8 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
9 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 healthMicrobial example : pathogens such as E. coli O157:H7
10 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 healthChemical examples : lead, PCBs, dioxin, mercury,radio-nucleotides, pesticides
11 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 healthRelates to unapproved substances added by man intentionally or non-intentionally
12 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 healthexample - solanine in potatoesNew level of consumptionMore susceptible population* meaning naturally presentSo could apply to a GMO
13 QuestionsWhat level of toxicant is tolerable, if any?What level of toxicant is detectable ?
14 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 additiveNote that “added” means intentional addition so would apply to GMO unless exempt as additive or GRAS
15 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.”
16 Additive testing history Based on traditional toxicity testingFDA Red Book st editionLD50 acute toxicitySub-acute toxicityLife time chronic feeding trialsSafety based on 100th of the level of NOAELAlso applied to GRAS substances
17 Decision process Rodricks Food Tech. March 1996 pg 114 EDI (estimated daily intake) < NRI (negligible risk intake)AssessmentNatural componentsUnintentional contaminantsIntentionally added constituents- ADIAdded 10x10 fold factor to estimate NRIGRAS related
18 Test design constraints for GMO food Generally max level of % 5 dry solids in test animal diet per dayEquivalent to dose of ~2500 mg/Kg /day in 50 g diet for 1 Kg animalIf no effect and use 100x factor then ADI = 25mg/Kg/day so in 70 Kg human ~1.8 g/day so if GMO with 95% moisture ~ 1 ounce serving
19 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
20 Delaney Clause exclusions GRAS substances prior to 1958Pesticides - FQP ActDietary supplements (note under NLEA FDA needs to prove unsafe)
21 GRASSec 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 through either scientific procedures or common use in food to be safe under the conditions of its intended use.
22 Natural CarcinogensMushroom Example Agaratine- DNA breaker at 1.2 mg/70 Kg personpresent in mushroomsCalculated safe dose < 4 g mushroom per day or 1 meal every 100 daysFoods are GRAS so exempt
23 Fmali Herb Inc. v Heckler 715 F 2d 1385, 1982 (DC ND CA 9/15/83)Block list on renshan-fenwang-jiang from KoreaBasis not GRAS since not consumed in US prior to 1958Fmali sues to lift banCourt agrees that GRAS means anywhere in world not just US thus if used can bring in53 FR /10/88 - substantial use as an ingredient for food by a significant number of consumers
24 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
25 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
26 Classical Breeding History Discussion at Hort. Science meetingpublished in Spiher A.T. The Growing of GRAS Hort Sci. 10:Approval based on nutrient level and toxicological levels
27 The IssuesWhat 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?
28 1987 National Academy of Sciences Introduction of recombinant DNA-engineered organisms into the environment: Key issuesNo evidence of unique hazardsRisks similar to introduction of unmodified organisms or those modified by other methods
29 The FDA Policy57 FR 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 toxicGenetic transferred material may be subject to food additive or GRAS process(DNA itself not a concern IFBC 1990Miragila et al 1990 safety assessment of genetically modified food products Microchem J 59;154-9)
30 The FDA Policy57 FR May 29, 1992 The safety of foods derived from new plant varietiesToxicant 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:Current working policy products have been evaluated12 corn, 7 canola, 6 tomato, 5 cotton, 4 potatosee IFT Expert Report on Biotechnology
31 Basis of policy 402 (a)(1) of FFDC see Ronk et al Hort Sci 25;Animal feeding studies problematicAnimal tests not sensitive as cannot supplement at high enough levelNeed multidisciplinary assessment process based ongenomic traitsAgronomic and quality analysisAllergenicity potentialAnalysis of toxicants and nutrientsMaryanski, J. FDA’s policy for Foods Developed from Biotechnology in Genetically Modified Foods: Safety Issues Engle et al Eds. ACS Symposium Series # pgs 12-22
32 Basis of policy 402 (a)(2) of FFDC will need approval as food additive if introduced protein is different than normal otherwise GRASSpecial 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 # 94N-0053 also in 59 FR April 1, 1994
33 OSTP 1994 Coordinated Framework for US Biotechnology Policy 51 FR June 26, 1986Exercise of Federal oversight57 FR 6753 FebUse risk based scientific approach rather than process used (ie don’t focus on biotech process rather use the standard safety evaluation process)
34 The Genetic Raw PotatoEwan and Pusztai Lancet 354: Oct. 16, 1999Effect of diets containing genetically modified potatoes expressing Galanthus nivalis lectin on the rat small intestine (insect resistance)crypt hyperpalsia suggested expression of other genes
35 Early Genetic Engineering of GRAS Ingredients in Foods The first round: chymosinrecombinant technologyInserted gene for calf rennet into E. coli>80% of world cheese making
36 Early Genetic Engineering of GRAS Ingredients in Foods The first round: chymosinDeemed to be GRAS57 FR /3/90 E coli57 FR :1992 yeast58 FR : 1993 moldSee Flamm E.L. Bio/Technology 9: ; 1991Same protein structureMost impurities removedOrganism destroyed in processingAnti-biotic resistant marker destroyed
37 Early Genetic Engineering of GRAS Ingredients in Foods High-fructose corn syruprecombinant enzymesBound on reactor bead surface so does not go into food - processing aidConverts glucose to fructose
38 The first controversy - Monsanto Milk - Recombinant BST or rBGHNeither GRAS nor Food Additive ratherIt is an approved New Animal Drug
39 Flavor-Savr TomatoCalgene asks for food additive status for enzyme FDA Docket # 90A-0416, 91A-0330FDA findingsenzyme introduced well <0.16 ppm and digested 59 FR May 23, 1994Marker gene easily digested -FDA suggests that should use kanamycin marker in all GMONutrient level the sameNo change in toxic substances- tomatine alkaloidNo need for special labelingRedenbaugh et al Regulatory Issues for the commercialization of tomatoes with an anti-sense polygalacturonase gene In-Vitro Cell Devel Biol 29P:59 FR may 23, 1994
41 WHO-FAOmarker genes not a safety issue (< 1/250,000 of DNA consumed) Report 93.6reconfirms prior statement “safety aspects of genetically modified food of plant origin”
42 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.
43 Substantial Equivalence Principles Term is not in any FDA documentReduction by 10% in key nutrientsIncrease by 10% in natural non-added background toxicantsNew proteins well characterized and appear in other foodsSource of gene well characterizedNeed for feeding trials questionableConcern for allergenicity - from typical allergenic food or properties flag as allergen
44 The Legal Dilemma All plants approved have been patented Patents are NewNovelNon-obviousie Substantially different
45 OECD 2000 UN Organization for Economic Cooperation Safety of new and novel foodsSafety based on substantial equivalence
46 EPA FIFRA FQPA 1996 7 USC 136(a) -136® Regulates pesticides Pesticide is not a food additiveStricter evaluation process especially with respect to children exposure
47 EPA principles GMO’s are flagged if they are introduced as a pesticide Must submit for approvalUnder FPA pesticide compounds which include new GMO plant varieties are excluded from Delaney Clause ie they are not considered as additivesUse of precautionary principle
48 EPA Precautionary Principles Mission to protect human health and safeguard environment within “adequate margin of safety”Question of available data vs need to extrapolateNature of the risk ie if there is a carcinogen risk in introduction use of precautionary assumptions ie projection of risk on the safe side
49 USD - APHISFed Plant Pest Act 7 USC regulates introduction of “plant pests” that cause injury, death or damage to any plant 7 CFR 340
50 GMO: the new potential threat Crossing transgenic speciesBrazil nut with soybeans for methionineFish antifreeze protein in ice cream
51 Allergenicity flagsConcern for transgenic introduction of allergenic proteinto 70 KDa2. Resistant to digestion3. Stable to heat processing4. Similar to amino acid homology in binding sites
52 Social Concepts of Risk Dr. Peter Sandman Risk = Hazard + Outrage
53 Some Definitions Hazard = magnitude x probability magnitude-how bad it is when something happensprobability-how often it is going to happenWhen outrage is zero thenRisk = Hazard
54 Hazard is the expected annual mortality and morbidity, and risk assessment measures this.
55 Hazard: Scientific Evidence 1. A laboratory study by Cornell University entomologists indicated that Bt-corn pollen can kill 44% of Monarch butterflies2. British scientist reports that GM potatoes stunt rats’ growth and damage their immune system
56 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
57 The Social Concepts of risk Risk = Hazard + OutrageFear of the unknown (playing God)Voluntary vs in-voluntaryDreaded vs non-dreaded (cancer)The degree of outrage does not necessarily correlate to the degree of hazard r2 < 4%
58 According to Dr. Sandman: For GM Foods:RISK = HAZARD + OUTRAGE
59 The Social Concepts of risk Risk = Hazard + Outrage for GMO issueWho gets the risk ?Trust usThey are just dumb so if we educate them they will accept the technology
60 European Experience UK Ministry of Agr said “trust us” on BSE Consumer outrage as result of BSE incident ~ 80 dead1999 Belgium’s Dioxin contaminationEU concern over lack of data so invoke precaution “if don’t know enough, don’t approve
61 Risk PerceptionKnowledge does not necessarily lessen consumer concerns.
62 Outrage Outcome Public pays more attention to outrage Activists and media in outrage businessOutraged citizens don’t listen to hazard dataOutrage is a legitimate processWhen hazard is low - help reduce the outrage - Don’t make risk comparisonsDon’t say “they are dumb - all weneed to do is educate them”
63 Identity Preservation Outrage The Adventis Bt Corn scenario
64 The Transport Industry Farm truckSiloTrain carBargeBoattruckIdentity Preservation
65 On farm or at commercial silo Mixing in transport Cost of test GMO analytical NeedsProblems in evaluating %GMOOn farm or at commercial siloMixing in transportCost of testTime to doSample size and reliability
66 Allergen analysis failure Problemsextractiondenaturation +/-need for specific ELISAnot available for most allergens except peanuts and egg (Neogen)
67 Starlink Corn Starlink corn with Cry9C based Bt toxin protein 63FR28258 Bacillus Thuringiensis Subspecies tolworthi Cry9C Protein and the Genetic Material Necessary for its Production in Corn;Exemption from the Requirement of a Tolerance May 22, 1998
68 EPA allergenicity evaluation http://www. environmentaldefense 1. Homology - EPA says no known homology of the 8 amino acid sequence - but not all known2. Cry9c is resistant to digestion3. Cry9c is stable to thermal processing4. MW (68 kD) is in upper range for allergensThus EPA warned in approval that may be linked to allergensOther EPA arguments to allow approvalAbundance of protein low but patent argues high toxicityLow environmental exposure but what about corn dust
70 Starlink Corn problemStarlink corn produced by Adventis Corp (Research Triangle NC ) with Cry9c Bt toxin proteinApproval given by EPA in but restricted to animal feed as noted by potential for allergenic response in humans based on four criteriaSeptember 2000 Consumer group (FOE) analyzes taco shells and finds Cry9c Bt protein. Sept 11, 2000 calls on EPA to removeTaco Bell begins recall of tacos from supermarkets,as does Safeway product made by Kraft
71 EPA announcement 10/10/00Adventis CropScience (NC) is financially responsible for the screw-up and must pay for it. Not the farmers fault.
72 Seeds of DissentThe next step : Wednesday, October 11, :48 PM ESTWASHINGTON (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.
73 Starlink Corn problemKellogg’s shuts down corn flakes cereal plant ( 10/18/2000) as precaution against potential for allergenic response10/19/00 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 Starlinkcorn or 9 million bushels
74 Problem on the farm NY Times 10/17/00 Fred Rosenberger, who grew 40 acres of StarLink 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 StarLink 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 StarLink 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 anotherAventis product.
75 Millers and Grocers Reuters 10/10/00 Kroger and Albertsons remove cereal and tacosMission Foods recalls all Tacos (largest US maker)Azteca Milling will take back all yellow 2 corn flourConAgra stops operations at Kansas corn flour mill - will not disclose customersNov 3 FDA announces over 300 productswith potential risk
76 The IssueGreen 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 foodsupply, it cannot guarantee consumers that their food is safe."
77 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 riskLes 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 aprocess of protocols to be followed, Unfortunately people didn’t handle things correctly.”
78 Steve Taylor Univ. Nebraska Statement to EPAWould need repeated long time exposure to Starlink to develop allergy to itCry9C 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”
79 websites Northernlight 360 hits in 167 sites Friends of earthEnvironmental Defense FundThe CampaignLycos
81 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” flagBut Starlink a different storyIowa Governor says will make Adventis buy back all corn from farmersFeb 2001 Farmers say Adventis not paying up
82 Clinton Action May 3, 2000 Clinton proposes to finalize 1992 policy Require pre-market 75 day notification process to FDA
83 The New Next to Final Step 66 FR Jan 18, 2001Good history of regulation of GMOsProposed120 day premarketing notice to FDA
84 Proposed 21 CFR 192 PBN Premarket Biotechnology Notice IdentityFunctionLevelDietary exposureAllergenicityHistory of use of food in dietFDA response within 120 days
85 The Final Step Labeling - Informed Consent Required warningsSaccharinAspartameSulfiteAlcoholMeat handlingirradiation
86 Labeling - Informed Consent basis the consumer’s right to know so they can protect themselves from harmVoluntary serious warningsallergens
87 Labeling - Informed Consent basis the consumer’s right to know so they can have a freedom of choice Voluntary warningsNon-GMO
88 FDA Labeling Guidance Document 66 FR 4839 (Jan 18, 2001)Guidance DocumentLabeling is voluntaryFood labeling must be truthful ie no GMO need proofIf GMO significantly different, common and usual name should state soIf allergen present must state soExample GMO statements
89 European ApproachEC - PP is a political tool to be invoked when political interests judge the scientific evidence of safety to be insufficient , inconclusive or uncertainUse PP when need absolute proof of food safety neededRecently 2001 approved GMO for plants but will require labeling
90 Communication on GMO Old style Science alone provides objective truths - ie the proverbial “white paper”Science experts are only possible source of risk evaluationConsuming public will listen to “truths” - but they don’t
91 Communication on GMO New Paradigm Right of public to provide input on public policy decisionsFree flow of information (but don’t cry fire in the wrong place”Be honest, frank and openIssue burnout