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This is a legacy representation of this AOP. Please see the current version here:

AOP Title

Urinary bladder calculi leading to urothelial papillomas and carcinomas (in mouse and rat)
Short name: Urinary calculi- urothelial papilloma/carcinoma


Cancer AOP Workgroup. National Health and Environmental Effects Research Laboratory, Office of Research and Development, Integrated Systems Toxicology Division, US Environmental Protection Agency, Research Triangle Park, NC. Corresponding author for wiki entry (


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OECD Project 1.29: A catalog of putative AOPs that will enhance the utility of US EPA Toxcast high throughput screening data for hazard identification

Under development: Do not distribute or cite.

This AOP page was last modified on 12/11/2016.

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This putative adverse outcome pathway (AOP) outlines potential key events leading to a tumor outcome in standard carcinogenicity models. This information is based largely on modes of action described previously in cited literature sources and is intended as a resource template for AOP development and data organization. Presentation in this Wiki does not indicate EPA acceptance of a particular pathway for a given reference agent, only that the information has been proposed in some manner. In addition, this putative AOP relates to the model species indicated and does not directly address issues of human relevance.

Background (optional)

Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
Urinary bladder calculi, Increase

Key Events

Event Support for Essentiality
Cytotoxicity (urothelial cells), Increase
Regenerative cell proliferation (urothelial cells), Increase
Hyperplasia (urothelial), Increase

Adverse Outcome

Adverse Outcome
Adenomas/carcinomas (urothelial), Increase

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
Urinary bladder calculi, Increase Directly Leads to Cytotoxicity (urothelial cells), Increase
Cytotoxicity (urothelial cells), Increase Directly Leads to Regenerative cell proliferation (urothelial cells), Increase
Regenerative cell proliferation (urothelial cells), Increase Directly Leads to Hyperplasia (urothelial), Increase
Hyperplasia (urothelial), Increase Directly Leads to Adenomas/carcinomas (urothelial), Increase

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Life Stage Applicability

Life Stage Evidence Links

Taxonomic Applicability

Name Scientific Name Evidence Links
Mus musculus Mus musculus NCBI
Rattus norvegicus Rattus norvegicus NCBI

Sex Applicability

Sex Evidence Links

Graphical Representation

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Overall Assessment of the AOP

Domain of Applicability

Life Stage Applicability, Taxonomic Applicability, Sex Applicability
Elaborate on the domains of applicability listed in the summary section above. Specifically, provide the literature supporting, or excluding, certain domains.

Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
Provide an overall assessment of the essentiality for the key events in the AOP. Support calls for individual key events can be included in the molecular initiating event, key event, and adverse outcome tables above.

Weight of Evidence Summary

Summary Table
Provide an overall summary of the weight of evidence based on the evaluations of the individual linkages from the Key Event Relationship pages.

Quantitative Considerations

Summary Table
Provide an overall discussion of the quantitative information available for this AOP. Support calls for the individual relationships can be included in the Key Event Relationship table above.

Considerations for Potential Applications of the AOP (optional)


Garland, E. M., & Cohen, S. M. (1995). Saccharin-induced bladder cancer in rats. Prog Clin Biol Res, 391, 237-243.

International Agency for Research on Cancer (IARC), W. H. O. (1999). Saccharin and its Salts, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans (Vol. 73-24). France.