GMO and Food Safety Dr Ted Labuza Department

GMO* and Food Safety Dr. Ted Labuza Department of Food Science and Nutrition Univ. Of Minnesota St Paul 55108 tplabuza@umn. edu http: //fscn. che. umn. edu/Ted_Labuza/tpl. html * Frankenfoods ? ? ?

Safety issues over “GMO” • Classic toxicity testing • Substantial equivalence • Pre-cautionary principal vs risk benefit • Identity preservation • labeling

Poisonous or Deleterious Substances • • general toxicity carcinogens mutagens teratogens

FDA Regulation of GMO’s

Food Drug and Cosmetic Act • 402(a)(1) - a food is adulterated if it contains any poisonous or deleterious substance which may render the food injurious to health

Food Drug and Cosmetic Act • 402(a)(1) - a food is adulterated if it contains any poisonous or deleterious substance which may render the food injurious to health – Microbial example : pathogens such as E. coli O 157: H 7

Food Drug and Cosmetic Act • 402(a)(1) - a food is adulterated if it contains any poisonous or deleterious substance which may render the food injurious to health – Chemical examples : lead, PCBs, dioxin, mercury, – radio-nucleotides, pesticides

Food Drug and Cosmetic Act • 402(a)(1) - a food is adulterated if it contains any poisonous or deleterious substance which may render the food injurious to health – Relates to unapproved substances added by man intentionally or nonintentionally

Food Drug and Cosmetic Act • 402(a)(1) - however if not added*, the food is not adulterated if the quantity would not ordinarily render injurious to health example - solanine in potatoes – New level of consumption – More susceptible population * meaning naturally present So could apply to a GMO

Questions What level of toxicant is tolerable, if any? What level of toxicant is detectable ?

Food Additives Amendment 1958 • 402(a)(2) A food is adulterated if it contains any added poisonous or deleterious substance except one that is either: • • Food Additive (Sec 409) Generally Recognized As Safe 201(s) Color Additive (Sec 706) Pesticide (Sec 408) - clarified as not an additive • Note that “added” means intentional addition so would apply to GMO unless exempt as additive or GRAS

Additive Definition 201(s) • “ any substance, the intended use of which may reasonably be expected to result directly or indirectly in its becoming a component or otherwise affecting the characteristics of any food. ”

Additive testing history • • • Based on traditional toxicity testing FDA Red Book - 1982 1 st edition LD 50 acute toxicity Sub-acute toxicity Life time chronic feeding trials Safety based on 100 th of the level of NOAEL • Also applied to GRAS substances

Decision process • Rodricks Food Tech. March 1996 pg 114 • EDI (estimated daily intake) < NRI (negligible risk intake) • Assessment – Natural components – Unintentional contaminants – Intentionally added constituents- ADI • Added 10 x 10 fold factor to estimate NRI • GRAS related

Test design constraints for GMO food • Generally max level of % 5 dry solids in test animal diet per day • Equivalent to dose of ~2500 mg/Kg /day in 50 g diet for 1 Kg animal • If no effect and use 100 x factor then ADI = 25 mg/Kg/day so in 70 Kg human ~1. 8 g/day so if GMO with 95% moisture ~ 1 ounce serving

Sec 409 (c)(3) Delaney Clause No regulation shall issue if a fair evaluation before the Secretary (FDA) (a) fails to establish that the proposed use shall be safe provided that no additive shall be deemed safe it it is found to induce cancer when ingested by man or animal or if it is found after tests which are appropriate for their evaluation of the safety of food additives to induce cancer in man or animals

Delaney Clause exclusions • GRAS substances prior to 1958 • Pesticides - FQP Act • Dietary supplements (note under NLEA FDA needs to prove unsafe)

GRAS • Sec 201 (s) • Except food additive does not mean such substance that is generally recognized as safe (GRAS) among experts qualified by scientific training and experience to evaluate the safety, through adequately shown scientific procedures or in the case of a substance used in food prior to Jan. 1 1958 through either scientific procedures or common use in food to be safe under the conditions of its intended use.

Natural Carcinogens • Mushroom Example Agaratine. DNA breaker at 1. 2 mg/70 Kg person • present in mushrooms • Calculated safe dose < 4 g mushroom per day or 1 meal every 100 days • Foods are GRAS so exempt

Fmali Herb Inc. v Heckler • 715 F 2 d 1385, 1982 (DC ND CA 9/15/83) • Block list on renshan-fenwang-jiang from Korea • Basis not GRAS since not consumed in US prior to 1958 • Fmali sues to lift ban • Court agrees that GRAS means anywhere in world not just US thus if used can bring in • 53 FR 16544 5/10/88 - substantial use as an ingredient for food by a significant number of consumers

GRAS Review 21 CFR 170(f) • (1) modified substances of natural biologic origin consumed prior to 1958 but modified afterwards • (2) significant alteration of prior 1958 natural substances by breeding and in which the nutritive value or toxicity changes

Classical Breeding History • UM, NDSU and USDA potato research lab development of improved chipping variety of potato (Lenape) (Zitnak and Johnston Am Potato Jr 47: 256 -60) • Submitted to FDA for approval but found increased solanine level so withdrew from introduction

Classical Breeding History • Discussion at Hort. Science meeting • published in 1975 Spiher A. T. The Growing of GRAS Hort Sci. 10: 241 -42 1975 – Approval based on nutrient level and toxicological levels

The Issues • What category of food ingredients do GMO based varieties it into ? • What safety criteria are needed in testing, ie what are the protocols ? • What does substantial equivalence mean? • What does “precautionary principal mean?

1987 National Academy of Sciences • Introduction of recombinant DNAengineered organisms into the environment: Key issues – No evidence of unique hazards – Risks similar to introduction of unmodified organisms or those modified by other methods

The FDA Policy • 57 FR 22983 -23005 May 29, 1992 The safety of foods derived from new plant varieties • (Note never finalized -guidance to industry) – Basic premise is that plant breeding produces safe foods vs chemicals which may be toxic – Genetic transferred material may be subject to food additive or GRAS process – (DNA itself not a concern IFBC 1990 – Miragila et al 1990 safety assessment of genetically modified food products Microchem J 59; 154 -9)

The FDA Policy • 57 FR 22983 -23005 May 29, 1992 The safety of foods derived from new plant varieties – Toxicant level suggested ^ by 10% and Nutrient level suggested decrease of 10% – Is there a potential allergen ? – Kessler et. al. The safety of foods developed by biotechnology Science 256: 1747 1992 – Current working policy - 45 products have been evaluated – 12 corn, 7 canola, 6 tomato, 5 cotton, 4 potato – see IFT Expert Report on Biotechnology http: //courses. che. umn. edu/01 fscn 11021 s/general_food_safety/ gmo/gmo. html

Basis of policy • 402 (a)(1) of FFDC – see Ronk et al Hort Sci 25; 1482 -84 1990 • Animal feeding studies problematic • Animal tests not sensitive as cannot supplement at high enough level • Need multidisciplinary assessment process based on – – genomic traits Agronomic and quality analysis Allergenicity potential Analysis of toxicants and nutrients Maryanski, J. FDA’s policy for Foods Developed from Biotechnology in Genetically Modified Foods: Safety Issues Engle et al Eds. ACS Symposium Series # 605 1995 pgs 12 -22

Basis of policy • 402 (a)(2) of FFDC – will need approval as food additive if introduced protein is different than normal otherwise GRAS – Special attention should be given to potential allergens - see April 1994 FDA conference on “Scientific issues related to potential allergenicity in Transgenic Food Crops FDA Docket # 94 N-0053 also in 59 FR 15415 April 1, 1994

OSTP 1994 • Coordinated Framework for US Biotechnology Policy – 51 FR 23302 June 26, 1986 • Exercise of Federal oversight – 57 FR 6753 Feb 24 1992 – Use risk based scientific approach rather than process used (ie don’t focus on biotech process rather use the standard safety evaluation process)

The Genetic Raw Potato • Ewan and Pusztai Lancet 354: 1353 -4 Oct. 16, 1999 • Effect of diets containing genetically modified potatoes expressing Galanthus nivalis lectin on the rat small intestine (insect resistance) • crypt hyperpalsia suggested expression of other genes

Early Genetic Engineering of GRAS Ingredients in Foods • The first round: chymosin – recombinant technology – Inserted gene for calf rennet into E. coli – >80% of world cheese making

Early Genetic Engineering of GRAS Ingredients in Foods • The first round: chymosin – Deemed to be GRAS – 57 FR 10932 -6 23/3/90 E coli – 57 FR 6476 -9: 1992 yeast – 58 FR 27197 -203: 1993 mold • See Flamm E. L. Bio/Technology 9: 340 -351 ; 1991 – – Same protein structure Most impurities removed Organism destroyed in processing Anti-biotic resistant marker destroyed

Early Genetic Engineering of GRAS Ingredients in Foods • High-fructose corn syrup – recombinant enzymes – Bound on reactor bead surface so does not go into food - processing aid – Converts glucose to fructose

The first controversy - Monsanto Milk - Recombinant BST or r. BGH Neither GRAS nor Food Additive rather It is an approved New Animal Drug

Flavor-Savr Tomato • Calgene asks for food additive status for enzyme FDA Docket # 90 A-0416, 91 A-0330 • FDA findings – enzyme introduced well documented @ <0. 16 ppm and digested 59 FR 26700 -711 May 23, 1994 – Marker gene easily digested -FDA suggests that should use kanamycin marker in all GMO – Nutrient level the same – No change in toxic substances- tomatine alkaloid – No need for special labeling • • Redenbaugh et al Regulatory Issues for the commercialization of tomatoes with an anti-sense polygalacturonase gene In-Vitro Cell Devel Biol 29 P: 17 -26 1993 59 FR 26700 -711 may 23, 1994

FDA Approvals • • 1994 - squash resistant to diseases 1995 potato insect resistant 1996 Soybean - herbicide resistance 1997 corn - corn borer resistance

WHO-FAO • 1993 - marker genes not a safety issue (< 1/250, 000 of DNA consumed) Report 93. 6 • 2000 - reconfirms prior statement “safety aspects of genetically modified food of plant origin”

Nature Biotechnology Volume 18 Number 11 p 1119; 2000 First, food safety and labeling-the editorial says let's state once and for all that safety and labeling standards for foods, food ingredients, and feeds should be applied regardless of the techniques used in their production and manufacture. There is widespread Expert consensus about this (in fact, genetic engineering may be safer/more precise than conventional breeding), so why is it even discussed anymore? Foods should continue to be assessed on the basis of substantial equivalence, with labeling required only for (GM) foods that differ significantly in composition or nutritional value from their conventional counterparts.

Substantial Equivalence Principles • Term is not in any FDA document • Reduction by 10% in key nutrients • Increase by 10% in natural nonadded background toxicants • New proteins well characterized and appear in other foods • Source of gene well characterized • Need for feeding trials questionable • Concern for allergenicity - from typical allergenic food or properties flag as allergen

The Legal Dilemma • All plants approved have been patented • Patents are – New – Novel – Non-obvious – ie Substantially different

OECD 2000 • UN Organization for Economic Cooperation – Safety of new and novel foods – Safety based on substantial equivalence

EPA • FIFRA – 7 USC 136(a) -136® – Regulates pesticides • FQPA 1996 – Pesticide is not a food additive – Stricter evaluation process especially with respect to children exposure

EPA principles • GMO’s are flagged if they are introduced as a pesticide • Must submit for approval • Under FPA pesticide compounds which include new GMO plant varieties are excluded from Delaney Clause ie they are not considered as additives • Use of precautionary principle

EPA Precautionary Principles • Mission to protect human health and safeguard environment within “adequate margin of safety” • Question of available data vs need to extrapolate • Nature of the risk ie if there is a carcinogen risk in introduction use of precautionary assumptions ie projection of risk on the safe side

USD - APHIS • Fed Plant Pest Act 7 USC 150 regulates introduction of “plant pests” that cause injury, death or damage to any plant 7 CFR 340

GMO: the new potential threat • Crossing transgenic species • Brazil nut with soybeans for methionine • Fish antifreeze protein in ice cream

Allergenicity flags Concern for transgenic introduction of allergenic protein 1. 10 to 70 KDa 2. Resistant to digestion 3. Stable to heat processing 4. Similar to amino acid homology in binding sites

Social Concepts of Risk Dr. Peter Sandman • Risk = Hazard + Outrage

Some Definitions • Hazard = magnitude x probability – magnitude-how bad it is when something happens – probability-how often it is going to happen • When outrage is zero then – Risk = Hazard

Hazard is the expected annual mortality and morbidity, and risk assessment measures this.

Hazard: Scientific Evidence 1. A laboratory study by Cornell University entomologists indicated that Bt-corn pollen can kill 44% of Monarch butterflies 2. British scientist reports that GM potatoes stunt rats’ growth and damage their immune system

Outrage is everything about a risk that is relevant, EXCEPT how likely it is to hurt you. Outrage usually involves people’s concerns and fears about a risk rather than scientific evidence

The Social Concepts of risk • Risk = Hazard + Outrage – Fear of the unknown (playing God) – Voluntary vs in-voluntary – Dreaded vs non-dreaded (cancer) • The degree of outrage does not necessarily correlate to the degree of hazard r 2 < 4%

According to Dr. Sandman: For GM Foods: RISK = HAZARD + OUTRAGE

The Social Concepts of risk • Risk = Hazard + Outrage for GMO issue – Who gets the risk ? – Trust us – They are just dumb so if we educate them they will accept the technology

European Experience • UK Ministry of Agr said “trust us” on BSE • Consumer outrage as result of BSE incident ~ 80 dead • 1999 Belgium’s Dioxin contamination • EU concern over lack of data so invoke precaution “if don’t know enough, don’t approve

Risk Perception Knowledge does not necessarily lessen consumer concerns.

Outrage Outcome • Public pays more attention to outrage • Activists and media in outrage business • Outraged citizens don’t listen to hazard data • Outrage is a legitimate process • When hazard is low - help reduce the outrage - Don’t make risk comparisons • Don’t say “they are dumb - all we • need to do is educate them”

Identity Preservation Outrage • The Adventis Bt Corn scenario

The Transport Industry • • Farm truck Silo Train car Barge Boat Train car truck

GMO analytical Needs • Problems in evaluating %GMO – On farm or at commercial silo – Mixing in transport – Cost of test – Time to do – Sample size and reliability

Allergen analysis failure Problems extraction denaturation +/need for specific ELISA not available for most allergens except peanuts and egg (Neogen)

Starlink Corn Starlink corn with Cry 9 C based Bt toxin protein 63 FR 28258 Bacillus Thuringiensis Subspecies tolworthi Cry 9 C Protein and the Genetic Material Necessary for its Production in Corn; Exemption from the Requirement of a Tolerance May 22, 1998

EPA allergenicity evaluation http: //www. environmentaldefense. org/pubs/Filings/cry 9 c. html • 1. Homology - EPA says no known homology of the 8 amino acid sequence - but not all known • 2. Cry 9 c is resistant to digestion • 3. Cry 9 c is stable to thermal processing • 4. MW (68 k. D) is in upper range for allergens • Thus EPA warned in approval that may be linked to allergens • Other EPA arguments to allow approval – Abundance of protein low but patent argues high toxicity – Low environmental exposure but what about corn dust

Elisa Test Developed http: //www. agdia. com/cgi_bin/catalog. cgi/05600

Starlink Corn problem • Starlink corn produced by Adventis Corp (Research Triangle NC ) with Cry 9 c Bt toxin protein • Approval given by EPA in 1998 but restricted to animal feed as noted by potential for allergenic response in humans based on four criteria • September 2000 Consumer group (FOE) analyzes taco shells and finds Cry 9 c Bt protein. Sept 11, 2000 calls on EPA to remove • Taco Bell begins recall of tacos from supermarkets, as does Safeway product made by Kraft

EPA announcement 10/10/00 Adventis Crop. Science (NC) is financially responsible for the screw-up and must pay for it. Not the farmers fault.

Seeds of Dissent • The next step : Wednesday, October 11, 2000 4: 48 PM EST • WASHINGTON (Reuters) - A biotech corn variety found last month in Taco Bell taco shells and intended only for use as a livestock feed has been detected in a second human food product, a consumer advocacy group said on Wednesday. • Genetically Engineered Food Alert, a coalition of health, consumer and environmental groups, said it would announce the product at a news conference on Thursday. • • ``It'll be a product that people have heard about, '' said Matt Rand, biotechnology specialist for the National Environmental Trust and co-coordinator of the GE Food Alert campaign. The group's announcement last month that Taco Bell taco shells sold in grocery stores contained the Starlink corn variety prompted manufacturer Kraft Foods, a unit of Philip Morris Cos. Inc. (MO. N), to announce a voluntary recall. Starlink corn, which is made by Aventis SA (AVEP. PA), has been approved for animal feed but not for use in human food because of concerns about the potential for allergic reactions. The U. S. Agriculture Department has said it would buy all of the estimated 45 million bushels of Starlink corn produced this year to get it off the market. Aventis will reimburse the department for the expected $90 to $100 million cost of that action.

Starlink Corn problem • Kellogg’s shuts down corn flakes cereal plant ( 10/18/2000) as precaution against potential for allergenic response • 10/19/00 Adventis says problem is farmers co-mingled corn into human food destined corn. Of 260 grain elevators, about 106 sent out to food processors which is 12% of Starlink corn or 9 million bushels

Problem on the farm NY Times 10/17/00 Fred Rosenberger, who grew 40 acres of Star. Link corn in Rineyville, Ky. , this year, was quoted as saying, "We never found out until two weeks ago, "adding that because he stored the corn before realizing that it should be segregated, some 8, 000 bushels of Star. Link corn were mixed in with about 42, 000 bushels of other varieties. Mr. Rosenberger said that some neighbors, whom he declined to name, had unwittingly shipped it to local elevators. Duane Adams, who farms 1, 500 acres in Cosmos, Minn. , and is vice president of the Minnesota Corn Growers Association, was cited as saying that none of the papers that came with Star. Link seed he purchased from Garst last spring carried a warning about the crop's limited use or the notice that it should be planted at least 660 feet from any other corn. "I'm sick of it, " Mr. Smith said, vowing to never plant another Aventis product.

Millers and Grocers Reuters 10/10/00 Kroger and Albertsons remove cereal and tacos Mission Foods recalls all Tacos (largest US maker) Azteca Milling will take back all yellow 2 corn flour Con. Agra stops operations at Kansas corn flour mill - will not disclose customers Nov 3 FDA announces over 300 products with potential risk

The Issue Green Party (NZ) health spokeswoman Sue Kedgley was cited as saying on Monday (Oct 30) that Starlink corn was feared to cause allergic reactions and digestion problems in some humans, adding, "Unless the government sets up an immediate program to randomly monitor genetically engineered ingredients in our food supply, it cannot guarantee consumers that their food is safe. "

Is this a realistic problem ? • Ricki Hall Ark. Children’s Hospital “ Right now sensitivity to the protein is an unknown…” • FDA/USDA/EPA says little if any risk • Les Crawford Georgetown Univ. “It’s not the human health risk that is concerning. Its that it got there in the first place. “ • Cargill Chair W. Staley says although found in some silos that problem is under control. Will institute new tests. He notes that problem was irresponsible procedures by a few in the chain. “There is a process of protocols to be followed, Unfortunately people didn’t handle things correctly. ”

Steve Taylor Univ. Nebraska • Statement to EPA – Would need repeated long time exposure to Starlink to develop allergy to it – Cry 9 C accounts for 0. 013% of corn grain while most allergens at 1 to 40% in food – “this clearly would not produce proteins levels of any health concern”

websites • Northernlight 360 hits in 167 sites • Friends of earth http: //www. foe. org/act/getacobellpr. html • Environmental Defense Fund http: //www. environmentaldefense. org/pubs/Filing s/cry 9 c. html • The Campaign http: //www. thecampaign. org/newsupdates/sept 00 g. htm • Lycos http: //ens. lycos. com/ens/sep 2000/2000 L-09 -18 -04. html

Bottom Line • Many reports since 1990 say there is no problem with GMO • Reports include companies and researchers who might gain from process so raise the”risk” flag • But Starlink a different story • Iowa Governor says will make Adventis buy back all corn from farmers • Feb 2001 Farmers say Adventis not paying up

Clinton Action • May 3, 2000 Clinton proposes to finalize 1992 policy – Require pre-market 75 day notification process to FDA

The New Next to Final Step • 66 FR 4706 Jan 18, 2001 • http: //courses. che. umn. edu/01 fscn 11021 s/ general_food_safety/gmo. html • Good history of regulation of GMOs • Proposed – 120 day premarketing notice to FDA

Proposed 21 CFR 192 PBN Premarket Biotechnology Notice • • Identity Function Level Dietary exposure Allergenicity History of use of food in diet FDA response within 120 days

The Final Step Labeling - Informed Consent • Required warnings – Saccharin – Aspartame – Sulfite – Alcohol – Meat handling – irradiation

Labeling - Informed Consent basis the consumer’s right to know so they can protect themselves from harm • Voluntary serious warnings – allergens

Labeling - Informed Consent basis the consumer’s right to know so they can have a freedom of choice • Voluntary warnings – Non-GMO

FDA Labeling Guidance Document • 66 FR 4839 (Jan 18, 2001) • Guidance Document – http: //vm. cfsan. fda. gov/~dms/biolabgu. html – Labeling is voluntary – Food labeling must be truthful ie no GMO need proof – If GMO significantly different, common and usual name should state so – If allergen present must state so – Example GMO statements

European Approach • EC - PP is a political tool to be invoked when political interests judge the scientific evidence of safety to be insufficient , inconclusive or uncertain • Use PP when need absolute proof of food safety needed • Recently 2001 approved GMO for plants but will require labeling

Communication on GMO • Old style – Science alone provides objective truths - ie the proverbial “white paper” – Science experts are only possible source of risk evaluation – Consuming public will listen to “truths” - but they don’t

Communication on GMO • New Paradigm – Right of public to provide input on public policy decisions – Free flow of information (but don’t cry fire in the wrong place” – Be honest, frank and open – Issue burnout

URL’s Used in This Slide Show Presentation. • • www. soybeans. com/newscfm? docuementid=96 www. fmi. org/industry/biotech/ www. aphis. usda. gov/biotechnology/faqs. html www. ifst. org/hottop 10. htm www. fmi. org/media/bg/biotech. html www. fda. gov/bbs/topics/consumer/geneg. html www. extension. iastate. edu/feci/argmo/ www. 204202. 137. 114/onair/worldnewstonight/health/wmt 981109. genfood. html • http: //courses. che. umn. edu/01 fscn 11021 s/general_food_ safety/gmo. html

Other pertinent material • IFT Expert Panel Report on Biotechnology and Foods – http: // www. ift. org

“There’s a great day dawning if only we can get through the night