Abstract
When assessing the risk and hazard of a non-pharmaceutical compound, the first step is determining acute toxicity, including toxicity following inhalation. Inhalation is a major exposure route for humans, and the respiratory epithelium is the first tissue that inhaled substances directly interact with. Acute inhalation toxicity testing for regulatory purposes is currently performed only in rats and/or mice according to OECD TG403, TG436, and TG433 test guidelines. Such tests are biased by the differences in the respiratory tract architecture and function across species, making it difficult to draw conclusions on the potential hazard of inhaled compounds in humans. Research efforts have been therefore focused on developing alternative, human-relevant models, with emphasis on the creation of advanced In vitro models. To date, there is no In vitro model that has been accepted by regulatory agencies as a stand-alone replacement for inhalation toxicity testing in animals. Here, we provide a brief introduction to current OECD test guidelines for acute inhalation toxicity, the interspecies differences affecting the predictive value of such tests, and the current regulatory efforts to advance alternative approaches to animal-based inhalation toxicity studies. We then list the steps that should allow overcoming the current challenges in validating In vitro alternatives for the successful replacement of animal-based inhalation toxicity studies. These steps are inclusive and descriptive, and should be detailed when adopting in house-produced 3D cell models for inhalation tests. Hence, we provide a checklist of key parameters that should be reported in any future scientific publications for reproducibility and transparency.
Highlights
Inhalation is a major exposure route for humans, where the respiratory tract serves as both target tissue and portal of entry (POE) to the systemic circulation for inhaled substances
According to the Organization for Economic Co-operation and Development (OECD), acute inhalation toxicity testing is performed to define the effects of inhaled substances on (i) the respiratory tract and/or (ii) the whole body (OECD, 2018a)
In some cases In vitro alternative tests are at an advanced stage of development, to date all In vitro alternative models for inhalation toxicity studies still fall into the category of “nonguideline methods.”
Summary
Inhalation is a major exposure route for humans, where the respiratory tract serves as both target tissue and portal of entry (POE) to the systemic circulation for inhaled substances. The test under development could, provide a human-relevant In vitro alternative to current, animal-based acute inhalation toxicity studies. Currently there is no In vitro model that has been accepted by regulatory agencies as a stand-alone replacement for animal tests in acute inhalation toxicity studies, and the issues associated with interspecies differences remain unsolved. Predictive, human-relevant In vitro platforms are published in peer-reviewed scientific journals, but do not go through the validation process In this context, the following section presents the authors’ perspective on how, in our view, it may be possible to overcome the current challenges in validating In vitro alternatives for the successful replacement of animal-based inhalation toxicity testing studies
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