Toxicological Assessment of Newly Expressed Proteins (NEPs) in Genetically Modified (GM) Plants
DOI:
https://doi.org/10.21423/JRS-V09I1ROPERKeywords:
genetically modified, toxicological assessment, food and feed, hazard, exposure, risk, core studies, supplementary studiesAbstract
This paper details the weight of evidence (WOE) and stepwise approaches used to assess the food and feed safety of newly expressed proteins (NEPs) in genetically modified (GM) plants, based on previously reported principles. The WOE approach is critical, as in a vast majority of cases no single assay or biochemical characteristic can identify a protein as a hazard. A stepwise approach is recommended to evaluate the safety of NEPs taking the totality of information into account. Potential triggers for the need for supplementary toxicology studies are discussed, and an alternative in vitro method for the acute toxicology study is proposed.
doi: 10.21423/jrs-v09i1roper
References
Bushey, D. F., Bannon, G. A., Delaney, B. F., Graser, G., Hefford, M., Jiang, X., Lee, T. C., Madduri, K. M., Pariza, M., Privalle, L. S., Ranjan, R., Saab-Rincon, G., Schafer, B. W., Thelen, J. J., Zhang, J. X. Q., & Harper, M. S. (2014). Characteristics and safety assessment of intractable proteins in genetically modified crops. Regulatory Toxicology and Pharmacology, 69(2), 154-170. https://www.doi.org/10.1016/j.yrtph.2014.03.003
Cao, S., He, X., Xu, W., Ran, W., Liang, L., Luo, Y., Yuan, Y., Zhang, N., Zhou, X., & Huang, K. (2010). Safety assessment of Cry1C protein from genetically modified rice according to the national standards of PR China for a new food resource. Regulatory Toxicology and Pharmacology, 58(3), 474-481. https://www.doi.org/10.1016/j.yrtph.2010.08.018
Codex Alimentarius Commission. (2009). Foods derived from modern biotechnology, Second edition. Food and Agriculture Organization of the United Nations and World Health Organization, Rome. Retrieved from http://www.fao.org/3/a-a1554e.pdf
Constable, A., Jonas, D., Cockburn, A., Davi, A., Edwards, G., Hepburn, P., Herouet-Guicheney, C., Knowles, M., Moseley, B., Oberdorfer, R., & Samuels, F. (2007). History of safe use as applied to the safety assessment of novel foods and foods derived from genetically modified organisms. Food and Chemical Toxicology, 45(12), 2513-2525. https://www.doi.org/10.1016/j.fct.2007.05.028
Deikman, J., Petracek, M., & Heard, J. E. (2012). Drought tolerance through biotechnology: improving translation from the laboratory to farmers' fields. Current Opinion in Biotechnology, 23(2), 243-250. https://www.doi.org/10.1016/j.copbio.2011.11.003
Delaney, B. (2017). In vitro studies with human intestinal epithelial cell line monolayers for protein hazard characterization. Food and Chemical Toxicology, 110, 425-433. https://www.doi.org/10.1016/j.fct.2017.09.029
Delaney, B., Astwood, J. D., Cunny, H., Conn, R. E., Herouet-Guicheney, C., MacIntosh, S., Meyer, L. S., Privalle, L., Gao, Y., Mattsson, J., & Levine, M. (2008). Evaluation of protein safety in the context of agricultural biotechnology. Food and Chemical Toxicology, 46(Suppl 2), S71-S97. https://www.doi.org/10.1016/j.fct.2008.01.045
Eaton, A. D., Zimmermann, C., Delaney, B., & Hurley, B. P. (2017). Primary human polarized small intestinal epithelial barriers respond differently to a hazardous and an innocuous protein. Food and Chemical Toxicology, 106, 70-77. https://www.doi.org/10.1016/j.fct.2017.05.038
EFSA Panel on Genetically Modified Organisms. (2011). Guidance for risk assessment of food and feed from genetically modified plants. EFSA Journal, 9(5). doi: 10.2903/j.efsa.2011.2150
Erickson, R. H., & Kim, Y. S. (1990). Digestion and absorption of dietary protein. Annual Review of Medicine, 41(1), 133-139. https://www.doi.org/10.1146/annurev.me.41.020190.001025
Farmer, D. R., Edrington, T. C., Kessenich, C. R., Wang, C., & Petrick, J. S. (2017). Improving insect control protein activity for GM crops: A case study demonstrating that increased target insect potency can be achieved without impacting mammalian safety. Regulatory Toxicology and Pharmacology, 89, 155-164. https://www.doi.org/10.1016/j.yrtph.2017.07.020
Gardner, M. L. G. (1988). Gastrointestinal Absorption of Intact Proteins. Annual Review of Nutrition, 8(1), 329-350. https://www.doi.org/10.1146/annurev.nu.08.070188.001553
Goldberg, M., & Gomez-Orellana, I. (2003). Challenges for the oral delivery of macromolecules. Nature Reviews Drug Discovery, 2(4), 289-295. https://www.doi.org/10.1038/nrd1067
Habig, J. W., Rowland, A., Pence, M. G., & Zhong, C. X. (2018). Food safety evaluation for R-proteins introduced by biotechnology: A case study of VNT1 in late blight protected potatoes. Regulatory Toxicology and Pharmacology, 95, 66-74. https://www.doi.org/10.1016/j.yrtph.2018.03.008
Hamman, J. H., Enslin, G. M., & Kotze, A. F. (2005). Oral delivery of peptide drugs. BioDrugs, 19(3), 165-177. https://www.doi.org/10.2165/00063030-200519030-00003
Hammond, B., Kough, J., Herouet-Guicheney, C., & Jez, J. M. (2013). Toxicological evaluation of proteins introduced into food crops. Critical Reviews in Toxicology, 43(sup2), 25-42. https://www.doi.org/10.3109/10408444.2013.842956
Hammond, B. G., & Jez, J. M. (2011). Impact of food processing on the safety assessment for proteins introduced into biotechnology-derived soybean and corn crops. Food and Chemical Toxicology, 49(4), 711-721. https://www.doi.org/10.1016/j.fct.2010.12.009
Hefferon, K. L. (2015). Nutritionally enhanced food crops; progress and perspectives. International Journal of Molecular Sciences, 16(2), 3895-3914. https://www.doi.org/10.3390/ijms16023895
Hendriks, H. G., Kik, M. J., Koninkx, J. F., Van den Ingh, T. S., & Mouwen, J. M. (1991). Binding of kidney bean (Phaseolus vulgaris) isolectins to differentiated human colon carcinoma Caco-2 cells and their effect on cellular metabolism. Gut, 32(2), 196-201. https://www.doi.org/10.1136/gut.32.2.196
Hurley, B. P., Eaton, A. D., Zimmermann, C., & Delaney, B. (2016). Polarized monolayer cultures of human intestinal epithelial cell lines exposed to intractable proteins - In vitro hazard identification studies. Food and Chemical Toxicology, 98(Part B), 262-268. https://www.doi.org/10.1016/j.fct.2016.11.006
Hurley, B. P., Pirzai, W., Eaton, A. D., Harper, M., Roper, J., Zimmermann, C., Ladics, G. S., Layton, R. J., & Delaney, B. (2016). An experimental platform using human intestinal epithelial cell lines to differentiate between hazardous and non-hazardous proteins. Food and Chemical Toxicology, 92, 75-87. https://www.doi.org/10.1016/j.fct.2016.04.003
Ishiguro, M., Nakashima, H., Tanabe, S., & Sakakibara, R. (1992). Interaction of Toxic Lectin Ricin with Epithelial Cells of Rat Small Intesting in Vitro. Chemical and Pharmaceutical Bulletin, 40(2), 441-445. https://www.doi.org/10.1248/cpb.40.441
Juberg, D. R., Herman, R. A., Thomas, J., Brooks, K. J., & Delaney, B. (2009). Acute and repeated dose (28 day) mouse oral toxicology studies with Cry34Ab1 and Cry35Ab1 Bt proteins used in coleopteran resistant DAS-59122-7 corn. Regulatory Toxicology and Pharmacology, 54, 154-163. https://www.doi.org/10.1016/j.yrtph.2009.03.008
Kier, L. D., & Petrick, J. S. (2008). Safety assessment considerations for food and feed derived from plants with genetic modifications that modulate endogenous gene expression and pathways. Food and Chemical Toxicology, 46(8), 2591-2605. https://www.doi.org/10.1016/j.fct.2008.05.025
Lafont, J., Rouanet, J. M., Gabrion, J., Assouad, J. L., Infante, J. L. Z., & Besancon, P. (1988). Duodenal toxicity of dietary Phaseolus vulgaris lectins in the rat: an integrative assay. Digestion, 41(2), 83-93. https://www.doi.org/10.1159/000199736
Lodish, H. F., Berk, A., Kaiser, C. A., Krieger, M., Scott, M. P., Bretscher, A., Ploegh, H. L., & Matsudaira, P. (2008). Molecular Cell Biology, Sixth Edition. W.H. Freeman and Company.
Markell, L. K., Wezalis, S. M., Roper, J. M., Zimmermann, C., & Delaney, B. (2017). Incorporation of in vitro digestive enzymes in an intestinal epithelial cell line model for protein hazard identification. Toxicology in Vitro, 44, 85-93. https://www.doi.org/10.1016/j.tiv.2017.06.018
Mathesius, C., Barnett, J. F., Jr., Cressman, R. F., Ding, J., Carpenter, C., Ladics, G. S., Schmidt, J., Layton, R. J., Zhang, J. X. Q., Appenzeller, L. M., Carlson, G., Ballou, S., & Delaney, B. (2009). Safety assessment of a modified acetolactate synthase protein (GM-HRA) used as a selectable marker in genetically modified soybeans. Regulatory Toxicology and Pharmacology, 55(3), 309-320. https://www.doi.org/10.1016/j.yrtph.2009.08.003
Mendelsohn, M., Kough, J., Vaituzis, Z., & Matthews, K. (2003). Are Bt crops safe? Nature Biotechnology, 21(9), 1003-1009. https://www.doi.org/10.1038/nbt0903-1003
Moar, W. J., Evans, A. J., Kessenich, C. R., Baum, J. A., Bowen, D. J., Edrington, T. C., Haas, J. A., Kouadio, J. L. K., Roberts, J. K., Silvanovich, A., Yin, Y., Weiner, B. E., Glenn, K. C., & Odegaard, M. L. (2017). The sequence, structural, and functional diversity within a protein family and implications for specificity and safety: The case for ETX_MTX2 insecticidal proteins. Journal of Invertebrate Pathology, 142, 50-59. https://www.doi.org/10.1016/j.jip.2016.05.007
O'Hagan, D. T., Palin, K. J., & Davis, S. S. (1987). Intestinal absorption of proteins and macromolecules and the immunological response. Critical Reviews in Therapeutic Drug Carrier Systems, 4(3), 197-220.
Organisation for Economic Co-operation and Development. (2001). OECD Guideline for Testing of Chemicals: Acute Oral Toxicity - Up-and-Down Procedure, 425. Retrieved July 2019 from https://ntp.niehs.nih.gov/iccvam/suppdocs/feddocs/oecd/oecd_gl425-508.pdf
Rossi, M. A., Mancini Filho, J., & Lajolo, F. M. (1984). Jejunal ultrastructural changes induced by kidney bean (Phaseolus vulgaris) lectins in rats. British Journal of Experimental Pathology, 65(1), 117-123.
Rothstein, S. J., Bi, Y-M., Coneva, V., Han, M., & Good, A. (2014). The challenges of commercializing second-generation transgenic crop traits necessitate the development of international public sector research infrastructure. Journal of Experimental Botany, 65(19), 5673-5682. https://www.doi.org/10.1093/jxb/eru236
Schneeberger, E. E., & Lynch, R. D. (2004). The tight junction: a multifunctional complex. American Journal of Physiology - Cell Physiology, 286(6), C1213-C1228. https://www.doi.org/10.1152/ajpcell.00558.2003
Shah, R. B., Ahsan, F., & Khan, M. A. (2002). Oral Delivery of Proteins: Progress and Prognostication. Critical Reviews™ in Therapeutic Drug Carrier Systems, 19(2). https://www.doi.org/10.1615/CritRevTherDrugCarrierSyst.v19.i2.20
Sjoblad, R. D., McClintock, J. T., & Engler, R. (1992). Toxicological considerations for protein components of biological pesticide products. Regulatory Toxicology and Pharmacology, 15(1), 3-9. https://www.doi.org/10.1016/0273-2300(92)90078-N
Stagg, N. J., Thomas, J., Herman, R. A., & Juberg, D. R. (2012). Acute and 28-day repeated dose toxicology studies in mice with aryloxyalkanoate dioxygenase (AAD-1) protein expressed in 2,4-D tolerant DAS-40278-9 maize. Regulatory Toxicology and Pharmacology, 62(2), 363-370. https://www.doi.org/10.1016/j.yrtph.2011.10.018
Tornqvist, E., Annas, A., Granath, B., Jalkesten, E., Cotgreave, I., & Oberg, M. (2014). Strategic focus on 3R principles reveals major reductions in the use of animals in pharmaceutical toxicity testing. PloS One, 9(7), e101638. https://www.doi.org/10.1371/journal.pone.0101638
U.S. Environmental Protection Agency. (2002). Health Effects Test Guidelines: OPPTS 870.1100 Acute Oral Toxicity. Retrieved July 2019 from https://www.regulations.gov/document?D=EPA-HQ-OPPT-2009-0156-0003
U.S. Food and Drug Administration (2016). Generally Recognized as Safe (GRAS). Retrieved July 2019 from https://www.fda.gov/food/food-ingredients-packaging/generally-recognized-safe-gras
Vasconcelos, I. M., & Oliveira, J. T. A. (2004). Antinutritional properties of plant lectins. Toxicon, 44(4), 385-403. https://www.doi.org/10.1016/j.toxicon.2004.05.005
Weinman, M. D., Allan, C. H., Trier, J. S., & Hagen, S. J. (1989). Repair of microvilli in the rat small intestine after damage with lectins contained in the red kidney bean. Gastroenterology, 97(5), 1193-1204. https://www.doi.org/10.1016/0016-5085(89)91690-9
Xu, W., Cao, S., He, X., Luo, Y., Guo, X., Yuan, Y., & Huang, K. (2009). Safety assessment of Cry1Ab/Ac fusion protein. Food and Chemical Toxicology, 47(7), 1459-1465. https://www.doi.org/10.1016/j.fct.2009.03.029
Yoder, J. M., Aslam, R. U., & Mantis, N. J. (2007). Evidence for widespread epithelial damage and coincident production of monocyte chemotactic protein 1 in a murine model of intestinal ricin intoxication. Infection and Immunity, 75(4), 1745-1750. https://www.doi.org/10.1128/iai.01528-06
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Copyright (c) 2021 Jason Roper, Elizabeth A. Lipscomb, Jay S. Petrick, Rakesh Ranjan, Alaina Sauve-Ciencewicki, Laurie Goodwin
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