TY - JOUR
T1 - An Integrated Approach to Testing and Assessment to Support Grouping and Read-Across of Nanomaterials after Inhalation Exposure
AU - Braakhuis, Hedwig M.
AU - Murphy, Fiona
AU - Ma-Hock, Lan
AU - Dekkers, Susan
AU - Keller, Johannes
AU - Oomen, Agnes G.
AU - Stone, Vicki
N1 - Funding Information:
This research was funded by EU-project GRACIOUS funded by European Union’s Horizon 2020 research and innovation programme under grant agreement 7608640, with co-funding by the Dutch Ministry of Infrastructure and Water Management.
Publisher Copyright:
© Hedwig M. Braakhuis et al., 2021; Published by Mary Ann Liebert, Inc. 2021.
PY - 2021/9/17
Y1 - 2021/9/17
N2 - Introduction: Here, we describe the generation of hypotheses for grouping nanoforms (NFs) after inhalation exposure and the tailored Integrated Approaches to Testing and Assessment (IATA) with which each specific hypothesis can be tested. This is part of a state-of-the-art framework to support the hypothesis-driven grouping and read-across of NFs, as developed by the EU-funded Horizon 2020 project GRACIOUS.Development of Grouping Hypotheses and IATA: Respirable NFs, depending on their physicochemical properties, may dissolve either in lung lining fluid or in acidic lysosomal fluid after uptake by cells. Alternatively, NFs may also persist in particulate form. Dissolution in the lung is, therefore, a decisive factor for the toxicokinetics of NFs. This has led to the development of four hypotheses, broadly grouping NFs as instantaneous, quickly, gradually, and very slowly dissolving NFs. For instantaneously dissolving NFs, hazard information can be derived by read-across from the ions. For quickly dissolving particles, as accumulation of particles is not expected, ion toxicity will drive the toxic profile. However, the particle aspect influences the location of the ion release. For gradually dissolving and very slowly dissolving NFs, particle-driven toxicity is of concern. These NFs may be grouped by their reactivity and inflammation potency. The hypotheses are substantiated by a tailored IATA, which describes the minimum information and laboratory assessments of NFs under investigation required to justify grouping.Conclusion: The GRACIOUS hypotheses and tailored IATA for respiratory toxicity of inhaled NFs can be used to support decision making regarding Safe(r)-by-Design product development or adoption of precautionary measures to mitigate potential risks. It can also be used to support read-across of adverse effects such as pulmonary inflammation and subsequent downstream effects such as lung fibrosis and lung tumor formation after long-term exposure.
AB - Introduction: Here, we describe the generation of hypotheses for grouping nanoforms (NFs) after inhalation exposure and the tailored Integrated Approaches to Testing and Assessment (IATA) with which each specific hypothesis can be tested. This is part of a state-of-the-art framework to support the hypothesis-driven grouping and read-across of NFs, as developed by the EU-funded Horizon 2020 project GRACIOUS.Development of Grouping Hypotheses and IATA: Respirable NFs, depending on their physicochemical properties, may dissolve either in lung lining fluid or in acidic lysosomal fluid after uptake by cells. Alternatively, NFs may also persist in particulate form. Dissolution in the lung is, therefore, a decisive factor for the toxicokinetics of NFs. This has led to the development of four hypotheses, broadly grouping NFs as instantaneous, quickly, gradually, and very slowly dissolving NFs. For instantaneously dissolving NFs, hazard information can be derived by read-across from the ions. For quickly dissolving particles, as accumulation of particles is not expected, ion toxicity will drive the toxic profile. However, the particle aspect influences the location of the ion release. For gradually dissolving and very slowly dissolving NFs, particle-driven toxicity is of concern. These NFs may be grouped by their reactivity and inflammation potency. The hypotheses are substantiated by a tailored IATA, which describes the minimum information and laboratory assessments of NFs under investigation required to justify grouping.Conclusion: The GRACIOUS hypotheses and tailored IATA for respiratory toxicity of inhaled NFs can be used to support decision making regarding Safe(r)-by-Design product development or adoption of precautionary measures to mitigate potential risks. It can also be used to support read-across of adverse effects such as pulmonary inflammation and subsequent downstream effects such as lung fibrosis and lung tumor formation after long-term exposure.
KW - case study
KW - grouping
KW - IATA
KW - inhalation exposure
KW - nanomaterials
KW - read-across
KW - testing strategy
UR - http://www.scopus.com/inward/record.url?scp=85115616414&partnerID=8YFLogxK
U2 - 10.1089/aivt.2021.0009
DO - 10.1089/aivt.2021.0009
M3 - Article
C2 - 34746334
AN - SCOPUS:85115616414
SN - 2332-1512
VL - 7
SP - 112
EP - 128
JO - Applied In Vitro Toxicology
JF - Applied In Vitro Toxicology
IS - 3
ER -