FDA Approves Selenium for fighting Cancer

[Guest guest]

If you're not taking Selenium to prevent and fight cancer, you're making a

mistake. Even the FDA approves it.

Want to know where to get the BEST Selenium product?

<http://nutri.com> http://nutri.com

SeleniumMC: AS OF 2000, THE NEWEST AND BEST FORM OF SELENIUM

" The Essence of Garlic " **

SeleniumMCtm, or SeMC, are Wholesale Nutrition's names for Selenium

MethylselenoCysteine.

** - SeleniumMCtm and: The Essence of Garlictm are Trademarked.

SeleniumMC is a naturally occurring selenoamino acid synthesized by plants

such as garlic, broccoli, and onions, and is now available to the public

exclusively from Wholesale Nutrition.

From extracts of selenium enriched garlic, it has recently been found that

SeleniumMC IS THE ACTIVE INGREDIENT in the chemoprevention of mammary

cancer.

17 May 2002: The FDA considers the above sentence may be an illegal claim

that would make SeleniumMC a drug (despite the 40 references given below).

We have asked Dr Spallholz for a statement. Within a few days we may remove

the sentence, and may include the FDA letter right here, and probably

include Dr Spallholz's statement.

28 May 2002: Dr Spallholz replied that " the statement is true for animal

experimentation. There is a long article in 'Nutrition and Cancer', Dec

2001, showing the great (beneficial) effects of SeMC and other Se Compounds

on animal breast cancer. " He goes on to say that " we just got permission

(from the FDA) to move the upper limit of an adult daily dose of Se as SeMC

to 200 mcg/day. " Dr Spallholz also directed us to his twin journal articles

about selenium and SeMC, with over 70 more scholarly references, that can be

found at:

<http://www.stda.be/bull011.pdf> www.stda.be/bull011.pdf

<http://www.stda.be/B2001-2.pdf> www.stda.be/B2001-2.pdf

Since Dr Spallholz feels that health claims cannot be made directly from

animal results, we now will add " IN ANIMALS " to the previous statement under

question. Thus:

" From extracts of selenium enriched garlic, it has recently been found that

SeleniumMC IS THE ACTIVE INGREDIENT in the chemoprevention of mammary cancer

IN ANIMALS. "

SeleniumMC metabolism has been studied in animals and the chemoprevention

effect of SeleniumMC is believed to occur due to the generation of

monomethylated selenium species by endogeneous enzymes. Monomethylated

selenium species have been shown to generate superoxide and induce apoptosis

(cell death) to cancer cells in culture. Unlike L-selenomethionine (the form

found in yeast and meat) which is incorporated into proteins in place of

methionine in vivo, SeleniumMC is not incorporated into any proteins thereby

being fully bioavailable for chemoprevention and the synthesis of

selenium-containing enzymes such as glutathione peroxidase. Preliminary

animal data indicate that SeleniumMC is less toxic than L-selenomethionine

when included in diets which may be related to the known accumulation of

L-selenomethionine in tissues.

Patents are pending for the novel synthesis of SeleniumMC and its exclusive

use as a dietary supplement for humans and domestic animals.

SeleniumMC can be used as a human and animal food supplement as per the

Nutritional Supplement Regulations of the US Food and Drug Administration.

References

Publications:

Dimethyldiselenide and Methylseleninic Acid Generate Superoxide in an In

Vitro Chemiluminescence Assay: Implications for the Anticarcinogenic

Activity of L-Selenomethionine and L-Se-methylselenocysteine. J.E.

Spallholz, B.J. Shriver and T.W. Reid. Nutrition and Cancer. Submitted 2000

Effect of selenium in Combination with Adriamycin or Taxol on Several

Different Cancer Cells. J.V.Vadgama,Y. Wu, D.Shen, S.Hsia and J. Block.

Anticancer Research. 20,1391-1414,2000.

Chemical Speciation Influences Comparative Activity of Selenium-Enriched

Garlic and Yeast in Mammary Cancer Prevention. C. Ip, M. Birringer, E.

Block, M. Kotrebai, J.F. Tyson, P.C. Uden and D.J. Lisk. Journal of

Agriculture and Food Chemistry,40,2000.

Selenium Metabolism, Selenoproteins and Mechanisms of Cancer Prevention:

Complexities with Thioredoxin Reductase. H.E.Ganther. Cancinogenesis.

20,1657-1666,1999

Selenium-induced Inhibition of Angiogenesis in Mammary Cancer at

Chemopreventive Levels of (Dietary) Intake. C. Jiang, W.Jiang, Ip,C.,

Ganther, H. and Lu,I. Molecular Carcinogenesis. 26,213-225,1999.

Decreased Incidence of Prostate Cancer with Selenium Supplementation;

Results of a Double-blind Cancer Prevention Trial. ,L.C. et al British

Journal of Urology. 81,730-734,1998.

Chemopreventive Agents: Selenium. G.F. Combes and W.P. Grey. Pharmacological

Therapy. 79,179-192,1998.

Lessons from Basic Research in Selenium and Cancer Prevention. C. Ip.

Journal of Nutrition. 128,1845-1854,1998.

Should Selenium Enriched Vegetables be Consumed for the Prevention of

Cancer? P.D. Whanger, J.L. Green and J.A. . Proceedings of the Sixth

International Symposium on the Uses of Selenium and Tellurium. 57-61,1998.

sdale, AZ

Novel strategies in Selenium Cancer Chemoprevention Research. C. Ip and H.E.

Ganther. Selenium in Biology and Human Health, R.F. Burk, Ed. Chapter 9, pp.

170-180. Springer-Verlag, Publisher. New York. 1998,

Study of Prediagnostic Selenium Level in Toenails and the Risk of Advanced

Prostate Cancer. K. Yoshizawa, W.C. Willet, S.L. , S.J. Stampfer, D.

Spiegelman, E.B. Rimm and E. Giovannucci. Journal of the National Cancer

Institute. 90,1219-1224,1998.

Chemical Transformations of Selenium in Living Organisms. Improved Forms of

Selenium for Cancer Prevention. H.E. Ganther and J.R. Lawrence. Tetrahedron.

53,12299-12310,1997.

Speciation of Selenoamino acids and Organoselenium compounds in

Selenium-enriched Yeast using High-performance Liquid Chromatography

inductively-coupled Plasma Mass Spectrometry. S.M. Bird, P.C. Uden, J.F.

Tyson, E. Block and E. Denoyer. J. Analytical Atomic Spectrometry.

12,785-788,1997.

Naturally Occurring Selenium Compounds in Cancer Chemoprevention Trials: A

Workshop Summary. B.H. Paterson and O.A. Levander. Cancer Epidemiology

Biomarkers and Prevention. 6,63-69,1997.

Effects of Selenium Supplementation for Cancer Prevention in Patients with

Carcinoma of the Skin. L.C. et al. Journal of the American Medical

Association. 276,1957-1963,1996.

Effect of an Aqueous Extract of Selenium-Enriched Garlic on in vitro and in

vivo efficacy in Cancer Prevention. J. Lu, H. Pei, C. Ip, D.J. Lisk, H.

Ganther and H. J. . Carcinogenesis. 17,1903-1907,1996.

Allium Chemistry: Identification of Selenoaminoacids in Ordinary and

Selenium-Enriched Garlic, Onion, and Broccoli Using Gas Chromatography with

Atomic Emission Detection. X.J. Cai, E. Block, P.C. Uden, Z. Zhang, B. D.

Quimbly, and J.J. Sullivan. Journal of Agricultural Chemistry. 43,

1754-1757,1995.

Allium Chemistry: Identification of Selenoamino Acids in Ordinary and

Selenium Enriched Garlic , and Onions and Broccoli using Gas Chromatography

with Atomic Emission Detection. X-J Cai et al. Journal of Agricultural Food

Chemistry. 43,1754,1995.

On the Nature of Selenium Toxicity and Carcinostatic Activity. J.E.

Spallholz. Free Radical Biology and Medicine. 17,45-64,1994.

Characterization of Tissue Profiles and Anticarcinogenic Responses in Rats

Fed Natural Sources of Selenium-Enriched Products. C. Ip and J. Lisk.

Carcinogenesis. 15,573,1994.

Enrichment of Selenium in Allium Vegetables for Cancer Prevention. C.P. Ip

and D.J. Lisk. Carcinogenesis. 15,1881-1885,1994.

Novel Strategies in Selenium Cancer Chemoprevention Research. Ip, C. and

Ganther, H.E. in Selenium in Biology and Human Health. R.F. Burk, Ed.

Chapter 9. Springer-Verlag, Publisher New York pp 171-180,1994.

Bioavalibility of Selenium from Selenium-enriched Garlic. C. Ip and D.J.

Lisk. Nutrition and Cancer. 20,129-137,1993.

Nutrition Intervention Trials in Linxian, China: Supplementation with

Specific Vitamin/Minerial Combinations, Cancer Incidence, and

Disease-Specific Mortality in the General Population. W.L. Blot et al.

Journal of the National Cancer Institute. 85,1483-1491,1993.

The Prevention of Primary Liver Cancer by selenium in salt for 6 Years. W.

Li, Q Huang and B. Liu. Qiu Liver Cancer Research10, 665. 1993. (In Chinese)

Effect of Methylated Forms of Selenium on Cell Viability and the Induction

of DNA Strand Breaks. A.C. , H.J. , P.J. Schedin, N.W. Gibson,

and H.E. Ganther. Biochemical Pharamacology 43,1137-1141,1992.

Selenium: Mechanistic Aspects of Anticarcinogen Action. G.N. Schrauzer.

Biological Trace Element Research. 33,51-62,1992.

Comparison of Selenium and Sulfur Analogs in Cancer Prevention. C. Ip and

H.E. Ganther. Carcinogenesis 13,1167-1170,1992.

Mammary Cancer Prevention by Regular Garlic and Selenium-Enriched Garlic.

C.Ip, D.J. Lisk and G.S. Stoewsand. Nutrition and Cancer 17,279-286,1992.

Chemical Form of Selenium, Critical Metabolites, and Cancer Prevention C.

Ip, C. . R.M. Budnick and H. Ganther. Cancer Research 51,595-600,1991.

Serum Selenium and Subsequent Risk of Cancer Among Finnish Men and Women.

Knekt,P. et al. Journal of the National Cancer Institute. 82,864-868,1990.

The Metabolism of Selenomethionine, Se-methylselenocysteine. their

Selenonium Derivatives, and Trimethylselenonium in the Rat. S. J. ,

R.J. Kraus and H.E. Ganther. Archives of Biochemistry and Biophysics.

251,77-86,1986b.

Selenium Inhibition of Chemical Carcinogenesis. C. Ip. Federation

Proceedings. 44,2573-2578,1985

Association Between Serum Selenium and the Risk of Cancer. Salonen, J.T. et

al. American Journal of Epidemiology. 120,342-349,1984.

Biochemical and Clinical Effects of Selenium on Dimethylhydrazine-Induced

Colon Cancer in Rats. M.N. s et al. Cancer Research. 41,4458-4465,1981.

Biosynthesis of Se-methylselenocysteine and Se-methylcysteine in Astragalus

Bisulcatus. D.M. Chen, S.N. Nigam and W.B. McConnell. Canadian Journal of

Biochemistry. 48,1278-1283,1970.

Abstracts

Dimethyldiselenide Generates Superoxide in an In Vitro Chemiluminescence

Assay in the Presence of Glutathione. J.E. Spallholz, B.J. Shriver and T.W.

Reid. FASEB Journal. Part 2;12,A825,1998.

The Nutritional Prevention of Cancer with selenium. L.C. , G.S. Combes

and B.W. Turnbull. FASEB Journal.10,550,1996.

Titles in Review

In Vitro and In Vivo Studies of Methylseleninic Acid: Evidence that a

Monomethylated Selenium Metabolite is Critical for Cancer Chemoprevention.

Sometime in 2000.

Chemical Speciation Influences Comparative Activity of Selenium-Enriched

Garlic and Yeast in Mammary Cancer Prevention. 2000

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Office of Nutritional Products, Labeling and Dietary Supplements

April 28, 2003

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Selenium and Certain Cancers

(Qualified Health Claim: Final Decision Letter)

(Docket No. 02P-0457)

W. Emord, Esq.

Emord & Associates, P.C.

1050 17th Street, N.W.

Suite 600

Washington, D.C. 20036

RE: Health Claim Petition: Selenium and Reduced Risk of Certain

Cancers and Selenium and Anticarcinogenic Effects (Docket No. 02P-0457)

Dear Mr. Emord:

This letter responds to your health claim petition dated July 10, 2002,

submitted to the Food and Drug Administration (FDA or the agency), on behalf

of Wellness Lifestyles, Inc., pursuant to Section 403®(5)(D) of the

Federal Food, Drug, and Cosmetic Act (21 U.S.C. § 343®(5)(D)). Your

petition requested that the agency authorize health claims for use on

dietary supplements of selenium on the relationship between selenium and

reduced risk of certain cancers, and between selenium and anticarcinogenic

effects. FDA filed the petition for comprehensive review on October 28,

2002, in accordance with section 403®(4)(A)(i) of the Federal Food, Drug,

and Cosmetic Act (the Act) and with Title 21 of the Code of Federal

Regulations (CFR) section 101.70(j).

In a letter dated January 10, 2003, you notified FDA of your client's

agreement to extend the deadline for an FDA decision on the petition from

January 16, 2003 to February 20, 2003. On January 22, 2003, the agency sent

you a letter explaining its concerns associated with the above referenced

health claims. FDA sent another letter to you on January 24, 2003, with one

additional concern regarding the need for an upper limit of daily intake for

selenium dietary supplements. We discussed these concerns with you and your

client at a January 27, 2003 meeting. In a letter sent to you on February

11, 2003, the agency offered two disclaimers and explained the circumstances

under which it would consider the exercise of enforcement discretion for the

proposed claims and disclaimers. On February 12, 2003, you sent us a letter

announcing your client's agreement to the terms specified by FDA. On

February 21, 2003, FDA issued a letter memorializing the agreement and

announcing its intention to issue within 60 days a formal decision on the

selenium health claim petition. In a letter dated April 14, 2003, you and

your client agreed to a one-week extension, to April 28, 2003, for FDA to

issue the formal decision. This letter sets forth that decision.

After reviewing the scientific evidence in your petition and other evidence

relevant to your proposed claims, FDA evaluated the claims under the

" significant scientific agreement " (SSA) standard. FDA's current

regulations, which mirror the statutory language in 21 U.S.C.

343®(3)((i), provide that the agency may issue a regulation authorizing

a health claim only " when it determines, based on the totality of publicly

available scientific evidence (including evidence from well-designed studies

conducted in a manner which is consistent with generally recognized

scientific procedures and principles), that there is significant scientific

agreement, among experts qualified by scientific training and experience to

evaluate such claims, that the claim is supported by such evidence " (21 CFR

101.14©). For the reasons set forth below, your petition does not meet the

" significant scientific agreement standard. "

FDA next considered whether it would be appropriate to consider the exercise

of enforcement discretion for qualified claims about this substance-disease

relationship consistent with the agency's approach to evaluating proposed

health claims for use on dietary supplements when the SSA standard is not

met. This letter outlines FDA's rationale for its determination that the

current evidence supporting the dietary supplement selenium health claims

does not meet the significant scientific agreement standard, the rationale

for why the evidence is appropriate for consideration of qualified claims,

and the conditions under which the agency intends to consider the exercise

of its enforcement discretion for certain qualified claims with respect to

selenium dietary supplements.

I. Safety Review

Under 21 CFR 101.14((3)(ii), the use of selenium at levels necessary to

justify a claim must be demonstrated by the proponent of the claim, to FDA's

satisfaction, to be safe and lawful. The safety provisions in question

require, for example, that the dietary ingredient not present a significant

or unreasonable risk of illness or injury under conditions of use

recommended or suggested in the labeling or under ordinary conditions of use

(21 U.S.C. 342(f)(1)). Further, a dietary supplement must not contain a

poisonous or deleterious substance which may render the supplement injurious

to health under the conditions of use recommended or suggested in the

labeling (21 U.S.C. 342(f)(1)(D)).

Although selenium is known to be an essential mineral, it can also be toxic.

The Institute of Medicine (IOM) recently conducted a risk assessment of

dietary selenium as part of a larger project to evaluate the human

requirements and safety of antioxidant nutrients (IOM, National Academy of

Science (NAS) Dietary Reference Intake (DRI) Report, 2000). Adverse effects

reported from high intakes of selenium included selenosis (hair and nail

brittleness and loss), gastrointestinal disturbances, skin rash,

garlic-breath odor, fatigue, irritability, and nervous system abnormalities.

Based on considerations of causality, relevance, and the quality and

completeness of the database, hair and nail brittleness and loss were

selected as the critical endpoints on which to base a Tolerable Upper Intake

Level (UL). The IOM recognized the lowest-observed-adverse-effect level

(LOAEL) of selenium intake as 900 micrograms (µg) per day, and the

no-observed-adverse-effect level (NOAEL) of selenium intake as 800 µg per

day.

The IOM characterized the adverse health effects observed at the LOAEL as

not severe, but likely not readily reversible and therefore justifying an

uncertainty factor of 2. Dividing the NOAEL (800 µg per day) by this

uncertainty factor, the IOM concluded that 400 µg per day is the UL of

selenium from food and supplements likely to pose no risk of adverse health

effects in almost all people. The same NAS/IOM report indicates that current

average intake of selenium from foods is estimated to be approximately 100

µg per day.

FDA concludes that the use of selenium as a dietary supplement at levels no

greater than 400 µg/day is safe and lawful under 21 C.F.R. § 101.14. An

intake of 400 µg/day from a selenium dietary supplement and 100 ug/day from

foods would provide a total estimated intake of selenium of 500 µg/day,

which is below the NOAEL of 800 µg/day for selenium. Moreover, given the

IOM's tolerable upper intake level, the current estimated intake of selenium

from foods, and the IOM's NOAEL, FDA would likely consider a selenium

dietary supplement that encourages intakes (in the labeling or under

ordinary conditions of use) above the IOM's Tolerable Upper Intake Level of

400 µg/d to be misbranded under section 403(a) of the Federal Food, Drug,

and Cosmetic Act (the act). Such labeling would likely be misleading under

section 201(n) with respect to consequences which may result from the use of

the supplement. Further, selenium dietary supplements that encourage intakes

(in labeling or under ordinary conditions of use) above 400 µg/d would

likely be subject to regulatory action as a misbranded food under section

403®(1)( of the act (21 U.S.C. 343®(1)(), a misbranded drug under

section 502(f)(1) of the act (21 U.S.C. 352(f)(1)), and as an unapproved new

drug under section 505(a) of the act (21 U.S.C. 355(a)).

One form of selenium, selenium sulfide, is reasonably anticipated to be a

human carcinogen.(1 <http://www.cfsan.fda.gov/~dms/ds-ltr35.html#note1> ) As

such, the use of selenium sulfide as a dietary supplement ingredient can not

be considered safe and lawful and is thus outside of this consideration for

a health claim.

II. Scientific Evaluation

FDA focused its review of the evidence for the relationship between selenium

and cancer risk reduction on primary reports of human experimental data,

both interventional and observational. We considered results from this

review to also be applicable to anticarcinogenic effects because it is

synonymous with cancer risk reduction. Of the 101 references included in

your petition, 30 are human studies (5 interventional and 25 observational)

relating selenium to cancer-related outcome measures. The remaining 71

references were not considered because they did not directly relate diet to

cancer outcomes in humans (e.g., reports of plant metabolism of selenium,

experimental animal model studies, human studies other than cancer studies,

general review articles).

A. Assessment of Intervention Studies

Reports from five intervention cancer prevention trials(2

<http://www.cfsan.fda.gov/~dms/ds-ltr35.html#note2> ) were submitted with

the petition. Only one of these trials, the Nutritional Prevention of Cancer

Trial, tested the relationship between selenium and cancer risk under

conditions applicable to the U.S. population ( et al., 1996). This

randomized, double-blind, placebo-controlled trial of 1,312 subjects (75%

male) was designed to evaluate the effect of 200 µg supplemental selenium

per day on reduced risk of basal and squamous cell carcinomas of skin in

persons with a prior history of non-melanoma skin cancer, i.e., basal or

squamous cell carcinomas. Although the trial was designed as a 5-year

intervention, the actual time on treatment was 4.5 ± 2.8 years. This study

found no beneficial effects of selenium supplementation on the incidence of

the non-melanoma skin cancer which was the primary cancer endpoint of this

study.

In addition to the primary outcome for which the study was designed,

post-hoc analyses of cancer endpoints for which the study was not designed

(i.e., " secondary " end points) suggested that selenium supplementation may

reduce the risk of total and certain cancers ( i.e., prostate, lung, and

colorectal) ( et al., 1996). Apparent beneficial effects for secondary

cancer endpoints added late in the trial require independent confirmation.

Post-hoc evaluations of diet/cancer relationships for which the original

study was not designed must be interpreted cautiously, because they are

primarily useful for hypothesis-generation, not for demonstration of a

relationship. Thus, this sole intervention trial done under conditions

applicable to the U.S. population showed no benefit for the cancers for

which it was designed but suggested other beneficial selenium/cancer

relationships which require independent confirmation through additional

studies.

On the basis of the hypotheses generated through these post-hoc analyses,

the National Cancer Institute of the National Institutes of Health, has

initiated an intervention trial to evaluate the potential benefits of

selenium supplementation on reducing the risk of prostate cancer (Klein et

al., 2003). The initial report from the Nutritional Prevention of Cancer

Trial (e et al., 1996) evaluated data available through December 1993,

at which time there was an average of 6.4 years of follow-up data.

Subsequent post-hoc analyses of 7.9 years of follow- up data from this study

continued to find reductions in total cancer and prostate cancer risk among

the selenium-supplemented subjects (Duffield-Lillico et al., 2002; and Reid

et al., 2002), but the reductions in lung and colorectal cancer risk

initially reported by et al. (1996) were no longer observed.

Furthermore, sub-group analyses indicated that the protective effect of

selenium may be confined to males and also may be confined to subjects with

the lowest plasma selenium levels. In these post-hoc analyses, subjects with

plasma selenium levels at the average U.S. levels experienced no reduction

in risk. In fact, if the lowest and highest tertiles from these analyses

were compared directly, those in the highest tertile experienced a greater

than 2-fold increased risk compared with those in the lowest tertile. The

authors commented that " the pattern we observed was clearly unpredicted and

unsettling. " Given that these data are derived from post-hoc analyses,

further studies would be needed to reach any definitive conclusions

regarding these findings.

Of the four remaining intervention trials, two of these studies were done in

China (Blot et al., 1993; Blot et al., 1995; Li et al., 1993; Yu et al.,

1991), one in India (Prasad et al., 1995), and one in Italy (Bonelli et al.,

1998).

The intervention trial reported by Yu et al. (1991) of primary liver cancer

represents preliminary reports of three separate trials in Quidong county of

China, which has an exceptionally high rate of this cancer. The report notes

that the recognized potential risk factors responsible for the high liver

cancer rate in this county are aflatoxin contamination, hepatitis B viral

infection, and water pollution. Supplemental selenium of 15 ppm was given as

either anhydrous sodium selenite or selenium-enriched yeast tablets. The

baseline blood selenium levels of the subjects in these trials was about 10

micrograms/dL, which is below the 5th percentile of blood selenium levels in

the U.S. (NHANES III, 1988-1994 data). The results from these trials

indicate that the extremely high incidence of primary liver cancer in some

localities within this malnourished population in Quidong county could be

reduced by adding selenium to the diet. Although this effect can be

attributed directly to selenium per se, the physiological effects in

malnourished individuals could be quite different from the effects of the

same nutrient supplements in well nourished individuals. Moreover, the

etiologies of these cancers may differ between these two countries. Thus,

there is uncertainty as to whether these results are relevant to the U.S.

population

The General Population phase of the Linxian Trial (Blot et al., 1993; Blot

et al., 1995) examined the effect of a multi-nutrient supplement

(beta-carotene, vitamin E and selenium) on stomach cancer in a malnourished

Chinese population at high risk for this cancer. The General Population

phase of this trial (Blot et al., 1993) reported lower stomach cancer

mortality among subjects taking the selenium-containing supplement. The

Dysplasia phase of the trial (Li et al., 1993), in which subjects diagnosed

with esophageal dysplasia received either a multivitamin-mineral supplement

or a placebo, reported no benefit of the selenium-containing supplement on

esophageal or gastric cancer mortality or incidence. These results, although

not consistent, provide some evidence that a selenium-containing supplement

had some effect on lowering cancer mortality in a malnourished population

with a very high gastric cancer rate. However, since the supplement was a

cocktail of nutrients, these results cannot provide clear evidence of an

effect of selenium per se. The relevance of these results to the general

U.S. population, which does not have the same high incidence of stomach

cancer or malnutrition, is uncertain.

The intervention trial reported by Prasad et al. (1995) was designed to

examine the effects of a multiple-nutrient supplement cocktail (vitamin A,

riboflavin, zinc and selenium) in " reverse smokers of chutta " (3

<http://www.cfsan.fda.gov/~dms/ds-ltr35.html#note3> ) in India on potential

biomarkers of genetic damage in cells scraped from inside the subjects'

cheeks. This was not a cancer risk reduction study because these endpoints

(i.e., frequency of micronucleated cells and carcinogen DNA adducts as

indicators of DNA damage) are not recognized as validated surrogate measures

of cancer risk. Therefore, FDA did not include this study in its evaluation.

The intervention trial reported by Bonelli et al. (1998) was designed to

examine the effects of multiple nutrient supplements (selenium, zinc,

vitamin A, vitamin C and vitamin E) on incidence of colorectal adenomatous

polyps(4 <http://www.cfsan.fda.gov/~dms/ds-ltr35.html#note4> ). Colorectal

carcinomas grow from such polyps, although most polyps remain benign. This

report states that recruitment of study subjects was stopped at the end of

1995, and that the treatment period was 5 years. Thus, the results presented

in 1998 represent a preliminary report from the yet uncompleted study. The

report included in the petition (petition, tab 7) is a paper printed in a

conference proceeding. One of the four pages of this report is missing and

the paper lacks sufficient detail to evaluate study quality. FDA has not

found any final or published peer-reviewed reports of this study. As such,

there is no evidence that this trial was completed, and therefore there are

no results for FDA to consider.

In summary, the only available intervention trial with direct applicability

to the U.S. population showed no effect of selenium supplementation on the

cancer endpoint for which the study was designed, i.e., non-melanoma skin

cancer. Post-hoc analyses of this study for cancer endpoints not included in

the initial trial design suggest possible reductions in the risk of total

and certain cancers for which independent confirmation is required (i.e.,

prostate cancer, lung, and colorectal). One study in China (Yu et al., 1991)

indicated that selenium per se reduced the risk of primary liver cancer in a

malnourished population with an exceptionally high rate of this cancer.

Another study in China (Blot et al., 1993; 1995) reported that a

multi-nutrient supplement containing selenium reduced the risk of stomach

cancer in a malnourished population with a high risk of this cancer.

However, this study did not show any effect on early biomarkers of stomach

cancer risk. Although the Blot, et al. (1993 and 1995) and Yu, et al., 1991

studies suggest an effect of selenium on reduced risk of two types of cancer

the relevance of these findings to the U.S. population is uncertain.

B. Assessment of Observational Studies

Your petition included 25 observational studies pertaining to selenium and

cancer.(5 <http://www.cfsan.fda.gov/~dms/ds-ltr35.html#note5> ) These

studies included 16 prospective cohort studies, approximately one-third of

which were from U.S. populations, and 3 retrospective case-control studies.

The remainder of the observational studies were ecological and

cross-sectional. FDA identified 11 additional observational studies through

a literature search.(6 <http://www.cfsan.fda.gov/~dms/ds-ltr35.html#note6> )

None of these studies was able to isolate the effect of selenium intakes

from other nutrients. Among all 36 identified observational studies,

approximately one-half support an association between selenium intake and

reduced cancer risk, and one-half do not support such an association. Thus,

overall the available results from observational studies are equivocal.

We do note that there was some consistency within observational study

results for two cancer sites (breast and prostate). The results of the four

observational studies that focused on breast cancer were consistent in

finding no association of selenium intake and breast cancer risk in women.(7

<http://www.cfsan.fda.gov/~dms/ds-ltr35.html#note7> ) The results of four

other observational studies that assessed associations of breast cancer risk

and selenium intake in women were also consistent in finding no

association.(8 <http://www.cfsan.fda.gov/~dms/ds-ltr35.html#note8> ) The

four observational studies that focused on prostate cancer were consistent

in finding a significant inverse association between prostate cancer and

selenium intake.(9 <http://www.cfsan.fda.gov/~dms/ds-ltr35.html#note9> )

The equivocal nature of these results overall from the observational studies

is observed both within types of observational studies (e.g., within

prospective cohort or within retrospective case control studies) and across

types of observational studies. Therefore, although there can be found,

within the observational results, some evidence in support of a relationship

of selenium intake and reduced risk of certain cancers (e.g., prostate

cancer), the whole body of observational evidence does not provide strong

evidence for such a relationship.

C. Assessment of Authoritative Statements

FDA also considered whether other authoritative bodies had reviewed the

scientific evidence on dietary supplement selenium intakes and reduced risk

of certain cancers. The Food and Nutrition Board of the Institute of

Medicine, the National Academy of Sciences, as part of an evidence-based

process to update Dietary Reference Intakes (DRIs) for the U.S. population,

evaluated the relationship of selenium intakes to cancer risk reduction (

IOM, NAS DRI Report, 2000). It concluded that the available evidence was

insufficient to develop a DRI for selenium based on reduction in cancer risk

and that additional intervention trials are required before the validity of

this relationship can be confirmed. This strongly suggests that there is not

significant scientific agreement among qualified experts that a relationship

exists between selenium intake and reduction in risk of certain cancers.

III. Agency's Consideration of Significant Scientific Agreement

There were reports from 5 intervention and 36 observational studies

available for evaluating the relationship of selenium intake to reduced risk

of certain cancers. In general, intervention studies are more persuasive

than observational studies (Guidance for Industry: Significant Scientific

Agreement in the Review of Health Claims for Conventional Foods and Dietary

Supplement. December 22, 1999). Of the 5 intervention studies, only the

Nutritional Prevention of Cancer Trial had direct applicability to the

general U.S. population. This study found no benefit of selenium

supplementation on reducing the risk of non-melanoma skin cancer, the cancer

endpoint for which the study was designed. Post-hoc analyses of secondary

cancer endpoints for which the study was not designed suggested risk

reduction for certain cancers. However, post-hoc analyses are primarily

useful for hypothesis-generation, not documentation of a relationship. One

study in China indicated that selenium per se reduced primary liver cancer

in a malnourished population with a high rate of this cancer (Yu et al.,

1991). In another study in China (Blot et al., 1993; 1995), selenium

containing multi-nutrient supplements reported a reduction in stomach cancer

in a malnourished population with a high risk for this cancer. However,

applicability of results from these two studies to a well nourished U.S.

population in which the etiologies of these cancers may differ from those in

China is uncertain. Additionally, results from the Blot et al. studies

(1993; 1995) may not be attributed with certainty to selenium per se. The

two remaining intervention trials were not considered useful for this

review, because the Prasad et al. (1995) trial did not study cancer risk,

and there is no evidence that the trial by Bonelli et al. (1998) was ever

completed, thus, there are no results to consider from these studies. Thus,

evidence from intervention trials in support of a relationship between

dietary selenium and reduced cancer risk is limited to results from the two

studies conducted in China. Because the subjects were malnourished and

cancer etiologies in these two countries may differ, the relevance to the

general healthy U.S. population is uncertain. The evidence from

observational studies with respect to overall cancer risk in both males and

females is equivocal. The IOM expert panel recently found insufficient

evidence to base a selenium DRI on a relationship between selenium intake

and reduction in cancer risk (NAS DRI Report, 2000). Therefore, based on its

evaluation of the totality of the publicly available scientific evidence,

the agency concludes that there is not SSA among qualified experts that a

relationship exists between dietary supplement selenium intake and reduced

cancer risk.

IV. Agency's Consideration of Qualified Health Claims

For claims that do not meet the significant scientific agreement standard,

FDA considers whether the exercise of enforcement discretion might be

appropriate for qualified health claims about the relationship between the

substance and the disease. After reviewing the scientific evidence in your

petition and other relevant scientific evidence, FDA concludes that much of

the data do not support a relationship between selenium dietary supplement

intake and reduced risk of certain cancers. Although there is some basis for

qualified health claims for dietary supplement selenium intake and reduced

risk of certain cancers, the evidence is limited and not conclusive. There

was only one intervention study that showed an effect of selenium per se on

reduced risk of primary liver cancer (Yu et al., 1991). This study does

suggest a relationship of selenium dietary supplement intake and reduced

risk of this cancer in the select population studied, but its relevance to

the U.S. population is uncertain because of differences in population

nutritional status and in cancer etiologies between the two countries. One

other intervention trial suggests a relationship between selenium dietary

supplement intake and reduced risk of stomach cancer (Blot et al., 1993;

1995). However, similar to the Yu et al., 1991 study the relevance of the

results from the Blot, et al. studies to the U.S. population is uncertain.

Additionally because the Blot et al. studies used a test product that was a

multi-nutrient supplement, it is not possible to attribute these effects to

selenium per se. There are four observational studies that show an

association between selenium intake and reduced risk of prostate cancer.

These findings from observational studies are consistent with the post-hoc

analyses of secondary cancer end points in a U.S. intervention trial (e

et al., 1996). Therefore, although much of the available evidence is either

not supportive of, or equivocal relative to, the effect of selenium intake

on cancer risk reduction, some evidence from two of the intervention trials

and from four of the observational studies provide limited and inconclusive

evidence to suggest a possible relationship between selenium intake and

reduced risk of certain cancers.

V. Other Requirements

Selenium dietary supplements bearing the qualified claims for which FDA has

indicated that it intends to consider the exercise of its enforcement

discretion must still meet all applicable statutory and regulatory

requirements under the act. For example, such supplements must be labeled

consistent with 21 CFR § 101.36((3). Dietary supplements also must not

pose an unreasonable risk of illness or injury to the consumer or contain

substances that may render the product injurious to health, or be otherwise

adulterated or misbranded.

VI. Conclusions

We have considered the scientific evidence submitted with your petition and,

as appropriate, have also considered other pertinent scientific evidence.

Our conclusion is that there is not significant scientific agreement about

the science underlying the statements that " Selenium may reduce the risk of

certain cancers " and that " Selenium may produce anticarcinogenic effects in

the body. " However, the science provides sufficient evidence for qualified

health claims provided that the qualified claims are appropriately worded so

as to not to mislead consumers. Thus, FDA proposed the qualified claims as

presented below, which your clients agreed to as reflected in your letter

dated February 12, 2003.

Claim 1:

" Selenium may reduce the risk of certain cancers. Some scientific evidence

suggests that consumption of selenium may reduce the risk of certain forms

of cancer. However, FDA has determined that this evidence is limited and not

conclusive. "

Claim 2:

" Selenium may produce anticarcinogenic effects in the body. Some scientific

evidence suggests that consumption of selenium may produce anticarcinogenic

effects in the body. However, FDA has determined that this evidence is

limited and not conclusive. "

FDA intends to consider exercising enforcement discretion for the above

qualified claims when: (1) the applicable disclaimer is placed immediately

adjacent to and directly beneath your claim(s), with no intervening

material, in the same size, typeface, and contrast as the claim itself; (2)

the supplement does not recommend or suggest in its labeling, or under

ordinary conditions of use, a daily intake exceeding 400 µg of selenium per

day; and (3) the claim meets the general requirements for health claims in

21 CFR 101.14, except for the requirement that the evidence for the claim

meet the significant scientific agreement standard and the requirement that

the claim be made in accordance with an authorizing regulation.

Please note that scientific information is subject to change, as are

consumer consumption patterns. FDA intends to evaluate new information that

becomes available to determine whether it necessitates a change in this

decision. For example, scientific evidence may later become available that

will support significant scientific agreement or that will no longer support

the use of a qualified claim, or that may raise safety concerns about the

level of intake that FDA has outlined for the safe use of selenium

supplements. If and when such information becomes available, FDA intends to

inform you of this new information and its implications by letter.

Sincerely,

L. , Ph.D.

Director

Office of Nutritional Products, Labeling and Dietary Supplements

Center for Food Safety and Applied Nutrition

_____

1 Department of Health and Human Services, National Institute of

Environmental Sciences, National Toxicology Program. The Report on

Carcinogens, Tenth Edition. 2002.

Http://ehp.niehs.nih.gov/roc/tenth/profiles/s160sele.pdf

2 These trials are: Nutritional Prevention of Cancer Trial ( et al.,

1996); the Linxian General Population Trial (Blot et al., 1993; Blot et al.,

1995; Li et al., 1993); Qidong Primary Liver Cancer Trial (Yu et al., 1991);

Genova, Italy Colorectal Recurrent Adenoma Trial (Bonelli et al., 1998); and

Andhra Pradesh, India Precancerous Lesions of Oral Cavity Trial (Prasad et

al., 1995).

3 A reverse smoker of chutta is a person that inserts the lit end of a

rolled tobacco leaf into their mouth

4 According to Dorland's Medical Dictionary, 23rd edition polyp is defined

as a pedunculated or sessile growth arising from the mucosa and extending

into the lumen of a body cavity. Polyps are the result of hypertrophy of the

mucous membrane or are true tumors (Dorland's Medical Dictionary, 23rd

Edition).

5 These include: et al. (8), et al. (15), Coates et al. (20),

Garland et al. (35), Glattre et al. (36), Guo et al. (38), Helzlsouer et al.

(39), Hunter et al. (41), Kabuto et al. (52), Kok et al. (54), Mark et al.

(57), Navarrete et al. (61), Nomura et al. (63), van Noord et al. (64),

et al. (70), Russo et al. (71), Salonen et al. (72),Schrauzer et al.,

(73), Ujiie et al. (83), van den Brandt et al. (84), van den Brandt et al.

(85), van't Veer et al. (86), Willet et al. (92), Yoshizawa et al. (97), and

Yu et al. (101). The tab numbers by which these articles are filed in

Exhibit 5 of the petition are given in parentheses.

6 (1) Menkes et al. NEJM 315:1250-1254. 1986. (2) Kok et al. NEJM 316:1416.

1987. (3) Meyer and Verreault. Am J Epidemiology. 125:917-919. 1987. (4)

Schober et al. Am J Epidemiology. 126:1033-1041. 1987. (5) Virtamo et al.,

Cancer. 60:145-148. 1987. (6) Michaud et al., Cancer Epidemiol Biomarkers

Prev. 11:1505-1506. 2002. (7) et al., Diseases of the Colon and

Rectum. 38:1306. 1995. (8) Peleg et al., Med Oncol Tumor Pharmacother.

2:157-163. 1985. (9) Knekt, et al., J National Cancer Inst. 82:864-868.

1990. (10) Zeegers et al., Cancer Epidemiology, Biomarkers & Prevention.

11:1292-1297. 2002. (11) Hardell et al., European J Cancer Prevention.

4:91-95. 1995.

7 Hunter et al. (41), van Noord et al. (64), van't Veer et al. (86), and

Meyer and Verreault, 1987.

8 Garland et al. (35), Kok et al., (54), Knekt et al., 1990, and et

al. (70).

9 et al. (8), Willet et al. (92), Yoshizawa et al. (97), and Hardell

et al., 1995.

_____

REFERENCES (in addition to those included in the petition)

Costello, A.J. A randomized, controlled chemoprevention trial of selenium in

familial prostate cancer: Rationale, recruitment, and design issues.

Urology. 57 (Suppl 4A):182-184. 2001.

Dorland's Illustrated Medical Dictionary, 23rd Edition. W.B. Saunders

Company. Philadelphia. 1957.

Duffield-Lillico, A.J., M.E. Reid, B.W. Turnbull, G.F. Combs, Jr., E.H.

Slate, L.A. Fischbach, J.R. Marshall, and L.C. . Baseline

characteristics and the effect of selenium supplementation on cancer

incidence in a randomized clinical trial: A summary report of the

Nutritional Prevention of Cancer Trial. Cancer Epidemiology, Biomarkers and

Prevention. 11 " 630-639. 2002.

Hardell, L., A. Degerman, R. Tomic, S.L. Marklund, and M. Bergfors. Levels

of selenium in plasma and glutathione peroxidase in erythrocytes in patients

with prostate cancer or benign hyperplasia. European Journal of Cancer

Prevention. 4:91-95. 1995.

Institute of Medicine, National Academies of Science. Dietary Reference

Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Chapter 7,

Selenium. Pages 284-324. National Academy Press. Washington, D.C. 2000.

Available on the Internet at:

http://books.nap.edu/books/0309069351/html/index.html

Klein, E.A., I.M. , S.M. Lippman, P.J. Goodman, D. Albanes, P.R.

, and C. Coltman. SELECT: the selenium and vitamin E cancer prevention

trial. Urologic Oncology: Semnars and Original Investigations. 21:59-65.

2003.

Knekt, P., A. Aromaa, J. Maatela, G. Alfthan, R-K. Aaran, M. Hakama, T.

Hakilinen, R. Peto, and L. Teppo. Serum selenium and subsequent risk of

cancer among Finnish men and women. Journal of the National Cancer

Institute. 82:864-868. 1990.

Kok, F.J., C.M. van Duijn, A. Hofman, R. Vermeeren, A.M. de Bruijn, and H.A.

Valkenburg. Micronutrients and the risk of lung cancer. New England Journal

of Medicine. 316:1416. 1987.

Menkes,M.S., G.W. Comstock, J.P. Vuilleumier, K.J. Helsing, A.A. Rider, and

R. Brookmeyer. Serum beta-carotene, vitamins A and E, selenium, and the risk

of lung cancer. New England Journal of Medicine. 315:1250-1254. 1986.

Meyer, F., and R. Verreault. Erythrocyte selenium and breast cancer risk.

American Journal of Epidemiology. 125:917-919. 1987.

Michaud,D.S., T.J. Hartman, P.R. , P. Pietinen, G. Alfthan, J.

Virtamo, and D. Albanes. No association between toenail selenium levels and

bladder cancer risk. Cancer Epidemiology Biomarkers and Prevention.

11:1505-1506. 2002.

National Toxicology Program. National Institute of Environmental Sciences.

Department of Health and Human Services. The Report on Carcinogens, Tenth

Edition. 2002. Available on the Internet at:

http://ehp.niehs.nih.gov/roc/tenth/profiles/s160sele.pdf

et al. Serum selenium and colonic neoplastic risk. Diseases of the

Colon and Rectum. 38:1306. 1995.

Peleg et al. Is serum selenium a risk factor for cancer? Medical Oncology

and Tumor Pharmacotherapeutics. 2:157-163. 1985.

Reid, M.E., A.J. Duffield-Lillico, Garland, B.W. Turnbull, L.C. ,

and J.R. Marshall. Selenium supplementation and lung cancer incidence: An

update of the Nutritional Prevention of Cancer Trial. Cancer Epidemiology,

Biomarkers and Prevention. 11:1285-1291. 2002.

Schober, S.E., G.W. Comstock, K.J. Helsing, R.M. Salkeld, J.S. , A.A.

Rider, and R. Brookmeyer. Serologic precursors of cancer. I. Prediagnostic

serum nutrients and colon cancer risk. American Journal of Epidemiology.

126:1033-1041. 1987.

Virtamo, J., E. Valkeila, G. Alfthan, S. Punsar, J.K. Huttnen, and M.J.

Karvonen. Serum selenium and risk of cancer. A prospective follow-up of nine

years. Cancer. 60:145-148. 1987.

Zeegers, M.P.A., R. A. Goldbohm, P. Bode, and P.A. van den Brandt.

Prediagnostic toenail selenium and risk of bladder cancer. Cancer

Epidemiology Biomarkers and Prevention. 11:1292-1297. 2002.

_____

This document was issued on April 28, 2003.

For more recent information on Dietary Supplements

See http://www.cfsan.fda.gov/~dms/supplmnt.html

_____

Original letter at Dockets (available in PDF

<http://www.fda.gov/ohrms/dockets/dailys/03/May03/050503/02p-0457-pdn0001-01

-vol3.pdf> )

Original petition at Dockets (available in PDF

<http://www.fda.gov/ohrms/dockets/dailys/02/Oct02/101802/800330ab.pdf> )

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Hypertext updated by dav/las <http://www.cfsan.fda.gov/~dms/htmler.html>

August 15, 2003

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