05
Nov
Evaluation of EPA Safety Data on Neonicotinoid Insecticides Identifies Scientific Failures
(Beyond Pesticides, November 5, 2024) Published in the journal Frontiers in Toxicology, a recent study uncovers serious flaws in the pesticide registration process at the U.S. Environmental Protection Agency (EPA) with an in-depth evaluation of the agency’s failure to protect the public from the harmful effects of five neonicotinoid (neonic) insecticides—as mandated by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and amendments, including Food Quality Protection Act (FQPA) of 1996. This coincides with EPA’s ongoing review to renew their approval for the next 15 years (set to be announced in 2025). The report is based on the first comprehensive assessment of unpublished rodent-based Developmental Neurotoxicity (DNT) studies, conducted between 2000-2003 and submitted by pesticide manufacturers as part of the registration process.
All five neonicotinoids evaluated—acetamiprid, clothianidin, imidacloprid, thiacloprid, and thiamethoxam—are associated with significant shrinkage of brain tissue at the highest dosage, according to EPA data reports (see acetamiprid, clothianidin, imidacloprid, thiacloprid, and thiamethoxam). However, with little or no data regarding the chemicals’ impacts at low and mid-level dosages, EPA has either failed to find a “No Observed Adverse Effect Level†(NOAEL) or, seemingly at random, set the NOAEL at the mid-level dosage. The evaluation suggests that perinatal exposure to neonicotinoids and their metabolites results in nicotine-like neurotoxic effects in rodent studies, concluding that, “… the exposure limits set by EPA for human exposure are either not protective or not supported by available neurotoxicity data.†The study also finds that the agency ignored significant adverse effects, allowed DNT studies that did not conform with scientific protocols, and permitted “neonicotinoid registrants to unduly influence agency decision-making.â€Â
[The research was conducted by Jennifer Sass, PhD, senior scientist at Natural Resources Defense Council; Nathan Donley, PhD, environmental health science director at the Center for Biological Diversity; and, Bill Freese, science director at the Center for Food Safety. A press release on the evaluations notes, “Our study contributes to the growing body of evidence suggesting that neonicotinoids are hazardous to the developing human nervous system and should be avoided just as mothers abstain from smoking during pregnancy. EPA must act to reduce the use of and human exposure to these toxic insecticides.â€]
While the authors conclude that EPA regulatory changes are needed to better protect public health from developmental neurotoxic neonicotinoids, many public health and environmental advocates interpret the results as a signal—a need for a major shift that questions the registration of harmful pesticides, which can be replaced by organic management practices and organic-compatible production inputs. These advocates point to the study’s findings as identifying a fundamentally broken regulatory system in the face of the existential health, biodiversity, and climate crises stemming from petrochemical pesticide use, including highly toxic neonicotinoid insecticides. [Additionally, read more about recent U.S. Supreme Court decisions impacting environmental regulatory authority here: Daily News on Chevron decision, Daily News on Sackett decision, and the Clean Water Act here].
Background
Neonics are among the most widely used insecticides in the world, with the most common form of application as a treatment of seeds before dispersal. According to the report, at least 150 million acres were planted with neonic-treated seeds in 2012, which is six times the amount of land treated with the top ten insecticides combined in 2001. Outside of agricultural applications, neonics are commonly applied to parks and gardens, to pets as a flea treatment, and to control bed bug infestations. The result of such widespread use has led to rampant contamination in the food supply, human breast milk, and amniotic and cerebrospinal fluids. (See here, here, and here). Neonicotinoids have been linked to breast cancer by stimulating excess estrogen production, known to occur during the development of progressive hormone-dependent breast cancer. Due to their widespread use, neonicotinoids commonly contaminate water sources, including rivers and groundwater. This cumulative presence suggests, according to the authors, that children may be exposed at multiple developmental stages, including prenatally, through breastfeeding or formula mixed with contaminated tap water, and during childhood through food and water consumption. Given the likelihood of exposure, the authors argue that it is essential to sustain and enhance monitoring programs that identify pesticide residues in food, water, and biological samples. Furthermore, to address regular exposure to neonicotinoids, especially during critical early life stages, the study results suggest that risk assessments and regulatory decisions must adhere to (and ideally surpass) the safety standards established by current federal pesticide regulations.
EPA employs DNT studies with rodents under established guidelines (see here and here) to evaluate the risks that pesticides may pose during the early development of the brain and nervous system, determine dose-response relationships, and set regulatory exposure limits. The agency then, based on the data provided, sets acute (short-term) and chronic (long-term) exposure limits by identifying a No Observed Adverse Effect Level (NOAEL). A 100-fold uncertainty factor is then applied to the NOAEL to account for differences between animals and humans and the uncertainty associated with individual variability in humans. However, this approach does not fully consider the increased vulnerability of the developing brain when exposure occurs during fetal growth or infancy. These stages are critical periods when the brain’s structure is being formed via cell growth, differentiation, axon and synapse development, and cell migration. This damage is often irreversible due to the limited capacity for repair during these complex and fragile developmental processes.
FQPA mandates that EPA consider the increased susceptibility of infants and children, including differences in neurological development and potential in-utero exposure to pesticides, to ensure “reasonable certainty of no harm” from all forms of pesticide exposure, including dietary and other known sources. A protective, although arbitrary, measure of FQPA is the 10X-fold child safety factor, which aims to reduce permissible exposure levels to account for children’s vulnerability to developmental toxins. Additionally, FQPA requires cumulative risk assessments for pesticides with shared mechanisms of toxicity. By law, EPA can reduce or eliminate this safety factor only if reliable data demonstrate that doing so would not compromise the safety of infants and children. Despite this mandate, EPA has often reduced or removed the child safety factor in its pesticide evaluations, including for neonicotinoids. (See here, here, and see Daily News for one recent example of EPA failure to apply children’s safety factor here, specific to acephate).
Study Methodology
The report evaluates EPA’s Data Evaluation Records, in which data for five unpublished DNT studies with highly defined protocols were previously analyzed by EPA staff. (After feeding female rats different doses of pesticides during pregnancy and lactation, labs contracted by pesticide manufacturers administer a variety of morphological, neurological, and behavioral tests from birth to 60 days old).
Among the many irregularities that the report identifies:
- Contrary to DNT guidelines, the agency received no or partial data related to mid- and low-dosage groups. Despite the lack of evidence, EPA concluded that the five neonics only offered negative effects at the high-dose level.
- When presented with highly variable data from Nippon Soda in 2003 regarding impacts from acetamiprid, EPA at first rejected the application. However, after a secondary appeal by the manufacturer, the agency overruled its own conclusions. In 2008 and again in 2017, EPA raised the NOAEL, eventually reaching 40 times the level proposed by the European Food Safety Authority.
- In a 2000 DNT by Takeda Chemical Industries for clothianidin, EPA found the application to be missing data for low- and mid-dose tests. Even though the data was never submitted, and the study remains classified as “deficient,†EPA set the NOAEL at the mid-dose level.
- Similarly in 2001, Bayer conducted a DNT for imidacloprid where no information was provided for the mid- and low-dose categories. Nevertheless, EPA set the NOAEL at the mid-dose level.
- In 2001, Bayer’s DNT study of thiacloprid identified a reduction in brain weight significantly at the high- and mid-doses, while the age of male sexual maturation was delayed at all dose levels. However, EPA determined that only the high-dose effects were related to pesticide exposure and set the NOAEL at the mid-dose level.
Together, the report highlights a pattern of poor scientific practices and unjustified conclusions, with EPA making determinations contrary to the recommendations of the agency’s own scientists. For four of the five studies included in this analysis, appropriate data was either not received or not fully evaluated by EPA. EPA also identified study deficiencies including inadequate testing and reporting but failed to require any follow-up studies or data.
Meanwhile, pesticide registrants (manufacturers) face no consequences for failing to supply missing or inadequate data. “These are extremely disturbing findings that expose an agency strong-armed by pesticide makers into ignoring glaring problems with critical safety assessments,†notes Dr. Donley in a press release. “When the agency charged with protecting us all from harmful poisons doesn’t even require the necessary data to determine significant health risks, its pesticide approvals simply can’t be trusted as scientifically valid.â€
Developmental Neurotoxicity Studies: Future Approaches
While DNT studies allow for evaluating potential risks to brain development, the studies require proper design and oversight, as well as improvements to enhance their sensitivity, particularly in cognitive function assessments. The authors’ review of positive control studies (tests using chemicals known to affect neurological development) found significant deficiencies. For example, in four of the five DNT studies reviewed (excluding clothianidin), positive control data was missing or not fully evaluated by EPA. For thiacloprid, EPA noted that no study adequately demonstrated the lab’s capability to detect key neurotoxic effects.
Rather than updating rodent DNT methods to enhance their rigor and sensitivity, EPA’s Office of Pesticide Programs is moving toward using New Approach Methodologies (NAMs), like in vitro assays and in silico models. This approach uses a lack of bioactivity in NAMs as proof of safety, leading to less protective risk assessments for some pesticides. These methods are favored for their cost-effectiveness, faster results, and reduced animal use; however, in vivo DNT studies currently have no equivalent substitutes. Critics, including health experts and regulatory scientists, argue that this new methodology undermines public health. (See here and here).
The Organisation for Economic Co-operation and Development (OECD) recently reviewed in vitro DNT tests (using NAMs) and highlighted significant gaps in assessing neurodevelopmental processes, such as neuroectoderm formation, peripheral nervous system processes, and astrocyte maturation, among others. Similarly, the European Partnership for the Assessment of Risks from Chemicals (PARC) concludes that existing NAMs do not adequately assess cognitive and neurobehavioral outcomes or learning and memory.
Recommendations for Regulatory Improvement
The study recommends that to enhance the quality of rodent DNT and other toxicology studies, EPA should reject severely flawed studies, enforce data submissions, and suspend or deny approvals of pesticides when data is insufficient or unreliable.
- Require DNT Studies: EPA should mandate DNT studies for pesticide registrations, as recommended in 1999, reversing the trend of granting study waivers.
- Lower Exposure Limits for Neonicotinoids: Given their established neurotoxicity, neonicotinoids’ exposure limits should be reduced tenfold to protect developing nervous systems, per FQPA.
- Conduct Cumulative Risk Assessments: Since neonicotinoids share toxic mechanisms with nicotine, EPA should assess cumulative risks and assign relative potency factors for each compound.
- Retain the FQPA 10X Child Safety Factor: EPA should only reduce this safety factor when supported by reliable data, especially given NAMs’ limitations and existing uncertainties.
Unpublished, manufacturer-submitted rodent-based studies show, via the report, that neonics can disrupt mammalian brain development, like nicotine. Early exposure reduced brain region sizes, implying neuronal cell loss and diminished neurogenesis. Affected regions like the corpus callosum and caudate putamen may also be linked to attention-deficit/hyperactivity disorder (ADHD). The analysis also shows impaired auditory startle responses and possible effects on learning and memory. The authors conclude that further research is needed on neonics and their nicotine-like metabolites, given their widespread use and potential for lasting harm. While NAMs offer insights into cellular mechanisms, they cannot currently replace the value of well-designed in vivo studies for understanding complex neurodevelopmental impacts.
As a principle, Beyond Pesticides urges a systemic move toward the adoption of proven organic systems that do not use neonicotinoids and other toxic synthetic pesticides. Organic practices and products also address current existential crises, including microbial support for ecosystem health, and biodiversity. To stay informed on upcoming pesticide regulatory decisions and take action, click here to sign up for updates from Beyond Pesticides via our listserv.
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Plan to attend Beyond Pesticides’ 41st National Forum, Imperatives for a Sustainable Future! Thank you to all who attended our launch on October 30—the recording is LIVE on our website as of November 5, 2024! The second session will continue on Thursday, November 14, 2024, at 1 PM (EST) with Tracey Woodruff, PhD, MPH, the director of the Program on Reproductive Health and the Environment (UCSF). Dr. Woodruff’s work focuses on uncovering and addressing environmental determinants of disease and health inequities and has written groundbreaking material on endocrine-disrupting chemicals. Registration is complimentary, with contributions appreciated, and is valid for all sessions of the 2024 National Forum!Â
All unattributed positions and opinions in this piece are those of Beyond Pesticides.
Sources:
Neonicotinoid pesticides: evidence of developmental neurotoxicity from regulatory rodent studies, Frontiers in Toxicology, October 1, 2024
EPA Set to Greenlight Widely Used Neonicotinoid Pesticides, Overlooking Evidence of Harms to Brain, Nervous System, Press release, Center for Biological Diversity, Center for Food Safety, October 22, 2024
Poisoned Waterways: The Same Pesticide that Is Killing Bees Is Destroying Life in the Nation’s Streams, Rivers, and Lakes, Beyond Pesticides, Pesticides and You, Spring 2017
Sowing Uncertainty: What We Do and Don’t Know about the Planting of Pesticide-Treated Seed, BioScience, March 18, 2020
Schedule for Review of Neonicotinoid Pesticides, EPA website
Initial Recommendations on Evaluation of Data from the Developmental Neurotoxicity (DNT) In-Vitro Testing Battery, OECD Environment, Health and Safety Publications Series on Testing & Assessment No. 377, Organisation for Economic Co-operation and Development, November 3, 2023
New Approach Methodologies (NAMs): Scientific Challenges and Potential Solutions, presentation by Dr. Raashmi Joklekar, UCSF, and Dr, Jennifer Sass, NRDC, EPA documents, February 14, 2024
Please act to minimize toxins in the environment and our food.
November 6th, 2024 at 3:37 pm