Abstract
Adverse outcome pathways (AOPs) help to organize available mechanistic information related to an adverse outcome into key events (KEs) spanning all organizational levels of a biological system(s). AOPs, therefore, aid in the biological understanding of a particular pathogenesis and also help with linking exposures to eventual toxic effects. In the regulatory context, knowledge of disease mechanisms can help design testing strategies using in vitro methods that can measure or predict KEs relevant to the biological effect of interest. The AOP described here evaluates the major processes known to be involved in regulating efficient mucociliary clearance (MCC) following exposures causing oxidative stress. MCC is a key aspect of the innate immune defense against airborne pathogens and inhaled chemicals and is governed by the concerted action of its functional components, the cilia and airway surface liquid (ASL). The AOP network described here consists of sequences of KEs that culminate in the modulation of ciliary beat frequency and ASL height as well as mucus viscosity and hence, impairment of MCC, which in turn leads to decreased lung function.
Highlights
Regulatory frameworks are moving towards risk assessment approaches that better protect human health and are not reliant on testing in animals
The biological functions of cystic fibrosis transmembrane regulator (CFTR) and forkhead box J1 (FOXJ1) are extensively studied and established across different test systems, implying the high biological plausibility of both KERB and KERG
While oxidative stress leading to decreased lung function through the branch molecular initiating event (MIE) → KE1 → KE2 → KE5 and/or KE6 → KE7 → adverse outcome (AO) has a weakly supported link represented by KERC (KE2 → KE6, i.e., decreased airway surface liquid (ASL) height leading to decreased ciliary beating frequency (CBF)), the oxidative stress can lead to the AO through MIE → KE6 → KE7 → AO or via decreased FOXJ1 protein levels through MIE → KE3 → KE4→ KE5 and/or KE6 → KE7 → AO
Summary
Regulatory frameworks are moving towards risk assessment approaches that better protect human health and are not reliant on testing in animals. In vitro and in silico assays that measure each of the KEs of an AOP can be used to design testing approaches that closely predict human responses and replace the need for in vivo data in order to derive benchmark values for determining the potential adverse health impacts of chemicals. No single event has been attributed to MCC impairment This AOP work evaluates the major processes known to be involved in ensuring efficient MCC and consists of sequences of KEs that culminate in the modulation of ASL, ciliary beat frequency (CBF), and mucus viscosity. Together, these processes impair MCC, which—when persistent—leads to decreased lung function. Both empirical and quantitative evidence was captured, consolidated and transferred to the corresponding KE and KER pages on the AOPwiki following the recommendations in the AOP User’s Handbook
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