Comparative studies were conducted of the tumor-initiating activity in mouse skin and carcinogenicity in rat mammary gland of dibenzo[a,l]pyrene (DB[a,l]P) versus 7,12-dimethyl-benz[a]anthracene (DMBA), the most potent recognized carcinogenic polycyclic aromatic hydrocarbon (PAH); benzo[a]pyrene (B[a]P), the most potent recognized carcinogenic environmental PAH; DB[a,l]P 8,9-dihydrodiol, the K-region dihydrodiol; and DB[a,l]P 11,12-dihydrodiol, precursor to the bay-region diolepoxide. The tumor-initiating activity of DB[a,l]P and B[a]P was compared in the skin of female SENCAR mice at doses of 300, 100 and 33.3 nmol. The mice were promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA) twice-weekly for 13 weeks. DB[a,l]P at all doses induced significantly more tumors than B[a]P at the corresponding dose, with a significantly shorter latency. Subsequently, the tumor-initiating activity of DB[a,l]P was compared in the skin of female SENCAR mice to that of DMBA, B[a]P, DB[a,l]P 8,9-dihydrodiol and DB[a,l]P 11,12-dihydrodiol at doses of 100, 20 and 4 nmol. The mice were promoted with TPA twice-weekly for 24 weeks. In addition, groups of mice were initiated with 100 nmol of DB[a,l]P, DMBA, B[a]P, DB[a,l]P 8,9-dihydrodiol or DB[a,l]P 11,12-dihydrodiol and kept without promotion. This experiment showed that in the mouse skin, DB[a,l]P and DB[a,l]P 11,12-dihydrodiol displayed similar tumor-initiating activity with a response inversely proportional to the dose, presumably due to the toxicity of the compounds. At the high dose they elicited tumors earlier than DMBA, though DMBA produced a much higher tumor multiplicity. At the low dose, DMBA, DB[a,l]P and DB[a,l]P 11,12-dihydrodiol exhibited similar tumorigenicities. DB[a,l]P 8,9-dihydrodiol was a marginal tumor initiator. Once again, DB[a,l]P was by far a much stronger tumor initiator than B[a]P. Female Sprague-Dawley rats were treated with 1.0 or 0.25 mumol of DB[a,l]P, DMBA or B[a]P by intramammillary injection at eight teats. DB[a,l]P at both doses was a more potent carcinogen than DMBA at the corresponding dose in the rat mammary gland. B[a]P was a marginal mammary carcinogen, eliciting only a few fibrosarcomas. Thus, these data suggest that DB[a,l]P is the strongest PAH carcinogen ever tested.

Comparative studies of tumor-initiating activity in mouse skin and carcinogenicity in rat mammary gland were conducted with several dibenzo[a]-pyrenes (DBPs). SENCAR mice were initiated with DB[a, e]P, DB[a, h]P, DB[a, i]P, DB[a, l]P and anthanthrene, and promoted with tetradecanoyl-phorbol acetate. The same compounds were tested by intramammillary injection in female Sprague-Dawley rats. Anthanthrene was inactive in both mouse skin and rat mammary gland. DB[a, e]P was a very weak tumor-initiator in mouse skin and was inactive in rat mammary gland. DB[a, h]P induced twice as many papillomas in mouse skin as DB[a, i]P, although both compounds exhibited similar tumor latencies and percentages of tumor-bearing mice. These two compounds induced similar numbers of mammary tumors, but treatment of the rats with DB[a, i]P resulted in a significantly larger number of adenocarcinomas. DB[a, l]P was toxic to both the mice and rats. Treatment of mouse skin with this compound led to an erythema, which delayed the beginning of promotion until the 3rd week after initiation. Despite this delay, papillomas began appearing 5 weeks after initiation with DB[a, l]P and the number of tumors increased rapidly. The compound was so toxic in the rats that half of the animals died in the first 9 weeks and the remaining animals were sacrificed after 15 weeks. Nonetheless, DB[a, l]P was the strongest carcinogen tested, inducing seven tumors per rat within 10 weeks. These results demonstrate that DB[a, l]P, which is present in tobacco smoke, is an extremely potent carcinogenic aromatic hydrocarbon. Furthermore, some of these compounds can serve as useful models for elucidating their mechanisms of activation.

Syrian hamsters present a unique species for induction of pancreatic tumors that in many aspects resemble human pancreatic cancer. The specific response of Syrian hamsters, in contrast to may other rodents, for development of pancreatic ductal (ductular) tumors is not yet known. All pancreatic carcinogens thus far tested show certain common features. They are all nitrosamines that possess or can be metabolized to compounds with 2-oxopropyl- or 2-hydroxypropyl substituents. All but one, N-nitroso-methyl(2-oxopropyl)amine, occur or metabolize to nitrosamines with the ability to cyclize and form structures resembling glucose. Hence it is suggested that this cyclic structure may be responsible for the pancreatic carcinogenicity of these nitrosamines, as has been proposed for the pancreatotropic effect of streptozotocin. It is also of further interest that one pancreatic ductal (ductular) carcinogen, N-nitroso-2-methoxy-2,6-dimethylmorpholine, which possesses a totally cyclic structure, acts, like streptozotocin, as beta-cell cytotoxic and diabetogenic when given in a high single dose. Modification of pancreatic tumor induction has been demonstrated by specific procedures. A high fat diet significantly increases both the incidence and number of induced cancers. Methods for early diagnosis and therapy are being developed and their significance and applicabilities for clinical use will be of major importance. Compared with the other most common types of human cancer, pancreatic cancer has extraordinary characteristics, which make the disease one of the most mysterious of maladies. Consequently, pancreatic cancer represents a serious international problem and requires urgent resolution, especially with regard to its etiology, early diagnosis, prevention, and therapy.

Hamsters of three types designated as inbred cream (Epp/e/e), linebred white (EPP/cdcd/RB/A), and linebred albino (EPP/cdcde/e) were thoroughly examined histopathologically for spontaneous diseases. All hamsters were maintained simultaneously for life under identical standard laboratory conditions. Marked differences were found in longevity of the animals and in incidence, sites, patterns, and types of spontaneous diseases. In cream hamsters (CH), survival time was shorter than in white hamsters (WH) and albino hamsters (AH). More tumors and malignant lesions unrelated to survival were found in AH compared to CH and WH; also, the multiplicity of neoplasms were more pronounced in AH. The predominating tumor types differed in each line: Pancreatic islet cell neoplasms were most common in CH, adrenal gland tumors predominated in WH, and thyroid gland tumors in AH. Also, the relative incidence of spontaneous tumors varied among the lines. Some tumors seemed strain-specific and were not seen in other lines; malignant melanomas, for example, occurred only in CH and WH. Certain neoplasms, e.g., those of the thyroid and adrenal glands, were found more often in one sex than the other. The three hamster groups differed also in nonneoplastic diseases. Detailed histopathologic findings are presented and compared with data on the Syrian golden hamster, the ancestral line of these three groups.

Comparative studies of tumor-initiating activity in mouse skin and carcinogenicity in rat mammary gland were conducted with benzo[a]pyrene (BP) and 3-methylcholanthrene (MC) derivatives. SENCAR mice were initiated with BP, 6-fluorobenzo[a]pyrene (6-FBP), 6-methylBP, 7-FBP, 8-FBP, 9-FBP, 10-FBP, or 10-azaBP and promoted with tetradecanoyl phorbol acetate. The same compounds plus BP 7,8-dihydrodiol were tested by intramammillary injection in female Sprague-Dawley rats. Tumor-initiating activity in mice and/or carcinogenicity in rats were observed for BP, 6-methylBP, 6-, 7-, 8-, and 10-FBP, whereas 9-FBP was inactive in both experiments and 10-azaBP was only marginally active in the mammary gland. BP 7,8-dihydrodiol was carcinogenic in rat mammary gland, although it was less potent than BP. MC, 8-FMC, 10-FMC, and 3-methylcholanthrylene were also tested in Sprague-Dawley rats by intramammillary injection. All compounds were carcinogenic, with MC displaying the most potent activity. The less potent carcinogenic activity of BP 7,8-dihydrodiol in the mammary gland, compared with BP, and the moderate-to-weak tumor-initiating and/or carcinogenic activity of 7-, 8-, and 10-FBP suggest that the bay-region diol-epoxide pathway does not play a significant role in the activation of BP in these two target tissues. Similarly, the carcinogenic activity of 8-FMC and 10-FMC, in which the bay-region diol-epoxide pathway is blocked, suggests that this mechanism of activation is not important in the carcinogenicity of MC in rat mammary gland.