Pathway-based predictive approaches for non-animal assessment of acute inhalation toxicity. (October 2018)

• Record Type: Journal Article
• Authors: Clippinger, Amy J.; Allen, David; Behrsing, Holger; BéruBé, Kelly A.; Bolger, Michael B.; Casey, Warren; DeLorme, Michael; Gaça, Marianna; Gehen, Sean C.; Glover, Kyle; Hayden, Patrick; Hinderliter, Paul; Hotchkiss, Jon A.; Iskandar, Anita; Keyser, Brian; Luettich, Karsta; Ma-Hock, Lan; Maione, Anna G.; Makena, Patrudu; Melbourne, Jodie; Milchak, Lawrence; Ng, Sheung P.; Paini, Alicia; Page, Kathryn; Patlewicz, Grace; Prieto, Pilar; Raabe, Hans; Reinke, Emily N.; Roper, Clive; Rose, Jane; Sharma, Monita; Spoo, Wayne; Thorne, Peter S.; Wilson, Daniel M.; Jarabek, Annie M.;
• Is Part Of: Toxicology in vitro. Volume 52(2018)
• Page Start: 131
• Page End: 145
• Publication Date: 2018-10
• Subjects: Acute inhalation toxicity -- In vitro -- In silico -- Ex vivo -- Quantitative structure-activity relationships (QSAR) -- Adverse outcome pathway -- Aggregate exposure pathway -- Dosimetry -- Integrated approach to testing and assessment (IATA) -- Risk assessment; ADME absorption distribution metabolism and elimination -- AEP aggregate exposure pathway -- AOP adverse outcome pathway -- BAL bronchoalveolar lavage -- BEAS-2B adenovirus-12 SV40 hybrid transformed, non-tumorigenic human bronchial epithelial cells -- CFD model computational fluid dynamics model -- CxT concentration x time exposure -- dae aerodynamic diameter -- DAF dosimetric adjustment factor -- HBE cells human bronchial epithelial cells -- HEC human equivalent concentration -- IATA integrated approach to testing and assessment -- IVIVE in vitro to in vivo extrapolation -- KE key event -- LC50 lethal concentration 50% -- MMAD mass median aerodynamic diameter -- MIE molecular initiating event -- MPPD model Multiple-Path Particle Dosimetry model -- NICEATM NTP Interagency Center for the Evaluation of Alternative Toxicological Methods -- NSAIDs nonsteroidal anti-inflammatory drugs -- NTP National Toxicology Program -- OECD Organisation for Economic Co-operation and Development -- PBPK model physiologically based pharmacokinetic model -- POE portal of entry -- PCLS precision-cut lung slices -- QSAR quantitative structure-activity relationship -- RDDR regional deposited dose ratio -- REACH Registration, Evaluation, Authorisation and Restriction of Chemicals -- RGDR regional gas dose ratio -- RRDR regional retained dose ratio -- SAEC small airway epithelial cells -- TG test guideline -- TSE target site exposure; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2018.06.009
• Languages: English
• ISSNs: 0887-2333

Abstract

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. Highlights: Key events associated with inhalation toxicity are identified Physicochemical properties help inform whether inhalation exposure is likely Existing and emerging non-animal approaches are described A decision tree approach is proposed Case study examples illustrate the potential design of non-animal approaches