Séralini et al. study conclusions not supported by data, says EU risk assessment community

On 19 September 2012, the scientific journal Food and Chemical Toxicology published a paper on their website by Séralini et al. describing a 2-year feeding study in rats that investigates the health effects of genetically modified maize NK603 and of a herbicide containing the active substance glyphosate.

The authors of the study conclude that GM maize NK603 and low levels of glyphosate herbicide formulations, at concentrations well below officially-set safe limits, induce severe adverse health effects, such as tumours, in rats.

On 26 September, EFSA received an official request from the European Commission in relation to the Séralini et al. paper -  European Commission Mandate(76.07 KB) . The request contained five elements:

• to carry out a scientific review of the paper;
• to ask for any necessary clarifications from the paper’s authors; 
• to advise whether the paper contained any scientific elements that could lead EFSA to reconsider its previous safety assessments of GM maize NK603;
• to take into consideration the assessment of the papers by Member States;
• to take into consideration the assessment of the German authorities which are responsible for the evaluation of glyphosate. 

EFSA published an initial review of the Séralini et al. paper on 4 October 2012.

A multi-disciplinary task force set up by the Authority analysed the paper by Séralini et al. and published an initial scientific review as the first step in a two-stage process.
The initial review was a preliminary analysis of the study as published online, taking into account aspects such as the study objectives, its design and the statistical methods used. The aim was to identify any potential information gaps for which clarifications are needed from the authors of the study. It was also to advise the European Commission whether the paper contained any scientific elements that could lead EFSA to reconsider its previous safety assessments of GM maize NK603.

Germany is being asked to carry out the assessment of the study in relation to glyphosate because it is the Member State that has responsibility for the evaluation of this particular active substance (also known as the Rapporteur Member State).

• Why is Germany being asked to carry out the assessment of the reported study in relation to glyphosate?

EFSA has concluded that the Séralini et al. paper is of insufficient scientific quality to be considered as valid for risk assessment. EFSA’s initial review found that the design, reporting and analysis of the study, as outlined in the paper, are inadequate. The numerous issues relating to the design and methodology of the study as described in the paper mean that no conclusions can be made about the occurrence of tumours in the rats tested. To enable the fullest understanding of the study the Authority has invited the authors to share key additional information.

Under the leadership of the Director of Scientific Evaluation of Regulated Products, a group of EFSA scientists, with expertise in biostatistics, experimental design, mammalian toxicology, biotechnology, biochemistry, pesticide safety assessments and GMO safety assessments, carried out the initial review. A member from EFSA’s Panel on Genetically Modified Organisms (GMO) and a member from EFSA’s Plant Protection Products and their Residues (PPR) Panel were asked to peer review the paper prior to its publication.

As scientists with respective expertise in the area of GMOs and pesticides, the external reviewers were asked to peer-review EFSA’s statement. Their role was limited to providing an impartial third-party critique of the statement. The peer-review process is a standard scientific practice that takes place before an article is published in a scientific journal. Qualified experts are asked by peers to perform an independent review of the article in question.

Peer reviewers do not have control nor responsibility for the content of the final output. This system acts as a safeguard to ensure that scientific standards and credibility are maintained.

EFSA has asked the authors of the study to clarify certain issues in the paper. If received, this information will contribute to the second step of the evaluation process by EFSA, the results from which will be published in the coming weeks.

As part of the second step of the evaluation, EFSA will take into account any information received from the authors, reflect upon already ongoing assessment activities from the Member States (such as Belgium, France, Germany and The Netherlands) and will consider the assessment of the German authorities responsible for the evaluation of glyphosate.

Co-operation with Member States forms a key part of EFSA’s work and in particular in response to urgent requests for scientific advice. EFSA has been in close contact with Member States throughout the formulation of its initial review of the Séralini et al. paper.

EFSA has focused its questions on issues arising from the methodology or design of the study - Press Release: EFSA publishes initial review on GM maize and herbicide study . For example, clarifications have been sought on the objectives of the study, the protocol used for the feeding trials and the statistical analysis. EFSA has invited the authors to share additional information lacking in the published paper to enable the fullest understanding of the complete two-year study.

No. EFSA has not requested raw data for the study as this information is not required at this stage of the review process. EFSA has requested further information about the study methodology given the gaps found in the reporting of the study’s findings. This does not include a request for the raw data from the study and is limited to the type of information one usually finds reported in scientific publications.

No. Such conclusions cannot be drawn from the findings reported in the publication of the Séralini et al. paper.   EFSA’s initial review found that the design, reporting and analysis of the study, as outlined in the paper, are inadequate. The numerous issues relating to the design and methodology of the study as described in the paper mean that no conclusions can be made about the occurrence of tumours in the rats tested. For example, the limited number of rats used in the study is too low to distinguish between a chance effect – tumours that may have occurred naturally – and the possibility of an effect related to the consumption of GM maize NK603 and/or glyphosate.  In addition, the strain of rats used in the two-year study is prone to developing tumours during their life expectancy of approximately two years. This means the observed frequency of tumours is influenced by the natural incidence of tumours typical of this strain, regardless of any treatment.  Overall EFSA has concluded that the Séralini et al.  paper is of insufficient quality to be useful for risk assessment purposes.

In 2009, EFSA’s Panel on Genetically Modified Organisms (GMO) carried out a safety evaluation of an application for the cultivation, import and processing of GM maize NK603[1]. EFSA’s GMO Panel concluded that maize NK603is as safe as its conventional counterpart with respect to potential direct effects on human and animal health and the environment.

Regarding animal feeding studies with maize NK603, the applicant provided two such studies that were evaluated by the Panel. The first was an acute toxicity test performed using mice in which they were exposed to two proteins expressed by the GM plant. There was no indication of adverse effects from this study.

The second feeding study provided by the applicant was a 90-day toxicity study in rats of maize NK603 as a whole food. The Panel concluded that there were no indications of adverse effects in rats fed with a diet containing up to 33% grain from maize NK603.

Further details on the risk assessment of GM maize NK603, including animal feeding trials, can be found in the following   EFSA Scientific Opinion  .

GM maize NK603 has also been assessed by EFSA’s GMO Panel in the context of applications for stacked events.

As with all GMO applications, maize NK603 was assessed by the Panel following its guidance documents for GMO risk assessment . Each of the following aspects was evaluated:

• Molecular characterisation of the GM plant, taking into account the characteristics of the donor and recipient organism.
• Compositional, nutritional, and agronomic characteristics of the GM product,
• Potential toxicity and allergenicity of the GM product.
• Potential environmental impact following a deliberate release of the GM product and taking into account its intended uses either for import, processing or cultivation.

EFSA’s guidance on GMO risk assessment sets out when animal feeding trials are needed and which animal feeding trials should be carried out.

Owing to the specific nature and traits of each GMO, the type of tests needed to assess safety and the tests’ duration vary according to the results of thefirst phase of the risk assessment process: a comparative assessment between the GMO and its non-GM counterpart.[2]

An example of when tests are required is when EFSA estimates that the results of the comparative assessment show a potential toxic effect of the GM plant. In this case, EFSA would require that a 90-day animal feeding study be carried out in order to investigate this further prior to completing its risk assessment.

Depending on the specific type of GMO being tested and the results of the first phase of the risk assessment process (the comparative assessment) between the GMO and its non-GM counterpart, EFSA may recommend feeding trials of different durations.

For example, if this first phase of the risk assessment showed signs of the potential toxicity of the GMO, EFSA may recommend a 90-day feeding trial in rats. 

EFSA may also recommend a feeding trial with duration of more than 90 days, although the Authority has never required such a trial for GMO applications. A longer feeding trial might be required if the results of the comparative assessment or those of a 90-day feeding trial demonstrated the potential for adverse effects related to, for example, carcinogenicity. 

No. EFSA’s approach to animal feeding trials remains in line with the measures clearly set out in its guidance on GMO risk assessment. This guidance details when animal feeding trials are needed, as well as the type of animal feeding trials required and their duration.

EFSA recognises that risk assessment is a constantly evolving science. The Authority stands ready to provide further scientific assistance to help design a methodology and protocol for long-term feeding studies involving whole foods such as GM foods that provide scientifically sound findings to strengthen risk assessment as well as the substantiation of health benefits. In December 2012, EFSA Executive Director Catherine Geslain-Lanéelle highlighted the opportunity to better integrate the needs of risk assessment into the European Commission’s long-term research programme, including long-term feeding trials on whole foods. Horizon 2020 – an €80 billion initiative designed to promote research and innovation across the EU – has earmarked more than €4 billion for the area of food and agriculture.

EFSA’s Scientific Committee has defined guidance for the carrying out of animal feeding trials which recognises the inherent scientific challenges in developing protocols to assess the safety of whole foods. When assessing the safety of a chemical, it is possible to design animal trials in such a way as to expose animals to increasing levels of the substance in order to determine the level at which adverse effects occur. Such an approach however is not always feasible with whole foods as they are bulky and administering them at high-dose levels can disrupt the overall diet of animals making it difficult to determine whether any effect observed is linked to the food itself or the change in diet. A further challenge involves identifying which of the multitude of individual substances within a food is causing any observed effect - be it positive or negative – during a long-term feeding trial.

Robust methodologies and number of animals tested are needed in order to ensure sufficient statistical power and accurate interpretation of findings. Whether one is assessing the safety of a GMO, a novel food or assessing the possible health benefit associated with consumption of a particular foodstuff, careful analysis of findings is required in order to be able to determine whether any effect observed (positive or negative) in the animal trial is linked to a particular substance in the food, the food itself and/or the overall dietary pattern.

Germany is being asked to carry out the assessment of the study in relation to glyphosate because it is the Member State that has responsibility for the evaluation of this particular active substance (also known as the Rapporteur Member State).

Under EU rules, individual Member States have responsibility for carrying out initial evaluations and re-evaluations of different active substances. This information is shared with other Member States after which EFSA carries out a peer-review of the (re)evaluation.

EFSA’s final Statement is the second part of a two-stage evaluation of the Séralini et al. paper by a multi-disciplinary task force. Following on from EFSA’s initial review published on 4 October 2012, the appraisal has taken into account assessments by organisations from six EU Member States and given the authors of the paper time to respond to requests for further information on study documentation and design.

EFSA’s final review reaffirmed its initial findings that the authors’ conclusions cannot be regarded as scientifically sound because of inadequacies in the design, reporting and analysis of the study as outlined in the paper. It is not possible, therefore, to draw valid conclusions about the occurrence of tumours in the rats tested. Based on the information published by Séralini et al., EFSA finds there is no need to re-examine its previous safety evaluations of NK603 or to consider these findings in the ongoing assessment of glyphosate.

EFSA’s final statement considered the independent assessments of the Séralini et al. paper by organisations of six EU Member States: Belgium, Denmark, France, Germany, Italy and the Netherlands.

• Belgium: BAC (Biosafety Advisory Council);
• Germany: BVL (The Federal Office of Consumer Protection and Food Safety) and BfR (The Federal Institute for Risk Assessment);
• Denmark: DTU (The National Food Institute)
• France: ANSES (French Agency for Food, Environmental and Occupational Health & Safety);
• France: HCB (High Council For Biotechnology);
• Italy: ISS (Istituto Superiore di Sanità ) & IZSLT (Istituto Zooprofilattico Sperimentale delle Regioni Lazio e Toscana);
• Netherlands: NVWA (Nederlandese Voedsel-en Warenautoriteit).

No, the authors did not respond directly to EFSA’s request for access to their study documentation and procedures. However, on 9 November 2012 Séralini et al. published a paper online entitled ‘Answers to critics’ that provided further information about the study. This publication made no reference to EFSA’s first statement or to assessments from EU Member States. EFSA scientists examined this publication and concluded it provided only a limited amount of relevant additional information which does not address the majority of the open issues raised in the first EFSA Statement. In particular, issues such as statistical methods and endpoint reporting remain unresolved. Moreover, with regard to long term carcinogenicity and mortality, Séralini et al. (2012b) acknowledge that the sample size is too small to draw conclusions.

EFSA’s evaluation of the Séralini et al. study was in keeping with its mission to review all relevant scientific literature for GMO risk assessment. The Authority remains committed to monitoring relevant literature on an ongoing basis to ensure that the advice it provides is up to date and reflects the latest scientific thinking.