Incorporating Systematic Review, AOPs, and Emerging Risk Methods into the Safety Assessment Process

The following blog pertains to the 2017 SOT Annual Meeting Scientific Session "Modernizing Toxicological Risk Assessment for Compounds Released from Pharmaceutical, Consumer, Medical Device, and Combination Products: Alternative Tools and Methods."

For many of us working in the extractables and leachables world, evaluating the safety of a hexane or ethanol extract of a multi-component medical device evokes thoughts of massive spreadsheets populated with row after row of extracting chemicals. It is always challenging to quickly and accurately populate these spreadsheets with human daily exposure doses for extracting chemicals, estimating their tolerable intakes, and, ultimately, identifying adequate margins of safety to support the safety of an article for its intended use. Admittedly, the current risk assessment process is in need of an update, and this workshop featured four experts who demonstrated how to incorporate systematic review, Adverse Outcome Pathways (AOP), and emerging risk methods into the safety assessment process.

Andrew A. Rooney, National Institute of Environmental Health Sciences (NIEHS), spoke about his application of the systematic review process as part of evaluating the immunotoxicity of perfluorooctanoic acid (PFOA). He detailed a four-step review process used to assess more than 5,000 references on this endpoint, whose relevant evidence (including great data visualizations) are presented in a web-based project workspace.

Amgen’s presentation, “Advancing Understanding of Cramer Classification with Adverse Outcome Pathways (AOPs),” explored the link between safety and quality assessments. For combination products, this is a key question to be answered. Unlike safety assessments, conducting a quality assessment for a biologic is more challenging—devices and containers can leach substances that result in structural modification of proteins, impact product quality attributes, and reduce efficacy of the biologic. Is there a hidden treasure in the toxicology-based TTC that relates to an AOP’s Molecular Initiating Event (MIE)? Specifically, is it possible to relate Cramer TTC to risk of protein modification?

Cramer Class III structures are known for their reactive functional groups, such as cyano, N-nitroso, etc. This is important because targeting covalent binding with proteins is a key MIE. Avoiding protein binding may prevent the MIE (and subsequent toxicity) from occurring. Attendees were reminded to use tools such as Toxtree and QSAR Toolbox with caution, as predictions do not take the place of expertise in chemical interactions.

Ron Brown, MS, US Food and Drug Administration (US FDA) Center for Devices and Radiological Health (CDRH), spoke about the importance of capturing new technology to make more informed risk decisions. For example, instead of using analogs that are only structurally based, he reminded listeners to search for analogues that are biologically based. He underscored the US FDA’s commitment to modernizing risk assessment methods, as evidenced by CDRH’s 2017 Regulatory Science Priorities (FY2017) report that identified greater use of emerging risk assessment methods as being in CDRH’s top 10 regulatory science priorities.

It is encouraging to see first-hand how systemic review, AOPs, and emerging risk assessment methods are becoming part of the standard arsenal use by toxicologists in the protection of human health!

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