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from genomes known to replicate 
within the organism used to propagate 
the recombinant DNA." This is quali- 
fied, however, by a footnote stating 
that "recombinant DNA formed be- 
tween segments of eukaryotic viral 
DNA and any eukaryotic DNA * * * 
shall not be excluded • • * until such 
time as there is more information 
about the extent of naturally occur- 
ring recombinational events between 
these DNA's.” 
The public comments on these 
standards raised a number of issues. 
For example, some said that safety 
rather than novelty should be the cri- 
terion for exclusion. That is, any re- 
combinant molecule that poses a 
threat to the public health or the en- 
vironment should be covered by the 
Guidelines regardless of whether the 
molecule is a novel one. Others held 
that the proper criterion should not 
be safety, but rather whether the po- 
tential hazard of the recombinant 
DNA molecule differs significantly in 
degree or in kind from those found in 
nature or from biohazards that are 
successfully handled by conventional 
methods. It proved impossible to rec- 
oncile these differences of opinion in 
the deinition itself and so an “Exemp- 
tions” section was drafted by NIH 
staff in conjunction with an RAC 
working group. It should be noted that 
no provision in that 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, however, against the remote 
possibility 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 is 
more appropriately presented under 
the "Exemptions” section. 
The section exemption pertains to 
recombinant DNA molecules consist- 
ing entirely of DNA segments from a 
single non-chromosomal 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 indig- 
enous plasmids, viruses, mitochondria, 
or chloroplasts, when propagated only 
in that oranism (or a closely related 
strain of the same species). This par- 
tially responds to the suggestion made 
by many commentators that experi- 
ments previously classified as P1 + 
EK1 be excluded from the Guidelines. 
It also covers some of the cases the 
RAC was including in the concept of 
"novelty” and “different genomes.” 
This exemption, however, does not in- 
clude recombinant DNA molecules 
formed between viral DNA and eukar- 
yotic host DNA. In this regard it is 
analogous to footnote I 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 
“non-novel exchangers” proposed in 
the PRG-RAC. Appendix A to the 
PRG-NIH gives a proposed list for 
this exemption. This list is discussed 
in Appendix D to the present docu- 
ment. 
The fifth exemption allows the Di- 
rector, NIH, on the recommendation 
of the RAC and after appropriate 
notice and opportunity for public com- 
ment, to exempt other classes or re- 
combinant DNA molecules if he finds 
that "they do not present a significant 
risk to health or the environment.” 
This language for exempting classes of 
experiments is used in proposed legis- 
lation (H.R. 11192) recently reported 
out of the Committee on Interstate 
and Foreign Commerce and the Com- 
mittee on Science and Technology of 
the U.S. House of Representatives. 
In addition to these comments per- 
taining to the standards for exemption 
in the PRG-RAC, the following were 
directed toward the processes whereby 
exemption 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 to compile a 
list of novel exchangers that are sub- 
ject to the Guidelines. 
• The procedures and criteria used 
in the development of the list should 
be thoroughly explained, and ade- 
quate opportunity should be given for 
public review and comment. 
• Before an organism is 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- 
tions I-E-4 and I-E-5— the two that in- 
volve the development of “lists”— the 
Director, NIH, on the advice of the 
RAC, will develop lists after appropri- 
ate notice and opportunity for public 
comment. The initial list proposed in 
Appendix A to the PRG-NIH is sub- 
mitted for public comment along with 
the entire revision of the Guidelines. 
In the future, appropriate notice and 
opportunity for public comment will 
precede any additions to Appendix A 
or exemption I-E-5. 
Prohibitions 
Two changes in this section have 
been initiated to make it more com- 
patible with the new "Definition” and 
"Exemptions” sections. The first was 
to transfer this section from Part III 
of the Guidelines to Part I, reempha- 
sizing that the exemptions are not ap- 
plicable to the six activities listed as 
prohibited. The second was to drop all 
references to novel recombinant 
DNA’s and natural genetic exchange. 
Other alternatives suggested by com- 
menters: 
• There was a general endorsement 
for the provision in this section which 
grants to the Director, NIH, upon the 
recommendation of the RAC, the au- 
thority to waive any of the prohibi- 
tions. The widespread support for this 
authority reflects the realization that 
many important risk-assessment ex- 
periments would not be able to pro- 
ceed otherwise. NIH is now supporting 
and will continue to support experi- 
ments that will yield knowledge con- 
tributing to a better understanding of 
the nature of potential risks of recom- 
binant DNA. 
• It was urged that the advice of 
other Government agencies, such as 
the Environmental Protection Agency 
and the Occupational Safety and 
Health Administration, should be 
sought when the Director, NIH, con- 
siders invoking this waiver authority. 
The Federal Interagency Committee 
on Recombinant DNA Research pro- 
vides for coordination of policies in 
this area. EPA and OSHA are repre- 
sented on the Committee. The advice 
of relevant research and regulatory 
agencies will continue to be sought 
when appropriate. 
It was suggested that the RAC as 
presently constituted should not be 
the sole advisory body because societal 
as well as scientific considerations 
must enter into the waiver decision. As 
explained in greater detail in Part IV 
of this document, the membership of 
the RAC will be broadened modestly 
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