Neonicotinoid

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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.1 The neonicotinoids were developed in large part because they show reduced toxicity compared to previously used organophosphate and carbamate insecticides. Most neonicotinoids show much lower toxicity in mammals than insects, but some breakdown products are toxic.2 Neonicotinoids are the first new class of insecticides introduced in the last 50 years, and the neonicotinoid imidacloprid is currently the most widely used insecticide in the world.3 The neonicotinoids include acetamiprid, clothianidin, imidacloprid, nitenpyram, nithiazine, thiacloprid and thiamethoxam.

The use of some members of this class has been restricted in some countries due to some evidence of a connection to honey-bee colony collapse disorder.4567891011 In January 2013, the European Food Safety Authority stated 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. A study by Italian researchers, published by the Proceedings of the National Academy of Sciences of the United States of America on October 21, 2013, demonstrated that neonicotinoids disrupt the innate immune systems of bees, making them susceptible to viral infections to which the bees are normally resistant.1213

In March 2013, the American Bird Conservancy published a review of 200 studies on neonicotinoids including industry research obtained through the US Freedom of Information Act, calling for a ban on neonicotinoid use as seed treatments because of their toxicity to birds, aquatic invertebrates, and other wildlife.14 Also in March 2013, the US EPA was sued by a coalition of beekeepers, as well as conservation and sustainable agriculture advocates who accused the agency of performing inadequate toxicity evaluations and allowing registration of the pesticides to stand on insufficient industry studies.15

On May 24, 2013, the European Commission imposed a number of use restrictions on neonicotinoid insecticides, which are suspected to be a contributing factor of bee colony collapse disorder.1617 Recently published evidence that neonicotinoids disrupt the immune systems of bees may lend political support to the EU's actions.13

Market

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 2008.18

Eight neonicotinoids from different companies are currently on the market.18

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
Thiacloprid Bayer CropScience Calypso 112
Dinotefuran Mitsui Chemicals Starkle, Safari, Venom 79
Sulfoxaflor Dow Agrosciences Transform, Closer N/A
Nitenpyram Sumitomo Chemical Capstar, Bestguard 8

History

Nicotine acts as an insecticide but is also toxic to mammals19 , with a lower lethal dose for rats than flies.3 This spurred a scientific search for compounds that retain the insecticidal properties of nicotine but have selectively less effect on mammals, but initial investigation of nicotine related compounds (nicotinoids) as insecticides was not successful.19 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.1 Nithiazine was later found to be a postsynaptic acetylcholine receptor agonist,20 meaning it has the same mode of action as nicotine. Nithiazine does not act as an acetylcholinesterase inhibitor,20 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. Neonicotinoids were developed after the lack of commercial success of nithiazine. The first commercial neonicotinoid, imidacloprid, was developed by Bayer.1

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 were in use as well. Currently, virtually all corn that is planted in the Midwestern United States is treated with one of these two insecticides and various fungicides. In addition, most soybean seeds are also treated with a neonicotinoid insecticide, usually thiamethoxam.

US EPA reregistration and Congressional action

The US EPA has established a 15-year registration review cycle for all pesticides. As all neonicotinoids were registered after 1984, they were not subject to reregistration. The EPA granted a conditional, or temporary, registration to clothianidin in 2003. The same approval was given to thiamethoxam. Imidacloprid was registered in 1994. It was not conditional. The EPA is now re-evaluating the safety of neonicotinoids. According to the EPA, the registration review process will take several years. At the earliest, the new verdict for imidacloprid will be in 2016 and 2017 for clothianidin and thiamethoxam. The registration review docket for imidacloprid opened in December 2008 and the docket for nithiazine opened in March 2009. Stated topics for review include uncertainty in the effects of neonicotinoids on pollinators, including reports of beekill incidents. The EPA states, "To better ensure a 'level playing field' for the neonicotinoid class as a whole, and to best take advantage of new research as it becomes available," the other neonicotinoids (acetamiprid, clothianidin, dinotefuran, thiacloprid and thiamethoxam) were scheduled to begin registration review in 2012.21

On July 12, 2013, Rep. Earl Blumenauer, Democrat of Oregon, introduced The Save American Pollinators Act in Congress. If it becomes law, the Act will suspend the use of four neonicotinoids, including the three recently suspended by the European Union, until their EPA registration review is complete. The legislation will also require a joint Interior Department and EPA study of bee populations and the possible reasons for their decline.22

EU restrictions

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 results of the peer reviewed study were published in January 2013. EFSA reached the following conclusions:2324

  • 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 risk assessment that could be completed was for maize treated with thiamethoxam. In this case, field studies show an acute effect on honey bees exposed to the substance through guttation fluid.

EFSA’s scientists were unable to finalize risk assessments for some of the uses authorized in the EU, and identified a number of data gaps. EFSA also highlighted that risk to other pollinators should be further considered.

In response to the study, the European Commission recommended a restriction of their use across the European Union.17

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.1617 Temporary suspensions had previously been enacted in France, Germany, and Italy.25 In Switzerland, where neonicotinoids were never used in alpine areas, a ban has also been implemented due to accidental poisonings of bee populations and the relatively low safety margin for other beneficial insects.26

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."17 Great Britain, 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."17 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."25 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."17 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."25

In January 2013, the Humboldt Forum for Food and Agriculture e. V. (HFFA) published a report on the value of neonicotinoids in the EU. The study was commissioned by Bayer CropScience and Syngenta. COPA-COGECA, the European Seed Association and the European Crop Protection Association supported it. 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 of a potential ban, agricultural and total VA would decline by €2.8 and €3.8 billion, respectively. The greatest losses would affect the production of 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.27

Usage

Imidacloprid, a representative neonicotinoid, is effective against sucking insects, some chewing insects, soil insects, and is also used to control fleas on domestic animals.28

Imidacloprid is possibly the most widely used insecticide, both within the mode of action group 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,29 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.30

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 triggers 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 cells of the CNS. While low to moderate activation of these receptors causes nervous stimulation, high levels overstimulate and block the receptors.328 This receptor blockage causes paralysis and death. Nicotinic acetylcholine receptors are normally activated by the neurotransmitter acetylcholine. Normally, acetylcholine is broken down by acetylcholinesterase to terminate signals from these receptors. However, acetylcholinesterase cannot break down neonicotinoids, and the binding is irreversible.28 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.31

Basis of selectivity

R-nicotine
Desnitro-imidacloprid
R-nicotine (top) and desnitro-imidacloprid are both protonated in the body

Most neonicotinoids, such as imidacloprid, show low affinity for mammalian nicotinic acetylcholine receptors (nAChRs) while exhibiting high affinity for insect nAChRs.332 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.3132 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.3

Nicotine, like the natural ligand acetylcholine, has a positively charged nitrogen (N) atom at physiological pH.331 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 charges like nicotine. . Although the blood–brain barrier reduces access of ions to the central nervous system, nicotine is also 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, resulting is species specific toxicity33

However, desnitro-imidacloprid, which is formed in a mammal's body during metabolism31 as well as in environmental breakdown,34 has a charged nitrogen and shows high affinity to mammalian nAChRs.31 Desnitro-imidacloprid is quite toxic to mice.2

Independent studies show that while the photodegradation half-life time of most neonicotinoids is around 34 days when exposed to sunlight, 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 activists are concerned that neonicotinoids applied agriculturally might accumulate in aquifers.35

Environmental impacts

Environmental campaigner George Monbiot has called Neonicotinoids "the new DDT" because, he states, "they were licensed for widespread use before they had been properly tested" and "are now ripping the natural world apart".36

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.37 Investigation of the incident 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;38
  • and a higher application rate which had been authorized for a severe root worm infestation.

Clothianidin was also restricted for a short period for 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.3940

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 the pesticides belonging to the neonicotinoid group (clothianidin, thiamethoxam and imidacloprid) when used on corn. In addition, on the basis of new findings, the question arose as to whether drops of liquid from plants, which are taken in by bees, pose an additional risk.41

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 also based its decision on the known acute toxicity of these compounds to pollinators.4243

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.42

Links to decline in bee population

Since about 2006 there has been a world-wide dramatic rise in the number of hive losses and a reduction of wild bees.44 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 through low levels of contamination. It is thought that even low levels of contamination may impact bees’ ability to forage for nectar, learn and remember where flowers are located, and possibly impair their ability to find their way home to the nest or hive.45 A 2012 study suggested that neonicotinoids may be responsible for detrimental effects of pesticides on the bumble bee colony growth and queen production which may be related to a world-wide reduction in the number of wild bees.46

In 2012, several peer reviewed independent studies were published showing that neonicotinoids had previously undetected routes of exposure affecting bees including through dust, pollen, and nectar47 and that sub-nanogram toxicity resulted in failure to return to the hive without immediate lethality,48 the primary symptom of colony collapse disorder.49 Research also showed environmental persistence in agricultural irrigation channels and soil.50 These reports prompted a formal peer review by the European Food Safety Authority 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 several 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."5152 David Goulson, an author of one of the Science studies which prompted the EESA peer review, has suggested that industry science pertaining to neonicotinoids may have been deliberately deceptive, and the UK Parliament has asked manufacturer Bayer Cropscience to explain discrepancies in evidence they have submitted to an investigation.53

A two-year peer reviewed study published in 2012 showed the presence of two neonicotinoid insecticides, clothianidin and thiamethoxam, 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 — 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 extremely high levels of the insecticides — up to about 700,000 times the lethal contact dose for a bee. According to the research,

"Whatever was on the seed was being exhausted into the environment. This material is so concentrated that even small amounts landing on flowering plants around a field can kill foragers or be transported to the hive in contaminated pollen. This might be why we found these insecticides in pollen that the bees had collected and brought back to their hives."

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.54

In July 2010, a Dutch toxicologist examined the toxicity of neonicotinoid pesticides in relation to exposure time.55 He then authored and published a book in regards to his research called "A Disaster in the Making". The book explores the impact of neonicotinoids on the immune system of bees. The 2009 documentary Vanishing of the Bees suggests that a link between neonicotinoid pesticides and colony collapse disorder exists.56

In March 2014, Minneapolis-based Bachman’s gardening centers announced that they plan to no longer sell neonicotinoids or use them at their nurseries and outdoor growing areas. Bachman's vice president of production and wholesale said it was not an easy decision, but after receiving numerous calls from concerned gardeners they "decided to take precautionary action." 57

Health effects on birds, aquatic invertebrates, and other wildlife

In March 2013, the American Bird Conservancy published a review of 200 studies on neonicotinoids including industry research obtained through the US Freedom of Information Act, calling for a ban on neonicotinoid use as seed treatments because of their toxicity to birds, aquatic invertebrates, and other wildlife.14 A Dutch study determined that water containing the legal concentration of neonicotinoids had 50% fewer invertebrate species compared with uncontaminated water.58

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