This presentation highlights the history of risk and safety assessment approaches for GEOs/GMOs, the current application of risk and safety assessment approaches for GEOs/GMOs and the Implications for emerging applications of genome editing and their assessment.

1. Current risk assessment approaches for
environmental and food & feed safety
Jeffrey D Wolt
Iowa State University
OECD Genome Editing 28-29 Jun 2018

2. Plan of presentation
• History of risk and safety assessment approaches for
GEOs/GMOs
• Current application of risk and safety assessment
approaches for GEOs/GMOs
• Implications for emerging applications of genome editing and
their assessment
OECD Genome Editing 28-29 Jun 2018

3. Key foundational documents
• OECD (1986) rDNA safety considerations “Blue Book”
• WHO (1991) Strategies for assessing the safety of
foods produced by biotechnology
• OECD (1993a) Safety considerations for biotechnology:
scale-up of crop plants
• OECD (1993b) Safety evaluation of foods derived by
modern biotechnology: concepts and principles
• OECD (1993c) Traditional crop breeding practices
• WHO (2000) Safety aspects of genetically modified
foods of plant origin
OECD Genome Editing 28-29 Jun 2018

4. Technical information
• CAC (2003a) Principles for the risk analysis of foods derived
from modern biotechnology (CAC/GL 44-2003)
• CAC (2003b) Guideline for the conduct of food safety
assessment of foods derived from rDNA plants (CAC/GL 45-
2003)
• OECD Harmonization of Regulatory Oversight in
Biotechnology Consensus Documents
• OECD Safety of Novel Foods and Feeds Consensus
Documents
• CBD (2016) Guidance on risk assessment of living modified
organisms (UNEP/CBD/BS/COP-MOP/8/8/1)
OECD Genome Editing 28-29 Jun 2018

5. Key foundational documents
• OECD (1986) rDNA safety considerations “Blue Book”
• WHO (1991) Strategies for assessing the safety of
foods produced by biotechnology
• OECD (1993a) Safety considerations for biotechnology:
scale-up of crop plants
• OECD (1993b) Safety evaluation of foods derived by
modern biotechnology: concepts and principles
• OECD (1993c) Traditional crop breeding practices
• WHO (2000) Safety aspects of genetically modified
foods of plant origin
OECD Genome Editing 28-29 Jun 2018

6. Risk analysis context
• Risk assessments for rDNA organisms are in principle no
different than for traits developed through traditional
breeding
• Safety assessment of any new organism relies on
knowledge of the parent and differences from the parent
• “There is no scientific basis for specific legislation for the
implementation of rDNA techniques and applications.”
OECD Genome Editing 28-29 Jun 2018
OECD, 1986

7. Underlying scientific principles
• No new risks
• environmental impacts similar in principle to introductions
of existing species & their agricultural applications
• direct & indirect effects are relevant concerns for
traditional plant breeding
• evaluate incremental risk associated with GEOs/GMOs
• Potential environmental impacts
• non-target species; ecosystem function; responses of
species to each other & to their environment
• Unexpected adverse impacts often a low specific concern
• weediness, secondary metabolites & protein toxins in
food/feed, wide area monoculture
• assess as for conventionally bred crops
OECD Genome Editing 28-29 Jun 2018
OECD, 1986

8. Paradigm for risk/safety assessment
• Proceeds from an established baseline
• Involves characterization of
• the organism & its environmental release (in a way
amenable to probabilistic approaches)
• establishment & persistence in the environment
• human & ecological effects (analyzed in principle through
existing methods)
OECD Genome Editing 28-29 Jun 2018
OECD, 1986

9. Comparative risk
• Risk/safety is understood by comparison to what is familiar &
that which has a history of safe use
• Incremental risk is established relative to a baseline of
plants/derived foods from traditional plant breeding
• Familiarity & Substantial Equivalence
• ways to establish a risk analysis baseline for determining
whether/to what extent risk/safety assessment is needed
• substantial equivalence is not a safety assessment per se
• represents a method for hazard identification to
determine safety assessment needs
• uses baseline history of safe use
OECD Genome Editing 28-29 Jun 2018
OECD, 1993a; WHO, 2000

10. Risk to the environment
• Caution regarding “premature” implementation of guidance
for emerging technology
• Management principles guide initial field releases, but do not
infer risk
• Subsequent risk assessment
• proceeds from the concept of familiarity
• is case dependent
• uses a stepwise approach
• reflects knowledge of the crop, its environment, the trait
and their interactions
• comparative assessment to identify incremental risk
OECD Genome Editing 28-29 Jun 2018
OECD, 1986; 1992; 1993a

11. Safety of food for human consumption
• Demonstrates reasonable certainty that no harm results from
intended uses under the expected conditions of consumption
• Recognizes a ‘history of safe use’ of traditional foods as the
benchmark for the comparative safety assessment
• Uses an integrated and stepwise, case-by-case approach …
• And “comparative determination of similarities and
differences between the genetically modified food and its
conventional counterpart”
• Involves targeted evaluations, rather than conduct a
standard battery of toxicological tests
OECD Genome Editing 28-29 Jun 2018
OECD, 1993b; WHO, 1991

12. Current application of risk/safety assessment
to GEOs/GMOs
• OECD/WHO/Codex provide a RA/SA paradigm & sound
scientific guidance which are internally consistent
• Implementations within various regulatory regimes often
depart from the spirit of this guidance
• scientific guidance must be applied within the legal,
social, & political constraints of a given regulatory regime
• Regulatory implementations of the RA/SA paradigm have
skewed to increasingly complex portfolios of studies rather
than adhering to analysis which is formulated to fit the
risk/safety questions relevant to a given case
OECD Genome Editing 28-29 Jun 2018

13. Spiraling study complexity
unrelated to probable harm
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14. The problem of 2nd order risk
• Risk of the risk/safety assessment being wrong
• Miss a significant risk
• Overanalyze a non-significant risk
• Current knowledge suggests over-analysis of non-significant
risk for GEOs/GMOs
• Expectation of low probability for incremental risk above
the baseline of traditional plant breeding
• Reasonable certainty of no harm from 2+ decades of
environmental deployment & occurrence in foods/feeds
• No significant or unexpected harms shown in RA/SA of
products released to date
OECD Genome Editing 28-29 Jun 2018
OECD, 1986; EC, 2010; Nicolia et al., 2014; Pellegrino et al., 2018

15. A need for sound problem formulation
• “review of potential risks should be conducted on a case-by-
case basis, prior to application. Case-by-case means an
individual review of a proposal against assessment criteria
which are relevant to the particular proposal; this is not
intended to imply that every case will require review by a
national or other authority since various classes of proposals
may be excluded” (OECD, 1986).
• Stepwise
• Case-by-case
• Comparative baseline
• Developed from product history of safe use and familiarity
• Uses substantial equivalence as a “a starting point from
which to structure a program to demonstrate any potential
differences from the comparator which, if detected, can
be evaluated in terms of safety” (WHO, 2000).
OECD Genome Editing 28-29 Jun 2018

16. Implications for RA/SA of genome edited
plants
• No new risks
• deep experience with assessing traditional, mutational,
and molecular breeding
• Substantial interesting science questions
• improved efficiency & specificity of targeted mutations
• Science questions (nice to know) are not necessarily
regulatory questions (need to know)
• At this stage of technology development, risk management
may be more effective than risk assessment
• science governance mechanisms can assure best
practices in gene editing design, null sergeant selection,
process definition & product characterization
• Avoid conflating risk management with risk assessment
OECD Genome Editing 28-29 Jun 2018

17. Implications for RA/SA of genome edited
plants
• Problem Formulation
• Use risk analysis that implements sound problem formulation
to guide the need for and nature of risk/safety assessments.
• Flexibility
• Accommodate new knowledge in risk analysis framework
• Risk analysis framework – a process map, not a list of
actions/studies
• Avoid genome-wide assessments as a risk paradigm
• Insufficient reference genomes for comparative assessments
• Plant genome plasticity – signal to noise limits
• The process-product conundrum
• Scientific RA/SA for plants/derived foods (product focus)
• Regulatory constraints may argue otherwise (process focus)
OECD Genome Editing 28-29 Jun 2018

18. Summary points –
Historical risk/safety assessment paradigm
• GEOs/GMOs as a class do not represent new risks relative
to products of traditional plant breeding
• products of traditional plant breeding have an established
“history of safety use”
• incremental risk of the GEO/GMO is considered on a
stepwise case-by-case comparative basis
• existing crops and derived-foods serve as the comparative
baseline
• targeted evaluations should key to identified
hazards/reasonably anticipated harms
OECD Genome Editing 28-29 Jun 2018

19. Summary points –
Risk/safety assessment current practice
• OECD/WHO/Codex describe a workable RA/SA paradigm &
sound scientific guidance which are internally consistent
• Problem formulation is implied but explicit application is
lacking
• Techniques for risk/safety evaluation are emphasized over
processes for risk analysis to identify what needs evaluation
• Increasingly complex dossiers of studies vs. risk analysis
commensurate with recognized hazards/reasonably
anticipated harms
• Regulatory disconnects in intent vs. application of guidance
OECD Genome Editing 28-29 Jun 2018

20. Summary points –
Risk assessment for genome edited plants
• No new risks
• Explicit problem formulation guides the need for/nature of a
subsequent risk/safety assessment
• Process considerations may inform the problem formulation,
but product considerations drive the risk/safety assessment
• Safety and progress of emerging technologies may benefit
more from scientist-driven risk management practices than
from risk assessments per se …
• But the determination to manage an emerging technology
should not be conflated with the likelihood of harm
OECD Genome Editing 28-29 Jun 2018

21. Current risk assessment approaches for
environmental and food & feed safety
Jeffrey D Wolt
Iowa State University
OECD Genome Editing 28-29 Jun 2018
Thank You