Page Four 
September 13, 1978 
Also, ther terra "physiological process" must be more explicitly 
defined. 
In order to agrue that recombinants between "known" 
exchangers also pose "no significant risk", one would have to 
argue that on both qualitative grounds - that is, the nature 
of the exchange - and quantitative grounds - the frequency 
with which the exchange occurs in nature - that the conduct 
of a laboratory experiment constructing or using such a 
recombinant does not add to the risk already present. 
In cases where the risk is intrinsically negligible, 
exemptions could be made under I - E-5, regardless of the 
degree of novelty. However, in cases where a non-novel, 
or natural, exchange event does result in the creation of an 
organism which may pose a known hazard (e.g, the transfer of 
plasmids containing antibiotic resistance or virulence factors 
to knownpathogens ) , the criterion of non-novelty is not 
sufficient for an exemption, at least not without a careful 
assessment of the frequency of such natural exchanges and 
the relative degree of hazard already present. 
A few will argue that if some exchange event was ever 
observed even once in the laboratory, then it must have 
occurred countless times in nature and, the argument goes, 
the worst has already happened. To that I would respond 
that, indeed, microbial evolution is a continuing process, 
and that many or most of the known pathogens may well have 
arisen by natural exchange process, and that new ones will 
continue to arise. Non-novelty, per-se, is not equivalent 
to freedom from risk or even acceptable risk. 
Therefore, I would recommend that the standard of "no 
significant risk" be applied to all exemptions, or, at a 
minimum, that the added standard of "no significant increase 
in risk over that present in nature" be added to I - E -4 . 
In practice, I think you will find that such a change would 
have no effect upon the current list of exchangers to be 
exempted, and would simply tighten the criteria for granting 
future exemptions. Bear in mind that the foregoing paragraphs 
argue only against a total exemption from the Guidelines 
soley on the basis or whether or not a recombinantion event 
may have occured by a "known physiological process." 
[A-131] 
