The seminar on Problem Formulation for the Risk Assessment of Biopesticides stemmed from a previous CRP-sponsored event on Innovating Microbial Pesticide Testing that identified the need for an overarching guidance document to determine when in vivo tests are necessary. Problem Formulation, a common practice in pesticide risk assessment, was highlighted as a useful approach for addressing uncertainties in data requirements for biopesticides. The seminar featured presentations from various perspectives, including industry, regulatory bodies, and academia. Topics included the history and principles of Problem Formulation, industry perspectives on Problem Formulation and how it is applied internally for microbial pesticides, regulatory approaches, and specific case studies. The seminar provided an overview of the challenges, considerations, and potential solutions in harmonising Problem Formulation for biopesticide risk assessment. It emphasised the need for collaboration and discussion to develop Problem Formulation guidance for biopesticides.

1. ///////////
Considerations for
Problem Formulation
for Human Health
Safety Assessments of
Biopesticides
Leah Zorrilla, Ph.D.
Bayer Crop Science
On behalf of Crop Life International

2. 2) Establish criteria on how to address human safety
areas of potential concern via problem formulation:
- Is the natural substance a potential human pathogen?
- Is the natural substance capable of causing infection?
- Does the natural substance have toxic or genotoxic
properties?
- Does the natural substance have the capability to
produce clinically relevant antibiotics or contain
clinically relevant antibiotic resistance markers?
1) Use a specific strategy suited to the unique
characteristics of biopesticides (not using
irrelevant small molecule or protein strategies
or guidelines)
4) Limit the number of pathogenicity studies
(prioritize routes of administration based on
human exposure)
3) Use relevant new approach methodologies
(NAMs) or whole genome sequencing (WGS;
sequence identity with genomic actors of
concern) where possible to avoid unnecessary
animal studies because of outdated testing
strategies
Human Safety Assessments for Biopesticides should:
Goal: Globally
Harmonized
strategy to
evaluate
biopesticides
2

3. What are we doing and why?
Human Safety Evaluations for Biopesticides
Evaluation/Testing Strategy
Whole Genome
Sequencing (WGS)
Literature
Reviews
Acute Studies
Pathogenicity Studies
What Value Add
Evaluations of relevant and reliable (current –10
years) toxicity, pathogenicity or regulatory
information in public literature on genus/species.
Allows consideration of what additional
information or regulatory questions that may
come up during registration processes. Can help
with early identification of higher risk microbes.
Genome sequence evaluated for ability of
microbe to produce biological chemistries of
toxicological concern, genotoxicants, clinically-
relevant antibiotics, antibiotic resistance markers,
pathogen potential for bees.
Supports prioritization, addressing genes of
potential concern to manage for regulatory
purposes. This evaluation can significantly reduce
or eliminate need for animal studies.
Usually, confirmatory study (studies) based on the
WGS. These studies are resource and animal
intensive and do not add (much) value to human
risk assessment, as they are largely showing no
adverse effects.
Important for labeling purposes, however, CLP
calculation method could be used in lieu of animal
studies: no validated test method for skin
sensitization, work to be done on validation of
eye/skin irritation alternative methods.
Requirements on both “active ingredient/whole
broth” and formulated products to support
classification and labeling.
Evaluates the potential of a microbe to multiply
and cause infections in tissues throughout the
animal; each route of administration (oral, dermal,
inhalation, ip/iv injection) can be required in some
regions.
/// Zorrilla OECD BPSG Seminar// February 26 2024

4. In Summary……
Data needs to be generated to determine foreseeable risks for these unique
types of agriculture solutions.
Currently studies are focused on potential for pathogenicity, infectivity,
toxicity; however, these studies do not answer all of the questions
associated with identifying hazards for human safety.
Understanding the potential secondary metabolites is equally important.
Tools are available to assess hazards using WGS; building and
validation of databases containing all sequences with potential
hazards/genomic actors of concern need be developed, consistently
updated (similar to COMPARE Allergen database for proteins) and
widely available.
Validation efforts for NAMs for skin and eye irritation, and perhaps inhalation
could also be a focused effort to eliminate these testing requirements.
Finally, global harmonization of biopesticide testing strategies is critical to reduce
the in vivo tests to allow for more accurate predictions of potential human risk.
Problem Formulation for Human Health Safety Assessments of Biopesticides
4 /// Zorrilla OECD BPSG Seminar// February 26 2024

5. ///////////
Thank you!
Special Thank You to Bayer
Colleagues: Lisa Ortego, Nico
Visconti, Hanno Bothe, Elizabeth
Webb, Greg Watson