SUMMARY OF PEER REVIEW COMMENTS 

 ON THE TOXICOLOGY AND CARCINOGENESIS STUDIES OF 



NITROFURANTOIN 



On July 14, 1987, the draft Technical Report on the toxicology and carcinogenesis studies of nitrofu- 

 rantoin received peer review by the National Toxicology Program Board of Scientific Counselors' 

 Technical Reports Review Subcommittee and associated Panel of Flxperts. The review meeting was 

 held at the National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, 

 NC. 



Dr. J.E. French, NIEHS, introduced the studies by reviewing the experimental design, results, and 

 proposed conclusions (some evidence of carcinogenic activity for male rats, no evidence of carcino- 

 genic activity for female rats, no evidence of carcinogenic activity for male mice, clear evidence of car- 

 cinogenic activity for female mice). 



Dr. Popp, a principal reviewer, agreed with the conclusions for female rats and male and female mice; 

 he said that the Panel should discuss the concomitant ovarian toxicity in female mice Dr. Popp 

 opined that the results for male rats, a slight increase in renal tubular neoplasms (control, 0/50; low 

 dose, 1/50; high dose, 3/50) coupled with a corresponding lack of an increase in renal tubular hyper- 

 plasia, more closely supported equivocal evidence of carcinogenic activity. Dr. French acknowledged 

 that the lack of hyperplasia must be considered but felt that the presence of a carcinoma was evidence 

 supporting progression and, although the numbers of renal tubular cell tumors were relatively low, 

 there was a twentyfold difference between the high dose and mean historical control incidences. Dr. 

 Hughes pointed out that there was one study in the historical control data base with two tubular neo- 

 plasms. Dr. J. Haseman, NIEHS, reported that for the most recent 73 corn oil gavage and feed stud- 

 ies, 57 had a zero incidence of tubular neoplasms in controls, 15 had an incidence of one, and 1 had an 

 incidence of two. 



As a second principal reviewer, Dr. Ashby agreed with the conclusions for male and female rats and 

 male mice, while suggesting that the conclusion for female mice be changed to some evidence of carci- 

 nogenic activity. He stated that two of the three types of ovarian tumors were observed only in the 

 high dose groups. He questioned whether those tumors could be combined for assessment. Also con- 

 founding the interpretation was the presence of ovarian atrophy in almost all of the exposed animals. 

 Dr. French remarked that both ovarian tubular adenomas and benign mixed tumors were uncommon 

 and histogenetically it was considered appropriate to combine them. 



As a third principal reviewer. Dr. Chinchilli agreed with the conclusions for male and female rats and 

 male mice, noting that osteosarcomas of the bone and subcutaneous tumors observed in male rats are 

 uncommon. For female mice, he questioned why statistical analyses for the ovary were based on a 

 sample of 50 when tissues from only 39 control mice were available for microscopic evaluation Dr. S. 

 Eustis, NIEHS, explained that ovaries from all 50 control female mice were examined; however, ovar- 

 ian abcesses had destroyed much of the tissues from 1 1 animals. In his opinion, the examination was 

 sufficient to determine whether a tumor was present. Dr. Haseman commented that whether the de- 

 nominator was 39 or 50, the differences in tumor incidences were highly significant and quite 

 striking. Dr. Chinchilli inquired if a statistical comparison test using historical control data could be 

 used in analysis of uncommon tumors. Dr Haseman agreed that rare or uncommon tumors might be 

 the one instance in which a formal analysis incorporating historical data should be considered, al- 

 though lack of agreement as to which test is most appropriate was still a problem 



Dr. William H. Butler, of the British Industrial Biological Research Association and representing 

 Norwich Eaton Pharmaceuticals, Inc , presented a review of his observations from an examination of 

 the slides containing ovary sections from the female mice. He contended that the occurrence of ovari- 

 an abcesses in a number of controls obviated a proper analysis. He also suggested that the tubular 



11 Nitrofurantoin, NTPTR 341 



