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Periodic Report Summary 2 - G-TWYST (GMP Two Year Safety Testing)

Project Context and Objectives:
The G-TwYST project aims to enable risk assessors (applicants, authorities) and policy makers to evaluate and decide about the necessity of (long-term) feeding studies while at the same time

• clarifying about uncertainties raised through the outcomes and reports from recent (long-term) rodent feeding studies with whole GM food/feed and
• elaborating a scientifically sound approach for performing extended feeding studies based on the OECD test guideline 453 and subsequent EFSA recommendations.

In order to achieve this objective, G-TwYST will perform rat feeding trials with GM maize NK603 to test its potential subchronic toxicity, chronic toxicity and carcinogenicity. The studies will follow recently published EFSA recommendations in line with international standards and norms concerning feeding trials (OECD 408 and 453; under GLP conditions).

In addition, G-TwYST will define criteria to evaluate the scientific quality of long-term feeding studies and develop recommendations (scientific justification) on the added value of long-term feeding trials in the frame of the GMO risk assessment process. G-TwYST will inform stakeholders, the broader public and policy makers about the quality criteria for the evaluation and performance of (extended) feeding studies, their (added) value and necessity, and in this context will discuss broader societal issues. This will lead to an enhanced confidence in the GM food/feed risk assessment process by the public.

In the case of GM whole food/feed no internationally accepted specific guidelines for testing their chronic toxicity and carcinogenicity have been published up to now. Due to a request of the European Commission, EFSA recently provided supplementary guidance on key elements to be considered when performing a 2-year carcinogenicity trial in rats with whole food/feed based on the OECD Test Guideline 453. Based on the EFSA explanatory statement suggesting the incorporation of up to 50% maize into the feed when testing GM maize in a subchronic study, the OECD Test Guideline 453 as well as the scientific report by EFSA on the applicability of the OECD Test Guideline 453 to whole food/feed testing and taking into account possible concerns raised by a recent publication on the long-term toxicity of GM maize NK603, the G-TwYST consortium pursues the following detailed measures to achieve its overall objectives of informing risk assessors/policy makers, reducing scientific uncertainties and developing criteria to evaluate the scientific quality of long-term feeding studies:

1) Perform a 90-day study in rats with the GM maize NK603 at an incorporation rate of 11 and 33%;
2) Perform a 90-day study in rats with the GM maize NK603 at an incorporation rate of 11 and 50%;
3) Perform a combined 2-year chronic toxicity/carcinogenicity study in rats with the GM maize NK603;
4) Analyse and report the results of the feeding trials mentioned under 1) to 3);
5) Develop and define criteria to evaluate the scientific quality of long-term feeding studies;
6) Develop recommendations on the scientific justification and added value of long-term feeding trials for GMO risk assessment;
7) Allow for utmost transparency by making available plans, procedures, and protocols as well as results via an open access database;
8) Analyse the role of broader societal issues including ethical aspects (normative dimensions) issues in the ongoing debate about the animal studies in GM food/feed toxicity assessment;
9) Actively engage with risk assessment practitioners, risk managers, and a broad range of stakeholders in the two key steps of the project, the planning of the feeding studies and the interpretation of the results/conclusion of the studies;
10) Inform risk assessment practitioners, risk managers, a broad range of stakeholders, and general public about the results of the Project and their significance for GMO risk assessment through a website and by providing the media and policy institutions with media and policy briefs.

Project Results:
The first reporting period was essentially used to prepare the rat feeding trials (whole food/feed; subchronic, chronic toxicity, carcinogenicity) with maize NK603, and initial steps were undertaken to define the scientific quality of feeding trials and reconsider societal issues. An initially planned 2-year feeding study with MON810 was cancelled. Instead, an additional subchronic feeding trial with NK603 at a 50% incorporation rate of maize was included. This was done in accordance with a recent recommendation by EFSA (October 2014) to conduct tests with “high doses”. These changes were decided after a stakeholder consultation in Vienna in December 2014 and accordingly confirmed in an amendment to the Grant Agreement.

The EU projects G-TWYST and GRACE as well as the French project GMO90+ are joining efforts to generate and publish complementary data for feeding trials with transgenic maize using the same plant material and exchanging tissue samples. In March 2015 a joint meeting was held in Paris. A MoU was signed in spring 2016.

In December 2014 the maize material was imported to Europe. The material was analysed to ensure the quality for the further use in the feeding trials. A feed supplier was contracted after a public call for tender (contract signed May 2015). The feed material needed for the tests is produced on demand and shipped to the testing facility. Residues of maize kernels stored were attacked by a storage pest moth in autumn 2015, but successfully controlled through fumigation. Further batches for feed production will be analysed prior shipment. (WP2)

The study plans for the feeding trials have been elaborated, discussed with stakeholders and reviewed considering the stakeholder comments. Because of the high number of animals in the combined chronic toxicity and carcinogenicity feeding study, staff members of the test facility were trained to increase routine handling. Diagnostic wording was compiled and standardised in a glossary to enable a clear communication between interacting project partners when analysing the test results. The scheduled 2-year trial with 720 animals started in August 2015 and the first 90-day feeding trial with a 33% maximum inclusion rate of maize ended June 2016, while final analyses and data compilation are ongoing. (WP3)

The statistical planning of the feeding trials was tightly linked with the preparation of the study plans and intensely discussed at the stakeholder workshop in Vienna. Based on the data generated in the EU-funded project GRACE, the statistical planning for the analyses of the trials performed within G-TwYST is being conducted. The use of other data was analyzed, but ultimately these data were not deemed to be adequate for the planned G-TwYST feeding studies. The crucial element for a power analysis is to establish equivalence limits regarding the toxicological relevance of the results based on a toxicological-pathological consensus. (WP 4)

A literature review was conducted to identify quality criteria for the design of whole feed feeding studies as well as to survey compliance with these criteria. An expert workshop was held in June 2016 to discuss the relevance of the criteria. The criteria list has recently been published. An expert workshop on the further analysis of the normative dimensions of animal feeding trails with GMO and how they relate to the scientific aspects was held in early October 2016. A literature survey is ongoing. (WP 5)
The dissemination (open access) to detailed data is ensured by the web-portal CADIMA. The data generated by G-TwYST, GRACE and the French Project GMO90+ will become accessible in a standardised format to enable joint data analyses in the future. (WP6)

The first stakeholder consultation was held as a two-day workshop in Vienna in December 2014. This workshop was followed by a period for written comments. The main aim of this consultation was to discuss and improve the plans for preparation, conduct and analysis of the animal feeding trials.

An external web site representing G-TwYST and its activities, related topics and information has been launched ( (WP7)

Potential Impact:
The activities of the Project will result in the improvement of the design, conduct and interpretation of results of animal feeding trials for assessing the safety of GM food and feed. The project results and recommendations will enable risk managers and risk assessors to draw conclusions on the scientific value of and broader societal issues linked to long-term animal feeding trials in the framework of the currently applicable GM food/feed risk assessment requirements and procedures in the EU. The transparent communication strategy of the Project is being challenged by the tight timeline due the rearrangement of the experimental design after the stakeholder consultations in 2014 and the resulting delayed start of the actual feeding trials. Nevertheless, the communication strategy including stakeholder consultations and open access to detailed trial data allow any stakeholder to follow the project outcomes in detail and is a key element to build confidence in further decision making.

G-TwYST will
a) provide significant contributions to the scientific domain and to the controversy among scientists on the design, interpretation and conduct as well as the scientific value of long term feeding studies with GM plants;
b) support EU risk assessors, risk managers, and policy makers by providing scientific evidence on short- and long-term animal feeding studies with GM maize NK603 and MON810, quality criteria for evaluating such studies and recommendations regarding scientific the value of such studies in the risk assessment process of GM food and feed;
c) reduce the uncertainties on the design, interpretation and conduct as well as the scientific value of long term feeding studies and establish - in close cooperation with the EU-supported project GRACE - a transparent and inclusive process for scientific evaluation of research results from long-term feeding trials , thereby increasing overall confidence across the Member States in the EU risk assessment and management principles for GM food/feed;
d) inform EU risk managers and policy makers on broader societal issues linked to animal feeding studies in GM food/feed risk assessment and relevant to understand the controversy;
e) increase awareness amongst a broad range of stakeholders and general public of the rationale of food and feed safety assessment of GM plants and allow for a mutual learning experience of stakeholders and project members on the scientific and technical issues as well as the scientific value and broader societal issues associated with long-term feeding studies in the context of GM food/feed risk assessment;
f) facilitate discussions and allow for scrutiny by the scientific community, stakeholders and any other interested parties and thereby increase public and stakeholder confidence by applying utmost transparency and access to data. The project results and data will made accessible via the central access database CADIMA which was and is being developed by GRACE and PreSto GMO ERA Net. This database will bring together all relevant studies and data on GM food/feed toxicity assessment and will be continued after the end of the Project Access to all project documents developed for the planning stage and the interpretation and conclusions stage including draft version for commenting will be available at the project website.

G-TwYST will complement activities in key strategic areas including sustainable agricultural production, bio-resource efficiency, food safety and security and related socio-economic factors, regulations and decision-making including the involvement of stakeholder groups. The Project is entirely consistent with the overall objectives of the EC’s 7th Framework Programme on Knowledge Based Bio-Economy (KBBE): It will support exploitation of new and emerging technologies in crop production regarding the environmental and economic challenges, the growing demand for safer, healthier and higher quality food and the sustainable and efficient use of renewable bio-resources.
G-TwYST communication, stakeholder engagement, and transparency measures will be in line with principles of good governance, responsible research and innovation, and the upcoming EC Framework Programme Horizon 2020. These project tasks also reflect principles for food safety risk assessment developed by Codex Alimentarius and by EFSA. Thereby, the awareness and relevance of project results is likely to be higher compared to other research projects.

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