Phorbol myristate acetate and catechol as skin cocarcinogens in SENCAR mice.

Abstract

The enhancement of the carcinogenicity of benzo(a)pyrene (B[a]P) and 3-propiolactone (BPL) by the mouse skin cocarcinogens phorbol myristate acetate (PMA) and catechol were examined in female SEN-CAR mice, 30 per group. The carcinogen and cocarcinogen were applied simultaneously, three times weekly for 490-560 days. B(a)P and BPL were used at constant doses of5 and 50 jig, respectively, in all experiments.PMA was used at three doses, 2.5, 1.0, and 0.5 p.g per application, and catechol was used at one dose, 2 mg per application. Control groups included animals that received carcinogen only, cocarcinogen only, acetone only, and no treatment. The carcinogenicity of B(a)P and BPL were enhanced by the cocarcinogens, particularly in terms of tumor multiplicity. For both carcinogens, the most marked cocarcinogenic effects were observed at the lowest dose of PMA used (0.5 ,ug per application). This observation applied for days to first tumor, animals with tumors, tumor multiplicity, and incidence of malignant skin tumors. Catechol applied alone did not induce any tumors; with PMA alone there were significant incidences of benign and malignant tumors, e.g., at a dose of only 0.5 ,ug per application, 15 of 30 animals had 28 tumors, 5 of which were squamous carcinomas. In two-stage carcinogenesis experiments with 7,12-dimethylbenz(a)anthracene (DMBA) as initiator and PMA as promoter, SENCAR mice showed a greater susceptibility to tumor induction when compared to ICR/Ha mice used in earlier work. This susceptibility was most notable in terms of rate of tumor appearance and tumor multiplicity. The two-stage model for chemical carcinogenesis was first described in the classic work of Berenblum (1,2), who used mouse skin as the route of exposure. At the same time, Berenblum showed that remarkable enhancement of the carcinogenic activity of benzo(a)-pyrene [B(a)P] occurs when croton oil or its concentrate, croton resin, and B(a)P are applied simultaneously and repeatedly to mouse skin. The latter type of experimental protocol was referred to by Berenblum as cocarcinogenesis (1). Since that time, the mouse skin test system has been used in many laboratories for studies on two-stage carcinogenesis and, to a lesser extent, cocarcinogenesis, and these endeavors have been reviewed (3,4). The two protocols as used by Berenblum are summarized in Table 1 opment of sensitive mice was first accomplished in the pioneering work of Boutwell (5), who explored the development of skin tumor-susceptible (STS) mice by careful inbreeding experiments using two-stage carcinogenesis for selection of STS mice. The necessary requirements of inbreeding and the small sizes of colonies used for the development of STS mice resulted in the decline of reproductive performance in these mice. This poor breeding performance was alleviated by crossbreeding male STS mice with female Charles River CD-1 mice. The details and history of the susceptible mice thus developed were recently described (6). These mice, originally maintained at the Oak Ridge National Labor...

Spontaneous Tumors in SENCAR Mice

“…Our findings from the present work and from that presented elsewhere in this volume (1) indicate the need for further work on the utility of the SENCAR mouse in toxicology research.…”

Environmental Chemicals

“…The classical effect of skin co-carcinogenesis by scarification and liver co-carcinogenesis by partial hepatectomy are caused by this mechanism (Mottram, 1944;Deelman, 1924). Among chemical and physical agents acting as co-carcinogens by this mechanism are phorbol esters, catechol and asbestos (Kimizuka et al, 1987;Van Duuren et al, 1986). The co-carcinogenic action on formaldehyde carcinogenesis in the nasal epithelium of the rat by corrosive hydrochloric acid fumes is a classical example from carcinogenesis testing (Sellakumar et al, 1985).…”

Amended Final Report On the Safety Assessment of Pyrocatechol

“…A number of dermal and feeding studies have been published since this review, indicating that Pyrocatechol is a cocarcinogen when administered with a variety of other carcinogens (Hasagawa et al, 1990;Hirose et al, 1987Hirose et al, , 1988Hirose et al, , 1990bHirose et al, , 1993Kurata et al, 1990;LaVoie et al, 1985;Melikian et al, 1989;Mirvish et al, 1985;Nakamura et al, 1991;Van Duuren et al, 1986;Yamaguchi et al, 1989).…”