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[SANET-MG] APHIS is wrong in claiming RNA and DNA are never toxic
14 July 2007
Prof. Joe Cummins
Determination of Non-regulated Status for C5 Plum Resistant to Plum Pox
Virus a Proposal by the United States Department of Agriculture
The United Sates Department of Agriculture (USDA) put forward a proposal
to de-regulate C5 Virus Resistant Plums and that proposal was permitted
by USDAéAPHIS. Approval of USDA-ARS Request (04-264-01P) Seeking a
Determination of Non-regulated Status for C5 Plum Resistant to Plum Pox
Virus Finding of No Significant Impact and Decision Notice was published
Federal Register / Vol. 72, No. 134 / Friday, July 13, 2007 / Notices.
Response to Comments APHIS No. 04-264-01p APHIS received 1,725 comments
by the close of the comment period. These comments came from state farm
bureaus, organic growers, growers associations, consumer groups,
agriculture support industries, academic professionals and individuals.
There were 1,708 respondents that did not support granting the petition
for non-regulated status to the C5 plum. The majority of the comments in
opposition of deregulation were similar in content. There were 17
comments that supported deregulation. According to APHIS ``The majority
of academic researchers, as well as the state farm bureaus that
submitted comments, support granting non-regulated status to the C5
plum. The majority of those who submitted comments opposing granting
non-regulated status were submitted by organic grower or consumer
groups, organic growers, those who favor organic agriculture or those
who are opposed to genetic engineering technology in general``. There
were 100 times more comments opposing the non-regulated status than
there were supporting non-regulated status. Among the 1,708 opposing
non-regulated status there were a large number of academic researchers
contrary to the claims of APHIS. In fact APHIS was shockingly biased in
their Environmental Assessment (EA).
In the Finding of No Significant Impact and Decision Notice APHIS
maintains that, in general RNA and DNA have no toxic properties based
primarily on comments made by the Food and drug Administration in a 1992
GRAS notice which was based on observations on genetically modified (GM)
microbes used to produce animal proteins. However, it is very clear that
certain DNA preparations are well known to be cytotoxic as are several
small RNA molecules similar to those implicated in the virus resistance
of C5 plums. APHIs maintains “The‘HoneySweet’ plum relies upon a RNA
gene silencing mechanism for resistance to plum pox virus and does not
produce the plum pox virus coat protein or any other novel proteins.
Nucleic acids (i.e., RNA and DNA) are present in all living organisms
and are not known to have any toxic properties. Nucleic acids are
considered to be “generally recognized as safe” (GRAS) by the U.S. Food
and Drug Administration (FDA) (FDA 1992) and exempt from the requirement
of a tolerance under the Federal Food Drug and Cosmetic Act by the U.S.
Environmental Other comments questioned the safety of the small RNAs
that are responsible for providing resistance in C5 plum. One comment
specifically points out the use of RNA interference (RNAi) gene therapy
and its potential for adverse human health effects. As discussed above,
the safety of nucleic acids is widely accepted. Both RNA and DNA are
part of all food products that we consume. Further, given that plant
viruses infect a tremendous amount of the fruits and vegetables that we
consume, it is highly likely that humans have been exposed to the same
or similar viral RNA that may be expressed in a coat-protein expressing
plant. In terms of the concern about RNAi used in gene therapy, such
RNA’s would be specifically designed and intended for targeted use in
humans, and they would be significantly different than those found in
the C5 plum.” It is worth pointing out that potentially toxic small RNA
molecules are not produced in the virus but they are produced in the
plums in response to the insertion of viral RNA into the plum genome.
Virus infected plums would not bear quantities of the small RNA which
prevents virus replication. However, the GM virus resistant plums would
bear quantities of the small RNA which is potentially toxic to animals.
There is extensive evidence that the small RNA molecules may be toxic to
animal cells and it is noted that small RNA molecules may produce off
target effects in plants. The fact is, the small RNA molecules induced
in plums have never been tested for their toxicity in animals and they
have not previously been produced in quantities plums or any other crop
plants. A few cogent references showing that the small RNAs may be toxic
are listed below. These references certainly show that the general
conclusion that RNA molecules are safe for humans is fundamentally false
Grimm D, Streetz KL, Jopling CL, Storm TA, Pandey K, Davis CR, Marion P,
Salazar F, Kay MA. Fatality in mice due to oversaturation of cellular
microRNA/short hairpin RNA pathways. Nature. 2006 May 25;441(7092):537-41.
Marsden,P. RNA Interference as Potential Therapy — Not So Fast n engl j
Barik S. RNAi in moderation. Nat Biotechnol. 2006 Jul;24(7):796-7
Snove O Jr, Rossi JJ. Toxicity in mice expressing short hairpin RNAs
gives new insight into RNAi.Genome Biol. 2006;7(8):231.
Fish RJ, Kruithof EK. Short-term cytotoxic effects and long-term
instability of RNAi delivered using lentiviral vectors.BMC Mol Biol.
2004 Aug 3;5:9.1-15
Jackson AL, Burchard J, Schelter J, Chau BN, Cleary M, Lim L, Linsley
PS. Widespread siRNA "off-target" transcript silencing mediated by seed
region sequence complementarity. RNA. 2006 Jul;12(7):1179-87.
APHIS also maintains that DNA molecules are intrinsically without toxic
side effects based on the 1992 FDA GRAS determination. Even though toxic
DNA is not a major issue in the GM plums it is worth pointing out that
the toxicity of certain DNA molecules is well established and thses
finding show that the statements made about the general lack of toxicity
of DNA molecules are false and misleading. A few of the many references
on toxic DNA molecules are listed below.
Luyer MD, Buurman WA, Hadfoune M, Wolfs T, van't Veer C, Jacobs JA,
Dejong CH, Greve JW. Exposure to bacterial DNA before hemorrhagic shock
strongly aggravates systemic inflammation and gut barrier loss via an
IFN-gamma-dependent route.Ann Surg. 2007 May;245(5):795-802
Obermeier F, Dunger N, Deml L, Herfarth H, Schölmerich J, Falk W. CpG
motifs of bacterial DNA exacerbate colitis of dextran sulfate
sodium-treated mice. Eur J Immunol. 2002 Jul;32(7):2084-92
Khazanov E, Simberg D, Barenholz Y. Lipoplexes prepared from cationic
liposomes and mammalian DNA induce CpG-independent, direct cytotoxic
effects in cell cultures and in mice.J Gene Med. 2006 Aug;8(8):998-1007
In conclusion, APHIS wrongly claims that RNA and DNA molecules are
intrinsically safe for humans are based on old observations of FDA which
were refuted by numerous experiments. APHIS bases its decisions’ on the
safety of GM crops such as C5 plums on such refuted observations
rendering their judgement about the safety of the GM crop to be invalid.
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