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.

Characterizing “Adversity” of Pathology Findings in Nonclinical Toxicity Studies

“…The MOA and AOP frameworks have been developed to help facilitate the generation, organization, and application of newer data streams. In the future, these constructs are intended to help shift the classical concept of adverse effects based predominantly on morphologic outcomes to more integrated assessments that include newer molecular data streams (Keller et al 2012). …”

Challenges and opportunities in the risk assessment of existing substances in Canada: lessons learned from the international community

“…With further research and understanding of toxicity pathways, the potential for hazard identification and characterisation using HTS data and predictive models will continue to develop beyond current applications to prioritisation and screening after this workshop (US EPA, 2015b). However, as concluded by the HESI workshop, 2011, the most suitable use for high throughput technology is the prioritisation of chemicals (Keller et al, 2012). Another workshop, FuturTox II, held afterwards in 2014, discussed many of the same challenges, limitations, and issues outlined in this paper.…”

Moving from rats to cellular omics in regulatory toxicology: great challenge toward sustainability or “up-shit-creek without a paddle”?

“…In its core, this debate culminates mostly on the one question of how alternative safety testing can provide a sufficient or even increased level of protection-if at all Andersen and Krewski 2010;Calabrese 2011;Hartung 2011;Judson et al 2010;Kavlock et al 2012;Keller et al 2012;Tralau et al 2012). While regulators tend to take a cautious stand in this matter, advocates of alternative testing continue to stress the benefits to be gained and point to tailored risk assessments and high-throughput testing.…”