27906 
NOTICES 
mittee under the auspices of the Phar- 
maceutical Manufacturers Association 
will be formed to review the guidelines 
for potential application to the drug in- 
dustry. Further meetings will be sched- 
uled with other groups that have an ac- 
tive interest in recombinant DNA re- 
search. 
It is my hope that the guidelines will 
be voluntarily adopted and honored by 
all who support or conduct such research 
throughout the United States, and that 
at least very similar guidelines -will ob- 
tain throughout the rest of the world. 
NTH places the highest priority on efforts 
to inform and to work with international 
organizations, such as the World 
Health Organization and the Interna- 
tional Council of Scientific Unions, with 
a view to achieving a consensus on safety 
standards in this most important re- 
search area. 
There has been considerable interna- 
tional cooperation and activity in the 
past, and I expect it to continue in the 
future. The aforementioned Ashby Re- 
port, presented to Parliament in Jan- 
uary 1975, describes the advances in 
knowledge and possible benefits to so- 
ciety of the experiments involving re- 
combinant DNA molecules, and attempts 
to assess the hazards in these techniques. 
The Asilomar meeting also had a num- 
ber of international representatives, as 
mentioned previously. The European 
Molecular Biology Organization <EMBO> 
has been involved in considering guide- 
lines for recombinant DNA research. 
They have closely followed the activities 
of NIH, and will thus be encouraged. I 
believe, to monitor their research with 
augmented cooperation and coordina- 
tion. For example, EMBO recently an- 
nounced plans for a voluntary registry of 
recombinant DNA research in Europe. 
Following this EMBO initiative, NIH 
shall similarly maintain a voluntary 
registry of investigators and institu- 
tions engaged in such research in the 
United States. Plans for establishing this 
registry are under way. 
D. Environmental policy considerations 
A number of commentators urged NIH 
to consider preparing an environmental 
impact statement on recombinant DNA 
research activity. They evoked the pos- 
sibility that organisms containing re- 
combinant DNA molecules might escape 
and affect the environment in poten- 
tially harmful ways. 
I am in full agreement that the poten- 
tially harmful effects of this research on 
the environment should be assessed. As 
discussed throughout this paper, the 
guidelines are premised on physical and 
biological containment to prevent the 
release or propagation of DNA recom- 
binants outside the laboratory. Delib- 
erate release of organisms into the en- 
vironment is prohibited. In my view, the 
stipulated physical and biological con- 
tainment ensures that this research will 
proceed with a high degree of safety and 
precaution. But I recognize the legiti- 
mate concern of those urging that an en- 
vironmental impact assessment be done. 
In view of this concern and ensuing pub- 
lic debate, I have reviewed the appro- 
priateness of such an assessment and 
have directed that one be undertaken. 
The purpose of this assessment will be 
to review the environmental effects, if 
any, of research that may be conducted 
under the guidelines. The assessment 
will provide further opportunity for all 
concerned to address the potential bene- 
fits and hazards of this most important 
research activity. I expect a draft of the 
environmental impact statement should 
be completed by September 1 for com- 
ment by the scientific community. Fed- 
eral and State agencies, and the gen- 
eral public. 
It should be noted that the develop- 
ment of the guidelines was in large part 
tantamount to conducting an environ- 
mental impact assessment. For example, 
the objectives of recombinant DNA re- 
search. and alternate approaches to 
reach those objectives, have been con- 
sidered. The potential hazards and risks 
have been analyzed. Alternative ap- 
proaches have been thoroughly con- 
sidered, to maximize safety and mini- 
mize potential risk. And an elaborate re- 
view structure has been created to 
achieve these safety objectives. From a 
public policy viewpoint, however, the 
environmental impact assessment will be 
yet another review that will provide 
further opportunity for the public to 
participate and comment on the conduct 
of this research. 
II. METHODS OF CONTAINMENT 
Comments on the containment pro- 
visions of the proposed guidelines were 
directed to the definition of both phys- 
ical and biological containment and to 
the safety and effectiveness of the pre- 
scribed levels. Several commentators 
found the concept of physical contain- 
ment imprecise and too subject to the 
possibility for human error. Others ques- 
tioned the concept of biological contain- 
ment in terms of its safety and purported 
effectiveness in averting potential haz- 
ards. .The commentators were divided on 
which method of containment would 
provide the most effective and safe sys- 
tem to avoid hazards. Several suggested 
that each of the physical containment 
levels be more fully explained. 
W. Emmett Barkley, Ph.D., Direc- 
tor of the Office of Research Safety, 
National Cancer Institute, was asked to 
review the section on physical contain- 
ment in light of these comments. Dr. 
Barkley convened a special committee 
of safety and health experts, who met 
to consider not only this section of the 
guidelines but also the section on the 
roles and responsibilities of researchers 
and their institutions. The committee 
thoroughly reviewed the section on phys- 
ical containment and recommended a 
number of changes. The Recombinant 
Advisory Committee, meeting on April 
1-2, 1976, reviewed the recommendations 
of the Barkley group. These are incorpo- 
rated, with editorial revisions, in the final 
version of the guidelines. 
The present section on physical con- 
tainment is directly responsive to those 
commentators who asked for greater de- 
tail and explanation. Although different 
in detail, the four levels of containment 
approximate those given by the Center 
for Disease Control for human etiologic 
agents and by the National Cancer In- 
stitute for oncogenic viruses. For each of 
the proposed levels, optional items have 
been excluded, and only those items 
deemed absolutely necessary for safety 
are presented. Necessary facilities, prac- 
tices, and equipment are specified. To 
give further guidance to investigators 
and their institutions, a supplement to 
the guidelines explains more fully safety 
practices appropriate to recombinant 
DNA research. And a new section has 
been added to ensure that shipment of 
recombinant DNA materials conforms, 
where appropriate, to the standards, pre- 
scribed by the U.S. Public Health Service, 
the Department of Transportation, and 
the Civil Aeronautics Board. 
The section on physical containment 
is carefully designed to offer a construc- 
tive approach to meeting potential haz- 
ards for recombinant experiments at all 
levels of presumed risk. Certain commen- 
tators had suggested that the first level 
of physical containment (PI) be merged 
with the second level (P2>. This sugges- 
tion. however, w'ould tend to apply overly 
stringent standards for some experi- 
ments and might result in a lowering of 
standards necessary at the second level. 
I believe the level of control must be con- 
sistent with a reasonable estimate of the 
hazard ; and the section on physical con- 
tainment does provide this consistency. 
Accordingly, the first and second levels 
of physical containment remain as sepa- 
rate sections in the guidelines. 
Because of the nature and operation of 
facilities required for experiments to be 
done at the fourth level of containment 
(P4> , a provision has been included that 
the NIH shall review such facilities prior 
to funding them for recombinant DNA 
studies. The situation merits the special 
attention of experts who have maximum 
familiarity with the structure, operation, 
and potential problems of P4 installa- 
tions. Several commentators advocated 
that NIH arrange for sharing of P4 fa- 
cilities, both in the NIH intramural pro- 
gram and in institutions supported 
through NIH awards. In response to 
these suggestions, we are currently re- 
viewing our facilities, including those at 
the Frederick Cancer Research Center 
(Fort Detrick), to determine how such 
a program can best be devised. It is most 
important that P4 facilities be made 
available to investigators. It should be 
noted that incidents of infection by even 
the most highly infectious and danger- 
ous organisms are extremely infrequent 
at P4 facilities, and therefore the poten- 
tial for hazard in certain complex ex- 
periments in recombinant DNA research 
is considerably reduced. 
III. PROHIBITED EXPERIMENTS 
1. Practically all commentators sup- 
ported the present prohibition of certain 
experiments. There were suggestions for 
a clearer definition of the prohibition of 
certain experiments where increased 
antibiotic resistance may result. And it 
FEDERAL REGISTER, VOL. 41, NO. 131 — WEDNESDAY, JULY 7, 1976 
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