An integrated approach to testing and assessment of high aspect ratio nanomaterials and its application for grouping based on a common mesothelioma hazard

Our plain-English summary of An integrated approach to testing and assessment of high aspect ratio nanomaterials and its application for grouping based on a common mesothelioma hazard, by F. Murphy, S. Dekkers, H. Braakhuis, et al (NanoImpact, 2021).

The study

• Authors: F. Murphy, S. Dekkers, H. Braakhuis, L. Ma-Hock, H. Johnston, G. Janer, L. di Cristo, S. Sabella, N.R. Jacobsen, A.G. Oomen, A. Haase, T. Fernandes, V. Stone
• Journal: NanoImpact
• Published: 2021;22:100314
• Cited by: 40 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Here we describe the development of an Integrated Approach to Testing and Assessment (IATA) to support the grouping of different types (nanoforms; NFs) of High Aspect Ratio Nanomaterials (HARNs), based on their potential to cause mesothelioma. Hazards posed by the inhalation of HARNs are of particular concern as they exhibit physical characteristics similar to pathogenic asbestos fibres. The approach for grouping HARNs presented here is part of a framework to provide guidance and tools to group similar NFs and aims to reduce the need to assess toxicity on a case-by-case basis. The approach to grouping is hypothesis-driven, in which the hypothesis is based on scientific evidence linking critical physicochemical descriptors for NFs to defined fate/toxicokinetic and hazard outcomes. The HARN IATA prompts users to address relevant questions (at decision nodes; DNs) regarding the morphology, biopersistence and inflammatory potential of the HARNs under investigation to provide the necessary evidence to accept or reject the grouping hypothesis. Each DN in the IATA is addressed in a tiered manner, using data from simple in vitro or in silico methods in the lowest tier or from in vivo approaches in the highest tier. For these proposed methods we provide justification for the critical descriptors and thresholds that allow grouping decisions to be made. Application of the IATA allows the user to selectively identify HARNs which may pose a mesothelioma hazard, as demonstrated through a literature-based case study. By promoting the use of alternative, non-rodent approaches such as in silico modelling, in vitro and cell-free tests in the initial tiers, the IATA testing strategy streamlines information gathering at all stages of innovation through to regulatory risk assessment while reducing the ethical, time and economic burden of testing.

Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.

In plain English

This article described an Integrated Approach to Testing and Assessment (IATA), a decision-tree method from the EU-funded GRACIOUS project. It aims to group high aspect ratio nanomaterials (HARNs), which share physical characteristics with pathogenic asbestos fibres, by their potential mesothelioma hazard after inhalation. It works in tiers, from simple laboratory tests to animal studies. It asks whether a material reaches the deep lung, dissolves very slowly, has enough fibres longer than 5 μm (first-tier threshold: 10% of counted fibres), is rigid, and causes 'frustrated phagocytosis'. The authors tested it on 14 rodent studies (2008 to 2020) covering 16 multiwalled carbon nanotubes (MWCNT). Of these, 10 were categorized mesothelioma-positive and 6 mesothelioma-negative. The method rejected 6 MWCNT as not sufficiently long or rigid; none of those had caused mesothelioma in the rodents tested. Enough information was found to confirm acceptance of the grouping hypothesis for one MWCNT, Mitsui-7; data gaps remained for 3 other mesothelioma-positive MWCNT. The authors concluded the method was stringent enough to distinguish mesothelioma-positive from mesothelioma-negative MWCNT. They noted that most studies applied the tubes directly to the mesothelium rather than by inhalation.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Development of a tiered testing and assessment framework (decision tree) for grouping nanomaterials, evaluated with a literature-based case study
• Who was studied: Published rodent studies (14 in vivo studies, 2008 to 2020) assessing 16 different multiwalled carbon nanotubes for mesothelioma development
• Exposure: High aspect ratio nanomaterials, with multiwalled carbon nanotubes as the case study. In the reviewed studies they were given by injection into the peritoneal cavity (8 studies), the pleural cavity (1) or the scrotal sac (1), by capsule implantation into a 'Kertai fold' in the peritoneal cavity (1), or by intratracheal spraying into the lungs (3).
• Main results:
  • Based on reported mesothelioma incidence, 10 of the 16 MWCNT were categorized as mesothelioma-positive and 6 as mesothelioma-negative.
  • The IATA rejected the grouping hypothesis for 6 MWCNT because they were not sufficiently long or rigid.
  • None of the MWCNT rejected by the IATA had caused mesothelioma in the rodent models tested.
  • After a targeted search for additional studies, enough information was found to confirm acceptance of the grouping hypothesis for one MWCNT, Mitsui-7.
  • For the other 3 mesothelioma-positive MWCNT with additional studies, supporting information was collected but data gaps remained.
  • Ranking the MWCNT by additional descriptors (purity, contaminants, surface defects) showed no trend reflecting mesothelioma development.
  • For the length question, the first tier uses the size distribution of individual fibres, reported as the percentage of fibres longer than 5 μm. The authors proposed a pragmatic threshold of 10% of counted fibres to class a sample as 'pathogenically long'.
• The authors' conclusion: The authors concluded that the case study showed the IATA decision points were stringent enough to differentiate mesothelioma-positive from mesothelioma-negative MWCNT.
• Limitations the authors state:
  • Most studies applied MWCNT directly to the mesothelium (intraperitoneal, intrapleural or intrascrotal injection), so information on deposition in the deep lung was lacking.
  • The animal models used do not replicate realistic inhalation exposure, so risk cannot be extrapolated to inhalation.
  • Most studies did not examine how MWCNT interact with macrophages, so the frustrated phagocytosis question could not be addressed.
  • The studies had gaps in how the MWCNT were characterized, such as impurity levels, and relied on summary size measures.
  • The case study required some expert opinion because of the limitations and quality of the available data.
  • The IATA was developed on 'simple' HARNs and may not reflect industrially relevant, more complex forms and mixtures.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Aspect Ratio (Length-to-diameter ratio), Mesothelioma, biopersistence.

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