ABSTRACT
This chapter described the setting of NOAELs in the whole context of toxicity endpoints, rather than simply histopathological changes, but it nevertheless provided an excellent grounding for addressing the adversity question in an objective way which has been largely built upon by subsequent efforts at tackling the topic. Considering that the incidence and severity of such spontaneous findings can, in many cases, vary considerably from study to study, there is a tendency to utilize finding incidences from control animals from previous studies. With the societal pressure to reduce laboratory animal use for testing novel drugs and chemicals, the publication of the National Research Council of the USA in 2007 placed the onus on the toxicology community to derive high-throughput, non-animal, alternative assays for assessing the human risk. The concept of an adverse outcome pathway (AOP) arose from a need to apply molecular markers to risk assessment and regulatory decision-making.
