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Linking Environmental Exposure to Toxicity
Citation:
Oki, N., J. Leonard, M. Nelms, S. Bell, C. Tan, L. Burgoon, AND S. Edwards. Linking Environmental Exposure to Toxicity. Chapter 4, Issues in Toxicology: Computational Systems Pharmacology & Toxicology. Royal Society of Chemistry, Cambridge, Uk, , 60-88, (2017). https://doi.org/10.1039/9781782623731-00060
Impact/Purpose:
High throughput toxicity testing (HTT) holds the promise of providing data for tens of thousands of chemicals that currently have no data due to the cost and time required for animal testing. Interpretation of these results require information linking the perturbations seen in vitro with adverse outcomes in vivo and requires knowledge of how estimated exposure to the chemicals compare to the in vitro concentrations that show an effect. This chapter describes how Adverse Outcome Pathways (AOPs) can be used to link HTT with adverse outcomes of regulatory significance and how Aggregate Exposure Pathways (AEPs) can connect concentrations of environment stressors at a source with an expected target site concentration designed to provide exposure estimates that are comparable to concentrations identified in HTT. Methods for developing both AOPs and AEPs are discussed with an emphasis on tiered approaches to provide differing levels of detail based on the information needs for a given regulatory decision. Lower tier AOPs and ADME predictions provide limited information but have limited input data requirements. Higher tiers provide more information, including quantitative dosimetry and dose-response information, but require additional data and modeling. Lower tiers are designed to inform experimental approaches to fill data gaps and provide the information needed for higher tier analyses in an efficient manner.
Description:
As the number of chemicals and environmental toxicants in commerce continue to increase, so does the need to understand the links between exposure to these stressors and any potential toxic reactions. Assessing the impact of these stressors on public health as well as our environment requires an understanding of the underlying mechanistic processes connecting their introduction into the environment to the associated adverse outcomes. Traditional in vivo methods of toxicity testing have become too costly, unreliable and inefficient. In recent times, in vitro high-throughput toxicity screening methods have been introduced to reduce the burden of in vivo testing and keep pace with the ever increasing number of required tests. The adverse outcome pathway (AOP) concept has been adopted by many in the toxicology community as a framework for linking the biological events that occur from the point of contact with these stressors and the resulting adverse outcome. This provides a mechanistic framework for understanding the potential impacts of perturbations that are measured via in vitro testing strategies. The aggregate exposure pathway (AEP) has been proposed as a companion framework to the AOP. The goal of the AEP is to describe the path the introduction of the stressor into the environment at its source to a target site within an individual that is comparable with the concentrations in the in vitro toxicity tests. Together, these frameworks provide a comprehensive view of the source to adverse outcome continuum. Standardizing our representation of the mechanistic information in this way allows for increased interoperability for computational models describing different parts of the system. It also aids in translating new research in exposure science and toxicology for risk assessors and decision makers when assessing the impact of specific stressors on endpoints of regulatory significance.
