User:She's Za JJ/Isofenphos
Introduction
[edit]Isofenphos is an organophosphate (OP) insecticide, classified as Class 1 toxicity by the EPA (Environmental Protection Agency). Insecticides are pesticides mainly used in agriculture to control pests such as flies, soil insects, worms and larvae.
Isofenphos is a colorless oil that is insoluble in water under normal conditions of temperature and pressure[1]
Historical background
[edit]Isofenphos was first registered in the USA by Bayer Corporation, which holds a German patent on pesticide composition, in 1985. This compound, marketed under the name Oftanol, was intended for use on corn to control corn rootworm.
Initially, the pesticide was used for food, domestic and agricultural purposes. However, the product turned out to be dangerous because of its impact on the environment and human health.
Today, isofenphos is a Restricted Use Product (RUP), subject to certification and even banned in some countries.
Synthesis
[edit]In the first stage, isopropanol reacts with salicylic acid in an esterification reaction. This is followed by dehydrochlorination with thiophosphoryl chloride. Finally, the addition of isopropylamine and ethanol leads to the formation of isofenphos.[2][1]
The reactions are carried out in an acid medium according to the mechanism below.
Applications and mechanisms of action
[edit]Applications
[edit]Isofenphos is currently used in the USA on turf and ornamental trees and shrubs to control insects. According to recent usage data, around 60% of annual production of the active ingredient is used on golf courses. The remainder is used on residential and public land.[3]
Mechanisms of action
[edit]Isofenphos blocks the activity of the enzyme acetylcholinesterase (AChE ), creating a build-up of acetylcholine (ACh) at the synaptic level and inducing hyperstimulation of the cholinergic system. As a result, the cells will die of excitotoxicity, leading to the death of the insects..
In the presence of an organophosphorus pesticide, there is an interaction between the compound and acetylcholinesterase (AChE), leading to the inhibition of the enzyme. The inhibition mechanism is an addition-elimination mechanism. A covalent bond is formed between the phosphorus of isofenphos and the oxygen of serine Ser203. The reaction produces a stable phosphorylated enzyme complex that renders the enzyme non-functional, preventing the degradation of acetylcholine. Non-covalent interactions stabilize the complex.[4]
Once the phosphorus has been bound to the oxygen of serine, two phenomena can take place. The first is a spontaneous hydrolysis where the phosphorylated enzyme is restored to AchE. This reaction is generally very slow and almost does not occur. However, in the case of overuse of isofenphos, it is possible to reactivate the enzyme by using a powerful nucleophile, such as oximes, to break the phosphorus-oxygen bond and regenerate acetylcholinesterase. The second phenomenon is called "aging" hydrolysis. This generally involves the hydrolysis of the oxygen-containing group of the organophosphate, leading to an even more stable neurotoxic AChE complex. This phenomenon is irreversible: it is no longer possible to have spontaneous hydrolysis possible. Aging time depends on the organophosphate used[4].
The formed complex is very stable because several non-covalent interactions stabilize it, preventing nucleophiles from reaching the phosphorus, which limits dephosphorylation, such as interactions with the oxyanion hole, the acyl pocket, and the histidine of the catalytic triad. The localized negative charge around the oxygen hinders the attack of a nucleophile with the aim of regenerating the free enzyme.[4]
Dangers (Ecotoxicity and Risks)
[edit]The use of insecticides containing isofenphos exposes humans and animals, particularly aquatic organisms[5], to isofenphos, which is a toxic compound. Regular and long-term exposure notably causes inhibition of acetylcholinesterase in plasma, red blood cells, and brain tissues. In a professional or domestic setting, the duration of exposure to isofenphos should not exceed 7 days.[6]
There are several exposure routes: through direct contact with the skin, through inhalation, or through oral ingestion. For example, in residential settings, personal use of insecticides in the garden, coupled with regular walks near vegetation, exposes individuals to the aforementioned risks.[6]
To prevent risks associated with isofenphos, precautions should be taken, including wearing protective gloves and clothing, avoiding any contact with the eyes, skin, or clothing, not breathing in dust, and avoiding environmental release.[7]
Role in chronic myeloid leukemia
[edit]Persistent exposure to isofenphos initially causes a loss of bone function, leading to the onset of myeloid metaplasia. Then, acute myeloid leukemia can quickly develop. [8]
A study has demonstrated the risk of developing cancer with regular exposure to isofenphos[8]. The study explains that isofenphos molecules inhibit the oxidation of glucose that we ingest. However, the oxidation of glucose is a source of energy and proper functioning for our cells. [9]
Role in polyneuropathy
[edit]Isofenphos can cause polyneuropathy, a disease of the nervous system.
Studies have been carried out on humans who ingested isofenphos and demonstrated the development of severe polyneuropathy followed by mild choligernic toxicity. This is due to the inhibition of acetylcholinesterase (AChE) and neurotoxic esterase (NTE) by isofenphos, two enzymes necessary for the transmission of nerve signals.[10]
Indeed, isofenphos, very lipophilic, can cross biological barriers and bind covalently to cholinesterases such as acetylcholinesterases of the human central nervous system. As with insects, the organophosphate will occupy the site of the acetylcholinesterase enzyme which will then no longer be able to catalyze the hydrolysis reaction of acetylcholine into choline and acetic acid, which will lead to nervous problems.[11]
Organophosphates like isofenphos can also phosphorylate neurotoxic esterase, a central nervous system protein found in leukocytes and platelets. This will cause a reduction in its lymphocytic form, which may result in post-intervellary neuropathy.[11]
Role in type 2 diabetes
[edit]A study[12] showed that the risk of developing type 2 diabetes is higher when the level of isofenphos increases. The mechanisms linking the influence of exposure to isofenphos on the risk of developing type 2 diabetes are controversial.
On the one hand, organophosphate pesticides such as isofenphos can inhibit the activity of glutamate dehydrogenase (GDH) which allows insulin secretion: insulin release will therefore be reduced, which will lead to the development of diabetes type 2.
On the other hand, glycogenolysis and gluconeogenesis, allowing the synthesis of glucose in the body, are also two mechanisms associated with hyperglycemia induced by isofenphos.
Effects on drinking water
[edit]Since insecticides are distributed on vegetation, surface drinking water sources are most likely to be impacted by the use of isofenphos, so there is a risk of water contamination. Exposure rates have been estimated by researchers and studies[6] have shown the harmful impact on some terrestrial and aquatic animals[5], but today we do not know the real impact of this water contamination on all biodiversity and on Man.
Isofenphos treatment
[edit]In the case of poisoning with an organophosphorus pesticide, several treatments have been developed. [4] Treatments are based on the use of cholinergic antagonists. The first treatment to come out is Atropine, developed in 1835. Used in 1863, Atropine counteracts the effect of acetylcholine on muscles and relaxes them. Unfortunately, it was found after several studies dating from the Second World War [13] that Atropine alone was insufficient. Thus, the combination of anticonvulsants such as Benzodiazepine or Diazepam is much more effective than Atropine or an oxime alone in reducing mortality.
In 1951, the first in vitro reactivation of phosphorylated AChE was realized with hydroxylamine. Interest then turned towards reactivators : oxamines having a congugatedpyridinium. From 1956, 2-PAM, which is around 1 million times more efficient than hydroxylamine, was synthesized in the United States. This was followed by the synthesis of several oximes: bispyridium, trimédoxime (TMB-4), obidoxime (LüH-6), HI-6 and HLö-7.[4]
Legislation
[edit]In 2002, the European Commision decided to not include isofenphos in the list of active ingredients of authorized pesticides. [14]
According to the latest updates from the University of Hertfordshire (11/09/2023)[5][15]:
Isofenphos is listed in the European Union (EU) database and was approved for use by the European Commission on 11/07/2009 in the following EU member states : Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Greece, Spain, Finland, France, Croatia, Hungaey, Ireland, Italy, Lithuania, Luxembourg, Latvia, Malta, Netherlands, Poland, Portugal, Romania, Sweden, Slovenia, Slovakia. It was also approved for use by the same commision in the following European Economic Area countries ( EEE) : Iceland, Norway.
The EPA (Environmental Protection Agency) registers pesticides that meet the safety standards of the FQPA (Food Quality Protection Act) and can be used without posing unreasonable risk to human health or the environment. Isofenphos, designated under the EPA case number 0105, was subject to a re-engistrement decision in 1999. Consequently, the EPA reviewed the existing database and developed preliminary assessments of risks to human health and the environment.
In 1998, a public file was opened, and initial measures were taken to reevaluate isofenphos as well as other organophosphorus pesticides. However, before the EPA could complete the re-registration process, the primary manufacturer of the pesticide provided official notification. They would no longer support Isofenphos through re-registration.
According to the Food and Agriculture Organization (FAO), the specifications that must appear during the marketing of isofenphos are as follows:[16] :
- In the description: The material must consist of isofenphos and corresponding manufacturing impurities and should be a yellowish to brown liquid free from visible foreign matter and added modifying agents.
- In the active ingredients: The content of isofenphos must be declared (not less than 900 g/kg), and when determined, the obtained content must not differ from the declared content by more than ± 25 g/kg.
Notes and references
[edit]- ^ a b PubChem. "Isofenphos". pubchem.ncbi.nlm.nih.gov. Retrieved 2024-04-06.
- ^ Thomas A. Unger, éd. « Isofenphos ». In Pesticide Synthesis Handbook, 378. Park Ridge, NJ: William Andrew Publishing, 1996. https://doi.org/10.1016/B978-081551401-5.50781-4.
- ^ US EPA, OA. « Pesticides - Fact Sheet for Isofenphos », décembre 1999. https://www3.epa.gov/pesticides/chem_search/reg_actions/reregistration/fs_PC-109401_1-Dec-99.pdf.
- ^ a b c d e f g Ophélie Kwasnieski. « Etude Théorique de La Réactivation de l’AChE Inhibée Par Le Tabun », 2010.
- ^ a b c Lewis, Kathleen A., John Tzilivakis, Douglas J. Warner, et Andrew Green. « An international database for pesticide risk assessments and management ». Human and Ecological Risk Assessment: An International Journal 22, nᵒ 4 (18 mai 2016): 1050‑64. https://doi.org/10.1080/10807039.2015.1133242.
- ^ a b c United States Environmental Protection Agency. « Memory of isofenphos », 1998.
- ^ GESTIS. « Base de données de substances GESTIS ». Consulté le 26 février 2024. https://gestis-database.dguv.de/data?name=510266.
- ^ a b Boros, Laszlo G, et Robert D Williams. « L’isofenphos a induit des modifications métaboliques dans les cellules blastiques myéloïdes K562 1 ». Leukemia Research 25, nᵒ 10 (1 octobre 2001): 883‑90. https://doi.org/10.1016/S0145-2126(01)00043-1.
- ^ Furelaud, Gilles. « Glucides et lipides, des sources d’énergie pour l’organisme ». Planet-Vie, 2002. https://planet-vie.ens.fr/thematiques/cellules-et-molecules/metabolisme-cellulaire/glucides-et-lipides-des-sources-d-energie.
- ^ Moretto, Angelo, et Marcello Lotti. « The Relationship between Isofenphos Cholinergic Toxicity and the Development of Polyneuropathy in Hens and Humans ». Archives of Toxicology 76, nᵒ 5 (1 juin 2002): 367‑75. https://doi.org/10.1007/s00204-002-0352-8.
- ^ a b Kouraichi, N, et H Thabet. « Prise en charge des intoxications organophosphorées aux urgences », 2008.
- ^ Geng, Jintian, Dandan Wei, Lulu Wang, Qingqing Xu, Juan Wang, Jiayu Shi, Cuicui Ma, et al. « The association of isocarbophos and isofenphos with different types of glucose metabolism: The role of inflammatory cells ». Journal of Environmental Sciences 147 (1 janvier 2025): 322‑31. https://doi.org/10.1016/j.jes.2023.11.004.
- ^ Mahé, Inès, Christian Gauvrit, Frédérique Angevin, et Bruno Chauvel. « Quels enseignements tirer du retrait de l’atrazine dans le cadre de l’interdiction prévue du glyphosate ? » Cahiers Agricultures 29 (2020): 29. https://doi.org/10.1051/cagri/2020026.
- ^ Byrne, David. « Verordnung (EG) Nr. 2076/2002 der Kommission », 2002, 319/3.
- ^ « university of Hertfordshire », s. d. https://sitem.herts.ac.uk/aeru/ppdb/en/Reports/406.htm.
- ^ « food and agriculture organization of the united nations ». Consulté le 8 mars 2024. https://www.fao.org/3/cb2796en/cb2796en.pdf.
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