1. GMO* and Food Safety Dr. Ted Labuza
Department of Food Science and Nutrition
Univ. Of Minnesota
St Paul 55108
* Frankenfoods ???

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

6. Poisonous or Deleterious Substances
general toxicity
carcinogens
mutagens
teratogens

7. FDA Regulation of GMO’s

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 health
Microbial 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 health
Chemical 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 health
Relates 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 health
example - solanine in potatoes
New level of consumption
More susceptible population
* meaning naturally present
So could apply to a GMO

13. Questions
What 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 additive
Note 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 testing
FDA Red Book st 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

17. 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 10x10 fold factor to estimate NRI
GRAS related

18. 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

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

21. 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 through either scientific procedures or common use in food to be safe under the conditions of its intended use.

22. 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

23. 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 /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 meeting
published in Spiher A.T. The Growing of GRAS Hort Sci. 10:
Approval based on nutrient level and toxicological levels

27. 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?

28. 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

29. The FDA Policy
57 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 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)

30. The FDA Policy
57 FR 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:
Current working policy products have been evaluated
12 corn, 7 canola, 6 tomato, 5 cotton, 4 potato
see IFT Expert Report on Biotechnology

31. Basis of policy 402 (a)(1) of FFDC
see Ronk et al Hort Sci 25;
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 # 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 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 April 1, 1994

33. OSTP 1994 Coordinated Framework for US Biotechnology Policy
51 FR June 26, 1986
Exercise of Federal oversight
57 FR 6753 Feb
Use 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 Potato
Ewan and Pusztai Lancet 354: 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

35. 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

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

37. 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

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

39. Flavor-Savr Tomato
Calgene asks for food additive status for enzyme FDA Docket # 90A-0416, 91A-0330
FDA findings
enzyme introduced well <0.16 ppm and digested 59 FR 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 29P:
59 FR may 23, 1994

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

41. WHO-FAO
marker genes not a safety issue (< 1/250,000 of DNA consumed) Report 93.6
reconfirms 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 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

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

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

46. EPA FIFRA FQPA 1996 7 USC 136(a) -136® Regulates pesticides
Pesticide is not a food additive
Stricter 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 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

48. 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

49. USD - APHIS
Fed 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 species
Brazil nut with soybeans for methionine
Fish antifreeze protein in ice cream

51. Allergenicity flags
Concern for transgenic introduction of allergenic protein
to 70 KDa
2. Resistant to digestion
3. Stable to heat processing
4. 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 happens
probability-how often it is going to happen
When outrage is zero then
Risk = 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 butterflies
2. 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 + 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 < 4%

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

59. 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

60. 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

61. Risk Perception
Knowledge does not necessarily lessen consumer concerns.

62. 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”

63. Identity Preservation Outrage
The Adventis Bt Corn scenario

64. The Transport Industry
Farm truck
Silo
Train car
Barge
Boat
truck
Identity Preservation

65. On farm or at commercial silo Mixing in transport Cost of test
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

66. Allergen analysis failure
Problems
extraction
denaturation +/-
need for specific ELISA
not 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 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

69. Elisa Test Developed

70. Starlink Corn problem
Starlink corn produced by Adventis Corp (Research Triangle NC ) with Cry9c Bt toxin protein
Approval given by EPA in 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

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

72. Seeds of Dissent
The next step : Wednesday, October 11, :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.

73. 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

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 another
Aventis product.

75. 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

76. 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."

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 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.”

78. 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”

79. websites Northernlight 360 hits in 167 sites
Friends of earth
Environmental Defense Fund
The Campaign
Lycos

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” 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

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, 2001
Good history of regulation of GMOs
Proposed
120 day premarketing notice to FDA

84. 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

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

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

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

88. FDA Labeling Guidance Document
66 FR 4839 (Jan 18, 2001)
Guidance Document
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

89. 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

90. 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

91. 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

92. URL’s Used in This Slide Show Presentation.

93. Other pertinent material
IFT Expert Panel Report on Biotechnology and Foods

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