Re: Vitamin E Linked to Higher Death Rates

[Guest guest]

--- In , " aequalsz " <aequalsz@y...>

wrote:

>

> http://www.forbes.com/lifestyle/health/feeds/hscou

> t/2004/11/10/hscout522256.html

>

> I wish those guys would make up their minds.

>

> A

This link works better.

http://snipurl.com/ajmu

A

[Guest guest]

"But the antioxidant vitamins react chemically to the free radicals in the body. Because doctors can't accurately measure free radicals, a recommended dose of antioxidants is difficult."

Another thing we can't quantify (free radicals).

Regards.

----- Original Message -----

From: aequalsz

Sent: Wednesday, November 10, 2004 12:49 PM

Subject: [ ] Re: Vitamin E Linked to Higher Death Rates

--- In , "aequalsz" <aequalsz@y...>wrote:> > http://www.forbes.com/lifestyle/health/feeds/hscou> t/2004/11/10/hscout522256.html> > I wish those guys would make up their minds.> > AThis link works better.http://snipurl.com/ajmu

[Guest guest]

Hi folks:

Many years ago I calculated how much more vitamin E I would get,

compared with those who took no supplements and only got theirs from

food, if I took 400 I.U. once a week.

It was a long time ago, but IIRC I found I would be getting ten times

more than they would. Then I asked myself whether I really was

likely to need seventy times as much, decided I probably didn't, and

have taken it only weekly since. The same applied to another

supplement I did the same calculations for at the time. I think it

was folic acid.

Apart from calcium + D, I only take supplements once a week.

Rodney.

> >

> > http://www.forbes.com/lifestyle/health/feeds/hscou

> > t/2004/11/10/hscout522256.html

> >

> > I wish those guys would make up their minds.

> >

> > A

>

> This link works better.

>

> http://snipurl.com/ajmu

[Guest guest]

Hi folks:

I just re-did the calculation for the amount of vitamin E one gets if

one takes 400 I.U. once a week, compared with someone who takes no

supplements.

ANSWER: 6.7 times as much. Seems like plenty. I will be continuing

to take it once a week.

Now that folic acid is being added to foods I doubt the 'ten times as

much' still applies. But I am going to continue taking that once a

week also. Same with beta carotene ...............

fwiw

Rodney.

> > >

> > > http://www.forbes.com/lifestyle/health/feeds/hscou

> > > t/2004/11/10/hscout522256.html

> > >

> > > I wish those guys would make up their minds.

> > >

> > > A

> >

> > This link works better.

> >

> > http://snipurl.com/ajmu

[Guest guest]

If you're eating a diet heavy in vegetables, I can't imagine you

really require any supplemental folic acid or beta-carotene.

On Thu, 11 Nov 2004 13:12:15 -0000, Rodney <perspect1111@...> wrote:

>

>

> Hi folks:

>

> I just re-did the calculation for the amount of vitamin E one gets if

> one takes 400 I.U. once a week, compared with someone who takes no

> supplements.

>

> ANSWER: 6.7 times as much. Seems like plenty. I will be continuing

> to take it once a week.

>

> Now that folic acid is being added to foods I doubt the 'ten times as

> much' still applies. But I am going to continue taking that once a

> week also. Same with beta carotene ...............

>

> fwiw

>

> Rodney.

>

>

> > > >

> > > > http://www.forbes.com/lifestyle/health/feeds/hscou

> > > > t/2004/11/10/hscout522256.html

> > > >

> > > > I wish those guys would make up their minds.

> > > >

> > > > A

> > >

> > > This link works better.

> > >

> > > http://snipurl.com/ajmu

>

>

>

>

[Guest guest]

The point is not whether you're getting " enough " but what is the

DOSE-EFFECT RELATIONSHIP. personally, I prefer existing in that range

of optimum values for a specific nutrient/antioxidant etc as opposod

to just getting enough. Some compounds may have " pharmaceutical-like

effects " at certain dosages and this is the sweet spot I like to shoot

for.

Also, can anyone direct me to website/articles/studies that provide

comprehensive and detailed education on cholesterol and it's subfractions?

TIA.

> > > > >

> > > > > http://www.forbes.com/lifestyle/health/feeds/hscou

> > > > > t/2004/11/10/hscout522256.html

> > > > >

> > > > > I wish those guys would make up their minds.

> > > > >

> > > > > A

> > > >

> > > > This link works better.

> > > >

> > > > http://snipurl.com/ajmu

> >

> >

> >

> >

[Guest guest]

First how about a web site that provides all the "DOSE-EFFECT RELATIONSHIP"s? And "pharmaceutical-like effects"s? And identification of all those "sweet spot"s? This vitamin E study seems to me to place a lot more questions on the whole supplement world, not just E. We have RDA's of known goodies, calculated to fit 97% of people. How sweet is that?

All the guys who dig into this subject keep crawfishing back to eat your veggies and fruits. A lot of that is unsureness of the OTHER 1000 chemicals in the food. Try doing an analysis on Duke's data. A cursory look (maybe 700 chemicals) showed me that common foods of today contain a LOT of stuff. Things like carrots, onions, garlic, tomatoes, papaya, prunes, spices, common herbs - actually more stuff than I could eat in a day.

Regards.

----- Original Message -----

From: freebird5005

Sent: Thursday, November 11, 2004 8:12 AM

Subject: [ ] Re: Vitamin E Linked to Higher Death Rates

The point is not whether you're getting "enough" but what is theDOSE-EFFECT RELATIONSHIP. personally, I prefer existing in that rangeof optimum values for a specific nutrient/antioxidant etc as opposodto just getting enough. Some compounds may have "pharmaceutical-likeeffects" at certain dosages and this is the sweet spot I like to shootfor.Also, can anyone direct me to website/articles/studies that provide comprehensive and detailed education on cholesterol and it's subfractions?TIA. > If you're eating a diet heavy in vegetables, I can't imagine you> really require any supplemental folic acid or beta-carotene.>

[Guest guest]

Vitamin E has always been interesting to me. I first saw it on a label of a MV given to me in 1956. I noticed then it didn't have an RDA and I wondered why it was in there. Ever wonder why they put something in when there's no RDA? Now my pill bottle say 60 IU, 200% of RDA.

Per DRI, "The RDA for both men and women is 15 mg (35 µmol)/day of a-tocopherol"

So like Rodney I wonder why I would need more than that.

Today I have the best reference, IMO, that I could want:

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

{This is very long and well worth reading the full report - here is excerpts:}

Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids

Types of Data Used

"A number of disciplines have made key contributions to the evidence linking antioxidants to outcomes that may relate to human health (e.g., Hennekens and Buring, 1987). Basic biological research often involving animal models, provides crucial information on mechanisms that may link nutrient consumption to beneficial or adverse health outcomes. "

Human Feeding Studies

Controlled feeding studies, usually in a confined setting such as a metabolic ward, can yield valuable information on the relationship between nutrient consumption and health-related biomarkers.

Pathways to Nutrient Requirements

The possible pathways that were considered in determining the requirement for each nutrient include the following:

The availability of a convincing totality of evidence, including randomized clinical trial data, that the nutrient reviewed reduces the risk of important health outcomes—demonstration that a biomarker of exposure influences a specific health outcome constitutes a key component of this body of evidence.

The availability of a convincing totality of evidence, including randomized clinical trial data, that the nutrient reviewed favorably affects a selected functional marker—this pathway was used with caution in view of the many examples where intervention effects on an intermediate outcome (biomarker) proved to be inconsistent with intervention effects on the chronic disease of interest.

The presence of a clinically important deficiency disease or nutritional syndrome that has been demonstrated to relate specifically to an inadequate intake of the nutrient reviewed—this pathway is facilitated by considering intakes needed to ensure adequate body stores or reserves of the nutrient or of pertinent compounds that the body produces in response to adequate intake of the nutrient.

DIETARY INTAKES IN THE UNITED STATES AND CANADA

Sources of Dietary Intake Data

The major sources of current dietary intake data for the U.S. population are the Third National Health and Nutrition Examination Survey (NHANES III), which was conducted from 1988 to 1994 by the U.S. Department of Health and Human Services, and the Continuing Survey of Food Intakes by Individuals (CSFII), which was conducted from 1994 to 1996 by the U.S. Department of Agriculture (USDA). NHANES III examined 30,000 subjects aged 2 months and older.

Vitamin E

SUMMARY

Vitamin E is thought to function primarily as a chain-breaking antioxidant that prevents the propagation of lipid peroxidation. Overt deficiency is very rare, seen only in individuals unable to absorb the vitamin or with inherited abnormalities that prevent the maintenance of normal blood concentrations. Thus, current dietary patterns appear to provide sufficient vitamin E to prevent deficiency symptoms such as peripheral neuropathy.

The RDA for both men and women is 15 mg (35 µmol)/day of a-tocopherol. Vitamin E activity of a-tocopherol as defined in this report is limited to that available from the naturally occuring form (RRR-) and the other three synthetic 2R-stereoisomer forms (RSR-, RRS-, and RSS-) of a-tocopherol for purposes of establishing the human requirement for vitamin E. Other naturally occurring forms of vitamin E (ß-, γ-, and d-tocopherols and the tocotrienols) do not contribute toward meeting the vitamin E requirement because (although absorbed) they are not converted to a-tocopherol by humans and are recognized poorly by the a-tocopherol transfer protein (a-TTP) in the liver. Therefore, the RDA is based only on the a-tocopherol form of vitamin E which represents a change from most recent recommendations. A large and growing body of experimental evidence suggests that high intakes of vitamin E may lower the risk of some chronic diseases, especially heart disease. However, the limited and discordant clinical trial evidence available precludes recommendations at this time of higher vitamin E intakes to reduce chronic disease risk. The Tolerable Upper Intake Level (UL) for adults is set at 1,000 mg (2,325 µmol)/day of any form of supplemental a-tocopherol based on the adverse effect of increased tendency to hemorrhage.

others:

Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc (2000)Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline (1998)

[Guest guest]

I am not so sure I understand your argument.

If you eat a predominately plant food diet, for instance, you will

exceed the RDA's in most of the known nutrient/vitamins, sometimes by

a great amount. So, do you cut back the amounts of food you eat to

remain close to the RDA's??

> > If you're eating a diet heavy in vegetables, I can't imagine you

> > really require any supplemental folic acid or beta-carotene.

> >

[Guest guest]

--- In , " Rodney " <perspect1111@y...>

wrote:

>

> Hi folks:

>

> I just re-did the calculation for the amount of vitamin E one gets

if

> one takes 400 I.U. once a week, compared with someone who takes no

> supplements.

>

> ANSWER: 6.7 times as much. Seems like plenty. I will be

continuing

> to take it once a week.

>

> Now that folic acid is being added to foods I doubt the 'ten times

as

> much' still applies. But I am going to continue taking that once a

> week also. Same with beta carotene ...............

>

> fwiw

>

> Rodney.

Hi All,

Folic acid intake level is important in maintaining human health.

Following the discussion of folic acid levels and their association

with neural tube defects (NTDs) in the below, is a nice overview, I

thought, of the implications of high and low folic acid on our health,

especially, our risk of development and progression of cancer.

I will let the below do the talking, since it is an extensive

overview on the topic.

However, first below, are several quotes from it that I thought

highlight

some of the risks of high, especially, and low folic acid intakes in

our

foods plus supplements.

" If, however, folate intervention is started after the es-tablishment

of neoplastic foci, dietary folate has the opposite

effect on the development and progression of CRC (43, 44).

Some animal studies have also shown that dietary folate defi-ciency

inhibits rather than enhances the development of breast

cancer in rats (45, 46), which is in contrast to the inverse asso-

ciation

between folate status and breast cancer risk observed in

epidemiologic studies (46). In conjunction with some clinical

observations, these animal studies suggest that folate possesses

dual modulatory effects on carcinogenesis depending on the tim-ing

and dose of folate intervention (1). Folate deficiency has an

inhibitory effect, whereas folate supplementation has a promot-ing

effect on the progression of established neoplasms (1, 32). In

contrast, folate deficiency in normal epithelial tissues appears to

predispose them to neoplastic transformation, and modest

amounts of folate supplementation (4 –10 times the basal dietary

requirement) suppress, whereas supraphysiologic doses en-hance,

the development of tumors in normal tissues (1, 32). "

" children with acute leu-kemia

treated with folate supplementation experienced an accel-erated

progression of leukemia (47). Analogous to this situation,

beta-carotene supplementation has been shown to promote the de-

velopment

of lung cancer in smokers who likely harbored pre-neoplastic

or neoplastic foci before supplementation (48, 49). "

" It is

evident from this statistic that the potential effect of folic acid

fortification on adenoma progression to CRC and on CRC pro-gression

to metastasis far outweighs the effect on NTD risk

reduction. "

" The potential

cancer-promoting effect of folic acid fortification in the vast

majority of the US population, who are not at risk of NTDs but

have been unintentionally exposed to high amounts of folic acid,

is a legitimate public health concern and needs careful

monitoring. "

Commentary:

Am J Clin Nutr. 2004 Nov;80(5):1123-1128.

Will mandatory folic acid fortification prevent or promote cancer?

Kim YI.

... neural tube defects (NTDs) ... The success of folic acid

fortification in

improving folate status and in reducing NTD rates is truly a public

health

triumph and provides a paradigm of collaboration between science and

public

health policy. Although folic acid is generally regarded as safe,

there

continues to be concern that folic acid fortification may have

adverse effects

in subpopulation groups not originally targeted for fortification. In

this

regard, an emerging body of evidence suggests that folic acid

supplementation

may enhance the development and progression of already existing,

undiagnosed

premalignant and malignant lesions. Over the past few years, the US

population

has been exposed to a significant increase in folate intake, for which

essentially no data on safety exist. The potential cancer-promoting

effect of

folic acid supplementation needs to be considered in carefully

monitoring the

long-term effect of folic acid fortification on the vast majority of

the US

population, who are not at risk of NTDs.

PMID: 15531657 [PubMed - as supplied by publisher]

Folate is a water-soluble B vitamin that appears to play an

important role in the pathogenesis of several disorders in hu-mans,

including anemia, cardiovascular disease, thromboembo-litic

processes, neural tube defects (NTDs) and other congenital

defects, adverse pregnancy outcomes, neuropsychiatric disor-ders,

and cancer (1). Folic acid is the fully oxidized monoglu-tamyl

form of this vitamin and is used commercially in supple-ments

and in fortified foods. The expanding role of folate

nutrition in health and disease has major public health implica-tions.

For example, evidence from intervention trials (2– 4) and

observational studies (5) for a protective effect of periconcep-tional

folic acid supplementation against NTDs was considered

to be sufficiently conclusive and led public health policy makers,

including the US Public Health Service in 1992 and the Institute

of Medicine in 1998, to recommend that all women who were of

reproductive age or were capable of becoming pregnant consume

daily 400 microg folic acid from supplements or fortified foods in

conjunction with consumption of folate-rich foods (6, 7). This

recommendation was followed by a US Food and Drug Admin-istration

regulation in 1996 requiring that all flour and uncooked

cereal-grain products in the United States be fortified with folic

acid (140 microg/100 g) by January 1998 (8). Mandatory folic acid

fortification was also implemented in Canada in 1998 (9) and in

Chile (10), and limited voluntary folic acid fortification of spec-

ified

foods was implemented in Western Australia in 1995 (11).

The effectiveness of folic acid fortification in improving folate

status has already been shown to be quite striking, with a dra-matic

increase in blood measurements of folate (serum, plasma,

and red blood cell) and a substantial decrease in plasma homo-cysteine

(an accurate inverse indicator of folate status) concen-trations

in the United States and Canada (10 –17). Preliminary

reports suggest a significant reduction (~15–50%) in the prev-alence

and incidence of NTDs in the United States, Canada, and

Western Australia (18 –23). However, it is impossible to defi-nitely

attribute the decrease in the incidence of NTDs in the

United States solely to fortification (24) because NTDrates in the

United States (and worldwide) were decreasing even before for-

tification

began, possibly as a result of factors such as improved

nutrition or prenatal diagnosis and termination.

Despite the observed beneficial effects of folic acid fortifica-tion

on folate status and NTDs in countries that adopted either

mandatory or limited voluntary fortification, there continues to

be some concern that folic acid fortification may have adverse

effects in subpopulation groups not originally targeted for forti-

fication.

Although folate is safe and almost free of toxicity (25),

concerns that folic acid fortification may mask symptoms of

vitamin B-12 deficiency, primarily in the elderly population,

have been raised (7). Vitamin B-12 deficiency has been esti-mated

to affect up to 10–15% of the population over 60 y of age

(7). Because of this concern, the amount of fortification chosen

was estimated to provide on average 100 microg additional folic

acid/d, with only a very small proportion of the population re-ceiving

>1 mg (7). The upper limit of 1 mg was a round number

chosen by the Institute of Medicine as unlikely to produce mask-ing

(7), although the folate intake that produces masking is con-

troversial,

with some arguing that intakes <1 mg may cause this

effect (24). Several European countries decided not to adopt

mandatory folic acid fortification, and the United Kingdom's

Food Standards Agency Board and the Dutch Health Council

even recommended against mandatory folic acid fortification, in

part because of the potential for masking the diagnosis of a

vitamin B-12 deficiency (5). The debate on the folic acid forti-

fication

controversy has become highly emotional; delaying fo-lic

acid fortification in some European countries was even la-beled

as public health malpractice (26).

A more logical alternative to generalized mandatory folic acid

fortification might be targeted folic acid supplementation in a

specific group at risk of NTDs (eg, women with a previous

NTD-affected pregnancy). However, efforts to increase pericon-

ceptional

folic acid supplements have been proven to be disap-pointing,

and public health efforts to influence those persons

most at risk are generally perceived to have been a failure. Sur-veys

taken in the United States, Puerto Rico, Netherlands, and

Western Australia have shown that the public health policy rec-

ommendations

and massive folic acid education and promotion

programs advocating daily consumption of supplements contain-ing

folic acid among women of childbearing age fail to substan-tially

increase the proportion of women of reproductive age who

take a daily supplement containing folic acid (5). What is most

disturbing in these surveys is that although most of these women

had knowledge of the importance of folic acid, only ~30–35%

of womenof reproductive age reported taking a daily supplement

containing folic acid (5). Knowing that folic acid awareness does

not necessarily translate into behavior change and that the neural

tube closes during the fourth week of gestation, a time when

many women are unaware of their pregnancy, public health pol-icy

makers opted for generalized folic acid fortification instead of

targeted folic acid supplementation in subpopulations at risk of

NTDs. However, there is evidence of success regarding reduc-tions

in NTDs and increased compliance with recommendations

to take folic acid supplements in targeted geographic areas (27).

For example, in response to the NTD Intervention Awareness

Campaign in South Carolina, overall NTD rates decreased sig-

nificantly,

and no NTDrecurrences were reported in womenwith

a previous NTD-affected pregnancy who periconceptionally

consumed supplements containing folic acid (27). The drop in

overall NTD rates preceded fortification and coincided with

higher reported supplemental folic acid intakes (27).

Implicit in the folic acid fortification recommendation and

policy was that improving folate status in the general population

may provide other health benefits in addition to the reduction in

NTD rates. Over the next few years, there will likely be many

epidemiologic studies that will attempt to elucidate the long-term

effect of folic acid fortification on the incidence of anemia, car-

diovascular

disease, thromboembolitic processes, congenital de-fects,

adverse pregnancy outcomes, neuropsychiatric disorders,

and cancers in countries that adopted mandatory and limited folic

acid fortification. In this regard, a recent Canadian study (28)

reported evidence supporting other potential health benefits of

folic acid fortification. Using the database of the Pediatric On-

cology

Group of Ontario, which captures 95% of all pediatric

cancers in Ontario, this study determined the effect of folic acid

fortification on the incidence of neuroblastoma among children

aged </=17 y (28). The study showed that folic acid fortification

was associated with a significant (60%) reduction in the inci-dence

of neuroblastoma (from 1.57 cases per 10 000 births in

1996 to 0.62 cases per 10 000 births after 1997, when folic acid

fortification of food became mandatory in Canada) (28). How-ever,

the incidence of infant acute lymphoblastic leukemia and

hepatoblastoma remained almost the same (28). The results of

this study corroborate those of previous epidemiologic studies,

which reported a protective effect of the prenatal and perinatal

maternal use of folic acid against the incidence of brain tumors in

offspring (29 –31). Therefore, the findings of this Canadian study

suggest that, in addition to reducing NTD rates, mandatory folic

acid fortification may prevent the development of certain can-cers.

Because of significant public health implications, the po-tential

health benefits, including cancer prevention, of improved

folate status in the general population make a strong case for

mandatory folic acid fortification and for providing even higher

amounts of folic acid as argued for by some proponents of man-datory

generalized folic acid fortification.

Often neglected and lost in public health policy making and

debate concerning folic acid fortification is the effect of folate on

cancer development and progression. Perhaps one of the most

speculative and provocative new medical applications of folate

nutrition is the potential role of folate as a cancer preventive agent

(1, 32). The concept that folate deficiency enhances, whereas

folate supplementation reduces, the risk of neoplastic transfor-mation

appears counterintuitive and contradictory to our con-ventional

understanding of folate biochemistry. Folate is an es-sential

cofactor for the de novo biosynthesis of purines and

thymidylate, and in this capacity, folate plays an important role

in DNA synthesis and replication. Consequently, folate defi-ciency

in tissues with rapidly replicating cells results in ineffec-tive

DNA synthesis. In neoplastic cells, in which DNA replica-tion

and cell division occur at an accelerated rate, interruption of

folate metabolism causes ineffective DNA synthesis, resulting in

inhibition of tumor growth (32, 33). Indeed, this has been the

basis for cancer chemotherapy with several antifolate agents (eg,

methotrexate) and 5-fluorouracil (32, 33). Furthermore, folate

deficiency has been shown to induce regression and suppress the

progression of preexisting neoplasms in experimental models

(34 –36). In contrast to the inhibitory and promoting effect of

folate deficiency and supplementation, respectively, on estab-lished

neoplasms, folate status appears to have the opposite effect

in normal tissues. An accumulating body of epidemiologic, clin-ical,

and experimental evidence over the past decade suggests

that folate deficiency in normal tissues appears to predispose

them to neoplastic transformation, and folate supplementation

suppresses the development of tumors in normal tissues (1, 32).

The potential causal relation between folate status and cancer risk

has been further strengthened by the existence of several biolog-

ically

plausible mechanisms relating to the sole biochemical

function known for folate (mediating the transfer of one-carbon

moieties), by which folate status may modulate the development

and progression of cancer in normal tissues (32, 33). As an

essential cofactor for the de novo biosynthesis of purines and

thymidylate, folate plays an important role in DNA synthesis,

stability and integrity, and repair, aberrations of which have been

implicated in colorectal carcinogenesis (32, 33). Folate may also

modulate DNA methylation, which is an important epigenetic

determinant in gene _expression, maintenance of DNA integrity

and stability, chromosomal modifications, and the development

of mutations (32, 33). A growing body of evidence from in vitro,

animal, and human studies indicates that folate deficiency is

associated with DNA strand breaks, impaired DNA repair, in-creased

mutations, and aberrant DNAmethylation and that folate

supplementation can correct some of these defects induced by

folate deficiency (32, 33).

Epidemiologic studies have suggested an inverse association

of folate with the risk of cancer of the colorectum, lungs, pan-creas,

esophagus, stomach, cervix, ovary, and breast and the risk

of neuroblastoma and leukemia (1, 32). The precise nature and

magnitude of the inverse relation between folate status and the

risk of these malignancies, however, have not yet been clearly

established (1, 32). The role of folate in carcinogenesis has been

best studied for colorectal cancer (CRC) in the general popula-tion

and in persons with chronic ulcerative colitis (1, 5, 32, 37).

Most of the published epidemiologic and clinical studies found

either a significant inverse relation between folate status (as-sessed

by using dietary folate intakes or measurement of blood

folate concentrations) and the risk of CRC or its precursor, ade-noma,

or an equivocal inverse relation that was not significant. In

the case of equivalent inverse relations, either those relations

became nonsignificant after adjustment, or folate status could not

be distinguished from other factors in its relation to the risk of

CRC or adenoma (1, 5, 32, 37). A recent meta-analysis of 11

prospective epidemiologic studies from the United States, Can-ada,

Netherlands, and Sweden that included >500 000 male and

female subjects showed a significant inverse association be-tween

folate intake (dietary and supplemental) and the risk of

CRC (DJ Hunter, personal communication, 2003). This meta-analysis

also showed a 20% reduction in the risk of CRC in

subjects with the highest folate intake compared with those with

the lowest intake. In some epidemiologic studies, the observed

inverse association between folate status and CRC risk was fur-ther

modified by the intake of alcohol and other nutritional fac-tors

(eg, methionine and vitamins B-6 and B-12) that are involved

in the folate metabolic pathway and by polymorphisms of critical

genes (eg, methylene tetrahydrofolate reductase gene 677C3T)

that are involved in folate metabolism (1, 5, 32, 37). At present,

human intervention trials provide no conclusive evidence sup-porting

the protective effect of folate supplementation against

CRC, although several small pilot studies have shown that folate

supplementation may improve or reverse surrogate endpoint bi-omarkers

of CRC (1, 32), and some epidemiologic studies have

shown a beneficial effect of multivitamin supplements contain-ing

>/=400 microg folic acid on CRC risk and mortality (38, 39).

Although animal studies performed in chemical carcinogen

and genetically engineered murine models of CRC generally

support a causal relation between folate depletion and CRC risk,

these studies have shown that the dose and timing of folate

intervention are critical in providing safe and effective chemo-

prevention;

exceptionally high supplemental folate doses and

folate intervention after microscopic neoplastic foci are estab-lished

in the colorectal mucosa promote rather than suppress

colorectal carcinogenesis (1, 32). For example, in a standard

chemical carcinogen rodent model of CRC, supraphysiologic

doses of folate (>20 times the basal daily dietary requirement)

were shown to increase the development and progression of CRC

(40 –42). Furthermore, in 2 genetic models of CRC (Apc Min and

Apc +/- x Msh2 -/- mice), moderate folate deficiency enhanced,

whereas modest doses of folate supplementation suppressed, the

development and progression of CRC if folate intervention was

started before the establishment of neoplastic foci in the intestine

(43, 44). If, however, folate intervention is started after the es-

tablishment

of neoplastic foci, dietary folate has the opposite

effect on the development and progression of CRC (43, 44).

Some animal studies have also shown that dietary folate defi-ciency

inhibits rather than enhances the development of breast

cancer in rats (45, 46), which is in contrast to the inverse asso-

ciation

between folate status and breast cancer risk observed in

epidemiologic studies (46). In conjunction with some clinical

observations, these animal studies suggest that folate possesses

dual modulatory effects on carcinogenesis depending on the tim-ing

and dose of folate intervention (1). Folate deficiency has an

inhibitory effect, whereas folate supplementation has a promot-ing

effect on the progression of established neoplasms (1, 32). In

contrast, folate deficiency in normal epithelial tissues appears to

predispose them to neoplastic transformation, and modest

amounts of folate supplementation (4 –10 times the basal dietary

requirement) suppress, whereas supraphysiologic doses en-hance,

the development of tumors in normal tissues (1, 32).

Although some similarities do exist, tumor development in

chemical and genetically engineered animal models of CRC dif-fers

in several important histologic, clinical, and molecular ge-netic

aspects from that observed in humans. Therefore, any ex-trapolation

of observations from these models to human

situations should be made cautiously. Notwithstanding these

limitations, however, the data from animal studies suggest that

the optimal timing and dose of folate intervention should be

established before folate supplementation can be used as a safe

and effective chemopreventive agent against CRC. Although

folate appears to be an ideal candidate for chemoprevention

because of its proven safety and cost (25), the safe and effective

dose range of folate supplementation and optimal timing of folate

chemoprevention have not been clearly established in humans.

Animal studies and some clinical studies have suggested that

folate supplementation may increase cancer risk and accelerate

tumor progression if too much is given or if it is provided after

neoplastic foci are established in the target organ. Therefore,

modest doses of folate supplementation should apparently be

implemented before the development of precursor lesions in the

target organ or in persons free of any evidence of neoplastic foci.

However, determining the presence of neoplastic foci in the

general population is obviously an almost impossible task. Fur-

thermore,

folate might prevent the progression of certain precur-sor

or preneoplastic lesions to frank malignancy but promote the

progression of other lesions. What constitutes safe precursor or

preneoplastic lesions on which folate may exert a protective

effect has not yet been established. For example, should folate

chemoprevention be started before there is evidence of estab-lished

premalignant lesions, such as aberrant crypt foci or mi-croscopic

adenomatous lesions in the colorectum, or should fo-late

chemoprevention be started even after these lesions are

present?

It is apparent from the above discussion that folic acid sup-

plementation

should not be adopted as a chemopreventive agent

against CRC and other cancers until definitive evidence indicates

that such supplementation is indeed safe and effective. However,

what are the effects of folic acid fortification on the risk of CRC

and other malignancies? Is there any reason to believe that folic

acid fortification may actually increase the risk of certain can-cers?

Although folic acid fortification may prevent NTDs as

evidenced by preliminary reports suggesting a significant reduc-tion

(~15–50%) in the prevalence and incidence of NTDs in the

United States, Canada, and Western Australia (18 –23), the long-term

effect of folic acid fortification on the risk of CRC and other

malignancies may not be as clear as that observed for NTDs.

Although folic acid fortification may prevent the development of

new cancers in persons without preexisting premalignant lesions

or neoplastic foci, it may promote the progression of these lesions

in persons harboring them. The addition of folate to established

tumors has previously been shown to cause an " acceleration

phenomenon " in humans. For example, children with acute leu-kemia

treated with folate supplementation experienced an accel-erated

progression of leukemia (47). Analogous to this situation,

beta-carotene supplementation has been shown to promote the de-

velopment

of lung cancer in smokers who likely harbored pre-neoplastic

or neoplastic foci before supplementation (48, 49).

The success of folic acid fortification in improving folate

status and in reducing NTD rates is truly a public health triumph

and provides a paradigm of collaboration between science and

public health policy. Improved folate status in the general pop-

ulation

resulting from folic acid fortificaion may also lead to

reduction in anemia, cardiovascular disease, thromboembolitic

processes, congenital defects, adverse pregnancy outcomes, and

neuropsychiatric disorders. However, an emerging body of evi-dence

suggests that folic acid supplementation may promote the

progression of preexisting, undiagnosed premalignant and ma-lignant

lesions. Over the past few years, the US and Canadian

populations have been exposed to a significant increase in folate

intake, for which essentially no data on safety exist (24). No

studies have been done to look directly or even indirectly for the

adverse effects of greatly increased folate intakes (24). Several

studies that assessed food composition and dietary intakes sug-gested

that the increased postfortification folate intake in the US

population may be about twice that originally anticipated (14,

50–52). However, these estimates of folate intake based on food-

composition

databases are likely underestimates because of lim-itations

in the analytic methods previously used to analyze food

folate (7).

Although the potential masking effect of folate on vitamin

B-12 deficiency, especially in the elderly, has been the major

concern of folic acid fortification, other adverse effects, such as

the potential cancer-promoting effect of folic acid supplementa-tion,

need to be considered in carefully monitoring the long-term

effect of folic acid fortification on health and disease in the vast

majority of the US and Canadian populations, who are not at risk of

NTDs. Furthermore, because intracellular and systemic folate con-

centrations

are important determinants of the sensitivity of cancer

cells to chemotherapy (53) and in the treatment of inflammatory

and seizure disorders with the use of antifolates (25), the occurrence

of resistance or tolerance to antifolate chemotherapy and anti-

inflammatory

and anti-seizure drugs should be added to the list of

potential unwanted complications of folic acid fortification.

Another potential harmful consequence of folic acid fortifica-tion

in relation to cancer risk modification concerns DNA meth-ylation.

DNA methylation of cytosine located within the

cytosine-guanine (CpG) dinucleotide sequences is an important

epigenetic determinant in gene _expression (inverse relation),

maintenance of DNA integrity and stability, chromatin modifi-cations

and remodeling, and the development of mutations (54).

Neoplastic cells simultaneously harbor widespread genomic hy-

pomethylation

and more specific regional areas of hypermeth-ylation

(54). Genomic hypomethylation is an early and consis-tent

event in carcinogenesis and is associated with genomic

instability and increased mutations. In addition, site-specific

hypermethylation at promoter CpG islands of tumor suppres-sor

and mismatch repair genes is an important mechanism

in gene silencing in carcinogenesis (54). Folate, in the form

of 5-methyltetrahydrofolate, is involved in remethylation

of homocysteine to methionine, which is a precursor of

S-adenosylmethionine, the primary methyl group donor for most

biological methylations, including that of DNA (55). Although

the effect of folate deficiency on DNA methylation is highly

variable and complex, folate supplementation appears to signif-icantly

increase the extent of genomic and site-specific DNA

methylation in certain situations (55). This then begs a question:

can folic acid fortification methylate normally unmethylated

promoter CpG islands of tumor suppressor or mismatch repair

genes and inactivate these genes, thereby promoting the devel-opment

of cancer? This is a theoretical possibility and warrants

investigation. In this regard, a recent animal study using viable

yellow agouti (A vy ) mice showed that maternal dietary methyl

group supplementation with a modest amount of folic acid, vi-tamin

B-12, choline, and betaine may permanently alter the phe-notype

of the offspring via increased CpG methylation at the

promoter CpG site of the agouti gene (56). The investigators

found that the methylaton status of the promoter CpG region of

the agouti gene was highly correlated with the methylaton status

of the adjacent transposon gene (56). Transposons are common

and potentially mobile sequences of DNA that are scattered

throughout the genome (57). More than 35% of human DNA is

estimated to be derived from transposons (57). Depending on

where they are inserted in DNA, transposons can end up silenc-ing

neighboring genes (57). Therefore, this study by Waterland

and Jirtle (56) showed that there is a localized epigenetic insta-

bility

in methylation that arises from an interaction between the

transposon and its nearby genetic region and that genes that

manifest a transposon region adjacent to a promoter region of

DNA could be influenced by early nutrition containing methyl

group donors, including folic acid. These investigators specu-lated

that " population-based supplementation with folic acid,

intended to reduce the incidence of NTD and long presumed to

be purely beneficial, may have unintended deleterious influ-ences

on the establishment of epigenetic gene-regulatory mech-anisms

during human embryonic development (57). "

Some proponents of mandatory folic acid fortification have

labeled the delay in folic acid fortification in some European

countries as public health malpractice (26). However, a reason-able

conclusion from the above discussion is that inertia on folic

acid fortification in these European countries should not be con-

strued

as public health malpractice but should be regarded as

public health prudence. The effect of folic acid fortification on

cancer risk has a greater effect on public health than on NTDs

because of the incidence and prevalence of cancer and prema-lignant

precursors in the general US population. For example, in

the United States, CRC is the fourth most frequently diagnosed

and the second most common cause of cancer-specific death for

both men and women (58). In 2004 alone, 146 940 new cases of

CRC are expected to be diagnosed, and ~40% of these are

expected to die within 5 y (58). In 2004 an estimated 56 370

deaths will have been caused by CRC (58). The lifetime risk of

developing CRC is ~6% (59), and treatment costs nearly $6

billion annually (60). Colorectal adenomas, the well-established

precursor of CRC (59), are found in ~25%of people by 50 y of

age in the United States, and the prevalence increases with age

(59). On the basis of autopsy series, which are probably less

susceptible to selection and detection bias than are clinical series,

the prevalence of adenomas is estimated to reach ~50% by 50 y

of age (59). It has been estimated that ~25%of adenomas

progress to CRC over 5–10 y (59). In contrast, NTDs occur in ~1

of every 1000 births in the United States, and spina bifida and

anencephaly, the most common NTDs, together affect ~4000

pregnancies resulting in 2500–3000 US births annually (61). It is

evident from this statistic that the potential effect of folic acid

fortification on adenoma progression to CRC and on CRC pro-gression

to metastasis far outweighs the effect on NTD risk

reduction. Given the prevalence and incidence of colorectal ad-enomas

and CRC in the general population in the United States,

therefore, whether or not folic acid fortification promotes the

progression of adenomas to CRCin the colorectum is a legitimate

public health concern and needs careful monitoring.

A recent study showing that folic acid fortification signifi-cantly

reduced the incidence of neuroblastoma in Ontario (28) is

an encouraging piece of information in this regard. However,

long-term follow-up studies are urgently warranted to determine

the effect of folic acid fortification on the incidence of cancer and

on DNA methylation and other epigenetic regulatory machinery

in countries that have adopted mandatory generalized folic acid

fortification. Furthermore, safe and effective amounts of folic

acid fortification need to be scientifically determined by using

relevant animal, experimental, and clinical models. The potential

cancer-promoting effect of folic acid fortification in the vast

majority of the US population, who are not at risk of NTDs but

have been unintentionally exposed to high amounts of folic acid,

is a legitimate public health concern and needs careful

monitoring.

Cheers, Alan Pater

[Guest guest]

I don't think this latest Vit E study you refer to says anything at

all about the " whole supplement industry. " It's just one study, and

studies stand or fall on their own merit. Does one " negative " caloric

restriction study call into question the " whole caloric restriction

industry " ?? (and there have been negative studies, more than one)

Now, here's an example to make my previous point that specific doses

can have beneficial " pharmaceutical-like " effects: NIACIN

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstra\

ct & list_uids=15529025

Niacin therapy in atherosclerosis.

Meyers CD, Kamanna VS, Kashyap ML.

Endocrinology Section, and Gerontology Section, VA Long Beach

Healthcare System, Atherosclerosis Research Center, and Department of

Medicine, University of California, Irvine, California, USA.

PURPOSE OF REVIEW: Well designed, randomized, placebo-controlled

studies show that niacin prevents cardiovascular disease and death.

Unfortunately, early studies and anecdotal evidence have limited its

use by promoting the opinion that niacin is intolerable and

contraindicated in diabetes. As evidence mounts that treating multiple

lipid risk factors decreases cardiovascular risk, the use of niacin in

the treatment of atherosclerosis is experiencing somewhat of a

renaissance. RECENT FINDINGS: Emerging clinical evidence shows that

niacin is both safe and effective in diabetes. Niacin beneficially

alters lipoprotein subclass distribution and when used in combination

with statins, has additional effects on lipoproteins. Niacin

selectively and directly inhibits hepatic diacylglycerol

acyltransferase 2, but not diacylglycerol acyltransferase 1, thus

inhibiting hepatic triglyceride synthesis and very low density

lipoprotein secretion. The recent discovery and characterization of a

membrane-bound nicotinic acid receptor (HM74) explains niacin's acute

inhibition of adipocyte lipolysis, but the role of HM74 in lowering

triglycerides is unclear. Niacin possesses antioxidant,

antiinflammatory, and other beneficial effects on atherosclerosis

unrelated to lipid lowering. Finally, niacin appears to activate

nuclear transcription factors such peroxisome proliferator activator

receptor gamma, possibly via prostaglandin metabolism. SUMMARY: New

data indicate that niacin alters lipoprotein metabolism in novel ways,

and mediates other beneficial nonlipid changes that may be

atheroprotective. This information forms the rationale for the use of

niacin in combination with agents possessing complementary mechanisms

of action (e.g. statins) for cardiovascular risk reduction beyond that

observed with monotherapy. Further research into the specific

mechanisms of niacin may identify additional targets for future drug

development.

> > If you're eating a diet heavy in vegetables, I can't imagine you

> > really require any supplemental folic acid or beta-carotene.

> >