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1.2.2 OASIS LMC Models: Toxicological models - Protein/DNA Based
1.2.2.1. Simulating Metabolism
A probabilistic approach to simulating metabolism was developed in LMC. The
approach is based on the sets of hierarchically ordered principal molecular
transformations used to simulate the specific metabolic fate of chemicals. Databases of
documented metabolic pathways for different environmental niches, such as aerobic
microbial degradation or rat liver metabolism, were collected. This empiric knowledge
was used to extract specific molecular transformations to simulate metabolism, assess
their probability of occurrence and their reliability. Due to the limited quantitative
metabolism data reported for some tissue compartments, such as skin, the quantification
of transformations was assigned also on the basis of expert knowledge. The quantitative
assessment of the principal transformations is an advantage of this approach to simulate
metabolism in terms of confining the propagation of metabolic pathways, prioritization of
generated metabolites and defining the applicability domain of simulators. The
developed software systems CATABOL and TIMES (see section 1.2.2.2 for further
details) provide not only ability to model biodegradation or bioaccumulation of chemicals
but also a unique ability to merge metabolism simulation with specific toxic endpoints as
acute aquatic toxicity, skin sensitization, mutagenicity, estrogenicity, etc. The
compilation of traditional (Q)SARs for assessing toxic endpoints with metabolism
simulators and estimates of the applicability domains affords a new perspective in the
(Q)SAR methodology.
Two metabolism models have been developed recently in the lab simulating molecular
transformations in skin and rat liver S9.
1.2.2.2. Skin Sensitization Model
Skin sensitization potential depends upon the ability of chemicals to react with skin
proteins either directly or after appropriate metabolism. The model was built as a
composite of two sub models:
Skin metabolism simulator - The metabolic simulator was constructed to mimic the
enzyme activation of chemicals in the skin. It contains hierarchically ordered
spontaneous and enzyme controlled reactions. The formation of macromolecular
immunogens was used to identify probable structural alerts in parent chemicals or
their metabolites.
COREPA 3D-QSARs /COmmon REactivity PAttern/ for intrinsic reactivity of
compounds having substructures associated with activity: these models depend on
both the structural alert and the rate of skin sensitization. Steric effect around the
active site, molecular size, shape, solubility, lipophilicity, and electronic properties
are taken into account. These models generally may involve combinations of
molecular parameters or descriptors, which trigger the alerting group.
The model was derived from a data set compiled from chemicals tested in the LLNA
(local lymph node assay), GPMT (guinea pig maximization test) and BgVV list (German
Federal Institute for Health Protection of Consumers and Veterinary Medicine). Skin
sensitization potency for these chemicals was assigned to one of three classes: strong,
weak or nonsensitizing. For chemicals whose potency was assessed by more than one
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