A strategy for structuring and reporting a read-across prediction of toxicity

Abstract

Category formation, grouping and read across methods are broadly applicable in toxicological assessments and may be used to fill data gaps for chemical safety assessment and regulatory decisions. In order to facilitate a transparent and systematic approach to aid regulatory acceptance, a strategy to evaluate chemical category membership, to support the use of read-across predictions that may be used to fill data gaps for regulatory decisions is proposed. There are two major aspects of any read-across exercise, namely assessing similarity and uncertainty. While there can be an over-arching rationale for grouping organic substances based on molecular structure and chemical properties, these similarities alone are generally not sufficient to justify a read-across prediction. Further scientific justification is normally required to justify the chemical grouping, typically including considerations of bioavailability, metabolism and biological/mechanistic plausibility. Sources of uncertainty include a variety of elements which are typically divided into two main issues: the uncertainty associated firstly with the similarity justification and secondly the completeness of the read-across argument. This article focuses on chronic toxicity, whilst acknowledging the approaches are applicable to all endpoints. Templates, developed from work to prepare for the application of new toxicological data to read-across assessment, are presented. These templates act as proposals to assist in assessing similarity in the context of chemistry, toxicokinetics and toxicodynamics as well as to guide the systematic characterisation of uncertainty both in the context of the similarity rationale, the read across data and overall approach and conclusion. Lastly, a workflow for reporting a read-across prediction is suggested.

Read-across of 90-day rat oral repeated-dose toxicity: A case study for selected β-olefinic alcohols

“…This evaluation of selected -olefinic alcohols followed a read-across workflow proposed by Schultz et al (2015) [6]. It is in accord with the guidance proposed by Organization for Economic Co-Operation and Development (OECD) (2015) [24].…”

Evaluating the mutagenic potential of aerosol organic compounds using informatics-based screening

“…The present study focuses only on genotoxicity because (a) it can be associated with any kind of exposure, (b) it can be induced at very small doses, (c) it leads to adverse health effects on humans upon chronic exposure (and the increase in mortality risk for PM is much higher for chronic than for short-term exposures; Pope et al, 2011), and (d) it is a well-studied endpoint with defined mechanisms of action (Worth et al, 2011;Schultz et al, 2015). Most importantly, genotoxicity has been characterized in real PM samples and it is subject to monitoring in several countries (e.g.…”

Read-across for Hazard Assessment: The Ugly Duckling is Growing Up

“…the soundness of the resulting hazard information cannot be judged). Schultz et al 11 have recently published a proposal on how to structure and assess the acceptability of a read-across approach. Their strategy of including any helpful information from non-guideline studies to QSAR models is -at least in terms of REACH terminology -turning any read-across into a so-called 'weight-of-evidence' assessment.…”

“…The call for good science and documentation in hazard assessment, that was made by Russell and Burch, 2 is as relevant now as it was in 1959. Indeed, guidance documents and reporting templates have undergone several refinements, [21][22][23] strategies have been published, 11,24,25 and recently, the ECHA has published the Read-Across Assessment Framework (RAAF). 1 The latter aims at the quality control and transparency of read-across evaluations.…”