TY - JOUR
T1 - NAM-based prediction of point-of-contact toxicity in the lung
T2 - A case example with 1,3-dichloropropene
AU - Moreau, Marjory
AU - Fisher, Jeff
AU - Andersen, Melvin E.
AU - Barnwell, Asayah
AU - Corzine, Sage
AU - Ranade, Aarati
AU - McMullen, Patrick D.
AU - Slattery, Scott D.
N1 - Funding Information:
We thank the American Chemistry Council Long-Range Research Initiative for funding for this work, the PETA Science Consortium International for donation of the Vitrocell exposure system, and Rick Becker, Madhuri Singal, Athena Keene, and Paul Hinderliter for scientific consultation.
Funding Information:
This work was funded by the American Chemistry Council (ACC) under its Long-Range Research Initiative (Project # 2020-SV1 ). The ACC approved the project proposal, reviewed results and provided scientific advice during the course of the study, and recommended publication after completion of the study.
Publisher Copyright:
© 2022 The Authors
PY - 2022/11
Y1 - 2022/11
N2 - Time, cost, ethical, and regulatory considerations surrounding in vivo testing methods render them insufficient to meet existing and future chemical safety testing demands. There is a need for the development of in vitro and in silico alternatives to replace traditional in vivo methods for inhalation toxicity assessment. Exposures of differentiated airway epithelial cultures to gases or aerosols at the air–liquid interface (ALI) can assess tissue responses and in vitro to in vivo extrapolation can align in vitro exposure levels with in-life exposures expected to give similar tissue exposures. Because the airway epithelium varies along its length, with various regions composed of different cell types, we have introduced a known toxic vapor to five human-derived, differentiated, in vitro airway epithelial cell culture models—MucilAir of nasal, tracheal, or bronchial origin, SmallAir, and EpiAlveolar—representing five regions of the airway epithelium—nasal, tracheal, bronchial, bronchiolar, and alveolar. We have monitored toxicity in these cultures 24 h after acute exposure using an assay for transepithelial conductance (for epithelial barrier integrity) and the lactate dehydrogenase (LDH) release assay (for cytotoxicity). Our vapor of choice in these experiments was 1,3-dichloropropene (1,3-DCP). Finally, we have developed an airway dosimetry model for 1,3-DCP vapor to predict in vivo external exposure scenarios that would produce toxic local tissue concentrations as determined by in vitro experiments. Measured in vitro points of departure (PoDs) for all tested cell culture models were similar. Calculated rat equivalent inhaled concentrations varied by model according to position of the modeled tissue within the airway, with nasal respiratory tissue being the most proximal and most sensitive tissue, and alveolar epithelium being the most distal and least sensitive tissue. These predictions are qualitatively in accordance with empirically determined in vivo PoDs. The predicted PoD concentrations were close to, but slightly higher than, PoDs determined by in vivo subchronic studies.
AB - Time, cost, ethical, and regulatory considerations surrounding in vivo testing methods render them insufficient to meet existing and future chemical safety testing demands. There is a need for the development of in vitro and in silico alternatives to replace traditional in vivo methods for inhalation toxicity assessment. Exposures of differentiated airway epithelial cultures to gases or aerosols at the air–liquid interface (ALI) can assess tissue responses and in vitro to in vivo extrapolation can align in vitro exposure levels with in-life exposures expected to give similar tissue exposures. Because the airway epithelium varies along its length, with various regions composed of different cell types, we have introduced a known toxic vapor to five human-derived, differentiated, in vitro airway epithelial cell culture models—MucilAir of nasal, tracheal, or bronchial origin, SmallAir, and EpiAlveolar—representing five regions of the airway epithelium—nasal, tracheal, bronchial, bronchiolar, and alveolar. We have monitored toxicity in these cultures 24 h after acute exposure using an assay for transepithelial conductance (for epithelial barrier integrity) and the lactate dehydrogenase (LDH) release assay (for cytotoxicity). Our vapor of choice in these experiments was 1,3-dichloropropene (1,3-DCP). Finally, we have developed an airway dosimetry model for 1,3-DCP vapor to predict in vivo external exposure scenarios that would produce toxic local tissue concentrations as determined by in vitro experiments. Measured in vitro points of departure (PoDs) for all tested cell culture models were similar. Calculated rat equivalent inhaled concentrations varied by model according to position of the modeled tissue within the airway, with nasal respiratory tissue being the most proximal and most sensitive tissue, and alveolar epithelium being the most distal and least sensitive tissue. These predictions are qualitatively in accordance with empirically determined in vivo PoDs. The predicted PoD concentrations were close to, but slightly higher than, PoDs determined by in vivo subchronic studies.
KW - 1,3-Dichloropropene
KW - Dosimetry
KW - In vitro
KW - Inhalation
KW - PBPK modeling
KW - Vitrocell
UR - http://www.scopus.com/inward/record.url?scp=85139313509&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85139313509&partnerID=8YFLogxK
U2 - 10.1016/j.tox.2022.153340
DO - 10.1016/j.tox.2022.153340
M3 - Article
C2 - 36183849
AN - SCOPUS:85139313509
SN - 0300-483X
VL - 481
JO - Toxicology
JF - Toxicology
M1 - 153340
ER -