This research grant proposal seeks funds for the support of a project that has as its ultimate goal the following: (1) an attempt to gain a more comprehensive understanding of the pathogenesis of adverse reactions to injections of the x-ray contrast media; (2) the development of a test based on the foregoing that will permit the screening of patients who are predisposed to develop contrast media reactions; (3) the development of a rational, laboratory-based plan for the therapy of such reaction when they occur. Earlier work by this group has brought to light the significance of contrast material-protein interactions in the pathogenesis of adverse reactions. Broadly, these have developed sequentially as follows: (1) a positive relationship between protein binding and contrast material toxicity in experimental animals was delineated; (2) the specific relevance of such contrast-protein interactions to inhibition of enzyme systems was shown; (3) the relationship between the molecular structure of the contrast molecule, protein-binding, and general hydrophobicity was established; (4) the specific application of these principles most recently has led us to the discovery that the constrast media were capable of activating serum complement and were capable of promoting Pro-coagulant activities under special circumstances. Furthermore, we have done pilot studies indicating that "hypersensitivity" could be induced in some dogs by a series of contrast media injections. The present project is designed to explore in depth the full range in vivo and in vitro of contrast material-complement interactions and the significance of these in systemic and localized contrast toxicity in laboratory animals. Studies of complement activation and coagulative processes will be carried out under three circumstances: (a) at normal dosage levels in normal (non-reactive) animals; (b) at lethal dosages in normal animals; and (c) at normal dosage levels in reactive animals.