Risk Assessment and Risk Management of GMOs

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					Risk Assessment and Risk
 Management of GMOs
    W. De Greef, IBRS
                      To cover:

   Historical background
   Why risk assessment and risk management?
   Which risks?
   How to conduct risk assessment and risk management
   Timing and uncertainties
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
                           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
       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
         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
       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
     – Prepare the necessary DATA for inclusion in the regulatory

   It has to be linked to a risk management strategy and a
    communication strategy
                  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
            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
A regulatory strategy distinguishes

   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
   Product Stewardship (the collection of technical and
    management measures needed to remain in
    compliance with the conditions of permits)
       Chosing the unit of regulatory

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)
               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 )
       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.
    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
                  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
    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)
         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
    – 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)
    5. Assessment of human health safety
   Nutritional trials for digestibility (on several animal
   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.
6. Environmental safety assessment

   Gene flow assessment in the future receiving
           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
           Assessment of impact on animals feeding on the seed or
            on the vegetative parts of the plant
    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
           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
                The food/feed permits

   Food/feed permits are the backbone of the procedure for
    rapid and hindrance–free movement of the crop across
    national borders:
    – Most of the data needed are generated in the original biosafety
    – 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
          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
   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
          Regulatory management

   The development and management of a large scale
    introduction of a GM crops requires complex

   It involves scientific, technical, legal and administrative

   It requires presence on the ground in several countries
    and experience with many jurisdictions
      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.
                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
   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
           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
            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
    – All major developer and user countries have elaborate
      biosafety regulatory structures in place

     Not a single safety issue in 10 years
          Safety and risk perception

   While scientific safety assessment and management
    points to a technology with a uniquely positive safety

   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
    – Lack of a risk-benefit approach
    – Non-safety issues reported as safety issues
   “Monarch Butterfly deaths from GM pollen”
Genetically modified crops may kill Monarch Butterfly

 Reality check: thanks to improved habitat protection and lower
       insecticide use, the monarch butterfly is doing well
    The need for risk/benefit approach

   Risk assessment does not consider potential beneficiary
    – 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
    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
     – Risk theory: fear and risk perception is mostly a
       matter of control

      Building trust through information and

   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.
Thank you

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