Risk Assessment and Risk Management of GMOs

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Risk Assessment and Risk Management of GMOs

• W. De Greef, IBRS

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To cover

• Historical background
• Why risk assessment and risk management?
• Which risks?
• How to conduct risk assessment and risk
  management
• Timing and uncertainties

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Historical background

• Questions on safety of GMOs arose from the
  earliest days of the emergence of gene
  technology
• 1975 Asilomar conference and voluntary
  moratorium on laboratory experiments
• 1976-1985 first generation of (national)
  regulations and guidelines on GMO work
  (essentially in laboratory)
• 1986 Publication of the Blue Book Safety
  considerations for industrial, agricultural and
  environmental applications of organisms derived
  by recombinant DNA techniques
• ? first major effort towards international
  harmonisation of biosafety assessment of GMOs
• ? Focus on GMOs destined for release in the
  environment

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More history

• 1987 1990
• first major wave of legally binding regulation of
  activities with GMOs
• Beginning of focus on GM crops (pressure by NGOs)
• ALL based on the Blue Book guidelines
• 1990 2000
• The development and distribution of the first
  generation of GM crops
• Putting into practice the recommendations of the
  Blue Book
• Verifying whether any biosafety hazard has
  escaped attention of RA
• Excellent safety record for GM crops no
  biosafety accident known
• 1997-2005
• Negotiation and implementation of the Cartagena
  Protocol
• Ongoing, deeply flawed international instrument

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Why do a Risk Assessment (RA) and organise Risk
Management (RM)?

• Biotech was the first technology which was
  regulated before the first accident
• Application of the Precautionary approach before
  it became enshrined in environmental policy (CBD)
• Recognition that it is possible to do harm to
  human health and to the environment
• Understanding that these risks can be managed to
  mitigate or eliminate risks

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Potential risks of GM crops

• Environmental
• Impact on biodiversity through escape,
  multiplication or replacement native gene pools
  (e.g. drought tolerant plants)
• Impact on ecosystems through toxic effects (e.g.
  insect tolerant plants) and potential elimination
  of non-target species
• Health
• Potential toxicity of the new gene(s)
• Potential allergenicity of new gene products
• Potential effect on expression of native toxins
  or allergens of the receiving plant

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RA and regulatory compliance

• Risk assessment is the first step towards a
  regulatory approval and compliance strategy.
• It is only effective if it fits in a regulatory
  strategy
• Identify where the crop will be grown, and where
  it will be traded
• Prepare the necessary DATA for inclusion in the
  regulatory dossiers
• It has to be linked to a risk management strategy
  and a communication strategy

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Points to consider

• A biotech project has a number of parallel
  sub-projects the regulatory project is one of
  them
• Regulatory time loss can start from the day of
  concept of the project
• Choice of a gene coding for a toxic or a stable
  protein
• Choice of an unacceptable selectable marker
• Regulatory compliance starts in the lab!
• There is a difference between the biosafety
  project and the regulatory project
• Biosafety assessment is a technical exercise
• In regulatory clearance, cost-benefit analysis,
  including non-technical parameters will enter the
  equation

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Points to consider

• After POC, regulatory clearance is almost always
  on the critical time path of a GM crop project
• The regulatory environment of biotechnology has
  not stabilized, and will change during a project
• Need to stay informed about policy changes!
• The best way to stay informed is to be actively
  involved!
• It is a good idea to develop the benefit file
  together with the regulatory file
• Environmental benefits
• Socio-economic benefits

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A regulatory strategy distinguishes between

• Biosafety research (an open-ended scientific
  inquiry)
• Biosafety assessment (the systematic evaluation
  of a number of  points to consider , according
  to standards set by a regulatory body)
• The regulatory dossier and its management (which
  requires thorough knowledge of the regulations
  but also of trading patterns of the seed and the
  grain of the crop)
• Product Stewardship (the collection of technical
  and management measures needed to remain in
  compliance with the conditions of permits)

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Chosing the unit of regulatory activity

• By law, the unit of biosafety assessment and
  regulatory oversight is the event.
• it is essential to use as few events as possible
  to avoid escalation of biosafety assessment and
  regulatory costs
• Most components of a biosafety assessment (and
  their compilation in a regulatory submission) can
  only be developed using the final event
• In most jurisdictions, stacked events require a
  new regulatory submission (exception USA)

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The Biosafety package

• There are big differences in biosafety policy
  between countries, BUT
• There is much less difference between the
  technical requirements in a biosafety package
• These requirements were first set by the Blue
  Book
• They form the technical annexes of the national
  regulations of all OECD member states
• They have been adopted by almost all other
  countries with a regulation! ( e.g. China, India,
  Brazil, Argentina, South Africa )

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Components of the package

1. Description of donor and recipient organism
2. Characterisation of the DNA to be inserted
3. Molecular characterisation of the event
4. Compositional analysis of the event
5. Assessment of health safety of the event
6. Assessment of environmental safety of the event
7. Development and validation of event-specific
   detection tools.

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1. Donor and recipient organisms

• This is the only part of the package which is
  essentially event-independent and
  geography-independent
• For most major crops, including maize, there are
  standards from which to work,
• For Bacillus thuringiensis, the same applies
• Ref OECD consensus documents on crop biology

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2. The DNA insert

• The requirements for molecular characterisation
  of the new DNA are very stringent
• importance of good documentation at research
  stage!
• need to ensure that reference material of the
  original vectors remains available for future
  verification by regulators.
• If vectors or genes come from others, ensure that
  this information is supplied as part of the MTA

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3. Molecular characterisation of the event

• Copy number
• Insertion site(s)
• Confirmation that the gene(s) have not inserted
  in an open reading frame
• Confirmation that no junk DNA or incomplete
  copies remain
• Sequencing of the insert(s) and flanking
  sequences
• Expression profile of the inserts
• Evaluation of genetic stability of the insert(s)

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4. Compositional analysis

• Components
• Major and minor nutrients (standards have been
  developed by OECD and by Codex alimentarius)
• Minerals and vitamins
• The challenge
• The applicant must demonstrate reproducibility of
  the figures produced
• Therefore the event has to be backcrossed in
  several germplasm backgrounds (usually 3)
• These materials (and their non-transgenic
  isogenics) have to be grown in a properly
  replicated design over at least 2 seasons in
  several locations)

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5. Assessment of human health safety

• Nutritional trials for digestibility (on several
  animal species)
• Suite of experiments required for confirmation of
  non-allergenicity of all newly expressed proteins
  (including selectable marker)
• Suite of experiments for confirmation of
  non-toxicity
• Acute and sub-chronic feeding trial
  (dose-response curve) of the expressed proteins
  on mouse
• Acute feeding trial on a range of other
  representative animals (birds, fish, mammals,
  invertebrates) of the proteins
• The challenge
• produce enough materials of the proteins (in
  purified form and in a plant matrix) for the
  tests.
• Find labs to do the tests according to
  international standards.

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6. Environmental safety assessment

• Gene flow assessment in the future receiving
  environment
• Outcrossing to other crop varieties (including
  landraces!)
• Outcrossing to wild relatives
• Interactions with biota in the receiving
  environment
• Assessment of impact on soil organisms
• Assessment of impact on organisms living on
  vegetative parts of the crop (with special
  attention to non-target insects)
• Assessment of impact on animals feeding on the
  seed or on the vegetative parts of the plant

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7. Event-specific detection tools

• Detection tools have to be developed for
  protein-based and DNA based detection.
• Protein based methods have to include both
  quantitative and (usually cheaper) qualitative
  tools
• The applicant has to demonstrate that the GM
  varieties released contain only the GM event
  which receives the regulatory permit
• Real-time PCR has become the standard for DNA
  based detection
• Needs to be event specific!!
• Need to create tail-PCRs for each candidate event

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From Biosafety package to Regulatory filing

• The original regulatory submission will contain
  all the data of the biosafety package
• In addition, it will contain (in the case of
  insect resistance)
• An IRM strategy, validated for the environment in
  which the crop is to be introduced
• A product stewardship programme
• A contingency plan, validated for the
  jurisdiction in which the crop is to be
  introduced
• These are the elements of a risk management
  strategy
• No risk management strategy is complete without a
  comprehensive risk communication program

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The food/feed permits

• Food/feed permits are the backbone of the
  procedure for rapid and hindrancefree movement
  of the crop across national borders
• Most of the data needed are generated in the
  original biosafety package
• Some authorities are very difficult about Mutual
  Acceptance of Data (especially for compositional
  analysis)
• Many authorities require at least one year of
  growing for compositional analysis in their
  borders ? significant cost!
• Analysis of the trading patterns in the expected
  growing markets is an essential early component
  of the regulatory strategy

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Post-release stewardship

• No large scale release comes without conditions
• The holder of the permit is accountable for
  compliance with the conditions of the permit and
  liable for damage if something goes wrong
• Need to upgrade all breeding and seed production
  methodologies
• Need to develop a post-release management program
• Need to ensure that reporting requirements are
  met
• A special problem
• Almost all permits today are time-limited

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Regulatory management

• The development and management of a large scale
  introduction of a GM crops requires complex
  management
• It involves scientific, technical, legal and
  administrative expertise
• It requires presence on the ground in several
  countries and experience with many jurisdictions

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Carrying out risk management

• Executing a risk management strategy requires
  close cooperation between practitioners and
  authorities
• Monitoring for specific and foreseeable effects
  is usually carried out by permit holder
• Research on potential unforeseen effects is
  usually done by outside scientists, on government
  funding
• Risk management is before all a communication
  exercise.

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Safety the ghost issue

• Biosafety in GMO work was an early concern for
  both scientists and governments
• Regulation and safety assessment started in late
  1970s
• GM crops have always been regulated in all
  industrialised countries
• Real safety concerns focused around
• Health toxicity, allergenicity
• Environment gene escape and invasiveness
• These are all addressed in all regulatory systems
• Result more than 1 billion tonnes of GM food
  produced, not a single health or environmental
  damage case

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Why is biotech so safe?

• Biotechnology is an information technology
• The only thing new in GM crops is the information
  contained in the rDNA
• No issues of residues
• Products of biotech are DNA and proteins
• All digestive systems have evolved to dismantle
  DNA and proteins

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Why is biotech so safe?

• Biotech was the first technology that was
  regulated before accidents happened
• First guidelines for lab work in U.S. and Europe
  in 1970s
• Harmonisation of regulations stimulated by OECD
  from 1983
• All major developer and user countries have
  elaborate biosafety regulatory structures in
  place
• ? Not a single safety issue in 10 years

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Safety and risk perception

• While scientific safety assessment and management
  points to a technology with a uniquely positive
  safety record
• Public perception is of a technology haunted by
  issues
• Monarch butterfly (U.S.), farm scale trials (UK),
  co-existence (EU), GM food aid, Starlink, Bt10,
  .
• What has gone wrong?
• Massive misunderstanding among policy makers on
  reality of risks
• Lack of a risk-benefit approach
• Non-safety issues reported as safety issues

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Monarch Butterfly deaths from GM
pollenGenetically modified crops may kill
Monarch Butterfly                               
                                             
Reality check thanks to improved habitat
protection and lower insecticide use, the monarch
butterfly is doing well
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The need for risk/benefit approach

• Risk assessment does not consider potential
  beneficiary effects
• Promoting zero tillage improved erosion control
  CO2 capture
• Reduced insecticide use less non-target effects
• Leads to quest for proof of zero risk ?
  impossible!
• Considering risk apart from benefits is a poor
  basis for risk management decisions

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How to connect perception with reality?

• In many places the perception of safety issues
  with GM crops has become received wisdom
• Very difficult to dislodge, in view of
• Ignorance of agriculture among end users and
  policy makers
• Risk theory fear and risk perception is mostly a
  matter of control
• Building trust through information and dialogue

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Conclusions

• GM crops are rapidly becoming mainstream in the
  most important agricultural production centres
• They have brought significant benefits to
  farmers, and new products will bring large
  consumer benefits
• They have been embroiled in a massive public
  safety controversy, for which there is no basis
  in fact
• The only way to restore consumer and policy maker
  confidence is quality communication.

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Thank you