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Published on: December 19, 2019
Evaluation of diuron (3-[3,4-dichlorophenyl]-1,1-dimethyl urea) in a two-stage mouse skin carcinogenesis assay
Bianca Ferrucio1, Carla Adriene da Silva Franchi, Natália Ferreira Boldrin
1Center for the Evaluation of the Environmental Impact on Human Health (TOXICAM), Department of Pathology, Botucatu Medical School, UNESP - São Paulo State University, Botucatu, São Paulo, Brazil.
Abstract:
Diuron (3-[3,4-dichlorophenyl]-1,1-dimethyl urea) is an herbicide with carcinogenic activity in rats and mice, which have developed respectively urothelial and mammary gland tumors in long-term studies. Accordingly, diuron has been categorized as a "likely human carcinogen" by the U.S. Environmental Protection Agency. Although the carcinogenesis-initiating activity of diuron has been reported in an early initiation-promotion mouse skin study, its genotoxic potential has been disputed. It is necessary to clarify the mode of action through which it has caused rodent neoplasia and verify its relevance to humans. Herein, two experiments were developed to verify the initiating and promoting potentials of diuron in a twenty-three- and a twenty-one-week-long mouse skin carcinogenesis protocol. In one, dimethylsulfoxide (DMSO) was the solvent for the herbicide; in the other, acetone was the alternative solvent in order to verify whether DMSO had inhibitory influence on a potential cutaneous carcinogenic activity. The adopted schedule for the tumor-promoting agent 12-O-tetradecanoylphorbol 13-acetate (TPA) resulted in skin ulcers, which demonstrates the need for careful selection of TPA dose levels and frequency of application in this model. In both studies, diuron did not exert any influence on the skin carcinogenesis process, in contrast with results already reported in the literature.
Insights
Diuron, a likely human carcinogen, did not initiate or promote skin cancer in mice during two long-term studies. This suggests diuron
Area of Science:
- Toxicology and Carcinogenesis
- Environmental Health
- Dermatology
Background:
- Diuron (3-[3,4-dichlorophenyl]-1,1-dimethyl urea) is an herbicide classified as a likely human carcinogen by the U.S. EPA.
- Previous studies suggested diuron's carcinogenic activity in rodents, but its genotoxic potential and skin carcinogenesis role remain debated.
- Clarifying diuron's mechanism of action in rodent neoplasia is crucial for assessing human relevance.
Purpose of the Study:
- To investigate the initiating and promoting potentials of diuron in a mouse skin carcinogenesis model.
- To evaluate the influence of different solvents (DMSO and acetone) on diuron's potential carcinogenic activity.
- To assess the relevance of rodent carcinogenicity findings to human health risks.
Main Methods:
- Two mouse skin carcinogenesis experiments were conducted over 23 and 21 weeks, respectively.
- Diuron was applied topically using either dimethylsulfoxide (DMSO) or acetone as solvents.
- The tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) was used, with careful dose and frequency adjustments due to observed skin ulcers.
Main Results:
- Diuron did not demonstrate any initiating or promoting effect on skin carcinogenesis in mice, irrespective of the solvent used.
- The study confirmed the need for optimized TPA application protocols in mouse skin models to avoid adverse effects like ulcers.
- These findings contrast with some previous reports suggesting diuron's carcinogenic activity.
Conclusions:
- Under the tested conditions, diuron does not appear to initiate or promote skin carcinogenesis in mice.
- The results question the direct relevance of previously reported rodent skin tumor findings to human exposure scenarios.
- Further research may be needed to fully elucidate diuron's complex toxicological profile and carcinogenic mechanisms.
