The effects on the pancreas of chronic dietary exposure to defatted soy flour and soy protein isolate have been studied in two two-year feeding trials in rats. Emphasis was placed on detecting changes that might accompany low levels of dietary trypsin inhibitor (TI) as might be found in edible grade soy products and on studying the influence of protein nutrition. The major pathological findings in the pancreas were nodular hyperplasia (NH), consisting of foci of hyperplastic acinar cells often grossly visible by six months, and the benign neoplastic lesion, acinar adenoma (AA), which developed more slowly. In the first feeding trial, the objectives were to obtain the dose-response relationship of pancreatic pathology to dietary TI provided by raw and heated soy flour and to study the nutritional interaction of protein level which was varied from 10% to 30% using casein supplementation. Also, the responses to raw and heated soy protein isolate were compared to determine whether the removal of more than 50% of the constituents found in soy flour would alter the development of pancreatic lesions. In the second trial, the effect of unusually low levels of TI in raw and heat-treated soy protein isolate, prepared through a salt extraction process and fed at 10% and 30% protein in the diet, was investigated. The incidence of both NH and AA was positively related to the TI content of the diet. The probit transformation of the percent incidence of AA was linearly related to the log of TI/g protein in the diet. A single curve best described the response to 20% and 30% protein, with a slope that was distinctly greater than that for 10% protein. The intersection of the two curves near the TI concentration of edible grade soy flour predicts that protein level in the diet can be expected to have essentially no effect on the incidence of AA when TI activity is in this range. But, for proteins containing greater concentrations of TI, increasing the level of protein in the diet will increase the incidence of pancreatic pathology, while for proteins with quite low levels of TI, increasing the protein in the diet above 10% will have a protective effect.(ABSTRACT TRUNCATED AT 400 WORDS)