33050 
NOTICES 
karyotlc viral DNA and any eukaryotic 
DNA * * * shall not be excluded • • • 
until such time as there is more infor- 
mation about the extent of naturally 
occurring recombinational events be- 
tween these DNAs.” 
The public comments on these 
standards raised the following issues: 
• That safety rather than novelty 
should be the criterion for exclusion; 
that is. any recombinant DNA mole- 
cule that poses a threat to the public 
health or the environment should be 
covered by the guidelines regardless of 
whether the molecule is a novel one. 
• Others argued that the proper cri- 
terion should not be safety but rather 
whether the potential hazard of the 
recombinant DNA molecules differs 
significantly in degree or in kind from 
those found in nature or from bioha- 
sards that are successfully handled by 
conventional methods. 
• That there is a question of quanti- 
fication that goes beyond novelty; that 
is. a recombinational event that occurs 
very rarely In nature can be mimicked 
more frequently in the laboratory. 
• That the PRG-RAC was ambigu- 
ous in describing the criteria to be 
used in judging novelty. 
• That the list of nonnovel exchang- 
ers should not be limited to the ex- 
change of chromosomal DNA. but 
should also Include plasmid DNA ex- 
change. 
• That the list should not be drawn 
broadly at the species level, but should 
deal with exchange at subspecies 
levels. 
• That footnote 1 of the PRG-RAC 
unjustly discrimated against natural 
recombinants involving eukaryotic 
viral DNA and other eukaryotic DNA. 
Others urged that this footnote be ex- 
panded to ensure that recombinants 
involving pathogenic bacteria not 
appear on the list. 
• That experiments classified as 
P1+EK1 be exempted from the guide- 
lines. Apparently harmless experi- 
ments do not warrant the administra- 
tive burden that accompanies inclu- 
sion within the guidelines. 
• That it was unclear whether the 
PRG-RAC definition woud permit 
"seif-cloning" experiments (such as 
the cloning of B. subtilis genes in B. 
subtil is). 
It proved impossible to reconcile 
these differences of opinion in the 
definition itself, but in my opinion the 
"Exemptions" section of the PRG- 
NIH as drafted does so successfully. 
This section was drafted by NIH staff 
in conjunction with a working group 
of the RAC; it was then modified 
slightly and endorsed by the full RAC 
at its meeting on April 27-28. 1978. 
and subsequently modified slightly for 
clarity by NIH staff. Before proceed- 
ing to a discussion of these exemp- 
tions. however. I w’ant to emphasize 
that no provision in this section may 
be cited to exempt from the guidelines 
an activity listed in the "Prohibitions" 
section. 
The first exemption concerns recom- 
binant DNA molecules that are not in 
organisms or viruses. This is in recog- 
nition that "naked" DNA. which is 
rapidly Inactivated in nature, is ex- 
tremely unlikely to be hazardous 
under experimental conditions. To 
guard against the remote possibility, 
however, that potentially harmful 
naked recombinant DNA will be incor- 
porated into an organism, the han- 
dling of certain naked recombinant 
DNA molecules described in the "Pro- 
hibitions" section remains prohibited. 
It should also be noted that the con- 
cept of extremely low hazard of naked 
recombinant DNA was included in the 
PRG-RAC in the section on "Han- 
dling Recombinant DNA Molecules" at 
the end of part III. This language. I 
believe, is more appropriately present- 
ed under the "Exemptions" section. 
The second exemption pertains to 
recombinant DNA molecules consist- 
ing entirely of DNA segments from a 
single nonchromosomal or viral 
source. This statement clarifies a cate- 
gory of '"self-cloning" experiments 
that are considered safe enough to be 
excluded from the guidelines. This is a 
concept which the RAC tried to 
convey in the PRG-RAC definition by 
use of the phrase different genomes." 
but which some commentators found 
ambiguous. 
The third exemption concerns "self- 
cloning." It exempts from the guide- 
lines recombinant DNA molecules 
made entirely from the DNA of a 
single organism Including the plas- 
mids. viruses, mitochondria, or chloro- 
plasts indigenous to (l.e.. found in 
nature in) that organism, when propa- 
gated only in that organism (or a 
closely related strain of the same spe- 
cies). This partially responds to the 
suggestion made by many commenta- 
tors that experiments previously clas- 
sified as P1 + EK1 be excluded from 
the guidelines. It also covers some of 
the cases the RAC was including in 
the concepts of "novelty" and "differ- 
ent genomes." This exemption, howev- 
er. does not include recombinant DNA 
molecules formed between viral DNA 
and eukaryotic host DNA. In this 
regard it is analogous to footnote 1 of 
the PRG-RAC. 
The fourth exemption covers "cer- 
tain specified recombinant DNA mole- 
cules that consist entirely of DNA seg- 
ments from different species that ex- 
change DNA by known physiological 
processes." In this case a list is pre- 
pared and periodically revised by the 
Director. NIH. on the recommendation 
of the RAC. after appropriate notice 
and opportunity for public comment. 
This list is analogous to the list of 
“nonnovel exchangers" proposed in 
the PRG-RAC. 
The initial entries on the list speci 
fied under exemption I-E-4 are given 
in appendix A to the guidelines. Any 
recombinant DNA molecules composed 
entirely of DNA segments coming 
from organisms listed in appendix A. 
would be exempt from the PRG-NIH 
under exemption I-E-4. The inclusion 
of the particular organisms listed in 
appendix A was recommended by the 
RAC at its meeting on April 27-28. 
1978. (For further discussion of this 
list see appendix D to the accompany- 
ing Environmental Impact Assess- 
ment.) 
The fifth exemption allows the Di- 
rector. NIH. on the recommendation 
of the RAC. after appropriate notice 
and opportunity for public comment, 
to exempt other classes of recombin- 
ant DNA molecules if he finds that 
"they do not present a significant risk 
to health or the environment.” The 
exemption of classes of experiments 
that do "not present a significant risk 
to health or the environment" is the 
language used in proposed legislation 
(H.R. 11192), recently reported out of 
the committee on Interstate and For- 
eign Commmerce and the Committee 
on Science and Technology of the U S. 
House of Representatives. 
In addition to comments pertaining 
to the standards for exemption in the 
PRG-RAC. the following comments 
were directed toward the processes 
whereby exemptions would be made: 
• Rather than compile a list of non- 
novel exchangers exempt from the 
guidelines, the burden of proof should 
be on the Director. NIH. to compile a 
list of novel exchangers which are sub- 
ject to the guidelines. 
• The procedures and critieria used 
in the development of the list should 
be explained thoroughly, and ade- 
quate opportunity should be given for 
public review and comment. 
• Before being placed on the list, all 
the data pertaining to the application 
should be available for public review. 
In response to these comments, the 
PRG-NIH specifies that for exemp- 
tion I-E-4 and I-E-5— the two exemp- 
tions which involve the development 
of "lists”— these lists will be prepared 
by the Director. NIH. on the advice of 
the RAC. a/ter appropriate notice and 
opportunity for public comment Pub- 
lication of the PRG-NIH includes ap- 
pendix A giving an initial proposed list 
for exemption I-E-4. As part of the 
public comment which I am soliciting 
on the entire PRG-NIH. I include ap- 
pendix A. In the future, no additions 
will be made to appendix A. nor will 
any items be listed as exemptions 
under exemption I-E-5. without ap- 
FEDERAl REGISTER. VOL 43. NO. 144— FRIDAY, JULY 28, 1978 
HU 
