SUMMARY.-Four water-soluble carcinogens were injected at the same site subcutaneously into rats, mice or guinea-pigs, twice weekly for 5-8 weeks in order to study the evolution of the early tissue reaction. MNU was injected into rats as 0-1 ml. of 0.5% solution, and into mice as 0-1 ml. of 0-05% solution. NQO was administered to rats (0-1 or 0-2 ml. of 0.25 or 0-1 %) mice (0-1 of 0-05%) and guinea-pigs (0-5 of 0.1%). Propane sultone and BEI were administered to rats only, the former as 0-1 ml. of 3% and the latter as 0.5 ml. of 2-0% solution.The principal features of the tissue reaction produced by each of the four compounds in rats were similar and consisted of destruction of subcutaneous tissue, deposition of fibrin and " fibrinoid ", an abnormal pattern of fibroblastic proliferation with cytomegaly of some fibroblasts and deposition of mucopolysaccharide but little collagen formation. Moreover, the appearance of fibroblastic proliferation was delayed from the normal 2-5 days to 14-16 days.These features are consistent with the known early effects of carcinogens on proliferating target tissues, and differ considerably from those found in the early reactive lesions to repeated injection of solutions of substances possessing physical properties such as surface activity or hypertonicity, or which precipitate at the injection site.THiF, repeated subcutaneous injection of chemicals in rats and mice has often been used as a recommended method of carcinogenicity testing (Boyland, 1958).The production of local sarcomas by this means is not however, universally accepted as indicating carcinogenic potential, since physiologically important chemicals such as glucose or common salt will produce a high incidence of injection site sarcomas when this route of administration is used (Takizawa, 1940; Capellato, 1942; Grasso, 1968, unpublished results). In addition it has been known for some time that a wide range of substances which produce sarcoma when injected repeatedly at the same site fail to exhibit any tumorigenic affect when tested by other routes (Grasso and Golberg, 1966 Nelson, 1957; Jasmin, 1961) and carrageenan (Cater, 1961;Walpole, 1961). In the course of previous experimental work, we have found that aqueous solutions of some of these substances possess physical properties (surface activity, acidic pH, hypertonicity, lipophilic properties) capable of producing cell injury, or else precipitate at the injection site (Gangolli, Grasso and Golberg, 1967;Grasso et al., 1969 (Nakahara and Fukuoka, 1969; Mori, 1962). Propane sultone, a cyclic ester, is an alkylating agent producing local sarcomas in 100% of rats injected subcutaneously. Use of the oral and intravenous route has produced malignant tumours of the nervous system in rats (Druckrey, Kruse and Preussmann, 1968). The fourth carcinogen, BEI, is a monofunctional alkylating agent, which has produced local sarcomas in a high percentage of rats injected subcutaneously (Walpole, 1966, personal communication).We have found that the lesions produced by these car...
Summary.-The sequential histological changes and neoplastic response occurring in the subcutaneous tissue of rats after injection of surfactants or carcinogens were compared. Twice weekly subcutaneous injections of the surfactants Blue VRS and Light Green SF elicited a deranged connective tissue repair with continued proliferation of fibroblasts and extensive collagen desposition. In contrast, the carcinogens N-methyl-N-nitrosourea (MNU) and N-nitroquinoline-N-oxide (NQO) appeared to inhibit connective tissue repair and produce morphologically abnormal fibroblasts. The spectrum of neoplastic response was also found to differ. Surfactants gave rise to local sarcomata only after about 47 weeks, whereas carcinogens produced local sarcomata and adenocarcinomata after 20 and 12 weeks respectively.WE have previously reported the results of investigations of the chemical, physical and biological factors involved in the production of local sarcomata in rodents by repeated subcutaneous injection of a variety of chemicals. The relevance of these sarcomata in terms of the potential carcinogenic risk of such chemicals to man have been evaluated Hooson and CGrasso, 1971). These investigations were based on a sequential study of the local tissue reactions to repeated injections and the analysis of the physical properties of compounds involved. A correlation was found between the early lesion induced in the subcutaneous tissues by a shortterm series of 10-20 injections given at the same site and the production of local connective tissue tumouirs by a long-term series of injections. Histologically, it was found possible to distinguish 4 types of reaction (types I IV). Type I and II reactions were mild and self-limiting and did not progress to neoplasia. In contrast, type III and IV reactions were progressive and proliferative and injection site sarcomata were invariably produced subsequently (Grasso and Golberg, 1966a). It was found that compounds eliciting a type III or IV reaction possessed certain physicochemical properties (surface activity, hypertonicity, etc.) capable of pro-(lucing cell injury. Thus it appears that sarcomata which followed the induction of a tvpe III or IV reaction were an indirect result of repeated injury to local fibroblasts and not due to a process of direct chemical carcinogenesis.In contrast, a short-term study of the lesions induced by repeated subcutaneous injection of water soluble carcinogens, whose oncogenic potencies have been demonstrated by other methods of administration, gave different results. The lesion was characterized in all cases by an inhibition of the normal reparative response and the appearance of cytologically abnormal cells . WAe felt that it was important at this stage to extend these observations from the initial 5 weeks and to compare (1) the changes occurring from this time up to the appearance of tumours (the intermediate period)
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