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A study of a mechanism of toxicity ignored by regulators and risk assessors underscores the extraordinary harm and illogic of widespread pesticide use, identifying the ability of the neonicotinoid (neonic) insecticide acetamiprid (one of the first of this family of chemicals to be introduced) to kill brain cells.
The study, “Toxic effects of Acetamiprid on the human microglial cell line HMC3,” published in Neurotoxicology by Italian researchers at the National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy, demonstrates that, in vitro, the chemical changes the physiology of microglial cells in the brain.
Microglia act as the central nervous system’s primary health maintenance mechanism, scavenging for damaged cells, plaques and infectious agents.
The correct development, morphology and function of microglia are necessary for a healthy nervous system. They are essential to brain development, the ability of neuronal synapses to adapt to changing conditions and defense against inflammation.
Neonics are used against a vast variety of insects ranging from termites to dog and cat fleas and have become a ubiquitous seed treatment for plant crops. They distribute themselves throughout the plant as it matures.
Neonics were sold as an improvement over the even more toxic carbamate and organophosphate insecticides before them. Fluorinated neonics inhibit cholinesterase, a crucial enzyme for functional insect (and human) nervous systems.
This disruption is what kills them, but it is not as species-specific even in insects as the industry claims, and it is now known that neonics are devastating bee species across the globe.
Acetamiprid is a chlorinated neonic and less toxic to bees in particular, but the current study suggests that it has a different mechanism of action than the cholinesterase pathway that may be just as damaging and with wider species effects than the fluorinated compounds.
In humans, neonics are now routinely found in urine, blood, hair, breast milk, seminal fluid, cerebrospinal fluid, saliva, teeth and placental amniotic fluid. This means that their effects certainly reach the nervous system, including the developing brains of fetuses.
The authors cited animal research indicating acetamiprid and its related compounds disrupt the formation of neurons in the hippocampus and neocortex of developing mammalian brains. The emergence of evidence about human neurological effects is becoming more pressing.
See Beyond Pesticides’ comments to the U.S. Environmental Protection Agency (EPA) of Oct. 24, 2024 regarding the agency’s “Pesticide Registration Review: Draft Human Health and/or Ecological Risk Assessments for Several Pesticides,” including neonics such as clothianidin, imidacloprid and thiamethoxam.
The current study extends the evidence specifically to humans.
Using a validated in vitro model of human microglial cells, the authors observed both the cellular toxicity and the functional effects of microglial exposure to acetamiprid in two groups of cells: one group under control conditions and the other exposed to lipopolysaccharide (found in bacteria ubiquitous in the environment), which is known to trigger immune responses.
They found that over time, even though the cells’ metabolic activity slowed and they showed other signs of stress, the apoptotic process (cell death) did not result in significant programmed cell death.
The microglia treated with both acetamiprid and lipopolysaccharides stayed alive but appeared unable to fully engage their inflammatory responses to the challenges.
Acetamiprid by itself significantly increased the microglia’s phagocytic activity — the degree to which they engulfed foreign objects.
But when microglia are exposed to both acetamiprid and the inflammatory lipopolysaccharide, the phagocytic response is “drastically suppressed.”
This would obviously inhibit the brain’s ability to fight inflammation and remove toxic agents and lead to nervous system dysfunction.
The authors set the dosage concentration for the in vitro microglia at a level that corresponds to 90% of what the European Food Safety Agency considers a “safe” blood level based on daily oral intake of acetamiprid, “confirming the biological and environmental plausibility of our in vitro model under regulatory-relevant scenarios.”
The researchers add that acetamiprid “induced progressive dysfunction without causing overt acute toxicity,” and that over time cell stresses accumulated “prior to measurable effects on proliferation or survival,” resulting in “progressive loss of functional integrity similar to that observed with neonics in other experimental models.”
One consequence of this process is that during development, microglia may prune functional synapses indiscriminately or excessively, leading to neurodevelopmental and neurodegenerative disorders.
A review published this year in the Journal of Environmental Sciences by Chinese researchers examined both biomonitoring evidence of exposure and epidemiological evidence of adverse health effects from neonic exposure.
These included 20 laboratory studies finding a diverse set of neurotoxic effects in rats and mice, ranging from increased acetylcholine activity in the brain, spinal column and blood to inappropriate types and numbers of microglia in newborn brains.
Neurotoxicity is only one form of damage; there is also evidence of reproductive harm, liver and kidney damage, glucose and lipid metabolism disruption, and DNA damage, according to the authors. Some populations are highly exposed.
A check of 196 young Chinese adults found imidacloprid in 85% of the samples, and a study of 305 children in South China found the neonics imidacloprid, acetamiprid, thiacloprid, thiamethoxam, clothianidin and dinotefuran in 90% of them.
Levels in the U.S. general population were much lower, with the highest detection frequency of imidacloprid at 4.3%.
The Chinese researchers point out that neonics are easily metabolized by humans, meaning that these metabolites are also circulating in human bodies, sometimes at higher concentrations than their parent compounds, with effects that may also be different and potentially equal to or more toxic than the original chemical.
EPA’s history with neonics is a classic example of unexamined assumptions leading to major negative consequences. After their introduction in the 1990s, the assumption that insects were uniquely susceptible to neonics’ effects on the nicotinic acetylcholine receptor (nAChR) was largely unchallenged.
Two University of California researchers declared in 2002 that the “fundamental differences between the nAChRs of insects and mammals confer remarkable selectivity for the neonicotinoids.” Neonics were also assumed to be unlikely to cross the blood-brain barrier.
The first commercial neonic, imidacloprid, was registered by EPA in 1994 based on claims by its manufacturer, Mobay, a joint venture of Monsanto and Bayer, that it was not a reproductive toxicant, not carcinogenic, not genotoxic and not mutagenic.
But EPA was aware that imidacloprid is highly toxic to honey bees by at least 1993, according to an EPA memo reviewing the toxicity of imidacloprid residues on leaves.
In 1994, EPA waived neurotoxicity tests for hens and mammals because “no evidence of neurotoxicity [was] observed in acute or chronic exposure.”
Acetamiprid was registered in 2002. The fact sheet issued by EPA at registration made several statements that have since been proved seriously incorrect.
“This pesticide will be a significant organophosphate (OP) replacement for the labeled uses,” it states.
While this may be true, it illustrates the continuing problem that substitute pesticides usually turn out to be as harmful as their predecessors.
EPA made many assumptions such as the unlikelihood of children’s exposure, the “minimal risk to fish and wildlife,” and that acetamiprid is unlikely to be carcinogenic (despite evidence of testicular, breast and pituitary tumors in an initial rat toxicity study, as noted by a California Environmental Protection Agency report).
In the intervening decades, the evidence has mounted that neonics are indeed toxic to a number of animal physiological systems, not to mention aquatic and terrestrial ecosystems. See Beyond Pesticides’ Gateway on Pesticide Hazards and Safe Pest Management for details on all the neonics.
Yet EPA has done little to acknowledge and act on the clear evidence of harm beyond extending minimal protection for commercial honey bees, increasing requirements for personal protective equipment, and restricting some uses of some neonics.
The Proposed Interim Registration Review Decision for Acetamiprid from 2020 summarizes the risk of human exposure as follows:
“No risks of concern were identified for dietary, residential, aggregate, bystander, or occupational post-application exposures. Both acute and chronic estimated dietary risks were below 100% of the population adjusted dose and thus not of concern.
“Acetamiprid is classified as ‘not likely to be carcinogenic in humans.’
“The agency does not anticipate any further human health data needs for the acetamiprid registration review at this time.”
The Italian study of the molecular effects of acetamiprid on human microglia reinforces the knowledge that there is no magical protective barrier between humans and other species with respect to neonics.
Regulators and industry have been willfully blind to the multiple types of damage neonics do, knowing that all pesticides will outlive their usefulness eventually.
Thus, the pesticide industry remains on its chronically short-sighted merry-go-round of marketing the next generation of inevitably obsolete, yet terribly persistent, poisons. A switch to organic, regenerative agriculture could change this trajectory quickly.
The study adds to the body of science that illustrates the serious inadequacy of the regulatory review and risk assessment process that is used to allow widespread use of toxic pesticides.
Originally published by Beyond Pesticides.
