Abstract
To date there are no OECD validated alternative approaches to study toxicity following inhalation exposure to airborne chemicals. The available OECD test guidelines for acute inhalation toxicity aim to estimate a value of the lethal air concentration of the test chemical leading to the death of 50% of the exposed animals (LC50), to satisfy hazard classification and labelling requirements. This paper explores the view that alternative approaches must compare to outcomes of existing guideline methods to become accepted and implemented in a regulatory context. This case study describes the initiatives taken to validate the lung surfactant bioassay, an in vitro cell-free method, and discusses the challenges faced. While the lung surfactant bioassay could not predict the GHS classification for acute inhalation toxicity of 26 chemicals, the assay successfully predicted the clinical signs of respiratory toxicity observed during or shortly after exposure in vivo as reported in registration dossiers. The lung surfactant bioassay is a promising alternative approach to assess the potential of chemicals to cause changes to respiration remaining after exposure (indicating decreased lung function), and can be combined with other test methods in an integrated approach to testing and assessment of inhaled substances.
Highlights
To date there are no Organisation for Economic Co‐operation and Development (OECD) validated alternative approaches to study toxicity following inhalation exposure to airborne chemicals
The available OECD test guidelines for acute inhalation toxicity aim to estimate a value of the lethal air concentration of the test chemical leading to the death of 50% of the exposed animals (LC50), to satisfy hazard classification and labelling requirements
The available OECD testing guidelines (TGs) aim to determine a point or range estimate of the LC50, the lethal air concentration of the test chemical leading to the death of 50% of the exposed animals during the observation period, to satisfy hazard classification and labelling requirements of chemicals and mixtures under the United Nations (UN) Globally Harmonized System of Classification and Labelling of Chemicals (GHS) (European Commission, 2008)
Summary
To date there are no OECD validated alternative approaches to study toxicity following inhalation exposure to airborne chemicals. Current Research in Toxicology 2 (2021) 204–209 signs of toxicity (tremors, hypoactivity, irregular respiration, or bodyweight loss), either severe pain and enduring signs of severe distress, moribund condition or mortality would be observed in the majority of the animals at the highest fixed concentration (Sewell et al, 2015) It is questionable whether these OECD TGs and the determination of lethal concentrations are the most human relevant, cost‐effective, and ethically sound approaches to discern adverse lung effects following inhalation exposure to chemicals (Da Silva and Sørli, 2018). Lautenberg Chemical Safety for the 21st Century Act (Senate and House of Representatives of the United States of America in Congress, 2016) and in the Directive to Prioritize Efforts to Reduce Animal Testing of the US Environmental Protection Agency (EPA, 2019) These acts and directives prompted research within this field, and a growing body of literature describes the efficiency and predictivity of in silico and in vitro methods to study the toxicity of inhaled chemicals. There are no validated alternative approaches for hazard identification of inhaled chemicals: the OECD TGs described above remain the basis for regulatory decision‐making
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