Genetic Engineering (GE) and Omitted Health Research: Still No Answers to Ageing Questions

By Terje Traavik, PhD, DVM and Jack Heinemann, PhD
November 2, 2006

Introduction

Some of the most crucial scientific questions concerning health effects of GE and GEOs (genetically engineered organisms) were raised up to twenty years ago[1]. Most of them have still not been answered at all, or have found unsatisfactory answers. We believe, as Mayer and Stirling[2] said, "in the end it is often the case that those who choose the questions determine the answers". Will another twenty years pass before societies realize the urgent need for public funding of genuinely independent risk- and hazard-related research? The time for such investment is now so that a new scientific culture with working hypotheses rooted in the Precautionary principle (PP)[3] can discover other, possibly even more important questions of safety.

In the present article we will mainly confine ourselves to putative health hazards related to GE plants (GEPs) used as food or feed, with some brief notes on GE vaccines as well as the novel si RNA- and nanobio-technologies. This does not mean that we do not recognize the paramount, indirect threats to public health posed by social, cultural, ethical, economic and legal issues.

In the specific context of food or feed safety assessment "hazard" may be defined as a biological, chemical or physical agent in, or condition of, food with the potential to cause an adverse health effect. The hypothetical hazards of whole GM foods, i.e. those hazards that have been realized so far, fall into a few broad categories. They are either related to the random and inaccurate integration of transgenes into recipient plant genomes, uncertainty with regard to direct or indirect effects of the polypeptide product of the transgene, or uncertainty with regard to DNA types and circumstances promoting uptake and organ establishment of foreign DNA from mammalian gastro-intestinal tracts[4].

A number of scientific concerns have been raised in connection with public and animal health. In the following we will discuss, in some detail, a few of these. Some of them have been thoroughly discussed in excellent, very recent reviews[5].

Our contribution is based on "gene ecology"; a new, cross-disciplinary scientific field intended to provide holistic knowledge based on the precautionary principle[6].

Some of the concerns we raise will also be relevant for environmental risk assessments of GEOs due to the fact that the processes discussed can take place in an ecosystem at large as well as in the ecosystems represented by mammalian organisms.

Do we know that any GE food/feed is safe for consumption?

For a composite material like food/feed, reductionistic approaches testing single components in vitro are highly unsatisfactory and cannot by definition clarify important safety issues. In spite of the obvious need, very few studies designed to investigate putative effects of GE nucleic acids or food/feed on potential animal or human consumers have been published in peer-reviewed journals[7]. A consensus has emerged that the effects observed in some published studies[8] must be experimentally followed up. To this day, this has not been done.

Most of the animal feeding studies performed so far have been designed exclusively to reveal husbandry production differences between GEOs and their unmodified counterparts. Studies designed to reveal physiological or pathological effects are extremely few, and they demonstrate a quite worrisome trend[9]: Studies performed by the industry find no problems, while studies from independent research groups often reveal effects that should have merited immediate follow-up, confirmation and extension. Such follow-up studies have not been performed. There are two main factors accounting for this situation: The lack of funds for independent research, and the reluctance of producers to deliver GE materials for analysis[10].

Can we rely on the transgenic DNA sequences given by GE food/feed producers?

If the transgenic DNA sequences given in the notifications differ from the inserted sequences found in the GEPs, the risk assessments made prior to approval of the GEPs for marketing do not necessarily cover the potential risks associated with the GEPs.

The most thoroughly studied transgenic events are:

Even amongst the most thoroughly studied and some of the oldest commercial GEPs, recent independent work has revealed that the nature of the rearrangements vary, and deletions (Mon810, GA21, Bt176), recombinations (T25, GTS 40-3-2, Bt176), tandem or inverted repeats (T25, GA21, Bt176) as well as rearranged transgenic fragments scattered through the genome (Mon810) have been reported[11].

The transgenic modification techniques are prone to introduce such rearrangements because exogenous DNA transfer in plants elicits a "wound" response, which activates nucleases and DNA repair enzymes. This may result in either degradation of the incoming DNA, or insertion of rearranged copies into the plant DNA[12]. In addition, the nature of the DNA constructs used to make transgenic plants may influence the rearrangement tendencies for a given transgenic event. Some genetic elements in the constructs may act as "hotspots" and elicit recombinations at high frequencies[13].

While it was earlier assumed that integration of transgenic constructs took place at random locations in the recipient plant genome, it has now become apparent that integration sites are concentrated in or near elements such as retrotransposons (T25, Mon810, GA21) and repeated sequences (Bt11 maize)[14], and this poses additional risks. Firstly, by introducing a new promoter or new enhancer motifs, transgenic insertions into, or close to, such elements may lead to altered spatial and temporal expression patterns of plant genes located close to and even far from, the insert. Secondly, a strong retrotransposon LTR promoter may upregulate the transgene expression level. Thirdly, defective retrotransposons may start "jumping" under the influence of transacting factors recruited by the insert[15]. All these events may have unpredictable effects on the long-term genetic stability of the GEOs, as well as on their nutritional value, allergenicity and toxicant contents. These putative processes represent areas of omitted research with regard to health effects of GEOs.

Are transgenic DNA and proteins taken up from mammalian GIT (gastro-intestinal tracts)?

If DNA and proteins from GEOs persist in, and are taken up from mammalian GIT, this could theoretically, as will be further explained below, ultimately lead to development of chronic disease conditions. The fate and consequences of DNA persistence and uptake is, however, not extensively studied, and therefore represents yet another area of uncertainties connected to GEPs.

It has generally been claimed that DNA and proteins are effectively degraded in mammalian GITs. This has been based on assumptions that have never been systematically examined[16]. A restricted number of recent publications have demonstrated that foreign DNA and also proteins may escape degradation, to persist in the GIT and even to be taken up from the intestines and transported by the blood to internal organs in biologically meaningful versions[17]. These findings should not have come as such a surprise, since scientific articles from the 1990s[18] strongly indicated that this was an area of omitted research, as stated by a number of reports[19].

Briefly summarised, the present conception of DNA persistence and uptake includes long fragments of ingested DNA. DNA may be detected in the faeces, the intestinal wall, peripheral white blood cells, liver, spleen and kidney, and the foreign DNA may be found integrated in the recipient genome. When pregnant animals are fed foreign DNA, fragments may be traced to small cell clusters in foetuses and newborns. The state of GIT filling, and the feed composition may influence DNA persistence and uptake. Complexing of DNA with proteins or other macromolecules may protect against degradation.

So far only two published reports have investigated the fate of foreign/transgenic DNA in humans[20]. The consequences of DNA persistence and uptake thus represent yet another area of omitted research. Extrapolating from a number of experiments in mammalian cell cultures and in experimental animals, it is conceivable that in some instances insertion of foreign DNA may lead to alterations in the methylation and transcription patterns of the recipient cell genome, resulting in unpredictable levels of gene expression levels and products. Furthermore, even small inserts may result in a so-called "destabilisation" process, the end-point of which may be malignant cancer cells[21].

The BSE/new variant Creutzfeld-Jacob's Disease epidemics caused by the prion proteins painfully illustrated the phenomenon of protein persistence, uptake and biological effects. Two recent publications indicate that this phenomenon may be more general that realized[22]. A hallmark of prion diseases and a number of other debilitating, degenerative diseases, i.e. Alzheimer's and Huntington's diseases, is deposition of "amyloid fibrils". Recent studies indicate that any protein can adopt a confirmation known as "amyloid"[23] upon exposure to appropriate environmental conditions. Whether that is the case for GE food/feed that is already in the marketplace is unknown.

The consequences of protein persistence and uptake will vary with the given situation. Generally spoken there is a possibility that toxic, immunogenic/allergenic or carcinogenic molecules may gain entry to the organism via cells in the gastrointestinal walls. The persistence of the Bt-toxin Cry1Ab in faeces means a potential for spread on the fields through manure. The ecological effects, e.g. on insect larvae and earthworms[24], are at the moment an issue of shear speculation.

Have the protein contents of GE food been altered in unpredictable ways?

Transgenes or upregulated plant genes may give rise to toxicants, anti-nutritients, allergens and, putatively, also carcinogenic or co-carcinogenic substances. The concentration of a given transgenic protein may vary according to the location(s) in the recipient host cell genome of inserted GE construct DNA, and to environmental factors influencing the activity of the transgenic regulatory elements, e.g. the 35S CaMV promoter. The biological effects of a given transgenic protein, e.g. the Cry1Ab Bt-toxin, may be unpredictably influenced by posttranslational modifications, alternative splicings, alternative start codons for transcription, chimeric reading frames resulting from integration into the reading frame of a plant gene, and complex formation with endogenous plant proteins.

The influence of foreign DNA insertion on endogenous plant gene expression patterns may vary with local environmental factors, the actual insertion site(s), the number and stability of the inserts, transgenic promoter effects, methylation patterns of the insert(s), and post-transformational mutations in the transgenic protein coding as well as in regulatory sequences. Even a single nucleotide change may affect the properties of a protein, or it may create a new transcription factor-binding motif. Detailed studies of these phenomena under authentic conditions are lacking, and hence we are confronted with yet another area of omitted research.

May GE food/feed give allergies?

One of the major health concerns related to GEPs is that the transgenic product itself, e.g. a Bt toxin, or changed expression of endogenous plant genes may result in allergenic compounds. The risk assessment of allergens often follows an allergenicity decision tree[25]. These "trees" are based on in vitro tests comparing a limited number of structures, usually only one, of the transgenic protein with known allergens. Hence, these comparisons are hopeful that the protein isolated for the test matches all proteins produced from the same gene in the GEP. But in fact this is unlikely because allergenicity tests are usually carried out with bacteria-, not in planta-produced versions of the transgenic protein. Glycosylation invariably takes place in plants, but not in bacteria, so this form of post-translational modification of both the transgenic protein and endogenous proteins would not be tested. Allergenic characteristics of proteins, and also their resistance to degradation in the organism, can be affected by glycosylation. Other protein modifications may also take place, adding to the unpredictability of transgenic products[26].

Another important question related to allergenicity is whether post marketing surveillance can provide useful information about allergens in GE foods. For a number of reasons this is not likely to happen[27]. Treatment of allergy is symptomatic, whatever the cause may be. The allergic case is often isolated, and the potential allergen is rarely identified. The number of allergy-related medical visits is not tabulated. Even repeated visits due to well-known allergens are not counted as part of any established surveillance system. Thus, during the October 2000 Starlink episode, it proved very difficult to evaluate Starlink (containing Bt-toxin Cry9C) as a human allergen[28]. An additional reason for this was that the ELISA tests, used by FDA, that found no anti-Cry9C antibodies in suspected human cases were dubious because bacterial, recombinant antigens were used instead of the Cry9C maize versions that the individuals had been exposed to.

Case: Bt toxins in Bt-transgenic GEPs

It is very important to be aware of the fact that the Bt-toxins expressed in GEPs have never been carefully analysed, and accordingly, their characteristics and properties are not known. What is clear from the starting point, however, is that they are vastly different from the bacterial Bacillus thuringiensis protoxins, used in organic and traditional farming and forestry for decennia[29]. The difference is evident already at the gene level, since the versions found in GEOs are engineered to produce active Bt toxins. By extrapolation these have a number of potentially unwanted biological characteristics, ranging from solubilization of the protein under natural conditions and effects on insect and mammalian cells, to persistence and non-target effects in the environment[30]. In addition, the posttranslational modifications that may influence conformations, cellular targets and biological effects of GEP-expressed Bt-toxins are unknown, and hence we once more identify an area of omitted research.

During the last few years a number of observations that may be conceived of as "early warnings" of potential health and environmental risks, have appeared in the literature[31]. Most of them have, however, not been followed up by extended studies.

Case: Transgenic, glyphosate-tolerant (Roundup Ready) GEPs

These GEPs have an inserted transgene, cp4 epsps, coding for an enzyme that degrades the herbicide glyphosate. The whole idea is of course the combined use of the GEP and the herbicide. Recent studies indicate that in some cases such GEPs are associated with greater usage of glyphosate than the conventional counterparts[32]. A very restricted number of experimental studies have been devoted to health or environmental effects of the GEPs or the herbicide itself. Some of these may be considered "early warnings" of potential health and environmental risks, and they should be rapidly followed up to confirm and extend the findings[33]. Consequently: yet another area of omitted research.

Is the 35S CaMV promoter inactive in mammalian cells?

Cauliflower mosaic virus (CaMV) is a DNA-containing para-retrovirus replicating by means of reverse transcription (Poogin et al., 2001). One of the viral promoters, called 35S is a general, strong plant promoter. It has been used to secure expression of the transgenes in most of the GEOs commercialized so far.

Industry proponents have claimed unconditionally that the 35S is an exclusive plant promoter, and hence cannot, even theoretically, represent a food/feed safety issue[34].

In addition to studies in yeast[35] and in Schizosaccharomyces pombe[36], there are published studies indicating that the 35S CaMV promoter might have potential for transcriptional activation in mammalian systems[37]. And the final proofs have been made available during the last couple of years. First, 35S promoter activity was demonstrated in human fibroblast cell cultures[38], thereafter in hamster cells[39], and very recently one of us (TT) has demonstrated substantial 35S promoter activity in human enterocyte-like cell cultures[40]. Such cells are lining up the surface of human intestines. However, no published studies have investigated 35S CaMV activity in vivo, and this is hence an obvious area of omitted research.

May the use of antibiotic resistance marker genes (e.g. nptII)present health hazards?

The antibiotic kanamycin is used extensively in crop genetic engineering as a selectable marker, inter alia in GE oilseed rape event lines like MS1Bn x RF1Bn and Topas 19/2.

A selectable marker is a gene inserted into a cell or organism to allow the modified form to be selectively amplified while unmodified organisms are eliminated. In crop genetic engineering the selectable marker is used in the laboratory to identify cells or embryos that carry the genetic modifications that the engineer wishes to commercialize. The selection gene is used once briefly in the laboratory, but thereafter the genetically modified (GM) crop has the unused marker gene in each and every one of its cells.

There are multiple well-known mechanisms for cross-resistance to antibiotics of a particular type[41]. Kanamycin is a member of the family aminoglycoside antibiotics. There are approximately 17 different classes of aminoglycoside-modifying enzymes. Some of these inactivate up to four different aminoglycosides. Cross-resistance between kanamycin and other aminoglycosides, e.g. gentamycin and tobramycin, was found to vary markedly between isolates[42]. All of the antibiotics mentioned are used to treat human diseases.

Along with cross-resistance to aminoglycoside antibiotics, pathogenic bacteria frequently develop multiple drug resistance transmitted on a single plasmid[43]. Pathogenic bacteria do acquire plasmids with multiple antibiotic resistance genes in areas where the antibiotics are used extensively. Such incidents illustrate the potential health effects of HGT. Multiple resistance genes on a single plasmid can simultaneously adapt a bacterium to several unrelated antibiotics. One antibiotic at a time is all that is necessary to maintain the plasmid.

In spite of the belief of many genetic engineers that kanamycin is no longer employed in medical applications, there is evidence that the antibiotic is used extensively for some applications[44].

Concluding remarks: Where do we go from here?

We have discussed in some detail a handful of selected, unanswered risk questions related to the first generation of transgenic GEOs. There are many more risk issues. Among them are issues of Horizontal Gene Transfer (HGT)[45], the new generations of multitransgenic GEOs for pharmaceutical and industrial purposes[46], safety questions related to GE vaccines[47], the new nanobiotechnology approaches[48] and the applications of small inhibitory (si) RNAs for a number of medical purposes[49]. Furthermore, we have the "questions not yet asked", and we have the problem of whether available methods and regulatory frameworks will be able to pick up and manage the conceived risks once they become reality.

In recent publications it has been demonstrated that the presently used sampling and detection methods may fail to detect GE materials in food and feed[50]. In another article it was demonstrated that HGT events, that potentially carry very serious public health consequences, would not be detected in time for any meaningful preventive actions[51]. And it has been illustrated that the siRNA techniques are not as "surgically targeted" as initially indicated[52].

We are left with a high number of risk issues lacking answers, adding up to a vast area of omitted research, and this falls together in time with a strong tendency towards corporate take-over of publicly funded research institutions and scientists[53].

We must as citizens and professionals join together to reverse the present situation. Publicly funded, independent research grants must become a hot political issue. That would be the most efficient remedy for lacking answers and corporate take-over of science. And finishing off, we once more quote Mayer and Stirling[54]: "Deciding on the questions to be asked and the comparisons to be made has to be an inclusive process and not the provenance of experts alone". But then again, whom should the society rely on for answers and advice when the time comes that all science resource persons work directly or indirectly for the GE producers?

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Rice Farmers Biggest Losers Over Altered Rice, Exec Says

By Nancy Cole
Arkansas Democrat Gazette
November 4, 2006

Roughly 40 percent of U.S. rice exports have been negatively affected by what many experts consider to be their industry's worst crisis, a USA Rice Federation official said Friday.

Speaking in Little Rock to the Arkansas Rice Research and Promotion Board, federation Vice President Bob Cummings discussed the damage caused to the $1.3 billion U.S. rice export market after the U.S. Department of Agriculture's August revelation that traces of an unapproved, genetically engineered rice had been discovered in U.S. long-grain rice supplies.

Keith Glover, president and chief executive officer of Producers Rice Mill Inc. in Stuttgart, said at the meeting that farmers have been some of the biggest losers in this case.

"There's no doubt in my mind you'd be looking at 40 to 50 cents a bushel more for rice today than what it is... and when you look at 210 million bushels in Arkansas, you're talking about an $80 [million ] to $100 million hit," Glover said.

Cummings, who oversees international trade policy for the industry group based near Washington, D.C., said "the federation is not opposed to genetic engineering of rice, because it holds some real benefits to growers."

"However, you need to be able to sell the product that you grow, and you need to make sure that consumers are ready for it and that the U.S. and foreign countries have granted regulatory approval," he said.

Cummings described the federation's draft plan, developed earlier this week in Dallas by a group of 50-60 rice-industry experts, which is intended to "flush genetically engineered rice out of the long-grain system starting with the 2007 crop."

Board members, most of whom are rice farmers, acknowledged the importance of acting swiftly.

"We've got to do something or we're going to have a crop that we can't sell," said board member Marvin Hare, who farms rice near Newport.

Everyone in the rice industry has been bloodied by the loss in export market share, but none more so than farmers, Glover said.

"It's a mess, and the quicker we can clean it up, the faster you guys are going to get the premiums you have developed in the marketplace," he told board members.

The problem is of particular concern in Arkansas because the state produces roughly half of all the rice grown in the United States, and about half of all U.S. rice is exported.

Rice is Arkansas' single most valuable row crop, worth $810 million in 2005.

Since mid-August, more than 25 federal lawsuits have been filed by farmers seeking damage payments from Bayer Crop-Science, whose experimental LLRICE 601 is at the center of the controversy.

Stuttgart-based Riceland Foods Inc. also has been named in two of the lawsuits, which criticize how the cooperative has handled its investigation of the problem since January and allege negligence and fraudulent concealment.

The USDA, which announced discovery of the unapproved rice on Aug. 18, and the Food and Drug Administration have said that no health, food safety or environmental concerns are associated with LLRICE 601 and that "the domestic market is steady to date," Cummings said.

But the picture is far more bleak in export markets.

Trade with the 25-nation European Union, an $87 million market in 2005, has stopped because of the problem.

Other countries have banned U.S. rice imports, and many are requiring testing to prove that U.S. rice shipments are essentially free of material associated with LLRICE 601, Cummings said.

"Roughly 41 percent of our total rice exports have been impacted by this event," he said.

Although the problem involves only long-grain rice - which is produced primarily in Arkansas, Louisiana, Mississippi, Missouri and Texas - some markets that buy medium- and short-grain rice, produced primarily in California, have been affected by it, he said.

The current problem involves not only LLRICE 601 but also two other so-called Liberty Link rice varieties, LLRICE 62 and LLRICE 06, Cummings said.

"Liberty Link 62 has been detected in Europe and there's been some detection in U. S. testing," he said.

All three Liberty Link varieties contain genes that make them resistant to the herbicide Liberty, also known as glufosinate. While Bayer never sought USDA approval to commercialize LLRICE 601, the two other Liberty Link varieties were approved for sale - though Bayer has never marketed them.

The fact that LLRICE 601 has never been approved for sale in any county is significant, Cummings said.

"[The USA Rice Federation is ] supportive of biotechnology for rice, but we're only supportive to the extent that there's regulatory approval here in the United States and in foreign markets, and there's consumer acceptance," he said.

That policy is behind the draft plan to rid the U. S. long-grain rice system of the Liberty Link varieties, Cummings said.

"We want to provide confidence to customers that their preferences are being met," yet avoid use of the term "GE- or genetically-engineered-free," he said.

"If you talk to the folks who are really up to speed on sampling and testing... they'll always say that where we are today we will never get a GE-free statement that's valid," Cummings said. "The traits are in the system, you cannot guarantee statistically that you'll ever get rid of them."

Instead, the plan calls for seed testing at a level of sensitivity that is close to GE-free, he said.

In data collected from seven U.S. rice exporters, USA Rice Federation found that 32 percent of nearly 700 long-grain rice samples - collected between August and October and including everything from unmilled rice to parboiled rice - tested positive for Liberty Link traits.

Several Rice Research and Promotion Board members noted that the 31 percent rate of positive test results for Arkansas was almost three times the share of Cheniere variety rice that was planted in the state.

Cheniere, a rice variety developed by Louisiana State University AgCenter's Rice Research Station near Crowley, La., is the only seed rice that has tested positive for traces of LLRICE 601.

Because only 11 percent to 12 percent of all Arkansas rice acres are planted in Cheniere, Arkansas Agriculture Secretary Richard Bell and state Plant Board Director Darryl Little told a legislative committee last month that the scope of the genetic-engineering problem in the state probably was comparable to that 11 percent to 12 percent.

Cummings said the main points of the USA Rice Federation response plan are simple: Only seed that tests negative for Liberty Link traits at an 0.01 percent sensitivity level will be planted in 2007. No Cheniere variety rice will be planted in 2007. Mills will buy rice in 2007 only from farmers who provide evidence that their seeds tested negative.

Rice produced from farmsaved seed in 2007 will be purchased only if it tests negative.

Cummings said Chuck Wilson, rice agronomist with the University of Arkansas Cooperative Extension Service, will lead an education campaign that will explain the plan and seek acceptance for it from all interested parties, including farmers, seed dealers, mills, financial institutions and crop insurers.

Who will bear the cost of implementing the plan remains unclear, Cummings said.

"It will cost money," and most of the plan's architects believe Bayer bears some responsibility, he said.

The genetically engineered problem with rice is reminiscent of the December 2003 discovery of mad-cow disease in a Washington state cow. Both events have thrown export markets into disarray.

Although the 2005 U.S. rice export market is only about one-third the size of the 2003 U.S. beef and veal export market, the rice problem is likely to have a much greater impact on Arkansas given the state's dominant position in the market.

Biotech Rice Saga Yields Bushel of Questions for Feds

By Rick Weiss
Washington Post
November 6, 2006

USDA Approval Shortcut Emerges as Issue

When the biotech company Bayer CropScience AG requested federal permission in August to market a variety of gene-altered rice, it assured itself a small, unwanted place in history: the first to seek approval for a genetically engineered food that was already -- illegally -- on the market.

Now, as federal regulators consider that belated application, they are finding themselves under scrutiny, too -- from scientists and others who say the 20-year-old system of biotech crop oversight is failing.

The Bayer lapse is the latest in a string of problems, critics note, including taco shells and other foods contaminated in 2000 with unapproved StarLink corn, the accidental release in 2002 of crops engineered to make a pig diarrhea vaccine, and the growing prevalence of "superweeds" that have acquired biotech genes that make them impervious to weed killers.

Federal officials are still investigating how the experimental "LLRICE601" escaped from Bayer's test plots after the company dropped the project in 2001. When they announced 10 weeks ago that the unapproved variety had become widespread in the nation's long-grain-rice supply, countries around the world blocked imports from the United States, rice futures plummeted and hundreds of farmers sued Bayer.

Bayer's response -- a hasty application for government approval, expected to be granted within weeks -- has been greeted with concern by many agriculture experts who fear that the action, though likely to ease Bayer's legal woes, will make matters worse for farmers and the environment.

"Are we going to do this every time a new transgene that we didn't intend to get out gets out?" asked Norman Ellstrand, who directs the Biotechnology Impacts Center at the University of California at Riverside.

LL601 contains a bacterial gene that protects rice from Bayer's Liberty weed killer, allowing farmers to use the chemical without harming their crop. The prospect of widespread cultivation worries many experts, who say the key gene is sure to move via pollen into red rice, a weedy relative of white rice and the No. 1 plant pest for rice farmers in the South.

Thus endowed, red rice would become immune to the herbicide, increasing its economic havoc.

Experts point to other troubling elements of the Bayer petition.

Nearly 40 percent of its pages, for example, are blacked out as "CBI," or confidential business information, even though the approval process is by federal statute supposed to be public.

Also at issue is the regulatory shortcut that Bayer is using, which allows a company to skip many of the usual safety tests by claiming that the new variety is similar to ones already approved -- in this case, two approved varieties of biotech rice that Bayer never commercialized because farmers did not want it around their fields.

Bayer, with U.S. headquarters in Research Triangle Park, N.C., is adamant that LL601 poses no risk, and even critics generally agree that it is safe to eat. The bacterial gene that is in LL601 is also in several approved varieties of engineered corn, canola and cotton.

"We believe that our herbicide-tolerant rice would contribute significantly to rice productivity," said company spokesman Greg Coffey, adding that Bayer nevertheless has no immediate plans to market the product.

In a draft environmental assessment released with extraordinary rapidity last month, the Animal and Plant Health Inspection Service (APHIS), which handles biotech crop approvals for the Agriculture Department, announced a "preliminary decision" to approve -- or in agency parlance "deregulate" -- LL601.

Among those favoring approval is the USA Rice Federation, which represents many rice growers. The group has opposed introducing engineered rice to U.S. fields, but it is now more concerned about the European Union's ongoing refusal to buy American long-grain rice laced with LL601.

U.S. approval would not guarantee European acceptance. But it is "the best available response to a major commercial issue," the federation wrote to APHIS.

Many weed experts see the relative risks and benefits differently, however. They agree with APHIS and Bayer that cross-pollination between white rice and red rice is rare, probably occurring less than 1 percent of the time. But multiply that by millions and millions of rice plants, they say -- and then start using Liberty, which by killing conventional red rice will allow the resistant weed to dominate -- and within a few years, huge expanses of the South could be infested with Liberty-resistant red rice.

"Anyone who works with rice and red rice knows it," said Cynthia Sagers, a plant ecologist at the University of Arkansas. "It's going to happen."

The government's environmental assessment contends that farmers can fall back on other herbicides when that occurs, but opponents say that solution is shortsighted. They note that as gene-altered crops have become common -- some 70 varieties have been approved in the past 15 years, many of them engineered to be resistant to various weed killers -- it has become common to find weeds that are immune to two or even three weed killers.

"We have no ability to absolutely contain these things once they're grown outside," said Rene Van Acker, a weed ecologist at the University of Guelph in Canada.

Others are complaining that Bayer's application is effectively a secret document because of the material blacked out as confidential business information.

"It makes the public reliant on the interpretation of the data by Bayer, which is not a disinterested or unbiased party," wrote the Washington-based Center for Food Safety in comments to regulators.

Rebecca Bech, associate deputy administrator for biotechnology regulatory services at APHIS, defended the application, saying it is "fairly typical to have a lot" of redacted proprietary information in biotech crop applications.

But a review of the five most recently released applications submitted by companies, including ones for genetically engineered corn, grass, alfalfa and cotton, shows that four of those five had no such deletions. (The fifth notes that information has been deleted but does not say how many pages.)

Still others question the procedure Bayer is using to seek LL601 approval. Instead of going through a full deregulation process, it applied for an extension of approvals it won earlier for two other herbicide-resistant rice varieties developed nearly a decade ago.

That shortcut was created in 1997 to streamline approvals. But critics say the record of problems indicates a need for more careful oversight, not quicker approvals.

To allay concerns, Bayer has submitted with its application a "stewardship plan" -- voluntary farming practices, including extra dosings of Liberty, aimed at minimizing genetic crossovers to red rice.

Critics doubt that farmers will spend the extra time and money if they're not required to.

"Farmers are already under huge economic pressure," said Doug Gurian-Sherman, a senior scientist at the Union of Concerned Scientists. "It's just not going to happen."

But others, such as Johnny Saichuk, a rice specialist at the Louisiana State University AgCenter, support the approach. "People are becoming better stewards," he said. "The sloppy managers who let it outcross will lose the technology. The good farmers will not have problems."

Even if LL601 is approved, Bayer's problems will not be over. It may be impossible to get every last seed of LL601 out of the U.S. long-grain-rice supply. And negotiations between American and European Union officials broke down last month over how much contaminating LL601 will be considered acceptable in exported rice.

The company also faces dozens of lawsuits, which may soon be combined into a large class action.

Reassuringly to Bayer, and infuriatingly to others, the trouble appears not to have weakened regulators' trust in the company.

Since learning of the contamination this summer, APHIS has received applications from Bayer to start field experiments on nine new kinds of gene-altered crops.

To date, eight of those have been given a green light.

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