Mechanistic Applicability Domains for Nonanimal-Based Prediction of Toxicological End Points:  General Principles and Application to Reactive Toxicity

Abstract

In light of new legislation (e.g., the REACH program in the European Union), several initiatives have recently emerged to increase acceptance of (quantitative) structure-activity relationships [(Q)SARs] to reduce reliance on animal (in vivo) testing. Among the principles for assessing the validity of (Q)SARs is the need for a defined domain of applicability, i.e., identification of the range of compounds for which the (Q)SAR can confidently be applied for purposes of toxicity prediction. Here, we attempt to develop a "natural" classification into applicability domains based on considering how a compound and the target organism between them "decide" on the nature and extent of the toxic effect. With particular emphasis on reactive toxicity, we present rules, based on organic reaction mechanistic principles, for classifying reactive toxicants into their appropriate mechanistic applicability domains.

Read-across approaches - misconceptions, promises and challenges ahead

“…Known definitions of chemical categories and read-across reaction principles (Aptula and Roberts, 2006). these sorts of considerations are critical because structural similarity (using indices such as tanimoto, 1957; Willett et al, 1998) may give rise to very "similar" structures in terms of the commonality in "bits" but result in substances that will behave very differently on account of their chemistry.…”

Prediction of the Biodegradation and Toxicity of Naphthenic Acids

“…On the basis of calculated and experimental values for acute toxicity, the toxicity ratio (TR) as the ratio of the calculated baseline toxicity over the experimentally determined value was calculated (Table 3). A TR-value less than one could indicate rapid hydrolysis and/or biotransformation of the parent compound by the organism to non-toxic metabolites (Aptula & Roberts, 2006).…”

Modelagem in chemico: as bases mecanísticas entre a reatividade e a toxicidade

“…2011. 127 associados em estudo por Aptula et al, (2006), demonstrando uma alta confiabilidade na predição da sensibilização.…”