Dr. Michal Illana Freedhoff
Assistant Administrator, Office of Chemical Safety and Pollution Prevention
Environmental Protection Agency
1201 Constitution Ave. NW, Washington, D.C. 20004
Re: Pesticides: Concept for a Framework to Assess the Risk to the Effectiveness of Human and Animal Drugs Posed by Certain Antibacterial or Antifungal Pesticides (EPA-HQ-OPP-2023-0445-0002)
Dear Dr. Freedhoff,
°®¶¹´«Ã½ (ASM) appreciates the opportunity to provide feedback on the Concept for a Framework to Assess the Risk to the Effectiveness of Human and Animal Drugs Posed by Certain Antibacterial or Antifungal Pesticides. ASM is one of the oldest and largest single life science societies, with 36,000 members in the °®¶¹´«Ã½ States and around the world, whose mission is to promote and advance the microbial sciences. Combating antimicrobial resistance and promoting antimicrobial stewardship in humans, animals and the environment are top policy priorities for ASM.
Antimicrobial resistance (AMR) is a top public health threat and one of our most daunting challenges. AMR is associated with the deaths of 4.95 million people in 2019 and is projected to cause 10 million deaths by 2050. Each use of an antimicrobial drug or agent, whether used to treat disease in humans, animals or crops, contributes to antimicrobial resistance. As existing antimicrobial agents decline in effectiveness, infections will be more difficult and expensive to treat and epidemics harder to control. Therefore, it is important for regulatory agencies, such as the Environmental Protection Agency, the U.S. Department of Agriculture and the Food and Drug Administration to discourage the superfluous use of antimicrobials.
As antimicrobial resistance grows, it will create increasingly complex challenges in the hospital, the lab, on the farm and in communities. ASM supports EPA’s proposed Concept and sees this proposal as an opportunity for increased coordination with other regulatory agencies with responsibility for antimicrobial products and medicines. Currently, many countries lack effective regulation for pesticides, and none take antimicrobial resistance into account when regulating pesticides (Ramakrishnan 2019). This framework represents an opportunity for the U.S. to lead the way.
The Types of Pesticides That Should Be Evaluated Under the Framework (by Class or Function)
ASM encourages the EPA to include both antibacterial and antifungal agents in this framework, as well as to consider future regulation of non-agricultural consumer applications of antimicrobial products.
The EPA should coordinate with the National Antimicrobial Resistance Monitoring System (NARMS), including the environmental AMR pilot program and the FDA’s Veterinary Laboratory Investigation and Response Network (Vet-LIRN), to understand what classes of antibiotics are in use and developing resistance in the environment.
The Factors That Should Be Considered in Determining if a Proposed Pesticide Use Constitutes a Potential Risk to Human or Animal Health Due to Resistance (e.g., Are Existing Laboratory Studies Applicable to Field Situations or Would Field Studies Be Needed?)
ASM encourages EPA and federal agencies to pursue a multifaceted approach to determining the potential risk to human and animal health posed by pesticide use. This approach should mirror the approach of the Coordinated Framework for the Regulation of Biotechnology as much as possible, due to the overlap in regulatory authorities between the EPA, the FDA and the USDA for the use of antimicrobials.
We encourage agencies to support broader adaptation of methods to quantify and predict the presence of antimicrobials and antimicrobial resistance in the environment. Additionally, when evaluating a proposed use of a pesticide, we encourage agencies to evaluate the safety and efficacy of the proposed application in a risk-based framework that is comparable to FDA’s criteria to regulate antimicrobials for therapeutic applications in humans and animals.
Due to the lack of field studies, the scientific and regulatory community has limited knowledge about the long-term impacts of antimicrobial products, either in indoor environments where they may be in use for years or decades (e.g., antimicrobial surface finishes or durable goods) or in outdoor environments where they wind up as persistent contaminants. Additional field studies are needed to determine if a proposed pesticide constitutes a potential risk to human or animal health. Some pesticides are not necessarily used as antimicrobials but can have antimicrobial impacts in the environment, leading to resistance. The results of long-term studies should be incorporated into the risk-based framework.
Because the scientific community has limited knowledge about the sources of resistant microbes in the environment (point and non-point sources), increased surveillance is needed to better understand where resistant microbes are developing and spreading into the environment. Increased adaptation of genetic sequencing of environmental samples will increase understanding of sources, prevalence and their potential impact on human and animal health.
The Process for Determining Which Human and Animal Antibacterial and Antifungal Drugs Should Be Considered “Medically Important” and How This Term Should Be Defined.
ASM strongly encourages collaboration with the FDA to determine the list of medically important antimicrobials. In 2021, the FDA’s Center for Veterinary Medicine released a concept paper, updating their approach to considering the human medical importance of antimicrobial drugs when assessing and managing antimicrobial resistance risks associated with the use of antimicrobial drugs in animals. This framework categorizes classes of antimicrobials based on their potential impact on human health. Any further rulemaking should take a similar approach and follow existing federal and international frameworks for evaluating antimicrobials.
The number of antifungal agents that can be used as human therapeutics is very limited, making preserving the efficacy of antifungal drugs currently in use extremely important. Antifungal drugs are categorized into only 4 main classes, which may be used alone or in combination to treat a variety of fungal diseases, including those that are uniformly fatal without antifungal drug treatment. Most importantly, there are examples where azoles, that have been used on crops for decades, appear to have lost efficacy in treating fungal infections in humans. Similar to the approach of FDA Center for Veterinary Medicine’s concept paper, the EPA should classify antifungal agents used in agriculture as medically important based on their potential impact on human health, with agents that can be used as human drugs classified as highly medically important.
The Mitigation Strategies That Are Currently Available to Address Any Potential Risk of Antimicrobial Resistance Developing Due to Pesticide Use
Improved overall antimicrobial stewardship will slow the development of antimicrobial resistance due to pesticide use. ASM supports the targeted use of antimicrobials specific to the microbial infection being treated or prevented. Moreover, the types of antimicrobial agents used as pesticides in agriculture should overlap as little as possible with the current arsenal of antimicrobial drugs used to treat human disease. That is, agricultural agents should be developed and used with great care to avoid facilitating resistance among human pathogens.
Mitigating AMR also includes addressing antimicrobial pollution. Incomplete removal of pharmaceutical antimicrobials in wastewater treatment systems compounds environmental factors that drive evolution of resistance and contribute to geographic expansion. Wastewater reservoirs, including wastewater reservoirs at farm sites, serve as key points for potential AMR pollution and should be treated as such while regulating pollution from agriculture. An overall reduction of antimicrobial use will mitigate the spread of AMR in the environment (°®¶¹´«Ã½ Nations Environment Programme 2023).
ASM supports existing AMR stewardship initiatives through the Centers for Disease Control and Prevention, the National Institutes of Health and the U.S. Department of Agriculture in place to measure, respond to, contain and prevent antimicrobial resistance in the environment, health care settings and communities, as well as expanding AMR stewardship programs. In the clinical setting, effective policies for drug usage, drug testing, registration and development are necessary. As antimicrobial resistance continues to develop, reducing the burden of disease may require reforming existing policies and creating new ones that help progress novel drug development.
Encouraging and aiding in advocacy efforts and educating the public about over/underuse of antimicrobial drugs is also critical. The tendency to not finish the antimicrobial course and improper disposal of drugs are key drivers of resistance. Inadequate dosing may facilitate selective pressure that drives evolution of the very microbes being targeted for treatment.
A List of Knowledge Gaps Provided in the Concept Note
There are several additional existing knowledge gaps related to AMR and the environment relevant to risk assessment and mitigation. More research is needed to understand how and for how long AMR persists in the environment. Another gap is that further research is needed to understand how the release of new pesticides and drugs into the environment might influence the population dynamics and functioning of microbiome in soils or foliar regions significantly. The overall impact of pesticides on microbial evolution is also not clear. There are still gaps in understanding the synergies between types of different antimicrobials and synergies between different types of pathogens and interactions between specific microbes and pesticides and antimicrobials. Additionally, there are gaps in understanding the volume and use of antimicrobials in consumer products and how this contributes to AMR.
Information about pathogens, the environment and AMR is limited, and there are gaps in understanding both how ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) pathogens and other pathogens outside of this group develop AMR and spread resistance in the environment.
Thank you for the opportunity to provide feedback on the proposed framework to assess the risk to the effectiveness of human and animal drugs posed by antimicrobial agents. This framework exemplifies the One Health approach that ASM champions, taking into account the connections between agriculture, medicine and the environment. ASM and its members stand ready to assist the EPA, the Department of Health and Human Services and the Department of Agriculture in further developing and implementing this framework and meeting further research needs
For further information or questions, contact Nicole Zimmerman, Senior Specialist, Federal Affairs at nzimmerman@asmusa.org.
Sincerely,
Stacey L. Schultz-Cherry, Ph.D.
Chair, ASM Public and Scientific Affairs Committee
