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Toxicol In Vitro. 2018 Oct;52:131-145. doi: 10.1016/j.tiv.2018.06.009. Epub 2018 Jun 20.

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

Author information

1
PETA International Science Consortium Ltd., Society Building, 8 All Saints Street, London N1 9RL, United Kingdom. Electronic address: amyjc@piscltd.org.uk.
2
Integrated Laboratory Systems, Contractor Supporting the NTP Interagency Center for the Evaluation of Alternative Toxicological Methods, Research Triangle Park, NC, United States.
3
Institute for In Vitro Sciences, 30 West Watkins Mill Road, Suite 100, Gaithersburg, MD 20878, United States.
4
Cardiff School of Biosciences, Museum Avenue, CF10 3AX, Wales, United Kingdom.
5
Simulations Plus, Inc., 42505 10th Street West, Lancaster, CA 93534, United States.
6
NIH/NIEHS/DNTP/NICEATM, Research Triangle Park, North Carolina 27709, United States.
7
3M, 220-6E-03, St. Paul, MN 55144, United States.
8
British American Tobacco plc, Globe House, 4 Temple Place, London WC2R 2PG, United Kingdom.
9
Dow AgroSciences, Indianapolis, IN, United States.
10
Defense Threat Reduction Agency, Aberdeen Proving Ground, MD 21010, United States.
11
MatTek Corporation, 200 Homer Ave, Ashland, MA 01721, United States.
12
Syngenta, Greensboro, NC, United States.
13
The Dow Chemical Company, Midland, MI 48674, United States.
14
Philip Morris Products SA, Philip Morris International R&D, Neuchâtel, Switzerland.
15
RAI Services Company, 401 North Main Street, Winston-Salem, NC 27101, United States.
16
BASF SE, Carl-Bosch-Strasse 38, 67056 Ludwigshafen am Rhein, Germany.
17
PETA International Science Consortium Ltd., Society Building, 8 All Saints Street, London N1 9RL, United Kingdom.
18
E.I. du Pont de Nemours and Company, DuPont Haskell Global Center for Health Sciences, P. O. Box 30, Newark, DE 19714, United States.
19
European Commission, Joint Research Centre (JRC), Ispra, Italy.
20
The Clorox Company, 4900 Johnson Dr, Pleasanton, CA 94588, United States.
21
U.S. Environmental Protection Agency, Office of Research and Development, National Center for Computational Toxicology, Research Triangle Park, NC, United States.
22
U.S. Army Public Health Center, 8252 Blackhawk Rd. Bldg. E-5158, ATTN: MCHB-PH-HEF Gunpowder, MD 21010-5403, United States.
23
Charles River Edinburgh Ltd., Edinburgh EH33 2NE, United Kingdom.
24
Procter & Gamble Co, 11530 Reed Hartman Highway, Cincinnati, OH 45241, United States.
25
University of Iowa College of Public Health, Iowa City, IA, United States.
26
U.S. Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment, Research Triangle Park, NC, United States.

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.

KEYWORDS:

Acute inhalation toxicity; Adverse outcome pathway; Aggregate exposure pathway; Dosimetry; Ex vivo; In silico; In vitro; Integrated approach to testing and assessment (IATA); Quantitative structure-activity relationships (QSAR); Risk assessment

PMID:
29908304
DOI:
10.1016/j.tiv.2018.06.009
[Indexed for MEDLINE]
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