Neonicotinoids are a class of neuro-active insecticides chemically similar to nicotine. The development of this class of insecticides began with work in the 1980s by Shell and the 1990s by Bayer. The neonicotinoids show reduced toxicity compared to previously used organophosphate and carbamate insecticides. Most neonicotinoids show much lower toxicity in birds and mammals than insects, but some breakdown products are toxic. The neonicotinoid imidacloprid is currently the most widely used insecticide in the world. The neonicotinoid family includes acetamiprid, clothianidin, imidacloprid, nitenpyram, nithiazine, thiacloprid and thiamethoxam.
In the late 2000s some kinds of neonicotinoids began to come under increasing scrutiny over potential environmental impacts. The use of neonicotinoids was linked in a range of studies to a number of adverse ecological effects, including honey-bee colony collapse disorder (CCD) and loss of birds due to reduction in insect populations. Increased scrutiny eventually led to restrictions and bans on the use of different neonicotinoids in several countries.
Neonicotinoids are registered in more than 120 countries. With a turnover of €1.5 billion, they represented 24% of the global market for insecticides in 2008. Neonicotinoids are even more important in the market for seed treatments. After the introduction of the first neonicotinoids in the 1990s, this market has grown from €155 million in 1990 to €957 million in 2008. Neonicotinoids made up 80% of all seed treatment sales in 2008.
Seven neonicotinoids from different companies are currently on the market.
|Name||Company||Products||Turnover in million US$ (2009)|
|Imidacloprid||Bayer CropScience||Confidor, Admire, Gaucho, Advocate||1,091|
|Thiamethoxam||Syngenta||Actara, Platinum, Cruiser||627|
|Clothianidin||Sumitomo Chemical/Bayer CropScience||Poncho, Dantosu, Dantop||439|
|Acetamiprid||Nippon Soda||Mospilan, Assail, ChipcoTristar||276|
|Dinotefuran||Mitsui Chemicals||Starkle, Safari, Venom||79|
|Nitenpyram||Sumitomo Chemical||Capstar, Bestguard||8|
Nicotine acts as an insecticide.  It exhibits a higher lethal dose for rats than flies. This spurred a search for insecticidal compounds that have selectively less effect on mammals. Initial investigation of nicotine-related compounds (nicotinoids) as insecticides was not successful.
The precursor to nithiazine was first synthesized by a chemist at Purdue University. Shell researchers found in screening that this precursor showed insecticide potential and refined it to develop nithiazine. Nithiazine was later found to be a postsynaptic acetylcholine receptor agonist, the same mode of action as nicotine. Nithiazine does not act as an acetylcholinesterase inhibitor, in contrast to the organophosphate and carbamate insecticides. While nithiazine has the desired specificity (i.e. low mammalian toxicity), it is not photostable (it breaks down in sunlight), so it was not commercially viable.
Most neonicotinoids are water-soluble and break down slowly in the environment, so they can be taken up by the plant and provide protection from insects as the plant grows. During the late 1990s this class of pesticides, primarily imidacloprid, became widely used. Beginning in the early 2000s, two other neonicotinoids, clothianidin and thiamethoxam entered the market. Currently, virtually all corn that is planted in the Midwestern United States is treated with one of these two insecticides (and various fungicides). Most soybean seeds are treated with a neonicotinoid insecticide, usually thiamethoxam.
The US EPA operates a 15-year registration review cycle for all pesticides. The EPA granted a conditional registration to clothianidin in 2003. The EPA issues conditional registrations when a pesticide meets the standard for registration, but there are outstanding data requirements. Thiamethoxam is approved for use as an antimicrobial pesticide wood preservative and as a pesticide; it was first approved in 1999.:4 & 14 Imidacloprid was registered in 1994.
As all neonicotinoids were registered after 1984, they were not subject to reregistration, but due to environmental concerns, especially concerning bees, the EPA opened dockets to evaluate them. The registration review docket for imidacloprid opened in December 2008, and the docket for nithiazine opened in March 2009. To best take advantage of new research as it becomes available, the EPA moved ahead the docket openings for the remaining neonicotinoids on the registration review schedule (acetamiprid, clothianidin, dinotefuran, thiacloprid, and thiamethoxam) to FY 2012. The EPA has said that it expects to complete the review for the neonicotinoids in 2018.
In March 2012, the Center for Food Safety, Pesticide Action Network, Beyond Pesticides and a group of beekeepers filed an Emergency Petition with the EPA asking the agency to suspend the use of clothianidin. The agency denied the petition. In March 2013, the US EPA was sued by the same group, with the Sierra Club and the Center for Environmental Health joining, which accused the agency of performing inadequate toxicity evaluations and allowing insecticide registration based on inadequate studies. The case, Ellis et al v. Bradbury et al, was stayed as of October 2013.
On July 12, 2013, Rep. John Conyers, on behalf of himself and Rep. Earl Blumenauer, introduced the "Save American Pollinators Act" in the House of Representatives. The Act called for suspension of the use of four neonicotinoids, including the three recently suspended by the European Union, until their review is complete, and for a joint Interior Department and EPA study of bee populations and the possible reasons for their decline. The bill was assigned to a congressional committee on July 16, 2013 and did not leave committee.
In 2008, Germany revoked the registration of clothianidin for use on seed corn after an incident that resulted in the death of millions of nearby honey bees. An investigation revealed that it was caused by a combination of factors:
- failure to use a polymer seed coating known as a "sticker";
- weather conditions that resulted in late planting when nearby canola crops were in bloom;
- a particular type of air-driven equipment used to sow the seeds which apparently blew clothianidin-laden dust off the seeds and into the air as the seeds were ejected from the machine into the ground;
- dry and windy conditions at the time of planting that blew the dust into the nearby canola fields where honey bees were foraging;
In Germany, clothianidin was also restricted for a short period from use on rapeseed; however, after evidence had shown that the problems resulting from maize seed were not transferable to rapeseed, its use was reinstated under the condition that the pesticide be fixed to the rapeseed grains by means of an additional sticker, so that abrasion dusts would not be released into the air.
In 2009, the German Federal Office of Consumer Protection and Food Safety decided to continue to suspend authorization for the use of clothianidin on corn. It had not yet been fully clarified to what extent and in what manner bees come into contact with the active substances in clothianidin, thiamethoxam and imidacloprid when used on corn. In addition, the question of whether liquid emitted by plants via guttation, which is taken in by bees, pose an additional risk.
Neonicotinoid seed treatment uses are banned in Italy, but foliar uses are allowed. This action was taken based on preliminary monitoring studies showing that bee losses were correlated with the application of seeds treated with these compounds; Italy based its decision on the known acute toxicity of these compounds to pollinators.
Sunflower and corn seed treatments of the active ingredient imidacloprid are suspended in France; other imidacloprid seed treatments, such as for sugar beets and cereals, are allowed, as are foliar uses.
In response to growing concerns about the impact of neonicotinoids on honey bees, the European Commission in 2012 asked the European Food Safety Authority (EFSA) to study the safety of three neonicotinoids. The study was published in January 2013, which stated in January 2013 that neonicotinoids pose an unacceptably high risk to bees, and that the industry-sponsored science upon which regulatory agencies' claims of safety have relied may be flawed and contain data gaps not previously considered. Their review concluded, "A high acute risk to honey bees was identified from exposure via dust drift for the seed treatment uses in maize, oilseed rape and cereals. A high acute risk was also identified from exposure via residues in nectar and/or pollen." EFSA reached the following conclusions:
- Exposure from pollen and nectar. Only uses on crops not attractive to honey bees were considered acceptable.
- Exposure from dust. A risk to honey bees was indicated or could not be excluded, with some exceptions, such as use on sugar beet and crops planted in glasshouses, and for the use of some granules.
- Exposure from guttation. The only completed assessment was for maize treated with thiamethoxam. In this case, field studies showed an acute effect on honey bees exposed to the substance through guttation fluid.
EFSA’s scientists were unable to finalize risk assessments for some uses authorized in the EU, and identified a number of data gaps. EFSA also highlighted that risk to other pollinators should be further considered. The UK Parliament asked manufacturer Bayer Cropscience to explain discrepancies in evidence that they submitted to an investigation.
In response to the study, the European Commission recommended a restriction of their use across the European Union.
On 29 April 2013, 15 of the 27 European Union member states voted to restrict the use of three neonicotinoids for two years from 1 December 2013. Eight nations voted against the ban, while four abstained. The law restricts the use of imidacloprid, clothianidin and thiamethoxam for seed treatment, soil application (granules) and foliar treatment in crops attractive to bees. Temporary suspensions had previously been enacted in France, Germany and Italy. In Switzerland, where neonicotinoids were never used in alpine areas, neonics were banned due to accidental poisonings of bee populations and the relatively low safety margin for other beneficial insects.
Environmentalists called the move "a significant victory for common sense and our beleaguered bee populations" and said it is "crystal clear that there is overwhelming scientific, political and public support for a ban." The United Kingdom, which voted against the bill, disagreed: "Having a healthy bee population is a top priority for us, but we did not support the proposal for a ban because our scientific evidence doesn’t support it." Bayer Cropscience, which makes two of the three banned products, remarked "Bayer remains convinced neonicotinoids are safe for bees, when used responsibly and properly ... clear scientific evidence has taken a back-seat in the decision-making process." Reaction in the scientific community was mixed. Biochemist Lin Field said the decision was based on "political lobbying" and could lead to the overlooking of other factors involved in colony collapse disorder. Zoologist Lynn Dicks of Cambridge University disagreed, saying "This is a victory for the precautionary principle, which is supposed to underlie environmental regulation." A bee expert called the ban "excellent news for pollinators", and said, "The weight of evidence from researchers clearly points to the need to have a phased ban of neonicotinoids."
In January 2013, the Humboldt Forum for Food and Agriculture e. V. (HFFA), a non-profit think tank, published a report on the value of neonicotinoids in the EU. At their website HFFA lists as their partners/supporters: BASE FE, the world's largest chemical company; Bayer CropScience, makers of products for crop protection and nonagricultural pest control; E.ON, an electric utility service provider; KWS Seed, a seed producer; and the food company Nestle. 
The study was supported by COPA-COGECA, the European Seed Association and the European Crop Protection Association, and financed by neonicotinoid manufacturers Bayer CropScience and Syngenta. The report looked at the short- and medium-term impacts of a complete ban of all neonicotinoids on agricultural and total value added (VA) and employment, global prices, land use and greenhouse gas (GHG) emissions. In the first year, agricultural and total VA would decline by €2.8 and €3.8 billion, respectively. The greatest losses would be in wheat, maize and rapeseed in the UK, Germany, Romania and France. 22,000 jobs would be lost, primarily in Romania and Poland, and agricultural incomes would go down by 4.7%. In the medium-term (5-year ban), losses would amount to €17 billion in VA, and 27,000 jobs. The greatest income losses would affect the UK, while most jobs losses would occur in Romania. Following a ban, the lowered production would induce more imports of agricultural commodities into the EU. Agricultural production outside the EU would expand by 3.3 million hectares, leading to additional emissions of 600 million tons of carbon dioxide equivalent.
When the report was released, a spokesperson for the Soil Association, which has been working to ban neonicotinoids in the UK, commented that since the report was funded by Bayer Crop Sciences and Syngenta, "it was probably unlikely to conclude that neonicotinoids should be banned". The spokesperson further stated: "On the one hand, the chemical companies say we risk the additional costs to farmers amounting to £630 million. On the other, the possible cost of losing pollinating insects is thought to be worth three times as much (£1.8 billion*) to UK farmers."
Imidacloprid is effective against sucking insects, some chewing insects, soil insects and is also used to control fleas on domestic animals. It is possibly the most widely used insecticide, both within the neonics and in the worldwide market. It is now applied against soil, seed, timber and animal pests as well as foliar treatments for crops including: cereals, cotton, grain, legumes, potatoes, pome fruits, rice, turf and vegetables. It is systemic with particular efficacy against sucking insects and has a long residual activity. Imidacloprid can be added to the water used to irrigate plants. Controlled release formulations of imidacloprid take 2–10 days to release 50% of imidacloprid in water.
The application rates for neonicotinoid insecticides are much lower than older, traditionally used insecticides.
Mode of action
Neonicotinoids, like nicotine, bind to nicotinic acetylcholine receptors of a cell and trigger a response by that cell. In mammals, nicotinic acetylcholine receptors are located in cells of both the central and peripheral nervous systems. In insects these receptors are limited to the CNS.
While low to moderate activation of these receptors causes nervous stimulation, high levels overstimulate and block the receptors, causing paralysis and death. Nicotinic acetylcholine receptors are activated by the neurotransmitter acetylcholine. Acetylcholine is broken down by acetylcholinesterase to terminate signals from these receptors. However, acetylcholinesterase cannot break down neonicotinoids and the binding is irreversible. Because most neonicotinoids bind much more strongly to insect neuron receptors than to mammal neuron receptors, these insecticides are selectively more toxic to insects than mammals.
Basis of selectivity
Most neonicotinoids, such as imidacloprid, show low affinity for mammalian nicotinic acetylcholine receptors (nAChRs) while exhibiting high affinity for insect nAChRs. Mammals and insects have structural differences in nAChRs that affect how strongly particular molecules bind, both in the composition of the receptor subunits and the structures of the receptors themselves. The low mammalian toxicity of imidacloprid can be explained in large part by its lack of a charged nitrogen atom at physiological pH. The uncharged molecule can penetrate the insect blood–brain barrier, while the human blood–brain barrier filters it.
Nicotine, like the natural ligand acetylcholine, has a positively charged nitrogen (N) atom at physiological pH. This positive charge gives nicotine a strong affinity to mammalian nAChRs as it binds to the same negatively charged site as acetylcholine (which is positively charged like nicotine). Although the blood–brain barrier reduces access of ions to the central nervous system, nicotine is highly lipophilic and at physiological pH is quickly and widely distributed. This can be demonstrated by the fact that nicotine is well absorbed transdermally, one of the most difficult tissues to penetrate. Neonicotinoids, on the other hand, have a negatively charged nitro or cyano group, which interacts with a unique, positively charged amino acid residue present on insect, but not mammalian nAChRs.
However, desnitro-imidacloprid, which is formed in a mammal's body during metabolism as well as in environmental breakdown, has a charged nitrogen and shows high affinity to mammalian nAChRs. Desnitro-imidacloprid is quite toxic to mice.
Independent studies show that the photodegradation half-life time of most neonicotinoids is around 34 days when exposed to sunlight. However, it might take up to 1,386 days (3.8 years) for these compounds to degrade in the absence of sunlight and micro-organism activity. Some researchers are concerned that neonicotinoids applied agriculturally might accumulate in aquifers.
Decline in bee population
A dramatic rise in the number of annual beehive losses noticed around 2006 spurred interest in factors potentially affecting bee health. When first introduced, neonicotinoids were thought to have low-toxicity to many insects, but recent research has suggested a potential toxicity to honey bees and other beneficial insects even with low levels of contact. Neonicotinoids may impact bees’ ability to forage, learn and remember navigation routes to and from food sources. Separate from lethal and sublethal effects solely due to neonicotinoid exposure, neonicotinoids are also being explored with a combination with other factors, such as mites and pathogens, as potential causes of colony collapse disorder. Neonicotinoids may be responsible for detrimental effects on bumble bee colony growth and queen production.
Previously undetected routes of exposure for bees include particulate matter or dust, pollen and nectar Bees can fail to return to the hive without immediate lethality due to sub-nanogram toxicity, one primary symptom of colony collapse disorder. Separate research showed environmental persistence in agricultural irrigation channels and soil.
A 2012 study showed the presence of thiamethoxam and clothianidin in bees found dead in and around hives situated near agricultural fields. Other bees at the hives exhibited tremors, uncoordinated movement and convulsions, all signs of insecticide poisoning. The insecticides were also consistently found at low levels in soil up to two years after treated seed was planted and on nearby dandelion flowers and in corn pollen gathered by the bees. Insecticide-treated seeds are covered with a sticky substance to control its release into the environment, however they are then coated with talc to facilitate machine planting. This talc may be released into the environment in large amounts. The study found that the exhausted talc showed up to about 700,000 times the lethal insecticide dose for a bee. Exhausted talc containing the insecticides is concentrated enough that even small amounts on flowering plants can kill foragers or be transported to the hive in contaminated pollen. Tests also showed that the corn pollen that bees were bringing back to hives tested positive for neonicotinoids at levels roughly below 100 parts per billion, an amount not acutely toxic, but enough to kill bees if sufficient amounts are consumed.
A 2013 peer reviewed literature review concluded that neonicotinoids in the amounts that they are typically used harm bees and that safer alternatives are urgently needed. An October 2013 study by Italian researchers demonstrated that neonicotinoids disrupt the innate immune systems of bees, making them susceptible to viral infections to which the bees are normally resistant.
In March 2013, the American Bird Conservancy published a review of 200 studies on neonicotinoids calling for a ban on neonicotinoid use as seed treatments because of their toxicity to birds, aquatic invertebrates, and other wildlife.
A 2013 Dutch study determined that water containing allowable concentrations of neonicotinoids had 50% fewer invertebrate species compared with uncontaminated water.
In the July 2014 issue of the journal Nature, a study based on an observed correlation between declines in some bird populations and the use of neonicotinoid pesticides in the Netherlands demonstrated that the level of neonicotinoids detected in environmental samples correlated strongly with the decline in populations of insect-eating birds. An editorial published in the same edition found the possible link between neonicotinoid pesticide use and a decline in bird numbers "worrying," pointing out that the persistence of the compounds (half-life of 1000 days) and the low direct toxicity to birds themselves implies that the depletion of the birds' food source (insects) is likely responsible for the decline and that the compounds are distributed widely in the environment. The editors write that while correlation is not the same as causation, "the authors of the study also rule out confounding effects from other land-use changes or pre-existing trends in bird declines".
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