Identification and characterization of adverse effects in 21st century toxicology

Abstract

The practice of toxicology is changing rapidly, as demonstrated by the response to the 2007 NRC report on "Toxicity Testing in the 21(st) Century." New assays are being developed to replace animal testing; yet the use of data from these assays in decision making is not clear. A Health and Environmental Sciences Institute committee held a May 2011 workshop to discuss approaches to identifying adverse effects in the context of the NRC report. Scientists from industry, government, academia, and NGOs discussed two case studies and explored how information from new, high data content assays developed for screening can be used to differentiate adverse effects from adaptive responses. The terms "adverse effect" and "adaptive response" were defined, as well as two new terms, the relevant pathways of toxicological concern (RPTCs) and relevant responses for regulation (RRRs). RPTCs are biochemical pathways associated with adverse events and need to be elucidated before they are used in regulatory decision making. RRRs are endpoints that are the basis for risk assessment and may or may not be at the level of pathways. Workshop participants discussed the criteria for determining whether, at the RPTC level, an effect is potentially adverse or potentially indicative of adaptability, and how the use of prototypical, data-rich compounds could lead to a greater understanding of RPTCs and their use as RRRs. Also discussed was the use of RPTCs in a weight-of-evidence approach to risk assessment. Inclusion of data at this level could decrease uncertainty in risk assessments but will require the use of detailed dosimetry and consideration of exposure context and the time and dose continuum to yield scientifically based decisions. The results of this project point to the need for an extensive effort to characterize RPTCs and their use in risk assessment to make the vision of the 2007 NRC report a reality.

FIG. 1.

Present and future testing paradigms for understanding mechanisms of toxicity. Currently, MOAs are postulated followed by determination of intermediate networks and pathways, culminating in screening assays to detect compounds that present this MOA. In the future, screening assays will be used to postulate MOAs by prior understanding of the links between the screen, targets, pathways, networks, and MOAs.

FIG. 2.

Dose transitions for adverse toxicant response with four differentially susceptible nodes. A hypothetical toxicant has functional effects on four network nodes (N1–N4), inducing four distinct dose transitions detectable at increasing toxicant doses. At the highest cumulative dose, toxicant exposure produces high incidence of an apical endpoint (i.e., cell or organism death). In silico studies can link adverse effects to exposure to lower doses of the toxicant.

FIG. 3.

Future state of toxicity testing based on knowledge of key toxicity pathways and the critical nodes in the pathways. Boxes in red indicate the areas for research where the most emphasis is needed to allow use of this paradigm.