To determine the functional significance of physiological plasma concentrations of cholecystokinin, five volunteers each received graded doses of intravenous infusions of cholecystokinin octapeptide (CCK-8). At each dose plasma concentrations of CCK-8 were determined and pancreatic and biliary outputs were measured. Threshold plasma concentrations of CCK-8 for augmenting pancreatic trypsin secretion were undetectable (less than 3 pmol/l), and maximal trypsin output of 21.9 +/- 1.95 k-i.u./30 min was produced by 17.1 +/- 6.4 pmol of CCK-8/1. Calculated halfmaximal output was produced by 4.7 pmol of CCK-8/1. Maximal trypsin output during infusions of CCK-8 was significantly less than that after a combination of the CCK-like peptide, caerulein, and secretin (32.95 +/- 2.16 k-i.u./30 min, P less than 0.001). Biliary bile acid and bilirubin outputs were significantly augmented only when plasma concentrations of CCK-8 were greater than 5 pmol/l. Plasma concentrations of CCK-8 in the low picomolar range exert significant effects on pancreatic and biliary secretion. CCK-8 fulfills the criteria for a circulating hormone.