Toxicological assessment of novel (including GM) foods

1998: This paper briefly reviews the role of toxicological studies in the safety assessment of GM foods and focuses on the pros and cons of subjecting such foods to long term feeding studies. It does not aim to address the testing of novel foods for possible allergic reactions which is a separate, specialised, safety issue.

Summary
There has been much media interest in the safety of GM foods in recent months with several groups, including consumer and environmental Non Governmental Organisations suggesting that all GM foods should be subject to long term animal feeding studies before approval.

This paper was considered by the ACNFP at its 39th meeting on 24 September 1998. It briefly reviews the role of toxicological studies in the safety assessment of GM foods and focuses on the pros and cons of subjecting such foods to long term feeding studies. It does not aim to address the testing of novel foods for possible allergic reactions which is a separate, specialised, safety issue.

The Committee considered that long term feeding studies should be carried out where it is relevant and appropriate to do so. However each case needs to be considered on its merits as complicating factors, in the design and interpretation of such studies when applied to foods as opposed to pure chemicals, mean that it is unlikely that they would give rise to meaningful information in all cases. Nevertheless, a detailed data package must be provided under EU Guidelines to facilitate a rigorous safety assessment and the appropriateness of long term feeding studies is considered on a case by case basis.

Introduction
Animal studies are a major element in the safety assessment of many compounds such as pesticides, pharmaceuticals, industrial chemicals and food additives. In most cases, the test substance is well characterised, of known purity, of no nutritional value and human exposure is generally low. It is therefore relatively straightforward to feed such compounds to animals at a range of doses, some several orders of magnitude greater than the expected human exposure levels, in order to identify any potential adverse effects of importance to humans. In this way it is possible, in most cases, to determine levels of exposure at which adverse effects are not present, and so set safe upper limits by the application of appropriate safety factors.

By contrast, foods are complex mixtures of compounds characterised by wide variation in composition and nutritional value. Due to their bulk and effect on satiety they can usually only be fed to animals at low multiples of the amounts that might be present in the human diet. In addition, a key factor to consider in conducting animal studies on foods is the nutritional value and balance of the diets used, to try to avoid the induction of adverse effects which are not related directly to the material itself. Picking up any potential adverse effects and relating these conclusively to an individual characteristic of the food can therefore be extremely difficult. Another consideration in deciding the need for animal studies is whether it is appropriate to subject experimental animals to such a study if it is unlikely to give rise to meaningful information.

Very few foods consumed today have been subject to any toxicological studies. The safety assessment of the many thousands of food products launched each year in the UK is generally based on the assumption that since individual ingredients already have an extensive history of consumption a new combination of such ingredients will be equally safe. Nevertheless many existing foods would be likely to show adverse effects if they could be fed at high enough doses.

Safety assessment of novel foods
One of the first novel foods to be formally assessed in the UK was the mycoprotein 'Quorn'. At roughly, the same time the safety of irradiated foods was assessed through a vast array of animal feeding studies. In both cases practical difficulties were encountered. In contrast to many non nutritive substances, foods are intended to be consumed by man at levels which approach the maximum dose that could be used in animal studies. Toxicological studies are designed to characterize the toxicological profile of individual chemical substances not complex substances such as foods. Long-term feeding of high levels of individual 'foods' to animals can result in nutritional imbalances which make interpretation of such studies extremely difficult. Table 1 compares the differences between the safety assessment of chemicals and foods.

Table 1 Differences between Chemical and Food Toxicity Evaluation1

Chemical Food
Material usually simple, chemically precise substance Complex mixture of many compounds
Highest dose level should produce an effect Effects improbable at the maximum dose level that can be incorporated in the diet for the test species
Small dose (usually less than 1% of diet) High intake (usually greater than 10%)
Easy to give excessive dose Intakes above those normally present in the diet difficult
Acute effects obvious Acute effects difficult to produce (usually absent)
Generally independent of nutrition Nutrition dependent
Specific route of metabolism simple to follow Complex metabolism
Cause/effect relatively clear Cause/effect, if observed at all, may be confused

Substantial Equivalence
Recognising that traditional safety assessment techniques based on toxicological testing may not be applicable in the case of most foods or food ingredients produced by biotechnology the FAO and WHO held a consultation in 1990 to address the problem.

This recommended that safety assessment strategies be based on a consideration of the molecular, biological and chemical characteristics of the food to be assessed and that this should determine the need for, and scope of, traditional toxicological testing.

The consultation also established the comparative principle whereby the food being assessed is compared with one that has an accepted level of safety. In 1991 the OECD³ expanded upon this and formulated the concept of substantial equivalence. This was based on the concept that if a food or food ingredient under consideration can be shown to be essentially equivalent in composition to an existing food or food ingredient then it can be assumed that the new food is as safe as the conventional equivalent. The WHO and FAO refined the concept at an expert consultation meeting held in Rome in 1996. In the report of this meeting4 substantial equivalence was identified as being 'established by a demonstration that the characteristics assessed for the genetically modified organism, or the specific food product derived therefrom, are equivalent to the same characteristics of the conventional comparator. The levels and variation for characteristics in the genetically modified organism must be within the natural range of variation for those characteristics considered in the comparator and be based upon an appropriate analysis of data.'

Before a comparison can be undertaken it is necessary to characterise the GM variety to ensure that the appropriate characteristics are assessed. The 1996 FAO/WHO report identifies a number of pieces of information that will be of use in this respect. In addition to details of the host organism and details of how the host has been modified it is necessary to characterise the food product itself. It is essential to look not only for intentional changes but also to consider any unintentional changes. In characterising the food product it is important to consider both phenotypic characteristics and compositional analysis. The type of phenotypic characteristics assessed for a GM plant would include crop morphology, growth, yield and disease resistance. In assessing the composition of the GM product the FAO/WHO report identified the need to consider key nutrients and toxicants of the food in question. The report also commented that 'analysing a broader spectrum of components is generally unnecessary, but should be considered if there is an indication from other traits that there may be unintended effects of the genetic modification'. This approach to the assessment of GM foods is now accepted and applied worldwide.

Following a comparison of the GM product with a conventional counterpart, three outcomes are possible:

The GMO or food product obtained from it is substantially equivalent to a conventional counterpart.

The GMO or food product obtained from it is substantially equivalent to a conventional counterpart except for a few clearly defined differences.

The GMO or food product obtained from it is not substantially equivalent to a conventional counterpart - either because the differences cannot be defined or because there is no existing counterpart to compare it with.

Where a food can be shown to be substantially equivalent it is considered to be as safe as its counterpart and no further safety assessment is required. Where there are clearly defined differences between the GM food and its conventional counterpart the safety implications of the differences need to be fully assessed. Where a food is not substantially equivalent it does not mean that the food is unsafe. However, there would be a need for extensive data (which might include the results of animal feeding studies if considered appropriate) to be provided before the product's safety can be fully assessed.

ACNFP Decision tree
In 1990 the ACNFP developed a decision tree to indicate the types of information that were likely to be required for individual novel foods. This leads into a series of structured questionnaires depending upon the exit point. The ACNFP considered the role of animal studies in the safety assessment of novel foods when constructing this approach. At that time, it was decided that, while such studies could be an important tool in the testing armoury in certain specific circumstances, they were not likely to be universally applicable for the reasons given earlier. The Committee reaffirmed this view when it reviewed the decision tree in 1994 following a public consultation exercise.

To ensure that all member states follow a similar approach to the safety assessment of novel foods, the SCF has recently produced a detailed set of guidelines setting out the type of information that would be expected to support an application for approval of a novel food. These guidelines draw upon the structured approach developed by the UK's ACNFP. The need for animal studies is considered on a case by case basis. A copy of the relevant section from the SCF guidelines is attached at annex 1.

Conclusions
The ACNFP's approach to the safety assessment of novel foods, based on the concept of substantial equivalence, is fully consistent with the guidelines that accompany the EC Novel Foods Regulation and mirrors those used elsewhere in the world.

Animal tests represent an important tool in certain specific circumstances but the need for them should continue to be decided on a case by case basis. There is no scientific justification for insisting that all GM foods should be subject to long term feeding studies as such an approach would be unlikely to produce meaningful information in the vast majority of cases.

References
1. Based on a paper in OECD 1996 Food Safety Evaluation, OECD, Paris

2. Strategies for assessing the Safety of Foods Produced by Biotechnology. Report of a joint FAO/WHO consultation, WHO Geneva 1991

3. Safety Evaluation of Foods Produced by Modern Biotechnology - concepts and principles, OECD Paris 1993

4. Biotechnology and Food Safety, Report of a joint FAO/WHO consultation Rome 30 September - 4 October 1996, FAO Food and Nutrition Paper 61 1996