Assigning Adversity to Toxicologic Outcomes

The establishment of a no-observed-adverse-effect level (NOAEL) is one of the key endpoints arising out of nonclinical toxicity studies for the safety assessment of new chemical entities for either clinical or societal use. This is used to establish health-based guidance values for environmental and occupational chemicals or to set starting dose levels for subsequent clinical trials where drugs are concerned. The NOAEL is generally derived from an integrated analysis of many data points arising out of the study, although histopathology changes frequently occur at the lowest dose level on the study and hence have the potential to drive the establishment of the NOAEL. While the concept of an adverse event in a toxicity study appears on face value to be a relatively simple decision, it frequently results in heated debate both in the literature and in practice following interactions with regulatory authorities. The cause of this disagreement stems from the fact that a globally acceptable definition of what constitutes an adverse effect has been lacking, so the decision taken frequently lacks an objective scientific basis. This chapter describes how the decision-making process underpinning the assignment of adversity has evolved since the turn of the century and focuses especially on the role of histopathology endpoints in this process by providing case examples to illustrate key discussion topics. Lastly, the chapter provides guidance for pathologists on helping with the decision process by providing the scientific support for assigning any particular histopathology change as adverse or not.