Spinosad

Last updated

Contents

Spinosyns
Spinosyn A v2.svg
Spinosyn A
Spinosyn D v2.svg
Spinosyn D
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.103.254 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • A:InChI=1S/C41H65NO10/c1-10-26-12-11-13-34(52-36-17-16-33(42(5)6)23(3)48-36)22(2)37(44)32-20-30-28(31(32)21-35(43)50-26)15-14-25-18-27(19-29(25)30)51-41-40(47-9)39(46-8)38(45-7)24(4)49-41/h14-15,20,22-31,33-34,36,38-41H,10-13,16-19,21H2,1-9H3/t22-,23-,24+,25-,26+,27-,28-,29-,30-,31+,33+,34+,36+,38+,39-,40-,41+/m1/s1
    Key: SRJQTHAZUNRMPR-UYQKXTDMSA-N
  • D:InChI=1S/C42H67NO10/c1-11-26-13-12-14-35(53-37-16-15-34(43(6)7)24(4)49-37)23(3)38(45)33-20-31-29(32(33)21-36(44)51-26)17-22(2)28-18-27(19-30(28)31)52-42-41(48-10)40(47-9)39(46-8)25(5)50-42/h17,20,23-32,34-35,37,39-42H,11-16,18-19,21H2,1-10H3/t23-,24-,25+,26+,27-,28+,29-,30-,31-,32+,34+,35+,37+,39+,40-,41-,42+/m1/s1
    Key: RDECBWLKMPEKPM-PSCJHHPTSA-N
  • A:O([C@H]1C[C@]2([C@]3([C@]([C@]4(C(=C3)C(=O)[C@H](C)[C@@H](O[C@@H]5O[C@H](C)[C@@H](N(C)C)CC5)CCC[C@H](CC)OC(=O)C4)[H])(C=C[C@@]2(C1)[H])[H])[H])[H])[C@H]6[C@H](OC)[C@H](OC)[C@@H](OC)[C@H](C)O6
  • D:CC1=C[C@@]2([C@]([C@]3([C@]1(C[C@@H](O[C@H]4[C@H](OC)[C@H](OC)[C@@H](OC)[C@H](C)O4)C3)[H])[H])(C=C5[C@]2(CC(=O)O[C@@H](CC)CCC[C@H](O[C@@H]6O[C@H](C)[C@@H](N(C)C)CC6)[C@@H](C)C5=O)[H])[H])[H]
Properties
C41H65NO10 (A)
C42H67NO10 (D)
Molar mass 731.968 g·mol−1 (A)
745.995 g·mol−1 (D)
Pharmacology
QP53BX03 ( WHO )
Topical, by mouth
Legal status
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)
Spinosad
Clinical data
AHFS/Drugs.com Monograph
Identifiers
CompTox Dashboard (EPA)
ECHA InfoCard 100.103.254 OOjs UI icon edit-ltr-progressive.svg

Spinosad is an insecticide based on chemical compounds found in the bacterial species Saccharopolyspora spinosa . The genus Saccharopolyspora was discovered in 1985 in isolates from crushed sugarcane. The bacteria produce yellowish-pink aerial hyphae, with bead-like chains of spores enclosed in a characteristic hairy sheath. [4] This genus is defined as aerobic, Gram-positive, nonacid-fast actinomycetes with fragmenting substrate mycelium. S. spinosa was isolated from soil collected inside a nonoperational sugar mill rum still in the Virgin Islands. Spinosad is a mixture of chemical compounds in the spinosyn family that has a generalized structure consisting of a unique tetracyclic ring system attached to an amino sugar (D-forosamine) and a neutral sugar (tri-Ο-methyl-L-rhamnose). [5] Spinosad is relatively nonpolar and not easily dissolved in water. [6]

Spinosad is a novel mode-of-action insecticide derived from a family of natural products obtained by fermentation of S. spinosa. Spinosyns occur in over 20 natural forms, and over 200 synthetic forms (spinosoids) have been produced in the lab. [7] Spinosad contains a mix of two spinosoids, spinosyn A, the major component, and spinosyn D (the minor component), in a roughly 17:3 ratio. [4]

Mode of action

Spinosad is highly active, by both contact and ingestion, in numerous insect species. [8] Its overall protective effect varies with insect species and life stage. It affects certain species only in the adult stage, but can affect other species at more than one life stage. The species subject to very high rates of mortality as larvae, but not as adults, may gradually be controlled through sustained larval mortality. [8] The mode of action of spinosoid insecticides is by a neural mechanism. [9] The spinosyns and spinosoids have a novel mode of action, primarily targeting binding sites on nicotinic acetylcholine receptors (nAChRs) of the insect nervous system that are distinct from those at which other insecticides have their activity. Spinosoid binding leads to disruption of acetylcholine neurotransmission. [5] Spinosad also has secondary effects as a γ-amino-butyric acid (GABA) neurotransmitter agonist. [5] It kills insects by hyperexcitation of the insect nervous system. [5] Spinosad has proven not to cause cross-resistance to any other known insecticide. [10]

Uses

Spinosad has been used around the world for the control of a variety of insect pests, including Lepidoptera, Diptera, Thysanoptera, Coleoptera, Orthoptera, and Hymenoptera, and many others. [11] It was first registered as a pesticide in the United States for use on crops in 1997. [11] Its labeled use rate is set at 1 ppm (1 mg a.i./kg of grain) and its maximum residue limit (MRL) or tolerance is set at 1.5 ppm. Spinosad's widespread commercial launch was deferred, awaiting final MRL or tolerance approvals in a few remaining grain-importing countries. It is considered a natural product, thus is approved for use in organic agriculture by numerous nations. [8] Two other uses for spinosad are for pets and humans. Spinosad has been used in oral preparations (as Comfortis) to treat C. felis , the cat flea, in canines and felines; the optimal dose set for canines is reported to be 30 mg/kg. [5]

Spinosad is sold under the brand names, Comfortis, Trifexis, and Natroba. [12] [13] Trifexis also includes milbemycin oxime. Comfortis and Trifexis brands treat adult fleas on pets; the latter also prevents heartworm disease. Natroba is sold for treatment of human head lice. Spinosad is also commonly used to kill thrips. [14] [15] [16]

Comfortis and Trifexis were withdrawn in the European Union. [17] [18]

Spinosyn A

Spinosyn A does not appear to interact directly with known insecticidal-relevant target sites, but rather acts via a novel mechanism. [9] Spinosyn A resembles a GABA antagonist and is comparable to the effect of avermectin on insect neurons. [7] Spinosyn A is highly active against neonate larvae of the tobacco budworm, Heliothis virescens , and is slightly more biologically active than spinosyn D. In general, spinosyns possessing a methyl group at C6 (spinosyn D-related analogs) tend to be more active and less affected by changes in the rest of the molecule. [10] Spinosyn A is slow to penetrate to the internal fluids of larvae; it is also poorly metabolized once it enters the insect. [10] The apparent lack of spinosyn A metabolism may contribute to its high level of activity, and may compensate for the slow rate of penetration. [10]

Resistance

Spinosad resistance has been found in Musca domestica, [19] [20] Plutella xylostella , [21] [20] Bactrocera dorsalis , [22] [20] Frankliniella occidentalis , [23] [20] and Cydia pomonella . [24] [25] [20]

Safety and ecotoxicology

Spinosad has high efficacy, a broad insect pest spectrum, low mammalian toxicity, and a good environmental profile, a unique feature of the insecticide compared to others currently used for the protection of grain products. [8] It is regarded as natural product-based, and approved for use in organic agriculture by numerous national and international certifications. [11] Spinosad residues are highly stable on grains stored in bins, with protection ranging from 6 months to 2 years. [8] [ clarification needed ] Ecotoxicology parameters have been reported for spinosad, and are: [26]

Chronic exposure studies failed to induce tumor formation in rats and mice; mice given up to 51 mg/kg/day for 18 months resulted in no tumor formation. [27] Similarly, administration of 25 mg/kg/day to rats for 24 months did not result in tumor formation. [28]

Related Research Articles

<span class="mw-page-title-main">Pesticide</span> Substance used to destroy pests

Pesticides are substances that are used to control pests. They include herbicides, insecticides, nematicides, fungicides, and many others. The most common of these are herbicides, which account for approximately 50% of all pesticide use globally. Most pesticides are used as plant protection products, which in general protect plants from weeds, fungi, or insects. In general, a pesticide is a chemical or biological agent that deters, incapacitates, kills, or otherwise discourages pests. Target pests can include insects, plant pathogens, weeds, molluscs, birds, mammals, fish, nematodes (roundworms), and microbes that destroy property, cause nuisance, or spread disease, or are disease vectors. Along with these benefits, pesticides also have drawbacks, such as potential toxicity to humans and other species.

<span class="mw-page-title-main">Insecticide</span> Pesticide used against insects

Insecticides are pesticides used to kill insects. They include ovicides and larvicides used against insect eggs and larvae, respectively. Insecticides are used in agriculture, medicine, industry and by consumers. Insecticides are claimed to be a major factor behind the increase in the 20th-century's agricultural productivity. Nearly all insecticides have the potential to significantly alter ecosystems; many are toxic to humans and/or animals; some become concentrated as they spread along the food chain.

<span class="mw-page-title-main">Pesticide resistance</span> Decreased effectiveness of a pesticide on a pest

Pesticide resistance describes the decreased susceptibility of a pest population to a pesticide that was previously effective at controlling the pest. Pest species evolve pesticide resistance via natural selection: the most resistant specimens survive and pass on their acquired heritable changes traits to their offspring. If a pest has resistance then that will reduce the pesticide's efficacy – efficacy and resistance are inversely related.

<span class="mw-page-title-main">Bifenthrin</span> Chemical compound

Bifenthrin is a pyrethroid insecticide. It is widely used against ant infestations.

<span class="mw-page-title-main">Triclopyr</span> Chemical compound used as a herbicide

Triclopyr is an organic compound in the pyridine group that is used as a systemic foliar herbicide and fungicide.

<span class="mw-page-title-main">Pyrethroid</span> Class of insecticides

A pyrethroid is an organic compound similar to the natural pyrethrins, which are produced by the flowers of pyrethrums. Pyrethroids are used as commercial and household insecticides.

<span class="mw-page-title-main">Imidacloprid</span> Chemical compound

Imidacloprid is a systemic insecticide belonging to a class of chemicals called the neonicotinoids which act on the central nervous system of insects. The chemical works by interfering with the transmission of stimuli in the insect nervous system. Specifically, it causes a blockage of the nicotinergic neuronal pathway. By blocking nicotinic acetylcholine receptors, imidacloprid prevents acetylcholine from transmitting impulses between nerves, resulting in the insect's paralysis and eventual death. It is effective on contact and via stomach action. Because imidacloprid binds much more strongly to insect neuron receptors than to mammal neuron receptors, this insecticide is more toxic to insects than to mammals.

<span class="mw-page-title-main">Chlorfenvinphos</span> Chemical compound

Chlorfenvinphos is an organophosphorus compound that was widely used as an insecticide and an acaricide. The molecule itself can be described as an enol ester derived from dichloroacetophenone and diethylphosphonic acid. Chlorfenvinphos has been included in many products since its first use in 1963. However, because of its toxic effect as a cholinesterase inhibitor it has been banned in several countries, including the United States and the European Union. Its use in the United States was cancelled in 1991.

Demeton-S-methyl is an organic compound with the molecular formula C6H15O3PS2. It was used as an organothiophosphate acaricide and organothiophosphate insecticide. It is flammable. With prolonged storage, Demeton-S-methyl becomes more toxic due to formation of a sulfonium derivative which has greater affinity to the human form of the acetylcholinesterase enzyme, and this may present a hazard in agricultural use.

<span class="mw-page-title-main">Fipronil</span> Chemical compound

Fipronil is a broad-spectrum insecticide that belongs to the phenylpyrazole chemical family. Fipronil disrupts the insect central nervous system by blocking the ligand-gated ion channel of the GABAA receptor and glutamate-gated chloride (GluCl) channels. This causes hyperexcitation of contaminated insects' nerves and muscles. Fipronil's specificity towards insects is believed to be due to its greater binding affinity for the GABAA receptors of insects than to those of mammals, and for its action on GluCl channels, which do not exist in mammals. As of 2017, there does not appear to be significant resistance among fleas to fipronil.

<span class="mw-page-title-main">Dichlorvos</span> Insect killing chemical, organophosphate

Dichlorvos is an organophosphate widely used as an insecticide to control household pests, in public health, and protecting stored products from insects. The compound has been commercially available since 1961 and has become controversial because of its prevalence in urban waterways and the fact that its toxicity extends well beyond insects. Since 1988, dichlorvos cannot be used as a plant protection product in the EU.

<span class="mw-page-title-main">Nitenpyram</span> Insecticide

Nitenpyram is a chemical frequently used as an insecticide in agriculture and veterinary medicine. The compound is an insect neurotoxin belonging to the class of neonicotinoids which works by blocking neural signaling of the central nervous system. It does so by binding irreversibly to the nicotinic acetylcholine receptor (nACHr) causing a stop of the flow of ions in the postsynaptic membrane of neurons leading to paralysis and death. Nitenpyram is highly selective towards the variation of the nACHr which insects possess, and has seen extensive use in targeted, insecticide applications.

<span class="mw-page-title-main">Cyhalothrin</span> Synthetic pyrethroid used as insecticide

Cyhalothrin is the ISO common name for an organic compound that, in specific isomeric forms, is used as a pesticide. It is a pyrethroid, a class of synthetic insecticides that mimic the structure and properties of the naturally occurring insecticide pyrethrin which is present in the flowers of Chrysanthemum cinerariifolium. Pyrethroids such as cyhalothrin are often preferred as an active ingredient in agricultural insecticides because they are more cost-effective and longer acting than natural pyrethrins. λ-and γ-cyhalothrin are now used to control insects and spider mites in crops including cotton, cereals, potatoes and vegetables.

<span class="mw-page-title-main">Methiocarb</span> Chemical compound

Methiocarb is a carbamate pesticide which is used as an insecticide, bird repellent, acaricide and molluscicide since the 1960s. Methiocarb has contact and stomach action on mites and neurotoxic effects on molluscs. Seeds treated with methiocarb also affect birds. Other names for methiocarb are mesurol and mercaptodimethur.

<span class="mw-page-title-main">Acetamiprid</span> Chemical compound

Acetamiprid is an organic compound with the chemical formula C10H11ClN4. It is an odorless neonicotinoid insecticide produced under the trade names Assail, and Chipco by Aventis CropSciences. It is systemic and intended to control sucking insects (Thysanoptera, Hemiptera, mainly aphids) on crops such as leafy vegetables, citrus fruits, pome fruits, grapes, cotton, cole crops, and ornamental plants. It is also a key pesticide in commercial cherry farming due to its effectiveness against the larvae of the cherry fruit fly.

<span class="mw-page-title-main">Empenthrin</span> Chemical compound

Empenthrin (also called vaporthrin) is a synthetic pyrethroid used in insecticides. It is active against broad spectrum of flying insects including moths and other pests damaging textile. It has low acute mammalian toxicity (its oral LD50 is above 5000 mg/kg in male rats, above 3500 mg/kg in female rats and greater than 3500 mg/kg in mice). It is however very toxic to fish and other aquatic organisms (96-hour LC50 in Oncorhynchus mykiss is 1.7 μg/L, 48-hour EC50 in Daphnia magna is 20 μg/L).

<span class="mw-page-title-main">Tefluthrin</span> Synthetic pyrethroid used as insecticide

Tefluthrin is the ISO common name for an organic compound that is used as a pesticide. It is a pyrethroid, a class of synthetic insecticides that mimic the structure and properties of the naturally occurring insecticide pyrethrin which is present in the flowers of Chrysanthemum cinerariifolium. Pyrethroids such as tefluthrin are often preferred as active ingredients in agricultural insecticides because they are more cost-effective and longer acting than natural pyrethrins. It is effective against soil pests because it can move as a vapour without irreversibly binding to soil particles: in this respect it differs from most other pyrethroids.

Saccharopolyspora spinosa is a species of actinobacterium first isolated from soil in a rum still in an abandoned sugar mill on the Virgin Islands. It was discovered and described by researchers Mertz and Yao while collecting specimens to be screened for novel antibiotics. It develops aerial, pale, yellowish pink hyphae and bears long chains of spores encased in spiny spore sheaths. It can also reproduce by fragmentation in an aqueous environment. Its type strain is A83543.1.

<span class="mw-page-title-main">Novaluron</span> Chemical compound

Novaluron, or (±)-1-[3-chloro-4-(1,1,2-trifluoro-2-trifluoro- methoxyethoxy)phenyl]-3-(2,6-difluorobenzoyl)urea, is a chemical with pesticide properties, belonging to the class of insecticides called insect growth regulators. It is a benzoylphenyl urea developed by Makhteshim-Agan Industries Ltd.. In the United States, the compound has been used on food crops, including apples, potatoes, brassicas, ornamentals, and cotton. Patents and registrations have been approved or are ongoing in several other countries throughout Europe, Asia, Africa, South America, and Australia. The US Environmental Protection Agency and the Canadian Pest Management Regulatory Agency consider novaluron to pose low risk to the environment and non-target organisms and value it as an important option for integrated pest management that should decrease reliance on organophosphorus, carbamate and pyrethroid insecticides.

<span class="mw-page-title-main">Spinetoram</span> Chemical compound

Spinetoram is an insecticidal mixture of two active neurotoxic constituents of Saccharopolyspora spinosa. It is used to control pest insects in stored grain and on domestic cats.

References

  1. ↑ "Natroba- spinosad suspension". DailyMed. U.S. National Library of Medicine. 28 April 2021. Retrieved 1 July 2023.
  2. ↑ "Spinosad suspension". DailyMed. U.S. National Library of Medicine. 31 May 2023. Retrieved 1 July 2023.
  3. ↑ "Comfortis- spinosad tablet, chewable". DailyMed. U.S. National Library of Medicine. 1 July 2021. Retrieved 1 July 2023.
  4. 1 2 Mertz F, Yao RC (January 1990). "Saccharopolyspora spinosa sp. nov. Isolated from soil Collected in a Sugar Mill Rum Still". International Journal of Systematic Bacteriology. 40 (1): 34–39. doi: 10.1099/00207713-40-1-34 .
  5. 1 2 3 4 5 Snyder DE, Meyer J, Zimmermann AG, Qiao M, Gissendanner SJ, Cruthers LR, et al. (December 2007). "Preliminary studies on the effectiveness of the novel pulicide, spinosad, for the treatment and control of fleas on dogs". Veterinary Parasitology. 150 (4): 345–351. doi:10.1016/j.vetpar.2007.09.011. PMID   17980490.
  6. ↑ Crouse GD, Sparks TC, Schoonover J, Gifford J, Dripps J, Bruce T, et al. (February 2001). "Recent advances in the chemistry of spinosyns". Pest Management Science. 57 (2): 177–185. doi:10.1002/1526-4998(200102)57:2<177::AID-PS281>3.0.CO;2-Z. PMID   11455648.
  7. 1 2 Watson G (31 May 2001). "Actions of Insecticidal Spinosyns on γ-Aminobutyric Acid Responses for Small-Diameter Cockroach Neurons". Pesticide Biochemistry and Physiology. 71: 20–28. doi:10.1006/pest.2001.2559.
  8. 1 2 3 4 5 Hertlein M, Thompson GD, Subramanyam B, Athanassiou CG (12 January 2011). "Spinosad: A new natural product for stored grain protection". Stored Products. 47 (3): 131–146. doi:10.1016/j.jspr.2011.01.004.
  9. 1 2 Orr N, Shaffner AJ, Richey K, Crouse GD (30 April 2009). "Novel mode of action of spinosad: Receptor binding studies demonstrating lack of interaction with known insecticidal target sites". Pesticide Biochemistry and Physiology. 95: 1–5. doi:10.1016/j.pestbp.2009.04.009.
  10. 1 2 3 4 Sparks TC, Crouse GD, Durst G (October 2001). "Natural products as insecticides: the biology, biochemistry and quantitative structure-activity relationships of spinosyns and spinosoids". Pest Management Science. 57 (10): 896–905. doi:10.1002/ps.358. PMID   11695182.
  11. 1 2 3 Sparks T, Dripps JE, Watson GB, Paroonagian D (6 November 2012). "Resistance and cross-resistance to the spinosyns- A review and analysis". Pesticide Biochemistry and Physiology. 102: 1–10. doi:10.1016/j.pestbp.2011.11.004 . Retrieved 17 November 2011.
  12. ↑ "Spinosad international brands". Drugs.com. 3 January 2020. Retrieved 30 January 2020.
  13. ↑ "Spinosad US brands". Drugs.com. 3 January 2020. Retrieved 30 January 2020.
  14. ↑ "Spinosad - brand name list from". Drugs.com. Retrieved 20 October 2012.
  15. ↑ Bethke JA, Dreistadt SH, Varela LG, Phillips PA, O'Donnell CA (May 2014). Thripsm (PDF). University of California Statewide Integrated Pest Management Program. UCANR Publication. (Report). Integrated Pest Management for Home Gardeners and Landscape Professionals.
  16. ↑ Merchant M. "Safer Flea Control | Insects in the City". Texas A&M AgriLife Extension Service. Retrieved 20 October 2012.
  17. ↑ "Comfortis EPAR". European Medicines Agency. 26 June 2023. Retrieved 3 July 2023.
  18. ↑ "Trifexis EPAR". European Medicines Agency. 5 November 2020. Retrieved 3 July 2023.
  19. ↑ Liu N, Yue X (August 2000). "Insecticide resistance and cross-resistance in the house fly (Diptera: Muscidae)". Journal of Economic Entomology. 93 (4): 1269–1275. doi:10.1603/0022-0493-93.4.1269. PMID   10985042. S2CID   26611971.
  20. 1 2 3 4 5 Biondi A, Mommaerts V, Smagghe G, Viñuela E, Zappalà L, Desneux N (December 2012). "The non-target impact of spinosyns on beneficial arthropods". Pest Management Science. Society of Chemical Industry (Wiley). 68 (12): 1523–1536. doi:10.1002/ps.3396. PMID   23109262.
  21. ↑ Sayyed AH, Omar D, Wright DJ (August 2004). "Genetics of spinosad resistance in a multi-resistant field-selected population of Plutella xylostella". Pest Management Science. 60 (8): 827–832. doi:10.1002/ps.869. PMID   15307676.
  22. ↑ Hsu JC, Feng HT (June 2006). "Development of resistance to spinosad in oriental fruit fly (Diptera: Tephritidae) in laboratory selection and cross-resistance" (PDF). Journal of Economic Entomology. 99 (3): 931–936. doi:10.1603/0022-0493-99.3.931. PMID   16813333. S2CID   182038998.
  23. ↑ Bielza P, Quinto V, Fernandez E, Grávalos C, Contreras J (June 2007). "Genetics of spinosad resistance in Frankliniella occidentalis (Thysanoptera: Thripidae)". Journal of Economic Entomology. 100 (3): 916–920. doi:10.1603/0022-0493(2007)100[916:gosrif]2.0.co;2 (inactive 25 January 2024). PMID   17598556. S2CID   25560262.{{cite journal}}: CS1 maint: DOI inactive as of January 2024 (link)
  24. ↑ Reyes M, Franck P, Charmillot PJ, Ioriatti C, Olivares J, Pasqualini E, Sauphanor B (September 2007). "Diversity of insecticide resistance mechanisms and spectrum in European populations of the codling moth, Cydia pomonella". Pest Management Science. 63 (9): 890–902. doi:10.1002/ps.1421. PMID   17665366.
  25. ↑ See for continued updates: Mota-Sanchez D, Wise JC, et al. (Insecticide Resistance Action Committee). "Arthropod Pesticide Resistance Database". Michigan State University.
  26. ↑ Brunner JF. "Codling Moth and Leafroller Control Using Chemicals" (PDF). Tree Fruit Research and Extension Center. Washington State University. Archived from the original (PDF) on 3 August 2003. Retrieved 20 October 2012.
  27. ↑ Stebbins KE, Bond DM, Novilla MN, Reasor MJ (February 2002). "Spinosad insecticide: subchronic and chronic toxicity and lack of carcinogenicity in CD-1 mice". Toxicological Sciences. 65 (2): 276–287. doi: 10.1093/toxsci/65.2.276 . PMID   11812932.
  28. ↑ Yano BL, Bond DM, Novilla MN, McFadden LG, Reasor MJ (February 2002). "Spinosad insecticide: subchronic and chronic toxicity and lack of carcinogenicity in Fischer 344 rats". Toxicological Sciences. 65 (2): 288–298. doi: 10.1093/toxsci/65.2.288 . PMID   11812933.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.