Attachment II - Page 1 
fJU'ty 
Lilly Research Laboratories 
A Division of Eli Lilly and Company 
307 Easl McCarty Sired 
Indianapolis. Indiana 'I6?8‘. 
(317)261-2000 
September 14, 1983 
Dr. William J. Gartland, Jr. 
Director, Office of Recombinant 
DNA Activities 
National Institute of Allergy and 
Infectious Diseases 
National Institutes of Health 
Bethesda, Maryland 20205 
Dear Bill: 
As we indicated in yesterday's discussion, we are submitting herewith another 
proposal for consideration by the RAC. This will provide an alternative to 
the proposed amendment submitted on May 23. In light of comments received 
from Dr. McKinny and others, it seems clear that such an amendment would be 
very unlikely to receive a recommendation for approval. Because this issue of 
conducting manufacture of products of recombinant DNA technology with host- 
vector systems that have been shown not to present a significant risk to 
health or the environment remains under whatever constraints the guidelines 
may be interpreted to impose, we would prefer not to withdraw the proposed 
amendment. Rather, we would suggest that the committee refer it to the Large 
Scale Working Group where a thorough study of the proposal and its implica- 
tions for production processes may be carried out. In fact, it may be of some 
importance to note that Appendix K was introduced as "Physical Containment for 
Large Scale Uses of Viable Organisms Containing Recombinant DNA Molecules" by 
publication in the Federal Register on April 11, 1980. These original recom- 
mendations have not undergone any significant changes in content since that 
time. Meanwhile, however, there have been five revisions of the Laboratory 
Guidelines, with considerable relaxation of several containment features. 
Our strong concern for operator and environmental safety centers on the fact 
that the hazard posed by the large scale growth of exempt organisms lies not 
with the effects of application of recombinant DNA technology but with the 
presence of E. coli endotoxin. For example, the attached report (1) of the 
GMAG contains a "worst case" estimate of the maximum amount of a physiologi- 
cally active gene product which could be produced if all E. coli in the 
intestinal tract were synthesizing and secreting it. The amounts would 
represent at most a small fraction of the endogenous levels of hormones like 
insulin or growth hormone or other highly active protein. Accordingly, we 
have examined historical data, as well as producing workplace data of our 
own, to evaluate operator exposure and environmental losses where careful 
manufacturing technique is followed but absolute containment is not 
maintained. These results indicate that: 
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