Toxicity Testing in the 21st Century: Challenges and Perspectives

Abstract

Nonclinical toxicity testing of chemicals and chemically-derived small molecule pharmaceuticals as well as biotechnology-derived large molecule pharmaceuticals plays a critical role in risk assessment and risk mitigation. While toxicity testing of chemicals aims to identify and manage hazards to human health and the environment following intended or accidental exposure, pharmaceutical toxicity testing forms a critical part of the risk-benefit assessment which balances the intended beneficial effects on the patient health against observed toxicities and potential adverse effects. The importance of nonclinical toxicity testing and adequate data interpretation in ensuring human safety is underscored by the thalidomide calamity in the early 1960’s where world-wide approximately 10,000 children were born with limb malformations [1-3]. A more recent incident in 2006 involved TGN1412 [4,5]. Administration of TGN1412, a super-agonistic monoclonal antibody against the T-cell co-stimulatory molecule CD28 resulted in a severe, uncontrolled cytokine release syndrome and life-threatening multi-organ failure in 6 volunteers in a first time in human clinical trial. Although both incidents happened more than 4 decades apart from each other, the triggering event in both cases can be broadly attributed to the failure to adequately mirror the human toxicity with the nonclinical test systems used at the time. The growing insight in pathophysiological processes, the constantly evolving landscape of molecular targets for therapeutic intervention and the dramatically increasing heterogeneity of new molecular entities require a continuous adaptation and refinement of the guiding principles and practices of nonclinical toxicology assessments during drug development. In addition, the 2007 implementation of the REACH regulation (Registration, Evaluation, Authorization and Restriction of Chemical Substances) [6] in Europe has an impact on the established practice for toxicity testing of chemicals. The large number of marketed chemicals with limited or even absent toxicology data, which still must be tested and registered at the European Chemicals Agency, require alternative approaches beyond the classical in vivo testing in various animal species.