Pathway-based predictive approaches for non-animal assessment of acute inhalation toxicity

Abstract

New approaches are needed to assess the effects of inhaled substances on human health. These approaches will be based on mechanisms of toxicity, an understanding of dosimetry, and the use of in silico modeling and in vitro test methods. In order to accelerate wider implementation of such approaches, development of adverse outcome pathways (AOPs) can help identify and address gaps in our understanding of relevant parameters for model input and mechanisms, and optimize non-animal approaches that can be used to investigate key events of toxicity. This paper describes the AOPs and the toolbox of in vitro and in silico models that can be used to assess the key events leading to toxicity following inhalation exposure. Because the optimal testing strategy will vary depending on the substance of interest, here we present a decision tree approach to identify an appropriate non-animal integrated testing strategy that incorporates consideration of a substance's physicochemical properties, relevant mechanisms of toxicity, and available in silico models and in vitro test methods. This decision tree can facilitate standardization of the testing approaches. Case study examples are presented to provide a basis for proof-of-concept testing to illustrate the utility of non-animal approaches to inform hazard identification and risk assessment of humans exposed to inhaled substances.

Molecular Image-Based Prediction Models of Nuclear Receptor Agonists and Antagonists Using the DeepSnap-Deep Learning Approach with the Tox21 10K Library

“…The perturbation of the NR signaling pathway due to the action of agonists or antagonists of chemical compounds is associated with various adverse health outcomes [19,21]. Although chemical hazard assessments have traditionally relied upon toxicity data from animal bioassays and epidemiological studies, there are some drawbacks to this testing method, such as high cost, lengthy test durations, and ethical concerns [5,[22][23][24][25][26][27]. To resolve these issues, the in vitro high-throughput screening (HTS) assay has been developed as an alternative approach and improved by the Toxicity Forecaster (ToxCast TM ) program run by the U.S. Environmental Protection Agency (EPA) [5,[28][29][30] and The Toxicology in the 21st Century program (Tox21), an interagency federal collaboration launched by the consortium of the EPA, the U.S. Food and Drug Administration (FDA), the National Institutes of Health (NIH), and the National Toxicology Program (NTP) [5,31].…”

The genotoxicological assessment of a tobacco heating product relative to cigarette smoke using the in vitro micronucleus assay

“…For example, classical genotoxicity techniques have been adapted in line with NRC’s 21st century toxicity testing (TT21C) strategy, for higher throughput and aerosol exposures [ 26 ]; cytotoxicity methods have been adapted for NGPs aerosols [ 17 , 27 ] and contemporary high content and high throughput screening methods have been employed on both e-liquid and particulate test matrices [ 18 , 28 , 29 ]. The assessment of cellular perturbations in a systems biology approach have also been employed [ 21 , 30 , 31 , 11 , 18 ].…”

New Approach Methods to Evaluate Health Risks of Air Pollutants: Critical Design Considerations for In Vitro Exposure Testing

“…This is particularly important for air pollutant research, as many airborne chemicals and mixtures are currently lacking data required for hazard assessment. A few reviews have been published previously on the topic of in vitro models in inhalation toxicology [45,46], including some that were recently published [47,48]. Here, we contribute to this expanding body of literature by reviewing critical elements of study design to incorporate when planning and executing in vitro methods in air pollution research, with the ultimate goal of incorporating these NAMs into chemical hazard and risk assessment applications.…”

“…If the main route of exposure in humans is via inhalation for the particular chemical or particle of interest, then it is clearly advantageous to evaluate exposure effects in a similar fashion. It has become widely accepted that exposing cells at the ALI is advantageous to simulate an inhalation exposure [47,48]. Cells in the ALI condition are cultured on porous inserts that contain cell culture medium in the basolateral side to maintain viable cells, while the apical side is directly exposed to the air, permitting a direct exposure [88,89].…”