Summary of SAC-PCP’s recommendations on the fourth science question

This page describes a summary of the Committee's recommendations on the fourth science question (cumulative effects in environmental risk assessments) and the PMRA's response.

Context

One of the objectives of the October 5, 2023, Science Advisory Committee on Pest Control Products (SAC-PCP) meeting was to present the Committee members with their fourth scientific question for advice on the development of a framework to assess the cumulative environmental effects (CEE) of pesticides.

The PMRA is in the process of proposing amendments to the Pest Control Products Regulations. Proposed changes include giving the Minister of Health the explicit authority to require the submission of available information on CEE and require the Minister to consider the CEE of pesticides that have a common mechanism of toxicity, where information and methodology are available. As such, the Agency is in the beginning stage of developing a framework to assess the CEE of pesticides.

The PMRA initiated a discussion with the SAC-PCP by posing the first CEE science questions to the Committee and members of the Community of Specialized Experts. The objective was to engage the Committee in providing scientific advice and expertise to help guide the development of a CEE framework. The PMRA and other regulatory agencies have developed, or are in the process of developing, frameworks and guidance for human health cumulative effects assessments (e.g., EFSA, USEPA). No agency has functional guidance that is being used to perform cumulative environmental risk assessments for pesticides (except for co-formulated end-use products).

Meeting summary

The meeting summary from the October 5, 2023, SAC-PCP meeting can be found here: Science Advisory Committee on Pest Control Products: Meeting summary October 5, 2023.

Science questions

As a first step, the SAC-PCP considered the following initial science questions, taking into account the guidance and frameworks being developed in other regulatory agencies:

"Question #1: With the understanding that the PMRA is considering assessing cumulative environmental effects for pesticides that have a common mechanism of toxicity, what factors should be considered when grouping chemicals for assessing cumulative effects in environmental risk assessments?

Criteria for grouping chemicals have been developed for cumulative human health risk assessments, and often centered around the use of hazard-driven criteria (e.g., common mechanism of toxicity in mammals, toxicological effect, target organ, toxicokinetic parameters). Given that (i) pesticides may have more than one mechanism of toxicity among different taxa and (ii) information on the mechanisms of toxicity of a pesticide to all taxa may not be available, could these criteria be adapted for environmental risk assessment?

Other criteria used to group chemicals for the purposes of cumulative effects assessments include resistance management group (i.e., same mode of action on target pest), chemical structural similarity, common functional groups, common breakdown products, and likelihood of co-exposure. Which of these criteria would be most appropriate to consider for environmental risk assessments? Could the SAC-PCP recommend any other criteria that the PMRA should consider for grouping chemicals for cumulative environmental effects assessments?

Question #2: There is an exceedingly large number of potential pesticide exposure scenarios (i.e., specific taxa and their conditions of exposure) involving more than one chemical for organisms found in the environment. There are two broad types of exposure for pesticide mixtures, intentional exposure and unintentional exposure:

Intentional exposure: Organisms can be exposed to multiple pesticides through intentional use at a given application site. For example, co-formulated products, tank mixes, or multiple end-use products used on the same crop over the growing season to control various pests. Estimating exposure for such scenarios may be relatively straightforward (compared to unintentional exposures) for some organisms at a small scale (e.g., on field, or immediately off-field).

Unintentional exposure: Organisms can also be unintentionally exposed to multiple pesticides as residues are transported through the environment and as organisms themselves move through their landscape. Estimating these exposures, which vary spatially and temporally, is much more challenging.

Understanding the complexity of the issue and the limited ability to consider all possibilities, the PMRA plans to begin with simple exposure scenarios (e.g., actives applied at the same time to the same crop) from which we could build upon. Does SAC-PCP agree with this approach? Could the SAC-PCP provide suggestions and recommendations on factors that the PMRA should consider when selecting exposure scenarios for the assessment of environmental cumulative effects of pesticides?"

The Agency is in the beginning stage of developing a framework to assess the CEE of pesticides, which is expected to take many years. The current consultation with SAC-PCP was intended to initiate an ongoing discussion about CEE of pesticides. The initial recommendations provided by the SAC-PCP will be taken into consideration as outlined below. The PMRA will continue engaging the SAC-PCP as the development of the framework progresses.

Summary of SAC-PCP's recommendations and the PMRA's response

Use data, sales, and environmental monitoring (detection frequencies) to help inform what combinations are likely to be present in the environment and establish baseline environmental conditions (frequency of occurrence of mixtures, combinations and concentrations in soil, water) and priority chemicals or scenarios that require research on mixture effects. There are two approaches that will allow [the PMRA] to define critical mixtures in the environment/food/water:
- predictive modeling (in silico) based on submitted data and sales data.
- controlled lab experiments to simulate environmental fate of model mixtures.
Mine the data from registrants on product mixtures to determine which chemical groups are likely to co-occur and the predicted toxicity of these formulated product mixtures as most are not tested by independent scientists.

PMRA's response:

The PMRA agrees that data on pesticide use and environmental monitoring could be used to help determine what combinations of pesticides are likely to be present in the environment and that modeling can be used to help define critical mixtures. The PMRA also agrees that data from registrants can be used to estimate the toxicity of pesticide mixtures, and data on the characteristics of the environment in which products are used (e.g., climate, crop type) can also be used to help: (1) determine which pesticides are likely to co-occur and (2) estimate effects of pesticide mixtures.
Use an iterative approach from simple to more complex when developing a set of cumulative exposure scenarios. Use standardized scenarios that are reproducible and transparent to predict cumulative effects. Develop exposure scenarios (select habitats), a representative bird, mammal, etc., calculated under those conditions, and detail the assumptions for that set of conditions. Compare the predicted toxicity of the mixture scenarios relative to a baseline scenario based on single chemical exposures. Here the standardized scenarios should be based on a standardized set of organisms that may be affected (aquatic, terrestrial). Exposures can be set to reflect a range of conditions from best to worst case scenario.
PMRA's response:

The PMRA agrees with the use of an iterative approach, from simple to more complex, when developing standardized exposure scenarios. An iterative approach is currently the practice for risk assessments of single active ingredients. We also conduct our risk assessments of single active ingredients using standardized sets of aquatic and terrestrial organisms. We understand the need for the conditions and assumptions associated with each scenario to be clearly detailed in our assessments and any associated guidance. We will consider how to use baseline scenarios in the development of the CEE framework for pesticides.
Expand the use of trait-based approaches to prioritize over species-based approaches when developing both exposure and effects scenarios:
1. Calculate exposures for several traits (e.g., body size, lifespan, habitat, diet)
2. Assess toxicity and sensitivity based on trait characteristics (e.g., body size, reproductive timing, developmental rate, etc.)
3. Calculate risk under 5 to 6 scenarios to show the breadth of potential exposures.
4. Perform sensitivity analysis to see if one trait causes an overall fluctuation
PMRA's response:

The PMRA agrees with this recommendation, while recognizing the challenges the development of appropriate trait-based and exposure scenarios present.

The PMRA recognizes the need for a range of scenarios for evaluating the CEE of pesticides. We will review the literature on trait-based approaches and consider this information in the development of a risk assessment framework for the CEE of pesticides. Based on this information, we will investigate which traits and how many exposure scenarios can be considered depending on the specific organisms/taxa being assessed.
Test and evaluate the uncertainty in model output used in the pesticide assessment framework (e.g., impact assessment, valued ecologic components, human health risk assessments, decision matrix, relative risk management) by comparing with real-world data (e.g., monitoring data). If newly updated models and model inputs from more than one source are available, evaluate and use the best available model and its inputs. Clearly indicate what criteria and considerations result in particular selections. Regarding real-world data, look into what has been done in other jurisdictions (as per literature review) and start with what they have (especially peer-reviewed) and then try novel approaches (e.g., retrospective cumulative exposures).
PMRA's response:

The PMRA agrees with this recommendation, including evaluating uncertainty in model outputs, comparing estimates with real-world data, clearly defining criteria and considerations that inform our decisions, and considering the approaches taken in other jurisdictions. We will consider whether updated models and model inputs are available and applicable as the PMRA develops its CEE framework for pesticides.
Characterize and communicate uncertainty at all tiers of the risk assessment framework and show the range instead of an absolute number.
PMRA's response:

The PMRA agrees with presenting risk estimates as a range and that the uncertainties associated with these estimates should be characterized and communicated in CEE assessments of pesticides.
Consider how other chemical and physical stressors in the environment will enhance pesticide toxicity.
PMRA's response:

The PMRA partially agrees with this recommendation. As a starting point in the development of a CEE framework, the PMRA will focus on effects from pesticides. It is not feasible to account for all physical and chemical factors that may contribute to enhanced pesticide toxicity. However, effects from certain chemical and physical stressors may be considered as data and methodologies become available.
Aim to significantly reduce the number of registered active ingredients by removing older chemistries that have been replaced by newer actives with lower risk profiles and similar or improved efficacy. There should be a movement toward reducing chemical use overall – cumulative effects are increasingly difficult to monitor and assess with the large numbers of active ingredients and formulated products registered. Make formulated products more expensive to register as the risk assessments for the mixtures require significantly more effort.
PMRA's response:

This recommendation may be discussed further in the context of other PMRA initiatives.

The recommendation to reduce the number of registered active ingredients is outside the scope of PMRA's current objective with respect to CEE, which is to develop a framework to assess CEE of pesticides. The use of more active ingredients, whether concurrently applied, or spread out over a growing season, does not necessarily equate to greater risk to the environment than the use of a single active ingredient – it depends on the toxicity, fate and behaviour of the active ingredients in question, the timing, methods and rates of application. To manage multiple pests, it is often necessary to use more than one active ingredient at a particular use site.

The recommendation to make formulated products more expensive to register is also outside the scope of the PMRA's current objective with respect to CEE. Cost recovery is informed by the costs of Health Canada regulatory activities related to pesticides and is not a technical element of the PMRA's risk assessments.
Use a simple pesticide mixture with a common mode of action and the concentration addition model only as a first step, and then move into an improved system of evaluating risk – need to use different mode of action exposure scenarios with greater complexity and be transparent about the assumptions made (could focus on conservative and worst-case scenario assumptions). In other words, use a more rigorous model than the concentration addition model (as suggested by PMRA) to estimate cumulative effects (one that includes multiple modes of action).
PMRA's response:

The PMRA agrees with the SAC-PCP's recommendation of evaluating simple pesticide mixtures with common modes of action and the concentration addition model as a first step before moving to more complex mixtures and scenarios. We also agree that the scenarios, methods and assumptions used in the framework should be detailed in a transparent manner. As the development of the CEE framework for pesticides progresses, the PMRA may explore the development of exposure scenarios with greater complexity (e.g., from chemical mixtures with multiple modes of action).
When developing the framework for cumulative effects assessment, use science-based tools like computational modeling, to assist compound grouping based on their similarities in chemical structures, environmental fate processes, potential exposures and toxic effects. Consider this in an even broader chemical management approach for mixtures. Pesticides may co-occur with other anthropogenic contaminants that may have combined effects.
PMRA's response:

The PMRA agrees with using additional methods and tools, such as computational modeling, to inform certain aspects of the CEE risk assessment for pesticides. Although we currently model environmental fate processes and exposure in our environmental risk assessments for single active ingredients, additional models and tools are likely needed to perform CEE assessments for pesticides.

As a starting point in the development of a CEE framework, the PMRA will focus on effects from pesticides. Effects from broader chemical mixtures may be considered in the future as data and methodologies become available.
Think of biotic factors that will drive exposure rates (e.g., different generations of insects).
PMRA's response:

The PMRA agrees with the recommendation. Consideration of biotic factors affecting pesticide exposure is currently the practice for risk assessments of single active ingredients.
Increase rigor in the registration process to discourage industry use of product formulations that stack approved individual active ingredients. Complex formulated products create complex mixtures in the environment that are often poorly tested for cumulative effects. There should be clear justification and evidence that the product mixture is not going to cause additional risk. Studies of the mixture effects alongside individual actives on same test organisms should be put forward in the registrant's product registration package. Mixtures are difficult to assess/manage because they are so diverse and so variable in the environment.
PMRA's response:

The recommendation to discourage industry from using product formulations containing multiple active ingredients may be discussed further in the context of other PMRA initiatives, but is outside the scope of the PMRA's current objective of developing a framework to assess the CEE of pesticides. When such products are submitted for registration, the PMRA considers information for the single active ingredients and can also require additional studies for sensitive taxa that would be directly exposed to determine whether the potential risks posed by the products are acceptable.

With respect to the recommendation that studies of mixture effects be put forward in the registrant's registration package, it is not yet clear what information might be required from applicants. The PMRA is still in the beginning stage of developing a framework to assess the CEE of pesticides. It is expected, based on current international approaches to mixture assessments, that in most cases, existing environmental fate and toxicity data for individual substances can be used to predict the exposure and effects of chemical mixtures using a component-based approach (e.g., concentration addition model). This approach would also be in line with current initiatives to reduce animal testing.
Use principles from human health assessments of cumulative effects as a starting point.
PMRA's response:

The PMRA agrees with this recommendation. Many principles used in cumulative human health assessments of pesticide are also relevant to CEE assessments and can inform the development of the framework.
Use EC₁₀ and EC₂₀ as toxicity endpoints in chronic ecotoxicology studies. NOELs and LOELs are overused. There should be clear guidance to determine the EC₁₀ and EC₂₀ for chemical mixtures.
PMRA's response:

The PMRA partially agrees with this recommendation. The PMRA recognizes the shortcomings associated with NOEL/LOEL toxicity endpoints; chiefly that they are a function of the selected treatment levels, and that they are not conventionally presented with metrics of confidence or uncertainty. Standard chronic guideline studies for most taxa aim to establish NOEL/LOEL toxicity endpoints, and the data generated typically are not conducive to establishing EC₁₀ or EC₂₀ estimates. Because many of these studies look at multiple measures of effects, it is not feasible to bracket EC₁₀ and/or EC₂₀ values for all measurement endpoints. Regression-based study designs would generally involve more treatment levels, which would require reducing the number of replicates, if the total number of organisms would need to remain the same.
Inform the science community about which experiments are needed and work with them to develop ideas for assumptions and variables.
PMRA's response:

The PMRA agrees with this recommendation and recognizes the benefit of engaging with the science community in the development of a CEE framework for pesticides. The PMRA will continue to collaborate with partners in these efforts. As the development of the CEE framework for pesticides progresses, research needs will be identified and shared.
For most of these recommendations to be approached meaningfully, a more focused/thoughtful approach is required. For example, in piloting cumulative effects assessment for pesticides (i.e., mixtures, baseline scenario testing), a thorough science/evidence-based approach is required – which therefore needs peer-review (not just within the SAC-PCP but other independent reviewers). If PMRA wants to modernize the approach to include cumulative effects, it would be valuable to send out a call for proposals for academics, risks evaluators, etc., to develop such a framework, rather than doing things on its own. This improves transparency and public trust, especially if the material is peer-reviewed scientifically.
PMRA's response:

The PMRA agrees that scientific peer-review of the initial CEE framework and pilot assessments by the SAC-PCP as well as independent reviewers would be valuable to the development of the final framework. However, it is necessary that the CEE risk assessment framework for pesticides be fit-for-purpose and feasible in application. The PMRA recognizes the benefit of engaging with the science community in the development of a CEE framework for pesticides and will continue in these efforts.

More information

Consistent with Government principles of openness and transparency, SAC-PCP Advisory Reports are available upon request through Pest Management Information Services. For all other inquiries, please reach out to the SAC-PCP Secretariat: pmra.sacpcp-ccspa.arla@hc-sc.gc.ca.

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2024-05-21

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