IV. DISCUSSION AND CONCLUSIONS 



Metabolically, under aerobic conditions, the re- 

 duction of nitrofurantoin stimulates tlie con- 

 sumption of oxygen and tlie production of super- 

 oxide anion free radical and hydrogen peroxide 

 in avian liver and in mammalian liver, lung, 

 small intestine, kidney, and gastrointestinal 

 contents which may result in toxicity and lo- 

 calized injury (Mason and Holtzman, 1975a; 

 Biaglow et al., 1977; Aufrere et al., 1978; Boyd et 

 al., 1979a; Sasame and Boyd, 1979; Leskovac 

 and Popovic, 1980; Peterson et al., 1982a). Un- 

 der anaerobic conditions, nitrofurantoin is per- 

 manently reduced to nitroso and/or hydroxyl- 

 amine forms (Mason and Holtzman, 1975a; 

 Biaglow et al., 1977; Leskovac and Popovic, 

 1980), which may result in binding to cellular 

 macromolecules (DNA and protein) (Boyd et al., 

 1979b). The covalent binding to macromolecules 

 is apparently greatest in the kidney, liver, ile- 

 um, lung, and heart of rats (Aufrere et al., 1978). 

 Toxicity and DNA damage may increase as 

 oxygen tension decreases (Russo et al., 1982). 



The kidney is a primary organ of metabolism 

 and excretion and is the site of chemical-related 

 toxicity. The severity of chronic nephropathy 

 was greatest in high dose male rats. This spon- 

 taneous disease occurs in nearly all laboratory 

 rats, and the onset is generally earlier and the 

 effects are more severe in males than in females 

 (Chennekatu et al., 1986). Proteinuria begins 

 when the male rat is several months old and in- 

 creases progressively as the animal ages, which 

 indicates progressive impairment of some renal 

 functions. The reason for the apparent selective 

 toxicity of nitrofurantoin to the kidney of male 

 rats may be related to the fact that the kidneys 

 receive up to 20% of the cardiac output of blood, 

 have a large endothelial and epithelial surface 

 area that is exposed to the blood or glomerular 

 filtrate containing the chemical, perform diverse 

 metabolic functions, have a high concentrating 

 function for excreted and absorbed metabolites, 

 and have an age-related deterioration in kidney 

 function. The nonneoplastic lesions observed in 

 this study (parathyroid gland hyperplasia, fi- 

 brous osteodystrophy of the bone, and minerali- 

 zation of the glandular stomach) are character- 

 istic of renal secondary parathyroidism and are 

 believed to be secondary to the chronic nephrop- 

 athy (Burns, 1979). 



The kidney was identified as a target organ in 

 mice in the 13-week studies in which mineral- 

 ization of the renal medulla in dosed male and 

 female mice and dilatation of the renal tubules 

 in dosed male mice were observed. The original 

 evaluation of the kidney by standard procedures 

 (i.e., microscopic examination of single longitu- 

 dinal sections of the left and right kidney) iden- 

 tified small numbers of tubular cell neoplasms 

 in dosed male rats but not in controls (control, 

 0/50; low dose, 1/50; high dose, 3/50). The inci- 

 dences in dosed rats were not statistically 

 greater than that in concurrent controls, but tu- 

 bular cell neoplasms occur rarely in untreated 

 historical controls (8/1,929, 0.4%) (Table A4a). 

 Thus, an informal comparison of the incidences 

 in dosed male rats with historical controls sug- 

 gested that the neoplasms may be chemical 

 related. 



Kurokawa et al. (1983) compared results of 

 examination of single vs. multiple sections of 

 kidney and found that incidences were greater 

 with multiple sections. Therefore, the NTP pre- 

 pared step-sections of the remaining right and 

 left halves of the kidney to provide additional 

 data and to clarify the potential relationship of 

 the tubular cell neoplasms to the administration 

 of nitrofurantoin. The results of this subsequent 

 evaluation unequivocally demonstrated a dose- 

 related and significantly increased incidence of 

 renal tubular cell adenomas in male rats given 

 nitrofurantoin (low dose, P<0.05; high dose, 

 P< 0.001). The data are considered to represent 

 some, rather than clear, evidence of carcinogenic 

 activity for the following reasons: standard 

 histologic procedures (single sections of kidney) 

 showed only small numbers of tubular cell neo- 

 plasms in dosed male rats; the tubular cell neo- 

 plasms in dosed rats were predominantly ade- 

 nomas; the adenomas were small, microscopic 

 tumors; some were difficult to distinguish from 

 hyperplasia; and the biologic potential of many 

 of the small adenomas is uncertain. 



The liver has been identified as a major site of 

 metabolism, a minor site of excretion, and a 

 potential target organ Hepatocellular neo- 

 plasms (adenomas or carcinomas, combined) in 

 female mice occurred with a positive trend (see 

 Table 27). An Ito cell tumor of the liver was 



63 



Nitrofurantoin, NTPTR 341 



