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NOTICES 
tainment specified above (P4-»P3-»P2-> 
PI). 
(c) Fungal or similar lower eukaryotic 
host-vector systems. The containment 
criteria for experiments on recombinant 
DNAs using tijfse host-vectors most 
closely resemble those for prokaryotes, 
rather than those for the preceding 
eukaryotes, in that the host cells usually 
exhibit a capacity for dissemination out- 
side the laboratory that is similar to that 
for bacteria. We therefore consider that 
the containment guidelines given for ex- 
periments with E. coli K-12 and other 
prokaryotic host- vectors (Sections IIIB-1 
and -2, respectively) provide adequate 
direction for experiments with these 
lower eukaryotic host-vectors. This is 
particularly true at this time since the 
development of these host-vectors is 
presently in the speculative stage. 
IV. ROLES AND RESPONSIBILITIES 
Safety in research involving recombi- 
nant DNA molecules depends upon how 
the research team applies these guide- 
lines. Motivation and critical judgment 
are necessary, in addition to specific 
safety knowledge, to ensure protection 
of personnel, the public, and the envi- 
ronment. 
The guidelines given here are to help 
the principal investigator determine the 
nature of the safeguards that should be 
implemented. These guidelines will be 
incomplete in some respects because all 
conceivable experiments with recombi- 
nant DNAs cannot now be anticipated. 
Therefore, they cannot substitute for the 
investigator’s own knowledgeable and 
discriminating evaluation. Whenever this 
evaluation calls for an increase in con- 
tainment over that indicated in the 
guidelines, the investigator has a respon- 
sibility to institute such an increase. In 
contrast, the containment conditions 
called for in the guidelines should not 
be decreased without review and approval 
at the institutional and NTH levels. 
The following roles and responsibilities 
define an administrative framework in 
which safety is an essential and inte- 
grated function of research involving 
recombinant DNA molecules. 
A. Principal Investigator. The princi- 
pal investigator has the primary respon- 
sibility for: (i) Determining the real and 
potential biohazards of the proposed re- 
search, (ii) determining the appropriate 
level of biological and physical contain- 
ment, (iii) selecting the microbiological 
practices and laboratory techniques for 
handling recombinant DNA materials, 
(iv) preparing procedures for dealing 
with accidental spills and overt person- 
nel contamination, (v) determining the 
applicability of various precautionary 
medical practices, serological monitor- 
ing y and immunization, when available, 
(vi) securing approval of the proposed 
research prior to initiation of work, (vii) 
submitting information on purported 
EK2 and EK3 systems to the NIH Re- 
combinant DNA Molecule Program Ad- 
visory Committee and making the strains 
available to others, (viii) reporting to 
the institutional biohazards committee 
and the NTH Office of Recombinant DNA 
See footnotes at end of article. 
Activities new information bearing on 
the guidelines, such as technical infor- 
mation relating to hazards and new 
safety procedures or innovations, (ix) 
applying for approval from the NTH Re- 
combinant DNA Molecule Program Ad- 
visory Committee for large scale experi- 
ments with recombinant DNAs known 
to make harmful products (i.e., more 
than 10 liters of culture), and (x) apply- 
ing to NIH for approval to lower con- 
tainment levels when a cloned DNA re- 
combinant derived from a shotgun ex- 
periment has been rigorously character- 
ized and there is sufficient evidence that 
it is free of harmful genes. 
Before work is begun, the principal in- 
vestigator is responsible for: (1) Making 
available to program and support staff 
copies of those portions of the approved 
grant application that describe the bio- 
hazards and the precautions to be taken, 
(ii) advising the program and support 
staff of the nature and assessment of the 
real and potential biohazards, (iii) in- 
structing and training this staff in the 
practices and techniques required to en- 
sure safety, and in the procedures for 
dealing with accidentally created bio- 
hazards, and (iv) informing the staff of 
the reasons and provisions for any ad- 
vised or requested precautionary medical 
practices, vaccinations, or serum collec- 
tion. 
During the conduct of the research, the 
principal investigator is responsible for: 
(i) Supervising the safety performance 
of the staff to ensure that the required 
safety practices and techniques are em- 
ployed, (ii) investigating and reporting 
in writing to the NIH Office of Recom- 
binant DNA Activities and the institu- 
tional biohazards committee any serious 
or extended illness of a worker or any 
accident that results in (a) inoculation 
of recombinant DNA materials through 
cutaneous penetration, (b) ingestion of 
recombinant DNA materials, (c) proba- 
ble inhalation of recombinant DNA mate- 
rials following gross aerosolization, or (d) 
any incident causing serious exposure to 
personnel or danger of environmental 
contamination, (iii) investigating and 
reporting in writing to the NIH Office of 
Recombinant DNA Activities and the in- 
stitutional biohazards committee any 
problems pertaining to operation and im- 
plementation of biological and physical 
containment safety practices and pro- 
cedures, or equipment or facility failure, 
(iv) correcting work errors and condi- 
tions that may result in the release of 
recombinant DNA materials, and (v) 
ensuring the integrity of the physical 
containment (e.g., biological safety cab- 
inets) and the biological containment 
(e.g., genotypic and phenotypic charac- 
teristics, purity, etc.). 
B. Institution. Since in almost all cases, 
NIH grants are made to institutions 
rather than to individuals, all the respon- 
sibilities of the principal investigator 
listed above are the responsibilities of the 
institution under the grant, fulfilled on 
its behalf by the principal investigator. 
In addition, the institution is responsi- 
ble for establishing an institutional bio- 
hazards committee 7 to: (1) Advise the 
institution on policies, (ii) create and 
maintain a central reference file and li- 
brary of catalogs, books, articles, news- 
letters, and other communications as a 
source of advice and reference regarding, 
for example, the availability and quality 
of the safety equipment, the availability 
and level of biological containment for 
various host-vector systems, suitable 
training of personnel and data on the 
potential biohazards associated with cer- 
tain recombinant DNAs, (iii) develop a 
safety and operations manual for any 
P4 facility maintained by the institu- 
tion and used in support of recombinant 
DNA research, (iv) certify to the NIH on 
applications for research support and 
annually thereafter, that facilities, pro- 
cedures, and practices and the training 
and expertise of the personnel involved 
have been reviewed and approved by the 
institutional biohazards committee. 
The biohazards committee must be suf- 
ficiently qualified through the experience 
and expertise of its membership and the 
diversity of its membership to ensure re- 
spect for its advice and counsel. Its mem- 
bership should include individuals from 
the institution or consultants, selected 
so as to provide a diversity of disciplines 
relevant to recombinant DNA technology, 
biological safety, and engineering. In ad- 
dition to possessing the professional com- 
petence necessary to assess and review 
specific activities and facilities, the com- 
mittee should possess or have available 
to it, the competence to determine the 
acceptability of its findings in terms of 
applicable laws, regulations, standards of 
practices, community attitudes, and 
health and environmental considerations. 
Minutes of the meetings should be kept 
and made available for public inspection. 
The institution is responsible for report- 
ing names of and relevant background 
information on the members of its bio- 
hazards committee to the NIH. 
C. NIH Initial Review Groups (.Study 
Sections). The NIH Study Sections, in 
addition to reviewing the scientific merit 
of each grant application involving re- 
combinant DNA molecules, are responsi- 
ble for: (i) Making an independent 
evaluation of the real and potential bio- 
hazards of the proposed research on the 
basis of these guidelines, (ii) determin- 
ing whether the proposed physical con- 
tainment safeguards certified by the in- 
stitutional biohazards committee are ap- 
propriate for control of these biohazards, 
(iii) determining whether the proposed 
biological containment safeguards are 
appropriate, (iv) referring to the NIH 
Recombinant DNA Molecule Program 
Advisory Committee or the NIH Office of 
Recombinant DNA Activities those prob- 
lems pertaining to assessment of biohaz- 
ards or safeguard determination that 
cannot be resolved by the Study Sections. 
The membership of the Study Sections 
will be selected in the usual manner. Bio- 
logical safety expertise, however, will be 
available to the Study Sections for con- 
sultation and guidance. 
D. NIH Recombinant DNA Molecule 
Program Advisory Conimittee. The Re- 
combinant DNA Molecule Program Ad- 
visory Committee advises the Secretary, 
Department of Health, Education, and 
FEDERAL REGISTER, VOL. 41, NO. 1 31— WEDNESDAY, JULY 7, 1976 
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