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

Defining Molecular Initiating Events of Airway Sensory Irritation in Support of Predictive... AbstractAirway 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 hyper-responsiveness. 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Applied In Vitro Toxicology Mary Ann Liebert

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

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

Applied In Vitro Toxicology , Volume 4 (4): 15 – Dec 1, 2018

Abstract

AbstractAirway 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 hyper-responsiveness. 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.

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Publisher
Mary Ann Liebert
Copyright
Copyright 2018, Mary Ann Liebert, Inc., publishers
ISSN
2332-1512
eISSN
2332-1539
DOI
10.1089/aivt.2018.0007
Publisher site
See Article on Publisher Site

Abstract

AbstractAirway 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 hyper-responsiveness. 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.

Journal

Applied In Vitro ToxicologyMary Ann Liebert

Published: Dec 1, 2018

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