Selenium what is it?

http://www.chemistryexplained.com/elements/P-T/Selenium.html

Selenium is a reactive nonmetal and sometimes an metalloid which is located in period four and group 16 of the periodic table.  Selenium has an atomic weight of 78.971 and an atomic number of 34. Its electron configuration is 3d(10) 4s(2) 4p(4).

Selenium is a solid at atmospheric temperatures as it has a melting point of 430 F and a boiling point of 1265 F.

Typically solid selenium is black, red or grey. It exists as selenid, elemental selenium, selenite, and selenate.

Selenium was first discovered as a byproduct of sulfuric acid production which caused illness in the factory workers. (2)

That being said people who work or live near industries where selenium is produced or processed and near coal burning plants may be exposed to higher levels of selenium in the air.

Selenium is a considered a trace element. Selenium deficiency and over supplementation can cause adverse effects due to the nature of its use in our body. Deficency leads to Keshan disease which is due to nature of selenium as a cofactor to glutathione peroxidase. Oversupplementation can lead to amyotropic lateral sclerosis, malignancy, and increased risk of diabetes.

Due to the fact that selenium can cause adverse effects if under or over supplemented, the recommended daily allowance is 55 mcg/day. (3)

Biotransformative effects:

Biotransformation studies have been have been carried out extensively in plants to help understand the effect of selenium level deficiency in farm animals and humans.

Selenium is intricately related to glutathione pathways in the body so biotransformation is typically studied in relation to this pathway. These compounds include: 2,3-dihydroxypropionyl-selenolanthionine, selenohomolanthionine, methyltio-selenoglutathione, Se-methyl-selenocysteine, 2,3-dihydroxy-propionyl-selenocysteine-cysteine, selenomethionine, methyl-seleno-Se-pentose-hexose, deaminohydroxy-selenohomolanthionine, Se-methyl-selenoglutathione and γ-glutamyl-Se-methyl-selenocysteine. (4)

Glutathione fragmentation showing typical sidechains which nearly all include Selenium. Ruszczyńska, Anna. “Investigation of Biotransformation of Selenium in Plants Using Spectrometric Methods.” Spectrochimica Acta Part B: Atomic Spectroscopy, Elsevier, 4 Feb. 2017, www.sciencedirect.com/science/article/pii/S0584854717300678.

Selenium in the body is used for a variety of cellular processes. Selenoproteins help with oxidation-reduction reactions. These reactions are important for detoxification, glutathione production, and has antioxidant properties.  Additionally, selenium is part of the plasma proteins albumin and globulin, and allow for plasma proteins to bind these proteins for transport through the body. (3)

Toxicokinetics of Selenium:

Selenium typically is ingested or inhaled to cause toxic effects. Inhalation causes the most acute effects, although gastrointestinal absorption can cause toxicity.

Acute effects of selenium toxicity does not occur with elemental selenium but selenium salts, selenid, selenite, and selenate can cause toxicity.

Selenide ions typically are what goes through metabolic processes through the body and has 3 typical outcomes.

1. Glutathione peroxidase, triiodothyronine and other selenoprotein addition as a side chain.
2. Albumin or Globulin binding as a plasma protein sidechain to allow the transport of various substances through the body.
3. Phase I and Phase II biotransfomation typically in the liver where the selenide is methylated so it can be excreted.

Typical metabolism occurs as seen in the following diagram.

Figure 97-1 of goldfranks toxicologic emergencies.

Renal excretion of selenium is typically as trimethyselenide, and low levels of excretetion also occur in the feces.

Selenium will cause toxicokinetic effects through affecting metabolic pathways but this has not been investigated in-depth as of yet! (3)

Mechanism of Action of Selenium- deficency and toxicty:

The mechanism of action of selenium depend on whether or not deficiency is prominent. Typically this will cause decreases in glutathione peroxidase activity as selenium is its cofactor. This then leads to decreased detoxification of glutathione S-transferase dependent substances. Some very prominent examples of this are  alfatoxin B and acetaminophen. (3)

Additionally, selenium has been proposed as an antioxidant which during deficiency causes decreased erythrocyte glutathione peroxidase. This then leads to increased capillary permeability which can cause osmotic changes throughout the body. (4)

For more information on selenium as an antioxidant please see this paper for alot of useful information!

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2698273/

Selenium toxicity is typically due to extreme levels of oral, inhaled or oral exposure. The exposure is usually to selenious acid, selenium oxide and dioxide. The latter of the two are converted into selenious acid once in the body which causes irritation, circulatory, skeletal muscle and gastrointestinal effects. (3)

Carcinogenicity and Teratogenicity of Selenium:

Selenium is somewhat special since it actually is currently being investigated for its anti-cancer effects. Selenium is not considered a carcinogen, but rather shows interesting use as a treatment for cancer metastasis. The reasoning for this is it has it helps the body to deal with oxidative stress. The selenoprotein, GPX, as been associated with certain tumor development, but this is a down stream pathway which is not due to selenium ingestion itself. (5)

Teratogenesis is not common in people but has been shown to lead to birth defects in animals. Stunted growth, fetal death, and skeletal abnormalities have been shown. (6)

Selenium deficiency birth defects
https://www.thegoatspot.net/threads/what-causes-weak-legs.195330/

White muscle disease from selenium deficiency: 

I just wanted to mention also that the Environmental Protection Agency (EPA) has determined that one specific form of selenium, selenium sulfide, is a probable human carcinogen. This evidence of classification of selenium sulfide is based on inadequate data from human studies and sufficient evidence in animals.

Target Organs of Selenium:

Target organs of acute selenium exposure include dermal, ophthalmic, respiratory and oral mucosa. This is usually due to the direct exposure to selenious acid.

Chronic selenium exposure typically affects the skin, central nervous system, musculoskeletal system and nail beds. (3)

Chronic selenium exposure causing nail bed koilonychia:
https://www.sciencedirect.com/topics/medicine-and-dentistry/nail-abnormality

Signs and Symptoms of Selenium:

Signs of selenium exposure range dramatically depending on chronicity or acute nature of toxicity. Typically acute exposure presents as:

Caustic burns

Caustic burns:
https://en.wikipedia.org/wiki/Chemical_burn

Rose eye conjunctivitis

Rose eye conjunctivitis:
https://parenting.firstcry.com/articles/conjunctivitis-during-pregnancy-causes-symptoms-and-remedies/

Bronchospasm

Bronchospasm:
https://www.normalbreathing.com/d/bronchospasm.php

Circulatory failure

Circulatory Failure:
https://www.google.com/search?q=circulatory+failure&source=lnms&tbm=isch&sa=X&ved=0ahUKEwiHubOV9sHiAhVUtZ4KHRV7D_oQ_AUIDygB&biw=754&bih=385#imgrc=uadjVbcwh27rrM:

Chronic symptoms include fatigue, fever, nail deformities, diarrhea and skin lesions. These chronic symptoms tend to be few and far in between. When chronic exposure does occur, reduction in dietary selenium levels will lead to resolution of symptoms. (8)

Treatment for Selenium?

*****Below is adapted from my last Benzimidazole post:(9)****

As with any toxicity case which presents 6 steps are traditionally taken for management:(8)

1. Stabilizing the patient to ensure open airways, breathing and proficient circulation.
2. Evaluating how stabile the patient is through complete blood counts, blood gas and other assays.
3. Prevention of further contamination through removing clothing which has been exposed.
4. Enhancement of elimination through the use of activated charchoal. This has been found to be especially useful with selenium toxicity.
5. There is no antidote to selenium poisioning.
6. Supportive care to the patient through bronchodilators or mechanical ventilation.

Management of selenium toxicity is mainly related to pain management when caustic burns to the dermis or ophthalmic structures are seen. (7)

Essentiality and Biomarkers for Selenium?

Selenium is considered an essential trace element due to its properties as a glutathione peroxidase cofactor. Currently GPX3 and SEPP1 are considered useful biomarkers of selenium deficiency. Levels of less than 20 ug/kg in animals and <55 ug/day in humans is considered deficient levels.

Although GPX3 and SEPP1 are considered useful in the detection of selenium deficiency, they are not diagnostic in evaluation they are suggestive markers. (10)

Citations:

(1) Meija, Juris; et al. (2016). “Atomic weights of the elements 2013 (IUPAC Technical Report)”. Pure and Applied Chemistry. 88 (3): 265–91. doi:10.1515/pac-2015-0305.

(2) Weeks, Mary Elvira (1932). “The discovery of the elements. VI. Tellurium and selenium”. Journal of Chemical Education. 9

(3): Hoffman, Robert S, Mary A. Howland, Neal A. Lewin, Lewis Nelson, Lewis R. Goldfrank, and Neal Flomenbaum. Goldfrank’s Toxicologic Emergencies. , 2015. Print.

(4) Ruszczyńska, Anna. “Investigation of Biotransformation of Selenium in Plants Using Spectrometric Methods.” Spectrochimica Acta Part B: Atomic Spectroscopy, Elsevier, 4 Feb. 2017, www.sciencedirect.com/science/article/pii/S0584854717300678.

(4) Combs, G F, et al. “Mechanisms of Action of Selenium and Vitamin E in Protection of Biological Membranes.” Federation Proceedings, U.S. National Library of Medicine, Oct. 1975, www.ncbi.nlm.nih.gov/pubmed/1100438/.

(5) Chen, Yu-Chi et al. “Is selenium a potential treatment for cancer metastasis?.” Nutrients vol. 5,4 1149-68. 8 Apr. 2013, doi:10.3390/nu5041149

(6) EPA. “Selenium Compounds.” EPA.GOV, www.epa.gov/sites/production/files/2016-09/documents/selenium-compounds.pdf.

(7) Curtis D. Klaassen. Casarett And Doull’s Toxicology : the Basic Science of Poisons. New York :McGraw-Hill Education, 2013.

(8) Plahovinsak, J. “PHRM7588: Toxic Substances.” Carmen.com, 2019.

(9) Palillo, M. 2019. Benzimidazoles- Fungi and Helminths Beware! https://u.osu.edu/palillo.1/

Benzimidazoles what are they?

Benomyl, the most common of the Benzimidazoles. source: https://en.wikipedia.org/wiki/Benomyl

Benzimidazoles are a class of fungicides which was invented by DuPont industries as a methyl ester of [1-(butylcarbamoyl)-1H-benzimidazol-2-yl]carbamic acid. (1)

Production of Benzimidazoles are through a condesation reaction between phenylenediamine and formic acid as seen below in the equation below:(2)

C₆H₄(NH₂)₂ + HC(OCH₃)₃ → C₆H₄N(NH)CH + 3 CH₃OH

Benzimidazoles additionally have anti-helminthic effects on Nematodes, lungworms, some cestodies, some trematodes and adult flukes.(3)

The typical chemical conformation of benzimidazole- a imidazole and benzene bicyclic compound. source: https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+2797

https://www.google.com/search?biw=738&bih=657&tbm=isch&sa=1&ei=BHxAXdLmIZjPtQaW07XoBA&q=benzimidazole+product&oq=benzimidazole+product&gs_l=img.3…1060.4004..4119…0.0..0.235.947.5j2j1……0….1..gws-wiz-img…….0j0i8i30j0i24.QlI-Q1UndrI&ved=0ahUKEwjS-PGik93jAhWYZ80KHZZpDU0Q4dUDCAY&uact=5#imgrc=MOu66yWBhVAr0M:

Biotransformative effects:

Biotransformation studies have been have been carried out in various animal models ranging from rodents to ruminants to humans.

When in regards to the Benzimidazole, Albendazole, typically this process occurs as a 2 step process yielding albendazole sulphoxide and albendazole sulphone. albendazole sulphoxide is mediated by CYP3A and Flavine monooxygenases while albendazole sulphone is mediated through CYP1A.

When Fenbendazole is the Benzimidazole being used, typically biotransformation occurs into sulphoxide. The exact enzymes causing this are not definitively known but likely are due to CYP1A1/2. (4)

https://www.google.com/search?q=benzimidazole+biotransformation&source=lnms&tbm=isch&sa=X&ved=0ahUKEwiEifPtk93jAhVSHqwKHcgND0IQ_AUIESgB&biw=746&bih=657&dpr=1.8#imgrc=-QZcK7LI1fjDHM:

Toxicokinetics of Benzimidazoles:

Benzimidazole will cause toxicokinetic effects through affecting metabolic pathways. Research into the specific pathways involved is sparse, but some definitive toxicokinetics have been shown.

Oral injestion tends to be the most rapid route of absorption in the body and the Benzimidazoles tend to be more fat soluble than water soluble. Excretion is through in the urine as 5-hydroxythiabendazole.(11)

Mechanism of Action of Benzimidazoles:

Although the exact mechanism of action for Benzimidazoles are not known there are a few clear effects.

On fungi, growth is stunted through inhibiting microtubule formation (5).

In parasite nematodes, several different effects have been found to be associated with Benzimidazoles including: fumarate reductase inhibition, energy production inhibition, glucose transport and uptake inhibition, as well as, microtubule degeneration and dissolution.(6)(7)

Carcinogenicity and Teratogenicity of Benzimidazoles:

Typically benzimidazoles have been shown to cause liver tumors in rats. Benzimidazoles have not been shown to cause carcinogenesis normally in other species. (8)

Teratogenesis is common in benzimidazoles but is dependent on the dose and species. In cattle, pigs and horses this will present as skeletal defects in the animals.(9)

In humans teratogenesis has been reported to present as anopthalmia when the benzimidazole, benomyl is given. (5) Anopthalmia is the abscence of the globe and ocular tissue as seen below:

source: https://www.cdc.gov/ncbddd/birthdefects/anophthalmia-microphthalmia.html

When the law gets involved with Benzimidazoles Exposures:

The most historically relevant exposure to benzimidazoles was in Miami in 1996. A child was born with anopthalmia due to the mother’s occupation as a gardener. A law suit ensued with a final verdict of 4 million dollars!

Target Organs of Benzimidazoles:

Studies have shown that benzimidazole will affect the testes, Gastrointestinal tract, bone marrow and liver if exposure is chronic. (10) Additionally, benomyl can cause a contact dermititis. (5)

https://www.google.com/search?q=contact+dermatitis&source=lnms&tbm=isch&sa=X&ved=0ahUKEwiPhNCElN3jAhXDmq0KHb3YCVkQ_AUIESgB&biw=555&bih=657&dpr=1.8

Signs and Symptoms of Benzimidazoles:

Inhalation and dermal contact are the most common routes of exposure of benzimidazoles which can lead to toxicity. Signs can present nonspecifically as weakness, nausea, dizziness, headaches, and irritation to mucosa, skin and the lungs. When inhaled a hypersensitivity can occur leading to bronchospasm and wheezing. Dermal exposure can lead to hypersensitivity dermatitis. (11)

Treatment for Benzimidazoles?

As with any toxicity case which presents 6 steps are traditionally taken for management:(12)

1. Stabilizing the patient to ensure open airways, breathing and proficient circulation.
2. Evaluating how stabile the patient is through complete blood counts, blood gas and other assays.
3. Prevention of further contamination through removing clothing which has been exposed.
4. Enhancement of elimination through the use of activated charchoal. This has been found to be especially useful with benzimidazoles toxicity.
5. There is no antidote to benzimidazoles poisioning.
6. Supportive care to the patient through bronchodilators or mechanical ventilation.

Biomarkers for Benzimidazoles?

There are currently no biomarkers for benzimidazole. Scientists seem to have no interest in making a biomarker for benzimidazoles in the future.

BUT! Benzimidazoles has been recently found to be a useful stain for endoplasmic reticulum and golgi apparatus! Follow the link below for a video of the fluorescence in a live cell! (13)

https://figshare.com/articles/Video_1_New_Properties_of_a_Bioinspired_Pyridine_Benzimidazole_Compound_as_a_Novel_Differential_Staining_Agent_for_Endoplasmic_Reticulum_and_Golgi_Apparatus_in_Fluorescence_Live_Cell_Imaging_AVI/7021787/1

Additionally, specific benzimidazoles have been shown to be preliminarily useful as anti-inflammatories! see video below for the full details: (14)

Citations:

(1) ChEBI. 2015. https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:3015

(2) E. C. Wagner and W. H. Millett (1943). “Benzimidazole”. Organic Syntheses; Collective Volume, 2, p. 65.

(3) Bowman, Dwight D. Georgis’ Parasitology for Veterinarians. Philadelphia :W.B. Saunders Co., 1999.

(4) Velik, J, et al. “Benzimidazole Drugs and Modulation of Biotransformation Enzymes.” Research in Veterinary Science, W.B. Saunders, 24 Sept. 2003, www.sciencedirect.com/science/article/pii/S0034528803001498.

(5) Curtis D. Klaassen. Casarett And Doull’s Toxicology : the Basic Science of Poisons. New York :McGraw-Hill Education, 2013.

(6) L.C. Davidse, Ann. Rev. Phytopathol., 24 (1986), p. 43

(7) J.C. Havercroft, R.A. Quinlan, K. Gull. J. Cell. Sci., 49 (1981), p. 195

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