DNA adduct measurements, cell proliferation and tumor mutation induction in relation to tumor formation in B6C3F1 mice fed coal tar or benzo[a]pyrene.
Coal tar is a complex mixture containing hundreds of compounds, at least 30 of which are polycyclic aromatic hydrocarbons, including the carcinogen benzo[a]pyrene (BaP). Although humans are exposed to complex mixtures on a daily basis, the synergistic or individual effects of components within a mixture on the carcinogenic process remain unclear. We have compared DNA adduct formation and cell proliferation in mice fed coal tar or BaP for 4 weeks with tumor formation in a 2 year chronic feeding study. Additionally, we have analyzed tumor DNA for mutations in the K-ras, H-ras and p53 genes. In the forestomach of mice fed either coal tar or BaP an adduct indicative of BaP was detected, with adduct levels increasing in a dose-responsive manner. K-ras mutations were detected in the forestomach tumors, with the incidence being similar in mice fed coal tar or BaP. These results suggest that the BaP within coal tar is associated with forestomach tumor induction in coal tar-fed mice. DNA adduct levels in the small intestine were not predictive of tumor incidence in this tissue; instead, the tumors appeared to result from compound-induced cell proliferation at high doses of coal tar. K-ras mutations were detected in lung tumors. Since lung tumors were not increased by BaP, coal tar components other than BaP appear to be responsible for the tumors induced in this tissue. H-ras mutations, primarily occurring at codon 61, were the most common mutation observed in liver tumors induced by coal tar. Since this mutation profile is observed in spontaneous hepatic tumors, components in the coal tar may be promoting the expansion of pre-existing lesions.
Culp
S J
SJ
National Center for Toxicological Research, Jefferson, AR 72079 and Pathology Associates International, Jefferson, AR 72079, USA. sculp@nctr.fda.gov
Warbritton
A R
AR
Smith
B A
BA
Li
E E
EE
Beland
F A
FA
D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000633:toxicity*; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D003033:Coal Tar / Q000378:metabolism / Q000633:toxicity*; D018736:DNA Adducts / Q000096:biosynthesis*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D016158:Genes, p53 / Q000187:drug effects / Q000235:genetics; D011905:Genes, ras / Q000187:drug effects / Q000235:genetics; D007421:Intestine, Small / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009154:Mutation; D009374:Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013270:Stomach / Q000166:cytology / Q000187:drug effects
D002273:Carcinogens; D018736:DNA Adducts; D004273:DNA, Neoplasm; D001564:Benzo(a)pyrene; D003033:Coal Tar