Safety of Trypsin Inhibitors in the Diet: Effects on the Rat Pancreas of Long-Term Feeding of Soy Flour and Soy Protein Isolate

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Abstract
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. The basis for this interaction between dietary protein and TI is to be found in the nutritional demands for increased protein synthesis accompanying the adaptive response of the pancreas to TI and in the reported influence of low protein levels in sustaining elevated plasma cholecystokinin concentrations. No significant difference between the response to soy protein isolate, providing 30% protein and graded levels of TI, and that of diets containing soy flour was obtained. This indicates that the non-proteinaceous components removed from soy flour were not factors in the development of pancreatic pathology. The response to the low TI, extracted soy protein isolate (both raw and heated) fed at 30% protein was also equivalent to that of diets containing heated soy flour with casein. However, with 10% protein, the incidence of AA was greater than might be predicted from the probit model, particularly for the raw, low TI soy protein Isolate. Thus, with restricted protein in the diet, proteins of lower quality can be expected to stimulate greater development of pancreatic lesions than would be predicted from TI content alone. The results of the two feeding studies reported here with defatted soy flour and soy protein isolate indicate that low levels of residual TI equal to those encountered in commercially prepared soy products can be expected to increase the probability of pancreatic adenoma formation in the rat. However, the near exclusive use of the rat as a model has not supplied the breadth of information required to make a useful safety assessment of residual TI in man’s diet. The appearance of pre-neoplastic and neoplastic lesions of the pancreas in response to chronic dietary exposure of TI in the rat appears to be mediated by the endocrine system of the gastro-intestinal tract which regulates pancreatic function. There is no evidence that TI or other factors in soy are directly involved in the production of pancreatic tumors. Cholecystokinin, a key hormone, can essentially reproduce the early pancreatic alterations brought about by raw soy in the diet, including the development of hyperplasia. Whether the pancreas of the rat is unusually susceptible to the induction of neoplasia when stimulated by the normal regulatory mechanism for pancreatic adaptation to diet remains to be determined. With only limited information as to the generality of the long-term effects of TI on the pancreas in other species, it would be prudent to minimize the intake of dietary factors, such as TI, which may stimulate an undue proliferative response.