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Scientific review of folic acid fortification - causes for concern

Date Published
 09 November 2009
 Joe Lederman

FoodLegal Bulletin Editor's Note:

After receiving the following letter to the Editor (of FoodLegal Bulletin) from Mr David Franken, our attention has also been drawn to recent reports (published on 5 November 2009) of a scientific study from the University of Adelaide's Robinson Institute which has found that pregnant women who consume folate supplements throughout their pregnancy (as opposed to the short periconceptional window as advised by doctors) increase the risk of their child being born with asthma.

Previous FoodLegal Bulletin articles referred to by the writer are as follows:

All numbering in bold font refers to endnotes.

The following is a Letter to the Editor from Mr David Franken B.Sc(Hons). LL.B.  M.Sc.



Scientific review of folic acid fortification - causes for concern

Over recent months I have been following your various folic acid fortification articles, in FoodLegal Bulletin, with a significant degree of interest. As a consumer, with more than a passing interest in scientific and legal matters, I feel strongly obliged to comment on this important issue.

At the outset, I wish to state that the beneficial link between folic acid fortification and a subsequent reduction in babies born with neural tube defects (NTDs) is scientifically well documented and thus not contested in this communication. An expected reduction of 14 - 49 NTD-affected Australian pregnancies per year1, following a mandatory folic acid fortification scheme, would always be well received by clinicians and parents.

A consumer’s view

However, as a consumer, I am concerned that the mandatory folic acid fortification scheme (200-300µg/100g wheat flour, per Food Standard 2.1.1) will significantly raise my average blood folate level as well as those of other Australian consumers, on a population-wide basis. Whilst a narrow proportion of Australian society will enjoy the benefits of a reduction in NTDs in the immediate term (as well as an ongoing benefit every year thereafter), my personal concerns, regarding folic acid fortification, are more focussed on a longer timeframe (5 – 10+ years). Principally, these concerns relate to the postulated paradoxical role that folate may play in the development of various cancers (particularly colorectal) as well as its possible role in epigenetics issues.

The many facets of folic acid utilisation

Folic acid, as used in food fortification, is in a synthetic monoglutamate form (pteroylmonoglutamate) whereas naturally occurring folate is present in polyglutamate forms, circulating principally as 5-methyltetrahydrofolate, with the synthetic form being more rapidly absorbed than the natural form.2 Folate, as 5-methytetrahydrofolate, plays a critically important role in the provision of one-carbon units for DNA synthesis and also the conversion of homocysteine to S-adenosylmethionine (SAM) via methionine. SAM is the methyl group donor involved in methylation of cytosine residues in DNA (within cytosine-guanine, CpG, dinucleotide sequences) and of arginine and lysine residues in histones.3 As proposed by Fuks (2005)4, both forms of methylation (DNA methylation and histone methylation) may be involved in regulating gene expression. Histone proteins readily bind to chromosomal DNA and accordingly facilitate the efficient packing of a cell’s genetic material within its nucleus. Histone protein structure, which may be altered by a cell’s methylation status, could therefore readily affect the expression and replication of the genetic information within each cell.

Could folic acid play a dual role in (colorectal) cancer?

There exists an increasing body of peer-reviewed scientific literature that has suggested that folic acid plays an important role in various cancers, particularly colorectal cancer (CRC).

Several authors [Song et al 2000(1)5 & (2)6, Kim 2004(1)7], as cited by Smith et al8, have suggested that folic acid supplementation could play a dual (paradoxical) role in this regard. Animal studies on CRC have shown that the timing of folate administration as well as dosage can produce remarkably different outcomes, to the extent that folate supplementation prior to the potential formation of neoplastic foci would confer preventative benefits whereas, supplementation after the establishment of neoplastic foci would enhance their growth and progression. Determining the status (presence or absence) of neoplastic foci in the general population would, however, be an insurmountable task (Kim, 2006)9.

As a molecular basis underpinning the paradoxical effect following folic acid supplementation, Smith et al10 has suggested that possible tumour-inhibitory mechanisms could flow from enhanced DNA stability and integrity, decreased mutagenesis and prevention of aberrant DNA methylation. Conversely, possible tumour-promoting mechanisms, following folic acid supplementation, may be due to the provision of nucleotide precursors for proliferation and growth of neoplastic cells, de novo methylation of promoter CpG islands of tumour suppressor genes leading to inactivation of those genes, as well as hypermutability of methylated cytosines in globally distributed CpG dinucleotides.11

Smith et al12 has cited a number of articles in support of the paradoxical effect. In this regard, van Guelpen et al (2006), constituted a large population-based case control study in Sweden, where ‘…a significant association was found between folate plasma concentrations and CRC, with the lowest concentrations being protective and higher concentrations being related in a bell-shaped manner to increased risk’.13 In Cole et al (2007), the results from the first randomized trial of folic acid for the prevention of CRC in genetically predisposed patients, ‘showed that treatment with folic acid (1000µg per day) for up to 6 years did not prevent the recurrence of colorectal adenomas. On the contrary, at the second follow-up, there was a 67% increased risk of advanced lesions with a high malignant potential… along with a >2-fold increased risk of having ≥ 3 adenomas …’.14

Folic acid fortification and colorectal cancer

The trend of colorectal cancer incidence in the USA and Canada after folic acid fortification (140µg folic acid/100g wheat flour and 150µg folic acid/100g wheat flour, respectively) has been recently examined by Mason et al. (2007)15. Using the End Result Registry and Canadian Cancer Statistics (2006) data sets, respectively, they demonstrated that ‘concurrently, the United States and Canada experienced abrupt reversals of the downward trend in colorectal cancer (CRC) incidence that the two countries had enjoyed in the preceding decade: absolute rates of CRC began to increase in 1996 (United States) and 1998 (Canada), peaked in 1998 (United States) and 2000 (Canada), and have continued to exceed the pre-1996/1997 trends by 4 to 6 additional cases per 100 000 individuals’16. Based on those data sets (which, unfortunately, neither contained a control group) they hypothesised that the ‘institution of folic acid fortification may have been wholly or partially responsible for the observed increase in CRC rates…’.17

Following the initiation (January 2000) of a mandatory folic acid fortification programme (220µg folic acid/100g of wheat flour) by the Chilean government, the aim of the study by Hirsch et al (2009)18 was to compare the rates of Chilean hospital discharges (due to colon cancer) before (period 1992-1996) and after (period 2001-2004) the start of the flour fortification program. Results for colon cancer, in the groups of participants aged 45-64 years and 65-79 years, increased 162% and 190% respectively, in the period following mandatory fortification. According to the authors of this study ‘one possible explanation for this finding is that this increase is causally related to folate supplementation’.19

Whilst the hypotheses of these two publications does not, by any means, designate a definitive position on this issue, they may nevertheless collectively constitute the basis of a worrying trend that is worthy of further investigation. All Australian consumers should therefore expect that the Australian Institute of Health and Welfare (AIHW) (who has been given the overall responsibility of the folic acid monitoring programme),20 in conjunction with FSANZ and the various health agencies at State and Territory levels,21 to robustly and transparently address this issue in the design and implementation of their ongoing folic acid monitoring programme.

My above suggestion is by no means exquisitely unique, as Kim (2004)(2)22 has previously stated that, ‘[g]iven the prevalence and incidence of colorectal adenomas and CRC in the general population in the United States…[t]he 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’. Kim’s (2004) concerns resonate with a degree of prescience within the context of the above data presented by Mason et al (2007).    

Serum folate concentrations in the American public – post fortification

Notwithstanding the Code’s definition of bread (for the purpose of mandatory addition of folic acid to wheat flour) to exclude pizza bases, pastries, cakes and biscuits,23 current industry practice allows for folic acid fortified wheat flour to be used in the manufacture of those aforesaid items.24 Therefore ample opportunity would exist for the Australian population to routinely consume significant quantities of folic acid fortified food products, across a wide range of wheat flour containing products.

Following mandatory folic acid fortification of wheat flour (140µg/100g wheat flour) in the USA in 1998, the National Health and Nutrition Examination Survey (NHANES, 1999-2000) measured a high serum folate concentration (>45.3 nmol/L) in 23% of the overall US population, with 43% of children aged ≤ 5 years of age and 38% of elderly persons reporting results greater or equal to that high concentration.25 Whilst there is no consensus regarding a safe upper concentration of blood folate, serum folate concentrations > 45nmol/L may be considered supraphysiologic.26 Based upon FSANZ’s recommendation to fortify wheat flour with 200-300µg folic acid/100g flour, Australian consumers could quite readily achieve similar serum folate levels to those observed within the NHANES data set. Therefore, could potentially supraphysiologic folate concentrations have any longer term effects upon consumers, particularly amongst children?

Possible epigenetics effects following folic acid fortification – mammalian models

Epigenetics relates to information that is inherited based on gene expression levels rather than on the basis of gene sequence. DNA methylation and DNA-binding proteins (inclusive of histone protein modification due to methylation and other mechanisms) are the principal epigenetic mechanisms affecting gene expression and function.

Waterland & Jirtle (2003)27 have demonstrated a marked phenotypic variation in those mice carrying the agouti allele (with individuals having a yellow coat to those individuals displaying a dark coat) merely by varying the folic acid supplementation of their mother’s diet, which correspondingly increased the degree of (inherited) methylation at a particular gene promoter. It has been shown that yellow-coat and mottled coat agouti progeny were obese and prone to cancer and diabetes, whereas the dark-coated agouti progeny were lean, non-diabetic and had a healthier, normal lifespan.28, 29

Cropley et al (2006)30 has quite elegantly shown, (also using mice with the agouti phenotype), that with a maternal diet supplemented with folic acid, vitamin B12, methionine and other constituents, germ line modification could be attained and those epigenetic changes could be transmitted not only to the first generation of mice (who had been exposed to folate supplementation as foetuses) but also to the offspring of those first generation mice (thus the second generation offspring that were never exposed to any such supplementation). This outcome led those authors to speculate that ‘…in light of the roughly 20-year generation time of humans, our results suggest that current dietary habits may have an influence on grandchildren who will be born decades from now, independent of the diets that their parents consume’.31

However, it is currently uncertain if long-term folic acid supplementation could produce similar epigenetic effects in humans. The recently published Pune Maternal Nutrition Study (Yajnik et al 2008)32 may offer an important insight on this issue. This recent Indian study found that of the 653 children studied, (each having been followed from birth up to the age of 6 years), those children whose mothers had presented during pregnancy with a combination of high dietary folate and low vitamin B12 concentrations (due to their strict vegetarian status), were found to be the most insulin resistant. This led the authors to suggest that this was the ‘first report in humans to suggest that defects in one-carbon metabolism [as a result of high dietary folate and low vitamin B12 intake] might be at the heart of intra-uterine [epigenetic] programming of adult disease’.33

These mammalian studies collectively suggest that, at an epigenetic level, one’s ongoing folate status may have a profound effect on one’s health as well as the health of one’s future offspring. However, to the best of my knowledge, with more than 10 years of a mandatory folic acid fortification programme, neither the United States nor Canada has initiated any substantial longitudinal epigentics-related studies in relation to that programme. As a point of contemplation, how could one dismiss, with any degree of confidence, a possible folic-acid-mediated human epigenetics issue, should one choose not to actively investigate it? 

Concluding comments

The assertion by FSANZ that ‘…mandatory addition of low levels of folic acid to bread…is safe for the whole Australian community’34 would be reassuring if it wasn’t for the existence of a growing number of scientific publications adopting an opposing position.  

With the imminent publication of the AIHW baseline folate data analysis report35 could consumers expect that this baseline data set would serve as a useful framework beyond that of monitoring the efficacy of the fortification programme, with its outcome merely confirming the expected reduction in NTDs?

Should any cancerous and epigenetic trends, (as respectively illustrated above by Hirsch et al, Mason et al and Yajnik et al), be reinforced in future peer-reviewed human folate-fortification studies, at what point, under classic tort law, would this growing body of scientific evidence exceed a threshold such that a food manufacturer should have been able to ‘reasonably foresee’36 that their folate-fortified manufactured product could cause harm to their customers?

Although flour millers (and presumably food manufacturers) could absolve their liability, in this regard, under s 75AL of the Trade Practices Act 1974 (Cth), such a claim may only be substantiated if there was absolute compliance with the Standard. In this regard, Radler et al (2000) may be highly relevant, where it was found that ‘[f]or many enriched cereal-grain products, there were significant differences between amounts of folate found on analysis and amounts required by Federal regulations. In part because of this, label declarations of folate content were also in error’.37

From a risk management perspective, the food manufacturing industry would presumably have an interest in contemplating their possible future liabilities, should their purported statutory immunity fail to insulate them from the effects of any consumer harm that may directly flow from the fortification programme, following consumers’ long-term exposure to folic acid fortified food products (over a duration of 10+ years).

Notwithstanding the FSANZ First Review Report Proposal P29538, more recent scientific data suggests that a mandatory folic acid fortification programme has the potential, in the longer-term, to confer harm upon Australian consumers. The Food Safety Authority of the Republic of Ireland (FSAI), the Standing Advisory Committee on Nutrition (SACN) in the United Kingdom as well as the New Zealand Food Safety Authority (NZFSA) have all deferred implementing a mandatory folic acid fortification programme.39,40 Sweeney et al (2009) has further stated that the FSAI and SACN authorities deferrals were based on consumer safety grounds.41 As an Australian consumer I would have an expectation that further ongoing research will be conducted to more accurately define and quantify the possible risks.

Yours sincerely

David Franken  B.Sc(Hons). LL.B.  M.Sc.

I declare that I have no personal or financial conflict of interest in the matter of folic acid fortification and provide this communication in my personal and private capacity.


1 Australian User Guide, Mandatory Folic Acid Fortification: Implementing the requirements of the Mandatory Fortification with Folic Acid under Standard 2.1.1 – Cereals and Cereal Products (FSANZ, September 2009), p17
at 10 October 2009.

2 Smith, D. Kim YI. & Refsum, H. ‘Is folic acid good for everyone?’ (2008) 87 American Journal of Clinical Nutrition 517-533.

3 Ibid.

4 Fuks, F.  ‘DNA methylation and histone modifications: teaming up to silence genes’ (2005) 15 Current Opinion in Genetics & Development 490-495.

5 Song, J. Medline, A. Mason, JB. Gallinger S & Kim YI. ‘Effects of dietary folate on intestinal tumorigenesis in the apcMin mouse’ (2000) 60 Cancer Research 5434-40, cited by Smith et al, above note 2.

6 Song, J. Sohn, KJ. Medline, A. Ash, C. Gallinger, S & Kim, YI. ‘Chemopeventative effects of dietary folate on intestinal polyps in Apc+/-Msh2-/- mice’ (2000) 60 Cancer Research 3191-9, cited by Smith et al, above note 2.

7 Kim, YI. ‘Folate, colorectal carcinogenesis, and DNA methylation: lessons from animal studies’ (2004) 44 Environmental & Molecular Mutagenesis, 10-25, cited by Smith et al, above note 2.

8 Smith et al, above note 2.

9 Kim, YI. ‘Folate: a magic bullet or a double edged sword for colorectal cancer prevention?’(2006) 55 Gut 1387-89.

10 Smith et al, above note 2.

11 Ibid.

12 Ibid.

13 van Guelpen, B. Hultdin, J. & Johansson, I. et al. ‘Low folate levels may protect against colorectal cancer’ (2006) 55 Gut 1461-66, cited by Smith et al, above note 2.

14 Cole, BF. Baron, JA. Sandler RS. et al. ‘Folic acid for the prevention of colorectal adenomas: a randomized clinical trial’ (2007) 297 Journal of the American Medical Association 2351-9, cited by Smith et al, above note 2.

15 Mason, JB. Dickstein, A. Jacques, PH. et al. ‘A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles’ (2007) 16(7) Cancer Epidemiology, Biomarkers & Prevention 1325-1329.

16 Ibid.

17 Ibid.

18 Hirsch, S. Sanchez, H. Albala, C. et al. ‘Colon cancer in Chile before and after the start of the flour fortification program with folic acid’ (2009) 21 European Journal of Gastroenterology and Hepatology 436-439.

19 Ibid.

20 FSANZ user guide, Above note 1, p18-19.

21 Ibid.

22 Young-In Kim ‘Will mandatory folic acid fortification prevent or promote cancer’ (2004) 80 American Journal of Clinical Nutrition 1123-8.

23 FSANZ user guide, Above note 1, p2.

24 Ibid.

25 Pfeiffer, CM. Caudill, SP. Gunter, EW. Osterloch, J. & Sampson, EJ. ‘Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999-2000’ (2005) 82 American Journal of Clinical Nutrition 442-50.

26 Smith et al, above note 2.

27 Waterland, RA. Jirtle, RL. ‘Transposable elements: targets for early nutritional effects on epigenetic gene regulation’ (2003) 23 Molecular & Cellular Biology 5293-5300.

28 Wolff, GL. Roberts DW, & Mountjoy KG (1999) Physiol. Genomics 1, 151-163, cited by Cooney, CA. ‘Germ cells carry the epigenetic benefits of grandmother’s diet’ (2006) 103 Proceedings of the National Academy of Sciences 17071-17072.

29 Cooney CA (2006) in Nutrigenomics: Concepts and Technologies, Kaput J, Rodriguez RL (eds) (Wiley), pp 219-254, cited by Cooney, CA ‘Germ cells carry the epigenetic benefits of grandmother’s diet’ (2006) 103 Proceedings of the National Academy of Sciences 17071-17072. .

30 Cropley, JE. Suter, CM. Beckman, KB. & Martin DIK. ‘Germ-line epigenetic modification of the murine Avy allele by nutritional supplementation’ (2006) 103(46) Proceedings of the National Academy of Sciences 17308-312.

31 Ibid.

32 Yajnik, CS. Deshpande, SS. Jackson, AA. Et al ‘Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study’ (2008) 51 Diabetologia 29-38.

33 Ibid.

34 Vitamin folic acid must be added to bread-making flour from this weekend (FSANZ Media Release, 11 September 2009)
at 22 September 2009.

35 at 24 September 2009.

36 Donoghue v Steveson [1932] All ER Rep 1 (Lord Atkin).

37 Radler, JI. Weaver, CM. & Angyal, G. ‘Total folate in enriched cereal-grain products in the United States following fortification’ (2000) 70 Food Chemistry 275-89.

38 First Review Report, Proposal P295, Consideration of Mandatory Fortification with Folic Acid (attachments 4-8), (FSANZ, 23 May 2007)
at 24 September 2009.

39 Sweeney, MR, Staines, A et al (2009) ‘Persistent circulating unmetabolised folic acid in a setting of liberal voluntary folic acid fortification. Implications for further mandatory fortification 9 BMC Public Health 295-301.

40 Kate Wilkinson, Government defers folic acid fortification, New Zealand Government, (27 August 2009)
at 1 November 2009.

41 Sweeney et al (2009), above note 39.