Are adverse outcome pathways here to stay?

Natàlia Garcia-Reyero

doi:10.1021/es504976d

Abstract

Social pressure to minimize the use of animal testing and the ever-increasing concern on animal welfare, together with the need for more human-relevant and more predictive toxicity tests, are some of the drivers for new approaches to chemical screening. These approaches must also be able to accelerate the screening and assessment of the thousands of chemicals that are currently in use and in development for potential hazards to human and ecological health. Ideally, approaches are needed that decrease (or eliminate) animal testing while increasing predictivity. Efforts in many countries have focused on a toxicological pathway-based vision for human health assessments relying on in vitro systems and predictive models,1 vision equally applicable to ecological risk assessment.2 A pathway-based analysis of chemical effects opens numerous opportunities to apply nontraditional approaches for understanding the risks of chemical exposure. Conservation of molecular initiating and key events leading to adverse outcomes of regulatory concern provide a defensible framework for extrapolating chemical effects across species, even if the specific adverse outcomes differ between them.3.

Highlights

An Adverse Outcome Pathway (AOP) is a linear pathway composed of a Molecular Initiating Event (MIE), Key Events (KE), and an Adverse Outcome (AO) causally linked together
The workshop focused on the AOP concept as a framework to characterize, organize, and define predictive relationships between measurable key events that reflect the progression from a molecular perturbation to an adverse outcome considered relevant to regulatory decision-making
Many efforts are currently being applied toward developing pathway-based toxicology and linking it to the AOP framework, as well as toward exploring incorporation of systems biology approaches into risk assessment.[30−32] Ideally, the mapping of concentration-responsive genes to pathways would allow the use of pathways in a more traditional risk framework.[3]

Summary

Are Adverse Outcome Pathways Here to Stay?

These pathways can be examined as discrete pathways or as networks using cross-species comparative genomics.[28,29] In a pathway context, alternative species including embryo tests can show similar effects to those found in mammals, the concentration needed to have an effect and the potential mechanisms of compensation and recovery might be different These similarities and differences can be explored and extrapolated using omics and integrative systems approaches to identify signaling pathways and genes that can be mapped to functional pathways conserved across species.[3,28] Many efforts are currently being applied toward developing pathway-based toxicology and linking it to the AOP framework, as well as toward exploring incorporation of systems biology approaches into risk assessment.[30−32] Ideally, the mapping of concentration-responsive genes to pathways would allow the use of pathways in a more traditional risk framework.[3] Highthroughput screening (HTS) programs that assess toxicity are focused on MIEs relevant to human health.[33] When these MIEs are conserved among species, the HTS data can be informative for ecological risk assessment and to predict higher level effects across species.[3,34] High-throughput assays can be powerful and are certainly very promising in moving toward a reduction in animal testing.

■ CONCLUDING REMARKS

■ ACKNOWLEDGMENTS

■ REFERENCES