Development of a list of reference chemicals for evaluating alternative methods to in vivo fish bioaccumulation tests.

The aim to reduce the number of animals in experiments has highlighted the need to develop and validate nonanimal methods as alternatives to bioaccumulation studies using fish. The present study details a novel 3-tier approach to develop a list of reference compounds to aid this process. The approach was based on 1) the inclusion of relevant chemical classes supported by high-quality in vivo data for the bioconcentration factor (BCF), whole-body biotransformation rates (K(met)), and metabolism characterization for rainbow trout (Oncorhynchus mykiss) and common carp (Cyprinus carpio) (tiers I and II); and 2) the refinement to ensure a broad coverage of hydrophobicity, bioconcentration potential, molecular weight, maximum molecular diameter, whole-body biotransformation half-lives, and metabolic pathways (tier III). In silico techniques were employed to predict maximal log BCF and molecular and metabolic properties. Of the 157 compounds considered as reference compounds, 144 were supported by high-quality BCF data, 8 were supported by K(met) data, and 5 were supported by in vivo metabolism data. Additional criteria for refinement of the list of reference compounds were suggested to aid practical implementation in experimental efforts. The present list of reference compounds is anticipated to facilitate the development of alternative approaches, enhance understanding of in vivo and in vitro bioaccumulation relationships, and refine in silico BCF and metabolism predictions.

Quantitative and mechanistic read across for predicting the skin sensitization potential of alkenes acting via Michael addition.

Read across is a powerful tool to predict toxicity from structure: It relies on "obvious" chemical similarities to allow for interpolation of activity. This study has extended the read across concept within a known mechanism of action to be quantitative. The chemicals that have been chosen are skin sensitizers and are considered to elicit this response by direct interaction through a direct-acting Michael type addition electrophilic mechanism of action. The Michael addition domain is well-defined for skin sensitizers; however, developing quantitative models for predicting potency within the domain has proven to be difficult. This study highlights the ability of an electrophilicity index (omega) to be used as a measure of similarity for sensitizing chemicals acting through the Michael addition mechanism. The index is shown to offer a chemically interpretable qualitative ranking of the chemicals within the Michael acceptor domain, enabling potentially nonsensitizing and extremely sensitizing chemicals to be easily identified. This study also demonstrates the utility of omega to make predictions of skin sensitization using a mechanism-based read across model. Predictions were made for 19 chemicals within the Michael acceptor domain, with the majority being in good agreement with the experimentally determined values. The mechanism-based read across predictions are in keeping with the OECD principles of transparency and simplicity for quantitative structure-activity relationships and are likely to be of significant benefit to regulators and risk assessors.