Adverse outcome pathway (AOP): α2u-globulin nephropathy and kidney tumors in male rats

The National Research Council's vision of using adverse outcome pathways (AOPs) as a framework to assist with toxicity assessment for regulatory requirements of chemical assessment has continued to gain traction since its release in 2007. The need to expand the AOP knowledge base has gained urg...

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Bibliographic Details
Published inCritical reviews in toxicology Vol. 52; no. 5; pp. 345 - 357
Main Authors Goyak, Katy O., Sarang, Satinder S., Franzen, A., Borghoff, Susan J., Ryman-Rasmussen, Jessica P.
Format Journal Article
LanguageEnglish
Published England Taylor & Francis 28.05.2022
Subjects
adverse outcome pathway
Adverse Outcome Pathways
Animals
Humans
key event
kidney
Kidney Neoplasms
Male
molecular initiating event
nephropathy
Rats
Risk Assessment
United States
α2u-Globulin
United States
kidney
nephropathy
adverse outcome pathway
key event
α2u-Globulin
molecular initiating event
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Summary:The National Research Council's vision of using adverse outcome pathways (AOPs) as a framework to assist with toxicity assessment for regulatory requirements of chemical assessment has continued to gain traction since its release in 2007. The need to expand the AOP knowledge base has gained urgency, with the U.S. Environmental Protection Agency's directive to eliminate reliance on animal toxicity testing by 2035. To meet these needs, our goal was to elucidate the AOP for male-rat-specific kidney cancer. Male-rat-specific kidney tumors occur through the ability of structurally diverse substances to induce α2u-globulin nephropathy (α2u-N), a well-studied mode of action (MoA) not relevant in humans that results in kidney tumor formation in male rats. An accepted AOP may help facilitate the differentiation from other kidney tumors MoAs. Following identification and review of relevant in vitro and in vivo literature, both the MIE and subsequent KEs were identified. Based on the weight of evidence from the various resources, the confidence in this AOP is high. Uses of this AOP include hazard identification, development of in vitro assays to determine if the MoA is through α2u-N and not relevant to humans resulting in decreased use of animals, and regulatory applications.
ISSN:1040-8444
1547-6898
DOI:10.1080/10408444.2022.2082269