Alternative Methods for Acute Inhalation Toxicity

Acute inhalation systemic toxicity tests identify substances that could cause illness or death after a single inhaled exposure. NICEATM facilitates interactions among stakeholder groups interested in developing and promoting alternatives to animal use for these tests.

Predictive Models for Acute Inhalation Toxicity

In response to a need for efficient and humane alternatives to traditional in vivo studies, NICEATM has initiated a collaborative effort to develop a computational approach for predicting inhalation LC50 values. A curated data set of in vivo rat data, described in a poster presented at the  2024 annual meeting of the Society of Toxicology (Allen et al., Respiratory Toxicology I session) was assembled to support this effort. The Collaborative Modeling Project for Acute Inhalation Toxicity (CoMPAIT) was described in a presentation given at the 2024 SACATM meeting. Over 20 groups have contributed models to the project. The models are currently being evaluated according to defined criteria, with models and results expected to be published in 2025.

EpiAirway Validation Study

A cooperative agreement under the NIEHS Phase IIb Small Business Innovation Research provided funding to MatTek Corporation to validate its EpiAirway™ in vitro human bronchial tissue model to predict the toxicity of inhaled chemicals. Several ICCVAM agency representatives are members of the cooperative agreement steering committee. Testing of reference chemicals to determine the usefulness and limitations of EpiAirway for this purpose has been completed. 

Webinar Series and Workshop on Inhalation Toxicity

A 2016 webinar series and workshop on inhalation toxicity co-organized by NICEATM is summarized in a report published in Toxicology In Vitro (Clippinger et al. 2018a).

NICEATM and the PETA Science Consortium International (PSCI) offered a webinar series from March to September 2016 on Alternative Approaches for Acute Inhalation Toxicity to Address Global Regulatory and Non-regulatory Data Requirements. Webinar presenters:

• Reviewed regulatory guidelines relevant to assessing inhalation toxicity hazard potential.
• Described alternative approaches for identifying substances likely to cause acute systemic toxicity through inhalation.
• Identified mechanisms of acute toxicity that may constitute key events in adverse outcome pathways for acute inhalation toxicity.

More information and links to webinar recordings

At a 2016 workshop that expanded on the webinar series, experts from industry, government, academia, and nongovernmental organizations shared experiences using alternative approaches for acute inhalation toxicity testing and considered how to develop strategies acceptable to regulatory agencies. Workgroups were established to address the four primary workshop recommendations:

• Develop a database of acute inhalation toxicity data.
• Prepare a state-of-the-science review on mechanisms and assays for acute inhalation toxicity (Clippinger et al. 2018b).
• Develop an in silico decision tree for determining when acute inhalation testing should be performed.
• Optimize in vitro assays and standard protocols to be used across laboratories.

These workgroups have been meeting as needed to continue progress toward implementation.

In Vitro Testing Strategies to Assess Inhalation Toxicity of Nanomaterials

NICEATM collaborated with PSCI, EPA, and industry scientists to support a workgroup focused on inhalation toxicity. In 2014, NICEATM published a request for information (79 FR 35176, June 19, 2014) about devices and/or technologies currently used for identifying potential inhalation hazards.

Subsequently, the workgroup met in 2015 to define specifications for the development and evaluation of an in vitro system to assess the toxicity of multi-walled carbon nanotubes when inhaled. The workgroup determined that the proposed in vitro system should include different lung cells co-cultured at an air-liquid interface and consider relevant human dosimetry and nanomaterial lifecycle changes. Presentations from the meeting and a list of publications developed by meeting participants are available on the PSCI website.

PSCI used these recommendations in a request for proposals to develop an appropriate testing system; funding was awarded in September 2015.