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. The U.S. Perspective on Problem
Formulation for Biopesticides
PRESENTED AT THE 12 TH EXPERT GROUP ON BIOPESTICIDES SEMINAR:
PROBLEM FORMULATION FOR THE RISK ASSESSMENT OF BIOPESTICIDES
Shannon Borges, Deputy Director
Biopesticides and Pollution Prevention Division
Office of Pesticide Programs
U.S. Environmental Protection Agency

2. Problem Formulation Basics
• Begins with a planning dialog to ensure that the risk
assessment enables risk managers to make informed
decisions
• Define the regulatory action
• Establish management or protection goals (e.g., maintaining a
sustainable aquatic community)
• Determine management options (e.g., restricting uses,
requiring specific personal protective equipment)
• Determine the preliminary scope and complexity of the risk
assessment

3. Problem Formulation Basics
• Problem formulation – establishing a foundation for the risk
assessment
• Integrate available information – how much is available and of
what quality
• Evaluate the nature of the problem – use patterns,
environmental fate, nontarget hazard
• Select assessment endpoints – what entity and characteristics
of that entity are to be protected
• Develop conceptual model – visual depiction of fate in the
environment and exposure pathways
• Develop an analysis plan – establish risk hypotheses and
analyses to test them

4. Starter Questions – Framing the Analysis
• Is the biopesticide novel; have we seen something similar or is it completely new?
• If not novel (e.g., new strain of a microbial pesticide), what do we know about it already?
• What information was submitted from the applicant and are there data gaps?
• What is indicated in the scientific literature?
• Does it help address any data gaps?
• Does it raise additional questions?
• What are the hazards indicated, if any?
• What are the use patterns and potential routes of exposure?
• If risks are identified, what mitigations are available?

5. The Importance of Product Identity
• Establishes the foundation for biopesticide problem formulation
• Identifies the active ingredient and its defining characteristics
• Defines data needs and sets the scope of the analysis
• Due to complicated make-up of some microbial and biochemical pesticides, product identity can
also highlight uncertainties that need further investigation
• Microbials:
• Taxonomy of the microorganism and degree to which it has been identified
• Relatedness to microorganisms that are toxic or pathogenic to humans or nontarget
organisms
• Typical environment in which it is found; conditions that limit growth or presence in the
environment
• Secondary metabolites of concern
• For non-viable microorganisms, marker compounds that might help to quantify the active
ingredient
• Information gleaned from bioinformatics, such as known pathogenicity factors
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6. The Importance of Product Identity
• Biochemicals:
• Chemical identification and composition
• Physical and chemical properties
• Mode of action (non-toxic, by definition)
• Natural occurrence and where it is derived from, already know what is naturally exposed
• Active constituent(s) and/or marker compound for quantification
• Potential for residues
• Can range from purified substances to complex mixtures
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7. Use Patterns and Exposure
• Proposed uses, product formulation, and application methods and equipment can indicate
what exposure may occur
• Proposed uses
• Identifies crops, etc. that the pesticide will be used on
• Determines scope of exposure
• What human populations need consideration (e.g., residential, workers)
• What nontarget organisms need consideration
• Whether exposure through food or feed needs to be considered
• Geographic extent of exposure
• May determine the timing of exposure
• Can include restrictions or indicate human or environmental hazards

8. Use Patterns and Exposure
• Product formulation
• Intersects with application methods to influence exposure
• Can influence exposure route (e.g., inhalation, dermal)
• Microbial – sensitization to be considered
• Application methods and equipment
• Seed treatment, dips/cuttings – generally lower potential for exposure
• Soil applications – generally lower potential for exposure depending on incorporation
• Broadcast applications of liquids – generally higher potential for exposure
• Other considerations
• PPE
• Engineering controls (enclosed systems)
• Potential for residues

9. Other Exposure Considerations
• Minimal exposure or lack of exposure is one of the shortest paths to a risk conclusion
• Where some exposure can occur, it is not always easy to quantify for biopesticides
• Biopesticides can consist of complex mixtures
• Microorganisms are alive and population size is influenced by numerous biotic and abiotic factors
• Established environmental fate models are not always adaptable to biopesticides
• Modes of action do not necessarily have a clear dose-response relationship or are easily defined by
levels at which they do or do not occur
• Some questions to ask:
• How quickly does it break down in the environment or begin to have no effect (e.g., no residual effect
after drying)?
• How far beyond the treated area will significant amounts of the pesticide be deposited?
• If applied directly to water at the highest rate, would resulting levels cause effects or exceed natural
levels in the environment?
• What label clarifications would refine the understanding of exposure?

10. Hazard
• Because of difficulties quantifying some biopesticides, hazard assessment lies at the center of
risk assessment for biopesticides and can be essential to problem formulation
• Studies or other information that demonstrate minimal hazard under worst-case scenarios
leads to conclusions of minimal risk with high confidence ➔ The other shortest pathway to risk
conclusions
• Where hazard and exposure exist, further information may be needed to draw risk conclusions
• Some questions to ask:
• How much hazard data are needed based on product identity information? Is it available?
• If hazard is possible, what is the degree of the effect observed and what information would clarify how
concerning it is (e.g., if effects are observed, but at a low level)?
• Are studies available to discern trends overall or for specific taxa, including studies in the literature?
• What mitigation options are available (e.g., reduced application rate, limitations on use) and are they
feasible?

11. Example 1 - Microbial Pesticide
• New microbial active ingredient, identified to species though not officially, so limited
information available in the literature
• Intended for use in controlling plant diseases caused by bacteria and fungi
• Taxonomic information indicates potential relatedness to fish pathogen, though literature
indicates that pathogenicity observed primarily in fish farming operations
• Proposed use pattern includes wide variety of crops and spray application to foliar surfaces;
likely to be applied near aquatic areas
• All mammalian data are available, indicating no risk concerns for humans;
an exemption from the requirement of a tolerance is possible
• Nontarget data include guideline studies on a bird, a freshwater fish, and
honeybees; otherwise; data requirements are addressed with scientific
rationale
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12. Example 1 – Microbial Pesticide
• Questions to explore:
• Is the freshwater fish study acceptable and what are the results? Is the species tested appropriate?
• What information can be gained from studies on the related microorganism to understand exposure
levels of concern in aquatic environments?
• Is it possible to reach such exposure levels in aquatic environments given the proposed uses and
application methods?
• Given the reporting in the literature, is it possible to assess the environmental conditions leading to
pathogenicity? If so, are they likely to occur in nature?
• What is the normal environment for the microorganism and its potential to persist outside of it,
including in water?
• Is a study on a marine/estuarine fish needed (i.e., based on the above, are significant amounts
expected in these environments)?
• Is the honeybee study reliable? Are there any reasons why there should be concern for other insects?
• Are the rationales sufficient or, given the lack of information in the literature, is more testing needed?

13. Example 2 – Biochemical Pesticide
• New biochemical active ingredients, essential oils applied together in a mixture
• Intended for use as an insecticide in a variety of crops; includes residential (home garden) uses;
spray applications on soil only at planting
• Active ingredients present in high concentration in the product
• Some human health data on each active ingredient available in the literature; otherwise, no
mammalian data on some of the active ingredients; addressed with rationale arguing natural
exposure to humans
• Acute toxicity data on the product are available; two dermal irritation studies
on the product indicate it is corrosive
• Tier I nontarget data available on birds and honeybees, no adverse effects
observed; other data requirements addressed with rationale arguing natural
occurrence and nontarget exposure

14. Example 2 – Biochemical Pesticide
• Questions to explore:
• What human health toxicity data requirements must be addressed, considering use pattern
(food/nonfood), high concentration in the product, and concerns over corrosiveness?
• Is natural exposure sufficient to address toxicity data requirements?
• Are residential uses appropriate, or should the label be restricted? What are other mitigations?
• Where is the source plant normally found; does it have relatives in areas where the pesticide product
will be used, or are the essential oil active constituents found widely in plants?
• Is natural occurrence at background levels a sufficient reason to assume no hazard for all nontarget
taxa?
• Are the available data acceptable and indicative of the potential hazard?
• Is the bee study sufficient to understand effects on insects? Was exposure tested via a relevant route?
Can we understand the mode of action? (If it’s effective as an insecticide, why were there no effects
observed in the bee study?)
• If one assumes potential risk to insects on the treated area, is there sufficient exposure off the treated
area, given the application method? How does application timing affect exposure?

15. Conclusion
• Biopesticides are generally understood to be of low risk, but problem formulation is key to
establishing a robust risk analysis and arriving at informed risk management decisions
• Product identity can provide key information to guide problem formulation
• The potential for exposure can be clear in some cases, but uncertainties may require greater
reliance on hazard information; clear labeling helps to reduce uncertainty
• A full suite of Tier I hazard data (and higher tiers where necessary) can simplify problem
formulation if no effects are observed; however, problem formulation can identify what data
are actually needed

16. Thank you!