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AOP: 335


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

AOP for urothelial carcinogenesis due to chemical cytotoxicity by mitochondrial impairment

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Chemical cytotoxicity leading to urothelial carcinogenesis

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

a,bNathalia P Souza, a,bThania RR Lima, b,cLilian C Pereira, a,bJoao Lauro V de Camargo

aBotucatu Medical School, UNESP – Sao Paulo State University, Botucatu Campus, Department of Pathology. bCenter for Evaluation of Environmental Impact on Human Health (TOXICAM), Botucatu, SP, Brazil. cSchool of Agricultural Sciences, UNESP - Sao Paulo State University, Botucatu Campus, Department of Bioprocesses and Biotechnology, Botucatu, SP, Brazil.

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
Arthur Author   (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
  • Nathalia Pereira Souza
  • Thania Rios Rossi Lima
  • Arthur Author


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 April 29, 2023 13:02

Revision dates for related pages

Page Revision Date/Time
Mitochondrial impairment September 16, 2017 10:17
Urothelial cell injury/death April 21, 2020 18:09
Increase, Regenerative cell proliferation (urothelial cells) September 16, 2017 10:16
Increase, Hyperplasia (urothelial) September 16, 2017 10:16
Urothelial Tumor April 21, 2020 19:38
Mitochondrial impairment leads to cell injury April 21, 2020 18:42
cell injury leads to Increase, Regenerative cell proliferation (urothelial cells) April 21, 2020 18:42
Increase, Regenerative cell proliferation (urothelial cells) leads to Increase, Hyperplasia (urothelial) December 03, 2016 16:38
Increase, Hyperplasia (urothelial) leads to carcinogenicity April 21, 2020 18:43
Diuron May 24, 2018 15:29
DCA June 03, 2022 08:10
DCPMU June 03, 2022 08:11


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

We are proposing an AOP framework for urothelial cytotoxicity followed by regenerative hyperplasia and the development of benign and malignant proliferative lesions after long-term chemical exposure. In addition, we suggest direct mitochondrial dysfunction process as one of the possible Molecular Initiating Event (MIE) for this AOP. Our lab has a long experience with urothelial toxicity resulting from exposure to the herbicide diuron. Currently, we are adopting in vitro approaches using human bladder cells (1T1) exposed to diuron and its metabolites to confirm the mitochondrial damage and to identify the intracellular pathways that are compromised after exposure. We suggest that the mitochondrial impairment in urothelial cells leads to urothelial injury/death followed by regenerative cell proliferation and hyperplasia, culminating in urothelial tumors.

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


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


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 1261 Mitochondrial impairment Mitochondrial impairment
KE 1762 Urothelial cell injury/death cell injury
KE 795 Increase, Regenerative cell proliferation (urothelial cells) Increase, Regenerative cell proliferation (urothelial cells)
KE 796 Increase, Hyperplasia (urothelial) Increase, Hyperplasia (urothelial)
AO 1763 Urothelial Tumor carcinogenicity

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
rat Rattus norvegicus NCBI

Sex Applicability

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

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


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

Fava RM, Ferragut Cardoso AP, da Rocha MS, Nascimento E Pontes MG, de Camargo JL, de Oliveira ML. Evaluation of early changes induced by diuron in the rat urinary bladder using different processing methods for scanning electron microscopy. Toxicology. 3;333:100-6. 2015.

Ihlaseh-Catalano SM, Bailey KA, Cardoso AP, Ren H, Fry RC, de Camargo JL, Wolf DC. Dose and temporal effects on gene expression profiles of urothelial cells from rats exposed to diuron. Toxicology. 5;325:21-30. 2014

Da Rocha MS, Arnold LL, De Oliveira ML, Catalano SM, Cardoso AP, Pontes MG, Ferrucio B, Dodmane PR, Cohen SM, De Camargo JL. Diuron-induced rat urinary bladder carcinogenesis: mode of action and human relevance evaluations using the International Programme on Chemical Safety framework. Crit Rev Toxicol. 44(5):393-406. 2014.

Da Rocha MS, Arnold LL, Dodmane PR, Pennington KL, Qiu F, De Camargo JL, Cohen SM. Diuron metabolites and urothelial cytotoxicity: in vivo, in vitro and molecular approaches. Toxicology. 15;314(2-3):238-46. 2013.

Cardoso AP, Ihlaseh Catalano SM, da Rocha MS, Nascimento E Pontes MG, de Camargo JL, de Oliveira ML. Dose-response of diuron [3-(3,4-dichlorophenyl)-1,1-dimethylurea] in the urothelial mucosa of Wistar rats. Toxicology. 4;312:1-5. 2013.

Da Rocha MS, Arnold LL, Pennington KL, Muirhead D, Dodmane PR, Anwar MM, Battalora M, De Camargo JL, Cohen SM. Diuron-induced rat bladder epithelial cytotoxicity. Toxicol Sci. 130(2):281-8. 2012.

Ihlaseh SM, Bailey KA, Hester SD, Jones C, Ren H, Cardoso AP, Oliveira ML, Wolf DC, de Camargo JL. Transcriptional profile of diuron-induced toxicity on the urinary bladder of male Wistar rats to inform mode of action. Toxicol Sci.122(2):330-8. 2011.

da Rocha MS, Nascimento MG, Cardoso AP, de Lima PL, Zelandi EA, de Camargo JL, de Oliveira ML. Cytotoxicity and regenerative proliferation as the mode of action for diuron-induced urothelial carcinogenesis in the rat. Toxicol Sci. 113(1):37-44. 2010.

Nascimento MG, de Oliveira ML, Lima AS, de Camargo JL. Effects of Diuron [3-(3,4-dichlorophenyl)-1,1-dimethylurea] on the urinary bladder of male Wistar rats. Toxicology. 5;224(1-2):66-73. 2006.

Thania Rios Rossi Lima, Estela de Oliveira Lima, Jeany Delafiori, Rodrigo Ramos Catharino, João Lauro Viana de Camargo & Lílian Cristina Pereira (2022) Molecular signatures associated with diuron exposure on rat urothelial mitochondria, Toxicology Mechanisms and Methods, DOI: 10.1080/15376516.2022.2062271.