SUMMARY OF PEKR REVIEW COMMENTS (Continued) 



cell adenomas might have resulted from hormonal stimulation due to ovarian atrophy and that the 

 existence of other negative studies supported equivocal evidence of carcinogenic activity. Dr. Butler 

 opined further that there was no evidence of carcinogenic activity in male rats because the incidence 

 of renal tubular cell neoplasms was low and within the expected historical range, because there was 

 no evidence of similar lesions in female rats, because there was no increase in hyperplasia, and be- 

 cause there was a high incidence of chronic nephropathy. Dr. E. McConnell, NIEHS, emphasized that 

 both increases and decreases in hyperplasia are considered in the evaluations In the case of the renal 

 tumors in male rats, the lack of hyperplasia was noteworthy but did not necessarily offset the in- 

 crease in an uncommon tumor. 



Dr. Popp moved that the conclusion for male rats be changed to equivocal evidence of carcinogenic ac- 

 tivity and that the conclusion for female rats, no evidence of carcinogenic activity, be accepted as 

 written. Dr. Ashby seconded the motion, which was defeated by four votes (Dr. Ashby, l)r Chinchilli, 

 Dr. Hooper, and Dr. Mirer) to three (Dr. Gallo, Dr Popp, and Dr. Sivak), with two abstentions (Dr. 

 Capen and Dr. Hughes). Dr. Hooper moved that the conclusions be accepted as written for male rats, 

 some evidence of carcinogenic activity, and for female rats, no evidence of carcinogenic activity Dr 

 Ashby seconded the motion, which was approved by four votes (Dr. Ashby, Dr. Chinchilli, Dr. Hooper, 

 and Dr. Mirer) to three (Dr. Gallo, Dr Popp, and Dr. Sivak), with two abstentions (Dr. Capen and Dr. 

 Hughes). Dr. Popp moved that the conclusions for male mice, no evidence of carcinogenic activity, 

 and for female mice, clear evidence of carcinogenic activity, be accepted as written. Dr. Chinchilli 

 seconded the motion, which was approved by five votes to two (Dr. Ashby and Dr. Gallo), with two ab- 

 stentions (Dr. Capen and Dr. Hughes) 



Update and Reevaluation of Further I'athology on Kidneys from Male Rats 

 (April 18, 1988) 



At the Peer Review meeting on April 18, 1988, Dr French summarized the discussion from the Peer 

 Review meeting on July 14, 1987, when an important portion of the discussion focused on the tubular 

 cell neoplasms in the kidney of dosed male rats and the level of evidence for carcinogenic activity rec- 

 ommended by the staff. The level of evidence selected for male rats (some evidence of carcinogenic ac- 

 tivity) was based on: dose-related, albeit marginally increased, incidences of uncommon neoplasms of 

 the tubular cells in the kidney (0/50, 1/50; 3/50) (see Table 1 1 ), the possibility of progression to malig- 

 nancy as evidenced by a tubular cell carcinoma in the kidney in a high dose male rat, and comparison 

 with historical controls. 



Dr. French went on to explain that because of the microscopic size of the majority of these tumors and 

 questions concerning the dose-response relationship, additional histologic sections of the kidneys 

 were prepared for evaluation. The purpose was to obviate the possibility of bias due to chance and to 

 determine if the number of tumors found in each group would increase proportionally in relation to 

 dose. The data derived only from the additional step-sections are shown in Table 12. All of the addi- 

 tional kidney tumors were observed microscopically, and there was an increase in the number of mul- 

 tiple adenomas observed in the high dose male rats The composite results of both data sets are shown 

 in Table 13 The incidences of tubular cell neoplasms in the kidney of male rats were as follows: con- 

 trol, 3/50; low dose, 11/50; high dose, 20/50. The low dose incidence was statistically different from 

 that in the controls at the 0.05 level, and the high dose incidence was statistically different at the 

 0.001 level. 



Dr. French said that the data indicate that male rats receiving 0, 1,300, or 2,500 ppm nitrofurantoin 

 in feed at for 2 years developed compound related tubular cell neoplasms and that these data support 

 the conclusion previously written in the Technical Report and approved by the Panel. Summary 



Nitrofurantoin, NTPTR 341 12 



