Back to Search
Start Over
Weight of evidence and human relevance evaluation of the benfluralin mode of action in rodents (Part I): Liver carcinogenesis
- Source :
- Regulatory Toxicology and Pharmacology. 117:104758
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- Benfluralin, an herbicide of the dinitroaniline class used in weed control, was first registered in the United States in 1970. Increased incidence of liver tumors was observed in the 2 year dietary carcinogenicity studies. A review of the toxicology database provides evidence that the mode of action (MOA) of benfluralin responsible for hepatocellular adenoma and carcinoma in rodents depends on activation of the constitutive androstane (CAR)/pregnane X (PXR) receptors, that triggers enzyme induction and altered gene expression leading to hepatocyte proliferation. After prolonged exposures at high dose levels, altered hepatic foci and liver tumors are observed. This hepatocarcinogenic MOA has been described in rodents following long-term dietary exposures to other CAR/PXR activator chemicals, such as phenobarbital, and is generally considered as non-relevant in humans due to differences between human and rodent responses. We analyzed the existing and newly acquired toxicology data to establish that the hepatocarcinogenic MOA of benfluralin in rodents includes the same key events previously described in the rodent MOA of phenobarbital. A weight of evidence approach was taken to establish temporal and dose-related concordance of the causal key events supporting the conclusion that rodent liver carcinogenicity of benfluralin is unlikely to be relevant for human cancer risk.
- Subjects :
- Male
Benfluralin
Toluidines
Rodentia
010501 environmental sciences
Biology
Toxicology
Risk Assessment
030226 pharmacology & pharmacy
01 natural sciences
Rats, Sprague-Dawley
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
medicine
Animals
Humans
Toxicity Tests, Chronic
Mode of action
Carcinogen
0105 earth and related environmental sciences
Pregnane X receptor
Dose-Response Relationship, Drug
Mutagenicity Tests
Liver Neoplasms
Toxicity Tests, Subchronic
General Medicine
Hepatocellular adenoma
medicine.disease
Rats, Inbred F344
Rats
medicine.anatomical_structure
chemistry
Hepatocyte
Cancer research
Female
Phenobarbital
Androstane
Rats, Transgenic
medicine.drug
Subjects
Details
- ISSN :
- 02732300
- Volume :
- 117
- Database :
- OpenAIRE
- Journal :
- Regulatory Toxicology and Pharmacology
- Accession number :
- edsair.doi.dedup.....5e8ee89be83420a25b8a7b4f1b207e82