Selenium Yeast Gras.PDF

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20482 Jacklight LaneBend OR 97702-3074

mcquategras-associates.com541 678-5522

September 3,2008

Dr. Robert L. MartinFood and Drug AdministrationCenter for Food Safety Applied Nutritionoffi e of Food Additive Safety HFS-200)5100 Paint Branch ParkwayCollege Park, MD 20740-3835

Y:

Re: GRAS Notification for High-Selenium Yeast

Dear Dr. Martin:

On behalf of Cypress Systems, Inc. of Fresno, CAI we are submitting for FDA review a GRAS notification for High-Selenium Yeast. The attached documentation augments the information that had previously been identified as GRN 241.Questions raised and clarification requested by the agency during April 2008 telephone discussions as managed by Dr.Carrie Hendrickson McMahon have been thoroughly addressed in this resubmission.

In previous discussion with FDA personnel in December, 2007, the question was raised as to the possible applicability ofSection 912 of the Food, Drug, and Cosmetic Act. The response to this inquiry is reproduced below for your conveniencein applying t to the subject submission.

Section 912 Considerations.commerce if such foods contain an added FDA-approved drug or an unapproved) added drug for which substantial clinicalinvestigations have been instituted and for which the existence of such investigations has been publicly disclosed. Theamendment goes on to state that such prohibition does not apply if the drug in question was marketed in food before thedrug received FDA approval and if such marketing occurred prior to the institution of any substantial clinical investigationsinvolving that drug.

Section 912 prohibits the introduction or delivery for introduction of foods into interstate

Application to Hinh-Selenium Yeast. The high-setenium yeast that is the focus of the GRAS notification is not subject tothe Section 912 prohibition since the high-selenium yeast was introduced nto foods 1) prior to the initiation of clinical trials,and 2) well in advance of the public release of information regarding clinical investigations with this material.

Dr. Lon Baugh developed the high-selenium yeast in 1979-1980 while working with Dixie Yeast which was aquired byFleischmanns Yeast in 1985), and shortly thereafter the high-selenium yeast was sold in the US as a nutritionalsupplement through Nutrition 21. In the mid-l980s, Professor Larry Clark at the Arizona Cancer Center located at the

University of Arizona began the multi-center clinical investigation nto the possible cancer prevention benefits of high-selenium yeast nutritional supplement, in concert with several colleagues who constituted the Nutritional Prevention ofCancer Study Group. The randomized, double-blind, placebo-controlled clinical investigations mplemented under Clarksdirection extended over several years, during which time there were no public releases of the results, in part to preservethe integrity of the double-blinded nature of the investigation. In late December of 1996, the results of the Clark study were

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published in JAMA Clark, et all 1996), AMA, 276 24), 1957-1963). By this time, high-selenium yeast had been in the USmarketplace as a dietary supplement for over 15 years.

Conclusion. Since the high-selenium yeast is not an-FDA approved drug and since it was introduced into the USmarketplace as a dietary supplement prior to the initiation of clinical investigations as to its cancer prevention applications,and furthermore that there were no public disclosures of the clinical trials until late 1996, Section 912 of the Food, Drug,and Cosmetic Act does not prohibit the addition of GRAS designated high-selenium yeast into foods that would enter

interstate commerce in the US.f additional information or clarification is needed as you and your colleagues proceed with the review, please feel free to

contact me via telephone or email.

We look forward to your feedback.

Sincgrely,

Robert S. McQuate, Ph.D.CEO Co-FounderGRAS Associates, LLC20482 Jacklight LaneBend, OR 97702-3074

mcquat e@qr as- associ at es. comwww.gras-associates.com

541 -678-5522

Enclosure: GRAS Notification High Selenium Yeast in triplicate)

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GRAS ASSESSMENT

OF

HI H SELE N U M YEAST

Food Usage Conditions for General Recognition o f Safety

For

CYPRESS SYSTEMS INC

Evaluation By

Robert S McQuate Ph.D.

Richard C Kraska Ph.D. D BT

September 2 2008

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GRAS Assessment for Cypress Systems. IncSelenoExcellC3

TABLE OF CONTENTS

I GRAS EXEMPTION CLAIM 4

A Claim of Exemption from the Requirement for Premarket Approval Pursuant toProposed 2 1 CFR 170.36 c) 1) 4

B Name and Addressof Notifier 4C Comm on Name and Identityof the Notified Substance 4D Conditions of Intended Use in Food 5E Basis for GRAS Determination 5F Availability of Information 5

I1 DESCRIPTION OF INGREDIENT 6

A Background on Selenium and SelenoExcellB 6B Chemical Name and Comm on or Usual Name of Subject Material 10C Chemical Composition 10D SelenoExcellB Stability 11E Method of Preparation of SelenoEx cellB 12F Finished Product Specifications and Physical Characteristics 13

1) SelenoExcellB Specifications 132) Physical Characteristics 133) Yeast Composition and Performance Comparisons 14

G Intended Dietary Use 141) Intended Food Categories in W hich SelenoEx cellB W ill Be Used 142) Intended Technical Effect to be Achieved in Foods 16

I11 SCIENTIFIC EVIDENCE OF SELENO EXCELLB SAFETY 17

A Introduction 17B Hum an Experience and Testing 18

1) Sum maries of Safety Review s and Key Scientific Articles 182) On-Going Selenium Clinical Trials 243) Effects of Long-Term Selenium Suplementation and Type2 Diabetes 274) ADM E and Bioavailability 285) Genotoxicity 296) Reproductive Effects 307) Allergenicity 30

C Animal Testing 311) Background Considerations 312) Cancer Studies 323) Reproductive and Teratogenic Effects 33

IV EXPERT PANEL ASSESSMENT AND DISCUSSION OF COM POSITE SAFETYINFORMATION FOR SELENOEXCELL@ GRAS STATUS 35

V CONCLUSIONS 4

VI REFERENCES 41

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TABLE OF CONTENTS continued

APPENDIX A--Cypress Systems Production Quality Procedures for SelenoExcellB.. 45

APPENDIX B-Certificate of Analysis for SelenoExcellB.. 5

APPENDIX C-Absence of Diabetes Indicators with Selenium Supplementat ion.. 52

APPENDIX D - Expert Panel Credentials 6

LIST OF TABLES

Table 1 Claimed Favorable Health Effects Ascribed to Selenium 7

Table 2 Actual Selenium Intakes and Recommended Selenium Intakes 8

Table 3 US Reference Daily Intake RDI) and Tolerable Uppe r In tak e Levels UL)for Selenium 9

Table 4 Selenium Forms in Commercially Available SelenoExcellB. 11

Table 5 Specifications for SelenoExcellB.. 13

Table 6. Proposed Food Categories for Use of SelenoExcellB 15

Table 7. Summary of Selected Human Testing Studies with SelenoExcellB, Othe r

High-Selenium Yeast Products or Selenomethionine.. 25

Table 8 Summary of Expanded Clinical Studies with SelenoExcellB and Othe rHigh-Selenium Yeast Products. 9

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G U S Assessment for Cypress Systems, Inc.SelenoExcellB

I GRAS EXEMPTION C LAIM

A. Claim of Exemption From the Requirement for Premarket Approval Pursuant to Proposed

2 CFR 170.36 ~) 1)

High-selenium yeast Saccharomyces cerivisiae),meeting the specifications described below, has beendetermined to be Generally Recogn ized As Safe GRA S), in accordance with Section 201 s) of theFederalFood Drug, and Cosmetic A c t This determination was made by ex perts qualified by scientific trainingand experience; it is based on scientific procedures as described in the following sections; and theevaluation accurately reflects the cond itions of the ingredients intended use in foods.

Signed:

Robert S . McQuate, Ph.D.GRAS Associates, LLC20482 Jacklight LaneBend, OR 97702-3074 Date:

B Name and Address of Notifier

Cypress Systems, Inc.*3381 North Bond Avenue, Suite 101Fresno, CA 93726

As the notifier, Cypress Systems, Inc. accepts responsibility for the GRAS determination that has beenmade for high-selenium yeast a s described in the subject notification; consequently, high-selenium yeastmeeting the conditions described herein is exempt from pre-market approv al requiremen ts for foodingredients.

C. Comm on Nam e and Identity of the Notified Substance

High-selenium yeast; also see Sections 1I.B and 1I.C.

See 6 FR 18938 17 April 1997).

rCypress Systems, Inc. CSI) produc es and sells SelenoExcellQ9,a high-selenium yeast product.

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GRAS Assessment for Cypress Systems,IncSelenoExcell@

D Conditions of Intended se in Food

High-selenium yeast is intended to be added to the following food categories at a level yielding pgselenium per serving: baked products; non-alcoho lic beverages; breakfast cereals; grain products pastas;milk products; processed fruitd fruit juices; processed vegetabledveg etable juices; comm ercial soupssoup mixes; and medical foods. Foods that are intended for infants and toddlers, such a s infant formulas orfoods formulated for babies or toddlers, are excluded from the list of intended food uses o f the subject high-selenium yeast.

E

Pursuant to 21 CFR 170.30, high-selenium yeast has been determined to be GRAS on the basis ofscientific procedures a s discussed in the detailed description provided below.

Basis for the GRAS Determination

F Availability of Information

The data and information that serve as the basis for this GRAS Notification w ill be sent to theUS Food andDrug Administration FDA ) upon request or will be available for review an d copying at reasonable times atthe offices of GRA S Associates, LLC, located at 20482 Jacklight Lane, Bend,OR 97702-3074.

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GRAS Assessment for Cypress Systems, Inc.SelenoExcellB

11 DESCRIPTION OF INGREDIENT

A Background on Selenium and SelenoExcell@

The role of selenium in biological systems is both intriguing and complex. Regarding health and

physiological implications, selenium was first recognized as having toxic properties in animals in the mid-1900s and was later determined to be a trace mineral that is an essential human nutrient, as discussed byCombs Combs, 1997). An impressive collection of studies has noted the cancer prevention characteristicsof certain forms of selenium Combs, et al., 2001 Uden, 2004). In particular, epidemiological studiesinvolving subjects from 27 countries reveal an inverse relationship between selenium intake and theincidence of certain types of cancer Whanger, 2004). This conclusion was strongly supported by a 1990Finnish study that investigated nearly 40,000 subjects over more than a decade and concluded that seleniumintakes that are too low may place subjects at increased risk of some cancers Knekt, et al., 1990).

Selenium deficiency has also been observed in humans. Keshan disease, an endemic cardiomyopathy, hasbeen reported in selenium-deficient regions of China. Kashin-Beck disease, a musculoskeletal disorder,

muscular pain and muscular and cardiac dysfunction were noted in some patients, while others withinsufficient selenium status have experienced compromised immune function and viral infection EuropeanCommission, 2000, Expert Group, 2003).

Selenium occurs naturally in a variety of common foods, including cereals such as corn, wheat andsoybeans and other foods such as broccoli, onions, garlic, eggs, seafood, and Brazil nuts Expert Group,2003). Various foods with quantitative information on their selenium contents are compiled elsewhereNational Institutes of Health, 2006, Rayman, 2004, Rayman, 2008, Rayman, et al., 2008). Cereal grains

and enriched yeast contain selenomethionine as the predominant form of selenium whereas Se-methylselenocysteine is the major selenocompound found in onions, garlic, and broccoli Whanger, 2004Whanger, et al., 2000).

Seleniums natural occurrence on the earths surface is highly variable, with higher levels of seleniumfound in portions of the Great Plains in the US and selected regions of China. Other areas, such as thesouthern island of New Zealand and parts of China and Europe, are characterized as having particularlylow levels of selenium. Both geology and geography have historically played appreciable roles inachieving dietary sufficiency of selenium since the selenium content varies depending on the seleniumcontent of the soils where plants are grown. Locations where the soils are deficient in selenium tend toyield foods that have low levels of selenium which contribute toward a selenium deficiency status inhuman^ ^

Inorganic forms of selenium, such as sodium selenite, sodium hydrogen selenite, and sodium selenateInfante, et al., 2005), that are found in soils are taken into plants where they are converted into

organoselenium species such as selenocysteine, selenomethionine, selenium-methylselenocysteine nd y-glutamyl Se methylselenocysteine Ip, et al., 2000, Bird, et al., 1997,Whanger, 2004, Rayman, 2008,

With advanced and efficie nt food distribution sys tems that are in place in theUS and in other advanced countries worldwide),there is diminishing regionalizationof foods where compositional contents reflect the local or regional growing conditions.The increasing nationalization of theUS food supply is tending to level out the selenium deficiencies and excesses thatotherwise wouldbe manifes ted by geological and geographical considerations. Evenso, there remains variability in seleniumcontent in foods grown in different geographic regions, and this especially remains the case in less developed nations wherediets reflect more localized growing circu mstanc es. Dietary deficits and excesses are more likely to occur in these areasRayman, 2008). 9

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GRAS Assessment for Cypress Systems, Inc.SelenoExcell6)

Rayman, et al., 2008). Selenome thionine and selenocysteine are considered to be the most common form sof selenium contained in foods (Expert Group, 2003 European Food Safety Authority, 2008). Uponingestion by m an and animals, such organoselenium forms become incorporated into a number o f importanselenoproteins and en zymes which, am ong other functions, yield an antioxidant capability to help reducecellular damage due to free radicals (National Institutes of Health, 2006).

According to Com bs, it was no t until 195 7 that indications of a positive hea lth role for selenium wereestablished, and additional studies conducted during the intervening years have demonstrated convincinglythe essentiali ty of ~e le n iu m .~y the 1970s, it was conclusively determined that selenium played anessential role in the enzyme glutathione peroxidase which participates in the an tioxidant protection of cells(Combs, 1997). By 2003, over 30 selenoproteins were identified (Expert Group , 2003). Table 1 listsseveral health consequences o f consum ing adequate to somewhat elevated am ounts of dietary andsupplemental selenium.

Table 1 Claimed Favorable Health Effects scribed to Selenium

Reduced risks of certain typ es o f cancers (a), (b), (c)Provide metabolic d efense aga inst oxidative stress (a), (b), (c)Support male prostate function (a)Reduce menopausal symptom s in females (a)Provide hormonal regulation of energy metabolism (b)Enhance immune response (a), (c)Enhance fertility reproduction (c)Reduce inflammation (c)Alleged protection against bird flu (d)Treat HIV infection (c), (e), 0Maintain intracellular redox state QImprove skin disorders Q

Alleged benefit to elderly wom en in inhibiting lipid peroxidation (g)Protect against exposu re to heavy metals (a), (h)

(a) Schauss, 2006.(b) Combs, 2000.(c) Rayman, 2004.(d) http://www.nutraingredients,com /news/ng.asp?n=66089 m=lNIE227 c=fjbaapnlrdryleu.(e) http://www.healthy.net /scr/interview.asp?PageType=Interview ID=198.f ) Expert Group,2003; (g) http://www. nutraingredients.com/news/ng.asp?n=64658 m= NI ED 19 c=fjbaapnlrdryleu.

(h) http://www. nutraingredients.com/news/ng.asp?n=65560 m=1NIE202 c=fjbaapnlrdryleu

Since selenium is a normal constituent of both plant- and animal-derived foods, it has been consumed forgenerations world-wide (C omb s, 1 997). Rayman com piled estimated selenium intake levels for individuals

in various countries along with the minimum recommended selenium intake levels for adults in certain

The micronutrient status of selenium has been well-established, and from a historical standpoint, as noted in Table 1, variouspurported health benefits have been linked to dietary selenium. As noted in Sections111 and IV. health benefits associatedwith dietary selenium continue to be a topic of much interest to the scientific community. Numerous studies have beenconducted and continu e to be inve stigated in the search for positive health outc omes, In noting this, it is understood that foodingredient safety determinations, such asGRAS determinations, are based solely on safety or risk considerations andnot onrisWbenefit analyses Tho se studies addressing benefits, such as the cancer prevention trials addressed by Clark, et al., 1996and various subsequent or continuing investigations, are included becauseof the safety co nsiderations that can be derivedfrom them.

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GRAS Assessment for Cypress System s, Inc.SelenoExcellC3

countries. These data are consolidated in Table 2 Raym an, 2004; Raym an, 2008; Raym an, et al., 2008).Recommended Intakes have been established to be no less than30 pg/day per person and is morecommonly in the 50-70 pg/day range. Actual selenium intake by individuals across several countriesreveals adequacies in Japan, Ven ezuela, and Canada while other nations, especially those in Europe,consum e suboptimal levels falling in the range of 10-67 pg /day Raym an, 2004 Raym an, 2008). Chinais interesting in that it has regions where thereis a severe selenium deficiency while other regions havehigh selenium concentrations i n the soil. Consequently, selenium intake da ta in C hina have been estimatedto fall in the range of 7-4990 pg/day.

AustraliaAustriaBelgiumCanadaCzech RepublicChinaCroatiaDenmarkEC Scientific CommitteeFranceGermanyItalyJapanNetherlandsNew ZealandNordic Countries

PolandSerbiaSlovakiaSwedenSwitzerlandUnited KingdomUnited StatesVenezuelaWorld Health Organization

Table 2 Actual Selenium Intakes and Recommended S elenium Intakesa

Geographic Location Selenium Intake Per Person Recomm ended Intakes pgram dday )pgramdd ay) Males Females

57 748

28 6198 241 0 - 2 5

7 99027

38 47

29 335

104 19939 755 80

3 03038

70

106

31 -38

29 39

200 350

85 70

70 7055 55

30 70 30 7

55 5560 5

30 7055 55

55 0 45

30 70

65 5550 40

30 7 30 7075 6055 55

40 30

From Rayman, 2004 and references cited therein; also see Rayman, 2008 .

In the US, the Dietary Reference Intake for selenium, which is viewed as an adequate intake, has beenestablished for male and fem ale adults to be 55 pg/day per person Food and Nutrition Board, 2000), whilethe average intakes are nearly double that amount. Schrauzer also reports that selenium intake for theaverage adult in the US is 80-1 50 pg/day, exceeding by a factor of abou t2 the adequate intake amounts inthe US Schrauzer, 2001). Furthermore, the Tolerable Uppe r Intake Levels ULs) in the US to bediscussed in more detail in Section IV) for adult males and females was established to be400 pg/day Foodand Nutrition Board, 2000). See Table3 for more detail on the Dietary Reference Intakes and TolerableUpper Intake Levels in theUS.)

OOOQII

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GRAS Assessment for Cypress Systems Inc.SelenoExcell@

Along with the docum entation that selenium deficiencies exist in partsof the world it has also been well-

range of acceptable selenium intakes below which there are adve rse health consequen ces due to seleniumdeficiencies and above which selenium toxicity is observed.

established that selenium can be toxic when consum ed at higher levels. Therefore we note that there is

Table 3 US R eference Daily Intake RDI) and Tolerable Uppe r Intake Levels UL) for Seleniuma

Infants0-611107 - 1 2 m o

Children1 - 3 y4 - 8 y

Males9 - 1 3 y14 - 18 y1 9 - 3 O y31 -5Oy50-7Oy> 70 y

Females9 - 1 3 y14 - 18 y1 9 - 3 O y31 -5Oy5 0 - 7 O y> 70 y

Pregnancy1 8 - 5 O y

Lactation< 1 8 ~ - 5 0 y

1520

2030

405555555555

405555555555

4560

90150

280400400400400400

280400400400400400

60 400

70 400

a Extracted from Food and Nutrition Board 2000.

Understanding the nutritional and toxicological ramificationsof any element dependson the particularchemical forms of that element along with their relative quantities and possible chemical interactions.

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GRAS A ssessment for Cypress Systems, Inc.SeIenoExcellCO

Therefore, assessing the app ropriate dietary intake levels of selenium requ ires consideration of the actualselenium levels and the form(s) of selenium to be ingested. Seleno ExcellB isa high-selenium yeast andserves as the primary focus of this e~ a lu a ti o n .~ven so, the technical informationon inorganic seleniumand other readily available form s of this trace mineral, especially selenom ethionine, contributes appreciablyto the subject safety assessment. One of the complexities to be considered in assessing safe dietary levelsof selenium involves identifying the chemical forms o f selenium that are present (Ud en, et al.,998 &Raym an, et al., 2008). In fact, Bird, et al., unequivocally state that the nutritional bioavailability, toxicity,and cancer chemopreven tive activities of selenium have been found to be species-dependent (Bird, et al.,1997),and this was reinforced more recently by Rayman and co-workers (Raym an, 2008& Rayman, et al.,2008). Furthermore, the metabolic conversions of the different selenium fo rms are of interest in thisevaluation, as are the differing degrees o f bioavailability.

B Chemical Name and Com mon or Usual Name of the Subject Material

As reported in Section I.C., high-selenium yeast is the comm on name of the notified substance, andSelenoExcellB High S elenium Yeast is the comm ercial name of the subject material for which theGR S

evaluation has been undertaken. As discussed m ore fully in the following section, SelenoExcellB is amixture of four chemically characterized organoselenium forms which account for just over85 of theavailable selenium. Selenomethionine is the predominant form of selenium in the mixture.

C Chemical Com position

SelenoExcellB and other commercial selenium-enriched yeasts have been investigated by Uden andcolleagues at the University of Massachusetts to ascertain their respective chem ical compositions. Resultsof these studies have been reported recently (Uden, et al., 2004& Uden, et al., 1998 . Infante, et al., havereviewed analytical strategies and procedures with a particular focus on selenium forms within complex

mixtures such as are found in high-selenium yeasts, high selenium garlic, high selenium onions, and Brazilnuts (Infante, et al., 2005& Raym an, et al.,2008).

Uden , et al., and Infan te, et al., describe treatment of the subject materials with proteolytic enzymesfollowed by extraction procedures before applying the rigorous detection m ethods to yield the tabulatedresults. A combination o f procedures---fluoracidic ion pairHPLC with a n inductively couple plasma massspectrometer, along withGC erivatization linked with atomic emission detection---was employed.

Table 4 identifies the selen ium forms and amounts found in SelenoExceIlQ3 a s studied by Uden andcolleagues. The study also reports the presumed absence of otherknown organoselenium forms that havebeen found in other high-selenium yeast products. Selenomethionine was show n to be the predominant

selenium species in SelenoExcellB, as was the case with all other high-selenium yeast products tested. Itwas also noted that inorganic selenite was present in very low amounts(-0.1 ), and this would beexpected from the water washing steps noted in the manufacturing process as described in Section 1I.E.Method of Preparation. Replicate determinations with SelenoExcellB demonstrated a high degree ofreproducibility (Uden, et al, 2004).

Once it was established that supplementing the diet with selenium had the potential to impart improved health, different formsof selenium became commercially available. Besides SelenoExcellB, other high-selenium yeasts and other organoseleniumforms that are produced in Canada, Europ e, and the US, are available, as are inorganic selenium salts. The chem icalcompositions vary, depending on the manufacturer/supplier (Rayman, 2004). 1 3

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GRAS Assessment for Cypress Systems, Inc.SelenoExcelKB

Nearly 15 of the selenium content in SelenoExcellB has not been characterized. This aspect canconceivably have a bearing on the safety assessment of the subject commercial selenium mixture.Comparable findings were observed with all of the high-selenium yeast products that were tested. Of thesix different comm ercially available high-selenium yeast products tested compositionally by Uden, et al.,the total selenium accounted for ranged from a low o f67 to high of 88 . Raym an has explained thatthis observation is due to the challenges with inherent analytical limitations including variable extractiontechniques (Rayman,2004).

Table 4. Selenium Forms in Comm ercially Available SelenoExcell@'

Selenium forms Percentage

SelenomethionineSelenitey Glutamyl Se methyl Se cysteineSe adenosyl Se homocysteine

Se-lanthionineSe-methyl-Se-cysteineSe-cystathionineSe-cystineSe-cysteineSelenomethionine selenoxide or its hydrate)Methaneseleninic acid

840.10.50.5

nd/nrnd/nrnd/nrnd/nrnd/nrn d n rnd/nr

Sum of Identified forms 85.1

nd not detected ; nr not reported

From Uden, et al., 200 4 Rayman, 2004.

D SelenoExcellB Stability

While there are no indications that the subject material is unstable during normal conditions based o ninternal quality assurance records, the ques tion of high-selenium yeast stability was recently raised byUden , et al., who conducted compositional testing of the test materials that had been used by C lark, et al.,in the 1O year cancer clinical testing (Clark, et al, 1996). This highly regarded clinical testing utilizedSelenoExcellB as the adm inistered formof selenium that yielded favorab le clinical results. According toUden, et al, the tabletedform of SelenoExcell@ was stored at room temperature for mo re than ten years6,and testing results revealed that substantial amoun t of selenomethionine s elenox ide hydrate was present.Since this component---presumed to be an oxidation product---was unreported prior to the extended periodof time in uncontrolled sto rage, it is apparent that some conversion o f selenomethionine had occurred, atleast over an extended periodof storage without well-controlled storage cond itions (Uden, et al.,2004).How ever, there is no reason to expec t that this has any significant relation to safety.

1 4

Considering that the actual clinical trial lasted ten years and the results were published in1996, actual samples tested couldvery well have been twenty years old w hen the speciation testing was conducted.

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E Method of Preparation of SelenoExcellB

Demirci Pometto published details on the means of producing organically-bound-selenium yeast viacontinuous aerobic fermentation (Demirci Pometto, 1999). The process utilizes Saccharomycescerevisiae as the yeast into which inorganic selenium, as Na2Se03, is incorporated. The so-calledcontinuous fermentation utilizes a medium with minimal sulfur and methionine levels to enhance thedegree of selenium incorporation into the mother yeast. The production principles described by DemirciPometto portray the fundamental continuous fermentation process that is utilized by CSI in producingSelenoExcellQ3. Rayman also discusses the production processes for various selenium-enriched yeasts andthe quality and compositional features resulting from such preparations (Rayman, 2004). SI describes itsparticular production process and QNQC program in summary sheets that are found in Appendix A. Keycomponents are noted below:

The method utilizes standard baker s yeast strains---Saccharomyces cerevisiae---in all of itsprod~ct ion.~

The aerobic fermentation is precisely controlled to maintain yeast growth, nutrient feed streams,dissolved oxygen, pH temperature and the presence of alcohol. Such control was found to yieldoptimal growth conditions with the proper uptake of selenium.

Na2Se03 is added to the fermentation vessel at specific times to maximize selenium incorporationinto the yeast.

The resulting primary grown high protein yeast, which is fortified with biologically boundselenium, is separated from its growth medium, washed, and held in refrigerated storage to assurecell viability. The washings are effective in removing free minerals.

The chilled mineralized yeast cream is inactivated when pasteurized through a high temperaturesterilization system to achieve human food grade microbial standards, after which the material isspray dried to yield a uniformly homogeneous dry powder.

As part of its QNQC program, CSI collects composite samples during the spray drying phase andduring packaging for nutrient and microbial analyses. CSI utilizes Silliker Laboratories for allnutrient and microbiological testing of SelenoExcellB.

The resulting SelenoExcellQ3 s 99.9 organically bound with residual inorganic selenium levels of0 1 Y r less; the controlled process yields minimal batch-to-batch variations.

CSI reports that this particular yeast is considered w ithin the industry to be GR AS. In fact, selected dried yeasts, includingSaccharomyces cerivisiae are approved food additives as noted in 21 CFR 172.325. Othe r food additive regulations including21 CFR 172.590 and 172.898 authorize additives that are derived fromSaccharo myces cerivisiae. No FD A documentationwas located that explicitly ide ntifies the subject yeast to beGRAS except for a recent designation that the genetically modifiedstrain, ECMoO 1, was conc luded tobe GRA S. It was determined (seehttp://www.cfsan.fda.gov/-dms/opa-enzy.htm1 hat theenzyme, invertase, when derived fromSaccharo myces cerivisiae was considered by FDA t o be GRA S based on an FDAopinion letter issued in the early 1960s.

7

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G U S Assessment for Cypress Systems, Inc.SelenoExcellB

F. Finished Product Specifications and Physical Characteristics

(1) SelenoExcellB Specifications

The specifications shown in Table 5 were developed by CSI. These food grade specificationswere established in concert with the National Cancer Institute s Cancer Prevention Division whowanted a standardized composition of high-selenium yeast before selenium-derived materialswould be accepted for NCI-sponsored clinical trials. CSI specifications for SelenoExcellB asshown in Table 5 were accepted as part of the 998 Clinical Trial Agreement executed betweenCSI and the Cancer Prevention Division.

Table 5. Specifications for SelenoExcellB

Species: Saccharomyces cerivisiaeItems:

SeleniumProtein

Phosphorus (measured asP205MoistureExtraneous materialInorganic selenium

Microbiology:SalmonellaE ColiS aureusBacillus cereusTotal coliformsTotal plate countY east/mold

1,140 1,260 ppm49-55 o

2.0 .4o

2.5 7.5 Ynegative-0.1%

negativenegativenegativenegativeless than 0.3/gramless than lO/gramless than lO/gram

Heavy Metals:Lead less than &gramArsenic less than pg/gramCadmium less than 1 pg/gramMercury less than 1 &gram

The production process for high-selenium yeast involves sufficient water washings to yield negativeresults when testing with methylene blue indicator. Such an endpoint correlates with 0.1% freeinorganic selenium.

Appendix B contains a typical Certificate of Analysis for SelenoExcellB.

(2) Physical Characteristics

Color: tanBulk density: 0.6515 g/mLParticle size: through 60 mesh 100%

through 100 mesh 100%

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(3) Yeast Composition and Performance Comparisons

Both the chemical composition and yeast performance parameters were compared to establish that theunmodified yeast and the yeast with incorporated selenium that complies with the specificationsdetailed in Table 5 were virtually the same except for the significant presence of the selenium in placeof sulfur (see below) within the yeast.

According to Dr. Lon Baugh who developed the method of producing SelenoExcellQQ, he selenium-yeast and the standard bakers yeast can be compared as noted below (Baugh, 2008):

No significant differences were observed in the yeast growth rates, respiration rates,fermentation rates, or morphology, and the selenium-yeast is normal in all structural andmetabolic functions;

The single chemical difference noted when comparing the two yeasts is the reduction in totalsulfur in the protein fraction of about 14-20 of the standard bakers yeast; the mass balancedata following selenium speciation explains the substitution of selenium for sulfur in methionineand cysteine and their anabolic or catabolic forms;

Comparative gassing power rates, a direct yeast fermentation performance test, for theselenium-yeast and the standard bakers yeast were very similar or were equal, supporting theinterpretation that the selenium-yeast has the normal complement of proteins, enzymes, and co-enzymes needed to digest the sugar at rates comparable to the normal yeast; and

The high-selenium yeast must have the selenium content maintained at about 1325 pg/g of yeastor less to meet this performance criterion. Selenium-yeast containing selenium in place ofsulfur yielding selenium content of 1400 2000 pg/g of yeast did diminish the gassing powerrate, thereby indicating some alteration or loss of functionality in the yeast due to metabolicchanges or low-level toxicity. At even higher selenium levels, such as at 2400 pg/g of yeast, theyeast fails to digest the sugar, and no fermentation is observed.

G Intended ietary Use1 ) Intended Food Categories in Which SelenoExcellB Will Be Used

FDA has defined several food categories in 21 CFR 170.3(n). Those categories listed below,excluding products intended for use by infants or babies and toddlers---such as infant formula or babyand toddler foods (cereals, juices, etc.)---constitute the designated food categories in which CSIintends to add SelenoExcellB, along with the anticipated use levels and maximum numbers of dailyservings.

The estimated maximum number of servings per day of selected foods within each of the designatedfood categories is found in Table 6. It is difficult to forecast intake of specially formulated foods

because statistical data on normal intake do not distinguish specially formulated foods from others inthe same category. Moreover, some individuals will seek out such foods because of the specificfortification while others may choose other products because of possible extra costs resulting fromfortification. These estimates attempt to reflect a consumption pattern that probably exceeds theindividual consumption level.

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Table 6 Proposed Food C ategories for Use of SelenoExcellB

Food Category Intended Food Products Daily Servings Se Use Lev eldS ervin g Total Daily Se Exposure

21 CFR 170.3 n) l)21 CFR 170.3 n) 3)

21 CFR 170.3 n) 4)21 CFR 170.3 n) 23)21 CFR 170.3 n) 31)21 CFR 170.3 n) 35)21 CFR 170.3 n) 36)21 CFR 170.3 n) 40)

baked products 4beverages, nonalco holic 3

breakfast cereals 3grain products & pastas 2milk products 3processed fruits/fruit juice s 2processed vegetabledveg juices 2soups & soup mixes, commercial 2

Total Anticipated D ietary Selenium E xposure Per Adult Per Day from Designated F ood Categories: 4 pg

medical foods 20 5Pg 100 Pg

In particular, it seems to be unlikely that consumers would consistently choose an average of 20

servings per day with high-selenium yeast incorporated. Nevertheless, we have chosen this scenario toensure that potential exposure is not underestimated. This upper bound estimated daily intake, or EDI,of 100 pg of selenium from SelenoExcellQ3 will be compared to acceptable daily intakes, or ADIs, asdiscussed in Section IV.

To validate the assertion that the proposed numbers of servings per food category as depicted in Table6 are not underestimated, the USDA Continuing Survey of Food Intakes by Individuals was consultedUSDA, 1996). While the USDA food intake categories are not aligned precisely with the FDA food

categories found in Table 6 useful information for comparison purposes was extracted. Consideringeach of the designated food categories discussed below other than commercial soups and soup mixes),pertinent USDA food survey data were located and were found to support the view that the proposed

dietary consumptions to the subject high-selenium yeast constitute an exaggerated dietary exposure.

Baked Products, Breakfast Cereals, and Grain Products & Pastas. The USDA survey reveals that theaverage US consumer eats 6.7 servings of grain products per day. Three FDA food categories found inTable 6---baked products, breakfast cereals, and grain products and pastas---fall under the USDA grainproducts category. The total number of servings proposed in Table 6 for these FDA food categories is9, a figure that exceeds the actual consumption level reported by USDA.

Non-Alcoholic Beverages. FDAs description of non-alcoholic beverages is limited to soft drinks,coffee substitutes, and selected specialty beverages; a total of 2 daily servings was proposed in Table6. The corresponding USDA survey reports a daily consumption of non-alcoholic beverages

excluding teas and coffee) of 342 grams or about 12.2 ounces. Using 12 ounces as the serving sizefor such beverages, the average consumer ingests 1 O serving of non-alcoholic beverages per day. TheTable 6 projection is 2 times greater.

0 0 0 0 1 8Milk Products. Milk products as described by FDA include flavored milks and milk drinks, dry milk,toppings, snack dips, spreads, weight control milk beverages, and other milk products. This foodcategory does not include frozen dairy desserts, whole, low fat, or skim milk, or cheeses whichcomprise a major component of the dairy group as surveyed by USDA. The USDA survey reports that1.5 servings of dairy per day are consumed by the average US consumer, whereas Table 6 proposes a

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total of 3 servings of milk products per day for a narrower selection of dairy foods---an over estimateof more than 2.

Processed Fruits and Fruit Juices. The FDA category of processed fruits and fruit juices includes juicepunches, -ades, and juice concentrates, whereas the USDA survey also includes fresh fruits. Evenwith the inclusion of fresh fruits in the USDA food survey, it was reported that a total of 1.5 servingsof fruit are eaten daily by the average US consumer. Table 6 allows for a total of 2 servings of theprocessed fruits and fruit juices, again demonstrating the absence of underestimating consumerexposures as summarized in the table.

Processed Vegetables and Vegetable Juices. As with processed fruits and fruit juices above, the FDAfood category of processed vegetables and vegetable juices falls within a more broadly defined USDAfood category of vegetables since the USDA survey, which reports a daily consumption of 3.3 servingsper person, includes all vegetables and vegetable juices---fresh and processed. The estimated dailynumber of servings of processed vegetables and vegetable juices found in Table 6 is 2 Thus, theproposed consumption of processed vegetables and vegetable juices probably constitutes anexaggerated consumption level if one were to factor out the fresh vegetables and vegetable juices.

Commercial SOUPS nd Soup Mixes. USDA survey data on likely daily exposure to commercialsoups and soup mixes could not be located for a comparative analysis of consumption as suggested inTable 6 Nonetheless, the estimated consumption of 2 servings of soup on a daily basis would likelybe an overestimate for the average consumer since soups do not commonly seem to be consumed on aday in and day out basis by most individuals.

Medical Foods. If those individuals on a medical foods diet were to typically consume 20 foodservings of medical foods per day with the use levelkerving of SelenoExcellQ providing 5 pg ofselenium, the total daily dietary exposure of selenium would be 100 pg---an amount that is equal to thehighest amount considered to be generally recognized as safe. This estimate assumes that the medical

foods would functionally replace 20 servings of traditional foods from the diets of those requiringmedical foods. Because dietary management of such individuals is under the supervision of aphysician, intake of SelenoExcellB would be monitored to ensure safe use.8

2) Intended Technical Effect to be Achieved in Foods

SelenoExcellQ, when added into the foods listed in Section II.G. I), is to function as a nutrientsupplement as defined by FDA in 2 1 CFR 170.3 0) 20).

It is intended that the addition of SelenoExcellQ into food categories described above would facilitateavoidance of selenium deficiency to this essential micronutrient.

Rayman has recently pointed out that s ome caseso cardiomyopathy in the West have been reported with subjectswho are on intravenous nutrition that contain inadequate selenium content in their inf isio n solutions Rayman,2008).Consequently, incorporationo high-selenium yeast in selected medical foods would be desirable.

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111 SCIEN TIFIC EVIDE NCE OF SELENOEXCELLB SAFETY

A Introduction

In addressing selenium toxicities, Reid, et al., reference accounts o f toxicities du e to selenium ingestion

dating to the time of Marco Polo Reid, et al., 2004). The earlier reports of physiological manifestations ofselenium in the mid-1900s focused on anima l toxicities Com bs, 1997), and it was not until 1957 that theessential role of selenium in maintaining health was first docum ented Haw kes, et al.,2003 Combs,1997). Epidem iological data that surfaced in 19 69 first suggested an inverse correlation between cancermortality and geographic distribution of selenium in forage crops Com bs, 1997). Interest in the healthconsequences of selenium in animals and humans accelerated since the 1970s, and we now have anextensive collectionof scientific and medical information to draw upon a s the topic o f safety and toxicity isconsidered further.

An intriguing aspect of selen ium ingestion, as with other essential micronutrients, is the fact that negativehealth consequences are associated with both selenium deficiencies and excesses, whereas there is a rangeof intermediate selenium ingestion levels that is deemed essential for maintaining good health. Man hasconsumed selenium as partof the norm al diet dating to antiquity because of the natural presence ofselenium in various plant and anim al foods. The intake levels have historically been h ighly variable sincethe natural presence of selenium in soils around the world isknown to be highly variable. Hence , we noteboth the existence of selenium deficiencies and excesses.

several health conditions, including:CSI has compiled a foundational collection of scientific publications that add ress the role of selenium with

Selenium and overall cancer;Seleniums effect on prostate cancer;Selenium and lung cancer;Selenium and colon cancer;Selenium and thyroid regulation;Heart disease and its association to selenium;Selenium and bioavailability;HIV; andMale sperm motility.

8 2We can see from this co llection of scientific articles that selenium intake levels that are 2-4 times the USReference Dietary Intake reduce the incidence of selected types of can cers.

Schrauzer pointed out that the practice o f selenium supplem entation, including the use o f high-seleniumyeasts, increased in the mid-1970s Schrauzer, 2001.) This trend o selenium supplementation has

Section I1.A summarizes the variable consumption levelsof selenium from many countries around the world; note thatseveral official governmental assessments have designated recommended daily levels intended to prevent deficiencies.In May/June, 2008, an updated scientific literature review was conducted by Dr. MarkE. Whitacre, CSIs COO and Presidentof Operations. Whitacre, w ho was formally trained as a nutritional biochemist at Cornel1 University under the direction ofDr. G. F Combs, Jr., has selenium-specific research credentials in addressing the health consequences of selenium ingestionin humans and anima ls. The updated scientific literature review augments the earlier, foundation al scientific studies referredto above.

1

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continued, and several selenium supplements are presently available in theUS marketplace (Rayman,2008). From a historical perspective, we see that selenium has been a natural part of man s diet---albeit invariable and only sem i-quantified amounts (see Table 2)---and that supp lementation has increasinglybecome part of man s diet.

The incorporation of high-selenium yeast into specific foods as the leve ls designated in Table 6 is intendedto reduce/eliminate Se deficien cies in the US diet while also avoiding sustained dietary excesses. In otherwords, the proposed actions with high -selenium yeast will assist in avoid ing the extrem es as depicted in theU-shaped dose-response curve.

What are the clinical manifestations of selenium toxicity or selenosis? Symp toms of selenosis include:gastrointestinal upset; hair loss; derm atitis; mottled teeth; hypersalivation; white, blotchy and b rittle nails;garlic breath; fatigue; irritability; changes in selected biochemical param eters; and neurolog ical damage(National Institutes of Health, 2006, European Comm ission, 2000, Expert Com mittee,2003 Nuttal, 2006,FDA, 2008, EFSA, 2008).

It has been reported that a selenium intakeof 250,000 pg as a single dose, or multiple doses of 27,000-3 1,000 pg, result in acu te toxicity as demonstrated by theknown selenosis symptoms (EuropeanCom mission, 2000). In his review of human cases of selenium poisoning, Nuttal reported two instances ofselenosis that occurred because o f superpotency of selenium-containing su pplem ents. In the first case, thetablets contained 500- 1000 times the labeled amount, and in the second c ase, the selenium content wasestablished to be3 1,000 pg per tablet rather than the declared amo unt of 150 pg per tablet (Nuttal, 2006).In 2008, acute toxicity due to ingestion of superpotent dietary supplements resulted in4 cases of hum anselenosis that were reported to FDA (FDA, 2008).

According to FDA regulations, safety assessments that yield GRA S determinations can be based onscientific procedures or such determinations can be established through experience with common use infood prior to January 1, 1958. While we have unequivocal evidence regarding the long-term con sumption

of selenium by man that pre-dates 1958, this GRAS assessment relies primarily o n scientific proceduresand associated human and animal studies conducted over the past 40+ years. Furthermore, there existsalarge body of information dealing directly with human consumption of selenium. Those studies andreviews addressing the safety and toxicity manifestations of selenium , with a particular focus on the high-selenium yeasts, SelenoExcell@, and selenomethionine, are discussed below.

B Hum an Experience and Testing

(1) Summaries of Safety Reviews and Key Scientific Articles

A number of individuals and organizations, including three E uropean groups and the U S EnvironmentalProtection Agency, have undertaken detailed evaluations of the safety of selenium as a dietarycomponent. The published reviews have addressed safety and toxicity of selenium , including high-selenium yeast form s, based on generally available primary scientific literature. The original studiesthat are comm only cited in considering selenium safety in humans include the works o f Yang andcoworkers, Longnecker and coworkers, and Clark and coworkers (Yang, et al., 1983; Yang, et al, 1 989;Yang Zhou, 1994; Longnecker, et al., 1991; Clark, et al., 1996).

*

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European Commission In 2000, the Scientific Comm ittee on Foo d, working und er the auspices ofThe European Com mission's Health Consum er Protection Directorate-General, issued a report thataddressed the tolerable upper intake level of selenium (European Com mission, 2000). This evaluationincluded determining the actual intake levels of selenium in their various fo rms for various Europeancountries while also considering key scientific parameters that have an impact on overall safetyconsiderations. Metabo lism with bioavailability and physiological functions of selenium wereaddressed in the con text of ascertaining daily requiremen ts for the sub ject mineral. The report alsoacknowledged that selenium d eficiency was a particular concern for many populations, includingseveral European populations. The evaluation focused principally on adverse and toxic effects linkedwith selenium intake.

Acute toxicity was noted with the inorganic salts of selenium and with selenomethion ine. At doses of250,000 pg as a single do se or m ultiple doses of 27,000-3 1,000 pg, a cute toxicity was noted withclassical symptoms of selenosis. How ever, no serious cases of selenium toxicity were recorded.

Human exposures to selenium in different forms were discussed, and the results from several of theoriginal studies have been compiled into Tab le 7. Selected studies will be discussed more fully below.

Daily dosages ranged from a low o f 32 pg to nearly67 pg. More comm only, the daily dosagesconsidered tended to fall around 200 to 600 pg. The exposures were as short as weeks while otherslasted for years. Evidence of selenosis or selenium intoxication was absent except for the highestexposure groups.

The following conclusions that support a determination of dietary selenium safety were offered:

no data exist to suggest that selenium forms used in foods are carcinogenic;genotoxicity was detected in n v tro and n v vo systems but only at toxic doses that donot reflect nutritionally appropriate intakes; andno evidence w as found for teratogenicity in humans (or macaque m onkeys).

It was also concluded that the m inimum daily dietary intake sufficient to cause selenosis is about 1200pg. In fact, there were no clinical signs of selenosis in humans with a daily selenium intake of 850 pg.Interestingly, individuals with symptoms of selenosis when consuming 913 pg/day recovered fromselenosis when their mean intakes were reduced to 8 19 pg/day. Stud ies where daily Se intakes werefound to be 239 pg and 2 90 pg revealed no signs of toxicity.

Upon considering the accumulated information, the Commission indicated that the Lowest ObservedAdverse Effect Level (LOAEL ) for selenium would be 900-1000 pg/day since no clinical signs ofselenosis were reported for individuals with a daily intake of 850 pg. The Comm ission determined theNo Observed Adverse Effect Level (NOAE L) to be 850 pg based principally on the work of Y ang andcolleagues (Yang, et al, 1983; Yang, et al., 1989; Yang Zhou, 1994). The NOA ELof 850 pg/daywas reduced by an uncertainty factor of3 in yielding a Tolerable Upper Intake Level (UL) of 3 00 pg.

The Com mittee, in mak ing this determination, reported that the 300 day figure covered seleniumintake from all sources of food, including supplements. This particular Se level is compatible with thefindings of Clark, et al., who failed to observe any signs of selenosis over the course of a 10+ year study

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with 200 pg of high-selenium yeast supplementation, along with about 100 pg of selenium coming fromthe diet Clark, et al., 1996).

The Committee stated that the UL of 300 pg/day also applies to pregnant and lactating women since nodata suggest that other life-stage groups have increased susceptibilities to this selenium intake.Furthermore, children were not found to be at increased risk. Consequently, the UL was adjusteddownward for children in direct proportion to their body weights.

The following conclusion was offered by the Committee:

The Committee found sodium selenate, sodium selenite, and sodium hydrogen selenite acceptablefor use in food for particular nutritional uses, but did not find other forms of selenium acceptable onthe basis of current data. Therefore, the UL of this report relates only to the selenium compoundsfound acceptable and, in addition, to selenium naturally present in food.

The Committee did not extend its conclusion that the UL of 300 pg/day would apply to high-seleniumyeasts.

Rayman 2004. Rayman undertook a thorough review of the literature on high-selenium yeasts toassess its overall human safety. This was undertaken because of the findings by the EuropeanCommittee that did not extend the conclusions of safety of selenium at a level of 300 pg/day beyond theselenate and selenite forms to the high-selenium yeast forms. The Rayman evaluation took intoconsideration known levels of selenium consumption, biosynthesis and metabolism of the selenium-enriched yeasts, manufacturing methods with quality control procedures, speciation of the subjectyeasts, toxicity studies, and human intervention studies. Many of the studies considered are listed inTable 7.

In her review of the various studies, Rayman pointed out that the individual studies are consistent with

a NOAEL of 19 pg/day, the agreed-upon figure that was embraced by the European Committee and bythe Expert Group as outlined below. Other safety conclusions were offered:

the selenium-yeast supplement is without toxic effects even after chronic dosages at 3

there is no evidence that the high-selenium yeast supplementation causes a continuing rise intissue selenium as had been hypothesized;selenium-yeast used at 200,300,400, and even 800 pg/day for lengthy periods of time upto 12 years at the 200 pg/day dosage) were without indication of toxic effects; andhigh-selenium yeast is a safe, bioavailable form of selenium that mimics foods of seleniumwhich is useful as a precursor for selenoprotein synthesis and as a human anticancer agent.

pg/day;

European Food Safety Authority 2008. The European Food Safety Authority EFSA) was asked toprepare a scientific opinion on the safety and bioavailability of selenium-enriched yeast as a source forselenium when added to foods and nutritional supplements for nutritional purposes for the generalpopulation. The subject safety conclusion was limited to high-selenium yeast that is produced usingsodium selenite as the selenium source. This evaluation expands the safety assessment by the EuropeanCommission in 2000 that offered its finding on dietary selenium safety with its UL of 300 pg/day thatdid not extend to high-selenium yeast forms.

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EFSA recognized that selenomethionine accounted for60-85 of the total selenium species in thehigh-selenium yeast, and selenocysteine w as the next most abundant species which accounted for about2-4 of the total selenium species, It was noted that selenomethionine is readily absorbed from thegastrointestinal tract, that itis readily bioavailable, and that selenomethionine and other organoseleniumspecies tend to be 1.5 2 times more bioavailable than the inorganic forms o f selenium.

Repeated dietary exposure to high-selenium yeasts, as well as other dietary selenium sources, yieldsplasma and tissue levelsof selenium that reach a steady-state level within ab out 2-4 months. Theselenium levels do not con tinue to increase indefinitely, thereby mitigating concerns with seleniumtoxicity due to tissue accumulation of particularly high levels.

EFSA observed that the increased bioavailability of selenium from organ ic sou rces of selenium as withthe high-selenium yeasts did not translate to increased toxicity for the organic selenium species.Animal test results were cited as documentation that the toxicity was found to be lower than that ofinorganic selenite or selenate. This position was h rth er supported with results from clinical studieswith selenium-enriched yeast where no evidence of toxicity w as observed following selenium intakes ofup to 343 pg/day which extended over a period of 4 years.

The EFSA Panel reported that the highest long-term chronic dietary intakes of selenium withoutreported toxicity is abou t8 pg/day, while noting that prolonged intakes of seleniumat 1 pg/dayor higher did trigger adverse reactions. Similarly,a mean daily chronic intake of75 pg/day did notinduce selenosis.

Upon considering all of the accumulated information on high-selenium yeast, including bioavailability,metabolism, and toxicity of the subject material and selenomethionine, the Panel concluded that thehigh-selenium yeast when used in foods (including food supplements) for particular nutritionalpurposes and when co nsumed at levels up to100 pg/day does not presenta safety concern. ThePanel cautioned, however, that dietary augmentation with selenium at levels of 200 pg/day in addition

to dietary intakes occu rring naturally from foods could result in individua ls exceeding the TolerableUpper Intake Level of 30 0 pg/day.

Rayman 2008 Rayman et al 2008. In her ongoing evaluation into the roles of selenium onhuman health, Rayman has explored additional avenues to provide a more refined understanding intothe complexities potentially impacting an understandingof the optimal selenium intakes. Whileacknowledging that both selenium deficiencies and excesses can be detrimental, the questionof optimaldietary intakes between these extremes can be affected by several important variables. The number o ffactors that has a bearing o n the effects of dietary selenium makes it difficult to ascertain what seleniumlevels would be of greatest value while avoiding adverse experiences.

Natural variations in dietary intake as a consequence of foods being grown in different geographicvariations was recognized asa contributing factor since this influen ces baseline dietary selenium levels.Selenium content also varies among different foods, and the manner in which foods are cooked can alsoaffect the selenium availab le from the diets. An individuals unique health status will also have abearing on that individuals need for dietary selenium. Along with the amount of selenium ingested,the particular selenium spec ies consumed im pacts ones selenium status due to variability inbioavailabilities of different selenium species, a position echoed by others (Zeng Com bs,2008). Itwas noted that selenomethionine is the predominant selenium species present in high-selenium yeast(see Table 4), and Rayman reported that it is not very toxic to cells in culture nor to animals nor to

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humans, nor is there any ev idence to support the allegation that organic fo rms of selenium are moretoxic than inorganic forms Rayman , et al., 2008).

In recognizing the complexities associated with the above, Rayman commented that care should beexercised in supplementing the diets with selenium Rayman, 2008).

Food and Nutrition B oard 2000 Under the umbrella of the US National A cademies of Science, theInstitute of Medicines Food and Nutrition Board , as part of its broader m ission of providingquantitative assessments of various nutrients to benefit the health and well-being of Am ericans andCanadians, has unde rtaken its review of pertinent scientific literatureo selenium to provide itsrecomm endation for Dietary Reference Intake DRI), and the Tolerable Upp er Intake Levels UL).

As seen in Table 3, the selen ium DRI fo r adults is55 yg/day and the UL was determined to be 400Pg/daY*

Environmental Protection Agency 2006. As part of its Integrated Risk Information System IRIS),EPA evaluated the available health information on selenium. The assessm ent provides an oralReference Dose RfD) which is an estimate of a daily exposure to the human population includingsensitive subgroups) that is likely to be w ithout an appreciable risk of deleteriou s effects during alifetime.

EPA reported the LO AEL to be 1261 yg/day with the NOAEL of 853 yg/day, figures that are consistentwith the conclusions by others. The RfD was calculated by apply ing an uncertainty factor or3 to theNOAE L to account for sensitive individuals, yielding 5 y g k g o f body weight/day or about300 yg/dayfor a 6 kg adult.

Expert Group on Vitamins and Minerals 2003. The Department of H ealth in the United Kingdom ,working through the Medicines and Healthcare Products Regulatory Agency, convened an expert

comm ittee of independent expe rts to assess the Safe Upper Levels for various vitamins and minerals.Selenium was one o f the m inerals considered.

Along with a sum mary o f pertinent background information o n seleniums natural occurrence in foods,its chemistry, physiological functions, and pharm acokinetic characteristics, the safety and toxicityaspects were addressed in som e detail. Animal testing data will be presented in Section 1II.C.

Human exposures to selenium in various forms served as the principal focus o f this Committee, andthose individual studies that were considered by the Com mittee are incorporated in Table7 and aresumm arized elsewhere in Section 111. A s was done by the European Com mission, the dietary seleniumexposures were reviewed in an attempt to ascertain the LO AEL and NOA EL that would serve as the

basis to establish a Safe Upper Level for selenium.

Predictably, and as was the case with the European Commission, studies published by Yang andcolleagues, along with Longnecker, et al., and Clark, et al., were viewed as pivotal Yang, et al., 198 9,Yang Zhou, 1994, Longnecker, et al., 1991, Clark, et al., 1996).

The Expert Group calculated the estimated maximum selenium intake value from food and supplementstogether to be 400 yg/day.

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Selenosis is thought to develop when selenium intakes exceed 850 pg/day (or 14 pg/kg body weight fora 60 kg adult). Selenium supp lementation at a daily level of 300 pg is not associated with overt adverseeffects over a sho rt period o f time.

Marginal selenium toxicity was concluded to be present with daily intakes of 91 pg, and this figurewas considered to be the LOA EL. n uncertainty factorof 2 was applied to the LOA EL to yield theNOAEL of 450 pg/day. If one considers the daily selenium intake from food s to be100 pg,supplementing with an additional 200-250 pg falls within the calculated NOAEL of 450 pg/day. Thisconclusion was reinforced by the findings reported by C lark and colleagues and Longneck er andcolleagues who noted n o adverse effects following long-term selenium exposure at com parable levels(Clark, et al., 1996 Longnecker, et al., 1991).

As was the case with the European C omm ission, the Expert Group did not identify any specificvulnerable groups.

Yang et al. 1983. Yang and colleagues investigated endemic selenium intoxications due to highselenium in soils in China. When considering 248 individuals from five villages with a daily seleniumintake of approxim ately 5,000 pg, 49 morbidity was detected. Classical symptoms of selenosis thataffected hair, nails, and skin o n feet, hands, and outer sides of the legs, forearms, and n eck wereobserved, and neurological disturbances were particularly evident in one of the five villages. At a laterstage, num bness, convulsions, paralysis, and motor impairment developed.

The daily selenium intake level with those who exhibited clinical signs of selenosis was estimated torange from 3,200-6,690 pg with an average of 4,990 pg. The afflicted residents did recover fromselenosis as soon as the diets were modified with a downward adjustment in selenium to 240-1510 pgwith a mean intake of 750 pg. The principal form of selenium consumed from the diet of rice andmaize was established to be selenomethionine.

Yan g et al. 1989. Yang and colleagues continued their investigations of selenium ingestion indifferent regions of China, considering areas to be low, med ium, or high. Average dailyselenium intakes for adult males were foun d to be 70, 195, and 1438 pg, respectively; the average dailyselenium intakes for adult females were 62, 198, and 1288 pg, respectively. A total of 349 adults waspart of the study. Clinical selenosis was observed in the high selenium area, but no clinical signs wereobserved when the daily selenium intake was 853 pg or less. Five individuals who had long, persistentclinical signs of selenosis were found to have a daily intake ranging from 91 3-1907 pg with a m ean o f1260 pg. A selenium intake level of 9 10 pg/day was determined to be a level of marginal seleniumtoxicity. No specific neurological symptom s were found and there was no evidence of birth defects inhumans.

Yang Zhou 1994. Yang and Zhou performed a follow-up study on the5 selenosis subjects cited inYang, et al., 1989. Incorporating dietary changes with somew hat limited selenium con tent, witha dailyintake of 800 pg, yielded a loss of clinical signs of selenosis. The autho rs determined that a dailyselenium intake of 800 pg represented a NOAEL, and 400 pg/day was recommended as the maximumsafe daily dietary intake.

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Longnecker et al. 1991. A total of 142 subjects residing in regions of the US where selenium levelsare naturally high were followed over a 2-year period of time. The daily selenium dietary intake wasassessed, and subjects were monitored for adverse health effects. Selenium measurements were takenfrom whole blood, serum, urine, and toenails over the course of the study.

The average selenium intake was 239 pg/day, with the range spanning 68-724 pg/day. Half of thesubjects had intake levels above 200 pg/day, and 12 individuals had intake levels exceeding 400pg/day. Although it was noted that the alanine aminotranferase levels in serum were elevated, it wasconcluded that the values were within the reference range and were clinically insignificant. There was,however, an increased sense of lethargy associated with increased selenium values. It was concludedthat no physical characteristics of selenium toxicity had manifested, nor were there any other significanteffects attributed to elevated selenium intakes.

Clark et al. 1996. Clark and colleagues conducted a randomized, double blind, placebo-controlledstudy on the effects of selenium supplementation on the prevention of skin cancer. 13 12 patients with ahistory of basal cell or squamous cell carcinoma were treated with 200 pg of SelenoExcellQ3 or placebofor up to 10 years (mean of 4.5 years). Patients were assessed semiannually for known signs of frank

selenosis---no indications o dermatological or other signs of selenium toxicity were detected. A totalof 35 patients, including 14 from the control group, did experience gastrointestinal upset whichprompted them to withdraw from the study.

While the selenium supplementation did not have an effect in reducing non-melanoma skin cancer, thestudy did reveal a 50 reduction in total cancer mortality, 37 lower total cancer incidence, a 63reduction in prostate cancer, a 58 reduction in colon cancer, and 46 fewer cases of lung cancer.

The total dietary intake o selenium from supplementation (200 pg), along with the contributions fromfood (90 pg), totaled 290 pg/day. Also see Clark, et al., 1998.

(2) On-Going Selenium Clinical Trials

In addition to the selenium intake studies referenced above, other selenium supplementationinvestigations continue or are under development (Nutraingredients, 2006). Several studies focus onselenium prevention or inhibition of prostate cancer, and others address other forms, such as liver,colorectal, esophageal, breast, and lung cancer. Still other investigations seek information about apossible preventive role for selenium with Alzheimers disease, non-cancerous liver disease, andimproved immune function.

A multi-center, National Cancer Institute-sponsored program, the SELECT program (Selenium andVitamin E Cancer Prevention Trial) involving many thousands of subjects will continue through 20 13

(Nutraingredients, 2006). Another multi-center cancer clinical trial is underway under the auspices ofthe Eastern Cooperative Oncology Group (ECOG) with support from NCI (ECOG, 2007). In thisinvestigation, the potential role of orally administered selenium in preventing the development of asecond primary lung tumor in patients who previously underwent surgery to remove stage 1 non-smallcell lung cancer is under evaluation.

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Table 7. Summary of Selected Human Testing Studies with SelenoExcell@Other High SeleniumYeast Products or Selenomethionine12

2

4 Mper group6 Mper group

32 F

125FAactating

248

-400

5

142

1312

226

5

500

Small group

? lactatingmothers

22

186

?

36983698

29,584

298

304

350 600

32.4, 206, 388200

450- 5

90-350; 170-500; or 250-980

3200-6690 (4990 average)

M 70,195, 1438; F62,198, 1288

819

68-724 (239 average)

290

200

140,240, 340

143,243, 343

200-600

200

100 supplement

200 supplement

2005 + vitamin E+ p-carotene5 + vitaminE + p-carotene

5 + vitamin E + p-carotene

1 followed by5(combination formulation)

200 (combinationformulation)

18 m

?6 w

3 m

?

long-term (?)

long-term (?)

long-term (?)

2Y

up o IO+ y(4.5 ave)

4Y

2 y 8 m

4 y 8 m

3-8 m

3 m

6 m

2 (?)

2Y

8Y8Y

2+

6 m + 6 m

5Y

Marginal hematological changes; borderline increase in serumalanine amino transferaseNo adverse effects reportedNo adverse effects reportedHalf subjects experienced depression extreme tirednessfollowing termination of study

No evidence of selenosis

Selenium intoxication in 49 of subjects; observed skin, hair,nail, abnormalities neurological motor disturbances;exposures to 75 pg did not induce adverse effects;selenosis reversed with diet changes.Marginal selenium toxicity observed at 91 pg/daybut not ata daily intake levels of 853 pg or lessSymptoms of overt signs of selenosis at 1270 pg/day

disappeared after change in diet to8 19 pg/day; NOAELof 800 pg/day12 subjects daily exposure exceeded 400 pg; o clinicallysignifican t observa tions; increased lethargy noted insome subjectsNo clinical signs of selenium toxicity based on semiannualexams; limited patient withdrawals due to GI tract distressHepatitis surface-antigen positive patients; no side effectsnotedUK PRECISE program; no signs of selenium toxicity reportedas of Jan 2003; some reports of GI discomfortDanish PRECISE program; no evidence of selenium toxicityreported s of Aug 2003; some reports of GI discomfortRheumatoid arthritis patients experience pain morningstiffness relief without adverse effectsDoubling of infant intake of Se without reports of adverseeffects; Se levels remain 4-5 times below upper limit for infantsfrom Food and Nutrition BoardElderly subjects experienced improvement in age-relateddecline in immune responseBeneficial treatment adjuvant for HIV-positive subjects withoutreported adverse effectsLiver cancer preventive study using high-Se yeast withoutadverse effects notedModest protection against stomach cancerModest protection against stomach cancerCancer prevention study determined that total mortality

cancer mortality lowered when using the seleniumcombinationFrequency of micronuclei DNA adducts reduced by 9572 in different study groups; no adverse effects notedReduced incidence of metachronous adenomas in large bowelbv half

8 0 0 0 2 8a) European Com mission,2000 references found therein.(b) Yang, et al. 1983While two studies reported adverse effects depression and tiredness and age-related decline in imm une response), theseobservations were not repo rted in oth er studies and are unlikely to be related to inta ke of the test article.

2

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c) Yang, et al. 1989.d) Yang Zhou 1994.e) Longnecker, etal. 1991.

(0 Clark, et al. 1996.g) Rayman, 2004 references found therein

(h) Whanger, 2004 referencesfound therein.

The conclusions drawn from the clinical trials to date are compelling in that elevated levels of dietaryselenium that are 2-4 times or more) the US DR I level of 55 pg per day per adult impart healthbenefits, such as cancer prevention, inhibition of genetic dam age, or enhan ced imm une systemperformance W hanger, 2004). To expand the current state of knowledge and gain greater depth ofunderstanding, scientists and health care professionals in the US and around the world are activelyengaged in the design and execution of clinical trials involving selenium supplementation.

Long-term selenium supplem ent investigations continue at the Arizona Cancer C enter, University o fArizona, the Cancer Institute at the Ch inese Academy of M edical S cience in Beijing, in the UKs partof the PRECISE Prevention of Cancer by Intervention With Selenium) program, and in Denmark aspart of the PRECISE p rogram. The studies that are in process through the PRECISE program areconsidered to be pilot studies with the hope to expand the studies to 14,500 subjects covering7 years.

Several prostate cancer chemoprevention studies are in process at the University of Arizona as a resultof the profound results reported by Clark, et al. Clark, et al., 1996 Clark, et al., 1998). Accordingto M arshall, the study designs capture a continuum ranging from sh ort-term effects on healthy andcancerous prostatic tissues in men with diagnosed cancer, to long-term effects on healthy andpremalignant tissue in men with high-grade prostatic intraepithelial neoplasia, to long-term effects onhealthy tissue in high-risk men with negative biopsy, to long-term effects on cancerous tissue in menwith frank cancer M arshall,2001). Marshall has described the four studies as follows:

1. Negative Biopsy Trial elenium treatmentof men w ho received negative results fromprostate biopsies;

2. Selenium treatment of men with high-grade prostatic intraepithelial neoplasia;3. Preprostatectomy T rial selenium treatment of men with localized prostate cancer before

prostatectomy; and4. Watchful Waiting Trial use of selenium as a chemo therapeutic agent among men with

confirmed prostate cancer.

Experimental design details are contained within Table8.

Stratton et al. 2003a. The results of the Clark study were remarkable in the suggestion that theincidence of certain types of cancer, including prostate cancer, can be diminished as a result of high-selenium yeast supplem entation at the total daily exposure of300 pg food and supplement) Clark, et

al., 1996). There is need to confirm these findings to enable a more agg ressive use of selenized yeastin cancer prevention, and the subject investigation, along with the studies reported in the following twosummaries, are intended to d o just that.700 men considered to be at high risk for prostate cancer, butwho have had a negative prostate biopsy, were administered high-selenium yeast supplements daily atthe level of 200 or 400 pg . Can these selenium doses decrease the incidence of prostate cancer in highrisk men? The study design and initial results are described. In addition, the subjects are beingmonitored for specific serum m arkers that might indicate biochemical prog ression of prostate cancermore effectively. M easuring both alkaline phosphatase and chrom agraninA levels was built into thisstudy. 2 9

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As of June, 2003, a total of 514 m en were enrolled in the study. No new safety concerns were raisedduring the early stages of the study.

Stratton et al. 2003b. As was the case with the above-noted Negative Biopsy Trial, the WatchfulWaiting Trial is an extensionof the work reported by Clark, et al. Clark, et al., 1996). The watchfulwaiting approach is a m ore desirable option for some m en wh o are diagnosed with prostate cancersince selenized yeast supplementation cou ld delay the necessity for surg ery, radiation treatmen t, orsome other invasive treatment mod alities.

During the watchful waiting period, mo nitoring key biomarkers for progression of prostate cancerwould be particularly valuables health care providers can more confidently distinguish betweenslow- and fast-growing prostate cancer. The study design for the Watchful W aiting Trial includesadministration on a daily basis of either 200 or800 pg high-selenium yeast to 264 men with the trial tolast at least 4 years and possibly up to 5 years. Over the course of the study, certain biomarkers, suchas alkaline phosphatase and ch romagranin A, along with other potential biomarkers, will be measuredto provide insights into the progression of prostate cancer.

As of June, 2003, a total of 191 subjects of the targeted 264 had been recruited.No safety concernshad been raised du ring the ea rly stages of this trial.

Reid et al. 2004 As part of the W atchful Waiting Trial described above by M arshall, it was hoped togain insights into the toxicity o f selenium when administered in chemoprevention in appreciablyincreased dosages that exceeded the NOA EL of 400 pg dosage. 24 m en with biopsy-proven prostatecancer were given either 1600 or 3200 pg/day of high-selenium yeast. Selenium levels in plasma andsymptoms of selenium toxicity were assessed periodically over the course of 12 mon ths. Liver andkidney function tests and hematology were measured at 6-month intervals. The 3200 pg/day groupreported more selenium -related side effects, but blood chemistry and hematology resu lts were innormal limits for both dosage groups. No obvious selenium-related serious toxicities were observed.

This trial has presented the highest test doses of high-selenium yeast to hu mans over a sustained periodof time, and no serious toxicities w ere revealed. While these findings do not establish the safety oflong-term high-dose organic selenium supplementation in the general population, the observed toxicityprofiles suggest that doses greater than 400 pg/day can be given in controlled situations for extendedtime periods without serious toxicity.

Reid et al. 2006 Reid et al 2008. Reid and co-workers extended their inv estigation into thehealth effects of selenium supplem entation through the Nutritional Prevention of Cancer trial byfocusing the association between selenium supplementation with daily exposure of 200 pg of selenizedyeast and prevalent and incident colorectal adenomas and colorectal cancer. While reporting favorable

results with diminished cancers from this level of supplem entation, there w ere no indications ofadverse effects Reid, et al., 2006). An additional substudy involved adm inistering the selenized yeastat a daily exposure o f 400 pg, but no increased effect in diminished lun g, colon, prostate, or totalcancers was observed Reid , et al., 2008).

3) E ffects of Long-Term Selenium Supplementation and Type 2 Diabetes 3

Stranges and coworkers Stranges, et al., 2007) examined the effects of long-term seleniumsupplementation in hum ans on the incidence of type 2 diabetes by relying on a secondary analysis of

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information from a rando mized, double blind, placebo-controlled clinical trial. Yeast-bound seleniumwas orally administered to1312 participants at levels up to 200 pg per d ay for up to7 7 years. Despitenoting limitations in the study with secondary effects, self-reporting of the type 2 diabetes diagnoses,and reliance on a limited subpopulation, the authors concluded that selenium supplementation doesnot seem to prevent type 2 diabetes, and it may increase risk for the disease.

These findings prompted editorial comments from Bleys and colleagues (Bleys, et al.,2007) whoaddressed the need for high quality prospective studies and random ized trials to investigate the effectsof dietary selenium and selenium supplementation on the incidence of d iabetes. They embraced acautious approach regarding dietary supplementation with selenium in that routine supplementationshould be avoided until such studies were conducted.

Dr. G. F. Combs, Jr, Director of USDA s Grand Forks Hum an Nutrition Research C enter and co-author of the S tranges article cited above, has continued to investigate the potential linkage betweenselenium supplementation and the onset of type 2 diabetes. Under his direction, a year-longintervention study w as co nducted to characterize the dose response relationship between seleniumstatus and diabetes risk.

The results of this investigation have been published as an abstract (C ombs, et al., 2008 and seeAppendix C ) wherein the authors report thatthese results do not support rel tionship betweenselenium st tus nd di betes risk Appendix C. also contains a letter authored by D r. Combs thatconcludes that their study results do not indicate a relationship of Se stratus and diabetes risk. Whilewe recognize the inferential limitations inherent in a small study such as this, it is also the case thatthese are the m ost robust d ata relevant to the question of w hether selenium status may be related todiabetes risk. Thu s, it is our plan to continue to address this hypothesis in further studies; but for themoment, I consider the supporting evidence very weak.

(4) ADM E and Bioavailability

The metabolic conversions o f the different selenium fo rms have been well-studied and are summarizedby several research groups. Cereal and forage crops, as well asSaccharomyces cerivisiae absorbinorganic selenium w hich is converted into selenomethionine w hich, in turn, is subsequentlyincorporated into protein. Selenomethionine then undergoes other metabolic conversions. Excess Seis detoxified by successive methylation of H2Se to yield methyl selenol (CH 3SeO H), dimethyl selen ide((CH3)zSe) and trimethylselenonium ion (CH3)3Se+; he latter two species ar e excreted in the breathand urine (Rayman, 2004, Whanger, 2004, Infante, et al., 2005).

It is also known that the organoselenium forms of selenium, especially selenomethionine, are morebioavailable than the inorgan ic selenium salts (Burk, et al, 2006). Rayman reports that organic forms

of selenium are absorbed to the extent of about 80 , although the bioavailability is affected by thenutrient status of individuals, the manufacturing process for the subject organoselenium form, and thepresence of other dietary com ponents, including sulfur. Nonetheless, it was concluded that humansupplementation studies indicate that the selenium from high-selenium yeasts is more bioavailable thaninorganic selenium (Ray man, 2004).

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Table 8. Summary o Expanded Clinical Studies with SelenoE xcell@ and O therHigh Selenium Yeast Products

Negative Biopsy Trial; intend to assess prostate cancer status of individuals with

negative prostate cancer biopsies; 514 subjects were randomized to trial as of Juna), b) 700M

200 or 400 57 mIntend to assess prostate cancer status of men with high-grade prostaticintraepithelial neoplasia following selenomethionine supplementation.Preprostatectomy Trial; evaluation during the time interval between biopsyprostatectomy; 55 subjects recruited to trial in 2001.

3ta) 470 200

6-8 wa) 11 2 or 400

200, 800 Watchful Waiting; seeking pharmacological data from selenium exposures, alongwith chemotherapeutic outcomes 191 subjects recruited as of Jun 2003.d) 264 1600 or 32

(a) Marshall,200 1.b) Stratton, et al.,2003ac) Stratton, et al.,2003b.

(d) Reid, et al.,2004.

The Expert Group on V itamins and M inerals reported that selenium compou nds are readily absorbedfrom the small intestine, but the extent of absorption varies, depend ing on the nature of the specificcompound. Selenium was found to be widely distributed throughout the body, and its presence hasbeen detected in breast milk. Selenium levels are slightly higher in the liver and kidneys than in othertissues. It was also noted by Hawkes, et al., that the whole body reten tion of selenium is about5 mgwith 5 mg being retained in muscle tissue (Haw kes, et al, 2003). Selen ium is largely excreted in theurine, with volatile metabolites being excreted in the breath. So me fecal excretionof selenium occursfollowing chronic Se adm inistration (Expert Group,2003).

In addressing the ADME and bioavailability

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