The effects of diet-induced acid-base disturbances were examined in 4-week, 13-week and 18-month toxicity studies, and in a 30-month carcinogenicity study. Rats were fed a natural ingredient diet (controls), supplemented with 2% or 4% KHCO3 (base-forming diets), or with 1% or 2.1% NH4Cl (acid-forming diets). Additional controls were fed 3% KCl (neutral diet providing K+ and Cl- in amounts equimolar to those in the 4% KHCO3 diet and the 2.1% NH4Cl diet, respectively). NH4Cl induced the expected metabolic acidosis, as shown by decreased base excess in blood, decreased urinary pH and increased urinary net acid excretion. KHCO3 induced the opposite effects. KCl did not affect the acid-base balance. Clinical condition and death rate were not affected. The feeding of high levels of each salt resulted in growth retardation and increased water intake and urinary volume. Plasma potassium and urinary potassium excretion were increased with KHCO3 and KCl. Plasma chloride was increased with NH4Cl, but not with KCl. Urinary calcium and phosphate excretion were increased with NH4Cl, but there were no indications that bone minerals were involved (weight, calcium content and fat free solid of the femur were not affected). Standard haematological and clinical chemistry parameters were not affected. Kidney weights were increased with 2.1% NH4Cl. Hypertrophy of the adrenal zona glomerulosa occurred with KHCO3, KCl and NH4Cl, due to chronic stimulation of the adrenal cortex by either K+ or by NH 4Cl-induced acidosis. An early onset (from week 13) of oncocytic tubules was noted in the kidneys of rats fed KHCO3 and, after 30 months, the incidence of this lesion was much higher than the background incidence in ageing controls. No progression to oncocytomas was noted. KCl showed only slight effects on the early onset of oncocytic tubules (from 18 months). In contrast, the severity of nephrosis and the incidence of oncocytic tubules were decreased with 2.1% NH4Cl, suggesting a protective effect of acidosis. The feeding of KHCO3 resulted in hyperplasia, papillomas and carcinomas of the urinary bladder. With KCl only a slight increase in proliferative urothelial lesions was noted. Apart from these (pre-)neoplastic lesions in the urinary bladder there were no treatment-related differences in tumour response among the groups. We concluded that most of the observed changes represent physiological adaptations to the feeding of acid- or base-forming salts. Remarkable effects noted with KHCO3, and to a far lesser extent with KCl, consisted of renal oncocytic tubules and (pre-)neoplastic lesions of the urinary bladder epithelium. NH 4Cl-induced chronic metabolic acidosis was not associated with dissolution of alkaline bone salts in rats. Finally, a protective effect of chronic acidosis on tumour development was not found. © 2003 Elsevier Ltd. All rights reserved.