Comparative in vitro and in vivo genotoxicities of 7H-benzo[c]fluorene, manufactured gas plant residue (MGP), and MGP fractions

• Published in: Environmental and molecular mutagenesis 2004, Vol.43 (3), p.159-168
• Main Authors: Cizmas, Leslie, Zhou, Guo-dong, Safe, Stephen H., McDonald, Thomas J., Zhu, Li, Donnelly, Kirby C.
• Format: Article
• Language: English
• Subjects: Animals; benzo[c]fluorene; Biological and medical sciences; Carcinogens - toxicity; chemical mixture; coal tar; Coal Tar - toxicity; DNA adduct; DNA Adducts; DNA Damage - drug effects; Female; Fluorenes - toxicity; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; In Vitro Techniques; manufactured gas plant residue; Medical sciences; Mice; Mice, Inbred ICR; Microsomes, Liver - drug effects; Mutagenicity Tests - methods; polycyclic aromatic hydrocarbon; Polycyclic Aromatic Hydrocarbons - toxicity; Rats; Rats, Sprague-Dawley; Salmonella typhimurium - drug effects; Salmonella typhimurium - genetics; Toxicology
• ISSN: 0893-6692; 1098-2280
• DOI: 10.1002/em.20011

Manufactured gas plant residue (MGP) is a complex mixture of polycyclic aromatic hydrocarbons (PAHs) that is tumorigenic in the lungs of mice. This study compared the relative genotoxicity of 7H‐benzo[c]fluorene (BC), a PAH component of MGP, with MGP and MGP fractions in order to assess the contribution of BC to the genotoxicity of MGP. An MGP sample was separated into seven fractions (F1–F7) using silica gel column chromatography with petroleum ether (PE) followed by PE:acetone (99:1 v/v, then 98:2). PAHs were quantified using gas chromatography/mass spectrometry. An aliquot of F2, the fraction with the highest BC concentration and highest weighted mutagenic activity in Salmonella typhimurium strain TA98, was further separated using silica gel thin‐layer chromatography with hexane. The first F2 subfraction, sF2‐a, was enriched in BC and coeluting compounds and contained 35,000 ppm BC and 216,109 ppm carcinogenic PAHs (cPAHs, the sum of seven PAHs categorized by the U.S. EPA as class B2 carcinogens). The second F2 subfraction, sF2‐b, contained a ninefold lower concentration of BC, with 3,900 ppm BC and 45,216 ppm cPAHs. Female ICR mice received topical application of crude MGP, crude MGP spiked with analytical‐grade BC, F2, sF2‐a, sF2‐b, or analytical‐grade BC. DNA adduct levels were analyzed by nuclease P1‐enhanced 32P‐postlabeling. In lung DNA of mice receiving 0.48 or 3.0 mg/mouse, net total RAL × 109 values were F2, 30.8 and 87.2; sF2‐a, 24.8 and 106.7; and sF2‐b, 19.6 and 151.0, respectively. Mice dosed with 0.10 mg analytical‐grade BC (the mass of BC in 3.0 mg sF2‐a) exhibited a net total RAL × 109 value of 7.03 in lung DNA. This was equal to approximately 7% of the total RAL × 109 value produced by 3.0 mg sF2‐a. Thus, although BC appears to make an appreciable contribution to pulmonary adduct formation, the results suggest that MGP components other than BC play an important role in lung DNA adduct formation following topical MGP administration. Environ. Mol. Mutagen. 43:159–168, 2004. © 2004 Wiley‐Liss, Inc.