Position statement - Beta-carotene and cancer risk

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Position statement - Beta-carotene and cancer risk


Key messages

  • Beta-carotene (β-carotene) is a type of carotenoid, an important precursor to vitamin A. Vitamin A is essential for biochemical and physiological processes in the body including vision, reproduction, cellular differentiation and immunity.
  • β-carotene can be obtained from dark-green leafy vegetables and some (not all) yellow and orange coloured vegetables and fruits, as well as dietary supplements.
  • There appears to be a marked interaction between β-carotene, smoking and genotype. Studies have shown there is a convincing association between β-carotene supplements and an increased risk of lung cancer in current smokers. β-carotene supplements are unlikely to have a substantial effect on the risk of prostate and non-melanoma skin cancers.
  • However, foods containing carotenoids are associated with a probable reduced risk of lung, mouth, pharynx, and larynx cancer. Dietary β-carotene probably reduces the risk of oesophageal cancer and is unlikely to have a substantial effect on the risk of prostate and non-melanoma skin cancers.
  • Cancer Council recommends people obtain their nutritional requirements from whole foods, rather than individual nutrients in a supplement form, and avoid taking high doses (>18 mg) of β-carotene supplements, especially if they smoke.
  • Cancer Council supports the Australian Dietary Guidelines that recommend eating plenty of fruit and vegetables, and the population recommendation of at least two serves of fruit and five serves of vegetables daily. People should eat a wide variety of fruit and vegetables, including a range of different coloured fruit and vegetables, to obtain maximum benefits.

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Background

β-carotene is the most potent carotenoid precursor to vitamin A[1]. Vitamin A is essential for biochemical and physiological processes in the body including vision, reproduction, cellular differentiation, gene expression, immunity and growth[1][2].

Carotenoids are pigments in plants that are usually yellow or red[1]. The main dietary sources of β-carotene include dark-green leafy vegetables and some (not all) orange and yellow coloured vegetables and fruits such as carrots and dried apricots (see Table 1)[1]. Red palm oil is also rich in β-carotene, but is not often consumed in Australia[1].


Table 1. Common dietary sources of β-carotene[3]

Food β-carotene (mg/100 g) Food β-carotene (mg/100 g) Food β-carotene (mg/100 g)
Chilli powder 15.0 Beef liver 1.9 Spring onions 0.6
Sweet potato (baked) 7.2 Silverbeet (boiled) 1.6 Cherry tomato 0.5
Carrot (boiled) 6.8 Butternut pumpkin (baked) 1.4 Passionfruit 0.4
Parsley 4.9 Mango 1.4 Peas (boiled) 0.4
Basil 3.1 Tomato paste 1.3 Watermelon 0.4
Sundried tomato 2.9 Cos lettuce 1.2 Broccoli (boiled) 0.3
Dried apricot 2.4 Tabasco sauce 0.9 Red capsicum 0.3
Chives 2.2 Rockmelon 0.8 Pawpaw 0.2
English spinach (boiled) 2.2 Bok choi (stir fried) 0.7 Persimmon 0.2

Note: these amounts represent β-carotene equivalents per 100 g edible portion


Carotenes are not absorbed as well as other forms of vitamin A, such as retinol[1]. Carotenoids in the cells of dark-green leafy vegetables and carrots are not readily released in the body[1]. However carotenoids in the cell walls of fruits are more readily absorbed[1].

In the western diet, vitamin A is mainly obtained from animal products rich in retinol such as milk, butter, cheese, egg yolk, liver and some fatty fish[1]. However carotenes, particularly β-carotene, are the main source of vitamin A in countries where animal product consumption is low.

β-carotene may also be obtained from dietary supplement preparations.

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Rationale

Nutritional factors can play a role in the prevention of cancer. Epidemiological studies have shown that the intake of foods such as fruit and vegetables, which are rich in an array of phytochemicals and certain nutrients like carotenoids, are associated with a modest reduced risk of certain cancers. This evidence has encouraged research on individual nutrients and their association with cancer.

Vitamin A was one of the first nutrients to be evaluated, and β-carotene was initially believed to reduce the risk of lung cancer[4]. However in the 1990’s two large randomised controlled trials (RCTs)[5][6] investigating high doses (≥20 mg/day) of β-carotene from supplements challenged this finding and prompted an intense review of β-carotene and its association with cancer.

The trials highlighted the need for further research, particularly into the mechanisms involved for individual nutrients. They also highlighted the potential dangers of dietary supplements, particularly when administered at doses not naturally found in foods.

Cancer Council has an important role to play in determining the association between different nutritional factors and cancer, and promoting advice to the community about how to reduce cancer risk. The purpose of this position statement is to evaluate and summarise the evidence linking β-carotene with cancer prevention.

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Views on β-carotene in cancer prevention reports

Dietary β-carotene

The World Cancer Research Fund (WCRF) released a comprehensive report on food and the prevention of cancer in 2007 which found that foods containing carotenoids were probably protective against lung, mouth, pharynx, and larynx cancer[7]. Dietary β-carotene was associated with a probable reduced risk of oesophageal cancer, but was unlikely to have a substantial effect on the risk of prostate and non-melanoma skin cancers[7].

In 2003 an expert report by the World Health Organization (WHO) observed that there was possible/insufficient evidence that carotenoids decreased the risk of cancer[8]. However the report did not distinguish between dietary and supplemental sources of carotenoids.

The International Agency for Research on Cancer (IARC) published a review of the evidence on carotenoids and cancer in 1998[9]. The review found there was inadequate evidence for the cancer preventive activity of β-carotene at usual dietary levels[9]. However the incidence of lung, oral and pharyngeal cancer tended to be inversely related to dietary β-carotene intake[9].

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β-carotene from supplements

In 2007, the WCRF found that β-carotene supplements were convincingly associated with an increased risk of lung cancer[10]. This evidence was derived from studies using high-dose supplements (≥ 20 mg/day of β-carotene) in smokers (see Figure 1)[10]. The report noted that there was a marked interaction between β-carotene, smoking and genotype[10]. People who lack the carcinogen-detoxifying enzymes glutathione-S transferase 1 and 2, due to genetic variation, had a higher risk of lung cancer, particularly if they were smokers[10]. In addition, the risk of lung cancer among smokers taking higher does of β-carotene was greater than in smokers taking lower doses, despite adjustment for smoking habits and age[10].

The WCRF concluded that β-carotene supplements were unlikely to have a substantial effect on the risk of prostate and non-melanoma skin cancers[10].

A 2003 WHO expert report observed that there was possible/insufficient evidence that carotenoids decreased the risk of cancer[11].

The IARC review concluded in 1998 that the evidence suggested that β-carotene lacked cancer preventative activity when used as a supplement at high doses (≥15 mg/day of β-carotene)[5]. In fact it was noted that there was evidence of an increased risk of lung cancer among smokers and asbestos workers taking high doses of β-carotene supplements[5].


Figure 1. Trials identified by the WCRF investigating β-carotene and lung cancer risk[10]

Beta carotene and lung cancer.png


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Evidence from epidemiological studies for β-carotene as a supplement

All cancers

A 2011 meta-analysis of RCTs investigated the link between high-dose β-carotene supplements and cancer incidence and mortality[12]. The study reported that there was no significant association between β-carotene supplement use and all cancer incidence (RR= 1.08, 95% CI= 0.99-1.18) or mortality (RR= 1.00, 95% CI= 0.87-1.15)[12]. Findings were similar for studies investigating high-dose and low-dose supplements, with no effect seen for either[12]. Similarly, among smokers there was no significant effect (RR= 1.07, 95% CI = 0.99-1.17)[12].

The findings mirrored an earlier 2010 meta-analysis of RCTs which found no association between β-carotene supplementation and incidence of all cancers combined (RR= 1.01, 95% CI 0.98-1.04)[13].

In contrast to the 2010 study, a 2008 meta-analysis of RCTs reported an increased risk of cancer associated with β-carotene supplementation among smokers (RR= 1.10, 95% CI= 1.03-1.18), but not among non-smokers (RR= 1.00, 95% CI= 0.92-1.10)[14]. A trend toward increased all cancer mortality was reported, but this was not significant (RR= 1.16, 95% CI= 0.98-1.37)[14].


Table 2. Summary of findings from meta-analyses of all cancer risk associated with β-carotene supplement use

Study β-carotene Population RR (95% CI)
Jeon 2011[12] Supplement 25-75 mg/day General 1.08 (0.99-1.18)
Current smokers 1.07 (0.99-1.17)
Druesne-Pecollo 2010[13] Supplement 6-30 mg/day General 1.01 (0.98-1.04)
Bardia 2008[14] Supplement 6-30 mg/day Smokers 1.10 (1.03-1.10)
Non-smokers 1.00 (0.92-1.10)

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Lung cancer

A 2011 meta-analysis reported no effect of high-dose β-carotene supplement use on lung cancer risk in both the general population (relative risk (RR)= 1.08, 95% confidence interval (CI)= 0.93-1.25) and among current smokers (RR= 1.30, 95% CI= 0.57-2.94)[12].

Conversely, a 2010 meta-analysis reported an increase in lung cancer mortality associated with high-dose β-carotene supplement use[13]. The analysis of eight RCTs found an overall increased risk of lung cancer associated with β-carotene supplementation (RR= 1.13, 95% CI= 1.04-1.24) and with high-dose β-carotene supplementation (20 mg/day and above) (RR= 1.16, 95% CI= 1.06-1.27)[13]. Among smokers and asbestos workers the effect was strongest (RR= 1.20, 95% CI= 1.07-1.34)[13].

An earlier 2008 meta-analysis of six RCTs reported no association between β-carotene supplements and lung cancer risk (RR= 1.10, 95% CI= 0.89-1.36)[10]. Similarly, among cohort studies there was no association (RR= 0.92, 95% CI=0.83-1.01)[10]. This study did not analyse data specifically for smokers.

A second meta-analysis from the same year reported an association between high-dose β-carotene supplementation and lung cancer among current smokers[11]. The analysis, combining data from large scale RCTs, found that high-dose β-carotene supplementation increased lung cancer risk in current smokers (odds ratio (OR)=1.24, 95% CI= 1.10-1.39), but not among former smokers (OR= 1.10, 95% CI= 0.84-1.45)[11].


Table 3. Summary of findings from meta-analyses of lung cancer risk associated with β-carotene supplement use

Study β-carotene Population RR (95% CI)
Jeon 2011[12] Supplement 25-75 mg/day General 1.08 (0.93-1.25)
Current smokers 1.30 (0.57-2.94)
Druesne-Pecollo 2010[13] Supplement 6-30 mg/day General 1.16 (1.06-1.27)
Smokers and asbestos workers 1.20 (1.07–1.34)
Gallicchio 2008[10] Supplement 15-30 mg/day General 1.10 (0.89-1.36)
Tanvetyanon 2008[11] Supplement 20-30 mg/day Current smokers OR 1.24 (1.10-1.39)
Former smokers OR 1.10 (0.84-1.45)

Note: RR column represents relative risk, unless noted OR, which indicates odds ratio.

Randomised controlled trials

Early RCTs of β-carotene supplementation produced contradictory findings. Despite a number of RCTs of β-carotene supplementation being suspended after increased risk of lung cancer was observed[13][14], subsequent RCTs showed no association between β-carotene supplementation and lung cancer risk in both the general population and among smokers[6][15][16].

In 1996 the Beta-Carotene and Retinol Efficacy Trial (CARET) was stopped prematurely after it was found that in smokers, former smokers and workers exposed to asbestos, high-dose β-carotene and vitamin A supplementation led to a significantly increased risk of lung cancer (RR= 1.28, 95% CI= 1.04-1.57)[13]. Similarly, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) trial was stopped early after it was found that in male smokers, high-dose β-carotene supplements increased lung cancer risk (RR= 1.18, 95% CI= 1.03-1.36)[14].

Another study demonstrated that among former asbestos workers those taking retinol were significantly less likely to have malignant mesothelioma than those taking high-dose β-carotene supplements (RR= 0.24, 95% CI= 0.07-0.86) (note this trial did not include a placebo arm[17].

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Other cancers

A range of studies have been conducted investigating the link between β-carotene and cancer risk, for a number of cancer types. Table 4 summarises the findings from meta-analyses investigating the link between supplementary β-carotene and a range of cancer types.

There is an association between β-carotene supplement use and bladder cancer[12]. Stomach cancer risk is increased with β-carotene supplement use and this effect is stronger in smokers and asbestos workers[13]. Although β-carotene supplement use is associated with increased risk of bowel adenoma[18], there appears to be no association with bowel cancer[12][13].

The majority of studies have found no association between supplementary β-carotene and other cancer types[13][19][12].


Table 4. Summary of findings from meta-analyses investigating the link between β-carotene supplement use and various cancers

Study β-carotene Cancer type RR (95% CI)
Papaioannou 2011[18] Supplement 20-96 mg/day plus vitamin E Bowel adenoma 1.63 (1.01-2.63)
Jeon 2011[12] Supplement 25-75 mg/day Bowel 0.98 (0.81-1.19)
Urothelial 1.35 (1.01-1.81)
Bladder 1.52 (1.03-2.24)
Skin 1.00 (0.94-1.07)
Prostate 1.02 (0.93-1.12)
Head and neck 0.78 (0.48-1.27)
Druesne-Pecollo 2010[13] Supplement 6-30 mg/day Bowel 0.96 (0.85-1.09)
Breast 0.96 (0.85-1.10)
Melanoma 0.98 (0.65-1.46)
Non-melanoma skin cancer 0.99 (0.93-1.05)
Pancreatic 0.99 (0.73-1.36)
Prostate 0.99 (0.91-1.07)
Stomach 1.34 (1.06-1.70)
Stomach (in smokers and asbestos workers) 1.54 (1.08–2.19)
Jiang 2010[19] Supplement 6-30 mg/day Prostate 0.97 (0.90-1.05)


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Evidence from epidemiological studies for dietary β-carotene

There is some evidence that dietary β-carotene reduces the risk of a number of cancer types[20][21][22][23][24]. Table 5 summarises findings from meta-analyses of studies investigating the link between β-carotene and cancer.


Table 5. Summary of findings from meta-analyses investigating the link between dietary β-carotene and various cancers

Study β-carotene Cancer type RR (95% CI)
Aune 2012[20] Blood concentration Breast 0.74 (0.57-0.97)
Dietary intake 0.95 (0.91-0.99)
Hu 2012[25] Dietary intake Breast 0.94 (0.88-1.00)
Myung 2011[21] Dietary intake or serum level Cervical OR 0.68 (0.55-0.84)
Bandera 2009[26] Dietary or supplement Endometrial OR 0.88 (0.79-0.98)
Kubo 2007[22] Dietary Oesophageal OR 0.46 (0.36-0.59)
Cardiac OR 0.57 (0.46-0.72)
Huncharek 2001[23] Dietary Ovarian 0.84 (0.75-0.94)
Gandini 2000[24] Dietary Breast 0.82 (0.76-0.91)
Steinmaus 2000[27] Dietary Bladder 1.10 (0.93-1.30)

Note: RR column represents relative risk, unless noted OR, which indicates odds ratio.


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Potential mechanisms of action

Dietary carotenoids, including β-carotene, may lower cancer risk by[9][28]:

  • Acting as an anti-oxidant, which inhibits oxidative or free radical induced damage to cells;
  • Stimulating gap-junctional communication between cells, which may prevent the malignant transformation and proliferation of cells;
  • Enhancing cellular defence systems, possibly involving tumour-specific antigens; and/or
  • Formulating retinoic acid (particularly in those with low preformed retinol intake), which plays a role in gene regulation.

Cigarette smoke is highly oxidative and has been shown to destroy carotenoids in plasma[29]. Therefore β-carotene in the lungs of smokers may be susceptible to oxidative attack, leading to a pro-oxidant state which may promote cancer[29].

The protective effect seen for dietary β-carotene and cancer may also not be due to β-carotene specifically, but possibly another carotenoid or mix of compounds in the diet[7][9].

It is also possible that the protective effect of β-carotene at dietary intake amounts is lost or reversed with dietary supplementation and the higher levels that this can supply[7]. While excessive cellular oxidants can induce damage to cells, they are needed in moderate concentrations for several protective reactions, including apoptosis, phagocytosis and detoxification reactions provided by cytochrome P-450 complexes[30]. High doses of antioxidants can inactivate more cellular oxidants than necessary and interfere with these protective functions[30].

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Toxicity and recommended dietary intake

Vitamin A intakes are generally expressed as retinol equivalents (RE), where 6 mg of β-carotene gives rise to 1 mg RE[1][2]. The recommended dietary intake (RDI) for vitamin A in the Nutrient Reference Values for Australia and New Zealand (NRVs) is 0.9 mg RE/day for men and 0.7 mg RE/day, with an upper level of intake (UL) of 3 mg RE/day (see Table 6)[2].

Vitamin A is fat soluble and can be acutely toxic in adults at doses greater than 200 mg[1]. Chronic toxicity can occur after consuming at least 10 times the recommended daily allowance for a month or more[1]. Vitamin A toxicity can cause headache, visual impairment, skin disorders and death[1].

Despite being a precursor of vitamin A, the toxicity of carotenoids is low[1][2]. Large amounts of β-carotene from foods can cause hypercarotenaemia (increased plasma carotene) and yellow colouration of the skin, particularly on the palms of the hand and soles of the foot[1][2].

An UL for β-carotene from foods is not needed due to the lack of adverse effects[2]. However the UL for β-carotene for dietary supplement use has not been able to be established due to the lack of dose-response information in the literature[2].


Table 6. Estimated average requirements, recommended dietary intakes and upper level of intake of vitamin A (as retinol equivalents)[2]

Group and age range Retinol equivalents (mg/day)
EAR RDI UL
Men ≥19 years 0.625 0.9 3.0
Women ≥19 years 0.5 0.7 3.0
Pregnancy 14-18 years 0.53 0.7 2.8
19-50 years 0.55 0.8 3.0
Lactation 14-18 years 0.78 1.1 2.8
19-50 years 0.8 1.1 3.0

EAR= estimated average requirements, RDI= recommended dietary intake, UL= upper limit
Note: while no UL has been set for β-carotene specifically, 3 mg RE is equivalent to 18 mg β-carotene, which is less than the dose used in the ATBC study (20 mg) and CARET (30 mg)

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Current level of intake in Australia

The last National Nutrition Survey showed that men had a mean intake of 1.4 mg/day of vitamin A (RE) and women 1.1 mg/day[31].

The Blue Mountains Eye Study showed that the mean intake of β-carotene in Australian women aged 55 years or over was 7.6 mg/day, and in men 6.9 mg/day[32]. However these values may be overestimates due to the use of a food frequency questionnaire for measuring intake[32]. Carrots and pumpkin contributed the most to dietary β-carotene intake in this population[32].

Data on the use of specific dietary supplements (such as type and dose) is currently limited. Studies in the US have shown that dietary supplement use has increased over the past two decades[33]. Most people taking supplements are generally seeking health benefits, which could also be achieved by eating a healthy, well balanced diet.

Just under half (43%) of Australians aged 65-98 years reported using some form of dietary supplement in 2006[34]. Supplement use was significantly associated with gender (females) and conditions such as arthritis and osteoporosis, although the latter reason was likely to be representative of the population demographics in this particular study group[34].

In 2003, a similar number (49%) of American adolescents aged 11–18 years from a single co-educational government school consumed vitamin and mineral tablets[35]. Commonly cited reasons for use included health benefits, prevention of illness, sports performance, parental control, energy, poor diet and to do something positive for self[35].

Interestingly, studies have shown that dietary supplement use is similar between cancer survivors and cancer-free controls[36].

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β-carotene supplements available in Australia

Increasingly complex mixtures of ingredients, which often contain other herbal and botanical compounds with anti-oxidant properties, are available in the market[37]. Consumers have access to numerous brands and formulations, including those available on the internet.

In Australia, dietary supplements are sold at places such as supermarkets, chemists and health food stores. β-carotene is available as an individual supplement or as part of a multi-vitamin preparation. Vitamin A preparations usually contain retinyl palmitate as the active ingredient.

As an indication at the time of writing this position statement, supplements available in Australia contained between 1–6.6 mg of β-carotene per tablet. Common brands recommended taking one to three tablets per day, making the maximum dose of β-carotene from any supplement 9 mg if taken according to the supplement instructions. Therefore amounts greater than the equivalent UL of 18 mg β-carotene in the NRVs may be obtained if tablets are taken in excess of the recommended dosage (see Table 6 for recommended ULs).

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Recommendations

The NRVs do not contain an UL for β-carotene intake for dietary supplement use due to a lack of dose-response information in the literature[1]. β-carotene is of low toxicity and until recently was thought to only cause yellowing of the skin after sustained high intake{{Cite footnote|Citation:West CE. 2002}[2].

However recent epidemiological evidence shows that high doses of β-carotene supplements might increase the risk of lung cancer, particularly in smokers.

Therefore Cancer Council recommends people:

  • obtain their nutritional requirements from whole foods, such as fruits and vegetables, rather than individual nutrients in a supplement form; and
  • avoid taking high doses (>18 mg) of β-carotene supplements, especially if they smoke. Trials have shown that adverse consequences may result from doses of 20 mg.

Cancer Council supports the Australian Dietary Guidelines that recommend eating plenty of fruit and vegetables, and the population recommendation of at least two serves of fruit and five serves of vegetables daily (see Table 7)[38]. Cancer Council recommends that people eat a variety of fruit and vegetables, including a range of different coloured fruit and vegetables, to obtain maximum benefits.


Table 7. Sample fruit and vegetable serving sizes in the Australian Dietary Guidelines[38]

Fruit 1 serve equals:
  • One medium piece (150 g) of fruit e.g. apple, banana, orange, pear
  • Two small pieces (150 g) of fruit, e.g. apricot, kiwi fruit, plum
  • One cup (150 g) diced, cooked or canned fruit
  • Half a cup (125 ml) 100% fruit juice
  • 30 g dried fruit e.g. 4 dried apricot halves, 1½ tablespoons of sultanas
Vegetables 1 serve equals:
  • Half a cup (75 g) cooked green vegetables or orange vegetables, e.g. spinach, carrot
  • Half a cup (75 g) cooked dried or canned beans, chickpeas or lentils
  • Half a cup (75 g) raw vegetables e.g. green leafy vegetables, tomatoes
  • Half a cup (75 g) starchy vegetables e.g. potato, corn


Cancer Council also:

  • supports that β-carotene supplements sold in Australia should include a warning with regard to the increased risk of cancer from high doses, especially for smokers; and
  • supports the development of an UL for beta-carotene in the NRVs due to the increased risk of cancer from high doses, especially for smokers.

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Future research

In the future, there is a need for more studies that investigate:

  • The dose-response relationship for β-carotene and lung cancer risk so that a safe upper limit can be established. Although an RCT with high doses may not be ethically feasible, other study designs may be able to provide further guidance on this issue.
  • The mechanisms of action for β-carotene and cancer risk in order to determine if there is any difference between natural and synthetic β-carotene i.e. β-carotene from foods versus pharmacological supplements.

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Position statement details

This position statement approved by the Public Health Committee September 2009 and updated in February 2013.

Development

This position statement has been reviewed by:

  • Vicki Flood
  • Peter Clifton
  • Jill Sherriff
  • Erica James
  • Fiona Stacey
  • Craig Sinclair


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References

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  3. Food Standards Australia and New Zealand. Nutrient tables for use in Australia (NUTTAB)2010. FSANZ; 2010 Available from: http://www.foodstandards.gov.au/consumerinformation/nuttab2010/.
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