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Federal Register / Vol. 45, No. 12 / Thursday, January 17, 1980 / Notices 
that “While the Committee approves the 
entire project in principle, it is 
recognized that data from the first stage 
must be evaluated prior to removal of 
any clones from Plum Island. 
Accordingly, a Working Group shall be 
formed to examine data on the 
infectivity of subgenomic portions of the 
foot-and-mouth disease virus and to 
examine the testing data on infectivity 
of the clones produced at Plum Island. 
The collection of clones to be approved 
for removal from Plum Island shall not 
contain among them, collectively or 
individually, the full genome of the foot- 
and-mouth disease virus. This Working 
Group shall: 
“(a) report back to the full RAC on the 
infectivity data. RAC will then consider 
approval for further stages of the 
experiment. 
“(b) recommend to the RAC 
procedures for continued monitoring of 
these experiments.” 
Dr. Campbell stated that it was the 
sense of the RAC that this motion 
constituted the “major action" and that 
future recommendations of the RAC 
approving further stages of the 
experiment would be "minor actions.” 
The RAC further voted (9 in favor, 7 
opposed, with 2 abstentions) that once 
the clones are transferred to Genentech, 
experiments with them can be carred 
out at P1 + EK1 containment. 
The Decision of the Director, NIH, is 
to accept the first recommendation of 
the RAC (vote: 17-0-1) allowing the 
cloning of foot-and-mouth disease virus 
in the EK1 host-vector system consisting 
of an E. coli K-12 host and the vector 
pBR322, all work to be done at the Plum 
Island Animal Disease Center. I also 
accept the second recommendation of 
the RAC (vote: 13-4-1) that first a 
working group of the RAC and 
subsequently the full RAC examine data 
arising from the foot-and-mouth disease 
virus recombinant DNA work on Plum 
Island prior to the shipment of any 
clones off of Plum Island. I am not 
accepting, at present, the third 
recommendation of the RAC (vote: 9-7- 
2) concerning the containment levels for 
the work to be done at Genentech after 
the clones are sent from Plum Island. 
Since acceptance of the second 
recommendation entails review of data 
by a working group of the RAC and by 
the full RAC prior to any shipment of 
foot-and-mouth subgenomic virus clones 
from Plum Island, I will reserve my 
decision on the appropriate containment 
level for work with these clones at 
Genentech until the RAC has examined 
these data. 
Assessment of the potential 
environmental impact involved in the 
above recommendations touched upon 
the following considerations: 
Work has proceeded for many years 
on Plum Island with foot-and-mouth 
disease virus without any adverse 
environmental impact beyond the 
island. In September, 1978, there was an 
escape from the Plum Island high- 
security laboratory to other cattle on the 
island. The infection did not spread 
beyond Plum Island. Following this 
incident, there were a number of 
extensive analyses of safety at PLADC, 
including reports from: ad hoc Plum 
Island committees; the U.S. Department 
of Agriculture Office of Investigations; 
and an External Safety Review 
Committee. 
Improvements in safety at Plum Island 
which occurred subsequent to 
September 1978 are documented in: a 
January 12, 1979, memorandum from Dr. 
J.J. Callis, Director of PLADC; a July 12, 
1979, memorandum from External Safety 
Review Committee members; and a 
September 1979 PLADC Status Report. 
Among the changes: training and 
operating procedures were improved; 
PIADC biological safety regulations 
were rewritten; air filtration system 
gaskets were changed and the system is 
now checked daily; directional airflow is 
frequently monitored; and 17 new Class 
II biological safety cabinets were 
installed. 
All of the recombinant DNA work 
involving foot-and-mouth disease virus 
at PIADC will be done at a level of 
physical containment greater than P3. 
That is, all of the requirements of P3 in 
the NIH Guidelines (see Section II— B— 3 
of the Guidelines) will be followed, as 
well as certain of the additional 
requirements P4. Among these are II-B- 
4-a-9 (steam sterilization), II-B-4-a-13 
and -14 (clothing change and shower), 
and II-B-4-c-l (special laboratory 
design). Furthermore, the island location 
of Plum Island and the fact that the 
island is closed to the public adds an 
additional safety barrier. 
The host-vector system to be used for 
the cloning of foot-and-mouth disease 
virus in this proposal is an EK1CV 
system, consisting of the host E. coli 
strain K-12 and the plasmid pBR322. 
This host-vector system satisfies the 
criterion of EKlCV, since pBR322 is a 
vector certified for use in an EK2 
system. The EKlCV level of biological 
containment is higher than EKl. [See 
Decision Document accompanying NIH 
Guidelines in the Federal Register on 
December 22, 1978 (43 FR 60089).] The 
safety of the EKl host-vestor system, 
and the extremely low probability of its 
use causing an adverse environmental 
impact, have been extensively analyzed 
previously. Analyses appear in the NIH 
Environmental Impact Statement on the 
1976 Guidelines, in the report of the 
Falmouth meeting “Risk Assessment of 
Recombinant DNA Experimentation 
With Escherichia coli K-12" [Journal of 
Infectious Diseases 137, 615 (1978)], in 
the Environmental Impact Assessment 
accompanying proposed revised 
guidelines in the Federal Register on 
July 28, 1978 (43 FR 33042) and most 
recently, in the Decision Document/ 
Environmental Impact Assessment 
accompanying proposed revised 
guidelines in the Federal Register on 
November 30, 1979 (44 FR 69210). As 
discussed in the latter document, in 
order to cause a hazardous situation a 
series of steps must occur, each of which 
has a low probability; this results in an 
exceedingly low probability of harm. 
Analyzed in the latter document is the 
low probability of each of the following: 
significant escape of E. coli K-12 from a 
Pi laboratory (the work in this proposal 
will be done in a laboratory that 
exceeds the requirements of P3, thus 
making the probability of escape even 
lower than for a Pi laboratory); E. coli 
causing an epidemic by person-to- 
person spread; pathogenicity of E. coli 
K-12; E. coli K-12 being made 
pathogenic by the insertion of 
recombinant DNA; implantation of E. 
coli K-12 in the intestinal tract of 
laboratory animals or man; survival of 
E. coli K-12 carrying recombinant DNA; 
transfer of recombinant DNA E. coli K- 
12 to other organisms; and recombinant 
DNA in E. coli K-12 causing 
autoimmune disease. 
Further, the specific hazards of 
cloning viral recombinant DNA in E. coli 
K-12 were the subject of the “U.S.- 
EMBO Workshop to Assess Risks For 
Recombinant DNA Experiments 
Involving The Genomes of Animal, Plant 
and Insert Viruses,” held in Ascot, 
England, January 27-29, 1978. The report 
of this workshop, attended by American 
and European experts and published in 
the Federal Register both on March 31, 
1978 (43 FR 13748) and on July 28, 1978 
(43 FR 33159), concluded that "The 
probability that K-12 organisms carrying 
viral DNA inserts could represent a 
significant hazard to the community is 
so small as to be of no practical 
consequence. . . . Viral genomes or 
fragments thereof, cloned in E. coli K-12 
using approved plasmid or phge vectors 
pose no more risk than work with the 
infectious virus or its nucleic acid and in 
most, if not all cases, clearly present 
less risk. In fact, the workshop 
participants agreed that cloning of viral 
DNA E. coli K-12 may provide a unique 
opportunity to study with greatly 
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