Studies on the tumor initiation/promotion potential of six middle distillates (MDs) in mouse skin.

Six middle distillates (MDs) were tested for tumor initiating/promoting activity after application to the skin of 30 male CD-1 (ICR) BR mice per group. As the control, 7,12-dimethylbenz[a]-anthracene (DMBA) was used for initiation followed by 12-O-tetradecanoylphorbol-13-acetate (TPA) for promotion. For assessing the tumor-initiating activity, 50 microliters of neat MDs was administered for 5 days with subsequent TPA promotion. In the promotion bioassay, after DMBA initiation 50 microliters of the neat MDs was administered twice weekly until Week 28. For the examination of complete carcinogenic activity, one MD was given without DMBA initiation. Hyperkeratosis, hyperplasia, and dermal inflammation, occurring during the initiation with the MDs, were completely reversible during the 2-week treatment-free period after initiation. Similar skin findings were observed during promotion with the MDs. Regarding the number of affected animals and the severity of the response, TPA was more irritating than the MDs. The initiation study revealed skin tumors for the DMBA/TPA control (30/30), MD 57,389 (14/30), MD 57,396 (5/30), MD 57,383 (4/30) and MD 57,324 (2/30). The promotion study revealed tumor induction by MDs 57,389 (9/30), 57,324 (1/30), 57,393 (1/30), and 57,396 (1/30). Two of 30 animals treated with MD 57,389 developed tumors without DMBA initiation thus indicating that it also is a complete carcinogen. MD 57,399 caused neither initiating nor promoting effects. The tumors observed were diagnosed histopathologically predominantly as squamous cell papillomas.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of the carcinogenic potency of 4 environmental polycyclic aromatic compounds following intrapulmonary application in rats.

The carcinogenic potential of 4 highly purified polycyclic aromatic compounds (PAC) was studied in the respiratory tract of rats. Using a beeswax/trioctanoin mixture as vehicle, 10, 3 and 1 mg phenanthrene (PHE), 3 and 1 mg chrysene (CHR), 0.1 mg dibenz(a,h)anthracene (DBahA) and 6, 3 and 1 mg benzo(b)naphto(2,1-d)thiophene (BNT) were injected into the lungs of 35 female Osborne-Mendel rats per group. Benzo(a)pyrene (BaP, 0.3, 0.1 and 0.03 mg) was used as the reference substance. Whereas only one squamous cell carcinoma developed at the highest PHE dose, a dose-dependent tumor incidence was found for CHR. BNT showed a carcinogenic effect similar to CHR, but an increasing incidence of neoplasms was not seen between the median and high dose. DBahA induced carcinomas in even more than half of the animals at the dose level of 0.1 mg and, therefore, has to be classified as the most potent PAC under investigation. BaP resulted in a clear dose-response relationship. According to probit analysis of the results, the carcinogenic potencies of the PAC relative to BaP (1.00) rank as follows: DBahA, 1.91; CHR, 0.03; BNT, 0.02; and PHE, 0.001. The estimated ED10- values were 0.031 mg for BaP, 0.016 mg for DBahA, 1.02 mg for CHR, 1.65 mg for BNT and 22.84 mg for PHE.

Urinary and faecal excretion of pyrene and hydroxypyrene by rats after oral, intraperitoneal, intratracheal or intrapulmonary application.

The urinary and faecal excretion of pyrene and 1-hydroxypyrene after oral (53.4%), intraperitoneal (3.1%), intratracheal (30-37%) and intrapulmonary application (0.003%) to rats has been determined by means of gas chromatography/mass spectrometry and the excretion rates were found to depend on the mode of application. With regard to the low urinary excretion rates, 1-hydroxypyrene seems not to be very suitable as a biological marker for PAH exposure to man.

Dermal oncogenicity study of 2-ethylhexyl acrylate by epicutaneous application in male C3H/HeJ mice.

A carcinogenicity bioassay of 2-ethylhexyl acrylate (2-EHA) was conducted by applying 25 microliters 86.5%, 21%, or 2.5% 2-EHA in acetone three times a week to the clipped dorsal skin of male C3H/HeJ mice (80 per group) over their lifetime. Another group was treated with a 43% 2-EHA solution for 24 weeks and thereafter observed for lifetime (stop-test). An untreated group and a group that received only the diluent acetone served as controls. Treatment-related changes in the skin indicative of irritation (scaling, scabbing, hyperkeratosis, hyperplasia) were found in all 2-EHA-treated groups. These lesions were reversible in the 43% group immediately after treatment was stopped, and in the 2.5% group after the 11th week of treatment. Only in the 86.5% and 21% test groups showing chronic irritative skin damage was there a high incidence of nepolastic skin lesions (papillomas, carcinomas, and melanomas) with no dose dependency. In contrast, no skin tumors were found in the control groups, in the group treated with 2.5% 2-EHA for lifetime or in the group treated with 43% 2-EHA for about 6 months and observed for lifetime.

Exposure of rats and hamsters to sidestream smoke from cigarettes in a subchronic inhalation study.

A 90-day feasibility study was performed in which rats and hamsters were exposed to the sidestream smoke of cigarettes. The only histopathological changes observed were hyperplasia and metaplasia of the epithelium covering the dorsal nasal turbinate bones in rats. These effects were reversible within 90 days.

Contribution of polycyclic aromatic compounds to the carcinogenicity of sidestream smoke of cigarettes evaluated by implantation into the lungs of rats.

Particles and semivolatiles from sidestream smoke of cigarettes smoked on a smoking machine were collected by a filter combination consisting of a glass fibre filter and silanized polystyrene beads. The extract of the glass fibre filter was separated by a Sephadex LH-20 column chromatography into a fraction containing non-aromatic material plus polycyclic aromatic compounds (PAC) with 2 and 3 rings and a fraction consisting of PAC with 4 and more rings. To evaluate the carcinogenicity, both fractions as well as the semivolatiles were implanted into the lungs of Osborne-Mendel rats at a dose level of one cigarette per animal and compared with three dose levels of benzo[a]pyrene (BaP). The most pronounced carcinogenic effect of the sidestream smoke (100 ng BaP per cigarette) was caused by the fraction containing polycyclic aromatic hydrocarbons (PAH) with 4 and more rings (5 carcinomas of the lungs/35 rats). This fraction represents only 3.5% by weight of the total sidestream smoke condensate. By contrast, the semivolatile material did not provoke any tumors. Only a small contribution to the total carcinogenicity (1 carcinoma of the lungs/35 rats) was observed for the fraction containing non-aromatic material and 2- and 3-ring PAHs.

Urinary and faecal excretion of chrysene and chrysene metabolites by rats after oral, intraperitoneal, intratracheal or intrapulmonary application.

The urinary and faecal excretion of chrysene and its phenolic metabolites after oral, intraperitoneal, intratracheal, and intrapulmonary administration to rats have been studied by means of gas chromatography/mass spectrometry. The metabolite profile was found to depend on the mode of excretion and on the route of administration. In all cases the oxidation of chrysene in the 1,2- or 3,4-position predominates, whereas oxidation in the 5,6-position (K-region) seems be a minor pathway.