Aop: 451

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Interaction with lung resident cell membrane components leads to lung cancer

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Interaction with lung cells leads to lung cancer

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool
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Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Penny Nymark1

Hanna L. Karlsson1

Sabina Halappanavar2

Ulla Vogel3,4

1 Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden

2 Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada

3 National Research Centre for the Working Environment, Copenhagen, Denmark

4 DTU Health Tech, Technical University of Denmark, Kgs. Lyngby, Denmark

Funding: Swedish Fund for Research without Animals (grants N0005-2020 and F0005-2021)

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Penny Nymark   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Penny Nymark
  • Sabina Halappanavar

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite
This AOP was last modified on September 22, 2022 09:31

Revision dates for related pages

Page Revision Date/Time
Substance interaction with the lung resident cell membrane components May 04, 2022 12:11
Increased, secretion of proinflammatory mediators January 25, 2022 15:50
Increased, recruitment of inflammatory cells January 25, 2022 15:52
Increase, Cytotoxicity (epithelial cells) September 16, 2017 10:16
Increased, Reactive oxygen species November 27, 2017 13:15
Secondary genotoxicity May 25, 2022 05:25
Increased, DNA damage and mutation August 13, 2019 05:41
Increase, Cell Proliferation June 23, 2021 12:28
Lung cancer August 13, 2019 05:34
Interaction with the lung cell membrane leads to Increased proinflammatory mediators December 15, 2021 09:26
Interaction with the lung cell membrane leads to Increased, Reactive oxygen species May 25, 2022 05:44
Increased proinflammatory mediators leads to Recruitment of inflammatory cells November 29, 2022 12:42
Interaction with the lung cell membrane leads to Increased, DNA damage and mutation May 25, 2022 05:47
Increase, Cytotoxicity (epithelial cells) leads to Secondary genotoxicity May 25, 2022 05:51
Recruitment of inflammatory cells leads to Increase, Cytotoxicity (epithelial cells) May 25, 2022 05:32
Increase, Cytotoxicity (epithelial cells) leads to Increased, Reactive oxygen species May 25, 2022 05:35
Increased, Reactive oxygen species leads to Secondary genotoxicity May 25, 2022 05:35
Secondary genotoxicity leads to Increased, DNA damage and mutation May 25, 2022 05:35
Increased, DNA damage and mutation leads to Increase, Cell Proliferation July 03, 2019 11:53
Increase, Cell Proliferation leads to Lung cancer July 03, 2019 11:53
nanoparticles December 21, 2016 09:40
welding fumes May 25, 2022 07:02
Carbon black May 25, 2022 07:03
Diesel engine exhaust September 28, 2021 08:55
nanomaterials April 22, 2021 09:28
Titanium dioxide nanoparticles August 29, 2022 08:22

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

This AOP was developed and first presented in Nymark et al. 2021.

The particulate fraction of diesel exhaust is known to be required for carcinogenesis, since filtered exhaust does not cause lung cancer in rodents (Brightwell et al., 1989). Inhaled, nanosized particles deposit primarily in the alveolar region, where clearance is low, and lead to prolonged particle retention enabling particle-bio interaction (Oberdörster et al., 2005; Gaté et al., 2017). Interaction between particles and lung resident cell membrane components (Figure 1A below in the Background section, MIE) leads to inflammation (KE1A) which is proportional to the total deposited surface area (Schmid and Stoeger, 2016; Danielsen et al., 2020; Kokot et al., 2020). The persistence of particles results in long-lasting inflammation (Hougaard et al., 2010; Chézeau et al., 2018). Metabolic activity of pro-inflammatory cells induces formation of ROS, which may also be augmented by the surface reactivity of particles themselves (Jacobsen et al., 2008b; Bendtsen et al., 2020). The sustained inflammatory signaling and concomitant synthesis of reactive radicals, cause a chronic state of oxidant-antioxidant imbalance and loss of protective mechanisms, potentially resulting in secondary genotoxicity (KE1B) (Evans et al., 2019a). Diesel exhaust consists of nanosized particles of inorganic and organic carbon with associated metal oxides and polyaromatic hydrocarbons (PAHs) (Taxell and Santonen, 2016; Bendtsen et al., 2020). Both the carbon core and solvent-extractable fractions containing PAHs are mutagenic in vivo and several metal (oxides) have been classified as (possibly) carcinogenic (IARC, 2006, 2012b; Hashimoto et al., 2007). It is possible that such genotoxic agents leach from the pulmonary deposited particles leading to activation of alternative AOPs associated with the formation of bulky DNA adducts and resulting in accumulation of mutations (Li and Nel, 2006) as indicated by the alternative path in Figure 1A below in the Background section (in gray) (Sasaki et al., 2020). In addition, the insoluble carbon core generates particle-induced ROS leading to oxidative stress (KE1C) (Bendtsen et al., 2020; Gren et al., 2020). In a recent study of five diesel exhaust particles designed to differ in chemical composition, DNA strand breaks (KE2) in bronchoalveolar lavage cells were found to correlate with the ROS forming capacity of the particles (Bendtsen et al., 2020). Similarly, carbon black generates surface-dependent ROS, causing oxidative DNA damage (KE2) and mutagenicity (KE3) in vivo and in vitro (Jacobsen et al., 2008b). Finally, direct interactions between nanosized particles and DNA or the mitotic spindle are also possible, and the AOP features a direct link between the MIE and mutagenicity, i.e., KE3 (Buliaková et al., 2017; Patel et al., 2017).

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Lung cancer, one of the most common and deadly forms of cancer, is in some cases associated with exposure to certain types of particles. With the rise of nanotechnology, there is concern that some engineered nanoparticles may be among such particles. In the absence of epidemiological evidence, assessment of nanoparticle carcinogenicity is currently performed on a time-consuming case-by-case basis, relying mainly on animal experiments. Non-animal alternatives exist, including a few validated cell-based methods accepted for regulatory risk assessment of nanoparticles. Furthermore, new approach methodologies (NAMs), focused on carcinogenic mechanisms and capable of handling the increasing numbers of nanoparticles, have been developed. However, such alternative methods are mainly applied as weight-of-evidence linked to generally required animal data, since challenges remain regarding interpretation of the results. These challenges may be more easily overcome by the novel Adverse Outcome Pathway (AOP) framework, which provides a basis for validation and uptake of alternative mechanism-focused methods in risk assessment. Here, we propose an AOP for lung cancer induced by nanosized foreign matter, anchored to a selection of 18 standardized methods and NAMs for in silico- and in vitro-based integrated assessment of lung carcinogenicity (Figure 1). The AOP provides a basis for development of AOP-aligned alternative methods-based integrated testing strategies for assessment of nanoparticle-induced lung cancer.

Adverse Outcome Pathway Development for Assessment of Lung Carcinogenicity by Nanoparticles

Figure 1. A putative AOP for pulmonary deposition and retention of nanosized foreign matter leading to lung cancer, including anchored in silico and in vitro methods. (A) A putative AOP developed based on information and knowledge about the process-generated and engineered nanoparticles diesel exhaust, carbon black, and TiO2. Suggested relevant existing KEs in the AOP-Wiki, that could serve for informing development of the proposed AOP, are mentioned within parentheses. (B) The AOP supports integrated application of in silico- and in vitro-based standard OECD tests with new approach methodologies (NAMs), including models/approaches for prediction of deposited dose, detection of ROS generation, inflammation, DNA damage, mutations, and cell transformation. Examples of specific assays are provided at the bottom. MIE, molecular initiating event; KE, key event; AO, adverse outcome; AOP, adverse outcome pathway; IC-PMS, inductively coupled plasma mass spectrometry; AAS, atomic absorption spectroscopy; TEM, transmission electron microscopy; ROS, reactive oxygen species; DCFH-DA, 2'-7'dichlorofluorescin diacetate; GSH, glutathione; ELISA, enzyme-linked immunosorbent assay; HT, high-throughput; FPG, formamidopyrimidine DNA glycosylase; OECD, Organization for Economic Co-operation and Development; HPRT, hypoxanthine phosphorybosyl transferase; TK, thymidine kinase; FE1-MML, FE1-MutaMouse lung epithelial cells.

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 1495 Substance interaction with the lung resident cell membrane components Interaction with the lung cell membrane
KE 1496 Increased, secretion of proinflammatory mediators Increased proinflammatory mediators
KE 1497 Increased, recruitment of inflammatory cells Recruitment of inflammatory cells
KE 780 Increase, Cytotoxicity (epithelial cells) Increase, Cytotoxicity (epithelial cells)
KE 1115 Increased, Reactive oxygen species Increased, Reactive oxygen species
KE 2006 Secondary genotoxicity Secondary genotoxicity
KE 1669 Increased, DNA damage and mutation Increased, DNA damage and mutation
KE 870 Increase, Cell Proliferation Increase, Cell Proliferation
AO 1670 Lung cancer Lung cancer

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

List of the literature that was cited for this AOP. More help

Nymark P, Karlsson HL, Halappanavar S, Vogel U. Adverse Outcome Pathway Development for Assessment of Lung Carcinogenicity by Nanoparticles. Front Toxicol. 2021 Apr 29;3:653386. https://doi.org/10.3389/ftox.2021.653386. eCollection 2021.

Bendtsen, K. M., Gren, L., Malmborg, V. B., Shukla, P. C., Tunér, M., Essig, Y. J., et al. (2020). Particle characterization and toxicity in C57BL/6 mice following instillation of five different diesel exhaust particles designed to differ in physicochemical properties. Part Fibre Toxicol. 17:38. doi: 10.1186/s12989-020-00369-9

Brightwell, J., Fouiliet, X., Cassano-Zoppi, A.-L., Bernstein, D., Crawley, F., Duchosal, F., et al. (1989). Tumours of the respiratory tract in rats and hamsters following chronic inhalation of engine exhaust emissions. J. Appl. Toxicol. 9, 23–31. doi: 10.1002/jat.2550090106

Buliaková, B., Mesárošová, M., Bábelová, A., Šelc, M., Némethová, V., Šebová, L., et al. (2017). Surface-modified magnetite nanoparticles act as aneugen-like spindle poison. Nanomedicine 13, 69–80. doi: 10.1016/j.nano.2016.08.027

Chézeau, L., Sébillaud, S., Safar, R., Seidel, C., Dembélé, D., Lorcin, M., et al. (2018). Short- and long-term gene expression profiles induced by inhaled TiO2 nanostructured aerosol in rat lung. Toxicol. Appl. Pharmacol. 356, 54–64. doi: 10.1016/j.taap.2018.07.013

Danielsen, P. H., Knudsen, K. B., Štrancar, J., Umek, P., Koklič, T., Garvas, M., et al. (2020). Effects of physicochemical properties of TiO2 nanomaterials for pulmonary inflammation, acute phase response and alveolar proteinosis in intratracheally exposed mice. Toxicol. Appl. Pharmacol. 386:114830. doi: 10.1016/j.taap.2019.114830

Evans, S. J., Clift, M. J. D., Singh, N., Wills, J. W., Hondow, N., Wilkinson, T. S., et al. (2019a). In vitro detection of in vitro secondary mechanisms of genotoxicity induced by engineered nanomaterials. Part. Fibre Toxicol. 16:8. doi: 10.1186/s12989-019-0291-7

Gaté, L., Disdier, C., Cosnier, F., Gagnaire, F., Devoy, J., Saba, W., et al. (2017). Biopersistence and translocation to extrapulmonary organs of titanium dioxide nanoparticles after subacute inhalation exposure to aerosol in adult and elderly rats. Toxicol. Lett. 265, 61–69. doi: 10.1016/j.toxlet.2016.11.009

Gren, L., Malmborg, V. B., Jacobsen, N. R., Shukla, P. C., Bendtsen, K. M., Eriksson, A. C., et al. (2020). Effect of renewable fuels and intake O2 concentration on diesel engine emission characteristics and Reactive Oxygen Species (ROS) formation. Atmosphere 11:641. https://www.mdpi.com/2073-4433/11/6/641/htm 10.3390/atmos11060641

Hashimoto, A. H., Amanuma, K., Hiyoshi, K., Sugawara, Y., Goto, S., Yanagisawa, R., et al. (2007). Mutations in the lungs of gpt delta transgenic mice following inhalation of diesel exhaust. Environ. Mol. Mutagen 48, 682–693. doi: 10.1002/em.20335

Hougaard, K. S., Jackson, P., Jensen, K. A., Sloth, J. J., Löschner, K., Larsen, E. H., et al. (2010). Effects of prenatal exposure to surface-coated nanosized titanium dioxide (UV-Titan). A study in mice. Part Fibre Toxicol. 7:16. doi: 10.1186/1743-8977-7-16

IARC (2006). Cobalt in Hard Metals and Cobalt Sulfate, Gallium Arsenide, Indium Phosphideand Vanadium Pentoxide. Monograph 86. Available online at: https://monographs.iarc.fr/wp-content/uploads/2018/06/mono86.pdf

IARC (2010). Carbon Black, Titanium Dioxide, and Talc.Monograph 93. Available online at: https://publications.iarc.fr/111

IARC (2012a). Diesel and Gasoline Engine Exhausts and Some Nitroarenes. Monograph 105. Available online at: https://publications.iarc.fr/129

IARC (2012b). Review of Human Carcinogens (Package of 6 Volumes: A,B,C,D,E,F). Monograph 100. Available online at:: https://monographs.iarc.fr/wp-content/ uploads/2018/06/mono100C-10.pdf

IARC (2014). Some Nanomaterials and Some Fibres. Monograph 111. Available online at:: https://publications.iarc.fr/552

Jacobsen, N. R., Pojana, G., White, P., Møller, P., Cohn, C. A., Smith Korsholm, K., et al. (2008b). Genotoxicity, cytotoxicity, and reactive oxygen species induced by single-walled carbon nanotubes and C60 fullerenes in the FE1-Muta™Mouse lung epithelial cells. Environ. Mol. Mutagen 49, 476–487. doi: 10.1002/em.20406

Kokot, H., Kokot, B., Sebastijanović, A., Voss, C., Podlipec, R., Zawilska, P., et al. (2020). Prediction of chronic inflammation for inhaled particles: the impact of material cycling and quarantining in the lung epithelium. Adv. Mater. 32:2003913. doi: 10.1002/adma.202003913

Li, N., and Nel, A. E. (2006). The cellular impacts of diesel exhaust particles: beyond inflammation and death. Eur. Respir. J. 27, 667–668. doi: 10.1183/09031936.06.00025006

Oberdörster, G., Oberdörster, E., and Oberdörster, J. (2005). Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ. Health Perspect. 113, 823–839. doi: 10.1289/ehp.7339

Patel, S., Patel, P., and Bakshi, S. R. (2017). Titanium dioxide nanoparticles: an in vitro study of DNA binding, chromosome aberration assay, and comet assay. Cytotechnology 69, 245–263. doi: 10.1007/s10616-016-0054-3

Sasaki, J. C., Allemang, A., Bryce, S. M., Custer, L., Dearfield, K. L., Dietz, Y., et al. (2020). Application of the adverse outcome pathway framework to genotoxic modes of action. Environ. Mol. Mutagen. 61, 114–134. doi: 10.1002/em.22339

Schmid, O., and Stoeger, T. (2016). Surface area is the biologically most effective dose metric for acute nanoparticle toxicity in the lung. J. Aerosol. Sci. 99, 133–143. doi: 10.1016/j.jaerosci.2015.12.006

Taxell, P., and Santonen, T. (2016). Diesel Engine Exhaust. Occupational and Environmental Medicine. The Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals and the Dutch Expert Committee on Occupational Safety. Available online at: https://gupea.ub.gu.se/bitstream/2077/44340/1/gupea_2077_44340_1.pdf