GMO* and Food Safety

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GMO and Food Safety
Dr. Ted Labuza Department of Food Science and
Nutrition Univ. Of Minnesota St Paul
55108 tplabuza_at_umn.eduhttp//fscn.che.umn.edu/Ted
_Labuza/tpl.html
Frankenfoods ???
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Safety issues over GMO

• Classic toxicity testing
• Substantial equivalence
• Pre-cautionary principal vs risk benefit
• Identity preservation
• labeling

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Poisonous or Deleterious Substances

• general toxicity
• carcinogens
• mutagens
• teratogens

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FDA Regulation of GMOs
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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

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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
  O157H7

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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

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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 non-intentionally

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

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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.

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Additive testing history

• Based on traditional toxicity testing
• FDA Red Book - 1982 1st edition
• LD50 acute toxicity
• Sub-acute toxicity
• Life time chronic feeding trials
• Safety based on 100th of the level of NOAEL
• Also applied to GRAS substances

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Decision process

• Rodricks Food Tech. March 1996 pg 114
• EDI (estimated daily intake) lt NRI (negligible
  risk intake)
• Assessment
• Natural components
• Unintentional contaminants
• Intentionally added constituents- ADI
• Added 10x10 fold factor to estimate NRI
• GRAS related

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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 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

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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

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Delaney Clauseexclusions

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

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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.

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Natural Carcinogens

• Mushroom Example Agaratine- DNA breaker at 1.2
  mg/70 Kg person
• present in mushrooms
• Calculated safe dose lt 4 g mushroom per day or 1
  meal every 100 days
• Foods are GRAS so exempt

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Fmali Herb Inc. v Heckler

• 715 F 2d 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

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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

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Classical Breeding History

• UM, NDSU and USDA potato research lab
  development of improved chipping variety of
  potato (Lenape) (Zitnak and Johnston Am Potato Jr
  47256-60)
• Submitted to FDA for approval but found
  increased solanine level so withdrew from
  introduction

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Classical Breeding History

• Discussion at Hort. Science meeting
• published in 1975 Spiher A.T. The Growing of
  GRAS Hort Sci. 10241-42 1975
• Approval based on nutrient level and
  toxicological levels

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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?

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1987 National Academy of Sciences

• Introduction of recombinant DNA-engineered
  organisms into the environment Key issues
• No evidence of unique hazards
• Risks similar to introduction of unmodified
  organisms or those modified by other methods

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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
  59154-9)

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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 2561747 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/01fscn11021s/general_fo
od_safety/gmo/gmo.html
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Basis of policy

• 402 (a)(1) of FFDC
• see Ronk et al Hort Sci 251482-84 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. FDAs policy for Foods Developed
from Biotechnology in Genetically Modified Foods
Safety Issues Engle et al Eds. ACS Symposium
Series 605 1995 pgs 12-22
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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
  94N-0053 also in 59 FR 15415 April 1, 1994

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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 dont focus on biotech process
  rather use the standard safety evaluation
  process)

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The Genetic Raw Potato

• Ewan and Pusztai Lancet 3541353-4 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

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Early Genetic Engineering of GRAS Ingredients in
Foods

• The first round chymosin
• recombinant technology
• Inserted gene for calf rennet into E. coli
• gt80 of world cheese making

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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 6476-91992 yeast
• 58 FR 27197-203 1993 mold
• See Flamm E.L. Bio/Technology 9340-351 1991
• Same protein structure
• Most impurities removed
• Organism destroyed in processing
• Anti-biotic resistant marker destroyed

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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

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The first controversy - Monsanto Milk -
Recombinant BST or rBGH Neither GRAS nor Food
Additive rather It is an approved New Animal Drug
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Flavor-Savr Tomato

• Calgene asks for food additive status for enzyme
  FDA Docket 90A-0416, 91A-0330
• FDA findings
• enzyme introduced well documented _at_ lt0.16 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 29P17-26 1993
• 59 FR 26700-711 may 23, 1994

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FDA Approvals

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

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WHO-FAO

• 1993 - marker genes not a safety issue (lt
  1/250,000 of DNA consumed) Report 93.6
• 2000 - reconfirms prior statement safety aspects
  of genetically modified food of plant origin

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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.
Nature Biotechnology Volume 18 Number 11 p 1119
2000
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Substantial Equivalence Principles

• Term is not in any FDA document
• Reduction by 10 in key nutrients
• Increase by 10 in natural non-added 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

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The Legal Dilemma

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

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OECD 2000

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

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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

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EPA principles

• GMOs 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

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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

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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

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GMO the new potential threat

• Crossing transgenic species
• Brazil nut with soybeans for methionine
• Fish antifreeze protein in ice cream

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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
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Social Concepts of Risk Dr. Peter Sandman

• Risk Hazard Outrage

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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

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

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Outrage is everything about a risk that is
relevant, EXCEPT how likely it is to hurt
you. Outrage usually involves peoples concerns
and fears about a risk rather than scientific
evidence
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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 r2 lt 4

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According to Dr. Sandman

• For GM Foods
• RISK HAZARD OUTRAGE

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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

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European Experience

• UK Ministry of Agr said trust us on BSE
• Consumer outrage as result of BSE incident 80
  dead
• 1999 Belgiums Dioxin contamination
• EU concern over lack of data so invoke precaution
  if dont know enough, dont approve

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Risk Perception

• Knowledge does not necessarily lessen consumer
  concerns.

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Outrage Outcome

• Public pays more attention to outrage
• Activists and media in outrage business
• Outraged citizens dont listen to hazard data
• Outrage is a legitimate process
• When hazard is low - help reduce the outrage -
  Dont make risk comparisons
• Dont say they are dumb - all we
• need to do is educate them

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Identity Preservation Outrage

• The Adventis Bt Corn scenario

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The Transport Industry

• Farm truck
• Silo
• Train car
• Barge
• Boat
• Train car
• truck

Identity Preservation
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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

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Allergen analysis failure
Problems extraction denaturation /- need for
specific ELISA not available for most
allergens except peanuts and egg (Neogen)
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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
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EPA allergenicity evaluation http//www.environmen
taldefense.org/pubs/Filings/cry9c.html

• 1. Homology - EPA says no known homology of the
  8 amino acid sequence - but not all known
• 2. Cry9c is resistant to digestion
• 3. Cry9c is stable to thermal processing
• 4. MW (68 kD) 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

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Elisa Test Developed
http//www.agdia.com/cgi_bin/catalog.cgi/05600
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Starlink Corn problem

• Starlink corn produced by Adventis Corp (Research
  Triangle NC ) with Cry9c 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 Cry9c 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

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

• The next step Wednesday,
  October 11, 2000 448 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.

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Starlink Corn problem

• Kelloggs 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

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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 another
Aventis product.
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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 ConAgra stops operations at Kansas
corn flour mill - will not disclose
customers Nov 3 FDA announces over 300
products with potential risk
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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."
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Is this a realistic problem ?

• Ricki Hall Ark. Childrens Hospital Right now
  sensitivity to the protein is an unknown
• FDA/USDA/EPA says little if any risk
• Les Crawford Georgetown Univ. Its 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 didnt handle things
  correctly.

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Steve Taylor Univ. Nebraska

• Statement to EPA
• Would need repeated long time exposure to
  Starlink to develop allergy to it
• Cry9C 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

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websites

• Northernlight 360 hits in 167 sites
• Friends of earth http//www.foe.org/act/getacobell
  pr.html
• Environmental Defense Fund http//www.environmenta
  ldefense.org/pubs/Filings/cry9c.html
• The Campaign http//www.thecampaign.org/newsupdate
  s/sept00g.htm
• Lycos http//ens.lycos.com/ens/sep2000/2000L-09-18
  -04.html

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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 therisk 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

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Clinton Action

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

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The New Next to Final Step

• 66 FR 4706 Jan 18, 2001
• http//courses.che.umn.edu/01fscn11021s/general_fo
  od_safety/gmo/gmo.html
• Good history of regulation of GMOs
• Proposed
• 120 day premarketing notice to FDA

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Proposed 21 CFR 192PBN Premarket Biotechnology
Notice

• Identity
• Function
• Level
• Dietary exposure
• Allergenicity
• History of use of food in diet
• FDA response within 120 days

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The Final StepLabeling - Informed Consent

• Required warnings
• Saccharin
• Aspartame
• Sulfite
• Alcohol
• Meat handling
• irradiation

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Labeling - Informed Consentbasis the consumers
right to know so they can protect themselves from
harm

• Voluntary serious warnings
• allergens

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Labeling - Informed Consentbasis the consumers
right to know so they can have a freedom of choice

• Voluntary warnings
• Non-GMO

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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

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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

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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 dont

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Communication on GMO

• New Paradigm
• Right of public to provide input on public policy
  decisions
• Free flow of information (but dont cry fire in
  the wrong place
• Be honest, frank and open
• Issue burnout

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URLs Used in This Slide Show Presentation.

• www.soybeans.com/newscfm?docuementid96
• www.fmi.org/industry/biotech/
• www.aphis.usda.gov/biotechnology/faqs.html
• www.ifst.org/hottop10.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/w
  mt981109.genfood.html
• http//courses.che.umn.edu/01fscn11021s/general_fo
  od_safety/gmo/gmo.html

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Other pertinent material

• IFT Expert Panel Report on Biotechnology and
  Foods
• http// www.ift.org

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Theres a great day dawning if only we can get
through the night