Comparative tumorigenicity of benzo[a]pyrene, 1-nitropyrene and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine administered by gavage to female CD rats

Abstract

Agents that are ubiquitous in the environment and are known inducers of mammary cancer in rodents can be regarded as potential causes of human cancer and need to be evaluated more completely. Therefore, the purpose of this study was to determine under identical conditions the relative carcinogenic potency in the mammary glands of rats of benzo[a]pyrene (B[a]P), 1-nitropyrene (1-NP) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Thirty-day-old female CD rats were gavaged once weekly for 8 weeks with B[a]P, 1-NP or PhIP. Each compound was given at 50 mumol/rat/week in 0.5 ml trioctanoin for a total dose of 400 mumol/rat. Forty-one weeks after the last carcinogen administration, rats were killed. In the 1-NP-treated rats, treatment elicited primarily benign tumors. In contrast, the B[a]P- and PhIP-treated rats developed both malignant and benign tumors. The incidence of adenocarcinomas in rats treated with B[a]P or PhIP was comparable and significantly higher than that in animals receiving trioctanoin only. The incidence of benign tumors (fibroadenomas, desmoplastic adenomas and adenomas) observed in animals treated with B[a]P or 1-NP was comparable and significantly higher than that in animals given PhIP or trioctanoin. This is the first report describing the carcinogenic activity of PhIP, given by gavage, in the mammary gland of CD rats and ranking the carcinogenic potency observed under identical conditions, of three agents (B[a]P congruent to PhIP > 1-NP) that are prevalent in the human environment.

Cigarette smoke condensate-induced level of adenomatous polyposis coli blocks long-patch base excision repair in breast epithelial cells

“…It contains most of the particulate chemicals identified in the cigarette smoke (Smith and Hansch, 2000;Hecht, 2002;Stabbert et al, 2003). The transformation of the normal breast epithelial cells by pure cigarette smoke carcinogens such as B[a]P, DMBA and NNK have been well documented (Soule et al, 1990;el-Bayoumay et al, 1995;Mei et al, 2003;Currier et al, 2005). However, the effect of chemically complex cigarette smoke, which contains both carcinogenic substances as well as their inhibitors, still remains an unresolved question.…”

“…Individual cigarette smoke carcinogens such as polycyclic hydrocarbons benzo[a]pyrene (B[a]P), 7,12-dimethylbenz(a)anthracine (DMBA) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) have been found to transform cultured cells and/or induce mammary tumors in mammals (Soule et al, 1990;el-Bayoumay et al, 1995;Mei et al, 2003;Currier et al, 2005). On the other hand, when rats were exposed to tobacco smoke via inhalation for 4 h/day for 100 days, differences in the development of mammary tumors between exposed and unexposed animals were not observed.…”

U.S. dietary exposures to heterocyclic amines*

“…Our finding that, on a national basis, African American males, and boys in particular, are exposed to substantially more PhIP than white males is particularly interesting not only in view of PhIP's capacity to damage and mutate prostate DNA and cause prostate tumors in rats (see Introduction ), but also in view of studies in which as few as 8 ±10 doses of PhIP during the peak period of end -bud cell proliferation in young /adolescent mammary epithelium ( which like the prostate is a hormonally regulated tissue ) are sufficient to induce subsequent mammary cancer in female rats (Ghoshal et al, 1994;El-Bayoumy et al, 1995 ). In humans, race -ethnicity is the best predictor of PC occurrence besides age, and African Americans have the highest age -specific PC rates worldwide -incidence rates > 30% to 70% higher and mortality rates > 2 -fold higher than those among U.S. white men (Miller et al, 1996;Robbins et al, 1998;Hsing et al, 2000 ).…”

Xeroderma pigmentosum complementation group C genotypes/diplotypes play no independent or interaction role with polycyclic aromatic hydrocarbons-DNA adducts for breast cancer risk

“…19 PAH have been shown to induce mammary tumours in laboratory-based studies. 20 The major exposure sources include cigarette smoke, consumption of PAH-containing foods (such as grilled and smoked foods), and air pollutants (from industrial manufacturing, fires, and motor vehicle traffic). PAH-DNA adducts have been associated with a modest increase in breast cancer risk in several epidemiologic studies, 21-25 although no apparent dose-response and substantial variation associated with sources of PAH, such as cigarette smoking or consumption of grilled and smoked foods were observed.…”