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The carcinogenic activity of endogenously synthesized N-nitrosobis(2-hydroxypropyl)amine (BHP) was investigated in male Wistar rats administered bis(2-hydroxypropyl)amine (BHPA) mixed in powder diet at a concentration of 1%, and sodium nitrite (SN) dissolved in distilled water at concentrations of 0.15 and 0.3%, for 94 weeks. Urinary excretion of BHP was detected in rats given 1% BHPA and 0.3% SN but not in the groups receiving either of these precursors alone. Nasal cavity, lung, esophagus, liver and urinary bladder tumors were found in animals treated with combinations of 1% BHPA and 0.15 or 0.3% SN, suggesting that the target organs of the endogenously synthesized BHP are similar to those affected when the carcinogen is administered exogenously. The incidences of nasal cavity and lung tumors reached 74 and 58% in rats given 1% BHPA and 0.3% SN, respectively. Tumors at sites other than target organs were only found at levels similar to those previously reported for spontaneous tumors in male Wistars. The present results clearly indicated the tumor inducibility of a nitrosatable amine, BHA, through an endogenous nitrosation by feeding to rats in conjunction with nitrite, and provide further suggestive evidence that endogenous nitrosations of environmental nitrosatable amines can be a potential risk factor in human cancer development.

1 Kawaninii, hfiziiho-cfio, hfiztiho-ku. Nagoya 467. Japan, 2Laboratory of Radioclientistry, Gijii Pfiartnacetitical Utiiversity, 6-1 hfitahora-higasfii, 5-cfionie. Gifri 502, Japan, atid 3T0ky0 Biocfieniical Research Itistiliite, 3-41-8 Takada, Toshittia-kti, Tokyo 171, Japan A s s m c r A time-and dose-dependent study of N-ethyl-N-(4-hydroxybutyl)nitrosamine (EHBN) bladder carcinogenesis was performed in nude mice maintained on tap water containing 0.025% EHBN for 4, 12, and 20 weeks ad libitum. A total of 13 invasive tumors, comprising 1 1 transitional cell carcinomas (TCCs) (84.6%) and 2 squamous cell carcinomas (SCCs) (1 5.4%), were found. Compared with previous results for B6C3F, mice exposed to the same EHBN insult, the numbers of invasive carcinomas induced in nude mice, and especially of SCCs, were low. In order to ascertain whether this difference in cancer incidence between nude and B6C3Fl mice was due to variation in urinary excretion, the metabolism of EHBN was also investigated and compared with that of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Respective total urinary excretions over 48 hr of N-ethyl-N-(3-~arboxypropyl)nitrosamine (ECPN) or N-butyl-N-(3-carboxypropy1)nitrosamine (BCPN), the ultimate carcinogenic species of EHBN or BBN, were 822.4 f 41.4 pg and 530.4 * 81.0 pg, respectively, in nude mice, and 800.6 f 83.7 pg and 407.8 f 69.7 pg, respectively, in B6C3Fl mice. In conclusion, although it is apparent that nude mice have a low susceptibility to EHBN induction of urinary bladder cancer, this does not appear to be dependent on reduced metabolism to the active form. In the process of chemical carcinogenesis, in addition to the steps of initiation and promotion, a progression step, which relates to whether carcinoma cells eventually make themselves manifest as a malignant cancer, has been singled out for attention (3, 10). In this stage ofneoplasia the organism's immunity has been considered as one of the major determining factors. The requirement for investigation ofthis area in v i w prompted the present study of whether development of the EHBN-induced cancer with metastasis progresses more rapidly in nude mice in which immunological surveillance is re-.ducqd. -. t . ~ -. , . However, in fact, a low susceptibility, as compared to previous data for B6C3F, mice (14), was demonstrated. Therefore, the metabolism of EHBN and N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) were compared in nude and B6C3F, mice to elucidate any obvious correlation between cancer induction and carcinogen metabolism.

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