Defining Molecular Initiating Events of Airway Sensory Irritation in Support of Predictive Testing Approaches

Abstract

Airway irritant exposures in the workplace cause sensory irritation symptoms or signs such as nose and throat pain, rhinorrhea, cough, and airway obstruction, and are associated with nonallergic airway hyperresponsiveness. Using toxicity data to derive chemical-specific occupational exposure limits (OELs) is a critical step in protecting worker health. Respiratory irritation is one of the most common critical effects cited in risk assessments supporting OEL values. However, toxicity data capturing airway sensory irritation responses are often not available for chemicals requiring assessment, even when occupational exposure scenarios indicate inhalation as a route of exposure. As a result, many existing OELs may be inadequately protective against airway irritant responses. This highlights a need for hazard identification methods that are economical, ethical, and informative for sensory irritation effects. In this review, existing knowledge regarding mechanisms of irritancy in the airway is integrated into a mechanistic event framework that accommodates the chemical diversity of airway irritants. This framework identifies discrete molecular initiating events and outcome modifiers upstream of sensory irritation responses. These include activation of specific receptors by irritant ligands, as well as lipid peroxidation, oxidative stress, rapid saline changes, and membrane-detergent events that initiate neuroexcitatory and inflammatory processes in airway nerves and tissues. The use of an in vitro predictive assay suite to measure these events may allow for a low-cost, medium-throughput option for screening large numbers of chemicals for sensory irritant hazards, thereby indicating data needs necessary for setting OELs.

Exposure limits for indoor volatile substances concerning the general population: The role of population-based differences in sensory irritation of the eyes and airways for assessment factors

“…As experimental studies are difficult from an ethical perspective, other approaches are necessary to derive AFs for young children. For sensory airway irritation, Frank et al ( 2018 ) identified so-called KEs and MIEs, which describe initial points of interaction with a volatile substance that result in a perturbation / sensory irritation. Several studies have shown developmental changes in processes involved in MIEs.…”

“…Adverse outcome pathways represent the sequence of biological events that are caused by chemical exposures and disturb homeostasis (Frank et al 2018 ). Adverse outcome pathways for sensory irritation have been described (Frank et al 2018 ; Martinez and Eling 2019 ), and AOP key events have been defined that lead to a specific adverse outcome (OECD 2013 ). Such a sequence begins with MIEs, which describe initial points of interaction resulting in pertubation (OECD 2013 ).…”

“…Such a sequence begins with MIEs, which describe initial points of interaction resulting in pertubation (OECD 2013 ). Frank et al ( 2018 ) identified 5 MIEs for sensory airway irritation: Activation of nociceptors Peroxidation of membrane lipids Induction of reactive oxygen species (ROS) and oxidative stress Abrupt changes in extracellular saline Phospholipase activation during detergent–membrane interactions …”

“…Each of these MIEs is directly induced by irritant exposure and can result in sensory irritation symptoms (Frank et al 2018 ). Some studies show developmental aspects of these MIEs, such as nociceptors (increased physiological sensitivity to pain in neonates; Anand and Carr 1989 ; Bouza 2009 ), peroxidation of membrane lipids, and ROS and oxidative stress (Auten and Davis 2009 ).…”