Navigating through the minefield of read-across frameworks: A commentary perspective

Abstract

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Towards grouping concepts based on new approach methodologies in chemical hazard assessment: the read-across approach of the EU-ToxRisk project

“…3.2, 2004) and updated in 2014 (OECD 2014). In 2012, the European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC) reviewed published literature and regulatory guidance documents describing the development of chemical categories (ECETOC 2012) followed by several other peer-reviewed publications on structured workflows for read-across assessments (e.g., Patlewicz et al 2018;Schultz et al 2015;Lizarragad et al 2015;Blackburn and Stuard 2014). Most recently, ECHA published the readacross assessment framework (RAAF), originally developed to guide the regulators, to also support applicants with the assessment of grouped compounds (ECHA 2017).…”

Molecular fingerprint-derived similarity measures for toxicological read-across: Recommendations for optimal use

“…Of these, computational or (Q)SAR (in silico) approaches aim to predict the toxicity of compounds from descriptors of chemical structure and thus reduce testing. In particular, read-across is at the forefront of the prediction of toxicity and has been seen as the "new paradigm" for hazard assessment (Cronin et al, 2013;Berggren et al, 2015;Schultz et al, 2015;Schultz and Cronin 2017;Patlewicz et al 2018). Read-across relies on the ability to identify similar molecules with the assumption that similar molecules will tend to exhibit similar activity or, at least, show similar trends in activity (OECD, 2014).…”

“…For instance, there is a concern over effects such as activity cliffs, where structurally similar compounds have a significant difference in potency (Guha and van Drie, 2008;Stumpfe and Bajorath, 2011;Cruz-Monteagudo et al, 2014). In addition, there is the on-going problem of how to define similarity from a molecular level (Maggiora et al, 2014) as well as adequately for read-across (OECD, 2014;Shah et al, 2016;Patlewicz et al 2018;Schultz et al 2018). It is important to note that the similarity between any two objects may be calculated in a variety of different ways and relies on a definable set of features (or descriptors), as well as a means of qualitatively or quantitatively defining similarity based upon those variables.…”

Assessing uncertainty in read-across: Questions to evaluate toxicity predictions based on knowledge gained from case studies

“…Additional to the on-going activities described above there have been other recent efforts to address the issues raised by the OECD within academia, government and industries. These efforts began the process of the refinement and improvement of how read-across is documented and concentrated on clarifying the seminal issues and overcoming the challenges posed by the OECD (see Patlewicz et al [7,8] and Schultz and Cronin [9]). Several different frameworks for undertaking read-across are available, as described in both regulatory technical guidance and peer-reviewed scientific literature [6,[10][11][12][13][14][15][16].…”

“…Such guidance includes two multi-step procedures, one for the analogue-and one for the category-approach that includes several key features. Patlewicz and co-workers [7,8] note that the OECD framework is an endpoint specific, bottom-up approach that is a generalisation of the ECHA approach. These frameworks have recently been summarised and a more generic framework proposed [8].…”