Overcoming Persistence Challenges in Environmental Fate (E-Fate) Studies

Ensuring the safety and efficacy of active ingredients is crucial for environmental and human health. A critical part of this process involves understanding the environmental fate and behavior of the active substances– how they degrade and move through the environment. However, e-fate studies conducted in simplified model systems under laboratory conditions can sometimes present challenges when dealing with persistent substances as more realistic conditions are not always considered.

This article explores these challenges and how Battelle can help companies navigate them.

Why Standard Environmental Fate Studies Might Not Be Enough for Persistent Substances

Standard environmental fate studies conducted under controlled laboratory environments are often sufficient for regulatory approval of many test compounds. This approach ensures consistency and reproducibility, but it may not always accurately reflect real-world environmental conditions. This discrepancy can be particularly problematic for persistent substances, where laboratory studies show persistence that may not translate to the field where other conditions including a light-dark cycle and temperature variations occur. In real-world environments, degradation often occurs at a faster rate than what is observed in the laboratory.

This issue is especially relevant for certain study types, such as the OECD 309 (aerobic mineralization). Studies following this guideline often utilize a “pelagic” test design (without added sediment) that frequently leads to a misrepresentation of persistence for a wide range of test substances.

Addressing Limitations of Standard Environmental Fate Studies for Persistent Substances

In general, testing can be conducted that more closely mimics field conditions, yielding results more representative of the test substance’s behavior likely to be observed in the field.

There are two main approaches to address the limitations of standard environmental fate studies for persistent substances:

1. Utilizing Refined Standard Tests:

Many existing test guidelines offer flexibility within their framework. For instance, the OECD 309 guideline allows for modifications like:

• Sediment addition: Including sediment in the test system can better represent natural environments where sorption and degradation processes are influenced by soil or sediment.
• Diffuse illumination: Utilizing a light source that mimics natural sunlight patterns can provide a more realistic representation of degradation rates due to algae growth and co-metabolism compared to artificial laboratory lighting.

By incorporating such modifications, we can obtain more environmentally relevant data within the scope of standard tests.

2. Employing Higher-Tier Testing: 

In some cases (e.g. water-sediment studies), the limitations of standard tests necessitate a shift to "higher-tier" testing methods. These methods involve more complex experimental designs where the experiments contain modifications to the design set out in the test guideline, offering a closer simulation of real-world conditions.

Here are some examples of higher-tier testing:

• Fate-o-cosm: These studies utilize miniature environmental systems containing water, sediment, and microbial communities to assess degradation processes under controlled conditions that are closer to the natural environment.
• Field studies: Field studies directly assess the behavior of a test compound in its intended environmental setting, providing the most realistic data but also requiring careful design and considerations for environmental impact.

The choice between refined standard tests and higher-tier testing depends on the specific needs of the assessment and the level of environmental realism required. Overall, a combination of these approaches can be used to obtain a more comprehensive understanding of the environmental fate of potentially persistent active substances.

Higher-tier testing, or testing under new conditions such as illumination, may generate new metabolites not observed in previous testing. Battelle’s combination of extensive experience in metabolite ID and state-of-the-art equipment (accurate-mass LC-MS/MS capability) means that our clients are in safe hands when new metabolites arise.

As part of the consideration for the conduction of higher-tier tests, it is advisable to involve the Rapporteur Member State in discussions so that you can get their buy-in to the strategy and also ensure the test plans obtain regulatory acceptance. For this, a well-considered and detailed technical discussion with the Rapporteur Member State’s in-house experts is imperative so that your message can be properly delivered. Battelle’s environmental fate experts, laboratory study directors and regulatory advisors have the experience and are highly capable of taking the lead in these discussions on your behalf.  

Navigating the Nuances of Higher-Tier Testing

Standard environmental fate guidelines, while offering consistency, may not fully capture the environmental behavior of persistent substances under natural conditions. Moving to higher-tier testing allows for modifications that better mimic real-world scenarios. However, such modifications necessitate careful justification. This justification should specifically demonstrate how the chosen test conditions are more representative of the real-world environment compared to the standard guideline design. This enhances the likelihood of regulatory acceptance for higher-tier study results.

Our team of environmental fate specialists excels at designing and justifying higher-tier studies in close cooperation with our regulatory experts. We ensure the chosen test conditions demonstrably represent field environments, maximizing the likelihood of regulatory acceptance for the generated data and discussing the intended testing strategy with regulatory authorities.

Pioneering New Study Designs for Persistent Chemicals

Battelle has a history of innovation in environmental fate testing. We have pioneered a suite of modified and higher-tier test designs specifically for persistent substances, addressing limitations encountered during standard testing like OECD 309 (aerobic mineralization) and water-sediment studies. These approaches range from incorporating diffuse (non-photolyzing) irradiation to aerobic mineralization or water-sediment studies, to the development of complex "fate-o-cosm" systems.

Fate-o-cosm systems represent the pinnacle of environmental fate study design. These intricate setups incorporate water, sediment, plants, and natural sunlight, meticulously mimicking the processes occurring in natural water-sediment environments. This level of detail is invaluable for gaining a comprehensive understanding of a potentially persistent substance's fate in the field.

The Importance of Addressing Persistence Concerns

Failing to adequately address an active substance’s apparent persistence in standard study designs can have significant consequences. Regulatory authorities may withhold registration or re-registration for the active ingredient. Additionally, substances considered to be persistent might be targeted for replacement by alternative actives which show lower persistence in standard study designs, hindering market access and product viability.

Companies can significantly improve their chances of regulatory success and market acceptance by proactively addressing persistence concerns through appropriately designed environmental fate studies.

Balancing Robust Data with Economic Considerations

We recognize the importance of balancing the need for robust data with the economic constraints of conducting environmental fate studies. The transition from standard to higher-tier studies is a spectrum, not a binary choice. Often, relatively minor modifications to standard protocols can demonstrate reduced persistence, minimizing cost increases compared to a fully redesigned study.

Battelle's expertise lies in identifying the most cost-effective approach for each unique situation. We start with simpler modifications and reserve the most resource-intensive designs, like fate-o-cosm systems, for scenarios where simple modifications are not able to demonstrate the reduced persistence expected under field conditions.

Our Expertise, Your Success

Navigating the complexities of environmental fate studies doesn't have to be a challenge. At Battelle, we offer comprehensive support for both persistent and non-persistent substances. Our extensive experience allows us to tailor environmental fate services and solutions specific to your needs, maximizing the chance of demonstrating the non-persistence of your active ingredient under field-relevant conditions.

We offer a comprehensive partnership to support your environmental fate testing needs:

• Tailor-Made E-Fate Studies: Customizable study design to meet specific client needs, including non-GLP pre-studies for optimal results.
• Higher-Tier Expertise (Non-Guideline): Our team is well-versed in non-standard guidelines, enabling us to navigate more complex scenarios effectively.
• Comprehensive E-Fate and Metabolism Services: Provides extensive data on substance fate and degradation mechanisms, routes, and rates.
• Advanced Laboratory Capabilities: Modern laboratories and state-of-the-art analytic equipment ensure high-quality data generation.
• Highly Experienced Study Directors: Over 50 years of collective expertise in environmental fate and metabolism with in-depth knowledge of metabolic pathways and identification of unknown metabolites ensuring professionalism and scientific rigor in your studies.
• Project Management and Regulatory Support: Battelle’s regulatory expert group supports all product safety testing solutions, including study monitoring, risk assessment, and successful dossier preparation and submission. Our team can manage all aspects of your environmental fate study, ensuring adherence to timelines, budgets, and regulatory requirements.
• Robust Modeling: We leverage powerful modeling tools to enhance data analysis and support regulatory acceptance.
• Negotiations with the Authorities: Battelle’s regulatory experts can present your case for higher-tier or novel tests to the authorities to get their buy-in to the strategy and to ensure the study plan obtains regulatory acceptance. 
• Radiosynthesis: Our comprehensive services include the radiosynthesis of test items, offered as part of our end-to-end solution.

By partnering with Battelle, you will get precise, robust, defensible data into the behavior of your products in the environment with our extensive experience in environmental fate studies. Our comprehensive approach provides the critical data you need to support rapid development and successful registration of your products worldwide in a cost-effective and timely approach. Let us help you navigate the complexities of global registration processes, understand risks, and accelerate global product registrations.