Modeling hazard assessment of chemicals based on adducts formation. I. A basis for inclusion of kinetic factors in simulating skin sensitization

Computational Toxicology Volume 15 (2020) 100130

Skin sensitization is a multi-mechanistic toxicological progression consisting of several molecular and cellular events, typically presented as an adverse outcome pathway. Briefly, it is based on the molecular initiating event - covalent interactions between small electrophilic molecules and skin proteins. The electrophilic structural fragments that form protein adducts may be present in the parent structure or could be produced as a result of (a)biotic transformation. In this respect, the simulation of the most likely transformation pathways in skin, as implemented in TIMES-SS system, are critical to foretelling sensitization potency. The existing mechanistic approaches for predicting skin sensitization consist of expert systems based on the presence or absence of functional groups (i.e., structural alerts) that could alter skin proteins. An insufficiency of such systems, occur when these 'alerts' do not always present proper relationships between reactive functionalities and the  in vivo manifestation. Here, a new concept is proposed whereby the skin sensitization potency is related to the total estimated amount of hapten-protein adducts which could be related to protein damage. This concept is based on the supposition that thresholds exist for the amount of formed protein adducts which trigger different potency levels of skin sensitization and the amount of protein adducts formed is a function of time. Once the kinetics of (a)biotic transformation(s) is taken into account, a better mechanistic justification of the processes controlling skin sensitization potency is achieved. The introduction of this modeling concept and examples of the utility of results of such kinetic modelling for skin sensitization are the primary goals of this investigation.


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