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|Title:||Adverse Outcome Pathways for Regulatory Applications: Examination of Four Case Studies With Different Degrees of Completeness and Scientific Confidence|
|Authors:||PERKINS Edward; ANTCZAK Philipp; BURGOON Lyle; FALCIANI Francesco; GARCIA-REYERO Natalia; GUTSELL Steve; HODGES Geoff; KIENZLER AUDE; KNAPEN Dries; MCBRIDE Mary; WILLETT Catherine|
|Citation:||TOXICOLOGICAL SCIENCES vol. 148 no. 1 p. 14-25|
|Publisher:||OXFORD UNIV PRESS|
|Type:||Articles in periodicals and books|
|Abstract:||Adverse outcome pathways (AOPs) offer a pathway-based toxicological framework to support hazard assessment and regulatory decision-making. However, little has been discussed about the scientific confidence needed, or how complete a pathway should be, before use in a specific regulatory application. Here we review four case studies to explore the degree of scientific confidence and extent of completeness (in terms of causal events) that is required for an AOP to be useful for a specific purpose in a regulatory application: (i) Membrane disruption (Narcosis) leading to respiratory failure (low confidence), (ii) Hepatocellular proliferation leading to cancer (partial pathway, moderate confidence), (iii) Covalent binding to proteins leading to skin sensitization (high confidence), and (iv) Aromatase inhibition leading to reproductive dysfunction in fish (high confidence). Partially complete AOPs with unknown molecular initiating events, such as ‘Hepatocellular proliferation leading to cancer’, were found to be valuable. We demonstrate that scientific confidence in these pathways can be increased though the use of unconventional information (eg, computational identification of potential initiators). AOPs at all levels of confidence can contribute to specific uses. A significant statistical or quantitative relationship between events and/or the adverse outcome relationships is a common characteristic of AOPs, both incomplete and complete, that have specific regulatory uses. For AOPs to be useful in a regulatory context they must be at least as useful as the tools that regulators currently possess, or the techniques currently employed by regulators.|
|JRC Directorate:||Institute for Health and Consumer Protection Historical Collection|
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