Event: 1556

Key Event Title


Increase, lung cancer

Short name


Increase, lung cancer

Biological Context


Level of Biological Organization

Organ term


Key Event Components


Process Object Action

Key Event Overview

AOPs Including This Key Event


AOP Name Role of event in AOP
Ionizing energy leading to lung cancer AdverseOutcome



Taxonomic Applicability


Term Scientific Term Evidence Link
human Homo sapiens High NCBI
rat Rattus norvegicus High NCBI
mouse Mus musculus High NCBI

Life Stages


Life stage Evidence
All life stages High

Sex Applicability


Term Evidence
Unspecific High

Key Event Description


Abnormally high levels of cell proliferation in the lungs may eventually culminate in the formation of malignant tumours and thus lung cancer. The term lung cancer refers to all malignant neoplasms arising from the bronchial, bronchiolar, and alveolar epithelium (Keshamouni et al., 2009). The cellular origin(s) of lung cancer remains largely unknown. It has been speculated that different tumour histopathological subtypes arise from distinct cells of origin localized in defined microenvironments. Histological characteristics of lung cancers, as defined by light microscopy, have led to the categorization of lung cancers into four main subtypes: small cell carcinoma, adenocarcinoma, squamous cell carcinoma, and large cell carcinoma (Beasly et al., 2005). These histological subtypes are grouped under one of the two umbrella terms used to describe lung cancers:  small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). The term SCLC refers to small cell carcinoma. The term NSCLC, which represents approximately 85% of all lung cancers (Molina et al., 2008), encompasses squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. These three tumour types are grouped together due to similarities in their prognosis and management (Keshamouni et al., 2009); patients with NSCLC often have poor prognoses and low 5-year survival rates due to the high metastatic potential of the tumours (Spira and Ettinger, 2004; Herbst et al., 2008). Some of the most common sites for lung cancer metastasis are the other lobe of the lungs, skeleton, adrenal glands, liver, and brain (Simon et al., 2015).

How It Is Measured or Detected


Assay Name Reference Description OECD Approved Assay
Computed Tomography (CT) Scans: CT, High-Resolution CT (HRCT), and   Positron Emission Tomography-CT (PET-CT) Bach et al., 2012; Ollier et al., 2014 CT scans are described as a 3D X-ray; They provide cross-sections of organs/tissues/bones, and can thus be used to detect tumours N/A
Magnetic Resonance Imaging (MRI) Khalil et al., 2016; Wu et al., 2011 This technique uses magnetic fields and radio waves (NOT ionizing radiation) to generate a picture of organs, and can thus be used to detect tumours N/A
Sputum Analysis Hubers et al., 2013 Sputum is collected and analyzed for a variety of markers, including mutations in KRAS and TP53, specific RNA/protein biomarkers, and chromosomal aberrations N/A
Bronchoscopy: Conventional White Light Bronchoscopy, Autofluorescence Bronchoscopy (AFB), and Endobronchial Ultrasonography (EBUS) Ikeda et al., 2007 Bronchoscope (usually with a camera) is passed down through the throat to the lungs to provide a visual of the respiratory tract; Traditionally, visualization has been performed using conventional white light, but new technologies have also allowed for visualization using fluorescence and ultrasound technologies N/A
Transbronchial Needle Aspiration Navani et al., 2015; Aziz, 2012 A needle is used to aspirate a tissue sample from a lesion of suspected lung cancer  for analysis N/A
Analysis of Volatile Organic Compounds in the Breath Zhou et al., 2017 Volatile organic compounds, which may act as lung cancer biomarkers, are  collected from the breath and quantified (mostly using mass spectrometry) N/A
Cell Transformation Assays Redpath et al., 1987 Measurement of the tumourigenicity of a tumour/biopsy sample by analyzing changes in cell physiology and morphology in response to tumour-inducing radiation or chemicals Yes (No. 231)

Rodent Two-Year Cancer Bioassays


(Carcinogenicity Studies)

Matsumo, 2012; Nambiar, 2014; Maronpot, 2015 Animals are exposed to a possible carcinogen for a long period of time (often two years), allowing for long-term cancer-related studies Yes (No. 451)
Window Chamber Models Moeller, 2004; Schafer, 2014; Chen, 2016 Window chambers are implanted into the animal to observe tumour progression in living animals using imaging techniques such as in vivo microscopy, MRI or nuclear imaging N/A
Xenograft Assays Wang, 2018; Shi, 2017; Jin, 2018; Wang, 2017; Zhou, 2012 Tumour cells (usually human) are grown in vitro and injected into animals to induce tumour growth and/or to test the tumourigenicity of the injected cells N/A


Domain of Applicability


Lung cancer and subsequent metastasis occurs in multicellular eukaryotic vertebrate organisms that have lungs.

Evidence for Perturbation by Stressor

Regulatory Significance of the Adverse Outcome


At present the AOP framework is not readily used to support regulatory decision-making in radiation protection practices.The goal of developing this AOP is to bring attention to the framework as an effective means to organize knowledge and identify gaps associated with the mechanistic understanding of low dose radiation exposures. We have used lung cancer as the case example due to its relevance to both radiation and chemical risk assessment. This AOP will help build the concept of an “all hazards” approach to risk assessment, as it will be the first  with a molecular initiating event that is specific to a radiation insult. This in turn could serve to identify networks that are critical to both radiation and chemical exposure scenarios and contribute to prioritizing co-exposures of relevance to risk assessment. By developing this AOP, we will support the necessary efforts highlighted by the international and national radiation protection agencies such as, the United Nations Scientific Committee on the Effects of Atomic Radiation, International Commission of Radiological Protection, International Dose Effect Alliance and the Electric Power Research Institute Radiation Program to consolidate and enhance the knowledge in understanding the mechanisms of low dose radiation exposures from the cellular to organelle levels within the system.



Aziz, F. 2012. Endobronchial ultrasound-guided transbronchial needle aspiration for staging of lung cancer: a concise review. Transl Lung Cancer Res, 1(3), 208-213. doi:10.3978/j.issn.2218-6751.2012.09.08

Bach, P. B., Mirkin, J. N., Oliver, T. K., Azzoli, C. G., Berry, D. A., Brawley, O. W., & Detterbeck, F. C. 2012. Benefits and harms of CT screening for lung cancer: a systematic review. JAMA, 307(22), 2418-2429. doi:10.1001/jama.2012.5521

Beasley, M. B., Brambilla, E., & Travis, W. D. 2005. The 2004 World Health Organization classification of lung tumors. Seminars in Roentgenology, 40(2), 90-97. doi:10.1053/j.ro.2005.01.001

Chen Y, Maeda A, Bu J, DaCosta R. 2016. Femur Window Chamber Model for In Vivo Cell Tracking in the Murine Bone Marrow. J Vis Exp. (113). doi: 10.3791/54205.

Herbst, R. S., Heymach, J. V., & Lippman, S. M. 2008. Lung cancer. N Engl J Med. 359, 1367– 80.

Hubers, A. J., Prinsen, C. F., Sozzi, G., Witte, B. I., & Thunnissen, E. 2013. Molecular sputum analysis for the diagnosis of lung cancer. Br J Cancer, 109(3), 530-537. doi:10.1038/bjc.2013.393

Ikeda, N., Hayashi, A., Iwasaki, K., Honda, H., Tsuboi, M., Usuda, J., & Kato, H. 2007. Comprehensive diagnostic bronchoscopy of central type early stage lung cancer. Lung Cancer, 56(3), 295-302. doi:10.1016/j.lungcan.2007.01.009

Jin Y, Xu K, Chen Q, Wang B, Pan J, Huang S, Wei Y, Ma H. 2018. Simvastatin inhibits the development of radioresistant esophageal cancer cells by increasing the radiosensitivity and reversing EMT process via the PTEN-PI3K/AKT pathway. Exp Cell Res.362(2):362-369. Doi: 10.1016/j.yexcr.2017.11.037.

Keshamouni, V., Arenberg, D., & Kalemkerian, G. 2009. Lung Cancer Metastasis: Novel Biological Mechanisms and Impact on Clinical Practice. Springer Science + Business Media. Doi: 10.1007/978-1-4419-0772-1.

Khalil, A., Majlath, M., Gounant, V., Hess, A., Laissy, J. P., & Debray, M. P. 2016. Contribution of magnetic resonance imaging in lung cancer imaging. Diagnostic and Interventional Imaging, 97(10), 991-1002. doi:10.1016/j.diii.2016.08.015

Maronpot RR, Thoolen RJ, Hansen B. Two-year carcinogenicity study of acrylamide in Wistar Han rats with in utero exposure.Exp Toxicol Pathol. 2015 Feb;67(2):189-95. doi: 10.1016/j.etp.2014.11.009.

Matsumoto M, Suzuki M, Kano H, Aiso S, Yamazaki K, Fukushima S. 2012. Carcinogenicity of ortho-phenylenediamine dihydrochloride in rats and mice by two-year drinking water treatment. Arch Toxicol. 86(5):791-804. doi: 10.1007/s00204-012-0800-z. Epub 2012 Jan 21.

Moeller BJ, Cao Y, Li CY, Dewhirst MW. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell. 2004 May;5(5):429-41.

Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. 2008. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 83(5):584-94. doi: 10.4065/83.5.584.

Nambiar PR, Morton D, Dochterman LW, Houle C, Thomford PJ, Fate G, Bailey SA, Finch GL. 2015. Two-year carcinogenicity study in rats with a nonnucleoside reverse transcriptase inhibitor. Toxicol Pathol. 43(3):354-65. doi: 10.1177/0192623314544381.

Navani, N., Nankivell, M., Lawrence, D. R., Lock, S., Makker, H., Baldwin, D. R., & Stephens, R. J. 2015. Lung cancer diagnosis and staging with endobronchial ultrasound-guided transbronchial needle aspiration compared with conventional approaches: an open-label, pragmatic, randomised controlled trial. Lancet Respir Med. 3(4), 282-9. doi: 10.1016/S2213-2600(15)00029-6

Ollier, M., Chamoux, A., Naughton, G., Pereira, B., & Dutheil, F. 2014. Chest CT scan screening for lung cancer in asbestos occupational exposure: a systematic review and meta-analysis. Chest, 145(6), 1339-1346. doi:10.1378/chest.13-2181

Redpath, J. L., Sun, C., Colman, M., & Stanbridge, E. J. 1987. Neoplastic Transformation of Human Hybrid Cells by y Radiation: A Quantitative Assay. Radiat.Res. 110, 468-472.

Schafer R, Leung HM, Gmitro AF. 2014. Multi-modality imaging of a murine mammary window chamber for breast cancer research. Biotechniques. 57(1):45-50. Doi: 10.2144/000114191.

Sher, T., Dy, G. K., & Adjei, A. A. 2008. Small cell lung cancer. MayoClin Proc. 83(3), 335-367. doi: 10.4065/83.3.355

Shi ZM, Wang L, Shen H, Jiang CF, Ge X, Li DM, Wen YY, Sun HR, Pan MH, Li W, Shu YQ, Liu LZ, Peiper SC, He J, Jiang BH. 2017. Downregulation of miR-218 contributes to epithelial-mesenchymal transition and tumor metastasis in lung cancer by targeting Slug/ZEB2 signaling. Oncogene. 36(18):2577-2588. Doi: 0.1038/onc.2016.414.

Simon,  G.R., & Brustugun, O.T. 2015. Metastatic Patterns of Lung Cancer. Oncolex Oncology Encyclopedia. http://oncolex.org/Lung-cancer/Background/MetastaticPatterns.

Spira, A., & Ettinger, D. S. 2004. Multidisciplinary management of lung cancer. Engl J Med. 350(4), 379–92. doi: 10.1056/NEJMra035536

Wang T, Hu P, Li B, Zhang JP, Cheng YF, Liang YM. Role of Nrf2 signaling pathway in the radiation tolerance of patients with head and neck squamous cell carcinoma: an in vivo and in vitro study. Onco Targets Ther. 2017 Mar 23;10:1809-1819.

Wang L, Zhao Y, Xiong Y, Wang W, Fei Y, Tan C, Liang Z. 2018. K-ras mutation promotes ionizing radiation-induced invasion and migration of lung cancer in part via the Cathepsin L/CUX1 pathway. Exp Cell Res. 362(2):424-435.

Wu, N. Y., Cheng, H. C., Ko, J. S., Cheng, Y. C., Lin, P. W., Lin, W. C., . . .& Liou, D. M. 2011. Magnetic resonance imaging for lung cancer detection: experience in a population of more than 10,000 healthy individuals. BMC Cancer, 11, 242. doi:10.1186/1471-2407-11-242.

Zhou J, Wang L, Xu X, Tu Y, Qin S, Yin Y. 2012.  Antitumor activity of Endostar combined with radiation against human nasopharyngeal carcinoma in mouse xenograft models. Oncol Lett. 4(5):976-980.

Zhou, J., Huang, Z. A., Kumar, U., & Chen, D. D. Y. 2017. Review of recent developments in determining volatile organic compounds in exhaled breath as biomarkers for lung cancer diagnosis. Anal Chim Acta, 996, 1-9. doi:10.1016/j.aca.2017.09.021