safety assessment process to register gm...

• Regulatory Science Seeds & Traits • March 2013

Safety Assessment Process To Register GM Products

Laura Privalle, Ph.D.August 12, 2014


Agenda/Content

Introduction to the technologySafety AssessmentsSummary


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


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


• 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


Most Studied Food – Safety Reviewed by Agencies all Around the World

Production Countries Importing countries


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

http://www.who.int/features/factfiles/food_safety/en/


#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


Gene(s)

Protein(s)

Crop Characteristics

Food/Feed Composition

Environmental Safety

Food / Feed

and


Crop Safety Gene / Protein

Safety Assessment is a multi-pronged undertaking


Regulatory Studies are grouped

in four categories:

• Molecular characterization

• Protein Characterization/Food/feed safety

• Agronomic and Compositional Equivalence

• Environmental safety


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


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

Weight of Evidence Approach

Two Tiers:

Basic Assessment

Supplementary Assessment

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

m

of corn for lunch.

Proteins are tested at levels equal to a 75 kg man eating

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


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 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


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.

Thank you!

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