Toxicity testing is evolving!

Abstract

The efficient management of the continuously increasing number of chemical substances used in today's society is assuming greater importance than ever before. Toxicity testing plays a key role in the regulatory decisions of agencies and governments that aim to protect the public and the environment from the potentially harmful or adverse effects of these multitudinous chemicals. Therefore, there is a critical need for reliable toxicity-testing methods to identify, assess and interpret the hazardous properties of any substance. Traditionally, toxicity-testing approaches have been based on studies in experimental animals. However, in the last 20 years, there has been increasing concern regarding the sustainability of these methodologies. This has created a real need for the development of new approach methodologies (NAMs) that satisfy the regulatory requirements and are acceptable and affordable to society. Numerous initiatives have been launched worldwide in attempts to address this critical need. However, although the science to support this is now available, the legislation and the pace of NAMs acceptance is lagging behind. This review will consider some of the various initiatives in Europe to identify NAMs to replace or refine the current toxicity-testing methods for pharmaceuticals. This paper also presents a novel systematic approach to support the desired toxicity-testing methodologies that the 21st century deserves.

Keywords: 21st century toxicology; NAMs; Q(SAR); TOX21; TOX21c; animal testing; drug development; high-throughput screening; innovation; new approach methodologies; organ-on-a-chip; pharmaceuticals; read-across; regulatory toxicology; risk assessment; toxicity testing; toxicology.

Figure 1

Research methodology scheme. Subject-specific books, journals articles and websites were mainly used as a source of information. Before conduction of research inclusion/exclusion criteria, findings and key terms were identified. When collected information was found to be irrelevant or inadequate, parameters and key terms were refined, and new search was conducted. When all requirements met, data were recorded; however, findings were revised continuously.

Figure 2

The five stages to regulatory acceptance. Test is optimized during the first two stages. Data are gathered during the third stage from prospective studies. Data are then peer reviewed by internal and external examiners to reduce bias and submitted to a regulatory body to be accepted or rejected.

Figure 3

Overview of steps for IATA and AOPs are used to support IATA (diagram adapted from OECD [38]).

Figure 4

Timeline of highlighted initiatives for NAMs. Chronological order and brief summary of NAMs are listed in this paper. Initiatives with shaded backgrounds are the American ones, while all listed with white background are located in Europe.

Figure 5

Schematic representation of the suggested AISNAMs and IDBNAMs. The categorization system could feed into the international database (TT: toxicity testing).