This AOP is licensed under the BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

AOP: 505


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

Reactive Oxygen Species (ROS) formation leads to cancer via inflammation pathway

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
ROS formation leads to cancer via inflammation pathway

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


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

Of the originating work: Jaeseong Jeong and Jinhee Choi, School of Environmental Engineering, University of Seoul, Seoul, Republic of Korea

Of the content populated in the AOP-Wiki:  John R. Frisch and Travis Karschnik, General Dynamics Information Technology, Duluth, Minnesota; Daniel L. Villeneuve, US Environmental Protection Agency, Great Lakes Toxicology and Ecology Division, Duluth, MN

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
John Frisch   (email point of contact)


Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • John Frisch


This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help


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
Handbook Version OECD status OECD project
This AOP was last modified on October 11, 2023 14:22

Revision dates for related pages

Page Revision Date/Time
Increased, Reactive oxygen species July 26, 2023 14:34
Oxidative Stress March 21, 2023 15:16
Increase, Inflammation October 18, 2023 12:08
General Apoptosis October 18, 2023 12:20
Increase, Cancer August 22, 2023 14:32
Increased, Reactive oxygen species leads to Oxidative Stress October 19, 2023 09:32
Oxidative Stress leads to Increase, Inflammation October 19, 2023 09:39
Increase, Inflammation leads to General Apoptosis October 19, 2023 09:41
General Apoptosis leads to Increase, Cancer October 19, 2023 09:46
Polyethylene AS low Mol.Wt. July 31, 2023 09:43
Polyvinyl chloride July 31, 2023 09:45


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

Reactive oxygen species (ROS) are derived from oxygen molecules and can occur as free radicals (ex. superoxide, hydroxyl, peroxyl) or non-radicals (ex. ozone, singlet oxygen).  ROS production occurs via a variety of normal cellular process; however, in stress situations (ex. exposure to radiation, chemical or biological stressors) reactive oxygen species levels dramatically increase and cause damage to cellular components.  In this Adverse Outcome Pathway (AOP) we focus on the inflammation response to increases in oxidative stress.  Inflammation pathways include a molecular response (ex. interleukins, cytokines, interferons) and produces visible tissue swelling during histology examinations.  In this AOP we focus on the apoptosis response to cellular damage.  Pathways leading to apoptosis, or single cell death, have traditionally been studied as both independent and simultaneous from pathways leading to necrosis, or tissue-wide cell death, with both overlap and distinct mechanisms (Elmore 2007). For the purposes of this AOP, we are characterizing cancer due to widespread cell-death, and recognize the complications in separating the related apoptosis and necrosis pathways.

AOP Development Strategy


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

This Adverse Outcome Pathway (AOP) focuses on the pathway in which an established molecular disruption, increased levels of reactive oxygen species (ROS), leads to increased cancer through inflammation and cell/death/apoptosis.  Environmental stressors leading to increased reactive oxygen species result in a variety of stress responses, visible through inflammation.  These stress responses have been studied in many eukaryotes, including mammals (humans, lab mice, lab rats), teleost fish, and invertebrates (cladocerans, mussels).


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

This AOP was developed as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki.  Jeong and Choi (2020) and Jeong and Choi (2019) provided initial network analysis from microplastic stressors, guided by weight of evidence from ToxCast assays.  These publication, and the work cited within, were used create and support this AOP and its respective KE and KER pages.

The AOP-wiki authors did a further evaluation of published peer-reviewed literature to provide additional evidence in support of the AOP.  A companion adverse outcome pathway is planned for an additional pathway initiated by reactive oxygen species (ROS), leading to increased cancer: Decreased, PPARalpha transactivation of gene expression leads to Alteration, lipid metabolism.

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


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 1115 Increased, Reactive oxygen species Increased, Reactive oxygen species
KE 1392 Oxidative Stress Oxidative Stress
KE 149 Increase, Inflammation Increase, Inflammation
KE 1513 General Apoptosis General Apoptosis
AO 885 Increase, Cancer Increase, 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
Life stage Evidence
All life stages High

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
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Unspecific High

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

1. Support for Biological Plausibility of Key Event Relationships: Is there a mechanistic relationship  between KEup and KEdown consistent with established biological knowledge?

Key Event Relationship (KER)

Level of Support

Relationship 2009: Increased, Reactive oxygen species leads to Oxidative Stress

Strong support.  The relationship between increases in reactive oxygen species and oxidative stress is broadly accepted and consistently supported across taxa.

Relationship 2975: Oxidative Stress leads to Increase, Inflammation

Moderate support.  The relationship between oxidative stress and increased inflammation is established.

Relationship 2976: Increase, Inflammation leads to General Apoptosis

Moderate support. The relationship between increased inflammation and general apoptosis is established.  Inflammation has been shown as an initiating event for activation of apoptosis; arguably more studies have been conducted linking inflammation to necrosis pathways.

Relationship 2977: General Apoptosis leads to Increase, Cancer

Strong support.  The relationship between failure of apoptosis pathways to initiate cell death pathways and increases in cancer is broadly accepted and consistently supported across taxa.

2. Essentiality of Key Events: Are downstream KEs and/or the AO prevented if an upstream KE is blocked?

Key Event (KE)

Level of Support

MIE 1115: Increased, Reactive oxygen species

Moderate support.  Increased Reactive oxygen species (ROS) levels are a primary cause of oxidative stress.  However, other stressors do exist.

KE 1392: Oxidative Stress

Moderate support. Oxidative stress is a cause of inflammation.  However, inflammation is a general response to injury or foreign agents.

KE 149: Increase, Inflammation

Moderate support. Inflammation is a cause of apoptosis.  However, apoptosis is a general pathway for elimination of abnormal cells.

KE 1513: General Apoptosis

Moderate support. Failure of apoptosis allows cancer cells to proliferate.  However, cancer cells increase due to a variety of stressors, and breakdown of multiple cellular processes.

AO 885: Increase, Cancer

Moderate support. Cancer proliferates due to a variety of stressors and breakdown of multiple celluar processes.

3. Empirical Support for Key Event Relationship: Does empirical evidence support that a  change in KEup leads to an appropriate change in KEdown?

Key Event Relationship (KER)

Level of Support

Relationship 2009: Increased, Reactive oxygen species leads to Oxidative Stress

Strong support. Increases in ROS lead to increases in oxidative stress, primarily from studies examining responses in enzyme and gene levels for enzymes that catalyze reactions that reduce ROS levels.

Relationship 2975: Oxidative Stress leads to Increase, Inflammation

Strong support. Increases in oxidative stress leads to increases in inflammation, primarily from histology studies measuring tissue swelling, and increases in gene levels for proinflammatory mediators.

Relationship 2976: Increase, Inflammation leads to General Apoptosis

Moderate support. Increases in inflammation leads to apoptosis, primarily from studies of increased gene expression of tumor necrosis factor.

Relationship 2977: General Apoptosis leads to Increase, Cancer

Strong support. Mechanistic studies show that failure for apoptosis to eliminate cancer cells allows increases in cancer proliferation.

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

Life Stage: The life stage applicable to this AOP is all life stages.  Older individuals are more likely to manifest this adverse outcome pathway (adults > juveniles > embryos) due to accumulation of reactive oxygen species.

Sex: This AOP applies to both males and females.

Taxonomic: This AOP appears to be present broadly, with representative studies including mammals (humans, lab mice, lab rats), teleost fish, and invertebrates (cladocerans, mussels).

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

Support for the essentiality of the key events can be obtained from a wide diversity of taxonomic groups, with mammals (lab ice, lab rats, human cell lines), telost fish, and invertebrates (cladocerans and mussels) particularly well-studied.

Evidence Assessment

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



Increased, Reactive oxygen species leads to Oxidative Stress

Biological plausibility is high.  Representative studies have been done with mammals (Liu et al. 2015; Deng et al. 2017; Schrinzi et al. 2017; Jeong and Choi 2020); fish (Oliveira et al. 2013; Lu et al. 2016; Alomar et al. 2017; Chen et al. 2017; Veneman et al. 2017; Barboza et al. 2018; Choi et al. 2018; Espinosa et al. 2018); invertebrates (Browne et al. 2013; Avio et al. 2015; Jeong et al. 2016, 2017; Paul-Pont et al. 2016; Imhof et al. 2017; Lei et al. 2018; Yu et al. 2018).

Oxidative Stress leads to Increase, Inflammation

Biological plausibility is high.  Representative studies have been done with mammals (Gamo et al. 2008; Jeong and Choi 2020); fish (Lu et al. 2016; Jin et al. 2018); invertebrates (Lei et al. 2018).  For review (Wright and Kelly 2017).

Increase, Inflammation leads to General Apoptosis

Biological plausibility is high.  Representative studies have been done with mammals (Gamo et al. 2008); fish (Karami et al. 2016; Lu et al. 2016; Jin et al. 2018).  For review (Balkwill 2003, Villeneuve et al. 2018).

General Apoptosis leads to Increase, Cancer

Biological plausibility is high.  Representative studies have been done with mammals (Pavet et al. 2014; Jeong and Choi 2020).  For review (Heinlein and Chang 2004; Vihervaara and Sistonen 2014).

For overview of the biological mechanisms involved in this AOP, see Liu et al. (2015) and Jeong and Choi (2020); their studies analyzed ToxCast in vitro assays of mammalian acute toxicity data to identify correlations between toxicity pathways and chemical stressors, providing support for the key event relationships represented here.

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
Modulating Factor (MF) Influence or Outcome KER(s) involved

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


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

Alomar, C., Sureda, A., Capo, X., Guijarro, B., Tejada, S. and Deudero, S.  2017.  Microplastic ingestion by Mullus surmuletus Linnaeus, 1758 fish and its potential for causing oxidative stress.  Environmental Research 159: 135-142.

Avio, C.G., Gorbi, S., Milan, M., Benedetti, M., Fattorini, D., D’Errico, G., Pauletto, M., Bargelloni, L., and Regoli, F.  2015.  Pollutants bioavailability and toxicological risk from microplastics to marine mussels.  Environmental Pollutants 198: 211-222.

Barboza, LG.A., Vieira, L.R., Branco, V., Figueiredo, N., Carvalho, F., Carvalho, C., and Guilhermino, L. 2018.  Microplastics cause neurotoxicity, oxidative damage and energy-related changes and interact with the bioaccumulation of mercury in the European seabass, Dicentrachus labrux (Linneaeus, 1758).  Aquatic Toxicology 195: 49-57.

Balkwill, F. 2003.  Chemokine biology in cancer.  Seminars in Immunology 15: 49-55.

Browne, M.A. Niven, S.J., Galloway, T.S., Rowland, S.J., and Thompson, R.C.  2013.  Microplastic moves pollutants and additives to worms, reducing functions linked to health and biodiversity.  Current Biology 23: 2388-2392.

Chen, Q., Gundlach, M., Yang, S., Jiang, J., Velki, M., Yin, D., and Hollert, H.  2017 Quantitative investigation of the mechanisms of microplastics and nanoplastics toward larvae locomotor activity.  Science of the Total Environment 584-585: 1022-1031.

Choi, J.S., Jung, Y.J., Hong, N.H., Hong, S.H., and Park, J.W. 2018.  Toxicological effects of irregularly shaped and spherical microplastics in a marine teleost, the sheepshead minnow (Cyprinodon variegatus).  Marine Pollution Bulletin 129: 231-240.

Deng, Y., Zhang, Y., Lemos, B., and Ren, H.  2017.  Tissue accumulation of microplastics in mice and biomarker responses suggest widespread health risks of exposure.  Science Reports 7: 1-10.

Elmore, S.  2007.  Apoptosis: A Review of Programmed Cell Death.  Toxicologic pathology 35 (4): 495-516.

Espinosa, C., Garcia Beltran, J.M., Esteban, M.A., and Cuesta, A.  2018.  In vitro effects of virgin microplastics on fish head-kidney leucocyte activities.  Environmental Pollution 235: 30-38.

Gamo, K., Kiryu-Seo, S., Konishi, H., Aoki, S., Matushima, K., Wada, K., and Kiyama, H.  2008.  G-protein-coupled receptor screen reveals a role for chemokine recepteor CCR5 in suppressing microglial neurotoxicity.  Journal of Neuroscience 28: 11980-11988.

Heinlein, C.A. and Chang, C.  2004.  Androgen receptor in prostate cancer.  Endocrine Reviews 25: 276-308.

Imhof, H.K., Rusek, J., Thiel, M., Wolinska, J., and Laforsch, C. 2017.  Do microplastic particles affect Daphnia magna at the morphological life history and molecular level?  Public Library of Science One 12: 1-20.

Jeong, J. and Choi, J.  2019.  Adverse outcome pathways potentially related to hazard identification of microplastics based on toxicity mechanisms. Chemosphere 231: 249-255.

Jeong, J. and Choi, J.  2020.  Development of AOP relevant to microplastics based on toxicity mechanisms of chemical additives using ToxCast™ and deep learning models combined approach.  Environment International 137:105557.

Jeong, C.B., Kang, H.M., Lee, M.C., Kim, D.H., Han, J., Hwang, D.S. Souissi, S., Lee, S.J., Shin, K.H., Park, H.G., and Lee, J.S.  2017.  Adverse effects of microplastics and oxidative stress-induced MAPK/NRF2 pathway-mediated defense mechanisms in the marine copepod Paracyclopina nana.  Science Reports 7: 1-11.

Jeong, C.B., Wong, E.J., Kang, H.M., Lee, M.C., Hwang, D.S., Hwang, U.K., Zhou, B., Souissi, S., Lee, S.J., and Lee, J.S.  2016.  Microplastic size-dependent toxicity, oxidative stress induction, and p-JNK and p-p38 activation in the Monogonout rotifer (Brachionus koreanus). Environmental Science and Technology 50: 8849-8857.

Jin, Y., Xia, J., Pan, Z., Yang, J., Wang, W., and Fu, Z.  2018.  Polystyrene microplastics induce microbiota dysbiosis and inflammation in the gut of adult zebrafish.  Environmental Pollution 235: 322-329.

Karami, A., Romano, N., Galloway, T. and Hamzah, H.  2016.  Virgin microplastics cause toxicity and modulate the impacts of phenanthrene on biomarker responses in African catfish (Clarias gariepinus).  Environmental Research 151: 58-70.

Lei, L., Wu, S., Lu, S., Liu, M., Song, Y., Fu, Z., Shi, H., Raley-Susman, K.M., and He, D.  2018.  Microplastic particles cause intestinal damage and other adverse effects in zebrafish Danio rerio and nematode Caenorhabditis elegans.  Science of the Total Environment 619-620: 1-8.

Liu, J., Mansouri, K., Judson, R.S., Martin, M.T., Hong, H., Chen, M., Xu, X., Thomas, R.S., and Shah, I.  2015.  Predicting hepatoxicity using ToxCast in vitro bioactivity and chemical structure.  Chemical Research in Toxicology 28: 738-751.

Lu, Y., Zhang, Y., Dengy, Y., Jiang, W., Zhao, Y., Geng, J., Ding, L., Ren, H.  2016.  Uptake and accumulation of polystyrene microplastics in zebrafish (Danio rerio) and toxic effects in liver.  Environmental Science and Technology 50: 4054-4060.

Oliveira, M., Ribeiro, A., Hylland, K., and Guilhermino, L. 2013.  Single and combined effects of microplastics and pyrene on juveniles (0+ group) of the common goby Pomatoschistus microps (Teleostei, Gobiidae).  Ecological Indicators 34: 641-647.

Paul-Pont, I., Lacroix, C., Gonzalez Fernandez, D., Hegaret, H., Lambert, C., Le Goic, N., Frere, L., Cassone, A.L., Sussarellu, R. Fabioux, C., Guyomarch, J., Albentosa, M., Huvet, A., and Soudant, P.  2016.  Exposure of marine mussels Mytillus spp. to polystyrene microplastics: Toxicity and influence on fluoranthene bioaccumulation.  Environmental Pollution 216: 724-737.

Pavet, V., Shlyakhtina, Y., He, T., Ceschin, D.G., Kohonen, P., Perala, M., Kallioniemi, O., and Gronemeyer, H.  2014.  Plasminogen activator urokinase expression reveals TRAIL responsiveness and support fractional survival of cancer cells.  Cell Death and Disease 5: e1043.

Schrinzi, G.F., Perez-Pomeda, I., Sanchis, J., Rossini, C., Farre, M., and Barcelo, D.  2017.  Cytotoxic effects of commonly used nanomaterials and microplastics on cerebral and epithelial human cells. Environmental Research 159: 579-587.

Veneman, W.J., Spaink, H.P., Brun, N.R., Bosker, T., and Vijver, M.G.  2017.  Pathway analysis of systemic transcriptome responses to injected polystyrene particles in zebrafish larvae.  Aquatic Toxicology 190: 112-120.

Vihervaara, A. and Sistonen, L.  2014.  HSF1 at a glance.  Journal of Cell Scientce 127: 261-266.

Villeneuve, D.L., Landesmann, B., Allavena, P., Ashley, N., Bal-Price, A., Corsini, E., Halappanavar, S., Hussell, T., Laskin, D., Lawrence, T., Nikolic-Paterson, D., Pallary, M., Paini, A., Pietrs, R., Roth, R., and Tschudi-Monnet, F.  2018.  Toxicological Sciences 346:352.

Wright, S.L. and Kelly, F.J.  2017.  Plastic and human health: a micro issue?  Enviromental Science and Technology 51: 6634-6647.

Yu, P., Liu, Z., Wu, D., Chen, M., Lv, W., and Zhao, Y.  2018.  Accumulation of polystyrene microplastics in juvenile Eriocheir sinensis and oxidative stress effects in the liver.  Aquatic Toxicology 200: 28-36.