7H-BENZO[C]FLUORENE: A POTENT SYSTEMIC LUNG CARCINOGEN

Abstract

7H-Benzo[c]fluorene (B[c]F) is a major lung deoxyribonucleic acid (DNA) adductor in mice treated with coal tar suggesting that B[c]F may be capable of inducing lung tumors. This study evaluated the tumorigenic potential of B[c]F in comparison to benzo[a]pyrene (B[a]P) using the A/J mouse model. Female A/J mice 7 weeks of age were administered B[c]F or B[a]P (100 mg/kg) by i.p. injection. These mice were fed Purina Rodent 2001 diet for the remainder of the study. Groups of mice were also fed diets containing B[c]F (397 or 27 μmol/kg diet) or B[a]P (397 μmol/kg diet). In addition, a mixture of 20 synthetic polycyclic aromatic hydrocarbons (PAHs) known to be present in coal tar was also fed to mice in the presence or absence of B[c]F. A basal gel diet system was used to administer hydrocarbons within the diet. Mice were maintained on control or adulterated diets for 260 days. B[c]F administered i.p. induced multiple lung tumors in 92% of the treated mice, with an average of 4.0 tumors per mouse. Similarly, B[a]P administered i.p. induced an average of 6.7 tumors per mouse in 90% of the treated mice. The highest level of lung tumor induction was observed in mice fed 397 μmol/kg diet B[c]F. A 100% tumor incidence and an average of 46 lung tumors per mouse was observed. In contrast, mice fed a diet containing 397 μmol/kg of B[a]P, had a 77% tumor incidence with an average of 1.4 tumors per mouse. Mice fed a 27 μmol/kg B[c]F diet, or the mixture of synthetic hydrocarbons with or without B[c]F resulted in tumor incidences and multiplicity not different from controls. Forestomach lesions were greatest in mice treated with B[a]P. Evaluation of chemical:DNA adduct formation in mice indicates that B[c]F is better than B[a]P in forming lung DNA adducts when fed to mice at 397 μmol/kg food. These results demonstrate that B[c]F is tumorigenic in lung of mice when administered by i.p. injection and in particular when fed to mice in the diet. These data strongly suggest that B[c]F is a systemic carcinogen that likely contributes to the potent mouse lung tumorigenicity previously demonstrated with coal tar when fed to mice.

Keywords:

• benzo[a]pyrene (B[a]P)
• benzo[c]fluorene (B[c]F)
• polycyclic aromatic hydrocarbon (PAH)

This work was supported by funds from the Electric Power Research Institute, Palo Alto, California, USA.

Present address of Eric H. Weyand is Maple City Research, Inc., Hornell, New York, USA. Present address of Lawrence S. Goldstein is World Health Organization, Geneva, Switzerland.

Notes

^a The amount of each hydrocarbon approximates the amount that is present in a 0.25% coal tar gel diet previously shown to induce lung tumors in female A/J mice (5).

^b The B[c]F content of neat coal tar has been found to be in the range of 10% to 20% of the B[a]P content of coal tar (T. A. Roy, Petrotec Inc., Hornell, N.Y., personal communication, February 14, 2001).

^a The effective number refers to the number of mice that survived 260 days of diet administration.

^b Mean ± SE. Means that bear

* are significantly different (p < .001) as compared with the control. Means that bear

** are significantly different (p < .01) as compared with the vehicle. Significance was determined by ANOVA.

^a Animals treated with B[a]P displayed a number of distinct forestomach lesions. When they presented as distinct lesions within the same forestomach, each received a separate score, leading to a composite score exceeding 100%. Where two histological presentations coexisted within the same lesion (e.g., hyperplasia and squamous cell carcinoma), only the most severe lesion was counted.