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BIGMAP
& Perspectives on Biotechnology Risk
Analysis
Jeff Wolt
23 Feb 06
BIGMAP
Biosafety Institute
for Genetically Modified Agricultural Products
Iowa State University
BIGMAP will provide science-based
analysis of the risks and benefits of
genetically modified plant and animal
products. It will provide guidance and
education to help safeguard consumers
and the environment.
BIGMAP Core Personnel
Manjit Misra, Director
Jeff Wolt, Plant Biotechnology
Scott Hurd, Animal Biotechnology
Adelaida Harries, International Training
Yuh-Yuan Shyy, IT and Detection Methods
Paul Christensen, Business and Policy
Ted McDonald, Policy
Saharah Moon Chapotin, Regulatory Policy
23 Feb 06 BIGMAP & RA 3
Risk Analysis for New Technologies in
Agriculture
Protein Fate and Behavior
Plant Biofactories Plant Inputs
(PMPs/PMIs) Food Safety (PIPs)
Field Confinement
NTO RA and Monitoring
Regulation of Small/Emerging Markets
23 Feb 06 BIGMAP & RA 4
BIGMAP Areas of Current Emphasis
Understanding Risk
Risk analysis
Confinement & Channeling
Physical confinement of non-food crops
Fate & Behavior
Human and ecological fate and effect
Regulatory Process
Biotechnology policy & regulation
23 Feb 06 BIGMAP & RA 5
Understanding Risk
risk analysis
risk assessment
risk management
risk communication
risk perception
23 Feb 06 BIGMAP & RA 6
Enterprise Perspective of Risk Analysis
minimizing value loss
regulatory need
address human, animal, & environmental health
product stewardship
outreach to build trust and knowledge
anticipate and defend
mitigate against economic loss of market
rejection
science and public policy
communicate science-based principles
provide “hard” information
23 Feb 06 BIGMAP & RA 7
Street Calculus
by Garry Trudeau
Risk perception
concern-based
vs.
Risk assessment
consequence-based
23 Feb 06 BIGMAP & RA 8
goals of risk analysis
science-based approach to address
questions of risk and safety
build knowledge and trust through
transparency
shape policy for approaches to safeguard
consumers and the environment
23 Feb 06 BIGMAP & RA 9
risk versus safety
risk (science-based) – probability of harm to
be manifested under relevant conditions
risk (broadly) – knowledge, trust, perception
safety – societal judgment of the
acceptability of risk
science informs safety judgments through the
science-based assessment of risk
23 Feb 06 BIGMAP & RA 10
dilution and filtering of science-based
risk in policy decisions
Science Philosophy
Tradition
Ways of
Belief Knowing
perception
trust
Knowledge
judgment Filters
Safety
Policy
Decisions
23 Feb 06 BIGMAP & RA 11
risk assessment …
a bridge between science and policy
Data Acquisition, Verification, & Monitoring
Risk Assessment
Problem Exposure & effects Risk
Formulation characterization Characterization
Risk Management
risk assessment
a method for dealing with uncertainty
“do-the-best-with-what-you’ve got”
seeks to describe the likelihood of harm to
be manifested under environmentally
relevant conditions
23 Feb 06 BIGMAP & RA 13
risk assessment …
scientific, but not science per se
Science Risk Assessment
empirically driven limited empirical data
fully documented incomplete
documentation
reports reports lack of
heterogeneities knowledge
peer review peer review is arduous
full and open debate nature of process
hinders debate
Morgan and Henrion. 1990. Uncertainty: A Guide to Dealing
with Uncertainty in Quantitative Risk and Policy Analysis. Cambridge
23 Feb 06 BIGMAP & RA 14
integrity of risk assessment
formalism
transparency
iterative approach
delineation of known and unknown
parsing of heterogeneity from lack-of-knowledge
quantitative (probabilistic)
23 Feb 06 BIGMAP & RA 15
biotechnology risk assessment
a formal framework and approach to
understanding the risk and uncertainties
associated with products and processes of
modern biotechnology
frequently weight-of-evidence but amenable
to quantitative approaches
23 Feb 06 BIGMAP & RA 16
risk assessment for plant biotechnology
a conceptual framework
Formation
Risk Characterization
Release
Genetic Dispersal within Exposure
change/transfer the Environment Characterization
Establishment within an
Ecosystem
Human Ecological Hazard
Effects Effects Characterization
23 Feb 06 BIGMAP & RA 17
the problem of scale
risk is well-
addressed at
the molecular
scale…
the greatest uncertainties exist at the scale of use
23 Feb 06 BIGMAP & RA 18
understanding physical confinement
an instance of the problem of scale
Define processes for PMP confinement/channeling
Christensen et al. 2005. BIGMAP Bulletin
Develop methodology for exposure analysis
(a concern)
Wolt et al. 2005. Environ Biosafety Res 3:183-196
Assess risk (a consequence of exposure)
Wolt et al. 2006. Human & Ecol Risk Assess (in press)
Establish pollen flow monitor and response systems
Westgate et al. 2005. USDA-BRAG Project
Element 3: Iowa Mesonet as a real-time predictor of pollen
confinement loss
23 Feb 06 BIGMAP & RA 19
confinement
pharma crop systems by
design are intended to
be uniquely separate
from the food supply
through rigorously
managed confinement
measures
Christensen et al. 2005. Confined production processes for non-food corn. BIGMAP Bull.
23 Feb 06 BIGMAP & RA 20
Remove &
Pollination of No Destroy
Surrounding in
confinement
Surrounding
Tolerance ?
Crop
process
Yes
All No
Removed
?
Yes
Identify critical Move Plant
Material to
processes Containment
Analyze all processes,
including inputs, outputs Yes Plant
Material
No
B
and material that Moved ?
escapes Remove Off-types
After Flowering
Document critical
processes Yes
Train employees and Within No Will
Roguing
No
B
communicate
Standard ?
Work ?
expectations Yes Clean
Harvester
Harvester
Define measurement
criteria Training Harvest Crew
Audit the process
23 Feb 06 BIGMAP & RA 21
Harvest Ears
confinement state-of-the-art
commercial seed supply shows 99+% trait
purity UCS. 2004. Gone to Seed
Federal seed law mandates ≤10-3
frequency of unintended trait presence in
foundation seed (99.9% pure)
… and 99.5% purity for certified corn
current practice meets or exceeds this
standard Halsey et al. 2005. Crop Sci 45:2172-2185
23 Feb 06 BIGMAP & RA 22
s en c e
biomagnification of exposure
through ation of trait pre
s up pl y
Line Deve
lopment
Breeder S
eed
th e s e e d
Foundatio
n Seed
Commercia
l Seed
magnific
5 × 108x Grain
5 ,0 0 0 x
500x
pre-foundat
m
ion QC meas 1x
control again ures are use
maximu
st magnifica d to
tion of unint
traits ended
(see for insta
nce,
Mumm and
W alters, Crop
Science 200
1)
23 Feb 06 BIGMAP & RA 23
why not use a conventional risk
assessment perspective?
risk = f (exposure, effect)
exposure characterization based on
analysis of confinement integrity
effects characterization for dietary intake
23 Feb 06 BIGMAP & RA 24
exposure characterization
QEA for process integrity
describe process flows for confinement
use QEA to
identify process uncertainties
identify critical control points
understand nature of magnitude of
process failures
23 Feb 06 BIGMAP & RA 25
QEA for crop confinement
problem formulation
an unwanted
consequence of
confinement loss
Risk = f (Exposure, Hazard)
an attribute of the product
Exposure = f (Expression, Confinement)
Expression
an attribute of the system
as Confinement 100%
Risk 0%
regardless of product specific attributes
23 Feb 06 BIGMAP & RA 26
QEA for crop confinement
conceptual model
Confinement best practices
a general property of the agronomic system
Hazard Process flows Crop biology
an intrinsic conceptual description of management & Environment
property of the
pharma-active
compound
Materials flows
mathematical description of
management x environment
Expression
a property
Risk Exposure
of genes
x environment
23 Feb 06 BIGMAP & RA 27
QEA for crop confinement
analytical model
pollen management
23 Feb 06 BIGMAP & RA 28
QEA for crop confinement
characterize exposure
No confinement practice Rigorous confinement practice
confinement loss (seeds per hectare)
Outcrossing
1,500 6
Harvest mixing
30,000 nil
Dropped seed
60,000 2,500
Key finding is the relative magnitude of confinement that is achieved.
Lack-of-knowledge restricts purely quantitative interpretations.
23 Feb 06 BIGMAP & RA 29
effects characterization
food safety considerations
Food Crop Pharma Crop
Food safety expectation for a plant- Current product concepts for a human
Product attribute incorporated pesticide therapuetic protein
allergenic potenial no homology to known allergens allergenic compounds managed to control
exposure
expression low to negligible in processed food fraction maximize in an readily processed food
fraction
familiarity history of human dietary exposure to the varies
expressed product
food tolerance exempt from tolerance no tolerance
functionality loss of activity in processing stable to processing
glycosolation absence of post-translational glycosolation utilize the plant system to maximize
potential for post-translantional
glycosolation
heat stability loss of activity at moderate temperatures stable to heat extrusion temperatures
over short periods
mammalian activity non-active highly active
pepsin digestion must be rapidly degraded in simulated digestive stability is preferred
digestion fluid
substantial equivalence an existing organism used as food with a an existing organism used as food with a
history of safe use, can serve as a history of safe use, can serve as a
comparator when assessing the safety of the comparator when assessing the safety of
23 Feb 06 genetically modified food BIGMAP & RA the pharmaceutical purified from the food
30
crop
approach to provisional assessment for E. coli
enterotoxin subunit B (LT-B)
effect threshold
LT-B is widely established as non toxic
… but a definitive toxicity endpoint is lacking
use the functional dose (1.1 mg LT-B)
exposure
use high expression to account for reasonably
anticipated line improvement
(5 mg LT-B/g maize)
posit various scenarios for exposure to the
most affected population
Wolt et al. 2006. Human Ecol Risk Assess (in press)
23 Feb 06 BIGMAP & RA 31
PMP dietary exposure
reasonable worst case exposure
1 in 50
Tortilla chips
3 servings
PMP Admixed w/ Food
0.00125% adulterated
Dry mill
2000 Mg/d
Most highly
exposed population
Males, 13-19 yrs
PMP 25 kg 1 in 1000 receive
≈1/200th
of a functional dose
Non-dedicated combine
PMP
23 Feb 06Field BIGMAP & RA 32
1 ha
why such a conservative approach for
LT-B?
uncertain interaction with immune system
possible indirect toxicity through adjuvant
effect on toxic protein
Williams. 2000. Intl J Med Microbiol 290:447-453
stable to food processing
Streatfield et al. 2003. In Vitro Cell Devel — Plants 38:11-17
Chikwamba et al. 2003. Proc Nat Acad Sci 100:11127-11132
confinement is not fail safe
Wolt et al. 2005. Environ Biosafety Res 3:183-196
23 Feb 06 BIGMAP & RA 33
why not use a conventional risk
assessment perspective?
risk = f (exposure, effect)
exposure characterization is uncertain
broad base of products, production
strategies, and little knowledge of
confinement integrity
effects data are limited
appropriate toxicity testing data are often
lacking
no tolerance/no regulatory path or policy
23 Feb 06 BIGMAP & RA 34
the quandry
safety of biogenic products expressed in crop
plants will be closely scrutinized for intended uses
http://www.fda.gov/cber/gdlns/bioplant.htm
… but there is no mechanism for consideration of
inadvertent exposure in food
there is no food tolerance
recall is the only recourse when confinement
failure occurs
human health risk is likely low to negligible
… but market disruption and market deselection
pose risk of a different kind
23 Feb 06 BIGMAP & RA 35
biotechnology policy & regulation
Expert consultation with authorities
APHIS EIS backgrounder on seed
Joint USDA/EPA guidance on non-target testing
CFIA consultation on non-target research priorities
CSREES Specialty Crops Regulatory Initiative (SCRI)
Planning Committee
Develop science-based positions
Codex ad hoc TF Biotech research priorities
EPA-SAP consideration of protein digestion methods
Provide guidance for developers of biogenic plants
Client manual for regulatory data package development
IOBC-WPRS tiered risk assessment for non-target effects
23 Feb 06 BIGMAP & RA 36
biotechnology policy & regulation
Develop scientific underpinnings for policy-
making
Chapotin – regulatory empowerment of
small/niche market data developers
survey to stakeholder concerns
identify impediments
partner with opinion leaders
address state-of-science
communicate state of knowledge
23 Feb 06 BIGMAP & RA 37
protein fate & behavior
Novel extraction systems based on worm gut
fluids Shan et al. 2005. J Agric Food Chem
Bioactive protein fate in soil
Digestive and process fate
kinetics of plant-expressed PMP
degradation
23 Feb 06 BIGMAP & RA 38
Risk Analysis for New Technologies in
Agriculture
OUTPUTs INPUTs
Biofeedstocks PMPs/PMIs PIPs HT DR DT
Confinement and Channeling
pollen and gene flow
food safety
Regulatory Process
GRAS experimental use permits
manufacturing permitting post-registration monitoring
facilitating small market opportunities
Fate and Behavior
protein environmental fate
protein process fate
cost/benefit analysis
23 Feb 06 BIGMAP & RA 39
directions
refine and communicate the means for assessing
risk
identify uncertainties and champion their elucidation
provide tools and approaches for developers and
regulators
through science, press for policies that deal with the
tolerance conundrum
23 Feb 06 BIGMAP & RA 40
BIGMAP Presentations and Publications
http://www.bigmap.iastate.edu
3rd Annual BIGMAP Symposium
18 April 2006
Gateway Center
Communication of Agricultural Biotechnology Risks and Benefits
Paul Elias, Associated Press
Thomas Hoban, NCSU
Stig Albinus, Burson-Marsteller
Science and Policy Issues in Agricultural Biotechnology
Mary Ditto, FDA
Guy Cardineau, Arizona Biodesign Institute
Greg Jaffe, CSPI
23 Feb 06 BIGMAP & RA 41
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