Diuron-induced rat urinary bladder carcinogenesis: Mode of action and human relevance evaluations using the International Programme on Chemical Safety framework

Abstract

Diuron, a high volume substituted urea herbicide, induced high incidences of urinary bladder carcinomas and low incidences of kidney pelvis papillomas and carcinomas in rats exposed to high doses (2500 ppm) in a 2-year bioassay. Diuron is registered for both occupational and residential uses and is used worldwide for more than 30 different crops. The proposed rat urothelial mode of action (MOA) for this herbicide consists of metabolic activation to metabolites that are excreted and concentrated in the urine, leading to cytotoxicity, urothelial cell necrosis and exfoliation, regenerative hyperplasia, and eventually tumors. We show evidence for this MOA for diuron using the International Programme on Chemical Safety (IPCS) conceptual framework for evaluating an MOA for chemical carcinogens, and the United States Environmental Protection Agency (USEPA) and IPCS framework for assessing human relevance.

Keywords:

• bladder cancer
• cell proliferation
• cytotoxicity
• diuron
• metabolites
• hyperplasia
• urothelium

Acknowledgements

We gratefully acknowledge the assistance of Jeanne Bradford in the preparation of this manuscript.

Declaration of interest

The employment affiliation of the authors is shown on the cover pages. All of the authors were associated with academic institutions when the paper was prepared. One of the authors (Shadia M. Ihlaseh Catalano) has subsequently become an employee of BASF, an international firm that manufactures and markets herbicides. Research funds were provided by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, Grants 2006/60506-1, 2009/02754-7), Conselho Nacional de Pesquisa (CNPq, 472330/07-1), Center for Evaluation of The Impact of the Environment on Human Health (TOXICAM), UNESP, and University of Nebraska Medical Center. The Coordenadoria para Aperfeiçoamento de Pessoal de Ensino Superior (CAPES), Brazilian Ministry of Education (MEC), provided a scholarship to Dr. Da Rocha for a training period at the University of Nebraska Medical Center (UNMC) during her PhD program. FAPESP provided fellowships to Shadia M. I. Catalano and Merielen G. N. Pontes, and the CAPES to Ana Paula F. Cardoso for their PhD programs. None of the authors have appeared before regulatory agencies or participated in legal proceedings concerned with the safety of diuron. The research findings reported, the preparation of the review, and the conclusions drawn are exclusively the academic work product of the authors and do not necessarily represent the views of the organizations that provided financial support or the authors’ employers. The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.