Abstract
Current guidelines used by the US Food and Drug Administration to establish a safe level of pyrogens in veterinary parenteral products were derived from work designed for products intended for human use, and there is no consensus on what levels of endotoxin or other pyrogens are safe for domestic animals. The accepted biological measures for endotoxins and other pyrogens have been based on measurement of relatively small changes in body temperature in rabbits rather than an assessment of the inflammation caused by the endotoxins. It is difficult to accurately assess the small changes in body temperature caused by low levels of endotoxin in food-producing animals such as dairy cattle. Thus, the true relevance of guidelines to domestic animals is unknown. Accordingly, a whole-blood assay as a measure of endotoxin-induced inflammation was developed to serve as an in vitro surrogate model for either the rabbit pyrogen test or tests in cattle. Induction of interleukin-6 (IL-6) mRNA occurred at concentrations of lipopolysaccharide that ranged from 1 μg/mL through 1 pg/mL. Because there were still differences in IL-6 induction compared with unstimulated cultures, blood from a second set of animals was treated with lipopolysaccharide concentrations ranging from 1 μg/mL to 1 fg/mL. These results demonstrated that induction of IL-6 occurred somewhere between 100 fg/mL and 1 pg/mL. Because the most sensitive chemical assay can detect endotoxin only at a similar range, the whole-blood assay may be a biological assay that could be used in place of the rabbit pyrogen assay.
Published Version
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