Testing of Fat Emulsions for Toxicity

Extensive studies were conducted at four separate laboratories to evaluate the chemical and physical properties, and the biological effects of two fat emulsions: Intralipid (20 per cent) and Lipofundin (15 per cent). In addition, a variety of experimental emulsions and emulsion components, produced in the laboratory, were tested to evaluate the effects of various formulas and individual components in order to evaluate more adequately the results obtained with the two commercial preparations tested, and to compare laboratory and commercial lots of the same type of product. Lipomul, which had previously received extensive chemical, physical and biological testing, was also subjected to the same test procedures as applied to the experimental products to serve as a control. For the parameters investigated, the results of these studies indicated that the emulsion best tolerated was a laboratory preparation composed of 10 per cent soybean oil and 1.2 per cent egg yolk phosphatide in a 2.5 per cent aqueous solution of glycerol (test preparation 107). Adverse clinical findings and abnormal liver functions were not observed in animals given infusions of test preparation 107, nor were histopathological findings encountered which are known to represent a functionally damaged liver. Commercial Intralipid proved to be the next best tolerated emulsion. Intravenous fat pigment was present in hepatocytes and reticuloendothelial cells (rabbits, rats and dogs) following infusion with Intralipid or test preparation 107; however, it was present in lesser amounts (rabbits and rats) when compared with other products tested with the exception of a synthetic glyceride emulsion, which did not produce pigment but was very toxic. Intralipid, more so than any other product tested, did cause a marked dilation of the profiles of the rough endoplasmic reticulum of the hepatocytes as observed by electron microscopy (rabbits and rats). The cause of this lesion and its functional significance are not known and requires further investigation. It was observed that the extent of this change was inversely related to the amount of intravenous fat pigment produced by the emulsion. In addition to these findings, a new simplified procedure was developed for purifying crude egg phosphatide and for using this phosphatide as the sole emulsifier of fat emulsions for intravenous alimentation. A method was also developed, employing a Research Coulter Counter, for determining the range of particle sizes in fat emulsions and the statistical distribution of the various particle size in terms of volume per cent. The occurrence of intravenous fat pigment could not be correlated with the type or presence of an emulsifier, the per cent fat content of the emulsion (although fat must be present) or particle size. Pigment deposition was also not related to the extent of acute reactions produced by the emulsions. However, the type of oil in the emulsion did influence the amount of pigment produced, being absent with a synthetic triglyceride and minimal in rabbits and rats with soybean oil emulsions (Intralipid and test preparation 107). Although phagocytic capabilities of reticuloendothelial cells containing the pigment were impaired, abnormal liver function, as evaluated by several methods, could not be demonstrated regardless of the amount of pigment present (rabbits and dogs), even in the presence of proliferative reaction associated with the pigment (dogs). The use of a drug, contraindicated in hepatic disease, did not cause any adverse effect when given to rabbits and dogs known to contain intravenous fat pigment deposits within their hepatocytes.