Academic journal article Environmental Health Perspectives

Chemical Safety Assessment Using Read-Across: Assessing the Use of Novel Testing Methods to Strengthen the Evidence Base for Decision Making

Academic journal article Environmental Health Perspectives

Chemical Safety Assessment Using Read-Across: Assessing the Use of Novel Testing Methods to Strengthen the Evidence Base for Decision Making

Article excerpt

Introduction

The research initiative "Safety Evaluation Ultimately Replacing Animal Testing (SEURAT)" (SEURAT-1 2011) was inspired by the considerations presented in the report of the U.S. National Research Council entitled Toxicity Testing in the 21st Century: A Vision and a Strategy (National Research Council 2007). The European Union (EU) policy to protect laboratory animals (EU 2010) and the need for a new systemic toxicity testing arising from the complete ban on animal testing for cosmetic ingredients within the EU (2009) provided additional impetus for this large-scale collaborative effort. SEURAT-1 is a first step to addressing the long term strategic target and is focusing on the replacement of current repeated dose systemic toxicity testing in vivo used for human safety assessment. Six research projects and a coordination action contribute to the initiative, and combine the research efforts of over 70 European universities, public research institutes, and companies. SEURAT-1 is a public-private partnership co-financed by the European Commission's FP7 Health Programme (EC 2007) and Cosmetics Europe (2015).

The SEURAT-1 strategy (Whelan et al. 2011) adopts a toxicological mode-of-action (MoA) framework to describe how any substance may adversely affect human health (Ankley et al. 2010; Boobis et al. 2008; Krewski et al. 2010) and uses this knowledge to develop complementary theoretical, computational (in silico), and experimental (in vitro) models that predict quantitative points of departure, needed for safety assessment (Sturla et al. 2014). The research initiative aims to prove this concept on three levels (Whelan et al. 2012, 2013) by a) theoretical descriptions of adverse outcome pathways (AOP) based on existing knowledge, b) hypothesis-based testing strategies employing alternative in vitro and in silico methods with a clearly defined toxicity prediction goal, and c) applying existing information (e.g., physical chemical properties, in vivo animal data, human data) and, with selected data generated from alternative methods, achieving a regulatory-accepted safety assessment, based on MoA knowledge of the compound.

MoA describes a biological response to a specific chemical challenge, whereas an AOP is a conceptual construct describing biological activities, beginning with a molecular initial event (MIE), and progressing through different biological levels to an observable adverse effect in a population (Ankley et al. 2010; Boobis et al. 2008). AOP constructs primarily related to hepatotoxicity were developed within SEURAT-1 (Landesmann and Vinken 2013) and included in the inventories of the AOP Development Programme [Organisation for Economic Co-operation and Development (OECD) 2013a] and the AOP Wiki (OECD 2014b) initiatives of the OECD.

Predictive toxicity testing at the level 2 proof of concept is currently about to be finalized by the SEURAT-1 partners (Berggren 2014) and will be used in the level 3 case studies. The consortium will carry out two separate case studies for applied safety assessment: the ab initio and the read-across case study. The ab initio case study will use results from the SEURAT-1 methods to make a risk assessment for repeated dose toxicity predicting a no-effect level of a cosmetic ingredient, assuming a certain exposure scenario. The primary goal of the read-across case study is to increase confidence in read-across assessment by using data from alternative methods. This approach will use a no-effect level based on existing data for one substance and read it across to a similar substance, and the resulting safety assessment is expected to reach regulatory acceptable standards within the SEURAT-1 time frames. In contrast, the ab initio case study, which relies solely on data from alternative methods, is considered an initial step towards a new alternative risk assessment strategy. The Joint Research Centre, European Commission, organized a workshop with invited experts to define the read-across case study in Ispra, Italy, 29-30 April 2014, entitled "The read-across case study for safety assessment contributing to the SEURAT-1 proof of concept. …

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