A Proof-of-Concept for Safety Evaluation of Inhalation Exposure to Known Respiratory Irritants Using In Vitro and In Silico Methods
There is increased interest in developing non-animal test systems for inhalation exposure safety assessments. However, defined methodologies are absent for predicting local respiratory effects from inhalation exposure to irritants. The current study introduces a concept for applying in vitro and in...
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MDPI AG
2025-01-01
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| Series: | Toxics |
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| Online Access: | https://www.mdpi.com/2305-6304/13/1/35 |
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| author | Nikaeta Sadekar Holger Peter Behrsing Tanja Hansen Vivek Patel Hazel Paulo Alex Rae Detlef Ritter Katharina Schwarz Anne Marie Api |
| author_facet | Nikaeta Sadekar Holger Peter Behrsing Tanja Hansen Vivek Patel Hazel Paulo Alex Rae Detlef Ritter Katharina Schwarz Anne Marie Api |
| author_sort | Nikaeta Sadekar |
| collection | DOAJ |
| description | There is increased interest in developing non-animal test systems for inhalation exposure safety assessments. However, defined methodologies are absent for predicting local respiratory effects from inhalation exposure to irritants. The current study introduces a concept for applying in vitro and in silico methods for inhalation exposure safety assessment. Three in vitro systems, representing the upper (MucilAir™—nasal epithelial tissue) and lower (A549 cells and human precision-cut lung slices) human respiratory regions, were exposed to six respiratory irritants. These irritant exposures were conducted as liquid droplets, aerosol, or vapors, and samples were collected over 24 h. Cytotoxicity, cytokine release, epithelial resistance, oxidative stress, and mitochondrial membrane potential were measured. To determine the human relevance of in vitro exposures, airway surface depositions were predicted by simulating airborne concentrations equivalent to the Cramer class III inhalation threshold of toxicological concern limit of 0.47 mg/person/day using an in silico model. A > 100-fold margin of exposure was calculated comparing lowest concentrations showing in vitro effects to in silico simulated values. While further studies are needed, this manuscript presents a basic requirement for employing non-animal methods to inform inhalation exposure safety assessments by combining in vitro and in silico assays. |
| format | Article |
| id | doaj-art-5d39fcdeb1874150ab0add88a32cd8de |
| institution | Kabale University |
| issn | 2305-6304 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Toxics |
| spelling | doaj-art-5d39fcdeb1874150ab0add88a32cd8de2025-01-24T13:51:00ZengMDPI AGToxics2305-63042025-01-011313510.3390/toxics13010035A Proof-of-Concept for Safety Evaluation of Inhalation Exposure to Known Respiratory Irritants Using In Vitro and In Silico MethodsNikaeta Sadekar0Holger Peter Behrsing1Tanja Hansen2Vivek Patel3Hazel Paulo4Alex Rae5Detlef Ritter6Katharina Schwarz7Anne Marie Api8Research Institute for Fragrance Materials, Inc., Mahwah, NJ 07420, USAInstitute for In Vitro Sciences, Inc., Gaithersburg, MD 20878, USAFraunhofer Institute for Toxicology and Experimental Medicine ITEM, 30625 Hannover, GermanyInstitute for In Vitro Sciences, Inc., Gaithersburg, MD 20878, USACharles River Laboratories Edinburgh Ltd., Elphinstone Research Centre, Tranent EH33 2NE, UKCharles River Laboratories Edinburgh Ltd., Elphinstone Research Centre, Tranent EH33 2NE, UKFraunhofer Institute for Toxicology and Experimental Medicine ITEM, 30625 Hannover, GermanyFraunhofer Institute for Toxicology and Experimental Medicine ITEM, 30625 Hannover, GermanyResearch Institute for Fragrance Materials, Inc., Mahwah, NJ 07420, USAThere is increased interest in developing non-animal test systems for inhalation exposure safety assessments. However, defined methodologies are absent for predicting local respiratory effects from inhalation exposure to irritants. The current study introduces a concept for applying in vitro and in silico methods for inhalation exposure safety assessment. Three in vitro systems, representing the upper (MucilAir™—nasal epithelial tissue) and lower (A549 cells and human precision-cut lung slices) human respiratory regions, were exposed to six respiratory irritants. These irritant exposures were conducted as liquid droplets, aerosol, or vapors, and samples were collected over 24 h. Cytotoxicity, cytokine release, epithelial resistance, oxidative stress, and mitochondrial membrane potential were measured. To determine the human relevance of in vitro exposures, airway surface depositions were predicted by simulating airborne concentrations equivalent to the Cramer class III inhalation threshold of toxicological concern limit of 0.47 mg/person/day using an in silico model. A > 100-fold margin of exposure was calculated comparing lowest concentrations showing in vitro effects to in silico simulated values. While further studies are needed, this manuscript presents a basic requirement for employing non-animal methods to inform inhalation exposure safety assessments by combining in vitro and in silico assays.https://www.mdpi.com/2305-6304/13/1/35in vitroin silicoexposure assessmentsafety assessmentinhalationthreshold of toxicological concern |
| spellingShingle | Nikaeta Sadekar Holger Peter Behrsing Tanja Hansen Vivek Patel Hazel Paulo Alex Rae Detlef Ritter Katharina Schwarz Anne Marie Api A Proof-of-Concept for Safety Evaluation of Inhalation Exposure to Known Respiratory Irritants Using In Vitro and In Silico Methods Toxics in vitro in silico exposure assessment safety assessment inhalation threshold of toxicological concern |
| title | A Proof-of-Concept for Safety Evaluation of Inhalation Exposure to Known Respiratory Irritants Using In Vitro and In Silico Methods |
| title_full | A Proof-of-Concept for Safety Evaluation of Inhalation Exposure to Known Respiratory Irritants Using In Vitro and In Silico Methods |
| title_fullStr | A Proof-of-Concept for Safety Evaluation of Inhalation Exposure to Known Respiratory Irritants Using In Vitro and In Silico Methods |
| title_full_unstemmed | A Proof-of-Concept for Safety Evaluation of Inhalation Exposure to Known Respiratory Irritants Using In Vitro and In Silico Methods |
| title_short | A Proof-of-Concept for Safety Evaluation of Inhalation Exposure to Known Respiratory Irritants Using In Vitro and In Silico Methods |
| title_sort | proof of concept for safety evaluation of inhalation exposure to known respiratory irritants using in vitro and in silico methods |
| topic | in vitro in silico exposure assessment safety assessment inhalation threshold of toxicological concern |
| url | https://www.mdpi.com/2305-6304/13/1/35 |
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