Acute Oral and Inhalation Toxicity: Impressions on Finding Alternatives for Testing

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Nikki Gellatly of the National Centre for the Replacement, Refinement & Reduction of Animals in Research (NC3Rs) is the author of this post.

Acute toxicity test data are required by regulatory agencies across many regions and sectors and are used for a wide range of purposesfrom classification and labeling to risk assessment and risk management (e.g., requirements for transportation and the need for personal protective equipment). Traditional acute oral and inhalation tests aim to establish the median lethal dose (LD50) or concentration (LC50), respectively. During the SOT 58th Annual Meeting and ToxExpo, the Symposium Session “Establishing Effective Alternatives for Acute Oral and Inhalation Systemic Toxicity Testing,” chaired by Dr. Agnes Karmaus, showcased a range of efforts to replace the need for in vivo testing to derive this information.

Dr. Anna Lowit gave an overview of the regulatory context for acute oral and inhalation toxicity data, focusing on US agencies. Whilst she started by outlining the range of current requirements, the need for change was a common theme. This included the need for test method developers and “end users” (from both regulatory agencies and industry) to work together from an early stage to ensure that new methods are fit for purpose, as underpins the ICCVAM Strategic Roadmap. Another change in mind-set that was highlighted was the willingness of the US Environmental Protection Agency to now make use of the flexibility already within regulations to allow alternative approaches to fulfill data requirements and waivers, and Dr. Lowit went on to showcase a number of examples where this was being applied in practice.

The next two talks covered different aspects of a program of work on quantitative structure-activity relationship (QSAR) models for acute oral toxicity. Session Co-Chair Dr. Nicole Kleinstreuer described efforts to collate and curate historic LD50 values, emphasizing the importance of ensuring a robust dataset is available to support model development and that this requires a significant amount of time and effort. Analysis of the variability of these data was also performed to provide a benchmark for the predictivity that could be expected from models trained on this data. Acknowledging and quantifying the variability of “gold standard” animal data is a crucial step in developing new, more mechanistic approaches. Next, Dr. Kamel Mansouri told us about a workshop attended by QSAR modelers from across the world, held after this curated data had been made available as a training dataset. The resulting models were evaluated for both qualitative and quantitative aspects, including model documentation and predictivity. Most importantly, this feedback allowed the developers to refine their models in the iterative approach promoted in the ICCVAM Strategic Roadmap.

The focus of the session then moved on to acute inhalation toxicity testing. Dr. Amy Clippinger described anatomical differences between the respiratory systems of humans and rodents and the range of in vitro models availablefrom mono- and coculture of cell lines all the way to precision-cut human lung slices. A lack of in vitro models of the lower respiratory tract had been identified as a data gap, and work with MatTek to address this was presented. That several CROs are now offering in vitro systems to assess acute inhalation toxicityand can advise on how to use themis an exciting development. Dr. Jon Hotchkiss then illustrated how collaboration between inhalation toxicologists and computational modelers can allow integration of nonanimal data to assess acute inhalation toxicity. The differences between inhaled, deposited, absorbed, and cellular doses were explained, and the importance of having an understanding at each of these levels was clear. In vitro testing of models of different parts of the respiratory tract, and different methods of exposure (for example, direct pipetting or aerosolization), were described, as were potential readouts offering mechanistic understanding such as cytotoxicity, inflammation, metaplasia, and oxidative stress. It will be great to see how future work aimed at enabling the assessment of sensory irritants and respiratory sensitizers progresses.

From this session, it is clear that there is a real momentum gathering toward the nonanimal assessment of acute oral and inhalation toxicity, which has the potential to replace a large number of animal tests. Achieving change at a regulatory level can be a difficult and lengthy process, as has been the case with the adoption and uptake of refined test guidelines in this area (OECD Test Guidelines 420 and 433, which use evident toxicity rather than death as an endpoint); hopefully, nonanimal approaches to meet these data requirements will be more easily welcomed.

This blog was prepared by an SOT Reporter. SOT Reporters are SOT members who volunteer to write about sessions and events they attend during the SOT Annual Meeting and ToxExpo. If you are interested in participating in the SOT Reporter program in the future, please email Giuliana Macaluso.

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