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evolutionary process of insulin purification spanning half a century. Of 
course, the state of the art in natural product purification and 
characterization, the analytical capability to recognize contaminants in 
both a qualitative and q uantitative sense, and the awareness of clinical 
implications of contaminants, make the difference in time. Today, we 
recognize that products of recombinant ONA technology will be at a very high 
degree of purity the first time they are used clinically. 
In considering the toxicity of asparaginase lots, it is difficult to 
distinguish between certain toxic effects arising from the pure enzyme, 
per se , and those caused by bacterial contaminants. In Table 1, I have 
attempted to classify the toxic effects into the two groups. From the 
clinical point of view, pancreatitis, hepatotoxicity, and occasionally 
severe hypersensitivity reactions, such as anaphylasis, were the more 
important toxic manifestations. Pancreatitis was relatively rare and was 
dose related, but when it did occur it was usually of a fulminating, life 
threatening nature. Chills, fever, nausea and vomiting shortly after drug 
administration were definitely related to bacterial contaminants. Hyper- 
sensitivity reactions occurred with both crude and purified preparations, 
and investigators were unable to differentiate between these with respect to 
incidence. It would be ideal for our purpose to have a comparative toxicity 
study of crude versus highly purified preparations of the enzyme in order to 
have a better understanding of toxicity due to contaminants. The nearest 
approach to this is the report of Dr. Herbert Oettgen and associates at the 
Sloan-Kettering Institute, concerning the toxicity of _E. col i asparaginase 
in man (3). Pertinent information from the protocol of this study is shown 
in Table 2. 
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