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Evaluation of testing transgenic plants in a 90-day animal study using trait-directed selection of sensitive and specific biomarkers

This result comprised a number of 90-day feeding and toxicity studies in rats, which are the core studies of the project.

The specific objectives of this task were to:
- Design an animal study with a selection of biomarkers, which will render the 90-day studies sensitive and specific to possible adverse effects of the tested transgenic rice strains.

- Test high amounts of the transgenic rice implemented in a purified diet to mimic and challenge the potential human exposure situation.

- Use pure recombinant protein spiked to the transgenic rice as the parallel positive controls.

Three 90-day studies addressing the safety of transgenic rice lines expressing PHA-E-lectin, GNA-lectin and Cry1Ab-protein were carried out. All transgenic rice lines were tested against the respective parental lines. In the study with PHA-E-lectin, an additional dose group given PHA-E rice spiked with pure recombinant PHA-E was included to increase the specificity of the study. The amounts of recombinant Cry1Ab-protein and GNA-lectin available were not sufficient to be used as spiking material and therefore no positive control group was included in either of these studies.

When assessing the safety of genetically modified crops the most common approach is to test whether the GM-crop is substantial equivalent to the conventional parental crop. In the present SAFOTEST project, it was the idea to include in the test design of the animal studies a third group where the rats should be given a diet based on the transgenic rice and spiked with either Bt toxin, GNA lectin or PHA-E lectin. The levels of the recombinant proteins added to the diets should correspond to the lowest observed adverse effect level, which should be identified in 28-day studies and in vitro studies. As mentioned earlier this concept was only possible to conduct for PHA-E rice, due to lack of Bt toxin and GNA lectin.

The 90-day studies with Bt rice GNA rice were therefore conducted s conventional safety studies where the transgenic rice was tested against its parental line.

In the study with Bt rice very few significant findings were observed. The most striking findings were a significant increase in testis and uterus weight of the rats fed Bt rice. When it comes to uterus weight, the female rats being in different stages of the estrous cycle could explain these differences. This is in accordance with observations of estrous related hyperemia and edema of the uterine wall of more animals in the group fed on Bt rice. The differences in testis weight could be explained by histopathological findings of degeneration of the seminiferous tubules.

In the study with GNA rice the most striking effect observed was increased water intake of both male and female rats fed GNA rice. Although not an adverse effect it self, it could indicate some kind of disturbance in the organisms of the rats resulting from a change in the chemical composition of the transgenic line. However, the compositional analysis of the GNA rice and the parental line did not reveal any changes that could be directly linked to an increase in water consumption.

The study with PHA-E rice following the original SAFOTEST concept with an additional group fed the PHA-E rice spiked with 0.1% pure recombinant PHA-E lectin was performed with only female rats, which in preliminary studies had shown to be the most sensitive sex towards the lectins.

In the group given PHA-E rice spiked with PHA-E lectin, a large number of parameters (body weight, food and water consumption, blood biochemistry, microbiology and organ weights) were found to be significantly affected compared to the group given parental rice. For some of the parameters significant differences were also seen between the group fed PHA-E rice and the group fed parental rice.

The outcome of the 90-day study with PHA-E rice showed that we by using the SAFOTEST concept could perform scientific meaningfully studies. The use of an additional group given the transgenic rice spiked with the recombinant protein, the so-called positive control, did not increase the sensitivity of the study. However, it enables us to demonstrate the sensitivity and specificity of the study and thereby to increase the confidence to the animal model used.

More information on the project can be found at:

Reported by

Danish Institute for Food and Veterinary Research
Morkhoj Bygade 19
2860 Soborg
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