PGS is blazing a trail for the biotechnology industry with its application for marketing approval for its transgenic oilseed rape. Although Member States and the European Commission have already approved a few applications for commercial release - including that of a genetically engineered tobacco crop - PGS's rape is the first transgenic crop likely to be grown on a large scale in several EC countries. As Such, it is running the gauntlet of scientists and environmental groups who remain unconvinced that trials of the PGS crop to date have yielded sufficiently reassuring data about its safety for man or the environment.
The plant breeding industry has hailed the arrival of genetic engineering techniques as a quantam leap forward from traditional, hit and miss, crossing techniques to a speedier and more predictable process. PGS's Regulatory Affairs Manager, Patrick Ruddlesheim, points to estimates of increased yields of 20-25% for other transgenic oilseed rape hybrids, but says it is too early to give specific estimates for PGS's own crop.
The company intends its modified rape to be used for the same range of applications as conventional rape, which include use in margarine, vegetable oil, animal feed, industrial feedstock and, more recently, as a biofuel. Proponents of biodiesel have been eagerly awaiting the new modified rape as it could boost the economic attractions of the plant as a fuel.
PGS says that its product will offer seed companies a "100% guaranteed" method of growing only the required hybrid plant. The system is designed to prevent self-pollination of plants, which leads to reduced vigour of crops in successive generations. This is achieved by crossing two genetically engineered lines, one of which is male sterile.
The genes introduced in the two lines come from four species of bacteria and two other plants - tobacco and a herbaceous plant, arabidopsis. "Guarantees" are built into the system in the form of two "marker genes" which have been widely used in transgenic crops. One of these makes the seeds resistant to an antibiotic, kanamycin, enabling in vitro selection of successfully engineered cells by treating them with the antibiotic. The second makes the seeds tolerant to herbicides based on phosphinothricin, a property intended to be used during the very early stages of shoot formation to select only the required hybrid plants.
The controversy over PGS's product centres on the presence of the two marker genes. PGS addressed some of the arguments in a summary of its application placed on the public register last April when it was considered by the Government's Advisory Committee on Releases to the Environment (ACRE).
One aspect considered by PGS was that its transgenic oilseed rape may become more invasive or weedy than ordinary oilseed rape because of the protection afforded by its herbicide tolerance gene. This would exacerbate the growth of oilseed rape as a weed in hedgerows, roadsides and wastelands.
Herbicide resistance implications
PGS concluded that its product would only have a competitive advantage over other species in the presence of the herbicide. Otherwise, it said, "there has been no intended or unintended change in the basic biology of the crop plant making it more 'weedy'." In wild areas, where phosphinothricin is not applied, there is unlikely to be competitive advantage. PGS ruled out the possibility of unintentional exposure to the herbicide through dispersion via water or wind on the grounds that the chemical has a relatively short lifetime.
In managed situations, where oilseed rate is grown as a crop, PGS says that "since products based on phosphinothricin are not used today for the control of "volunteer" oilseed rape in subsequent cropping, no particular problems are anticipated." Volunteer plants are those from previous growing seasons which grow amongst different crops subsequently planted in the same field. Dr Ruddlesheim said he was sure that companies selling such products would not get approval for spraying it on the herbicide-resistant rape as a method of weed control. He also said the PGS would label the seed to warn farmers that it was resistant to phosphinothricin.
PGS points out that it has carried out more than 40 field trials over three years and these have not found the modified oilseed rape to be any more invasive than ordinary rape. It therefore concludes that the likelihood of this in reality will be "negligible". Still, it observes somewhat blithely that if its product did cause a weed problem, this could be dealt with by herbicides or some form of mechanical control.
Another outcome considered in PGS's risk assessment was the likelihood of the novel genes in its plants being transferred to wild relatives of oilseed rape such as hoary mustard and linseed, both of which are found near oilseed rape plantations in the UK. PGS's application says that on the basis of "models" it has used to judge the likelihood of this happening, it considers the probability to be "extremely low" and the likely consequences of such an occurrence as "negligible".
Taking a somewhat less conservative line, PGS's Dr Ruddlesheim told ENDS: "No-one is arguing about the fact that the genes will be transferred. But we will argue about the extent to which they will be transferred and what the consequences of this will be." Again, he contended that such an event would only pose a problem if phosphinothricin herbicides were used in unmanaged areas.
Greenpeace contested PGS's conclusions in a letter to the chairman of ACRE. The group said that the company was wrong to dismiss the possibility of phosphinothricin herbicides being used to control volunteer oilseed rape. It pointed out that the active ingredient is already licensed for use in the UK to control weeds growing amongst potato and french bean crops - including volunteer plants such as oilseed rape.
The group also points to a more ominous development. The German chemical firm Hoechst has recently conducted trials with modified oilseed rape. Their apparent purpose was to support the registration with the Ministry of Agriculture, Fisheries and Food (MAFF) of the use of its phosphinothricin herbicide, Challenge, on the transformed rape. Greenpeace is concerned that a proliferation of crops engineered for resistance to particular herbicides will lead to increased use of chemical means of control and to the spread of herbicide tolerance.
The group takes a purist view of the likelihood of the "foreign" genes in PGS's oilseed rape being transferred to wild relatives. It describes this as "genetic pollution" because the genes would not have been transferred by natural means, and says the consequent damage will be "fundamental and irreversible".
Greenpeace was also critical of PGS's statement that even if a weed problem did arise, other control mechanisms could be used. "If susceptibility to some herbicide or other alone were the determining factor in weed control, weeds would not be the problem they are...It may take a considerable period of time to recognise that there has either been transfer of the herbicide resistance gene to weedy relatives or that the oilseed rape has become a problem itself." Several different herbicides may be applied in the interim with potentially damaging consequences for other plants and surface and groundwaters, it warned.
Greenpeace also gave voice to a concern raised by several scientific bodies over the last two years - that field trials of transgenic crops yield only limited information because safeguards are put in place to contain potential risks and because their duration is often limited to one generation.
For instance, a recent OECD report summarising the knowledge gleaned from over 1,000 field trials of transgenic crops since 1986 states: "The requirement for reproductive isolation [for small-scale field trials] has significantly limited the amount of biosafety information that can be gathered from releases which have taken place to-date and which can be used in establishing biosafety measures in relation to scale-up."1 Greenpeace sums up: "Although the estimated frequency of a harmful event happening is low, the potential scale of the release is enormous. Therefore rare events will occur."
In April, ACRE approved PGS's oilseed rape for marketing, essentially accepting the company's risk assessment. However, there was one dissenting voice among its 12 members. Julie Hill, Director of the Green Alliance, objected on the grounds of the uncertainty about the degree to which modified genes may be transferred to wild species, and whether this will enable them to resist weed control methods and result in contamination of the gene pool.
Speaking in her capacity as Director of the Green Alliance, Ms Hill has since pointed out that there are other issues that need to be addressed. Under the Environmental Protection Act 1990, the objective of the approval system for releases is to prevent or minimise "harm" to living organisms, but the term has not been defined in a way which would guide ACRE or other regulators in considering whether it matters that novel genes will escape into the environment.
Ms Hill has also recently voiced other general concerns about the regulatory process based on four years' experience as a member of ACRE. She notes that even though ACRE is the body advising on whether marketing approval should be given to crops, the wider implications, such as the impact on herbicide use, are considered to be outside its remit.
Similarly, when ACRE considers applications for permission to carry out field trials, it is restricted to commenting solely on that application, and cannot raise concerns about potential impacts if the modification in question was to be applied on a commercial scale. In a briefing document published in November, the Green Alliance proposed the creation of a non-governmental national Biotechnology Commission comprising consumer, environmental and industry groups which could debate the wider issues raised by genetic engineering and feed their views to the relevant Government Departments.2Fingers point to MAFF as the body responsible for assessing these wider issues. MAFF's thinking on the implications of the release of herbicide resistant crops was outlined in a paper published last year by the Director of Policy at its Pesticides Safety Directorate (PSD), Dr John Bainton.3According to Dr Bainton, "the development of herbicide resistant crops may have both benefits and disbenefits for agriculture, the environment generally and possibly for the health and safety of people and of animals who may be exposed to those crops. However, herbicide resistant crops do no form a uniform group with similar properties or implications. Each one will have to be assessed on its merits for the foreseeable future."
"Subject to the safety requirements being met," Dr Bainton added, "the assessment of the value of the benefits is for the market to decide. However, where farmers seek advice on these crops, it would be advisable to draw attention to their potential disbenefits to farmers as well as their advantages."
Over 97% of arable crops in the UK were treated with herbicides in 1990. But Dr Bainton argued that it is unwise to speculate whether the development of herbicide-resistant crops will lead to increased herbicide applications because usage already fluctuates from year to year and from crop to crop. "It is consequently not possible to predict accurately how levels of herbicide usage would change following the introduction of new resistant crops. There is, however, no evidence which would suggest that herbicide use would increase."
"Although foreseeable risks to health and the environment can be prevented there remains the possibility of unforeseen problems arising," he concluded. "Thus there will be a need to monitor, to be alert for any unforeseen problems, and to take appropriate action."
However, one of the other issues raised by Ms Hill is that the regulatory system places no duty upon companies to monitor the environmental impacts of their crops once they have been cleared for marketing. They are simply required to inform the authorities if any new evidence of damage comes to light.
ENDS understands that the Department of the Environment is commissioning a one-off study to monitor the environmental impacts of crops grown on a commercial scale, with the PGS crop a likely candidate. But this does not address the general problem.
A further issue raised by the Green Alliance is the need for more effective means of public consultation before approval is given for field trials of GMOs. At present, companies are obliged to advertise in local newspapers in advance of releases and a summary of their application is placed on the public register. But Ms Hill points out that new fast track procedures for applications introduced in the last year have curtailed the time available for public comment on releases.
To facilitate public participation, she proposes a new mechanism to enable interested parties to request public hearings at short notice where a planned release raises important principles or new concerns. The DoE has taken note of this problem. In a discussion paper issued in December, it proposed increasing the time available for public comment where applications are made under fast-track procedures.4EC dispute
PGS applied for marketing approval in the UK because it intends to sell its product first here. However, under the EC Directive on deliberate release of genetically modified organisms (GMOs), approval in any one country paves the way for EC-wide marketing authorisation. If any country objects to the authorisation, then the final decision is taken on the basis of a qualified majority vote. Denmark is understood to have objected to the authorisation for PGS's crop. In December, Member States were voting on the application through a written procedure.
Denmark's objections are understood to rest on two concerns: that the implications of marketing herbicide-resistant plants on the level and pattern of use of herbicides are not taken into account at the time the crop is authorised, and that there is still uncertainty over the degree to which genes will be transferred to wild relatives. Denmark's Danish Environment Minister raised the issue at the EC Environment Council in December. However, other Ministers simply took note of his statement and said it would be taken up by the appropriate experts.
The same objection was raised earlier this year when Member States considered an application to market a genetically engineered tobacco plant which is resistant to the herbicide bromoxynil. Approval was finally given but the text of the Commission's decision states that the authorisation of chemical herbicides applied to plants and assessment of the impact of their use on the environment falls within the scope of another item of legislation - the 1991 EC Directive on pesticide authorisation - and not within the scope of the Directive on deliberate release of GMOs under which the tobacco was assessed for marketing approval.5Green members of the European Parliament were outraged by this development and are planning to challenge the Commission's ruling on tobacco early next year. They contend that it was based on a false premise inasmuch as the pesticide authorisation Directive does not authorise regulators to assess the likelihood of increased herbicide use where genetically modified resistant crops are grown.
Another aspect of the PGS product that has raised concern is its resistance to the antibiotic kanamycin. This is recommended as a treatment for infections in humans where resistance to other antibiotics has developed. It is also recommended for treatment of a variety of infections, including tuberculosis, in animals. The worry is that by ingesting foods containing the antibiotic-resistance gene the trait may be transferred to bacteria in humans or animals and render them resistant to treatment.
ACRE made it clear when it approved PGS's oilseed rape that it had no authority to sanction its sale for human food or animal feed purposes, and that separate approval would have to be obtained for these uses. PGS duly applied voluntarily to MAFF's Advisory Committee on Novel Foods and Processes (ACNFP), which was due to give its advice to Ministers on the application in December.
ENDS understands that the ACNFP is minded to approve PGS's crop for human consumption. However, it is not clear whether any conditions will be attached to its use because both the ACNFP's deliberations and its final advice to Ministers are confidential. A MAFF spokesman also told ENDS that it is up to the company to make details of its application public because MAFF would presume it was commercially sensitive.
The ACNFP published a report in July assessing in general the potential for spreading antibiotic resistance genes through novel organisms.6 It concluded that the most likely danger is the possibility of transferring marker genes to gut micro-organisms which would subsequently express the same trait. The greatest likelihood of this happening would be if live, genetically modified food bacteria were to be ingested.
The risk from genetically modified plant material eaten raw or from uncooked seeds would be "far less likely", and that from highly processed food bacteria or plant material "least likely of all". Nevertheless, the ACNFP recommended that "the use of antibiotic resistance marker genes in foods from genetically modified plants and from non-viable genetically modified micro-organisms should be evaluated on a case-by-case basis". In each case, the clinical use of the antibiotic, the likelihood of transfer of the gene into gut micro-organisms and the toxicity of the gene product should be considered. It further recommended that "researchers developing food GMOs should be encouraged to develop and use alternatives to antibiotic resistance markers and/or methods to jettison those used."
A major point of concern from a human health standpoint is that companies are not obliged to submit their products to the ACNFP for approval, although the Government has long promised to make this mandatory. A MAFF spokesman told ENDS that "if companies are spending time and money on researching a new product, it is in their own interest to get this kind of approval...If they do not then Ministers might in the future ban it or recommend it is taken off the shelves." Just how this would address the spread of antibiotic resistance once it had occurred remains open to question.
Moreover, the Genetics Forum, a London-based group funded by several environmental organisations and institutions, says the damage may be caused while the crop is in the field. For example, it suggests that genes may be spread along the food chain if the oilseed rape is eaten by slugs which are then eaten by higher animals such as badgers. Tuberculosis already poses a major threat to the UK's badger population and their resistance to kanamycin could prove an unhelpful development.
As for the use of the rape as an animal fat, MAFF's Veterinary Medicines Division (VMD) told ENDS that at present there is no statutory process for approving material for this purpose, although one is being developed at EC level. In the meantime, a new body - the Inter-departmental Group on New Food Materials - has recently been established to prepare guidelines for manufacturers who have requested an official stamp of approval for their products.
The VMD says the SCNFP recommendations echo its own view - that it would prefer companies not to use antibiotic resistance markers. It says that alternatives are now being developed and that theoretically there is no reason why companies cannot remove markers from plants once they have served their purpose. However, it points out that in the case of oilseed rape its use as an animal feed should place it in a low risk category because it would be processed once to remove oils for human consumption and again to create the feed.
PGS's rapeseed is a harbinger of the challenges that regulators will face as they seek to ensure that no new risks are posed to humans or the environment by these novel crops. Regulators, scientists, the public and, despite their protestations to the contrary, industrialists, are entering uncharted waters.
The wide-scale growth of a large number of crops, sometimes in close proximity, each of which may be deliberately engineered in different ways to be resistant to a variety of herbicides, is a new phenomenon. The spread of antibiotic resistance is no less formidable a prospect. These concerns led support to the arguments of those calling for a body to given responsibility for assessing the wider implications of such releases in the long term - as well as the closure of the gaps which are already apparent in regulatory system.