In silico toxicology

The tools for in silico toxicology are broadly applied in the drug development process. The particular use of the tools is clearly context-dependent, which includes the quality of the prediction and the applicability domain of the model. 

For noncancer effects the use of PBTD models has elucidated the fundamental mechanisms of toxicological interactions. Such mechanistic knowledge linked with Monte Carlo simulations has initially been employed in in silico toxicology to develop models that predict the toxicity of mixtures in time. The combination of PBTK/TD models for individual compounds with binary PBTK/TD models can be achieved by incorporating key mechanistic knowledge on metabolism inhibitions and interactions through shared enzyme pathways. Simulations of such models can then be compared to experimental data and allow conclusions to be reached about their pharmacokinetics and the likelihood of effects being dose additive. 

Risk assessment of potential adverse human health effects from chemical mixture exposures may be conducted using health effects information from 1) toxicological bioassays, 2) epidemiological studies, and 3) computer models of toxicokinetic and toxicodynamic processes (i.e., in silico toxicology). 

Dobrev I, Andersen ME, Yang RSH. 2002. In silico toxicology simulating interaction thresholds for human exposure to mixtures of trichloroethylene, tetrachloroethylene, and 1,1,1-trichloroethane. Environ Health Perspect 110 1031-1039. 

Yang RSH, El-Masri HA, Thomas RS, Dobrev ID, Dennison IE, Bae DS, Campain IA, Liao KH, Reisfeld B, Andersen ME, Mumtaz M. 2004. Chemical mixture toxicology from descriptive to mechanistic, and going on to in silico toxicology. Environ Toxicol Pharmacol 18 65-81. 

Anadon, A., Martinez-Larranaga, M.R. (1985). Effects of crotoxin on autonomic neuromuscular transmission in the guinea-pig myenteric plexus and vas deferens. Toxicon 23 963-72. Arvidson, K.B., Valerio, L.G., Jr., Diaz, M., Chanderbhan, R.F. (2008). In silico toxicological screening of natural products. Toxicol. Mech. Meth. 18 229-42. 

Hewitt M, Ellison CM. Issues in Toxicology 2010 7(In Silico Toxicology) 301-333. 

Valerio, L. G., Jr. (2009). In silico toxicology for the pharmaceutical sciences. Toxicology and Applied Pharmacology, 241, 356. 

Arvidson, K.B., Valerio Jr., L.G., Diaz, M., et al., 2008. In silico toxicological screening of natural products. Toxicol. Mech. Meth. 18,229-242. 

Valerio Jr., L.G., 2011. In silico toxicology models and databases as FDA critical path initiative toolkits. Hum. Genomics 5, 200-207. 

Valerio Jr., L.G., Cross, K.P., 2012. Characterization and validation of an in silico toxicology model to predict the mutagenic potential of drug impurities. Toxicol. Appl. Pharmacol. 1, 209-221. 

In Silico Toxicology Principles and Applications 8 Environmental Cardiology... 

Schultz, T. W. Adverse outcome pathways a way of linking chemical structure to in vivo toxicological hazards In In Silico Toxicology Principle and Applications, Cronin, M. Madden, J. (Eds.), The Royal Society of Chemistry, London, 2010, pp. 351-376. 

Raunio, H. In silico toxicology— non-testing methods. Frontiers Pharmacol, 2011, 2, 33. 

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