Induction of hyperplasia in the bladder epithelium of rats by a dietary excess of acid or base: implications for toxicity/carcinogenicity testing.
In previous studies we observed an increased incidence of hyperplasia in the epithelium of the urinary bladder of rats fed cereal-based stock diet supplemented with 6% monosodium glutamate (MSG) for 3 months. Hyperplasia was not enhanced, however, when 6% MSG was fed in a purified casein diet. Further studies have been conducted to identify the dietary factor that caused the different response with the two diets. Feeding MSG had a marked alkalizing effect on the urine. Rats fed purified diet produced urine of higher acidity than did those fed stock diet, a finding attributed to the greater excess of base in the stock diet. When diets with a considerable excess of cations were fed, urinary pH showed a characteristic pattern of widely differing values during a 24-hr period, with high values (pH greater than or equal to 8] for several hours of darkness, when food intake was high, declining during the day to a minimum at the end of the light period. Hyperplasia of the bladder epithelium was induced not only by feeding MSG, but also by feeding 5% of the alkalizing salt KHCO3, both in purified diet and in stock diet. The epithelial response to an alkalizing substance was prevented by simultaneous feeding of the acidifying salt NH4Cl. These findings indicate that the bladder changes induced by MSG are attributable to its alkalizing properties rather than to MSG per se. Moderate to severe hyperplasia of the bladder epithelium was induced also by feeding 5% NH4Cl in purified diet, a procedure accompanied by a further lowering of urinary pH. These findings showed that hyperplasia of the bladder epithelium of rats can be induced both by acidifying and by alkalizing the urine through manipulation of the acid-base balance of the basal diet. There is thus a possibility that, in carcinogenicity studies, administration of compounds to rats in the form of a salt may lead to erroneous conclusions.
de Groot
A P
AP
TNO-CIVO Toxicology and Nutrition Institute, Department of Biological Toxicology, Zeist, The Netherlands.
Feron
V J
VJ
Immel
H R
HR
D000136:Acid-Base Equilibrium; D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D002254:Carbonates / Q000494:pharmacology; D002940:Circadian Rhythm; D004032:Diet; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D006863:Hydrogen-Ion Concentration; D006965:Hyperplasia; D008297:Male; D009152:Mutagenicity Tests; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D001743:Urinary Bladder / Q000187:drug effects* / Q000473:pathology; D014556:Urine
D002254:Carbonates; D000643:Ammonium Chloride; C037593:potassium carbonate; D011188:Potassium