Chapter 13: Mechanisms of Toxic Action in In Silico Toxicology Check Access

The activity of a compound in any biological endpoint is a function of its chemical identity. In toxicology, biological activity is often interpretable mechanistically in terms of physical chemistry and/or reaction chemistry. This is particularly the case with aquatic toxicology and skin sensitisation, and makes it possible to develop mechanism-based QSARs for these endpoints. In aquatic toxicity both physical chemistry mechanisms, leading to general narcosis or polar narcosis, and reaction chemistry mechanisms are encountered, whereas in skin sensitisation only reaction chemistry mechanisms, in particular electrophilic reactions with skin protein nucleophiles, are encountered. The difference between general and polar narcosis can be explained in terms of different mechanisms of partitioning from water to membranes. For reactive toxicity, both in aquatic toxicity and skin, compounds can be classified into reaction mechanistic applicability domains according to how they react as electrophiles with nucleophiles. For successful reactive toxicity mechanism-based QSAR development it is important to work with compounds in the same reaction mechanistic domain. In the absence of clear knowledge of the identities of the in vivo nucleophilic proteins involved, it is necessary to use reactivity parameters from in chemico data for reaction with model nucleophiles, or from in silico calculations. The scope and limitations of these model reactivity parameters can be assessed from the perspective of the Swain-Scott principle and the hard and soft acids and bases (HSAB) concept. This assessment reinforces the importance of working in the same mechanistic domain, or sub-domains where the domain covers a wide hard-soft range.