In 2013, the question of a toxicological assessment of the safety of humans and animals consuming GMOs was pushed back into the limelight by a scientific publication by Gilles-Eric Seralini's team in 2012. Several ongoing research projects have taken an interest in the problem at national and international level. In France, as part of the RiskOGM call for projects, the Ministry of Ecology launched a new research project in 2014 entitled GMO90+.
To help us understand the research in progress and its benefits in terms of a toxicology assessment of Genetically Modified Crops (GMCs), Bernard Salles, Professor of Toxicology in the Toulouse Pharmaceutical Faculty, director of the INRA Toxalim unit (UMR1331) and coordinator of the GMO90+ project, answers our questions.
Q1: Several French and European research projects about the toxicological evaluation of GMCs are in progress: how do they fit together?
BS: In my view, the French and European research projects in progress are very complementary. They are all interested in the issue of the safe consumption of genetically modified crops (GMCs) by humans and animals, though they approach the question from different entry points. The three European research projects (MARLON, GRACE and G-TwYST) represent applied research aiming to provide scientific answers to questions that directly confront the European Commission. Meanwhile, the French GMO90+ project, funded by the Ministry of Ecology, is a complementary project guided more by a logic of basic research.
GMO90+ aims in particular to use still-developing "omic" techniques to try to identify early biomarkers for exposure to GMOs, or even any subsequent pathogenic effects. This slightly complex expression of "early biomarkers" simply means trying to find biological indicators (messenger RNA, circulating enzymes, hormones, stress proteins etc.) that would be significant in screening for harmful effects that may arise in the longer term. These biomarkers, dosed at the end of 90-day toxicology studies, for example, would provide an alert, if they evolve, about the need for longer-term studies.
The MARLON project is an epidemiological study, which means that it seeks to compare the state of health of production livestock fed with GMOs with that of animals fed conventionally, under normal rearing conditions. The project is due to end on 31/07/2015, and should confirm whether GMOs have effects under real conditions of use that are not observable in the laboratory.
The GRACE project is a regulatory toxicology project that uses laboratory animals (rats) fed with MON 810 corn for 90 days (the standard length of the toxicology tests required for GMOs) and for one year (to study whether certain effects may arise later in the life of the GMO-consuming animal). The project, initiated in July 2012, is due to end in November 2015 and should provide scientific answers to the question of the usefulness and possible improvement of the 90-day protocols required since 2013 in the regulatory evaluation of GMCs.
The G-TwYST project, also a regulatory toxicology project, was launched in April 2014 and has several objectives set by the European Commission. First, it aims to repeat a part of the study by Gilles-Eric Seralini's team on NK603 corn, treated or not treated with Round-Up, under better experimental conditions, such as a larger number of animals. It excludes the part of the study concerned solely with the toxicity of glyphosate and its co-formulants via drinking water. The project also aims to examine the usefulness of two-year studies and the conditions under which these studies should be conducted.
Q2: We hear a lot about these 90-day studies, but what are they for, and why are they so controversial?
BS: The health assessment of GMO cases is based on a large number of complementary studies. For example, one series of studies aims to verify that the conditions by which the genetic modification has been inserted into the plant's DNA do not lead to specific risks. Other studies compare the nutritional composition of the genetically modified crop with its unmodified equivalent, or study the potential allergy risks. In terms of toxicology, tests are carried out to ensure that the new protein synthesised by the plan following the genetic modification is not toxic at the levels being studied. The main aim of the evaluation is thus to ensure that all the foreseeable risks of toxicity have been eliminated.
The 90-day toxicity study on the whole plant is a supplementary study that has recently become obligatory at European level, and which the French government has strongly supported based on the ANSES recommendations (external link). These studies complete the health evaluation by ensuring there are no "unexpected" effects, i.e. effects that could occur due to complex unforeseen interactions between living organisms. Normal toxicology studies test an isolated chemical substance to determine the concentration at which a toxic effect begins to be observed. In the case of a 90-day study, we test the toxicity of a whole plant (corn grains, for example) in all its complexity, rather than a single chemical substance, and we are limited by the quantity of feed the animals can ingest.
Detractors of these studies say they are unnecessary as so many of them indicate no harmful effects, while their defenders consider that they are essential for evaluating unexpected effects and that, on the contrary, they should either be extended or their sensitivity improved by highlighting, for example, early biomarkers of effects.
Q3: I understand better, but in the context of the GMO90+ project, what does the work on these early effect biomarkers consist of?
BS: The GMO90+ project has two primary goals. The first involves determining early biomarkers for exposure or effects, and the second is to explore certain potential effects of GMOs that are studied little in exploratory studies and 90-day studies. With regard to the 90-day study, to verify whether this experiment duration is long enough to observe early variations and identify biomarkers, the animals will be monitored for 180 days. Moreover, through our partnership with the G-TwYST programme, we will have body fluids and organs from rats fed with a ration of genetically modified corn for one year and two years. The goal essentially is to evaluate little-studied effects such as effects on the permeability of the intestinal barrier, the first contact between GMCs and the organism, on the hormonal and reproductive systems and on hepatic and renal function. To achieve this, the GMO90+ project is divided into five separate sections: management and coordination, production and characterisation of feeds, statistics and experimental modelling, the effects of formulations on tissues, hormones and functions and the identification via omics of physiopathological and exposure biomarkers.
The project's experimental protocol is available online, but briefly it involves conducting a six-month study on eight batches of 30 male and 30 female rats:
- two control batches fed without GMOs (one for MON 810 corn and one for NK 603 corn),
- six batches tested with 11% and 33% MON 810 or NK 603 corn (treated or not treated with Round-Up) over 90 days for 10 male and 10 female rats, extended to six months for 20 males and 20 females.
Throughout the experiment, the animals, whose accommodation and handling will be tightly controlled, will be subjected to regular monitoring and sampling of blood and urine. At two stages (90 days and six months), animals will be sacrificed and their blood, urine and organs sampled for analysis using standard toxicology techniques, other more specific techniques taken from physiopathology research and techniques for quantifying metabolites and gene expression. A particular feature of the project is the use of so-called "omic" techniques to analyse these samples, which have never previously been used on such a large scale in the context of GMC toxicology.
Q4: Can you tell us more about the specific nature of these "omic" techniques?
BS: The so-called "omic" techniques, such as genomics and large-scale DNA sequencing, emerged during the 1990s in parallel with the development of the Human Genome Project (the complete sequencing of the DNA in the human genome). These "omic" technologies make it possible to generate huge quantities of data on various biological levels based on the principles of gene sequencing (genomics), gene expression (transcriptomics), protein production (proteomics) and the effects observed by studying cellular metabolism (metabolomics). Conventionally, scientists base their work on research hypotheses and then obtain targeted data that confirms or invalidates the hypothesis. With the emergence of the "omic" technologies, it is no longer necessary to pose a specific question before beginning research – this is an approach with no preconceptions. Scientists can gather large quantities of genomic, transcriptomic or proteomic data in their studies without basing their work on an initial hypothesis and wait for the data to be generated before formulating and testing biological hypotheses. These new technologies and the new research framework they bring with them are thus perfectly suited to the problem raised by the 90-day study, an exploratory study that looks for unexpected effects. However, these results obtained by experiments with no preconceptions need to be compared with observations by anatomo- and histopathologists based on tissues and organs and analysed by toxicology specialists.
Q5 : Why expose rats during 6 months only and not 1 or 2 years ?
BS: To put things into context, European projects GRACE and G-TwYST already study long-term effects (1 and 2 years) in the frame of regulatory toxicology. When elaborating GMO90+, the objective was to be complementary to other projects and to follow the current approach in toxicology oriented toward mechanistic analysis and biomarker identification with omics. The chosen protocol allows having data at 0-3-4.5 and 6 months. These data will be combined with data obtained in collaboration from G-TwYST, from the analysis of samples of 1 and 2 years rats (to do this, the same strain and rats provider were chosen, food for rats will be made according to the same formula from the same maize harvests). This will confirm or infirm the predictive character of early signals eventually found after 6 month GM feeding and linked to effects.
Q6: Who is taking part in GMO90+, and who funds it?
BS: The project receives 2.5 million euros from the Ministry of Ecology as part of the RiskOGM research programme. The GMO90+ project was selected following a call for a consortium to be put together issued in 2013 under the aegis of this research programme. The project was initiated in February 2014 and is due to end in December 2016. At the request of its sponsors, a close link has been established with colleagues coordinating projects at European level, and particularly the GRACE and G-TwYST projects. The results of GMO90+ and the raw data will be made publicly available on a platform developed for these European projects (CADIMA).
GMO90+ brings together a consortium of varied partners including INRA, INSERM, CNRS, universities (Toulouse, Rennes 1, Paris Descartes, Bordeaux and Lyon) and ANSES. Most of the scientists taking part in the project have never worked on GMOs before; their specialisms are mostly toxicology and the processing and interpreting of data generated using omic techniques. For the purposes of transparency, we also plan to have all the project participants complete a public declaration of interests that will be available online.
Q7: What role do you assign to civil society in this debate and within a technical subject?
BS: Right from the start of the project, we felt it necessary to bring together all the stakeholders concerned with the GMO issue throughout the process. Initially, we intended to set up a dialogue body operated by ANSES in line with its usual practice. Given the difficulties we encountered setting up this dialogue body [see the "News" section], the association of stakeholders will be constructed in the form of information meetings about the GMO90+ study at key stages of the project (about three-four meetings). Following these meetings, a summary document will be made public (published online on the web page dedicated to the GMO90+ project and sent to the stakeholders) and a decision can be taken if necessary on whether to allow public consultation of some of the documents.
Online 02.17.2015, updated 07.21.2015