Integrated analysis of in vitro data and the adverse outcome pathway framework for prioritization and regulatory applications: An exploratory case study using publicly available data on piperonyl butoxide and liver models. (February 2019) - Oki, Noffisat O.
Abstract: The integration of existing knowledge to support the risk assessment of chemicals is an ongoing challenge for scientists, risk assessors and risk managers. In addition, European Union regulations limiting the use of new animal testing in cosmetics makes already existing information even more valuable. Applying a previous SEURAT-1 program framework to derive predictions of in vivo toxicity responses for a compound, we selected piperonyl butoxide (PBO) as a case study for identification of knowledge and methodology gaps in understanding a compound's effects on the human liver. This is investigated through integration of data from human in vitro transcriptomics studies, biological pathway analysis, chemical and disease associations, and adverse outcome pathway (AOP) information. The outcomes of the analysis are used to generate AOPs of liver-related endpoints, identifying areas of concern for risk assessors and regulators. We demonstrate that integration of data through already existing and publicly available tools can produce outcomes comparable to those that may be found through more conventional time- and resource-intensive methods. It is also expected that, with more refinement, this approach could in the future provide evidence to support chemical risk assessment, while also identifying data gaps for which additional testing may be needed. Highlights: Liver fibrosis, steatosis and cancer are found as adverse outcomes (AO) of PBO. Workflow yields AO networks of biological pathways, phenotypes, and diseases. Workflow is applicable to most chemicals when transcriptomics data are available. The workflow also identifies data gaps for which additional testing may be needed.