IV. DISCUSSION AND CONCLUSIONS 



observed in one low dose and in one high dose fe- 

 male mouse (Table Dl). Although these Ito cell 

 neoplasms are relatively uncommon, they were 

 considered to be unrelated to nitrofurantoin 

 administration. 



Osteosarcomas observed in the bone (Table Al) 

 of dosed male rats are also of marginal incidence 

 but are rare in control animals (8/1,937, 0.4%). 

 The incidences of subcutaneous fibromas or fi- 

 brosarcomas (combined) were greater in dosed 

 male rats than in controls (see Table 14). 



Effects on the testis in male rats and mice in the 

 13-week studies included aspermatogenesis and 

 degeneration. Nitrofurazone, an analog of nitro- 

 furantoin, inhibits spermatogenesis in rats, 

 which results in testicular atrophy after long- 

 term administration (Prior and P'erguson, 1950; 

 Nissim, 1957; Montemurro, 1969). A similar 

 effect was reported in mice, together with inter- 

 stitial cell hyperplasia and seminal vesicle hy- 

 pertrophy. In the current 2-year studies, admin- 

 istration of nitrofurantoin was associated with 

 the induction of atypical cells of the epididymis, 

 testicular degeneration, and a decrease in the in- 

 cidence of interstitial cell adenomas of the testis 

 in rats (see Table 15) and an increase in the in- 

 cidence of atypical cells and depletion of the epi- 

 didymis in high dose male mice (Table C5). In 

 high dose male mice, testicular aspermato- 

 genesis and degeneration of the germinal epithe- 

 lium were observed. No reports have been pub- 

 lished on whether this effect has been observed 

 or studied in humans. Other compound-related 

 changes in the reproductive tissues of dosed 

 male animals relative to those of controls were 

 decreases in adenomas or carcinomas (combined) 

 of the preputial gland in high dose male rats (see 

 Table 17). 



No neoplastic lesions in dosed female rats or 

 dosed male mice were considered to be compound 

 related at the doses of nitrofurantoin admin- 

 istered in these 2-year studies. The absence of 

 any observed toxicity-related effects suggests 

 that female rats might have been able to toler- 

 ate higher doses. Only the incidence of clitoral 

 gland neoplasms in low dose female rats (Tables 

 Bl and B4a) gave any indication of a potential 

 compound-related effect; this effect was not sup- 

 ported by a similar observation in the higher 

 dose group. 



Ovarian atrophy was associated with increased 

 incidences of tubular adenomas of the ovary, be- 

 nign mixed tumors, and granulosa cell tumors in 

 dosed mice (see Table 25). Ovarian follicular ne- 

 crosis was associated with nitrofurantoin admin- 

 istration in the 13- week studies. Biskind and 

 Biskind (1944) reported the influence of gonado- 

 tropic hormones on the biologic behavior of 

 ovarian tumors. Ovarian atrophy is recognized 

 as an event that is common to and associated 

 with the development of ovarian tumors. In a 

 model developed for studying ovarian tumori- 

 genesis. Murphy (1972) reported that B6C3Fi- 

 W'^IW" mice, (C57BL/6J X C3H/HeJ)Fi-WVWy 

 hybrids, develop spontaneous complex tubular 

 adenomas (mesothelial adenomas) (95%-100% 

 incidence). Homozygous recessive W allele mu- 

 tants are sterile, develop macrocytic anemia, 

 and lack hair pigmentation. Ovaries of these 

 hybrid mice contain less than 1% of the normal 

 complement of oocytes. Tumor development is 

 associated with loss of oocytes and follicular cells 

 and increased levels of pituitary gonadotropic 

 hormones (luteinizing hormone and follicle stim- 

 ulating hormone, two to four times normal 

 values) (Murphy, 1972; Murphy and Beamer, 

 1973). Prolonged stimulation of the ovary by go- 

 nadotropins apparently induces tubular adeno- 

 mas of the ovary. More recently, Tennent and 

 Beamer (1986) and Beamer and Tennent (1986) 

 reported that gonadotropins are necessary for 

 normal follicular atresia and stromal leuteiniza- 

 tion following oocyte death (x-irradiation) but 

 were not sufficient to induce adenomas in hypo- 

 gonal ihpglhpg) mice, which retain follicular 

 structure in the absence of oocytes and are de- 

 ficient in gonadotropin-releasing hormone. 



Ovarian atrophy and loss of follicular cells result 

 in increased gonadotropin stimulation. Pro- 

 longed stimulation may promote hyperplasia of 

 ovarian cells, resulting in benign tumors; how- 

 ever, under certain conditions (e.g., oocyte death 

 due to irradiation or possibly to chemical toxic- 

 ity), prolonged stimulation alone is insufficient 

 to induce complex tubular adenomas. Increased 

 gonadotropin stimulation may promote tumor 

 mass by hypertrophy and/or hyperplasia. The 

 initiating events are not clear; however, genetics 

 and age may influence the progression of events. 

 Although the majority of ovarian tumors 

 observed in the current studies were not 



Nitrofurantoin, NTP TR 341 



64 



