Epidermal growth factor (EGF) is mainly produced in the submandibular glands (SMG) and in the kidneys. It has recently been reported that EGF-related ligands may induce their own biosynthesis (autoinduction) in vitro. In the present paper, we investigated whether chronic systemic treatment with EGF influenced the amount of endogenous EGF in the SMG and kidneys. Eight-week-old female Wistar rats were treated with subcutaneous injections of placebo (n = 16) or human recombinant EGF (150 micrograms/kg per day, n = 8) for 4 weeks. Urine was sampled the last 24 h of the study period. At the time of killing, the SMG and the kidneys were removed. The SMG was larger in the EGF-treated animals, 229.8 +/- 35.5 (mean +/- SD) mg than in the control animals, 181.7 +/- 18.1 mg (P <0.01). The total EGF content was smaller (0.51 +/- 0.15 vs. 1.12 +/- 0.40 nmol EGF/SMG, P <0.001). The kidneys were larger in the EGF-treated animals (1.38 +/- 0.08 vs. 1.28 +/- 0.08 g, P <0.05), but the EGF content and urinary excretions were not changed. In conclusion, chronic systemic treatment with EGF causes growth of the SMG with concomitantly reduced contents of EGF, and growth of the kidneys with unchanged content and excretion of EGF. These findings suggest that EGF may play a part in the regulation of the growth of the SMG and in EGF biosynthesis.