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Neonicotinoids (sometimes shortened to neonics /ˈniːoʊnɪks/) are a class of neuro-active insecticides chemically similar to nicotine. In the 1980s Shell and in the 1990s Bayer started work on their development. The neonicotinoid family includes acetamiprid, clothianidin, imidacloprid, nitenpyram, nithiazine, thiacloprid and thiamethoxam. Imidacloprid is the most widely used insecticide in the world. Compared to organophosphate and carbamate insecticides neonicotinoids cause less toxicity in birds and mammals than insects. Some breakdown products are also toxic.

In the late 1990s neonicotinoids came under increasing scrutiny over their environmental impacts. Neonicotinoid use was linked in a range of studies to adverse ecological effects, including honey-bee colony collapse disorder (CCD) and loss of birds due to a reduction in insect populations. In 2013, the European Union and a few non EU countries restricted the use of certain neonicotinoids.

History

The precursor to nithiazine was first synthesized by Henry Feuer, a chemist at Purdue University, in 1970; Shell researchers found in screening that this precursor showed insecticide potential and refined it to develop nithiazine. In 1984 nithiazine's mode of action was found to be as a postsynaptic acetylcholine receptor agonist, the same 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—that is, it breaks down in sunlight, and thus is not commercially viable.

In 1985, Bayer patented imidacloprid as the first commercial neonicotinoid.

During the late 1990s, primarily, imidacloprid became widely used. Beginning in the early 2000s, two other neonicotinoids, clothianidin and thiamethoxam entered the market. As of 2013, virtually all corn planted in the United States was treated with one of these two insecticides and various fungicides. As of 2014, about a third of US soybean acreage was planted with neonicotinoid treated seeds, usually imidacloprid or thiamethoxam.

Market

Neonicotinoids have been registered in more than 120 countries. With a global turnover of €1.5 billion in 2008, they represented 24% of the global market for insecticides. 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.

As of 2011, seven neonicotinoids from different companies are on the market.

Agricultural usage

Efficacy

Imidacloprid is effective against sucking insects, some chewing insects, soil insects and fleas on domestic animals. 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. It is applied against soil pests, seed, timber and animal pests as well as foliar treatments.

As of 2013 neonicotinoids have been used In the U.S. on about 95 percent of corn and canola crops, the majority of cotton, sorghum, and sugar beets and about half of all soybeans. They have been used on the vast majority of fruit and vegetables, including apples, cherries, peaches, oranges, berries, leafy greens, tomatoes, and potatoes, to cereal grains, rice, nuts, and wine grapes. Imidacloprid is possibly the most widely used insecticide, both within the neonicotinoids and in the worldwide market.

Seed coatings

In agriculture, usefulness of neonicotinoid seed treatments for pest prevention depends upon the timing of planting and pest arrival. For soybeans, neonicotinoid seed treatments typically are not effective against the soybean aphid, because the compounds break down 35–42 days after planting, and soybean aphids typically are not present or at damaging population levels before this time. Neonicotinoid seed treatments can protect yield in special cases such as late-planted fields or in areas with large infestations much earlier in the growing season. Overall yield gains are not expected from neonicotinoid seed treatments for soybean insect pests in the United States, and foliar insecticides are recommended instead when insects do reach damaging levels. Health Canada estimated that neonicotinoids provide benefits equivalent to over 3% of the national farm gate value of corn and 1.5% to 2.1% of the national farm gate value of soybean in 2013 .

Regulation

United States

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. 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.

Europe

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 use was also restricted in 2008 for a short period on rapeseed. After it was shown that rapeseed treatment did not have the same problems as maize, its use was reinstated under the condition that the pesticide be fixed to the rapeseed grains by 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 clothianidin use 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. The question of whether liquid emitted by plants via guttation, which bees ingest, posed an additional risk was unanswered.

Neonicotinoid seed treatment is banned in Italy, but foliar use is 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.

In France, sunflower and corn seed treatment with imidacloprid are suspended; imidacloprid seed treatment for sugar beets and cereals are allowed, as is foliar use.

In 2012, the European Commission asked the European Food Safety Authority (EFSA) to study the safety of three neonicotinoids, in response to growing concerns about the impact of neonicotinoids on honey bees. The study was published in January 2013, stating 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 identified a number of data gaps and were unable to finalize risk assessments for some uses authorized in the EU. EFSA also highlighted that risk to other pollinators should be further considered. The UK Parliament asked manufacturer Bayer Cropscience to explain discrepancies in the evidence they submitted.

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 EU member states voted to restrict the use of three neonicotinoids for two years starting 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 UK, 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." Simon Potts, Professor of Biodiversity and Ecosystem Services at Reading University, 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."

Economic impact

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: BASF 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 Nestlé.

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 decrease 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, Peter Melchett, policy director of 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.”

Canada

In Montreal, Quebec, nearly all corn seeds and a majority of soybeans get treated with neonicotinoids. In the summer of 2015, Montreal passed a law to reduce the presence of neonicotinoids. Montreal’s regulations were written to reduce the percent of seeds and beans covered with neonicotoids to 20 percent within two years.

Agricultural businesses oppose Montreal’s ban. CropLife Canada is a trade association that represents manufacturers of agricultural plant science and pest management products. The main argument against Montreal’s ban is that once farmers are no longer allowed to use neonicotinoids, they would likely use dangerous pesticide sprays on seeds. The industry’s opposition centers around a White House pollinator health task force report and a Canadian Senate report. The reports said that bees face more serious threats than "scientifically safe neonics."

On December 10, 2015, Montreal banned all neonicotinoids - without exception - on all properties within the city limits, including the Botanical Garden, all agricultural areas and all golf courses.

Mode of action

Neonicotinoids, like nicotine, bind to nicotinic acetylcholine receptors (nAChRs) of a cell and trigger a response by that cell. In mammals, nicotinic acetylcholine receptors are located in cells of both the central nervous system and peripheral nervous systems. In insects these receptors are limited to the central nervous system. Nicotinic acetylcholine receptors are activated by the neurotransmitter acetylcholine. While low to moderate activation of these receptors causes nervous stimulation, high levels overstimulate and block the receptors, causing paralysis and death. Acetylcholinesterase breaks down acetylcholine to terminate signals from these receptors. However, acetylcholinesterase cannot break down neonicotinoids and their binding is irreversible.

Basis of selectivity

Mammals and insects have different composition of the receptor subunits and the structures of the receptors. Because most neonicotinoids bind much more strongly to insect neuron receptors than to mammal neuron receptors, these insecticides are more toxic to insects than mammals.

The low mammalian toxicity of imidacloprid has been explained by its inability to cross the blood–brain barrier because of lack of a charged nitrogen atom at physiological pH. The uncharged molecule can penetrate the insect blood–brain barrier.

Other neonicotinoids 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, the breakdown product 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.

Chemical properties

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. 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.

Toxicity

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. An eighteen year English study linked neonicotinoid use on oilseed rape to the "large-scale, long-term decline in wild bees". 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. For example, Bombus affinis, a bumblebee endemic to North America, has decreased in nearly 90% of its natural habitats, much of which has been attributed to the use of neonicotoid based pesticides.

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. 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 review concluded that neonicotinoids as they are typically used harm bees and that safer alternatives are urgently needed. An October 2013 study by Italian researchers demonstrated that neonicotinoids disrupt bees' immune systems, making them susceptible to viral infections to which the bees are normally resistant.

In April 2015 EASAC conducted a study of the potential effects on organisms providing a range of ecosystem services like pollination and natural pest control which are critical to sustainable agriculture. The resulting report concludes "there is an increasing body of evidence that the widespread prophylactic use of neonicotinoids has severe negative effects on non-target organisms that provide ecosystem services including pollination and natural pest control." Two studies published in Nature provided further evidence of the deleterious effect of neonicontinoids on bees, although the further research is needed to corroborate the findings: Oilseed rape seed coated with a combination of clothianidin and a pyrethroid “reduced wild bee density, solitary bee nesting, and bumblebee colony growth and reproduction under field conditions”. In a feeding experiment, bees preferred sucrose solutions with imidacloprid or thiamethoxam, even though it “caused them to eat less food overall”.

An October 2015 study demonstrates significant effects on the survival and reproductive capacities of honey bee queens exposed to neonicotinoids. Those exposed to neonicotinoids had 60% survival rates, as compared to 80% for control groups. Lower worker egg production and alterations to surviving queens' reproductive anatomy "likely corresponded to reduced queen success (alive and producing worker offspring)." The authors further claim "our study suggests that these substances are, at least partially, responsible for harming queens and causing population declines of social bee species. Failure of queens exposed to neonicotinoids during development to successfully lay fertilised eggs that subsequently develop into workers or queens is worrisome; both castes are vital to colony survival..."

Other wildlife

In March 2013, the American Bird Conservancy published a commentary on 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 found that water containing allowable concentrations of imidacloprid had 50% fewer invertebrate species compared with uncontaminated water. A later study found the analysis was confounded with other co-occurring insecticides and did not show imidacloprid directly affected invertebrate diversity.

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”.

From June to October 2014 a comprehensive Worldwide Integrated Assessment of the impact of Systemic Pesticides on biodiversity and ecosystems (WIA) was published in the journal Environmental Science and Pollution Research. In a series of papers it concludes that these systemic insecticides pose a serious risk of harm to a broad range of non-target invertebrate taxa often below the expected environmental concentrations. Their present scale use is therefore not a sustainable pest management approach and compromises the actions of numerous stakeholders in maintaining and supporting biodiversity and subsequently the ecological functions and services the diverse organisms perform.

References

1. ^ Kollmeyer, Willy D.; Flattum, Roger F.; Foster, James P.; Powell, James E.; Schroeder, Mark E.; Soloway, S. Barney (1999). "Discovery of the Nitromethylene Heterocycle Insecticides". In Yamamoto, Izuru; Casida, John (eds.). Nicotinoid Insecticides and the Nicotinic Acetylcholine Receptor. Tokyo: Springer-Verlag. pp. 71–89. ISBN 443170213X.
2. ^ Yamamoto, Izuru (1999). "Nicotine to Nicotinoids: 1962 to 1997". In Yamamoto, Izuru; Casida, John (eds.). Nicotinoid Insecticides and the Nicotinic Acetylcholine Receptor. Tokyo: Springer-Verlag. pp. 3–27. ISBN 443170213X.
3. ^ Tomizawa M, Casida JE (2005). "Neonicotinoid insecticide toxicology: mechanisms of selective action". Annu Rev Pharmacol Toxicol. 45: 247–68. doi:10.1146/annurev.pharmtox.45.120403.095930. PMID 15822177.
4. http://www.nytimes.com/2007/04/24/science/24bees.html?pagewanted=all&_r=0
5. Cressey, D. (2013). "Europe debates risk to bees". Nature. 496 (7446): 408. doi:10.1038/496408a. PMID 23619669.
   Gill, R. J.; Ramos-Rodriguez, O.; Raine, N. E. (2012). "Combined pesticide exposure severely affects individual- and colony-level traits in bees". Nature. 491 (7422): 105–108. doi:10.1038/nature11585. PMC 3495159. PMID 23086150.
   Dicks, L. (2013). "Bees, lies and evidence-based policy". Nature. 494 (7437): 283. doi:10.1038/494283a. PMID 23426287.
   Stoddart, C. (2012). "The buzz about pesticides". Nature. doi:10.1038/nature.2012.11626.
   Osborne, J. L. (2012). "Ecology: Bumblebees and pesticides". Nature. 491 (7422): 43–45. doi:10.1038/nature11637. PMID 23086148.
   Cressey, D. (2013). "Reports spark row over bee-bothering insecticides". Nature. doi:10.1038/nature.2013.12234.
   "Nature Studies by Michael McCarthy: Have we learned nothing since 'Silent Spring'?" The Independent 7 January 2011
   "Do people know perfectly well what’s killing bees?" IO9.com 6 January 2011
6. ^ Bees & Pesticides: Commission goes ahead with plan to better protect bees. 30 May 2013.
7. ^ Charlotte McDonald-Gibson (29 April 2013). "'Victory for bees' as European Union bans neonicotinoid pesticides blamed for destroying bee population". The Independent. Retrieved 1 May 2013.
8. See:
   • Feuer, H. ; Lawrence, J.P. (1969) "The alkyl nitrate nitration of active methylene compounds. VI. A new synthesis of α-nitroalkyl heterocyclics," Journal of the American Chemical Society, 91 : 1856-1857.
   • P. Jeschke and R. Nauen, Chapter 3: "Neonicotinoid insecticides" in: Lawrence I. Gilbert, Sarjeet S. Gill, ed.s, Insect Control: Biological and Synthetic Agents (London, England: Academic Press, 2010), p. 62.
   • Bernd Schaefer with David Smith and Bernd Janssen, trans., Natural Products in the Chemical Industry (Berlin, Germany: Springer Verlag, 2015), p. 734.
9. ^ Schroeder, M. E.; Flattum, R. F. (1984). "The mode of action and neurotoxic properties of the nitromethylene heterocycle insecticides". Pesticide Biochemistry and Physiology. 22 (2): 148–160. doi:10.1016/0048-3575(84)90084-1.
10. Stokstad Erik (2013). "Pesticides Under Fire for Risks to Pollinators". Science. 340 (6133): 674–76. doi:10.1126/science.340.6133.674. PMID 23661734.
11. US EPA. 15 October 2014. Benefits of Neonicotinoid Seed Treatments to Soybean Production
12. ^ Jeschke Peter; Nauen Ralf; Schindler Michael; Elbert Alfred (2011). "Overview of the Status and Global Strategy for Neonicotinoids". Journals of Agricultural and Food Chemistry. 59: 2897–2908. doi:10.1021/jf101303g.
13. ^ Gervais, J.A.; Luukinen, B.; Buhl, K.; Stone, D. (April 2010). "Imidacloprid Technical Fact Sheet" (PDF). National Pesticide Information Center. Retrieved 12 April 2012.
14. Adak, T.; Kumar, J.; Shakil, N. A.; Walia, S. (2012). "Development of controlled release formulations of imidacloprid employing novel nano-ranged amphiphilic polymers". Journal of Environmental Science and Health, Part B. 47 (3): 217–225. doi:10.1080/03601234.2012.634365.
15. Grossman, Elizabeth (30 April 2013). "Declining Bee Populations Pose A Threat to Global Agriculture". Yale Environment 360. Yale School of Forestry & Environmental Studies. Retrieved 9 November 2014.
16. ^ Myers, Clayton (15 October 2014). "Benefits of Neonicotinoid Seed Treatments to Soybean Production" (PDF). Letter to Neil Anderson. US EPA. Retrieved 6 November 2014.
17. Ragsdale, D.; et al. (September 2010). "Ecology and Management of the Soybean Aphid in North America" (PDF). Annual Review of Entomology. 56: 375–399. doi:10.1146/annurev-ento-120709-144755. Retrieved November 6, 2014.
18. ^ Hodgson, E.; et al. (2012). "Management Recommendations for Soybean Aphid (Hemiptera: Aphididae) in the United States" (PDF). Journal of Integrated Pest Management. 3. doi:10.1603/IPM11019. Retrieved November 6, 2014.
19. Re-evaluation Note REV2016-03, Value Assessment of Corn and Soybean Seed Treatment Use of Clothianidin, Imidacloprid and Thiamethoxam
20. EPA Registration Review Process Last updated on April 17, 2014. Page accessed June 7, 2014
21. EPA: Pesticide Fact Sheet: Clothianidin Conditional Registration, Issued May 30, 2003
22. EPA Conditional Pesticide Registration Last updated on April 17, 2014. Page accessed June 7, 2014
23. EPA Dec 21, 2011: Thiamethoxam Summary Document Registration Review Initial Docket; entire docket is available here
24. EPA Dec 17, 2008: Imidacloprid Summary Document; entire docket is available here
25. ^ EPA Groups of Pesticides in Registration Review: Neonicotinoids Last updated on April 17, 2014. Page accessed June 7, 2014
26. ^ Press release: Pesticide Action Network, Center for Food Safety, and Beyond Pesticides. March 21, 2013: Beekeepers and Public Interest Groups Sue EPA Over Bee-Toxic Pesticides
27. Carrington, Damian (22 March 2013). "US government sued over use of pesticides linked to bee harm". The Guardian. Retrieved 25 March 2013.
28. Justia Dockets & Filings. Ellis et al v. Bradbury et al Page accessed June 7, 2014
29. "Legislation to restrict pesticide use proposed by Rep. Blumenauer". The Oregonian at 'OregonLive'. July 12, 2013. Retrieved July 17, 2013.
30. Govtrack.us H.R. 2692: Saving America’s Pollinators Act of 2013; accessed June 7, 2014
31. Benjamin, Alison (23 May 2008). "Pesticides: Germany bans chemicals linked to honeybee devastation". The Guardian.
32. "EPA Acts to Protect Bees | Pesticides | US EPA". Epa.gov. Retrieved 2011-10-11.
33. "Background information: Bee losses caused by insecticidal seed treatment in Germany in 2008". German Federal Office of Consumer Protection and Food Safety (BVL). 2008-07-15.
34. "Maize seed may now be treated with "Mesurol flüssig" again". German Federal Office of Consumer Protection and Food Safety (BVL). 2002-02-09.
35. ^ "Colony Collapse Disorder: European Bans on Neonicotinoid Pesticides | Pesticides | US EPA". Epa.gov. Retrieved 2011-10-11.
36. Brandon Keim (Dec 13, 2010). "Leaked Memo Shows EPA Doubts About Bee-Killing Pesticide". Wired.
37. European Food Safety Authority (2013). "Conclusion on the peer review of the pesticide risk assessment for bees for the active substance clothianidin" (PDF). EFSA Journal. 11 (1): 3066.
38. European Food Safety Authority (2012). "Assessment of the scientific information from the Italian project 'APENET' investigating effects on honeybees of coated maize seeds with some neonicotinoids and fipronil" (PDF). EFSA Journal. 10 (6): 2792.
39. EFSA: EFSA identifies risks to bees from neonicotinoids. 16 January 2013.
40. European Food Safety Authority (2013). "Conclusion on the peer review of the pesticide risk assessment for bees for the active substance clothianidin". EFSA Journal. 11 (1): 3066.
41. Damian Carrington (16 January 2013) "Insecticide 'unacceptable' danger to bees, report finds" The Guardian
42. ^ Damian Carrington (29 April 2013). "Bee-harming pesticides banned in Europe". The Guardian. Retrieved 1 May 2013.
43. S. Kusma (May 2013). "Was soll die Einschränkung der Neonicotinoide bringen?" (in German). Neue Zürcher Zeitung. Retrieved 9 May 2013.
44. http://www.hffa.info/index.php/about-us/supporterspartners.html
45. Steffen Noleppa, Thomas Hahn: The value of Neonicotinoid seed treatment in the European Union: A socio-economic, technological and environmental review. Humboldt Forum for Food and Agriculture (HFFA), 2013.
46. Soil Association comment: The Humboldt Forum for Food and Agriculture report 15 January 2013, Soil Association Certification
47. "Ontario wants 80% reduction of bee-killing neonicotinoid use in 2 years". CBC News. Toronto, Canada: CBC/Radio-Canada. 9 June 2015. Retrieved 29 September 2015.
48. "CropLife Canada highlights safety of neonics amid Montreal's pesticide ban". Crop Protection News. 12 June 2015. Retrieved 29 September 2015.
49. "Montreal neonicotinoid ban". City of Montreal. 10 December 2015. Retrieved 10 December 2015.
50. ^ Tomizawa, M. (2004). "Neonicotinoids and Derivatives: Effects in Mammalian Cells and Mice". Journal of Pesticide Science. 29 (3): 177–172. doi:10.1584/jpestics.29.177.
51. ^ Tomizawa, Motohiro; Latli, Bachir; Casida, John E. (1999). "Structure and Function of Insect Nicotinic Acetylcholine Receptors Studied with Nicotinic Insecticide Affinity Probes". In Yamamoto, Izuru; Casida, John (eds.). Nicotinoid Insecticides and the Nicotinic Acetylcholine Receptor. Tokyo: Springer-Verlag. pp. 271–292. ISBN 443170213X.
52. Tomizawa, M.; Casida, J. E. (2003). "Selective toxicity of neonicotinoids attributable to specificity of insect and mammalian nicotinic receptors". Annual Review of Entomology. 48: 339–364. doi:10.1146/annurev.ento.48.091801.112731.
53. Koshlukova, Svetlana (9 February 2006). "Imidacloprid: Risk Characterization Document: Dietary and Drinking Water Exposure" (PDF). California Environmental Protection Agency, Department of Pesticide Regulation. Retrieved 11 April 2012.
54. Lee Chao, S.; Casida, J. E. (1997). "Interaction of Imidacloprid Metabolites and Analogs with the Nicotinic Acetylcholine Receptor of Mouse Brain in Relation to Toxicity". Pesticide Biochemistry and Physiology. 58: 77–88. doi:10.1006/pest.1997.2284.
55. "Interview with microbiologist: "This place is filled with multinational lobbyists"". Delo.si. 2011-05-14. Retrieved 2011-10-11.
56. Copping, Jasper (April 1, 2007). "Flowers and fruit crops facing disaster as disease kills off bees". The Telegraph.
57. Vanengelsdorp, D.; Evans, J.; Saegerman, C.; Mullin, C.; Haubruge, E.; Nguyen, B.; Frazier, M.; Frazier, J.; Cox-Foster, D.; Chen, Y.; Underwood, R.; Tarpy, D. R.; Pettis, J. S. (2009). Brown, Justin (ed.). "Colony collapse disorder: a descriptive study". PLoS ONE. 4 (8): e6481. Bibcode:2009PLoSO...4.6481V. doi:10.1371/journal.pone.0006481. PMC 2715894. PMID 19649264.{{cite journal}}: CS1 maint: unflagged free DOI (link)
58. McGrath, Matt (2016-08-16). "Neonic pesticide link to long-term wild bee decline". bbc.com.
59. Woodcock, Ben A.; Isaac, Nicholas J. B.; Bullock, James M.; Roy, David B.; Garthwaite, David G.; Crowe, Andrew; Pywell, Richard F. (2016-08-16). "Impacts of neonicotinoid use on long-term population changes in wild bees in England". Nature Communications. 7. doi:10.1038/ncomms12459. {{cite journal}}: Unknown parameter |subscription= ignored (|url-access= suggested) (help)
60. What is a neonicotinoid? | Insects in the City. Citybugs.tamu.edu. Retrieved on 2013-05-02.
61. USDA (October 17, 2012). Report on the National Stakeholders Conference on Honey Bee Health National Honey Bee Health Stakeholder Conference Steering Committee (PDF) (Report). Retrieved June 4, 2014.
62. Whitehorn, P. R.; O'Connor, S.; Wackers, F. L.; Goulson, D. (2012). "Neonicotinoid Pesticide Reduces Bumble Bee Colony Growth and Queen Production". Science. 336 (6079): 351–352. doi:10.1126/science.1215025. PMID 22461500.
63. Jepsen, Sarina, et al. "Petition to List the Rusty Patched Bumble Bee Bombis Affinis (Cresson, 1863) as an Endangered Species Under the U.S. Endangered Species Act." The Xerces Society for Invertebrate Conservation, 31 Jan 2013. PDF File. 12 Oct 2015.http://www.xerces.org/wp-content/uploads/2013/01/Bombus-affinis-petition.pdf
64. Tapparo, A.; Marton, D.; Giorio, C.; Zanella, A.; Soldà, L.; Marzaro, M.; Vivan, L.; Girolami, V. (2012). "Assessment of the Environmental Exposure of Honeybees to Particulate Matter Containing Neonicotinoid Insecticides Coming from Corn Coated Seeds". Environmental Science & Technology. 46 (5): 2592–9. doi:10.1021/es2035152. PMID 22292570.
65. Schneider, C. W.; Tautz, J. R.; Grünewald, B.; Fuchs, S. (2012). Chaline, Nicolas (ed.). "RFID Tracking of Sublethal Effects of Two Neonicotinoid Insecticides on the Foraging Behavior of Apis mellifera". PLoS ONE. 7 (1): e30023. doi:10.1371/journal.pone.0030023. PMC 3256199. PMID 22253863.{{cite journal}}: CS1 maint: unflagged free DOI (link)
66. Pettis, J. S.; Vanengelsdorp, D.; Johnson, J.; Dively, G. (2012). "Pesticide exposure in honey bees results in increased levels of the gut pathogen Nosema". Naturwissenschaften. 99 (2): 153–158. Bibcode:2012NW.....99..153P. doi:10.1007/s00114-011-0881-1. PMC 3264871. PMID 22246149.
67. Krupke, C. H.; Hunt, G. J.; Eitzer, B. D.; Andino, G.; Given, K. (2012). Smagghe, Guy (ed.). "Multiple Routes of Pesticide Exposure for Honey Bees Living Near Agricultural Fields". PLoS ONE. 7 (1): e29268. doi:10.1371/journal.pone.0029268. PMC 3250423. PMID 22235278.{{cite journal}}: CS1 maint: unflagged free DOI (link)
68. Purdue Newsroom – Researchers: Honeybee deaths linked to seed insecticide exposure. Purdue.edu (2012-01-11). Retrieved on 2013-05-02.
69. van der Sluijs, Jeroen P; et al. (September 2013). "Neonicotinoids, bee disorders and the sustainability of pollinator services". Current Opinion in Environmental Sustainability. 5 (3–4): 293–305. doi:10.1016/j.cosust.2013.05.007. Retrieved 6 July 2014.
70. Di Prisco, G.; Cavaliere, V.; Annoscia, D.; Varricchio, P.; Caprio, E.; Nazzi, F.; Gargiulo, G.; Pennacchio, F. (2013). "Neonicotinoid clothianidin adversely affects insect immunity and promotes replication of a viral pathogen in honey bees". Proceedings of the National Academy of Sciences. 110: 18466–18471. doi:10.1073/pnas.1314923110.
71. Timmer, John (21 October 2013). "An insecticide-infection connection in bee colony collapses". Ars Technica. Retrieved 22 October 2013.
72. EASAC (2015-04-08). "Ecosystem services, agriculture and neonicotinoids". Retrieved 2015-04-10.
73. EASAC (2015-04-08). "Ecosystem services, agriculture and neonicotinoids" (PDF). Retrieved 2015-04-10. There is an increasing body of evidence that the widespread prophylactic use of neonicotinoids has severe negative effects on non-target organisms that provide ecosystem services including pollination and natural pest control.
74. Maj Rundlöf (22 April 2015). "Seed coating with a neonicotinoid insecticide negatively affects wild bees". Nature. 521: 77–80. doi:10.1038/nature14420. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
75. Sébastien C. Kessler (22 April 2015). "Bees prefer foods containing neonicotinoid pesticides". Nature. 521: 74–76. doi:10.1038/nature14414. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
76. Geoffrey R. Williams (13 October 2015). "Neonicotinoid pesticides severely affect honey bee queens". Scientific Reports. 5: 14621. doi:10.1038/srep14621. Retrieved 2015-10-15. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
77. Pierre Mineau; Cynthia Palmer (March 2013). "The Impact of the Nation's Most Widely Used Insecticides on Birds" (PDF). Neonicotinoid Insecticides and Birds. American Bird Conservancy. Retrieved 19 March 2013.
78. T.C. Van Dijk (2013). "Macro-Invertebrate Decline in Surface Water Polluted with Imidacloprid". PLoS ONE. 8: e62374. doi:10.1371/journal.pone.0062374. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)CS1 maint: unflagged free DOI (link)
79. "Study links insecticide use to invertebrate die-offs". www.guardian.com. 2013-05-01. Retrieved 2013-09-03.
80. Martina G. Vijver (February 2014). "Macro-Invertebrate Decline in Surface Water Polluted with Imidacloprid: A Rebuttal and Some New Analyses". PLoS ONE. 9: e89837. doi:10.1371/journal.pone.0089837. {{cite journal}}: Unknown parameter |coauthor= ignored (|author= suggested) (help)CS1 maint: unflagged free DOI (link)
81. Caspar A. Hallmann (July 2014). "Declines in insectivorous birds are associated with high neonicotinoid concentrations". Nature. 511: 341–3. doi:10.1038/nature13531. PMID 25030173. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
82. editorial (July 2014). "Be concerned". Nature. 511 (7508): 126. doi:10.1038/511126b.
83. "Worldwide Integrated Assessment of the impact of Systemic Pesticides on biodiversity and ecosystems (WIA)". The Task Force on Systemic Pesticides. 2014-10-10. Retrieved 2014-11-27.
84. "Environmental Science and Pollution Research". Springer. 2014-10-10. Retrieved 2014-11-27.
85. J. P. van der Sluijs (10 October 2014). "Conclusions of the Worldwide Integrated Assessment on the risks of neonicotinoids and fipronil to biodiversity and ecosystem functioning". Environmental Science and Pollution Research. Springer. Retrieved 27 November 2014. {{cite web}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

• Insecticides
• Pollinator decline pesticides