Neurons and Exercise

Neurons and Exercise

Monday, July 22, 2019

Mercury Detox Using the Selenium Method

Targeted Mercury Detox Using the Selenium Method (1/5/2020)
Mercury can be inhaled as mercury vapor, absorbed in the gut from ingested food and water, or injected in the body by vaccinations. Common sources of mercury include amalgam fillings, fish, and vaccines containing Thimerosal.  Mercury’s toxicity primarily stems from its ability to tightly bind with the essential element selenium and thereby lower available selenium levels in the body creating a selenium deficiency1. 
Selenium is used in some enzymes to protect us from oxidative effects of toxic metals commonly found in the body such as aluminum, manganese, nickel, lead, cadmium, and mercury. Selenoenzymes are involved in reducing the oxidative effects of these metals by reducing the amount of reactive oxygen species (ROS) induced by these metals in the body.  ROS causes damage to our bodies by weakening and killing mitochondria and the cells powered by these mitochondria.
Mercury is particularly toxic because it creates selenium deficiency, inhibits selenoenzymes, and induces ROS formation.  The resulting ROS kills mitochondria because mercury prevents selenoenzymes from providing protection from ROS. Selenium supplementation provides four levels of protection from mercury:
1)      Prevents mercury induced selenium deficiency in the brain2,3
2)      Prevents mercury induced mitochondrial death and neurotoxicity in the brain due to ROS2,3,4
3)      Facilitates mercury detoxification by urinary excretion of mercury5
4)      Facilitates mercury detoxification by formation of inert mercury selenide (HgSe)1
Targeted Detox during Chronic Mercury Exposure
It has been demonstrated that targeted detox of humans being chronically exposed to mercury is possible by taking 100mcg of selenomethionine daily for twelve weeks. The group being supplemented with selenomethionine had significantly enhanced urinary excretion of mercury5. In those with mercury induced selenium deficiency it may take on average 2 - 4 weeks to first restore the body’s selenium reserves before enhanced mercury excretion is observed (Figure 1)

Figure 1. Mercury concentrations in urine samples on different days, where the supplementation group took 100mcg/day selenium-enriched yeast (SelenoPrecise, Pharma Nord, Denmark) and the placebo group did not take a selenium supplement.  The supplementation group was 53 volunteers (27 men and 26 women) and the placebo group was 50 volunteers (25 men and 25 women). The results were statistical significance, as indicated with ++ p < 0.01 and +++ p < 0.001, compared with the placebo group5.
Selenomethionine supplementation for 4 months has been shown to lower mercury level in hair samples. This study involved 23 people randomly divided into two groups all with serum selenium less than 90mcg/L. Thirteen people were given selenomethionine (100mcg/day of selenium enriched yeast) and 10 people were given a placebo. In only those given the selenomethionine supplement, mercury level in pubic hair was lowered 34%, serum selenium rose by 73%, and blood selenium rose by 59%, on average6.  
Therefore supplementation with selenomethionine produced by selenium-enriched yeast (100mcg/day) has been proven to provide targeted detox during chronic mercury exposure. Selenomethionine supplementation enhances urinary mercury excretion in humans and lowers accumulated mercury in three to four months as measured in human pubic hair samples5,6. This selenium method of mercury detox is targeted because it does not remove essential trace metals from the body as does non-targeted chelation treatments with thiols and dithiols.
Essentiality of Selenium
In mammals the amount of selenium in the brain is actively maintained at the expense of selenium in other tissues.  Mice fed a selenium deficient diet had only 13% of their normal whole-body selenium, but still had 56% of their normal brain-selenium and 100% of their normal hippocampal-selenium7,8. Therefore, there is a selenium hierarchy among the lobes of the brain and all the organs, with the hippocampus at the apex and the whole brain just below. The hippocampus is responsible for spatial memory creation and storage.
It is not an evolutionary accident that the brain is at the top of the selenium hierarchy with the hippocampus at the apex. Homo sapiens evolved to be the top predator on the food chain by using their hippocampus to remember locations where in the past they had optimal hunting and gathering. The hippocampus allows humans to create and store maps in their brains in order to again find these optimal locations. Selenium protects the hippocampus from a variety of neurotoxic metals, such as aluminum, lead, and mercury, allowing maps and dreams to chart the course of human survival9.         
Absorption and Translocation of Oral Selenium
Oral treatment of rats with selenomethionine containing radioactive selenium-75 (Se-75) revealed the highest concentration of Se-75 in the cerebellum followed by identical levels in the cerebral hemisphere and spinal cord. Retention of Se-75 in all parts of the central nervous system (CNS) was longer after oral administration of radioactive selenomethionine than radioactive sodium selenide10. This work proves that the selenium in orally administered selenomethionine does cross the BBB and is retained longer in the CNS than sodium selenide.    
The active maintenance of selenium in the brain involves a selenium carrying protein named Sepp1 (a.k.a. selenoprotein P) and its receptor (apolipoproteinE receptor 2) interacting on the blood-brain-barrier (BBB) to translocate selenium from the blood to the brain8. Each human Sepp1 protein carries 10 selenocysteines across the BBB. Selenomethionine is converted to selenocysteine by the transsulfuration pathway in the liver, where Sepp 1 is biosynthesized and released into the blood11,12. In mice, unable to make Sepp1, the amounts of selenium in the cortex, midbrain, brainstem, cerebellum, and hippocampus are all significantly lower than normal7. Sepp 1 is required for both protection against oxidative injury and for transport of selenium from the liver to peripheral tissues and organs including the brain13.
Selenocysteine biosynthesized from selenomethionine and transported to the brain by Sepp 1 has an affinity for methylmercury many orders of magnitude greater than cysteine’s binding affinity for methylmercury14. This is due to mercury having a million times greater binding force with selenium than sulfur15. Selenocysteine is enzymatically metabolized to L-alanine and selenide in the body12. Selenide and inorganic mercury react by a non-biological process in the body to form mercury selenide16. Mercury and selenium in mercury selenide are so tightly bonded that the mercury is metabolically inert and therefore non-toxic17,18. 
Supplementation for mercury detox with forms of cysteine not containing selenium, such as N-acetylcysteine (a.k.a. NAC), is not recommended. The sulfur in both cysteine and NAC has much lower affinity for mercury than selenocysteine14.  This lower affinity may account for why the selenium in sodium selenite (Na2SeO3) is more effective than NAC at lowering mercury levels in the brain, liver, and kidney of rats19. There are currently no studies showing NAC facilitates elimination of mercury in humans and on the safety of long-term supplementation with NAC.     
Sources of Dietary Selenium
Plants growing on selenium rich soil take up the inorganic salts selenite and selenate. Plants incorporate this inorganic selenium into organic compounds, such as the amino acids selenomethionine and selenocystiene20. These selenium containing amino acids are significantly less toxic to humans than are selenite and selenate salts21.
When humans consume vegetables, grain, and nuts grown on selenium rich soil they ingest selenium primarily as selenomethionine and seleneocysteine. There are selenium deficient areas where crops do not contain sufficient selenium for routine human consumption.  Also because selenium is not usually added to soil as fertilizer, many farming areas in the world that were in the past producing selenium rich crops are now producing crops with declining selenium content. In these areas of the world selenium supplementation is recommended.
Selenomethionine Supplementation
The selenium method of mercury detox requires taking orally a selenomethionine supplement, daily for at least 12 weeks:
·         Children 0 to 3 years of age: 25mcg/day
·         Children 4 to 8 years of age: 50mcg/day
·         Children 9 to 13 years of age: 100mcg/day
·         Adolescents 14 to 18 years of age and adults: 100-200mcg/day
Supplements for human use are not regulated by the U.S. FDA. Because of this some supplement manufacturers have incorrectly labeled product on the market that contains no selenomethionine or less than the amount stated on the label22-24. Therefore products with third party certification are recommended.  Certifying agencies include:, NSF International, U.S. Pharmacopeia (USP), and UL.  There are commercial test laboratories that also perform third party testing for purity and percent of selenium as selenomethionine.   
The European Food Safety Authority (EFSA) has published a scientific opinion on acceptable selenium-enriched yeasts produced as selenomethionine supplements for human use. The source of selenium must be sodium selenite and the resulting product should contain 60 to 85% selenomethionine with less the 10% additional organic selenium and less than 1% inorganic selenium, such as residual sodium selenite. The dried product should contain no more than 2.5mg of selenium per gram25.
I am aware of only one selenium-enriched yeast supplement that has been tested by third parties. This is Bio-SelenoPrecise® tablets manufactured in Denmark by Pharma Nord under patent no. 1 478 732 B1. This type of L-selenomethionine supplement is 88.7% absorbed in Danish men with high habitual selenium intake26, however only about 34% may actually be free selenomethionine after gastrointestinal digestion27.  Pharma Nord packages tablets of Bio-SelenoPrecise® as 50, 100, and 200mcg of selenomethionine. Pharma Nord selenomethionine has been checked by two laboratories and it has 69-83% L-selenomethionine, 5% or less additional organic selenium, including selenocysteine, less than 1% inorganic selenium, and less than 2.2mg/gram of selenium. These results are summarized as product 3a, 3b, and 4 in EFSA’s Table 1 and they meet EFSA specifications for selenium-enriched yeast25.
Some selenomethionine supplements are made with higher purity than supplements made from selenium-enhanced yeast. However, it has been reported that plasma selenium is significantly higher when taking Pharma Nord Bio-SelenoPrecise® than seen in a comparable population of human subjects taking the same dose of higher purity selenomethionine28.
Manufactures of high purity yeast-free selenomethionine who have their product third party certified and/or tested include Sabinsa Corporation. Their Selenium SeLECT® product contains a minimum of 1.25% of L-selenomethionine, measured by HPLC, and 98.75% of dicalcium phosphate, measured by titration. Therefore it is 100% selenium as selenomethionine. Sabinsa Corp. has both UPC and NSF International product certification. Selenium SeLECT® is packaged and sold by Swanson (100mcg capsules) and Vitacost (200mcg capsules). Make sure the Supplement Facts on the bottles state: “Selenium from (as) Selenium SeLECT® L-selenomethionine”. 
The Food and Nutrition Board (FNB) of the U.S. Institute of Medicine has set the tolerable upper intake levels (UL) for selenium based upon age, including both selenium obtained from food and selenium obtained from supplements, as indicated in Table 129.

Symptoms of Chronic Mercury Exposure and Selenium Deficiency

The risk of hypothyroidism is increased with exposure to mercury and/or selenium deficiency because a selenoenzyme (e.g. T4 deiodinase) is required to make the thyroid bioactive hormone T3 (a.k.a. triiodothyronine ) from prohormone T4 (a.k.a. levothyroxine)30.  Mercury both inhibits this enzyme and slows its production by creating a selenium deficiency31.  Symptoms of hypothyroidism, mercury toxicity and selenium deficiency all include:
·         Memory Loss
·         Fatigue
·         Brain Fog
·         Muscle Weakness
·         High TSH (a.k.a. thyroid-stimulating hormone) secretion

Mercury and/or selenium deficiency also causes a number of additional symptoms not seen in hypothyroidism:
·         Physical Tremors32
·         Seizures33
·         Impaired Language Skills34-37
·         Impaired Psychomotor Functions34-37
·         IQ Loss in Children37,38
·         Mild Cognitive Impairment in Adults33,34
Outcomes associated with prenatal mercury exposure include the loss of IQ points, and decreased performance on tests, including memory, attention, language skills, visuospatial cognition and psychomotor fuctions34,35. Outcomes associated with prenatal selenium deficiency also include both impaired language skills and psychomotor function36,37.
Non-Targeted Detox after Acute Mercury Exposure
When acutely exposed to a large dose of mercury during a relatively short time period you should seek immediate medical assistance.  Severe acute elemental mercury exposure has been managed by a combination of selenium and N-acetylcysteine (NAC)41,42.  There are also chelators available by prescription that will remove some mercury after acute exposure. Unlike selenium that binds and detoxifies mercury irreversibly, chelators reversibly bind and redistribute mercury in the body without detoxification.  Some of this chelated mercury is eliminated in the urine and bile, while some mercury is redistributed to the brain. For this reason chelators should only be used cautiously under a doctor’s supervision.  
Pharmaceutical Chelators for Acute Mercury Exposure
There are 11 pharmaceuticals that chelate metals approved by the U.S. FDA, although only one of them (e.g. BAL) has been approved for treating acute mercury toxicity43.  Unlike selenomethionine, the natural form of selenium that humans ingest primarily from plants, pharmaceutical chelators are non-natural manmade chemicals. Because of safety concerns, pharmaceutical chelators can’t be recommended for routine use. The pharmaceutical chelators are dithiols and do not contain selenium. Since these dithiols reversibly bind to both essential and toxic divalent cations they can both transport these ions to other organs and facilitate their elimination44. For instance in some cases they have been found to chelate selenium45. The following is a list of four pharmaceutical chelators with the first two being FDA approved with the third being used without approval:
·         Dimercaprol (a.k.a. British Anti-Lewisite, BAL) used by injection for mercury toxicity
·         Dimercaptosuccinic acid (a.k.a. Succiner, DMSA) used orally for lead toxicity
·         Dimercaptopropane sulfonate (a.k.a. DMPS) used for mercury toxicity46.
·         N,N’,-bis(2-mercaptoethyl)isophthalamide (a.k.a. BDET, BDTH2, OSR#1, NBMI)
The last compound on the list, also called “Boyd Haley’s compound”, is not approved by the U.S. FDA for use as a pharmaceutical chelator and has been taken off the market as a supplement because it is non-natural. The FDA concluded in 2008 that this compound had inadequate safety testing and therefore may “present a significant or unreasonable risk of illness or injury”47.     

Alpha Lipoic Acid for Acute Mercury Exposure
Alpha lipoic acid (a.k.a. ALA) is naturally found in the body and when reduced in vivo to dithiol-ALA it can protect the body from metal induced reactive oxygen species (ROS).  ALA is not approved by the U.S. FDA for treating acute mercury exposure even though one dithiol (e.g. BAL) is approved by the U.S. FDA for such a purpose43. When ALA was compared with other dithiols (e.g. DMPS and DMSA) it proved to be significantly less effective at removing inorganic mercury from the kidneys of rabbits48. ALA removed only 35% while DPMS removed 86% of the mercury48. There is no human clinical trial showing that oral administration of ALA as a supplement facilitates the excretion of mercury or lowers mercury in the body and brain49.
Injection of ALA in rats after injection of mercury results in an increase in biliary excretion of inorganic mercury but high doses of ALA results in a decreased biliary excretion of methylmercury50.  This study by Gregus, et al., had a “large influence on determining the ALA chelation protocol” as described by A.H. Cutler51.  Cutler also said “I suggest people get the actual paper and read it … if they are going to draw conclusions about what they will or won’t do.”51 I will summarize the paper here in some detail so you can draw your own conclusions:
The study by Gregus, et al., found that the amount of mercury excreted in the bile depends upon both on the dosage of ALA and the time between injections of inorganic mercury and ALA50. Using a medium dose of ALA (150mcg/Kg) with one minute between these injections there is a 30 fold increase in biliary excretion of mercury. But when this dose of ALA is administered 1 and 24 hours after mercury there is only 3.3 and 1.4 fold increases in biliary excretion of mercury, respectively50.  This indicates ALA is only efficacious for acute, not chronic, mercury exposure as it significantly increases biliary excretion of mercury only if taken within a few hours of exposure. ALA does not significantly facilitate the excretion of mercury once mercury is stored in tissues and organs.
This study also provides evidence that ALA redistributes mercury in the body of rats.  For instance, ALA administered 1 minute after inorganic mercury decreased mercury levels in the rat kidney by half, but increased mercury in the rat brain 2.9 fold, lung 2.7 fold, heart 4.3 fold, and muscle 3.1 fold50. In addition, ALA at 300mcg/Kg decreases biliary excretion of methylmercury and ALA at 150mcg/Kg increases methylmercury levels in the rat brain 2.6 fold50. This indicates that ALA redistributes both inorganic and methylmercury and significantly increases mercury in many tissues and organs of the rat including the brain.  
The fact that ALA provides non-targeted chelation is reinforced by a study showing ALA redistributes selenium in the bodies of aged rats by lowering levels of selenium in the brain, heart, muscle, and blood plasma52. For this reason it is recommended that serum selenium levels should be monitored if taking ALA as a supplement52.  If you have been taking ALA and seen improvement it may be preventing metal toxicity (i.e. ROS) due to metals other than mercury.
Because ALA likely redistributes inorganic and methylmercury in the human body as well as in rats and increases mercury in rat and human tissues and organs including the brain, both I and the FDA do not recommend taking ALA as an oral supplement or injection for either acute mercury exposure or detox from chronic mercury exposure. 
Selenium is an essential trace atom required by the body that is normally supplied as selenomethionine in the vegetables and grains our ancestors have eaten for thousands of years.  The selenium in selenomethionine is quickly converted in the liver to a selenium-carrier that crosses the blood-brain-barrier enriching and protecting the brain with selenium.   Because there are selenium deficient areas where crops do not contain sufficient selenium for routine human consumption, daily selenomethionine supplementation is recommended and can provide four levels of protection from mercury toxicity:
1)      Prevents mercury induced selenium deficiency in the brain2,3
2)      Prevents mercury induced mitochondrial death and neurotoxicity in the brain due to ROS2,3,4
3)      Facilitates mercury detoxification by urinary excretion of mercury5
4)      Facilitates mercury detoxification by formation of inert mercury selenide (HgSe)1
Daily selenomethionine supplementation is proven to facilitate urinary mercury excretion and decrease accumulation of mercury in human hair. Other methods of mercury detoxification, such as NAC and ALA, should be avoided due to a lack of such proven testing in humans.
1)      Spiller, H.A.; Rethinking mercury: the role of selenium in the pathophysiology of mercury toxicity; Clin. Toxicology; DOI: 10.1080/15563650.2017 . 1400555 (2017)
2)      Ralston, N.C.V., et al.; Dietary and tissue selenium in relation to methylmercury toxicity; Neurotoxicology; 29:802-11 (2008)
3)      Ralston, N.C.V., et al.; Importance of molar ratios in selenium dependent protection against methylmercury toxicity; Biol. Trace Elem. Res.; 119:225-268 (2007)
4)      Glaser, V., et al.; Diphenyl diselenide administration enhances cortical mitochondrial number and activity by increasing hemeoxygenase type 1 content in a methylmercury-induced neurotoxicity mouse model; Mol. Cell Biochem.; 390:1-9 (2014) 
5)      Li, Y-F, et al.; Organic selenium supplementation increases mercury excretion and decreases oxidative damage in long-term mercury exposed residents from Wanshan, China; Environ. Sci. Technol.; 46:11313-18 (2012)
6)      Seppanen, K., et al.; Effect of supplementation with organic selenium on mercury status as measured by mercury in pubic hair; J. Trace Elem. Med. Biol.; Jun.; 14(2):84-7 (2000)
7)      Nakayama, A., et al,; All regions of mouse brain are dependent on selenoprotein P for maintenance of selenium; J. Nutr.; Mar.; 137(3):690-3 (2007)
8)      Burk, R.F., et al.; Selenoprotein P and apolipoprotein E receptor-2 interact at the blood-brain-barrier and also within the brain to maintain and essential selenium pool that protects against neurodegeneration; FASEB J.; Aug.; 28(8):3579-88 (2014)
9)      Brody, H.; Maps and Dreams; Gardners Books (2002)
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11)  Hill, K.E., et al.; Production of selenoprotein P (Sepp 1) by hepatocytes is central to selenium homeostasis; J. Biol. Chem.; Nov.; 287(48):40414-24 (2012)
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15)  Zhang, H.; Impacts of selenium on the biogeochemical cycles of mercury in terrestrial ecosystems in mercury mining areas; Section 2.3 Mechanisms of selenium and mercury interactions; Springer (2014)
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19)  Joshi, D., et al.; Methylmercury toxicity: amelioration by selenium and water-soluble chelators as N-acetyl cysteine and dithiothreitol; Cell Biochem. Funct.; 32:351-60 (2014)
20)  Meyer, C.A.C.; Dietary selenium supplementation: Effects on neurodegeneration following traumatic brain and spinal cord injury; Theses and Dissertations, Univ. Kentucky (2015)
21)  Salbe, A.D., and Levander, O.A.; Comparative toxicity and tissue retention of selenium in methionine-deficient rats fed sodium selenate or L-selenomethionine; J. Nutr.; 120:207-12 (1990)      
22)  Bakidere, S., et al.; Speciation of selenium in supplements by high performance liquid chromatography  - inductively coupled plasma  - mass spectrometry; Anal. Lett.; 48(9):1511-23 (2015)
23)  Gosetti, F., et al.; Speciation of selenium in diet supplements by HPLC – MS/MS methods; Food Chem.; 105:1738-47 (2007)
24)  Kubachka, K.M., et al.; Evaluation of selenium in dietary supplements using elemental speciation; Food Chem.; March; 218:313-20 (2017)
25)  Aguilar, F., et al.; Selenium-enriched yeast as source for selenium added for nutritional purposes in foods for particular nutritional uses and foods (including food supplements) for the general population; Scientific Opinion of the Panel on Food Additives; The EFSA J.; 766:1-42 (2008)
26)  Bugel, S., et al.; Absorption, excretion, and retention of selenium from a high selenium yeast in men with a high intake of selenium; Food Nutr. Res.; (2008) 
27)  Reyes, L.H., et al.; Selenium bioaccessibility assessment in selenized yeast after “in vitro” gastrointestinal digestion using two-dimensional chromatography and mass spectrometry; J. Chromatogr. A.; 1110(1-2):108-116 (2006)
28)  Larsen, E.H., et al.; Speciation and bioavailability of selenium in yeast-based intervention agents used in cancer chemoprevention studies; J AOAC Int.; Jan.-Feb.; 87(1):225-32 (2004)
29)  Food and Nutrition Board, Institute of Medicine, Selenium. Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. Washington, D.C.: National Academy Press; 284-324 (2000)
30)  Peeters, R.P. and Visser, T.J.; Metabolism of thyroid hormone; NCBI Bookshelf (2017)
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34)  Bose-O’Reilly, et al.; Mercury exposure and children’s health; Curr. Probl. Rediatr. Adolesc. Health Care; Sept.; 40(8):186-215 (2010)
35)  Grandjean, P., et al.; Cognitive defict in 7-year-old children with prenatal exposure to methylmercury; Neurotoxicology and Teratology; 19(6):417-28 (1997)
36)  Polanska, K., et al.; Selenium status during pregnancy and child psychomotor development – Polish mother and child cohort study; Pediatric Res.; 79(6):863-69 (2016)
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38)  Ralston, N.V. and Raymond, L.J.; Dietary selenium’s protective effects against methylmercury toxicity; Toxicology;  Nov.; 278(1):112-23 (2010)
39)  Cardoso, B.R., et al.; Effects of Brazil nut consumption on selenium status and cognitive performance in older adults with mild cognitive impairment: a randomized controlled trial; European J. Nutr,; Feb.; 55(1):107-16 (2016)
40)  Weil, M., et al.; Blood mercury levels and neurobehavioral function; JAMA; Apr.; 293(15):1875-82 (2005)
41)  Spiller, H.A., et al.; Severe elemental mercury poisoning managed with selenium and N-acetylcysteine administration; Tox. Comm.; 1(1):24-28 (2017)
42)  Joshi, D., et al.; Methylmercury toxicity: Amelioration by selenium and water-soluble chelators as N-acetyl cysteine and dithiothreitol; Cell Biochem. Funct.; June; 32:351-60 (2014)
43)  Wax, P.M.; Current use of chelation in American Health Care; J. Med. Toxicol.; 9:303-7 (2013)
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47)  Pellicore, L.S.; Department of Health and Human Services; July 8, 2008 Letter to Boyd E. Haley of CTI Science, Inc.; Regarding N,N’-bis(2-mercaptoethyl)isophthalamide (2008)
48)  Kieth, R.L., et al.; Utilization of renal slices to evaluate the efficacy of chelating agents for removing mercury from the kidney; Toxicol.; 116:67-75 (1997)
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50)  Gregus, Z., et al.; Effect of lipoic acid and biliary excretion of glutathione and metals; Toxicology Appl. Pharm.; 114:88-96 (1992)
51)  Cutler, A.H.; Comments by Andrew H. Cutler on the study by Gregus are found in Cutler’s bibliography of papers on ALA: “This is an excellent and useful paper. I suggest people get the actual paper and read it rather than relying on the abstract if they are going to draw conclusions about what they will or won’t do. This paper actually did have a large influence on determining the LA chelation protocol…”
52)  Cakatay, U., et al.; Postmitotic tissue selenium and manganese levels in alpha-lipoic acid-supplemented rats; Chem. Biol. Interact.; Feb.; 171(3):306-11 (2008)