Neurons and Exercise

Neurons and Exercise

Friday, September 6, 2019

High levels of Aluminum found in Brains of People with Alzheimer's - New study 2018


Aluminum in the Brains of those with Alzheimer’s Disease – Dennis N. Crouse
Prior Studies:
·         In 2005 Andrasi, et al. measured aluminum levels in specific brain regions (e.g. hippocampus, entorhinal cortex, and two areas of the frontal cortex) of three AD patients and 3 non-demented controls.  Compared to the controls there was a 2.6-fold to 6.8-fold higher aluminum levels in these regions of the AD brain1. In 2009 Fjell, et al., looking at 142 healthy controls and 122 people with AD, found that these same regions of the brain had the most atrophy in those with AD compared to controls2.
·         In 2011 Russina, et al, measured both aluminum and mercury in the brains of 28 histologically-confirmed cases of AD and 27 healthy controls. There was a four-fold higher level of aluminum in the hippocampus of the AD patients compared to the controls.  There was no difference in mercury levels3.
·         In 2017 Exley, et al. measured aluminum in the brains of 12 people diagnosed with familial AD.  Aluminum levels were in all cases higher than normal and in 5 of the 12 cases they were eight-fold higher than normal4.
These three studies involved measuring aluminum in a total of only 43 brains of people diagnosed with AD. Scientists who were still doubtful that the known neurotoxin aluminum is a causal factor of AD have called for a larger study measuring aluminum in more AD brains and controls and more studies demonstrating aluminum neurotoxicity at concentrations found at physiological conditions.
New Study:
A new study was published in 2018 by McLachlan, et al., of 186 autopsied brains taken from those diagnosed with AD and 53 controls.  The amount of aluminum in the temporal lobe (Brodmann areas A20-A22) was 6-fold greater in those with AD than the controls5.  This study has increased the total number of autopsied brains with AD having significantly above normal levels of aluminum to 229. It can now be concluded based upon the study of these 229 brains that higher than normal levels of aluminum are both a hallmark of AD and a causal factor of AD.  Particularly when coupled with Fjell’s work with 122 people with AD showing that the regions of the brain that are aluminum hot-spots also are same the regions with most atrophy in the brains of those with AD2.
What is perhaps most interesting about McLachlan’s paper is the author’s ambivalence toward aluminum chelation therapy for removing aluminum from the brains of those with AD.  It is pointed out that “… once bound, aluminum is particularly refractory to chelation-based removal …”.   But then the author goes on to describe some of his own work6, first reported in 1991, by saying “Interestingly, the only clinical trial specifically designed to remove aluminum from the brains of live control and 48 AD patients using the trivalent metal chelator desferrioxamine (DF) resulted in halving the rate of neuro-degeneration and cognitive decline in the DF-treated group”.   
This ambivalence toward chelation therapy evidently is due to the authors being unaware of the work published in 2006 by Exley, et al., who stabilized and in some cases reversed the cognitive decline in 15 AD patients by using silica rich drinking water for 12 weeks to facilitate aluminum excretion7,8.  The authors must also be unaware of the work published in 1998 by Belles, et al. showing that silica rich drinking water given to rats for just 5 weeks dramatically lowered aluminum levels in 6 regions of the brain (e.g.  cortex, hippocampus, striatum, cerebellum, thalamus, and olfactory lobe)9.  Even aluminum in bone was over 90% removed in just 5 weeks by silica rich drinking water9.   
References
1.      Andrasi, E., et al.; Brain Al, Mg, and P contents and Alzheimer-diseased patients; J. Alzheimer’s Dis.; 7:273-84 (2005)
2.      Fjell, A.M., et al.; One-year brain atrophy evident in healthy aging; J. Neurosci.; Dec.; 29(48):15223-31 (2009)
3.      Rusina, R., et al.; Higher aluminum concentrations in Alzheimer’s disease after Box-Cox data transformation; Neurotox. Res.; 20, 329-33 (2011)
4.      Mirza, A., et al.; Aluminum in brain tissue in familial Alzheimer’s disease; J. Trace Elements in Medicine and Biology; Mar.; 40:30-36 (2017)
5.      McLachlan, D.R.C., et al.; Aluminum in neurological disease – a 36 year multicenter study; J. Alzheimer’s Dis. Parkinsonism; 8: 457 (2018)
6.      McLachlan, D.R.C.; et al.; Intramuscular desferrioxamine in patients with Alzheimer’s disease; The Lancet; 337(8753):1304-8 (1991)
7.      Exley, C., et al.; Non-invasive therapy to reduce the body burden of aluminum in Alzheimer’s  disease; J. Alzheimer’s Dis.; Sept., 10(1):17-24 (2006)
8.      Davenward, S., et al.; Silicon-rich mineral water as a non-invasive test of the ‘aluminum hypothesis’ in Alzheimer’s disease; J. Alzheimer’s Dis.; 33(2):423-30 (2013)
9.      Belles, M., et al.; Silicon reduces aluminum accumulation in rats: Relevance to the aluminum hypothesis of Alzheimer’s disease; Alzheimer’s Dis. Assoc. Disorders; 12(2):83-7 (1998)

Sunday, August 11, 2019

Arsenic Detox Using the Selenium Method


Arsenic Detox Using the Selenium Method (8/20/2019)
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 inhaled or absorbed through the skin1. 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 their plasma selenium by 60% and women by 102% 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 AS3MT’s methylation of arsenite. Since selenium deficiency inhibits AS3MT’s production of DMA and thereby inhibits arsenic detox, 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. Note that 48% of the North American population has genotypes resulting in lower than normal levels of 5-MTHF and should be taking daily supplemental 5-MTHF. 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 have 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 Diseases1,17
·         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 on arsenic in drinking water should be immediately lowered to 2ppb.
Many regions of the world, including the U.S., currently have over 2ppb of arsenic in drinking water and this may be leading to an increased incidence of cancer as a recent clinical trial unexpectedly discovered.  The Nutritional Prevention of Cancer Trial was a double-blind, randomized, placebo controlled, clinical trial designed to test whether selenium supplementation would prevent non-melanoma skin cancer. It involved 1,312 people living in the Eastern United States who had previously been diagnosed with non-melanoma skin cancer. The trial ran for 13 years from 1983 to 1996 and unexpectedly revealed that by taking a daily selenium supplement (200mcg/day selenomethionine derived from baker’s yeast) there was a 25% decrease in total cancer incidence a 52% decrease in prostate cancer incidence, a 26% decrease in lung cancer incidence, a 54% decrease in colorectal cancer incidence, and a 41% decrease in total cancer mortality18.
Ironically, in spite of this trial revealing that selenium supplementation lowers the incidence of cancer, this trial has been used as an example of selenium causing cancer19. This is because the trial also found selenium supplementation might elevate the risk of squamous cell carcinoma and non-melanoma skin cancer.  However, the authors of the study admit that this data indicating selenium as a carcinogen “hovers at the margin of statistical significance” 18.  This data may also be suspect because the people selected for the trial had all been diagnosed with non-melanoma skin cancer prior to the trial and were more prone than normal to have a relapse. Because of this trial and recent research on selenium’s role in facilitating the detoxification of the known carcinogen arsenic, inhibition of cell proliferation, and tumor cell invasion, selenium is now considered to be an anticancer nutrient20.
Until the arsenic limit in drinking water is lowered to 2ppb, selenium supplementation is recommended in those areas of the country and world where arsenic in drinking water is over 2ppb. Either lowering the drinking water limit to 2ppb of arsenic or implementing selenium fortification through diet and supplementation would significantly lower cancer rates in adults and developmental delay and IQ loss in children.
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 selenomethionine 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 their product as containing a specific amount selenomethionine, when actually it contains no selenomethionine or less than the amount stated on the label21-23. Therefore products with third party certification are recommended.  Certifying agencies include: Consumerlab.com, NSF International, U.S. Pharmacopeia (USP), and UL.  There are commercial and university 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 and found to meet EFSA specifications. 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 intake24, however only about 34% may actually be free selenomethionine after gastrointestinal digestion with the rest being other organoselenium species25.  Pharma Nord packages tablets of Bio-SelenoPrecise® as 50, 100, and 200mcg of selenomethionine. Pharma Nord selenomethionine has been checked by two laboratories having 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 in Table 1 of EFSA’s report wherein Bio-SelenoPrecise® is product 3a, 3b, and 46.
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 selenomethionine26.
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 Selenium SeLECT® 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 127.


Table 1. Tolerable Upper Intake Level (UL) for Selenium27
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 in Food for Arsenic Detox
The amount of selenium in food depends upon both the type of food crop and where the crop is grown.  For instance lentils can contain high levels of selenium depending upon where they are grown (see Table 2)28,29.  The problem with using selenium in food for detox is the wide variability of selenium concentration in the food unless it is grown in soil that is naturally highly enriched with selenium or fertilized with selenium.  In the case of lentils the variability in selenium concentration is from 22mcg/kg in Syrian lentils to 672mcg/kg in Saskatchewan (SK) lentils28,29. Unfortunately it is difficult to purchase SK lentils because the location where they are grown is usually not indicted on the package. 
Table 2. Selenium in Lentils Grown in 7 Key Lentil Producing Countries28,29
Country
Mean Se Concentration (mcg/kg)
Australia
148
Canada (Saskatchewan)
672
Morocco
28
Nepal
180
Syria
22
Turkey
47
U.S.A.
26

Brazil nuts have been found to have high levels of selenomethionine, selenothionine, and selenocystine30. However, the problem with selenium variability in food is even worse with Brazil nuts than lentils.  In a random sample of 20 Brazil nuts it has been found that the selenium concentration varied from 0.816mcg/gr to 1390mcg/gr31. Since the mean weight of a single Brazil nut is 4 grams, it is possible by eating just one Brazil nut to either exceed the upper tolerable selenium intake level for adults (400mcg/day - see Table 1) by 1400% or consume only 0.8% of the upper tolerable selenium intake level for adults32.  This variability in selenium concentration makes Brazil nuts an unreliable daily selenium supplement. The variability of selenium in SK lentils is less than in Brazil nuts, making SK lentils a more reliable daily selenium supplement.
Selenium in Fertilizer for Arsenic Detox
Although crops take selenium from the soil and thereby slowly deplete the soil of selenium, in general no effort is made to replace or enhance the soil by fertilization with selenium.  Due to extremely low selenium intake (25mcg/day) by the people of Finland in the 1970’s, the government made a decision to require selenium crop fertilization. Starting in 1984 Finland became the first county in the world to use sodium selenate as a fertilizer ingredient for food crops33. Currently all crop fertilizers used in Finland contain 15mg of selenium per kilogram. Unfortunately Finland is still the only country to implement this country-wide measure33. 

After implementation of this program selenium concentration in spring cereals has increased 15-fold and the mean increase of selenium in beef, pork, and milk has increased 6-, 2-, and 3-fold, respectively. This has resulted in the mean human plasma selenium concentration of the Finish people increasing from almost deficiency (0.9mM/L) to normal selenium status (1.4 mM/L)33. 
Although the normal range of plasma selenium in adults is 0.9 to 1.9mmol/L (see Figure 1), levels of selenium above 1.9mmole/L have been found to provide protection from arsenic toxicity. Levels of plasma selenium greater than 1.9mmole/L 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. Therefore in order to see less developmental delay and less cancer, Finland’s 15mg/kg selenium addition to fertilizers should be more than doubled in order to increase the Finish population’s mean human plasma selenium concentration to 2mmole/L.  
Selenium in SK Lentils for Arsenic Detox

The total selenium in Saskatchewan (SK) lentils ranges from 425 to 673mcg/kg and 86-95% of this selenium is selenomethionine with 5-14% selenate and a very small amount of selenocysteine29,34.  In 2012 the use of a selenium rich lentil diet to prevent arsenic toxicity was proposed35. This proposal was first tested in 2013 with two groups of rats drinking 40ppm arsenic water that were fed either high-selenium 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 lentils36.  In 2016 a similar study with mice drinking 200ppm arsenic in water and eating SK lentils concluded that a diet of SK lentils will prevent arsenic-triggered atherosclerosis37.  

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 selenium35. 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 the people of Bangladesh ate SK lentils? In 2016 it was proposed to study two groups of 200 people each in Bangladesh with one group eating SK lentils and the other eating US lentils. It was also proposed that arsenic would be measured in the urine38.  The results were published in 2019 and the group eating SK lentils had significantly increased excretion of the urinary arsenic metabolite DMA at 6 months compared to the control group who ate lentils with low selenium content39.  The group eating SK lentils also had less respiratory disease (e.g. asthma and allergies) than the control group39. This is the first human study showing that eating high selenium food can increase arsenic excretion and improve health in the presence of continued arsenic exposure. 
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.
(GS)2AsSe- Excretion in Some Mammals
The data presented so far in this description of the “Arsenic Detox Using the Selenium Method” is based primarily upon human data.  But there is data from studies involving some mammals that may be relevant to humans.  Selenium (Se) reacts with arsenic (As) and glutathione (GS) and then facilitates the elimination of arsenic as a seleno-bis(glutathionyl) arsinium ion [(GS)2AsSe-] in the bile and feces of rabbits40-42, rats43, and hamsters44. 
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 feces40-42.   It was observed in rats that the administration of selenite significantly increased the amount of arsenic in rat bile43.  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 intestine44. 
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-. If this is a major mode of arsenic elimination in humans, then there would be an equivalent elimination of selenium and an oral selenium supplement would be required to prevent a selenium deficiency due to chronic arsenic exposure.
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)  Duffield-Lillico, A.J., et al.; Selenium supplementation and secondary prevention of nonmelanoma skin cancer in a randomized trial; J. National Cancer Inst.; Oct.; 95(19):1477-81 (2003)
19)  Sun, H-J., et al.; Arsenic and selenium toxicity and their interactive effects in humans; Environ. Internat.; 69:148-58 (2014)
20)  Zeng, H., and Combs, Jr., G.F.; Selenium as an anticancer nutrient: roles in cell proliferation and tumor cell invasion; J. Nutr. Biochem.; 19:1-7 (2008)
21)  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)
22)  Gosetti, F., et al.; Speciation of selenium in diet supplements by HPLC – MS/MS methods; Food Chem.; 105:1738-47 (2007)
23)  Kubachka, K.M., et al.; Evaluation of selenium in dietary supplements using elemental speciation; Food Chem.; March; 218:313-20 (2017)
24)  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) 
25)  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)
26)  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)
27)  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)
28)  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)
29)  Thavarahjah, D., et al.; High potential for selenium biofortification of lentils (Lens culinaris L.); J. Agric. Food Chem.; Nov.; 56(22):10747-53 (2008)
30)  Vanderheide, A.P., et al.; Characterization of selenium species in Brazil nuts by HPLC-ICP-MS and ES-MS; J. Agric. Food Chem.; 50205722-5728 (2002)
31)  Infante, H., et al.; Current mass spectrometry strategies for selenium speciation in dietary sources of high-selenium; Anal. Bioanal. Chem.; 382:057-67 (2005) – data from ref. 29
32)  Thomson, C.D., et al.; Brazil nuts: an effective way to improve selenium status; Am. J. Clin. Nutr.; 87:379-84 (2008)
33)  Alfthan, G., et al.; Effects of nationwide addition of selenium to fertilizers on foods, and animal and human health in Finland: From deficiency to optimal selenium status of the population; J. Trace Elem. Med. Biol.; 31:142-7 (2015)
34)  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)
35)  Sah, S. and Smits, J.; Dietary selenium fortification: a potential solution to chronic arsenic toxicity; Toxicol. Environ. Chem.; Aug.; 94(7):1453-65 (2012)
36)  Sah, S., et al,; Treating chronic arsenic toxicity with high selenium lentil diets; Toxicol. Appl. Pharmacol.; Oct.; 272(1):256-62 (2013)
37)  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)
38)  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)
39)  Smits, J.E., et al.; Food as medicine: Selenium enriched lentils offer relief against chronic arsenic poisoning in Bangladesh; Environ. Res.; June; 176:108561 (2019)
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