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

AOP Title

HPPD inhibition leading to corneal papillomas and carcinomas (in rat)
Short name: HPPD- corneal papilloma/carcinoma


Cancer AOP group. 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
4-hydroxyphenyl-pyruvate dioxygenase (HPPD) enzyme, Inhibition

Key Events

Event Support for Essentiality
Plasma tyrosine, Increased
Cytotoxicity (corneal cells), Increase
Inflammation (corneal cells), Increase
Regenerative cell proliferation (corneal cells), Increase

Adverse Outcome

Adverse Outcome
Papillomas/carcinomas (squamous cells), Increase

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
4-hydroxyphenyl-pyruvate dioxygenase (HPPD) enzyme, Inhibition Directly Leads to Plasma tyrosine, Increased
Plasma tyrosine, Increased Directly Leads to Cytotoxicity (corneal cells), Increase
Cytotoxicity (corneal cells), Increase Directly Leads to Inflammation (corneal cells), Increase
Inflammation (corneal cells), Increase Directly Leads to Regenerative cell proliferation (corneal cells), Increase
Regenerative cell proliferation (corneal cells), Increase Directly Leads to Papillomas/carcinomas (squamous cells), Increase

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Life Stage Applicability

Life Stage Evidence Links

Taxonomic Applicability

Name Scientific Name Evidence Links
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
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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
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Quantitative Considerations

Summary Table
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Considerations for Potential Applications of the AOP (optional)


Lewis, R. W., & Botham, J. W. (2013). A review of the mode of toxicity and relevance to humans of the triketone herbicide 2-(4-methylsulfonyl-2-nitrobenzoyl)-1,3-cyclohexanedione. Crit Rev Toxicol, 43(3), 185-199. doi: 10.3109/10408444.2013.764279

U.S. Environmental Protection Agency. (September 7, 2007). Tembotrione Human Health Risk Assessment.: Retrieved from