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Federal Register / Vol. 44. No. 64 / Monday. April 2, 1979 / Notices 
DEPARTMENT OF HEALTH, 
EDUCATION, AND WELFARE 
National Institutes of Health 
Recombinant DNA Research; Proposed 
Plan For a Program to Assess Risks 
agency; National Institutes of Health. 
ACTION: Notice of proposed plan for a 
program to assess the risks of 
recombinant DNA research. 
Summary: This notice sets forth a 
proposed program to assess the risks of 
recombinant DNA research. Interested 
parties are invited to submit comments 
concerning the plan. After consideration 
of those comments and comments by the 
N1H Recombinant DNA Advisory 
Committee, the Director of the National 
Institutes of Health will publish the final 
plan in the Federal Register. 
date: Comments must be received by 
May 2, 1979. 
ADDRESS: Written comments and 
recommendations should be submitted 
to the Chief, Office of Specialized 
Research and Facilities. NLAID Building 
31. Room 7A04. National Institutes of 
Health. Bethesda. Maryland 20205. All 
comments received in timely response to 
this notice will be considered and will 
be available for public inspeciton in the 
above office on weekdays between the 
hours of 8:30 a.m. and 5 p.m. 
FOR FURTHER INFORMATION CONTACT: 
Additional information may be obtained 
from Dr. John Nutter, Chief. Office of 
Specialized Research and Facilities, 
NLAID, National Institutes of Health, 
Bethesda. Maryland 20205 (301-496- 
5643). 
SUPPLEMENTARY INFORMATION: 
L Introduction 
With the issuance in December 1978 
of revised guidelines for the conduct of 
recombinant DNA research, the 
Secretary DHEW requested that the 
National Institutes of Health (NIH) 
prepare and NIH Risk Assessment Plan 
which, after review by the Recombinant 
DNA Advisory Committee (RAC) and 
publication in the Federal Register for 
comment, would be made final and 
updated annually. The present 
document is the initial response to that 
request. 
The major concerns about 
recombinant DNA experimentation have 
included the possible conversion of non- 
pathogenic microorganisms to 
pathogenic agents, as well as the 
establishment of organisms containing 
recombinant DNA molecules in the 
ecosystem. Since the hypothetical risks 
and technical basis of recombinant DNA 
research are primarily microbioligical in 
nature, the responsibility for 
coordination and implementation of the 
plan was assigned by the Director NIH 
to the Director. National Institute of 
Allergy and Infectious Diseases 
(N1A1D). 
The vast majority of information 
relevant to recombinant DNA risk 
analysis has already come from 
research not primarily designed to 
provide information on risk. This will 
undoubtedly continue to be the case. 
This information will be obtained 
chiefly from publications in the 
scientific literature, from persons with 
special scientific knowledge, and from 
ongoing basic biomedical research. Risk 
assessment analysis will require 
continuing review of data developed in 
the fields of microbiology, infectious 
diseases, and related biological 
research. 
Some essential information has been, 
and will continue to be. derived from 
projects specifically designed to assess 
various aspects of potential risks 
associated with recombinant DNA 
experimentation. Such experiments will 
be supported by the Intramural and the 
Extramural programs of NIH. Many 
experiments may also be conducted in 
the private sector or may be funded by 
other agencies or governments. 
The essential goal of a successful risk 
assessment plan will be the 
development of means to collect, collate, 
coordiante, evaluate, and disseminate 
data obtained from all sources. 
II. Background and Present Program 
The revision of the guidelines for 
recombinant DNA research was 
developed primarily through the 
analysis of data generated from basic 
microbiological research, such as was 
done at the Falmouth and Ascot Risk 
Assessment Workshops. An example of 
such free-ranging research efforts which 
have generated data relevant to 
recombinant DNA experimentation was 
the discovery of the intervening 
sequences that interrupt genes in 
eukaryotic DNA. This finding virtually 
assures that shotgun cloning of 
eukaryotic chromosomal DNA into 
prokaryotes will not result in the 
production of bilogically acitve proteins. 
Special experiments have been and 
will continue to be specifically designed 
to assess the potential risks associated 
with recombinant DNA experiments. For 
example, within the Intramural Program 
of NLAID two experiments were 
undertaken to assess potential risks of 
this new technology. The first was an 
[ 89 ] 
evaluation of the infectivity of polyoma 
DNA when the entire viral genome was 
cloned in phage and plasmid vectors of 
Escherichia coli K-12. A second 
experiment was a study of the 
pathogenicity and stability of shotgun 
clones of E. coli K-12 containing yeast 
(Saccharomyces) DNA. In each case, 
there was no evidence that the inserted 
DNA produced any special hazard. 
Specific risk assessment experiments 
have also been undertaken using the 
NIH contract mechanism. Contracts 
have been used to (1) assess the 
potential for generating aerosols in 
laboratories where recombinant DNA 
research is conducted and (2) to 
examine the EK2 systems for their 
ability to survive and their capacity to 
transfer heterologous cloned segments 
to secondary hosts under conditions 
simulating natural environments. 
An important additional source of 
information is specific DNA risk 
assessment experiments that have been 
undertaken in foreign countries 
Scientists supported by the European 
Molecular Biology Organization (EMBO) 
have also examined the infectivity of 
recombinant polyoma plasmid and 
phage DNA in tissue culture. The results 
of these studies agree with those of 
biological in vivo assays carried out by 
the Intramural scientist of NIH already 
described. 
III. Recombinant DNA Risk Assessment Plan: 
Scientific Aspects 
There are three major types of host- 
vector systems presently being used for 
recombinant DNA research, and the risk 
assessment program will naturally be 
focused on these. They are (1) 
prokaryotic host-vector systems, 
primarily. E. coli and Bacillus subtilis; 
(2) lower eukaryotes, namely, 
Saccharomyces cerevisiae and 
Neurospora crassa; and (3) eukaryotic 
viruses in cultured cells of higher 
eukaryotes. 
A number of events must occur before 
a laboratory microorganism becomes a 
possible risk to people or higher 
organisms outside the immediate 
laboratory environment. The assessment 
of risk involves a determination of the 
probability for the occurrence of these 
various events. The particular data that 
are most susceptible to analysis, or most 
likely to provide a definitive answer 
concerning risk, will differ for the 
various host-vector systems. Data 
elements will include the probabilities of 
(1) Dispersal of the organism 
containing recombinant DNA into the 
environment. 
