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Dr. Michael Hansen: Allergy Risks from Genetically Engineered Foods

Sept. 7, 2005
GM WATCH daily http://www.gmwatch.org
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Here's a response from Dr. Michael Hansen, a researcher with Consumers Union, to an enquiry from Luke Anderson about the recent allergy study in which Portuguese researchers gave skin prick allergy tests to at a group of adults and children to see whether they reacted differently to GM corn and soy than conventional varieties. They reported finding no differences but the research has attracted marked criticism. http://www.gmwatch.org/archive2.asp?arcid=5669 Dr Hansen's response contains some fascinating and suggestive detail on the potential allergy risk of GM foods.
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Luke

We don't know the rate of potential allergy risk associated with GE corn, in part because we don't know the true level of exposure to GE corn. Even though a significant percentage of the corn grown in US in GE, we don't know what the true level is in food consumed by humans. Remember that 80% of US corn is fed to animals and a huge amount of the corn products that are consumed by people are highly processed--such as in the form of corn syrup. A few years ago, a number of NGOs did testing of food and found that although GE corn and soy could be found in food items containing corn and/or soy, the percentage of the corn or soy in those products that was GE was much, much smaller (e.g. more than 10X or 20X smaller) than expected from the percentage of the US crop acreage of soy and corn was GE. This suggested that most of the GE corn and/or soy was being diverted to animal feed. So, we don't know how widespread the real exposure is. Since most Americans consume the bulk of their corn in highly processed forms, the exposure could be very low, and corn represents a small percentage of their dietary intake. This could not be said for malnourished/starving people in Africa that are sent food aid in the form of corn. Also, since the exposure to GE corn products that could contain GE protein (such as corn muffins, tortillas, etc.) could be very intermittent, it would be very difficult for someone to determine that their allergy symptoms could be linked to corn. If you eat a meal that contains GE corn and you have an allergic reaction--it could be mild, it could be more severe--it would be very difficult to determine that it was the corn that caused the reaction. First you would do a dietary recall, then exclude all those items from your diet, then bring them back one at a time to see which one is associated with the symptoms. If the next time you ate the corn and it wasn't GE corn, you would dismiss that as the source of your problem. However, I do agree that the sample size--77--is very small. The most serious problem with the paper is that it doesn't answer the basic question of whether the inserted proteins--particularly the Cry proteins in the case of Bt crops--are allergens. The study only asks whether the process of genetic engineering increases the level of naturally-occurring proteins in corn that induce IgE-mediated food allergies, thereby increasing the severity of allergic symptoms. This kind of study is the type that Monsanto and the other companies would routinely do. But it doesn't tell you whether the protein that you've engineered the corn to produce is an allergen. The real problem is how do you test for the allergenicity of inserted proteins when those proteins have not been routinely eaten by humans. That's what led to the FAO/WHO Expert Consultation on the allergencity of GM foods, held in Rome in Jan. 2001. The report from that meeting, and the methodology that the experts developed is very, very good. A couple of conclusions from the Expert Consultation: "2. The Consultation emphasized that all foods derived from biotechnology must be assessed for allergenic potential. . . .

5. When the expressed protein is derived from a source with no known allergenicity [as would be the case with the Cry proteins from Bt crops], the FAO/WHO 2001 decision tree proposes that the initial investigation would also be analysis of sequence homology to known allergens from food and environmental sources. If positive matches are found with known allergens, then the protein is considered likely allergenic. . ."

Note that the authors of this new study say that the products they looked at--GE corn (Bt and herbicide-tolerant varieties) and RR soy--do not contain genes derived from sources known to trigger allergies. So, according to FAO/WHO, the first step should be to look at sequence homology (or similarity) between the inserted protein and known human allergens. But the authors didn't do that at all.

I would also point out that that a number of studies have shown that there is sequence homology (actually sequence similarity) between various transgenic proteins and known human allergens. One study, done by Dr. Steven Gendel, the head of FDA's Biotechnology Studies Branch (the research side of FDA, not the regulatory side) concluded, "although it is clear that some amino acid residues are critical for specific binding, some conservative substitutions may not affect allergenicity. Therefore, it may be prudent to treat sequence matches with a high degree of identity that occur within regions of similarity as significant even if the identity does not extend for eight or more amino acids. For example, the similarity between Cry1A(b) and vitellogenin [an egg allergen] might be sufficient to warrant additional evaluation." In addition, if you look at other characteristics of known allergens--such as molecular size, being glycoproteins, being resistant to digestion, being heat stable, etc.--some of those characteristics are shared with various Cry protein, but especially Cry9C.

A paper published by two Dutch scientists--that used the sequence homology protocol suggested by the FAO/WHO 2001 Expert Consultation, and added a couple of more conservative assumptions--found sequence homology between inserted proteins in GE products that are on the market and known human allergens. The study found that "a limited number of identical stretches shared by transgenic proteins (papaya ringspot virus coat protein, acetolactate synthase GH50, and glyphosate oxidoreductase) and allergenic proteins could be identified as (part of) potential linear epitopes" and concluded that "the positive outcomes of this approach warrant further clinical testing for potential allergenicity." See: http://www.biomedcentral.com/1472-6807/2/8 This study clearly shows that further research was needed into the potential allergenicity of GE foods. It should also be pointed out that none of the GE crops on the market have gone through the protocol/decision tree suggested by the 2001 FAO/WHO Expert
Consultation.

In sum, this paper dodges the main issue (it only looks at a subsidiary issue) and has such a small sample size that it's not surprizing that it didn't find anything. It should be stressed that even though it's a pretty poor study, it does call for routine postmarket testing to monitor the possibility of allergic reactions to GM foods. And that conclusion should be loudly promoted.

Michael

I thought I'd add some more information to counteract this study and to show that there is suggestive evidence that the Cry proteins (but especially Cry1Ab/Cry1Ac) associated with the Bt crops may be human allergens and may have adverse effects on the human gut. In 1999, an EPA-funded study, published in Environmental Health Perspectives and titled "Immune responses in farm workers after exposure to Bacillus thuringiensis pesticides," pointed out that "In 1992 the use of Bt in an Asian gypsy moth control program was associated with classical allergic rhinitis symptoms, exacerbations of asthma, and skin reactions among exposed individuals reporting possible health effects after the spraying operation (7). Unfortunately, there was no follow-up to determine whether these events were Bt-induced hypersensitivity or toxic reaction or merely due to common aeroallergens coincidental to the season during which the spraying occurred (8). Similar findings occurred during another Bt spraying in the spring of 1994 (8)" (Bernstein et al., 1999: pg. 575). Since there was no follow-up, how can one say that Cry proteins weren't the source of the allergic reactions? This clearly looks like an example of "don't look, don't find."

Data from the Bernstein et al. study of farm workers did implicate Cry proteins (also called delta-endo-toxins) in a couple of farm workers. The study consisted of a surveillance program of farm workers before and after exposure to Bt pesticide sprays. The study found that a number of workers exhibited skin sensitization and presence of IgE and IgG antibodies with those responses being more numerous in those workers with higher levels of exposure. Both skin sensitization and IgE antibodies are components of an allergic response.

As part of the study, the scientists used four different types of extracts of a microbial Btk spray (Javelin): a water extract (J-WS), a mercaptoethanol-sodium dodecyl sulfate extract (J-ME-SDS), a proteinase K extract (J-PK) and a pro-delta-endotoxin extract (J-PROTOX). Two farm workers had a positive skin-prick test to the J-PROTOX extract, which just contained the pro-delta-endotoxin. Separate genetic studies (utilizing the polymerase chain reaction) demonstrated the presence of Cry1Ab and Cry1Ac genes in the product Javelin that was used in the fields the farm workers worked in. This means that there are now skin and serologic agents that could be used to test the potential allergenicity of transgenic foods containing Cry1Ab or Cry1Ac. Although the authors say that their results should allay some of the concerns about the allergenicity of transgenic foods from Bt crops, they clearly say that they now have the skin and serologic agents to do such tests: "Because reactivity to the Btk pro-delta-endotoxin was only encountered in 2 of 123 workers sensitized by the respiratory route, it is unlikely that consumers would develop allergic sensitivity after oral exposure to transgenic foods (e.g. tomatoes [sic], potatoes) that currently contain the gene encoding this protein. However, future clinical assessment of this possibility is now feasible because of the availability of reliable Bt skin and serologic reagents developed during the course of this investigation" italic added (Bernstein et al., 1999: pg. 581).

In addition, a series of five studies published in the last seven years and carried out by a team of scientists from two Mexican universities (Universidad Autonoma de Mexico and Cinvestav-IPN) and from Cuba have suggested that the Cry1Ac protein (found in Bt cotton)-in both the full-length form (protoxin) and the truncated form (soluble form)-have immunogenic and allergenic properties. A mouse study using Cry1Ac from BtkHD73 (the source bacterium for the Cry1Ac in Bt cotton) in both "Crystalline (cCry1Ac) [protoxin] and soluble (sCry1Ac) [truncated form] were administered to mice by intraperitoneal (IP) or intragastric route and anti-Cry1Ac antibody responses were determined. Cry1Ac administered in microgram amounts by both routes induced an intense systemic antibody response as well as the secretion of specific mucosal antibodies" (Vazquez-Padron et al., 1999a: 1898). Another study demonstrated that the Cry1Ac was a potent systemic and mucosal adjuvant: "We conclude that Cry1Ac is a mucosal and systemic adjuvant as potent as CT [cholera toxin] which enhances mostly serum and intestinal IgG antibody responses" (Vazquez-Padron et al., 1999b: pg. 578). A third study which included testing of the intra-nasal (i.n.) route of exposure also found that "Immunization by the i.p., i.n. and rectal routes induced IgM, IgG and IgA in all the mucosal surfaces analyzed" (Moreno-Fierros et al., 2000: 885). In the fourth study, further characterization of the mucosal and systemic immune response induced in mice "confirm that the Cry1Ac protoxin is a potent immunogen able to induce a specific immune response in the mucosal tissue, which has not been observed in response to most other proteins" italics added (Vazquez-Padron et al., 2000a: 147). The fifth study also found that: "we demonstrated that Cry1Ac protoxin (pCry1Ac) binds to the mucosal surface of the mouse small intestine . . . six pCry1Ac-binding polypeptides present in brush border membrane vesicles isolated from the small intestine. Moreover, this protein induced in situ temporal changes in the electorphysiological properties of the mouse jejunum. The data obtained indicate a possible interaction in vivo of Cry proteins with the animal bowel which could induce changes in the physiological status of the intestine" (Vazquez-Padron et al., 2000b: 54). The authors conclude by saying that "We think that previous to commercialization of food elaborated with self-insecticide transgenic plants it is necessary to perform toxocological tests to demonstrate the safety of Cry1A proteins for the mucosal tissue and for the immunological system of animals" (Vazquez-Padron et al., 2000b: 58).

This fifth study is important because one of the arguments used to suggest that Cry proteins don't have an affect on mammals consists of saying that only susceptible insects have receptors in the gut that would bind to the truncated endotoxin (e.g. truncated Cry protein) and that mammals do not have such receptors so that the truncated endotoxin could not bind to the gut of mammals.

All of these studies appear to have been ignored by the various regulatory agencies, such as the U.S. EPA. There is now evidence that Cry1Ac is a potent, systemic and local immunogen, a strong adjuvant and that it binds to surface proteins in the mouse small intestine. In insects, the Cry proteins also bind to surface proteins in the gut. Finally, the Bernstein et al. study suggest that they have skin and serologic reagents from human to detect Cry1Ab and/or Cry1Ac. Why haven't these reagents been used to do the appropriate human studies? Dr. Bernstein has tried to follow up on his work, but has not been able to find funding to do this work. In addition, there has been no follow-up to the work done by Dr. Vazquez-Padron and colleagues. I wonder why?

Michael

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This GMO news service is underwritten by a generous grant from the Newman's Own Foundation, edited by Thomas Wittman and is a production of the Ecological Farming Association www.eco-farm.org <http://www.eco-farm.org/
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