title: A survey of EPA/OPP and open literature on selected pesticide chemicals. III. Mutagenicity and carcinogenicity of benomyl and carbendazim.
abstract: The known aneuploidogens, benomyl and its metabolite, carbendazim (methyl 2-benzimidazole carbamate (MBC)), were selected for the third in a series of ongoing projects with selected pesticides. Mutagenicity and carcinogenicity data submitted to the US Environmental Protection Agency's (US EPA's) Office of Pesticide Programs (OPP) as part of the registration process are examined along with data from the open literature. Mutagenicity and carcinogenicity profiles are developed to provide a complete overview and to determine whether an association can be made between benomyl- and MBC-induced mouse liver tumors and aneuploidy. Since aneuploidogens are considered to indirectly affect DNA, the framework adopted by the Agency for evaluating any mode of action (MOA) for carcinogenesis is applied to the benomyl/MBC data. Both agents displayed consistent, positive results for aneuploidy induction but mostly negative results for gene mutations. Non-linear dose responses were seen both in vitro and in vivo for aneuploidy endpoints. No evidence was found suggesting that an alternative MOA other than aneuploidy may be operative. The data show that by 14 days of benomyl treatment, events associated with liver toxicity appear to set in motion the sequence of actions that leads to neoplasms. Genetic changes (as indicated by spindle impairment leading to missegregation of chromosomes, micronucleus induction and subsequent aneuploidy in bone marrow cells) can commence within 1-24h after dosing, well within the time frame for early key events. Critical steps associated with frank tumor formation in the mouse liver include hepatotoxicity, increased liver weights, cell proliferation, hypertrophy, and other steps involving hepatocellular alteration and eventual progression to neoplasms. The analysis, however, reveals weaknesses in the data base for both agents (i.e. no studies on mouse tubulin binding, no in vivo assays of aneuploidy on the target tissue (liver), and no clear data on cell proliferation relative to dose response and time dependency). The deficiencies in defining the MOA for benomyl/MBC introduce uncertainties into the analysis; consequently, benomyl/MBC induction of aneuploidy cannot be definitively linked to mouse liver carcinogenicity at this time.
authors.affiliation: US Environmental Protection Agency, Office of Pesticide Programs, Health Effects Division (7509C), Washington, DC 20460, USA. mccarroll.nancy@epa.gov
authors.forename: Nancy E
authors.initials: NE
authors.lastname: McCarroll
authors.forename: Alberto
authors.initials: A
authors.lastname: Protzel
authors.forename: Yiannakis
authors.initials: Y
authors.lastname: Ioannou
authors.forename: H Frank
authors.initials: HF
authors.lastname: Frank Stack
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Jackson
authors.forename: Michael D
authors.initials: MD
authors.lastname: Waters
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Dearfield
mesh_terms: D000818:Animals; D001542:Benomyl / Q000493:pharmacokinetics / Q000633:toxicity*; D001562:Benzimidazoles / Q000493:pharmacokinetics / Q000633:toxicity*; D001711:Biotransformation; D016466:CHO Cells / Q000187:drug effects; D002219:Carbamates; D015197:Carcinogenicity Tests; D002277:Carcinoma / Q000139:chemically induced; D006224:Cricetinae; D003412:Cricetulus; D004260:DNA Repair / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005659:Fungicides, Industrial / Q000493:pharmacokinetics / Q000633:toxicity*; D006540:Herbicides / Q000493:pharmacokinetics / Q000633:toxicity*; D006801:Humans; D007940:Leukemia L5178 / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced; D051379:Mice; D008815:Mice, Inbred Strains; D009152:Mutagenicity Tests; D012441:Saccharomyces cerevisiae / Q000187:drug effects; D012486:Salmonella typhimurium / Q000187:drug effects; D012854:Sister Chromatid Exchange / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D001562:Benzimidazoles; D002219:Carbamates; D005659:Fungicides, Industrial; D006540:Herbicides; C006698:carbendazim; D001542:Benomyl