Parma, Italy
June 11, 2009
Question number:
EFSA-Q-2009-00589, EFSA-Q-2009-00593
Opinion
Summary
The following summary provides a consolidated overview of the
joint scientific opinion of the GMO and BIOHAZ Panels on the
“Use of Antibiotic Resistance Genes as Marker Genes in
Genetically Modified Plants” adopted on March 26, 2009 and the
scientific opinion of the GMO Panel on “Consequences of the
Opinion on the Use of Antibiotic Resistance Genes as Marker
Genes in Genetically Modified Plants on Previous EFSA
Assessments of Individual GM Plants” adopted on March 25, 2009.
Following a request from the European Commission to the European
Food Safety Authority (EFSA) the Panel on Genetically Modified
Organisms (GMO) and the Panel on Biological Hazards (BIOHAZ)
were asked to deliver a joint scientific opinion on the use of
antibiotic resistance genes as marker genes in genetically
modified (GM) plants. This opinion should take account of the
previous opinion and the statement of the GMO Panel on the use
of antibiotic resistance marker genes in GM plants intended or
already authorised to be placed on the market and their possible
uses as food and feed, for import and processing and for
cultivation. It was asked whether the Opinion could explain the
rationale leading to the conclusion of whether the use of each
particular antibiotic resistance marker gene is likely or not to
have adverse effects on human health and the environment and
outline the reasoning leading to each conclusion. The opinion
should also serve as a basis for the case-by-case safety
assessment of each GM plant and its processed products.
The antibiotic resistance traits as present in GM plants and/or
their derived products are evaluated on a case-by-case basis
with respect to their safety for humans, animals and the
environment by the GMO Panel according to the scientific
principles expressed by the Directive 2001/18/EC of the European
Parliament and the Council (EC, 2001) and detailed by the
regularly updated guidance documents of EFSA (EFSA, 2006). The
evaluation is based on molecular, biochemical, toxicological and
environmental evidence.
The joint opinion of the GMO and BIOHAZ Panels (Annex 1) focuses
on the two antibiotic resistance marker genes that are present
in GM plants for which an application has been submitted to
EFSA. One is functional in the plant (aph(3’)-IIa = nptII,
kanamycin/neomycin resistance); the other gene (ant-(3’’)-Ia =
aadA; streptomycin/spectinomycin resistance) is not expressed in
the GM plants as the expression is regulated by a bacterial
promoter not active in plants. The latter gene is used at the
initial steps to develop the genetic constructs before
introduction to the plant. An overview of relevant scientific
literature is given and a qualitative risk assessment is
provided. Whilst a detailed evaluation of aph(3’)-IIa and
ant-(3’’)-Ia genes is included in the appendices, the opinion
itself specifically addresses the indirect hazards.
From all the evidence gathered, the two Panels drew the
following conclusions:
The transfer of antibiotic resistance marker genes from GM
plants to bacteria has not been shown to occur either in natural
conditions or in the laboratory in the absence of sequence
identity in the recipient bacterial cell. Sequence identity is
necessary to allow homologous recombination between the
transformed DNA in the plant and bacterial DNA.
DNA transfer from GM plants to bacteria, if occurring, is
considered to be of low frequency compared with gene transfer
between bacteria.
Recent metagenomic analyses of total bacterial populations
(including non-cultivable bacteria) have demonstrated that
resistance determinants of kanamycin, neomycin and streptomycin
are present in all environments investigated. Such resistance
genes may be selected from this environmental reservoir and
disseminated among bacteria.
The antibiotic resistance marker genes, aph(3’)-IIa (nptII) and
ant(3’’)-Ia (aadA), in GM plants are of bacterial origin. These
antibiotic resistance genes occur at different frequencies in
different species, isolates and different environments, in
naturally occurring bacteria. The spatio-temporal relationship
between the prevalence of antibiotic resistance and selection
pressure is not fully understood.
The presence of antibiotics and antibiotic usage in different
environments are key factors in driving the selection and
dissemination of antibiotic resistance genes.
Kanamycin and neomycin are both categorized by the WHO Expert
Group on Critically Important Antimicrobials for Human Health as
‘Highly Important Antimicrobial’. Kanamycin is used as a
second-line drug for the treatment of infections with multiple
drug-resistant tuberculosis (MTB). The increasing occurrence
worldwide of “extensively drug-resistant” (XTB) isolates of MTB
with resistance to second-line antibiotics such as kanamycin is
a cause for global concern. The nptII gene has not been
implicated in such resistance. The above WHO group has also
categorised streptomycin as a ‘Critically Important
Antimicrobial’, and spectinomycin as a ‘Highly Important
Antimicrobial’.
There are limitations related among others to sampling,
detection, challenges in estimating exposure levels and the
inability to assign transferable resistance genes to a defined
source. The importance of taking these and other uncertainties
described in this Opinion into account requires to be stressed.
Notwithstanding these uncertainties, the current state of
knowledge indicates that adverse effects on human health and the
environment resulting from the transfer of these two antibiotic
resistance genes from GM plants to bacteria, associated with use
of GM plants, are unlikely.
Two members of the BIOHAZ Panel expressed minority opinions on
this last conclusion. Full details of the proposal for amendment
of the mentioned conclusion are provided in Appendix D of Annex
1.
In addition, the European Commission requested EFSA to indicate
the possible consequences of this new opinion on the previous
EFSA assessments of individual GM plants containing antibiotic
resistance marker genes. This aspect is addressed in the
scientific opinion of the GMO Panel (Annex 2).
The GMO Panel has issued previously scientific opinions about
the safety of two GM plant events that contain the aph(3’)-IIa
gene (nptII), i.e. maize MON 863 and hybrids and starch potato
EH92-527-1. In the light of the new EFSA scientific opinion “Use
of Antibiotic Resistance Genes as Marker Genes in Genetically
Modified Plants”, the GMO Panel is of the opinion that its
previous assessments on GMOs containing this antibiotic
resistance marker gene are in line with the risk assessment
strategy described in the above opinion, and that no new
scientific evidence has become available that would prompt the
Panel to change its previous opinions.
Following adoption of these opinions by the respective Panels,
EFSA consulted the Chairs of the GMO and BIOHAZ Panels as to
whether the completion of the mandate would require a
clarification of issues raised in the minority opinions of the
joint scientific opinion (Letter addressed to the Chairs of the
GMO and BIOHAZ Panels and to the Chair of the Joint Working
Group - Annex 3). The Chairs responded by confirming that the
scientific issues related to the minority opinions have already
been extensively considered during the preparation of the joint
scientific opinion and the formulation of the conclusions
therein and thus, from a scientific perspective, further
clarification of the joint scientific opinion is not required,
nor is further scientific work needed at this time (Annex 4).
[1] On a request from European Commission, DG SANCO, Mandate No
EFSA-M-2008-0411; issued on 14 May 2008.
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