Neurons and Exercise

Neurons and Exercise

Sunday, August 11, 2019

Arsenic Detox Using the Selenium Method


Arsenic Detox Using the Selenium Method
Arsenic (As) is an element found in the earth’s crust. Over 100 million people are exposed daily to toxic levels (greater than 50ppb) of arsenic in their drinking water1. There are two oxidized inorganic forms of arsenic that are both toxic: arsenite (As2O3) and arsenate (As2O5). Arsenite is 50 times more toxic that arsenate. Some organic metabolites of arsenite and arsenate, such as monomethylarsonate (MMA) and dimethylarsinate (DMA) are considered non-toxic. Arsenite’s toxicity primarily stems from its ability to inactivate up to 200 enzymes, some of which are involved with cellular energy pathways and DNA replication and repair1.
Arsenic enters the body primarily by being ingested, but can also be absorbed through the skin or inhaled1. The primary source of arsenic in the U.S. and worldwide is drinking water1. The urinary excretion of arsenic after ingesting a single 500mcg dose of arsenic as arsenite, DMA, or MMA has been studied as a function of time in human volunteers.   Excretion rate of arsenite was much slower than either DMA or MMA. After 4 days 46% of arsenite, 75% of DMA, and 78% of MMA had been excreted in the urine2.
Once ingested and absorbed by the body, arsenite is metabolized and excreted in the urine as 1/3 MMA and 2/3 DMA2.  Since both MMA and DMA have a shorter half-life in the body than arsenite and both MMA and DMA are considered non-toxic, any agent that facilitates the metabolism of arsenite to MMA and DMA will both detoxify arsenite3 and facilitate its elimination by urination2.
In 2006 it was shown that urinary selenium levels correlate with urinary arsenic levels in a study of 93 pregnant women3. In a prior study with adults, levels of DMA in the urine correlated positively with levels of selenium in the urine4.  In 2019 a case-control study of preschool children found that higher blood plasma selenium levels were associated with a higher percentage of DMA in their urine5. All of these human studies demonstrate that optimal selenium status helps to detoxify arsenic by conversion to DMA and thereby facilitate its elimination by urination. But even more importantly high plasma selenium has been found to lower the risk of developmental delay in pre-school children exposed to arsenic 5.
Supplements for Arsenic Detox
Maintaining high plasma selenium is best achieved with a daily seleneomethionine supplement because of its longer half-life (252 days) in the body than inorganic forms of selenium, such as selenite (102 days)6. Selenomethionine is also 50 to 100% more bioavailable than inorganic forms of selenium, such as selenite (SeO32-)6. In a study of 28 people (13 men and 15 women) taking 200mcg of selenomethionine daily for 2 years it was found after 9 months men had increased by 60% and women by 102% their plasma selenium as shown in Figure 17
 
Figure 1. Mean plasma selenium concentration, indicated with standard error bars, during 4 month baseline and over 28 months (mos) of selenomethionine supplementation (200mcg/day) in men (black boxes) and women (white boxes). The arrow indicates the start of selenium supplementation. Note that 158ppb is 2.0mmol/L of selenium.
The mechanism by which selenium enhances the conversion of arsenite to DMA involves both the enzyme AS3MT and reduced thioredoxin8.  AS3MT catalyzes the transfer of methyl groups from the amino acid derivative S-adenosyl methionine (a.k.a. SAM) to arsenite in order to make DMA. The selenium containing enzyme thioredoxin reductase regenerates reduced thioredoxin that is required for AM3MT’s methylation of arsenite. Since selenium deficiency inhibits AS3MT’s production of DMA, selenium supplements are beneficial for arsenic detox9. However, selenite inhibits AS3MT’s production of DMA in cultured human hepatocytes. This is another reason selenomethionine is a better choice than selenite for selenium supplementation10.
Supplements useful for converting arsenite to DMA for detox, in addition to selenomethionine, include: methyl folate (a.k.a. 5-methyl-tetrahydrofolate, 5-MTHF) and amino acid chelated zinc that both facilitate the production of SAM required for DMA biosynthesis. Recommended dosage is 400mcg per day of 5-MTHF and 25 to 30mg per day of amino acid chelated zinc.
Symptoms of Chronic Arsenic Toxicity
Epidemiology studies of people drinking water polluted with arsenic has revealed that arsenic is a causal factor of a number of pathologies.  Some of these pathologies are more prevalent in children than adults probably because arsenic negatively impacts brain development.  Symptoms of chronic arsenic toxicity include:
Children
·         Developmental Delay in Pre-School Children11
·         IQ Loss in Pre-school and Grade-school (3 to 5) Children12,13
Adults
·         Prostate12,13, Skin, Lung, Liver, Kidney, and Bladder Cancer16
·         Cardiovascular (Atherosclerosis), and Respiratory Disease1,17
·         Skin Thickening (Hyperkeratosis) of the Palms of the Hands and Soles of the Feet1
·         Diffuse Dark Spots on the Skin (Hyperpigmentation) 1
·         Low Neutrophil Count (Neutropenia) 1
·         Diabetes Mellitus1
·         Inflammation of the Kidneys (Nephritis) and Kidney Disease (Nephrosis)15
In 2001 the U.S. EPA lowered the arsenic limit in drinking water from 50ppb to 10ppb1. In 2014 IQ loss in children was observed at greater than or equal 5ppb of arsenic in drinking water from wells in Maine13. In 2017 a higher risk of prostate cancer in men was observed at greater than or equal 2.07ppb of arsenic in drinking water in Iowa14. Based upon this recent data the U.S. EPA’s limit should again be lowered from 10ppb to 2ppb. Until the arsenic limit in drinking water is lowered, selenium supplementation is recommended in those areas of the country and world where arsenic in drinking water is over 2ppb.
Arsenic Detox
Selenium supplementation can provide protection from chronic arsenic toxicity. Although the normal range of plasma selenium in adults is 70 to 150ppb (0.9 to 1.9mmol/L see Figure 1), levels of selenium above 150ppb (1.9mmole/L) have been found to provide protection from arsenic toxicity. High levels of plasma selenium (i.e. greater than 150ppb for adults) have been found to lower the risk of both arsenic-related developmental delay in pre-school children5 and arsenic-related premalignant skin lesions in adults17.
The selenium method of arsenic detox requires taking orally a selenomethonine supplement daily in order to increase plasma selenium to levels greater than 150ppb (1.9mmole/L – see Figure 1):
·         Children 0 to 3 years of age: 25mcg/day of selenomethionine
·         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: 200mcg/day
Supplements for human use are not regulated by the U.S. FDA. Because of this some supplement manufacturers have incorrectly labeled product that contains no selenomethionine or less than the amount stated on the label18-20. Therefore products with third party certification are recommended.  Certifying agencies include: Consumerlab.com, 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 gram8.
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 intake21, however only about 34% may actually be free selenomethionine after gastrointestinal digestion22.  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 specifictions for selenium-enriched yeast6.
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 selenomethionine23.
Manufactures of high purity 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 and 200mcg 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 124.
Table 1. Tolerable Upper Intake Level (UL) for Selenium24
Age  Group
UL (mcg/day)
Infants 0 - 6 months
45
Infants 6 - 12 months
60
Children 1 – 3 years
90
Children 4 – 8 years
150
Children 9 – 13 years
280
Adolescents 14-18 years
400
Adults 19 years and older
400

Selenium Data from Mammals other than Humans
The data presented so far in this description of the “Arsenic Method of Arsenic Detox” is entirely based upon human data.  But there is data from studies involving non-human mammals that may be relevant to humans.  There are two relevant discoveries:
1)      Selenium (Se) reacts with arsenic (As) and glutathione (GS) and then facilitates the elimination of arsenic as [(GS)2AsSe]- in the bile and feces of rabbits25-27, rats28, and hamsters29.  When sodium selenite or sodium selenate is mixed with arsenite in the required presence of glutathione and erythrocytes, [(GS)2AsSe]- is produced in rabbits and excreted by the liver into the bile and ultimately excreted in the feces25-27.   It was observed in rats that the administration of selenite significantly increased the amount of arsenic in rat bile28.  Thirty minutes after hamsters were injected with selenite and arsenite these metals were found to be concentrated as [(GS)2AsSe]- in the liver, gall bladder, and small intestine29. 

These experiments all involved sodium selenite or sodium selenate injection in non-human mammals and none of these experiments looked at the ratio and amounts of arsenic excreted in the urine as MMA and DMA versus arsenic excreted in the feces as [(GS)2AsSe]-.    More human data is needed before we can conclude that oral selenium supplementation safely enhances the formation and elimination of arsenic as [(GS)2AsSe].
 
2)      Lentils can contain high levels of bioavailable selenomethionine depending upon where they are grown (see Table 2)30,31.  In 2012 the use of a selenium rich lentil diet to prevent arsenic toxicity was proposed32.

Table 2. Selenium in Lentils Grown in 7 Key Lentil Producing Countries30,31
Country
Mean Se Concentration (mcg/kg)
Australia
148
Canada (Saskatchewan)
672
Moracco
28
Nepal
180
Syria
22
Turkey
47
U.S.A.
26
 The total selenium in Saskatchewan lentils ranged from 425 to 673mcg/kg and 86-95% of this selenium was selenomethionine with 5-14% selenate and a very small amount of selenocysteine31,33.

In 2013 two groups of rats drinking 40ppm arsenic water were fed either high-selenium Saskatchewan (SK) lentils or low-selenium U.S.A. (US) lentils.  The rats fed on SK lentils had significantly higher urinary and fecal arsenic excretion than did the rats fed on US lentils34.  In 2016 a similar study with mice drinking 200ppm arsenic in water concluded that a diet of SK lentils prevents arsenic-triggered atherosclerosis35.   

Lentils are a staple of the diet in Bangladesh where 45 million people are routinely drinking arsenic laden water. Soils in the Ganga-Nrahmaputra delta region of Bangladesh are naturally deficient in selenium32. This deficiency leads to crops and food that is deficient in selenium resulting in lower than normal plasma selenium levels in those eating only locally grown food.

 Would there be less pathology due to arsenic toxicity, if people in Bangladesh ate SK lentils? A study was proposed in 2016 to study two groups of 200 people each in Bangladesh. One group will be eating SK lentils and the other will be eating US lentils. Arsenic will be measured in the urine and stools and lipid profile, lung inflammation, and blood pressure will be measured36.  The results have not been published. 
Acute Arsenic Toxicity
When exposed to a large dose of arsenic during a relatively short time period you should seek immediate medical assistance.  The best indicator of recent ingestion (1-2 days) is the concentration of arsenic in the urine1.
References
1)      Ratnaike, R.N.; Acute and chronic arsenic toxicity; Postgrad Med. J.; 79:391-396 (2003)
2)      Buchet, J.P., et al.; Comparison of the urinary excretion of arsenic metabolites after a single oral dose of sodium arsenite, monomethylarsonate, and dimethylarsinate in man; Int. Arch Occup. Environ. Health; 48(1):71-9 (1981)
3)      Christian, W.J., et al.; Distribution of urinary selenium and arsenic among pregnant women exposed to arsenic in drinking water; Environ. Res.; 100:1165-122 (2006)
4)      Hsueh, Y.M., et al,; Determinants of inorganic arsenic methylation capability among residents of the Lanyang Basin, Taiwan; arsenic and selenium exposure and alcohol consumption; Toxicol. Lett.; 137(1-2):49-63 (2003)
5)       Su, C-T, et al.; Plasma selenium influences arsenic methylation capacity and developmental delays in preschool children in Taiwan; Environ. Res.; April; 171:52-9 (2019)
6)      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)
7)      Combs, G.F., et al.; Effects of selenomethionine supplementation on selenium status and thyroid hormone concentrations in healthy adults; Am. J. Clin. Nutr.; 89:1808-14 (2009) 
8)      Dheeman, D.S., et al.; Pathway of human AS3MT arsenic methylation; Chem. Res. Toxicol.; 27:1979-89 (2014)
9)      Pilsner, J.R., et al.; Associations of plasma selenium with arsenic and genomic methylation of leukocyte DNA in Bangladesh; Environ. Health Perspectives; Jan.; 119(1):113-8 (2011)
10)  Walton, F.S., et al.; Selenium compounds modulate the activity of recombinant rat AsIII-methyltransferase and the methylation of arsenite by rat and human hepatocytes; Chem. Res. Toxicol.; 16(3):261-5 (2003)
11)  Hsieh, R-L., et al.; Arsenic methylation capacity and developmental delay in preschool children in Taiwan; Int. J. Hygeine Environ. Health; July; 217(6):679-686 (2014)
12)  Hamadani, J.D., et al.; Critical window of exposure for arsenic-associated impairment of cognitive function in pre-school girls and boys: a population-based cohort study; Int. J. Epidemiology; 40:1593-1604 (2011)
13)  Wasserman, G.A., et al.; A cross-sectional study of well water arsenic and child IQ in Maine schoolchildren; Environ. Health; 13(23)1-10 (2014)
14)  Roh, T., et al.; Low-level arsenic exposure from drinking water is associated with prostate cancer in Iowa; Environ. Res.; 159:338-43 (2017)
15)  Lewis, D.R.; Drinking Water Arsenic: The Mallard County, Utah Mortality Study; arsenic exposure and health effects III; Proceedings of the third international conference on arsenic exposure and health effects; July 12-15 1998; San Diego, Cal.; P133-40 (1999)
16)  Rahman, M.M., et al.; Chronic arsenic toxicity in Bangladesh and West Bengal, India—a review and commentary; J. Toxicol. Clin. Toxicol.; 39(7):683-700 (2001)
17)  Chen, Y., et al.; A prospective study of blood selenium levels and the risk of arsenic-related premalignant skin lesions; Cancer Epidemiol. Biomarkers Prev.; 16:207-13 (2007)
18)  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)
19)  Gosetti, F., et al.; Speciation of selenium in diet supplements by HPLC – MS/MS methods; Food Chem.; 105:1738-47 (2007)
20)  Kubachka, K.M., et al.; Evaluation of selenium in dietary supplements using elemental speciation; Food Chem.; March; 218:313-20 (2017)
21)  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) 
22)  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):108-16 (2006)
23)  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)
24)  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)
25)  Gailer, J.; et al.; Identification of [(GS)2AsSe]-1 in rabbit bile by size-exclusion chromatography and simultaneous multielement-specific detection by inductively coupled plasma atomic emission spectroscopy; Appl. Organomet. Chem.; 16(2):72-5 (2002)
26)  Gailer, J.; et al.; Biliary excretion of [(GS)2AsSe]-1 after intravenous injection of rabbits with arsenite and selenite; Chem. Res. Toxicol.; 15:1466-71 (2002)
27)  Manley, S.A., et al.; The seleno bis(S-glutathionyl)arsinium ion is assembled in erythrocyte lysate; Chem. Res. Toxicol.; Apr.; 19(4):601-7 (2006)
28)  Levander, O.A., and Baumann, C.A.; Selenium metabolism. VI. Effect of arsenic on the excretion of selenium in the bile; Toxicol. Appl. Pharmacol.; 9(1):106-15 (1966)
29)   Ponomarenko, O., et al.; Selenium mediated arsenic excretion in mammals: a synchrotron-based study of whole-body distribution and tissue-specific chemistry; Metallomic; Nov.; 9(11):1585-95 (2017)
30)   Thavarajah, D., et al.; A global survey of effects of genotype and environment on selenium concentration in lentils (Lens culinaris L.): Implications for nutritional fortification strategies; Food Chem.; 125:72-6 (2011)
31)   Thavarahjah, D., et al.; High potential for selenium biofortification of lentils (Lens culinaris L.); J. Agric. Food Chem.; Nov.; 56(22):10747-53 (2008)
32)  Sah, S. and Smits, J.; Dietary selenium fortification: a potential solution to chronic arsenic toxicity; Toxicol. Environ. Chem.; Aug.; 94(7):1453-65 (2012)
33)  Thavarajah, D., et al.; Chemical form of selenium in naturally selenium rich lentils (Lens culinaris L.) from Saskatchewan; ; J. Agric Food Chem.; Nov.; 55(18):7337-41 (2007)
34)  Sah, S., et al,; Treating chronic arsenic toxicity with high selenium lentil diets; Toxicol. Appl. Pharmacol.; Oct.; 272(1):256-62 (2013)
35)  Krohn, R.M., et al.; High selenium lentil diet protects against arsenic-induced atherosclerosis in a mouse model; J. Nutr. Biochem.; Jan.; 27:9-15 (2016)
36)  Krohn, R.M.; A high-selenium lentil dietary intervention in Bangladesh to counteract arsenic toxicity: study protocol for a randomized controlled trial; Trials; 17:218 (2016)