Is the Bt Protein Safe for Human Consumption?

Bt proteins, naturally occurring insecticides produced by the soil bacterium, B. thuringiensis, have been used to control crop pests since the 1920s (1), generally as microbial products. Many strains of B. thuringiensis exist that produce different Bt proteins varying in the insects they target, e.g., larvae of butterflies and moths, beetles, and mosquitoes. The insecticidal Bt proteins form crystalline protein bodies inside the bacterium, hence the name Cry proteins. Full-sized Cry proteins are inactive until eaten by target insect larva, and inside the midgut they are cleaved and become active. The smaller, active peptides bind to specialized receptors, creating holes in the gut membrane that cause contents to leak and kill the larvae. The precision of different Bt proteins for their targets resides in the specificity of their tight binding to companion receptors in the insect gut (2).

Bt microbial products have a long history of safe use (∼40 years) with only two reports prior to 1995 of possible adverse human effects, neither of which was due to exposure to Cry proteins (3). In a 1991 study that focused on exposure via inhalation of Bt sprays, results showed immune responses and skin sensitization to Bt in 2 of 123 farm workers (4). In a 2006 article, the Organic Consumers Association linked this observation to possible impacts of Bt in GE foods, warning that “Bt crops threaten public health” (5). But the respiratory sensitization observed in the farm workers does not provide validation that oral exposure to Bt would result in allergic responses.

In recent years a variety of safety studies were conducted specifically on native Bt proteins to show that they do not have characteristics of food allergens or toxins (See 6, 2, and 7 for reviews). In its review of Bt proteins, the EPA stated that, “several types of data are required for Bt plant pesticides to provide a reasonable certainty that no harm will result from the aggregate exposure of these proteins.” The data must show that Bt proteins “behave as would be expected of a dietary protein, are not structurally related to any known food allergen or protein toxin, and do not display any oral toxicity when administered at high doses” (6).

The EPA does not require long-term studies because the protein’s instability in digestive fluids makes such studies meaningless in terms of consumer health (8). In vitro digestion assays were used to confirm degradation characteristics of Bt proteins, whereas murine feeding studies were used to assess acute oral toxicity (9, 6). Data on Cry1Ab in maize and cotton and Cry1Ac in tomato, maize, and cotton have been carefully reviewed by regulatory agencies in numerous countries, including the U.S., Canada, Japan, U.K., E.U., Russia, and South Africa (10).

The possibility for allergenic effects of four maize Bt varieties was specifically investigated in potentially sensitive populations (11). Skin prick tests were performed with protein extracts from MON810, Bt11, T25, and Bt176 and from nontransgenic control samples in two sensitive groups: children with food and inhalant allergies and individuals with asthma-rhinitis. Immunoglobulin E immunoblot reactivity of sera from patients with food allergies was tested versus Bt maize and pure Cry1Ab protein. No individual reacted differently to transgenic and nontransgenic samples; none had detectable IgE antibodies against pure transgenic proteins.

A truncated version of the full-length 131-kDa Bt protein, containing only the insect-toxic fragment, is used to engineer some crops. For example, Mon810 maize contains a truncated cry1Ab gene that codes for a 91-kDa protein. The potential for mammalian toxicity of the truncated protein was assessed by administering purified, truncated Cry1Ab protein from E. coli to groups of ten male and female CD-1 mice at ≤4000 mg/kg body weight (12). These doses represented a 200–1000-fold excess over the exposure level predicted on the basis of human consumption of MON810 grain. Mice were observed up to 9 days after dosing; no treatment-related effects on body weight, food consumption, survival, or gross pathology upon necropsy were observed for mice administered Cry1Ab truncated protein.

Despite extensive evaluations of Bt food safety, in June 2005 a Greenpeace press release, published in the New York Times and other international newspapers, stated, “There are strong warning signs that this GE Bt rice could cause allergenic reactions, as it did when tested on mice based on a study (13) and references therein”. However, in the Moreno-Fierros study (13) referred to in the press release, Cry1Ac was being tested as an oral adjuvant to boost vaccine titers. As such, the protein was used in large amounts and the stomachpHwas raised to prevent degradation of Cry1Ac. It had been chosen as an adjuvant precisely because it is nontoxic to vertebrates (14).

The native Cry9c, a protein effective against lepidopteran insects, was engineered into a variety of corn called Starlink^TM. Researchers knew the Cry9C protein did not originate from an allergenic source and had no amino acid homology with known toxins or allergens in available protein databases. However, when Starlink^TM corn was created, the Cry9C protein had no history of human dietary exposure, and in addition it was not readily digestible and was stable at 90ºC (15), both hallmarks of certain allergens (see “Were Foods Made From Bt Corn Removed from the Market Because of Allergenicity Concerns?”); Cry9C also had biochemical characteristics that differentiated it from other previously reviewed Cry proteins (16). To determine with reasonable certainty that no harm would result from human exposure to this protein, it was necessary for the EPA to determine if proteins with these biochemical characteristics were likely to affect the safety of a food. Because it was slow to digest, it provided longer lasting protection against insect damage, but the altered digestibility characteristics in humans and its relative stability to heat caused regulators to delay approval of the crop for human consumption (although it was approved for animals) so that they could reexamine its potential as a human allergen (see “Were Foods Made From Bt Corn Removed from the Market Because of Allergenicity Concerns?”).

A positive aspect of safety regarding Bt corn is the lower levels of mycotoxins compared with non-Bt corn. Mycotoxins are toxic and carcinogenic chemicals produced as secondary metabolites of fungal colonization (17) that occur as a result of insects such as the corn earworm carrying the mycotoxincontaining fungi that infest the kernels following wounding. In some cases, the reduction of mycotoxins in Bt corn results in a positive economic impact on U.S. domestic and international markets. More importantly, in less-developed countries certain mycotoxins are significant contaminants of food and their reduction in Bt corn could improve human and animal health.

In 2002, APHIS announced the deregulation of a corn variety, Mon863, with increased rootworm (Diabrotica spp.) resistance. Food safety assessments by the company used 90- day mouse feeding trials to demonstrate safety (18); independent assessments also demonstrated the safety of Mon 863 (19,  20, 21). Mon 863 contains a variant Cry3Bb1 with seven amino acid differences from wild-type Cry3Bb1 to enhance plant expression and insecticidal activity against corn rootworm (22).

A 2007 paper (23) contained a statistical reanalysis of the original data that was different from the earlier risk assessment analyses, which caused the authors to conclude that “with the present data it cannot be concluded that GM corn MON863 is a safe product.” After the 2007 peer-reviewed publication, the European Commission requested the European Food Safety Authority (EFSA) to determine what impact the reanalysis had on their earlier decision. The EFSA concluded that the reanalysis did not raise new safety concerns (24).

References:

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2. Federici B. 2002. Case study: Bt crops a novel mode of insect control. In Genetically Modified Crops: Assessing Safety, ed. KT Atherton, pp. 164–200. London: Taylor & Francis

3. McClintock JT, Schaffer CR, Sjoblad RD. 1995. A comparative review of the mammalian toxicity of Bacillus thuringiensis-based pesticides. Pestic. Sci. 45:95–105

4. Bernstein L, Bernstein JA, Miller M, Tierzieva S, Bernstein DI, et al. 1999. Immune responses in farm workers after exposure to Bacillus thuringiensis pesticides. Environ. Health Perspect. 107:575–82

5. Carman NJ. 2006. Gene-altered Bt crops threaten public health: Immune responses and skin sensitization to Bt in farm workers and presence of Bt in many genetically engineered foods. http://www.organicconsumers.org/articles/article_23.cfm. Last accessed 2011-11-25. PDF

6. Environ. Prot. Agency Off. Pestic. Programs Biopesticides Pollut. Prev. Div. 2000. Biopesticides registration document, preliminary risks and benefits section, Bacillus thuringiensis plantpesticides. Washington, DC: EPA

7. Mendelsohn M, Kough J,Vaituzis Z, Matthews K. 2003. Are Bt crops safe? Nat. Biotechnol. 21:1003–9

8. Shelton AM, Zhao J-Z, Roush RT. 2002. Economic, ecological, food safety and social consequences of the deployment of Bt transgenic plants. Annu. Rev. Entomol. 47:845–81

9. Betz FS, Hammond BF, Fuchs RL. 2000. Safety and advantages of Bacillus thuringiensis protected plants to control insect pests. Regul. Toxicol. Pharmacol. 32:156–73

10. Center for Environmental Risk Assessment (CERA).   2011. GM Crops Database. http://www.cera-gmc.org/?action=gm_crop_database. Last accessed 2011-11-25. PDF
Database for querying safety information on genetically engineered plants and plants with novel traits produced using accelerated mutagenesis and plant breeding.

11. Batista R, Nunes B, Carmo M, Cardoso C, José HS, et al. 2005. Lack of detectable allergenicity of transgenic maize and soya samples. J. Allergy Clin. Immunol. 116:403–10

12. CERA. 2011. Database Product Description: MON810. http://cera-gmc.org/index.php?evidcode[]=MON810&auDate1=&auDate2=&action=gm_crop_database&mode=Submit. Last accessed 2011-11-25. PDF

13. Moreno-Fierros L, García N, Gutiérrez R, López-Revilla R, Vázquez-Padrón RI. 2000. Intranasal, rectal and intraperitoneal immunization with protoxin Cry1Ac from Bacillus thuringiensis induces compartmentalized serum, intestinal, vaginal and pulmonary immune responses in Balb/c mice. Microbes Infect. 2:885–90

14. Rojas-Hernández S, Rodríguez-Monroy MA, López-Revilla R, Reséndiz-Albor AA, Moreno-Fierros L. 2004. Intranasal coadministration of the Cry1Ac protoxin with amoebal lysates increases protection against Naegleria fowleri meningoencephalitis. Infect. Immun. 72:4368–75

15. Environ. Prot. Agency (EPA). 1998. Bacillus thuringiensis subspecies tolworthi Cry9C protein and the genetic material necessary for its production in corn; Exemption from the requirement of a tolerance. Fed. Regist. 63(99):28258–61

16. Environ. Prot. Agency (EPA). 2008. Concerning Dietary Exposure to Cry9C Protein produced by Starlink Corn and the Potential Risks Associated with such Exposure. March 28, 2008. http://www.regulations.gov/fdmspublic/ContentViewer?objectId=0900006480509565&disposition=attachment&contentType=pdf. Last accessed 2011-11-25. PDF

17. Wu F. 2006. Mycotoxin reduction in Bt corn: potential economic, health, and regulatory impacts. Transgenic Res. 15:277–89

18. Monsanto. 2002. Safety Assessment of YieldGard Insect-Protected Corn Event MON 810. March 2002. http://www.epa.gov/oppbppd1/biopesticides/pips/starlink_corn.htm. Last accessed 2011-11-25. PDF

19. Grant RJ, Fanning KC, Kleinschmit D, Stanisiewski EP, Hartnell GF. 2003. Influence of glyphosate-tolerant (event NK603) and corn rootworm protected (event MON863) corn silage and grain on feed consumption and milk production in Holstein cattle. J. Dairy Sci. 89:1707–15

20. Hyun Y, Bressner GE, Fischer RL, Miller PS, Ellis M, et al. 2005. Performance of growing-finishing pigs fed diets containing YieldGard Rootworm corn (MON 863), a nontransgenic genetically similar corn, or conventional corn hybrids. J. Anim. Sci. 83:1581–90

21. Taylor ML, Hyun Y, Hartnell GF, Riordan SG, Nemeth MA, et al. 2003. Comparison of broiler performance when fed diets containing grain from YieldGard Rootworm (MON863), YieldGard Plus (MON810°—MON863), nontransgenic control, or commercial reference corn hybrids. Poult. Sci. 82:1948–56

22. Center for Environmental Risk Assessment (CERA). 2011. Database Product Description: MON863. http://cera-gmc.org/index.php?evidcode[]=MON863&auDate1=&auDate2=&action=gm_crop_database&mode=Submit. Last accessed 2011-11-25. PDF

23. Séralini GE, Cellier D, de Vendomois JS. 2007. New analysis of a rat feeding study with a genetically modified maize reveals signs of hepatorenal toxicity. Arch. Environ. Contam. Toxicol. 52:596–602

24. Eur. Food Saf. Auth. 2007. Statement on the analysis of data from a 90-day rat feeding study with MON 863 maize by the Scientific Panel on genetically modified organisms (GMO).  June 28, 2007. http://www.efsa.europa.eu/en/efsajournal/pub/753.htm. Last accessed 2011-11-25. PDF

Updated 2/16/12