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Slide 1 • Regulatory Science Seeds & Traits • March 2013
Safety Assessment Process To Register GM Products
Laura Privalle, Ph.D.August 12, 2014
Slide 2 • Regulatory Science Seeds & Traits • March 2013
Agenda/Content
Introduction to the technologySafety AssessmentsSummary
Slide 3 • Regulatory Science Seeds & Traits • March 2013
Desired Gene
X
Many genes are transferred
Donor Plant Commercial Plant Variety New Plant
Variety
+
A single gene is transferred
Desired Gene
Commercial Plant Variety
Improved Commercial Plant Variety
PLANT BIOTECHNOLOGY
Desired Gene
Donor
Biotechnology is an Extension of Traditional Plant Breeding
TRADITIONAL PLANT BREEDING
Slide 4 • Regulatory Science Seeds & Traits • March 2013
http:www.croplife.org/PhillipsMcDougall Study
DISCOVERY
Gene/Trait
Identification
PHASE I
Proof Of
Concept
PHASE IIEarly Development
PHASE IIIAdvanced Development
PHASE IV
Pre-launch
AVERAGE
DURATION1 53.9 MONTHS 27 MONTHS 30 MONTHS 37.2 MONTHS 48.8 MONTHS
Mean units
tested
10209
In silico
methods
511
Preliminary
Digestive
fate
1302
Molecular
Char. For EES
2
Full Regulatory
Study Package
1
Data Defense
single ELITE event
REGULATORY DATA GENERATION
Slide 5 • Regulatory Science Seeds & Traits • March 2013
• Safety assessment for plant biotech products is mandatory worldwide
• Considers human + animal health as well as environmental safety
• Approval only if authorities conclude:
Genetically optimized plant is as safe as a conventionally bred plant
Safety assessment starts early in the development process
Safety for humans, animalsand the environment
Slide 6 • Regulatory Science Seeds & Traits • March 2013
Most Studied Food – Safety Reviewed by Agencies all Around the World
Production Countries Importing countries
Slide 7 • Regulatory Science Seeds & Traits • March 2013
Food Safety is a Global Concern :
Consumers need assurance that food will not cause harm and covers contamination by chemical and biological agents and concerns about inherent food nature.
Key Global Concerns (http://www.who.int/features/factfiles/food_safety/en/) include:
Spread of microbiological hazards
Chemical Food Contaminants
WebMD
Bisphenol A
Genetic Modification
1,500,000 deaths/yr >300,000 affected
by melamine and
urea in milk in
2008
0 deaths or
illnesses resulting
from GM foods
Slide 8 • Regulatory Science Seeds & Traits • March 2013
#1 USA69.5 Million Hectares Maize, Soybean, Cotton, Canola, Sugarbeet, Alfalfa, Papaya, Squash
#4 Canada11.6 Million HectaresCanola, Maize, Soybean, Sugarbeet
#16 Mexico0.2 Million HectaresCotton, Soybean
# 17 Spain #22 Portugal #23 Czech Republic #27 Romania #28 Slovakia0.1 Million <0.05 Million <0.05 Million <0.05 Million <0.05 Million HectaresMaize Maize Maize Maize Maize
#2 Brazil #11 Bolivia #20 Honduras36.6 Million 1.0 Million <0.05 Million HectaresSoybean, Maize, Cotton Soybean Maize
#3 Argentina #24 Cuba #26 Costa Rica 23.9 Million <0.05 Million <0.05 Million HectaresSoybean, Maize, Cotton Maize Cotton, Soybean
#7 Paraguay #18 Chile3.4 Million <0.05 Million Soybean, Maize, Cotton Maize, Soybean, Cotton
#10 Uraguay #19 Colombia1.4 Million <0.05 Million HectaresSoybean, Maize Cotton
#8 South Africa2.9 Million HectaresMaize, Soybean, Cotton
#14 Burkina Faso0.3 Million HectaresCotton
#21 Sudan<0.05 Million HectaresCotton
#25 Egypt<0.05 Million HectaresMaize
#5 India10.8 Million HectaresCotton
#6 China4.0 Million HectaresCotton, Papaya, Poplar, Tomato, Sweet Pepper
#9 Pakistan2.8 Million HectaresCotton
#12 Philippines0.8 Million HectaresMaize
#13 Australia0.2 Million HectaresCotton, Canola
#15 Myanmar0.3 Million HectaresCotton
Slide 9 • Regulatory Science Seeds & Traits • March 20139
Gene(s)
Protein(s)
Crop Characteristics
Food/Feed Composition
Environmental Safety
Food / Feed
and
Environmental Safety
Crop Safety Gene / Protein
Safety Assessment is a multi-pronged undertaking
Slide 10 • Regulatory Science Seeds & Traits • March 2013
Regulatory Studies are grouped
in four categories:
• Molecular characterization
• Protein Characterization/Food/feed safety
• Agronomic and Compositional Equivalence
• Environmental safety
Slide 11 • Regulatory Science Seeds & Traits • March 2013
Molecular Characterization
• Number of DNA inserts, insert stability
• Number of copies
• Integrity of gene cassettes
• Presence of additional DNA (backbone)
• Sequence of genomic flanking DNA
• Sequence of the inserted DNA
Protein characterization, Food / Feed safety
• Gram quantity protein production and purification
• Establishing protein level in plant tissues
• Protein characterization and equivalence
• Allergenicity assessment
• Toxicity assessment
AAA
AP AP AP
substrateColor
Slide 13 • Regulatory Science Seeds & Traits • March 2013
Protein expression levels:Tissues and Stages Considered
• Need to know how much is out there at any time throughout the growing season
• For a PIP this information belongs on the label as for any pesticide
• Contributes to exposure assessments – if not in the seed (and the seed is consumed) = no exposure
• If not in the pollen – reduces environmental exposure
Crop and Trait Dependent
Why proteins do not typically represent a
hazard
Proteins are relatively large and labile.
Proteins are an essential part of the diet (avg. consumption 100 g/day).
Digestive systems have evolved to convert the protein to its building blocks for incorporation. (very efficient only 6 – 12 g protein lost/day)
The human body synthesizes approx. 300 g protein/day.
Protein Hazards
• Pathogenic bacterial toxins - botulinum, diptherium, active <100 mg/kg body weight.
• Plant toxins - ricin (0.5 mg MLD)
• Animal toxins - prions
• Allergens – Ara H2, b-lactoglobulin
• Antinutrients - trypsin inhibitors, some lectins
Basic Assessment
History of safe useBioinformatics sequence homology assessmentSource of geneMode of actionRange and pattern of expression levelsStability of protein to temperature, pH, and digestive enzymes
REQUIRE SMALL AMOUNTS OF PROTEINCAN BE PERFORMED DURING PHASE 1.2
Supplementary Assessment
• Acute toxicity testing with recombinant transgenic proteins14 day mouse study – single dose 2000 mg/kg body weight
• 28 day repeat dose toxicology testing at 1000 mg/kg body weight DAILY
• Hypothesis-based testing to be determined on a case-by-case basis
REQUIRE LARGE AMOUNTS OF PROTEIN
Bridging Study to Show Equivalence1. Is the plant producing what we expect it to produce?
2. Is the test substance used in toxicological studies the same
as what the plant produces?
• Size (SDS-PAGE, MALDI-TOF)
• Immunoreactivity (western analysis, ELISA)
• Functionality (enzymatic assay, bioassay)
• Post-translational modification (mass spectrometry, others)
• N-terminal amino acid sequence (Edman degradation)
Agronomic and Compositional Equivalence
• Agronomic / phenotypic assessments
• GM plant samples from multi-location, multi-year,
replicated field trials
• Nutrient / antinutrient analyses on grain and
processed products
• Animal feeding studies
• Weediness assessment
Agronomic ParametersCorn Cotton SoybeanYield Yield YieldGermination Days to Emergence GerminationDays to Silking Days to Flowering Seedling vigorDays to pollen shed Plant Height %Plant standDisease Days to Open Bolls Days to 50% full bloomWeediness Plan t Health Days to harvest# seed/ear Vigor Stay green% moisture Disease Plant heightEmerged plants Uniformity DiseaseTest weight Stand Count Insect damagePlant height Lodging Soil ecologyEar height Boll Type EarthwormsLodging Percent Open Bolls Soil microbesStay green Total Harvest weightDropped ears Insect damage
Analytes
Corn Cotton SoybeanProximates Proximates ProximatesFatty Acids Fiber Fatty AcidsMinerals Fatty Acids MineralsVitamins Minerals VitaminsAmino acids Vitamins Amino acidsFerulic acid Amino Acids LectinsCoumaric acid Gossypol IsoflavonesPhytate Phytate LecithinsXanthophylls Malvalic Acid PhytateStarch Sterculic Acid Trypsin inhibitor
Urease activityADF & DNFRaffinose & Stachyose
Slide 24 • Regulatory Science Seeds & Traits • March 2013
Typical Processed Fractions
• Ginned seed
• Linters
• Delinted seed
• Hulls
• Meals
• Crude oil
• RBD oil
• Seeds
• Presscake
• Toasted Meal
• Solvent extracted meal
• Crude oil
• RBD oil
• Seeds
• Meal
• Hulls
• Crude oil
• RBD oil
Cotton Canola Soybean
Animal Wholesomeness Studies
Rat 90 day subchronic study with grain
42 Day Poultry feeding study
Catfish study
Swine study
Dairy cattle study
Beef cattle study
Environmental Safety
• Environmental safety and fate
• Interactions with target and nontarget organisms
• Interactions with the abiotic environment and soil
For Pesiticidal Plants Ecotoxicological Studies:
• Collembola
• Honeybee
• Fish
• Daphnia
• Avian
• Ladybeetle
• Soil Stability
• Earthworm
• Lacewing
• Resistance management
Who Evaluates the Safety Assessment?US: EPA - pesticidal
FDA – food/feed
USDA – deregulates events
EU: EFSA – Scientific Evaluation
Canada: CFIA – Novel Plants
Health Canada – food/feed
Japan: MAFF
MHW
Brazil: CTNBIO
Slide 29 • Regulatory Science Seeds & Traits • March 2013
Summary
• Biotech foods are the most highly studied foods in the world
• Our dossiers are reviewed by many s
• The safety assessment requires a multipronged approach
• Approval is granted only if the biotech crop is determined to be as safe as its conventional counterpart.