Comparative bladder tumor promoting activity of sodium saccharin, sodium ascorbate, related acids, and calcium salts in rats.
Sodium saccharin and sodium ascorbate are known to promote urinary bladder carcinogenesis in rats following initiation with N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) or N-butyl-N-(4-hydroxybutyl) nitrosamine. Sodium salts of other organic acids have also been shown to be bladder tumor promoters. In addition, these substances increase urothelial proliferation in short term assays in rats when fed at high doses. When they have been tested, the acid forms of these salts are without either promoting or cell proliferative inducing activity. The following experiment was designed to compare the tumor promoting activity of various forms of saccharin and to evaluate the role in promotion of urinary sodium, calcium, and pH as well as other factors. Twenty groups of 40 male F344 rats, 5 weeks of age, were fed either FANFT or control diet during a 6-week initiation phase followed by feeding of a test compound for 72 weeks in the second phase. The chemicals were administered to the first 18 groups in Agway Prolab 3200 diet and the last 2 groups were fed NIH-07 diet. The treatments were as follows: (a) FANFT----5% sodium saccharin (NaS); (b) FANFT----3% NaS; (c) FANFT----5.2% calcium saccharin (CaS); (d) FANFT----3.12% CaS; (e) FANFT----4.21% acid saccharin (S); (f) FANFT----2.53% S; (g) FANFT----5% sodium ascorbate; (h) FANFT----4.44% ascorbic acid; (i) FANFT----5% NaS plus 1.15% CaCO3; (j) FANFT----5.2% CaS plus 1.34% NaCl; (k) FANFT----5% NaS plus 1.23% NH4Cl; (l) FANFT----1.15% CaCO3; (m) FANFT----1.34% NaCl; (n) FANFT----control; (o) control----5% NaS; (p) control----5.2% CaS; (q) control----4.21% S; (r) Control----control; (s) FANFT----5% NaS (NIH-07 diet); (t) FANFT----control (NIH-07 diet). NaS, CaS and S without prior FANFT administration were without tumorigenic activity. NaS was found to have tumor promoting activity, showing a positive response at the 5 and 3% dose levels, with significantly greater activity at the higher dose. CaS had slight tumor promoting activity but without a dose response, and S showed no tumor promoting activity. In addition, NaCl showed weak tumor promoting activity, but CaCO3 was without activity. NH4Cl completely inhibited the tumor promoting activity of NaS when concurrently administered with it. NaCl administered with CaS or CaCO3 administered with NaS showed activity similar to that of NaS. Sodium ascorbate was also shown to have tumor promoting activity, with slightly less activity than NaS. Ascorbic acid showed no tumor promoting activity.(ABSTRACT TRUNCATED AT 400 WORDS)
Cohen
S M
SM
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha 68198-3135.
Ellwein
L B
LB
Okamura
T
T
Masui
T
T
Johansson
S L
SL
Smith
R A
RA
Wehner
J M
JM
Khachab
M
M
Chappel
C I
CI
Schoenig
G P
GP
D000818:Animals; D001205:Ascorbic Acid / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D002085:Butylhydroxybutylnitrosamine; D002119:Calcium Carbonate / Q000633:toxicity; D004032:Diet; D004326:Drinking / Q000187:drug effects; D004357:Drug Synergism; D005200:FANFT; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000187:drug effects; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D012439:Saccharin / Q000633:toxicity*; D001743:Urinary Bladder / Q000187:drug effects / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced*; D014556:Urine
D002085:Butylhydroxybutylnitrosamine; D005200:FANFT; D012439:Saccharin; D002119:Calcium Carbonate; D001205:Ascorbic Acid