III. RESULTS: RATS 



Kidney: Chronic nephropathy occurred in 

 nearly all rats. This spontaneous disease was 

 characterized by varying degrees of tubular de- 

 generation with atrophy of the epithelium and 

 dilatation of the tubules, regeneration of tubular 

 epithelium, thickening of the tubular basement 

 membranes, interstitial fibrosis, chronic inflam- 

 mation, and glomerulosclerosis. The severity of 

 this disease in each rat was judged on a scale of 

 1 = minimal, 2 = mild, 3 = moderate, 4 = 

 marked. The mean severity of the nephropathy 

 was somewhat increased in dosed male rats 

 relative to controls but was decreased in dosed 

 female rats (male: control, 50/50 [severity, 3.1]; 

 low dose, 48/50 [3.31; high dose, 48/50 [3.5); fe- 

 male: 44/50 [2.41; 40/50 [2.2|; 48/50 [2.0|). Hy- 

 perplasia of the transitional epithelium lining 

 the renal pelvis and hydronephrosis were also 

 observed in some dosed male rats (transitional 

 epithelium hyperplasia: 0/50; 5/50; 2/50; hydro- 

 nephrosis: 0/50; 5/50; 2/50). 



A single section of the left and right kidney of 

 each rat was examined microscopically as a 

 standard procedure during the histopathologic 

 evaluation. With this procedure, renal tubular 

 cell adenomas were seen in 1/50 low dose and 



2/50 high dose male rats, and a tubular cell car- 

 cinoma was observed in 1/50 high dose male 

 rats; none was seen in controls (Table 11). Tu- 

 bular cell hyperplasia was seen in all groups of 

 males, including controls. 



Because the number of renal tubular cell neo- 

 plasms identified by standard procedures in the 

 dosed male rats was low, the marginally in- 

 creased incidence was not statistically signifi- 

 cant relative to concurrent controls. Since tubu- 

 lar cell neoplasms are often late appearing and 

 are seen only during microscopic examination in 

 2-year-old rats (i.e., they are often not seen 

 grossly at necropsy), step-sections of kidney 

 were made to provide additional data. The re- 

 maining half of the right and left kidney from 

 each male rat was embedded, and three or four 

 additional step-sections from each half kidney 

 were made at approximately 1-mm intervals. 

 These were examined microscopically, and addi- 

 tional tubular cell neoplasms were observed in 

 all groups (Tables 12 and 13). The tubular cell 

 adenomas occurred with a significant positive 

 trend, and the incidences in the low and high 

 dose groups were significantly greater than that 

 in the controls. 



TABLE 11. RENAL TUBULAR CELL LESIONS IN MALE RATS IN THE TWO-YEAR FEED STUDY OF 



NITROFURANTOIN: ORIGINAL EVALUATION (a) 



Control 



1,300 ppm (b) 



2,500 ppm (b) 



Hyperplasia 



Overall Rates 



Adenoma 



Overall Rates 



Carcinoma 



Overall Rates 



Adenoma or Carcinoma (c) 



Overall Rates 

 Adjusted Rates 

 Terminal Rates 

 Day of First Observation 

 Life Table Tests 

 Logistic Regression Tests 



(a) The statistical analyses used are discussed in Section II (Statistical Methods) and Table A3 (footnotes). 



(b)The estimated dose in milligrams per kilograms per day is given in Section III (Body Weights, Feed Consumption, and 



Clinical Signs) and in Appendix G. 



(c) Historical incidence at study laboratory (mean ± SD): 2/439(0.5% ± 0.9%); historical incidence in NTP studies: 8/1,929 



(0.4% ± 0.9%) 



43 



Nitrofurantoin, NTP TR 341 



