Neonicotinoids

Background

According to the National Toxicology Program web page on Neonicotinoids, this class of pesticides has been used widely in U.S. agriculture since 2005. These pesticides are commonly used to treat the seeds of agricultural crops and will travel to all parts of the plant once grown, providing long term protection [1]. There are 9 chemicals that make up this class (Figure 1). Neonicotinoids were developed out of a need for a less toxic alternative to nicotinoids which were historically used as insecticides. Neonicotinoids are also used to treat fleas and lice in domestic pets and livestock, as well as being a treatment for bed bugs. Sources of human exposure are environmental exposure and food consumption [2].

Biotransformation

Because neonicotinoids are approved to be used in mammals by the EPA, many in vivo assessments have been performed in rats, goats, and hens. Neonicotinoids are highly water soluble so it was found that a majority of the compounds, when given orally, are excreted unchanged in the urine. The highest amount of biotransformation that occurs is within the plant itself to create altered compounds but biotransformation once inside the body can also occur. Figure 2 shows common chemical transformations of oxidation (A), hydroxylation and cleavage (B), and further modifications (C). There are many factors that contribute to this class of insecticides undergoing biotransformation in both the plant and humans, which could lead to compounds that are more activated against human acetylcholine receptors [2].

As described by the authors in Figure 2, biotransformations involve initial oxidation or reduction as both activation and detoxification mechanisms [2].

Toxicokinetics

Studies have shown that toxicity for different routes of exposure is as follows: very low for dermal, moderate for ingestion, dust inhalation moderate, and aerosol inhalation is highly toxic [3]. Neonicotinoids are nicotinic acetylcholine receptor (nAChRs) agonists that bind to the α4β2 receptors in the brain (Figure 3). These chemicals are highly neurotoxic to insects and have a low affinity to mammalian nAChRs. All insect nAChRs have α4β2 sub-units where as mammals only have α4β2 sub-units on 8-10% of their receptors. Under normal circumstances, acetylcholine (ACh) binds to nAChRs, creating a neuronal impulse by activating the receptor. Then acetylcholinesterase enzyme (AChE) deactivates the complex and breaks down ACh. For these insecticides, AChE is not able to degrade neonicotinoids so the receptor is overstimulated and leads to neuronal cell death [4].

Target organs

The greatest density of α4β2 sub-units are found in the thalamus, effecting cognition, memory, and behavior. Historical changes in this receptors density in the brain has been linked to Parkinson’s disease, schizophrenia, and depression [4].

Signs and symptoms of toxicity

From cases of accidental ingestion and inhalation to attempted suicides, signs of toxicity are similar to those of nicotine. These signs include disorientation, drowsiness, dizziness, vomiting, agitation, and fever. There were reported cases as well of cardiotoxicity that lead to death 12 hours after exposure [3].

Historical exposures

The first neonicotinoid, imidacloprid, was introduced in 1990 and from there the group of insecticides has grown to make up >25% of the global insecticide market. Historical exposures come from accumulation of neonicotinoids in soil, drinking water, food, and milk. Currently governments are setting maximum residue limits(MRLs) and funding research to determine the impact of exposure. But, these limits vary dramatically- as of 2013, China’s MRL for imidacloprid in tea is 0.5 mg/kg compared to 0.05 mg/kg MRL in the European union, a 10 fold difference [5].

Treatments

There are no antidotes for neonicotinoid poisoning. Cases show that supportive care of symptoms is all that is required. [3]

References:

1. “Neonicotinoid Pesticides & Adverse Health Outcomes”. National Toxicology Program. U.S. Department of Health and Human Services. Available from: https://ntp.niehs.nih.gov/whatwestudy/assessments/noncancer/ongoing/neonicotinoid/index.html
2. Tomizawa M, Casida J E. “Neonicotinoid Insecticide Toxicology: Mechanisms of Selective Action.” Annual Review of Pharmacology and Toxicology. Vol 45:247-268. Sep 2005. Available from: https://doi.org/10.1146/annurev.pharmtox.45.120403.095930
3. Kumar A, Verma A, Kumar A. “Accidental human poisoning with neonicotinoid insecticide, imidacloprid: A rare case report from rural India with a brief review of literature.” Egyptian Journal of Forensic Sciences. Vol 3-4:123-126. Decc 2013. Available from: https://doi.org/10.1016/j.ejfs.2013.05.002
4. Buszewski B, Bukowska M, Ligor M, Staneszko-Baranowska I. “A holistic study of neopnicotinoids neuroactive insecticides- properties, applications, occurence, and analysis.” Environmental Science and Pollution Research. Vol 26:34723-34740. 2009. Available from: https://link.springer.com/article/10.1007/s11356-019-06114-w#Tab1
5. Han W, Tian Y, Shen X. “Human exposure to neonicotinoid insecticides and the evaluation of their potential toxicity: An overview.” Chemosphere. Vol192:59-65. Feb 2018. Available from: https://doi.org/10.1016/j.chemosphere.2017.10.149