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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 and invalid.

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 med 2006,355,953-4

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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