercise. Table 24.1 tabulates the relevant parameters that should be considered when designing a dermal penetration study or using literature date for a quantitative modeling study. 

If a cytotoxic chemical is capable of traversing the stratum corneum, it may cause toxicity to the skin as a function of its inherent potential to modify cellular function. Complex quantitative structure activity relationship (QSAR) models developed to assess general cytotoxicity may be applicable to define this inherent toxic potential. The clearest approach to assessing chemical-induced damage to skin is to assess what abnormalities occur when the specific anatomical structures discussed above are perturbed after exposure to topical compounds, since this will be the response modeled in a computational toxicology exercise. 

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