Evaluation of Endogenous Allergens for the Safety Evaluation of Genetically Engineered Food Crops: Review of Potential Risks, Test Methods, Examples and Relevance

Goodman RE, Panda R, Ariyarathna H
Journal of Agricultural and Food Chemistry
January 1, 2013

Task Force #12

Journal of Agricultural and Food Chemistry. 2013;61(35):8317-8332

Abstract: The safety of food produced from genetically engineered (GE) crops is assessed for potential risks of food allergy on the basis of an international consensus guideline outlined by the Codex Alimentarius Commission (2003). The assessment focuses on evaluation of the potential allergenicity of the newly expressed protein(s) as the primary potential risk using a process that markedly limits risks to allergic consumers. However, Codex also recommended evaluating a second concern, potential increases in endogenous allergens of commonly allergenic food crops that might occur due to insertion of the gene. Unfortunately, potential risks and natural variation of endogenous allergens in non-GE varieties are not understood, and risks from increases have not been demonstrated. Because regulatory approvals in some countries are delayed due to increasing demands for measuring endogenous allergens, we present a review of the potential risks of food allergy, risk management for food allergy, and test methods that may be used in these evaluations. We also present new data from our laboratory studies on the variation of the allergenic lipid transfer protein in non-GE maize hybrids as well as data from two studies of endogenous allergen comparisons for three GE soybean lines, their nearest genetic soy lines, and other commercial lines. We conclude that scientifically based limits of acceptable variation cannot been established without an understanding of natural variation in non-GE crops. Furthermore, the risks from increased allergen expression are minimal as the risk management strategy for food allergy is for allergic individuals to avoid consuming any food containing their allergenic source, regardless of the crop variety.

To download this article, click here.


  1. Guideline for the conduct of food safety assessment of foods derived from recombinant-DNA plants in foods derived from modern biotechnology (CAC/GL 45-2003). In Codex Alimentarius, 2nd ed.; World Health Organization and Food and Agricultural Organization of the United Nations: Rome, Italy, 2009; pp 7– 34. LINK
  2. Brookes, G.; Barfoot, P. GM Crops: The First Ten Years – Global Socio-economic and Environmental Impacts; ISAAA Brief 36; ISAAA: Ithaca, NY, 2006; p 116. LINK
  3. James, C.; Krattiger, A. F. Global Review of the Field Testing and Commercialization of Transgenic Plants: 1986–1995: The First Decade of Crop Biotechnology; ISAAA Briefs 1; ISAAA: Ithaca, NY, 1996; p 31. LINK
  4. James, C. Global Status of Commercialized Biotech/GM Crops; ISAAA Briefs 43; ISAAA: Ithaca, NY, 2011; p 324. LINK
  5. Springer, N. M.; Stupar, R. M. Allelic variation and heterosis in maize: how do two halves make more than a whole? Genome Res. 2007, 17, 264– 275 LINK
  6. Stupar, R. M. Into the wild: the soybean genome meets its undomesticated relative Proc. Natl. Acad. Sci. U.S.A. 2010, 107 ( 51) 21947– 21948 LINK
  7. Barros, E.; Lezar, S.; Anttonen, M. J.; van Dijk, J. P.; Rohlig, R. M.; Kok, E. J.; Engel, K.-H. Comparison of two GM maize varieties with a near-isogenic non-GM variety using transcriptomics, proteomics and metabolomics Plant Biotechnol. J. 2010, 8, 436– 451 LINK
  8. Abadie, V.; Sollid, L. M.; Barreiro, L. B.; Jabri, B. Integration of genetic and immunological insights into a model of celiac disease pathogenesis Annu. Rev. Immunol. 2011, 29, 493– 525 LINK
  9. Sicherer, S. H.; Sampson, H. A. Food allergy J. Allergy Clin. Immunol. 2010, 125, S116– S125 LINK
  10. Ventor, C.; Arshad, S. H. Epidemiology of food allergy Pediatr. Clin. N. Am. 2011, 58, 327– 349 LINK
  11. Imamura, T.; Kanagawa, Y.; Ebisawa, M. A survey of patients with self-reported severe food allergies in Japan Pediatr. Allergy Immunol. 2008, 19, 270– 274 LINK
  12. Goodman, R. E.; Vieths, S.; Sampson, H. A.; Hill, D.; Ebisawa, M.; Taylor, S. L.; van Ree, R. Allergenicity assessment of genetically modified crops—what makes sense? Nat. Biotechnol. 2008, 26, 73– 81 LINK
  13. Sancho, A. I.; van Ree, R.; van Leeuwen, A.; Meulenbroek, B. J.; van de Weg, E. W.; Gillissen, L. J.; Puehringer, H.; Laimer, M.; Martinelli, A.; Zaccharini, M.; Vazquez-Cortes, S.; Fernandez-Rivas, M.; Hoffmann-Sommergruber, K.; Mills, E. N.; Zuidmeer, L. Measurement of lipid transfer protein in 88 apple cultivars Int. Arch. Allergy Immunol. 2008, 146 ( 1) 19– 26 LINK
  14. Panda, R.; Ariyarathna, H.; Amnuaycheewa, P.; Tetteh, A.; Pramod, S. N.; Taylor, S. L.; Ballmer-Weber, B. K.; Goodman, R. E. Challenges in testing genetically modified crops for potential increases in endogenous allergen expression for safety Allergy 2013, 68, 142– 151 LINK
  15. EFSA 2011 Guidance document for risk assessment of food and feed from genetically modified plants EFSA J. 2011, 9 ( 5) 1– 50 LINK
  16. Goodman, R. E.; Tetteh, A. O. Suggested improvements for the allergenicity assessment of genetically modified plants used in foods Curr. Allergy Asthma Rep. 2011, 11 ( 4) 317– 324 LINK
  17. Herman, R. A.; Ladics, G. S. Endogenous allergen upregulation: transgenic vs. traditionally bred crops Food Chem. Toxicol. 2011, 49 (10) 2667– 2669 LINK
  18. Foucard, T.; Yman, I. M. A study on severe food reactions in Sweden – is soy protein an underestimated cause of food anaphylaxis? Allergy 1999, 54, 261– 265 LINK
  19. Ballmer-Weber, B. K.; Holzhauser, T.; Scibilia, J.; Mittag, D.; Zisa, G.; Ortolani, C.; Oesterballe, M.; Poulsen, L. K.; Vieths, S.; Bindslev-Jensen, C. Clinical characteristics of soybean allergy in Europe: a double-blind, placebo-controlled food challenge study J. Allergy Clin. Immunol. 2007, 119, 1489– 1496 LINK
  20. Holzhauser, T.; Wackermann, O.; Ballmer-Weber, B. K.; Bindslev-Jensen, C.; Scibilia, J.; Perono-Garoffo, L.; Utsumi, S.; Poulsen, L. K.; Vieths, S. Soybean (Glycine max) allergy in Europe: Gly m 5 (β-conglycinin) and Gly m 6 (glycinin) are potential diagnostic markers for severe allergic reactions to soy J. Allergy Clin. Immunol. 2009, 123 ( 2) 452– 458 LINK
  21. Kleine-Tebbe, J.; Vogel, L.; Crowell, D. N.; Haustein, U. F.; Vieths, S. Severe oral allergy syndrome and anaphylactic reactions cause by a Bet v 1-related PR-10 protein in soybean, SAM-22 J. Allergy Clin. Immunol. 2002, 110 ( 5) 797– 804 LINK
  22. Kosma, P.; Sjolander, S.; Landgren, E.; Borres, M. P.; Hedlin, G. Severe reactions after the intake of soy drink in birch pollen-allergic children sensitized to Gly m 4 Acta Paediatr. 2011, 100, 305– 307 LINK
  23. Pastorello, E. A.; Farioli, L.; Pravettoni, V.; Ispano, M.; Scibola, E.; Trambaioli, C.; Giuffrida, M. G.; Ansaloni, R.; Godovac-Zimmermann, J.; Fortunato, D.; Ortolani, C. The maize major allergen, which is responsible for food-induced allergic reactions, is a lipid transfer protein J. Allergy Clin. Immunol. 2000, 106 (4) 744– 751 LINK
  24. Hoff, M.; Son, D.-Y.; Gubesch, M.; Ahn, K.; Lee, S. I.; Vieths, S.; Goodman, R. E.; Ballmer-Weber, B. K.; Bannon, G. A.Serum testing of genetically modified soybeans with special emphasis on potential allergenicity of the heterologous protein CP4-EPSPS Mol. Nutr. Food Res. 2007, 51 ( 8) 946– 955 LINK
  25. Goodman, R. E.Performing IgE serum testing due to bioinformatics matches in the allergenicity assessment of GM crops Food Chem. Toxicol. 2008, 46, S24– S34 LINK
  26. Natarajan, S.; Xu, C.; Caperna, T. J.; Garrett, W. M.Comparison of protein solubilization methods suitable for proteomic analysis of soybean seed proteins Anal. Biochem. 2005, 342, 214– 220 LINK
  27. EMEA (European Medicines Agency, committee for medicinal products for human use).Guideline on allergen products: production and quality issues; London, Nov 20, (2008; EMEA/CHMP/BWP/204831/2007. LINK
  28. Pastorello, E. A.; Farioli, L.; Pravettoni, V.; Scibilia, J.; Conti, A.; Fortunato, D.; Borgonovo, L.; Bonomi, S.; Primavesi, L.; Ballmer-Weber, B. Maize food allergy: lipid-transfer proteins, endochitinases, and α-zein precursor are relevant maize allergens in double blind placebo-controlled maize-challenge positive patients Anal. Bioanal. Chem. 2009, 395, 93– 102 LINK
  29. Mari, A. IgE to cross-reactive carbohydrate determinants: analysis of the distribution and appraisal of the in vivo and in vitro reactivity Int. Arch. Allergy Immunol. 2002, 129, 286– 295 LINK
  30. Rouquie, D.; Capt, A.; Eby, W. H.; Sekar, V.; Herouet-Guicheney, C. Investigation of endogenous soybean food allergens by using a 2-dimensional gel electrophoresis approach Regul. Toxicol. Pharmacol. 2010, 58 ( 3 Suppl.) S47– S53 LINK
  31. Houston, N. L.; Lee, D.-G.; Stevenson, S. E.; Ladics, G. S.; Bannon, G. A.; McClain, S.; Privalle, L.; Stagg, N.; Herouet-Guicheney, C.; Macintosh, S. C.; Thelen, J. J. Quantitation of soybean allergens using tandem mass spectrometry J. Proteome Res. 2011, 10, 763– 773 LINK
  32. Stevenson, S. E.; Woods, C. A.; Hong, B.; Kong, X.; Thelen, J. J.; Ladics, G. S. Environmental effects on allergen levels in commercially grown non-genetically modified soybeans: assessing variation across North America. Front. Plant Sci. 2012, 3, 196-E.Publ. LINK
  33. Allergen products. European Phamacopoeia, 6th ed., Suppl. 6.6; Jan 2010; pp 5165– 5167. LINK
  34. Crevel, R. W. R.; Ballmer-Weber, B. K.; Holzhauser, T.; Hourihane, J. O. B.; Knulst, A. C.; Mackie, A. R.; Timmermans, F.; Taylor, S. L. Thresholds for food challenges and their value to different stakeholders Allergy 2008, 63, 597– 609 LINK
  35. Nordlee, J. A.; Taylor, S. L.; Townsend, J. A.; Thomas, L. A.; Bush, R. K. Identification of a Brazil-nut allergen in transgenic soybeans N. Engl. J. Med. 1996, 334 ( 11) 688– 692 LINK