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that allows various combinations of 
containment safeguards, (2) the ade- 
quacy of risk-assessment studies in re- 
lation to physical containment, (3) the 
adequacy of training in laboratory 
safety practices. (4) plans for dealing 
with emergencies, and (5) various as- 
pects of the biological safety concepts. 
NTH has considered a number of rec- 
ommendations by EMBO. Public com- 
mentators have made additional sug- 
gestions relating to actions at specific 
levels of physical containment and to 
shipment of recombinant DNA materi- 
als. 
Concept of "flexibility” 
Some commentators have expressed 
concern over the flexibility provided 
in tables I and II which allows various 
combinations of containment safe- 
guards. Some feel, for example, that 
work in a P3 facility conveys a desir- 
able sense of hazard, whereas a reduc- 
tion to the P2 level will promote an 
undesirable relaxation of vigilance. It 
has also been suggested that an in- 
crease in the options augments the dif- 
ficulty of control and implementation. 
Some commentators object to specific 
options provided at the P3 and P4 
levels. 
NTH has been urged to include a 
better explanation of the rationale for 
flexibility. Indeed, the calculus of 
switching physical and biological con- 
tainment levels has been questioned. 
Is reducing a physical containment 
level from P3 to P2 truly compensated 
by increasing biological containment 
from EK1 to EK2? 
The scale of either form of contain- 
ment from least to greatest is not nec- 
essarily linear, and substitutions are 
only roughly approximate. Neverthe- 
less. there are some numerical bases 
for comparison. At the P4 level, for ex- 
ample, a Class in biological safety 
cabinet is required (if a positive-pres- 
sure suit is not used); whereas one can 
work in an open-front biological safety 
cabinet at the P3 leveL Studies using 
molecular counts of gases have shown 
that there is a 4-5 log protection in 
going from a Class I or II biological 
safety cabinet to a Class III cabinet — 
that is, from P3 to P4. Similarly, in 
going from PI to P3 there may be a 4- 
5 log increase in safety. 
The measure of safety provided by 
open-front biological safety cabinets, 
used in work at the P2 and P3 levels, 
consists in design and performance cri- 
teria that permit fewer than 20 micro- 
organisms to escape through the open 
front when 1x10 s to 8x10 s 
(100,000.000 to 800,000,000) microor- 
ganisms are experimentally released 
within the cabinet. (See pp. 92-93 of 
the 1977 EIS for a more detailed dis- 
cussion of safeguards associated with 
use of biological safety cabinets.) 
HV2 is defined in terms of a prob- 
ability of escape of recombinant DNA 
of less than 10' s (1 in 100,000,000). In 
considering “equivalency” between P 
and EK levels, it is recognized that the 
two systems are conceptually differ- 
ent. Biological safety cabinets are de- 
signed primarily for the protection of 
the laboratory' worker, and all physi- 
cal containment protection stops at 
the walls of the laboratory. Biological 
containment continues to operate even 
if an organism should escape from the 
laboratory. 
The flexibility allowed in alternate 
P and HV levels are carefully ex- 
plained in the text of the PRG-NIH, 
and the investigator must follow the 
explicit requirements set forth in Part 
III of the PRG-NIH and in Tables I 
and H. 
Risk assessment 
Many commentators have urged 
more studies in risk assessment. It has 
been maintained that assumptions 
about biological containment may not 
be valid and that all components 
should be tested. Concern has been ex- 
pressed that the biological contain- 
ment safety systems may fail altogeth- 
er. 
Some risk-assessment studies are 
prohibited by the 1976 Guidelines. 
Under the PRG-RAC, however, the 
Director. NTH, on recommendation of 
the RAC. would have discretion to 
permit such risk-assessment experi- 
ments by granting a waiver from a spe- 
cific prohibition. There was virtually 
nr. amirr. mis support for this discretion 
at the public hearing in December 
1977. Of course, its exercise must be 
consistent with standards of due proc- 
ess for the scientific community and 
the public. 
Risk-assessment studies are proceed- 
ing both within and outside the 
United States. NIH is committed to 
the conduct and support of such stud- 
ies to determine the extent to which 
certain potentially harmful effects 
from recombinant DNA molecules 
may occur. It is intended that the NTH 
P4 facilities at the Frederick Cancer 
Research Center will serve as a focal 
point for such experiments. Provisions 
have already been made to share these 
facilities with non-Federal scientists. 
Training 
A number of commentators urge 
that specific curricula be developed for 
training of researchers and that the 
Guidelines stipulate requirements for 
certification in safety practices. NIH 
has a contract with the American Soci- 
ety for Microbiology to develop mini- 
mum standards for training partici- 
pants in recombinant DNA research. 
The work panel’s report is to be used 
by the IBCs and investigators to set 
appropriate standards. 
Emergency plans 
In response to the concerns of com- 
mentators. the elements of emergency 
plans to handle possible safety prob- 
lems are described more clearly in 
“Laboratory Safety Monograph— A 
Supplement to the NIH Guidelines for 
Recombinant DNA Research.” Fur- 
ther, NIH staff have recently met with 
representatives of CDC to establish a 
mechanism for providing advice, con- 
sultation, or assistance if necessary in 
case of an emergency, such as a labo- 
ratory accident involving recombinant 
DNA. 
Biological containment consider- 
ations 
Considerations of biological contain- 
ment related mainly to the develop- 
ment of alternative host-vector sys- 
tems. Many commentators from the 
scientific community believe that the 
PRG-RAC discriminate against host- 
vector systems alternate to E. coli K- 
12. They urge development of other 
systems, maintaining that they will be 
needed increasingly both in pure re- 
search and in industry and should be 
certified as soon as possible. It is un- 
likely, according to one commentator, 
that agriculture will best be served 
through the use of E. coli K-12 (or B. 
subtilis ) and that alternate host-vector 
systems are essential if the potential 
of recombinant DNA technology for 
agriculture is to be realized. In view of 
the support evident at the 1976 public 
meeting for NIH to encourage develop- 
ment of alternate host-vector systems, 
one commentator expressed disap- 
pointment that there was not a large 
NTH contract program in this area. 
Others view the introduction of al- 
ternate HV systems with some misgiv- 
ings. It was pointed out, for example, 
that if uncertainty continues to sur- 
round research with so well-studied an 
organism as E. coli K-12, our igno- 
rance must be that much greater with 
regard to any other organism— its eco- 
logical involvement, the organisms 
with which it can exchange DNA, etc. 
Moreover, the Guidelines, which have 
been developed around the use of E. 
coli K-12, are primarily focused on 
dangers to man, and the introduction 
of new systems may affect other life 
forms with which we should be equal- 
ly concerned. In the view of commen- 
tators who urge restraint, the larger 
the number of systems certified, the 
greater the problem of monitoring the 
w'ork. 
Clearly, however, research address 
to the development of other host- 
vector systems must proceed. This is 
particularly evident in the agricultural 
sector, where the potential for imme- 
diate benefits to man is great. At pres- 
ent, a number of alternate systems are 
being developed by N,IH grantees. In 
the use of such systems, the same ccn- 
FEDERAL REGISTER, VOL 43, NO. 146— FRIDAY, JULY 28, 1978 
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