Integrated Testing Strategies (ITS) for safety assessment.

Costanza Rovida

doi:10.14573/altex.1411011

Abstract

Integrated testing strategies (ITS), as opposed to single definitive tests or fixed batteries of tests, are expected to efficiently combine different information sources in a quantifiable fashion to satisfy an information need, in this case for regulatory safety assessments. With increasing awareness of the limitations of each individual tool and the development of highly targeted tests and predictions, the need for combining pieces of evidence increases. The discussions that took place during this workshop, which brought together a group of experts coming from different related areas, illustrate the current state of the art of ITS, as well as promising developments and identifiable challenges. The case of skin sensitization was taken as an example to understand how possible ITS can be constructed, optimized and validated. This will require embracing and developing new concepts such as adverse outcome pathways (AOP), advanced statistical learning algorithms and machine learning, mechanistic validation and "Good ITS Practices".

Highlights

Regulators from different agencies worldwide as well as the regulated scientific community in general are becoming increasingly aware of the limitations of the current safety testing paradigm
In order to better understand the mechanisms and factors involved, it is well recognized that the future of chemical safety assessment must move away from animal tests towards a combination of complementary approaches that address functional mechanistic endpoints tied to adverse outcomes of regulatory concern
In spite of the awareness of the scientific community of the need for integrated testing strategies (ITS) as a tool for safety assessment, its full applicability is still constrained by several factors including lack of agreement on the approach, testing methods that are not developed for the purpose and the lack of a validation procedure for regulatory acceptance

Summary

Introduction

Regulators from different agencies worldwide as well as the regulated scientific community in general are becoming increasingly aware of the limitations of the current safety testing paradigm. In order to better understand the mechanisms and factors involved, it is well recognized that the future of chemical safety assessment must move away from animal tests towards a combination of complementary approaches (in vitro, ex vivo, in silico, in chemico) that address functional mechanistic endpoints tied to adverse outcomes of regulatory concern In spite of this increasing shared awareness, the way toward this goal remains unclear. There are many challenges: to accommodate the flexibility ITS require, to quantify and respond to varying levels of uncertainty, to incorporate preexisting knowledge, to assess test method availability and reproducibility, to define applicability domains of ITS components or necessary accuracy, all with the requirements of standardization that are mandatory for regulatory applications For this reason, there is the need to develop transparent, objective and consistent ITS tools to support reliable hazard and risk assessments. This workshop was held in Ranco (Varese, Italy) on July 8-10, 2013

Background

Comparison of the European and American approaches

Composition of ITS

The example of skin sensitization

Validation of ITS

Discussion

Conclusions and recommendations