title: Inter-laboratory comparison of turkey in ovo carcinogenicity assessment (IOCA) of hepatocarcinogens.
abstract: In three independent laboratories carcinogens (diethylnitrosamine, DEN, 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone, NNK) and non-carcinogens (N-nitrosoproline, nicotine) were evaluated in turkey eggs for in ovo carcinogenicity assessment (IOCA). Compounds were injected into aseptic fertilized eggs. After incubation for 24 days, foci of altered hepatocytes (FAH), some with a pseudoglandular structure and/or signs of compression of the surrounding tissue were observed in the fetal liver. All laboratories were able to distinguish unequivocally the hepatocarcinogen-exposed groups from those exposed to non-carcinogens or the vehicle controls, based on the pre-specified evaluation parameters: tumor-like lesions, pseudoglandular areas and FAH. In addition to focal changes, only the carcinogens induced hepatocellular karyomegaly. Lower doses of the carcinogens, which did not induce FAH, were sufficient to induce hepatocellular karyomegaly. After exposure to 4 mg DEN, gall bladder agenesis was observed in all fetuses. The IOCA may be a valuable tool for early investigative studies on carcinogenicity and since it does not use rodents may complement chronic rat or mouse bioassays. Test substances that are positive in both rodents and fertilized turkey eggs are most probably trans-species carcinogens with particular significance for humans. The good concordance observed among the three laboratories demonstrates that the IOCA is a reliable and robust method.
authors.affiliation: Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM) Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Germany. harald.enzmann@bfarm.de
authors.forename: H
authors.initials: H
authors.lastname: Enzmann
authors.forename: K
authors.initials: K
authors.lastname: Brunnemann
authors.forename: M
authors.initials: M
authors.lastname: Iatropoulos
authors.forename: S
authors.initials: S
authors.lastname: Shpyleva
authors.forename: N
authors.initials: N
authors.lastname: Lukyanova
authors.forename: I
authors.initials: I
authors.lastname: Todor
authors.forename: M
authors.initials: M
authors.lastname: Moore
authors.forename: K
authors.initials: K
authors.lastname: Spicher
authors.forename: V
authors.initials: V
authors.lastname: Chekhun
authors.forename: H
authors.initials: H
authors.lastname: Tsuda
authors.forename: G
authors.initials: G
authors.lastname: Williams
mesh_terms: D000818:Animals; D015197:Carcinogenicity Tests / Q000379:methods / Q000592:standards; D004305:Dose-Response Relationship, Drug; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology; D007753:Laboratories / Q000592:standards*; D008099:Liver / Q000187:drug effects* / Q000196:embryology / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000196:embryology / Q000473:pathology; D015203:Reproducibility of Results; D012107:Research Design; D014422:Turkeys; D015053:Zygote / Q000187:drug effects / Q000473:pathology
keywords: 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; Carcinogenesis; DEN; FAH; Histopathology; IOCA; Liver; NNK; Preclinical safety-assessment; Preneoplasia; Risk identification; diethylnitrosamine; foci of altered hepatocytes; in ovo carcinogenicity assessment