Dose-Related In¯ammatory Effects of Intravenous Endotoxin in Humans: Evaluation of a New Clinical Lot of Escherichia coli O:113 Endotoxin

The administration of reference endotoxin (Escherichia coli O:113, Lot EC-5) to humans has been an important means to study in¯ammation in vivo; however, the supply of Lot EC-5 is depleted. A new lot of reference endotoxin (Clinical Center reference endotoxin [CCRE]), derived from the original bulk material extracted from E. coli O:113, was processed. The effects of 0-, 1-, 2-, and 4-ng/kg doses of intravenous CCRE and EC-5 were studied in 20 male subjects. CCRE resulted in dose-related increases in symptoms, temperature (),P 5.016 total leukocyte count (), tumor necrosis factor±a (), interleukin (IL)±1 re-P 5.014 P 5.004 ceptor antagonist (), IL-6 (), IL-8 (), cortisol (), and C-reactiveP 5.004 P 5.005 P 5.011 P!.05 protein (). These responses were attenuated (all) in subjects given Lot EC-5P 5.04 P!.012 (4 ng/kg) in comparison with those in subjects given CCRE, showing that, over several years, EC-5 had lost potency. Thus, in healthy subjects, the magnitude of exposure to CCRE results in a graded dose response of major components of innate immunity. Over 2 decades ago, endotoxin derived from Escherichia coli (E. coli group O 113:H10:K negative) was processed to serve as a national reference standard in assays of pyrogenicity usin