Surprising glutamate judgement

Chinese-Food

Chinese food often contain MSG

Yes, I am surprised by the European Food Safety Authority’s (EFSA’s) 2017 verdict on glutamate. As it happens I was involved in an assessment of glutamate in the mid 2000’s. At the highest government level in New South Wales (Australia) illness was claimed after consuming a Chinese meal containing glutamate. This led to a heated debate in the Parliament. Of course, being responsible for food safety in the state, we got ordered to investigate. And so we did read the available literature and reviewed testimonial websites.

Our conclusions didn’t please the politicians much. Although we found plenty of websites with testimonial evidence of even near death experiences after consuming meals with glutamate, no clear evidence of ill effects could be ascertained from the scientific literature. Naturally, the Glutamate Association, an industry funded organisation, on their website attempted to balance negative opinions by claiming that glutamate was the most natural substance you could find.

Glutamic acid is a naturally occurring amino acid

It is true that glutamic acid is a naturally occurring substance in some foods. Glutamic acid is a non-essential amino acid, a building block of proteins, naturally produced in humans and occurring in free form in tomatoes, soy sauce, cheeses (Parmesan in particular) and some other foods. Glutamic acid and its different salts, commonly referred to as glutamates, are also authorised food additives in many countries. They are added to a wide range of foods to enhance their flavour by giving them a “savoury” or “meaty” taste. The most commonly known salt is monosodium glutamate or MSG.

Glutamic acid is the most abundant free amino acid in the brain and functions as an excitatory or stimulating neurotransmitter. It also serves as an important potential energy source. When the glucose concentration in the brain is low, the brain mobilises glutamate. So it is actually quite useful.

Toxicity of glutamic acid/glutamate

Previous evaluations of glutamic acid/glutamates have in the main found little evidence of consistent toxic effects. There is some evidence that experimental ingestion of large amounts (≥3g) of glutamate salts in the absence of food may provoke some symptoms in humans that, although unpleasant, are neither persistent nor serious. However, there is little evidence that those effects occur in the presence of food, the real life situation.

JECFA_meeting

JECFA meeting to discuss food safety

Thus, at its meeting in February 1987, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) stated that glutamate salts were of low toxicity and did not constitute a health hazard as a result of their natural presence in food or use as flavouring agents. Meeting in May 1990, the European Union Standing Committee for Food also judged that the natural occurrence of glutamate in food and its use as a food additive did not present a hazard to health. In its 2003 review, Food Standards Australia New Zealand (FSANZ) concluded that there is no convincing evidence that MSG is a significant factor in causing systemic reactions resulting in severe illness or mortality.

The previous opinions were again supported by JECFA when, in its latest evaluation in 2004, it maintained the previously established ‘not specified’ group Acceptable Daily Intake (ADI) for glutamic acid and its salts. Equally, the Select Committee on GRAS Substances (SCOGS) of the US Food and Drug Administration in 2015 confirmed that glutamic acid and its salts posed no reasonable hazard when used at current levels and practices.

Surprising change of view

In the EU the addition of glutamates is generally permitted up to a maximum level of 10 g/kg of food. In salt substitutes, seasonings and condiments, there is no numerical maximum permitted level for glutamates, but they must be used in line with good manufacturing practices.

This might change after EFSA re-assessed the safety of glutamates used as food additives and derived a group Acceptable Daily Intake (ADI) of 30 mg/kg body weight (bw) for six glutamate salt additives. This safe level of intake was based on the highest dose at which scientists observed no adverse effects in animal toxicity studies.

EFSA also concluded that estimated dietary exposure to glutamic acid and glutamates may exceed not only the safe level, but also doses associated with adverse effects in humans for some population groups. On this basis, EFSA’s experts recommended reviewing the maximum permitted levels for these food additives.

So what’s behind the change of mind

Many animal studies of the effects of glutamate have included too few animals or shown conflicting results. Thus, EFSA in reviewing the scientific literature found no consistently reported adverse effects in available short-term, subchronic, chronic, reproductive, developmental, genotoxicity and carcinogenicity studies.

So far so good.

swiming_rat

Delayed swimming development

However, dietary neurodevelopmental toxicity was identified in several mouse and rat studies, some of limited quality. One study was adequate showing delayed early swimming development, diminished rearing frequency in the open field, altered active avoidance acquisition and prolonged passive avoidance retention caused by MSG.

Not so good.

Peculiar as the effects might sound, this study was used to set a dose of 3,200 mg MSG/kg bw per day as safe based on the absence of neurobehaviour effects which occurred at higher doses (a NOAEL – or no-observed-adverse-effect-level).

Toxicologist normally use an uncertainty factor of 100 when translating results from animal studies to humans giving the 30 mg/kg bw per day calculated as glutamic acid as an acceptable intake after rounding.

The study on which EFSA based its recommendations is not new as it was published in 1979 and available to all previous reviews cited above. It can only be assumed that EFSA considered also human findings where glutamate has been associated with the MSG symptom complex (> 42.9 mg/kg bw per day), headache (85.8 mg/kg bw per day), blood pressure increase (150 mg/kg bw per day) and also insulin increase (> 143 mg/kg bw per day).

None of these findings were robust enough on which to base calculation of an ADI. But the selected animal study allowed calculation of an ADI that would be protective for any of the reported human findings.

Are we safe now?

Good question and unfortunately the answer is no looking at the provided exposure assessments.

When EFSA’s scientists (including my good friend Davide Arcella) combined food consumption data with glutamate additive levels in food they found that exposure may exceed the proposed ADI for individuals of all population groups whose diet is high in foods containing these additives, as well as for toddlers and children with medium exposure. Exposure may also exceed doses associated with some adverse effects in humans (e.g. headache) for highly exposed infants, children and adolescents.

EFSA’s experts also considered other dietary sources of glutamate besides food additives (including natural presence and addition as nutrient). They found that exposure estimates largely exceed, in several population groups with medium to high exposure, both the proposed ADI and levels associated with some adverse effects in humans.

What do we do?

headache

Headache part of the MSG symptom complex

For years, consumer concerns about adverse effects of glutamate have been dismissed, but now when EFSA has confirmed possible health effects what should we do to limit the potential impact?

If taken seriously, the proposed ADI might trigger a rush by food manufacturers to remove glutamate additives where possible, but don’t hold your breath.

If agreed by other Government authorities, we might see new maximum use levels proposed and also a reduction of the number of food categories in which these additives are permitted. This might happen first in Europe, but countries outside Europe might await a recommendation from JECFA.

Finally, as a consumer you might find some reassurance in the fact that only 1-2 per cent of the population is considered to be extra susceptible to the adverse effects of high levels of glutamates.

We will see how the world reacts. EFSA has sometimes been criticised for being too lenient (see BPA and glyphosate). This time they have gone the opposite way.

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Additive ruling on nitrate and nitrites

sausages2IARC (International Agency for Research on Cancer) is sometimes very quick to nominate any chemical as at least a probable carcinogen. And so it is with nitrate and nitrite. Pointing to the endogenous nitrogen cycle in humans (that is ingested nitrate recirculated in saliva and converted to nitrite by microorganisms in the mouth and swallowed) IARC concluded that both nitrate and nitrite are probable human carcinogens as they can generate carcinogenic N-nitroso compounds under acidic gastric conditions.

Now let’s make it clear, EFSA in two recently published opinions on nitrate and nitrite partially supported the IARC conclusions on the link between nitrates and nitrites in processed meat and an increased risk of colorectal cancer. But, and this is a big BUT….

Both additives are considered safe to use at current approved levels without any concerns. So why is that?

Nitrate and nitrite cleared as additive at current levels

EFSA, in contrast to IARC, not only looks at the potential for a substance to cause cancer, but also the exposure level necessary. That is practical life conditions. And concluded that existing safe levels for nitrates and nitrites intentionally added to meat and other foods are sufficiently protective for consumers.

Case closed? Well, not so fast. Let’s look at some of the detail.

EFSA’s Panel on Food Additives and Nutrient Sources Added to Food said that there is some evidence in epidemiological studies of a link between dietary nitrite, preformed N-nitroso compounds and gastric cancers and also for the combination of nitrate plus nitrite from processed meat and colorectal cancers. However, they stressed that this included only very limited evidence.

Using refined exposure assessment scenarios, the Panel calculated that exposure to nitrites as a food additive accounts for 17% of total exposure to nitrite and exposure to nitrates as a food additive only accounts for up to 5% of total exposure to nitrates. Other sources making up the balance of exposure include their natural presence in other food products and environmental contamination.

The main contributors to exposure are vegetables and vegetable-based foods, such as starchy roots, leafy vegetables, such as spinach and lettuce, and prepared salads. Nitrates also contaminate water as a result of intensive farming, fertilisers and sewage discharge.

The remaining problem

rucola

Although the use of nitrate and nitrite as additives have little influence on overall exposure, there is still a remaining overall concern.

If all sources of dietary nitrate are considered, such as food additive use, natural presence in food and environmental contaminants, the Acceptable Daily Intake may be exceeded for individuals of all age groups with medium to high exposure.

If all sources of dietary nitrite are considered, the Acceptable Daily Intake may be exceeded for infants, toddlers and children with average exposure, and for highly exposed individuals of all age groups.

However, the estimated formation in the body of N-nitroso compounds from nitrites added to food items at the approved level were far below those that could be considered to be of risk to human health.

To further reduce uncertainties, the Panel made several recommendations, including:

  • additional studies to measure the excretion of nitrate into human saliva, its conversion to nitrites, and the resulting methaemoglobin formation (a potential problem in babies);
  • further studies on the levels of N-nitroso compounds formed in different meat products based on known amounts of added nitrites/nitrates;
  • large-scale epidemiological studies on nitrite, nitrate and nitrosamine intake and risk of certain cancer types.

In the meantime an Acceptable Daily Intake of 0.07 mg/kg body weight for nitrite and 3.7 mg/kg body weight for nitrate as food additives would be of no concern as most people would not exceed it through eating food to which the additives had been added and only some children would slightly exceed nitrite additive exposure.

New bad findings for bisphenol A

Canned food

Bisphenol A can be found in many canned food products.

We have covered bisphenol A, called BPA for short, several times before. In case you need to be reminded, it is a chemical widely used in plastic water bottles, metal food cans, and receipt paper. A large number of scientific publications have questioned the safety of BPA. High doses were found to influence the hormonal balance by acting as an endocrine disruptor with oestrogenic effects already in the 1930’s.

Debate over the toxicity of BPA is on-going with findings of potential low-dose effects particularly worrying. The European Food Safety Authority (EFSA) has so far refrained from suggesting that BPA should be banned, contrary to the opinion of government scientists from France and Denmark. At least EFSA lowered the temporary tolerable daily intake (tTDI) by more than 10 times in its latest opinion. And BPA has been removed from baby bottles in many countries.

New bad reports piling up

By setting a temporary TDI, EFSA committed to the re-evaluation of BPA when a two-year study by the U.S. National Toxicology Program becomes available in 2017. But in the meantime results from several other studies have been published.

A report by the Dutch National Institute for Public Health and the Environment (RIVM), critically examined two studies describing pre- and perinatal effects of BPA on the immune system. The report recommended supporting research on alternatives to BPA and advising consumers to reduce their exposure to BPA from food and other sources.

Third

Foetal exposure to BPA promotes obesity later in life for girls.

And another recent study equally points to the often neglected prenatal exposure to BPA. A team of U.S. researchers tracked 369 mother-child pairs from the third trimester of pregnancy until the children turned seven years old. They measured BPA levels in the mothers’ urine during pregnancy and then checked the children’s height, weight, waist circumference, and body fat as they aged, also measuring their BPA levels. They adjusted the results for factors that could potentially skew the results, including race and pre-pregnancy obesity among the mothers.

They found that the higher the mothers’ BPA exposure was during pregnancy, the more signs of obesity girls showed at age seven. There was no such association for boys; nor was there any relation between BPA levels in the children’s urine and obesity as they grew.

So it seems that the foetal period is when we’re most vulnerable to BPA and its ability to alter metabolism and the way our bodies generate fat cells. It is not surprising that BPA seems to affect girls differently than boys since as an endocrine-disrupting chemical it mimics or blocks hormones produced by the body. Boys and girls produce different hormones, so hormone-disrupting chemicals might be expected to affect them differently.

And if that’s not enough, experimental laboratory evidence suggests that BPA is a neurodevelopmental toxicant. In further disturbing findings, a longitudinal cohort study confirmed the association between prenatal BPA exposure and child behaviour in preschool-age children, accounting for postnatal BPA and other potential confounders. Among boys, prenatal BPA exposure was positively associated with higher scores on all syndromes and significantly associated with Emotionally Reactive and Aggressive Behaviour. Inverse associations were seen in girls for all syndromes and these associations were significant for Anxious/Depressed and Aggressive Behaviour.

How long to wait?

Protect your child from becoming obese.

Take your own action to protect your child from becoming obese.

So it seems pretty clear that BPA can have significant effects at levels of exposure seen in real life.

Do we really have to wait further for some real progress. Authorities seem reluctant to take decisive action despite overwhelming proof of harmful effects. Sure, not all findings point in the same direction and alternatives to BPA might be as bad.

But don’t despair, you can take your own action. To reduce exposure to BPA, the National Institute of Environmental Health Sciences recommends avoiding plastic containers numbers 3 and 7, shifting from canned foods to fresh or frozen foods, and, when possible, choosing glass, porcelain, or stainless steel containers, especially for hot food and liquids.

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Predictable BPA opinion released by EFSA

In mid December 2014 when the European Food Safety Authority (EFSA) flagged that they had finalised the bisphenol A (BPA) opinion and only some editorial work remained, I predicted in a blog that the EFSA Panel would once again clear the use of BPA in food contact materials. On 21 January 2015 EFSA published the new opinion, and surprise, surprise, BPA is considered harmless at current exposure levels. This is the summary wording of EFSA:

EFSA’s comprehensive re-evaluation of bisphenol A (BPA) exposure and toxicity concludes that BPA poses no health risk to consumers of any age group (including unborn children, infants and adolescents) at current exposure levels. Exposure from the diet or from a combination of sources (diet, dust, cosmetics and thermal paper) is considerably under the safe level (the “tolerable daily intake” or TDI).

This conclusion comes despite the fact that EFSA further firmed up the TDI to 4 µg/kg of body weight per day, more than 12 times lower than the previously recommended TDI of 50 µg/kg of body weight per day. The highest estimates for exposure from a combination of dietary, inhalation and dermal routes (called “aggregated exposure” in EFSA’s opinion) are three to five times lower than the new TDI when using a deterministic method (see comparison with probabilistic method further down). All clear then?

New BPA opinion published by EFSA

New BPA opinion published by EFSA.

Not so fast, there are still uncertainties as EFSA points out. Effects on the reproductive, nervous, immune, metabolic and cardiovascular systems, as well as in the development of cancer are not considered likely at present, but they could not be excluded on the available evidence the Panel concluded. The new TDI is thus temporary pending the outcome of a long-term study in rats by the US National Toxicology Program, which will help to reduce these uncertainties.

So what to believe?

EFSA and the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) have divergent views on the safety of BPA in food contact and other materials. If there are different views on the safety of a compound between a national food safety organisation and EFSA, it is compulsory to discuss and if possible reconcile their respective assessments. Such a discussion took place in December 2014. From the minutes of the meeting it is possible to deduce that the differences relate to:

  • results from two key toxicological studies selected by ANSES on the effects of BPA on brain and behaviour, and on the mammary gland;
  • on an extra safety factor of 3 added by ANSES to the normal safety factor of 100, while EFSA applied an extra safety factor of 1.5  to address uncertainties; and
  • on the use of a probabilistic method to determine exposure used by ANSES as opposed to the deterministic method used by EFSA.

Looking first at the selected toxicological studies it seems as if ANSES trusted the negative results from the two studies more than EFSA. EFSA on the other hand balanced the negative findings against similar studies showing no negative effects in the two areas in question. To be fair EFSA also included a study that was published after the ANSES opinion that showed no negative effects on the mammary gland, but still the opinions of the two organisations differed in relation to the validity of several of the studies.

Adding an extra safety factor of 3 makes sense in light of the remaining uncertainties and could have been adopted also by EFSA. EFSA instead selected to use a weight of evidence approach to cater for the remaining uncertainties, but such an approach relies solely on subjective expert judgement. You might be interested to know that EFSA involved an unprecedented 26 experts in the working group that developed the initial draft BPA opinion to arrive at the best possible balanced view, but still the extra safety factor used by ANSES might provide greater certainty.

Mother and child sensitive to oxidative stress pre birth (Photo: Nina Matthews)

Mother and child sensitive to prenatal oxidative stress caused by BPA exposure (Photo: Nina Matthews).

Finally, the differences in exposure methodology used between the two organisations might also cause some differences in the final result. ANSES has long used probabilistic methods to calculate exposure, while EFSA has stubbornly stuck to the simpler deterministic methods. To EFSA’s advantage is access to extensive Europe wide data for the input parameters for the calculations, BPA occurrence and food consumption. However, the use of probabilistic techniques will better cater for unusual occurrence and consumption patterns and thus cover a larger range of the population.

Considering the two latter points, combined they would probably take the highest estimates of exposure closer to the temporary TDI since the EFSA margin was three to five times lower than the new TDI. Adding the toxicological results that ANSES used we could have a problem. On the other hand, the might of EFSA’s scientific expertise very clearly concluded that there is no problem of any kind that they could identify using the present scientific knowledge.

More research results on BPA

However, already new toxicological results are piling up. In a first multispecies study combining human association and animal causal studies assessing the risk posed by prenatal BPA exposure to metabolic health, evidence was provided of the induction of nitrosative stress by prenatal BPA in both the mother and foetus at time of birth. The researchers concluded that:

Whether or not BPA is harmful to human health has been vigorously debated. These findings demonstrate that more studies like this one are needed to determine the disease risk of exposure to BPA. In the interim, these results indicate that pregnant women should minimize their exposure to BPA to safeguard their babies and themselves from oxidant injury.

I can safely predict that the EFSA opinion will not be the last word on potential human harm caused by BPA.

BPA opinion is nigh

BPA can be found in cans and plastic bottles

BPA can be found in cans and plastic bottles contributing to oral exposure.

Bisphenol A (BPA) is a chemical used in plastic bottles and inner coating of beverage cans, and its exposure is almost ubiquitous. The European Food Safety Authority (EFSA) has previously reviewed the use of BPA in food contact materials four times. It has now reviewed BPA for the fifth time and has at last settled on a final version of the new BPA opinion. But we don’t yet know what the EFSA Panel has decided since the opinion is undergoing final editorial work and will not be published until sometime in January 2015.

From the initial draft we know that EFSA believes that exposure to BPA is likely to adversely affect the kidney, liver and mammary glands and possibly also the reproductive, nervous, immune, metabolic and cardiovascular systems. It might also pose a risk for development of cancer.

Quite a list of negative effects you would think. But only at very high exposure levels, EFSA said.

Reduced tolerable levels proposed

To be brave EFSA proposes that the tolerable daily intake of BPA should be reduced to 5 µg/kg bodyweight from previously 50 µg/kg bodyweight. This allows EFSA to claim that the health risk for any population group is low. It is because the highest estimates for combined oral and non-oral exposure to BPA now would be 3-5 times lower than the proposed limit, depending on the age group.

Not everyone agreed with the EFSA view as evidenced by stakeholders submitting almost 500 comments during online public consultations of the draft opinion. Comments were received from a broad range of interested parties including NGOs, members of the public, academia, national food safety agencies and the food industry ranging from positive to negative. Predictably, industry thought that the draft opinion went too far, while some NGOs wanted an outright ban.

So a good compromise you would think. Not so sure.

The Americans and the French at opposing ends

The Americans are relaxed as usual. Just days before the adoption of the EFSA opinion, the Food and Drug Administration issued a statement saying that BPA is safe at current levels. The FDA said its verdict was based on a four-year review of more than 300 scientific studies. However, it mentioned three ongoing safety assessments and said that the agency might revise its conclusions pending their findings. A bit of hedging there.

But what about the food-loving French? Well, the French are not so sure that EFSA is right and has actually banned BPA from all packaging, containers, and utensils intended to be used in direct contact with food from 1 January 2015. Health issues potentially caused by BPA are thus taken much more seriously by the French Government. However, reasonably, there seems to be an allowance exempting packages introduced onto the market before this date to remain until stock is exhausted.

So what is a simple soul to believe? Just following the literature introduces further doubts.

Thermal receipts can contain high levels of BPA.

Thermal receipts can contain high levels of BPA contributing to dermal exposure.

New research findings

It is well-known that BPA is applied to the outer layer of thermal receipt paper as a print developer and can be present in very high quantities of around 20 mg BPA/g paper. Although EFSA’s assessment indeed did include exposure from thermal receipts, a recently published study showed that using hand sanitisers or other skin care products often containing mixtures of dermal penetration enhancing chemicals, can increase by up to 100-fold the dermal absorption of BPA. Significant free BPA was also transferred from hands to French fries leading to a rapid and dramatic increase in BPA exposure from the two sources.

There are some previous indications that BPA might be associated with hypertension and decreased heart rate variability. Now, a just published new study confirm without doubt that BPA can acutely increase blood pressure at normal exposure levels. In a randomised crossover trial, 60 non-institutionalised adults aged 60 years and over visited a study site three times, and were provided with the same beverage in two glass bottles, two cans, or one can and one glass bottle at a time. The researchers found that after consuming two canned beverages the systolic blood pressure increased by a statistically significant 4.5 mm Hg compared to consuming two glass bottled beverages and the urinary BPA concentration increased  by more than 1,600 per cent.

Don’t expect revolution

Of course those two late studies are not included in the EFSA review, but if they were would they change the conclusions? Not so sure. It seems overwhelming evidence is needed for the scientific experts to change their view. Thus don’t hold your breath, it is unlikely that the final opinion, when published, will change much from the earlier draft.

Wine contamination scare

Phtalates found in wine (Photo: boo_licious)

Phtalates found in wine (Photo: Boo Lee)

It is Friday evening and you are relaxing and enjoying a glass or two of a ten year old red wine. You roll the wine on your tongue and you detect a bouquet of raspberry and leather with a slight hint of phthalate. Hang on, what is phthalate? There shouldn’t be any phthalates in wine, should it? It is bad enough to have the sulfite preservative in the wine if you belong to the 5-10% of the population that is allergic to sulfite. But phthalates are hormone disrupting chemicals added to plastics to increase their flexibility and durability. They are considered carcinogenic, mutagenic and reprotoxic by the European Chemicals Agency. They don’t belong in wine, so what’s the story here?

Chinese consumer vigilance

Let’s go back a couple of years to 2012 and China. Following the catastrophic melamine-contamination scandal of 2008, Chinese consumers started to worry about other possible contamination problems. Thus, when elevated levels of phthalates were found in leading Chinese baijiu brands in November 2012, it caused a dramatic slump in sales. Baijiu is a popular white spirit produced from sorghum with 40-60% alcohol. Chinese authorities immediately lowered allowable phthalate levels in alcoholic drinks and clamped down on the maximum levels permitted in all wines and spirits. In March 2013, Chinese customs impounded containers of French wine and cognac on suspicion that they might contain phthalates. And they did, causing a flurry of testing, with laboratories in South West France suddenly swamped with samples from anxious exporters.

You may remember a previous scare regarding phthalates in cling film or glad wrap in the 1990s. They were found to migrate easily to fatty food products like cheese and meat.  Studies suggested that phthalates might be a factor in some cases of breast cancer, asthma, diabetes and attention deficit hyperactivity disorder in children. It is a group of chemicals that provoke universal anxiety, since they are now almost everywhere from household dust to the nasogastric tubes and surgical gloves used in hospitals.

New study quantifying the problem

Now a new study published in Food Additives and Contaminants provide some clarity of the extent of the problem of phthalates in a variety of French wines and spirits. The research showed that 59% of the wines analysed contained significant quantities of one particular form of phthalate, known as dibutyl phthalate, and only 17% did not contain any detectable quantity of at least one of the reprotoxic phthalates. Perhaps a more worrying statistic is that 11% of the wines analysed did not comply with EU specific migration limits (SML) for materials in contact with food, the only regulation applicable since no specific limits for phthalates in wine have yet been set in Europe.

Wine aged in oak barrels might be a safer bet (Photo: Ken Whytock)

Wine aged in oak barrels might be a safer bet (Photo: Ken Whytock)

So what is the origin of the phthalates in wine? The study analysed a variety of materials frequently present in wineries and found phthalates in winery equipment, especially tank linings, plastic vessels used in racking processes, the plastic tubing used to pump must or wine from one vessel to another, and pump components themselves. And ethanol as a solvent is a perfect way of extracting phthalates from plastics. That, of course, is why spirit producers need to be particularly vigilant.

As it happened, the French government stepped in to reassure consumers that this was an administrative issue and nothing to do with dangerous contaminant levels, adding that the change in the Chinese legislation affected tens of wine and spirit shipments from Bordeaux, Spain and Argentina, not only Cognac.

Should you be worried?

This might be an issue of limited toxicological impact in the overall scheme of things with so many other potential sources of phthalate exposure. More expensive wines aged in oak barrels might carry less risk. Australian wines have so far not been implicated in the contamination scare so there might be ample choices available to still enjoy a glass or two of wine on Friday evening.

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Aspartame deemed safe after a mammoth effort

Aspartame - EFSA's most comprehensive risk assessment ever

Aspartame – EFSA’s most comprehensive risk assessment ever

After its most extensive effort ever the European Food Safety Authority (EFSA) deemed aspartame to be safe at current use levels in an opinion just published in December 2013. This is a mammoth effort not only reviewing most of the available literature on aspartame and its breakdown products, but also consulting widely with the public before finalising the opinion. It will be seen as a breakthrough effort in improving consumer confidence in the scientific process of evaluating controversial food additives. But of course not everyone will be pleased, that is the nature of the beast.

The question could be raised why EFSA didn’t do as thorough a job in its previous evaluations of aspartame, but why be critical now when it is done. The work raises the bar for future opinions and I am thinking in particular of the Bisphenol A opinion in the immediate pipeline. That issue will be even more difficult to resolve with the low-dose hypothesis causing considerable angst among scientists. Another question is if EFSA can spend so much time on only one opinion without hampering overall progress on the many issues on EFSA’s plate. But that is an issue for their political masters.

So what did EFSA find

We all know that aspartame (E 951) is a sweetener authorised for use as a food additive in many countries. It is used extensively in diet soft drinks in particular. Chemically it is a dipeptide, that is the molecule is formed by the two amino acids, aspartic acid and the methyl ester of phenylalanine, binding together. In the gastro-intestinal system it is rapidly hydrolysed and fully degraded into its primary constituents of aspartic acid, phenylalanine and methanol with little or no aspartame available to be absorbed by the body. The amount of intact aspartame that enters the bloodstream has actually been reported as undetectable. Thus  potential toxic effects must be caused by any or all of these three major metabolites.

EFSA stated that it was clear from their literature review that the acute toxicity of aspartame as tested in mice, rats, rabbits and dogs was very low. Similarly, sub-acute and sub-chronic studies did not indicate any significant toxic effects in rats, mice or dogs. Neither did available data indicate a genotoxic concern for aspartame. Results from three chronic toxicity and carcinogenicity studies in rats and one in mice revealed no aspartame-related increase in any type of neoplasms at the doses tested.

There was a caveat though with debate raging about tumour findings reported by the European Ramazzini Foundation. However, EFSA and other authorities are of the view that many of the malignant neoplasms and the lymphoid dysplasias diagnosed in the studies were hyperplasias related to unknown chronic infection in the animals and not related to aspartame intake. Also hepatic and pulmonary tumour incidences reported fell within the institute’s own historical control ranges for spontaneous tumours.

There was also a problem with birth weight data from several reproductive and developmental toxicity studies performed in rabbits. However, EFSA stated that the findings were confounded both by a decrease in feed intake in the treated group and poor health of the animals.

What about human studies?

Artificially sweetened soft drinks a common source of aspartame

Artificially sweetened soft drinks a common source of aspartame

Looking at human studies, EFSA noted that there was no epidemiological evidence for possible associations of aspartame with various cancers in the human population.

A large prospective cohort study in Denmark found no consistent association between the consumption of artificially sweetened beverages in general (of which some might have been using aspartame) during pregnancy and the diagnosis of asthma or allergic rhinitis in children. Though they did find a small but significantly elevated risk of medically induced pre-term delivery in women with higher reported consumption of artificially sweetened drinks. This was countered by findings in another prospective study in Norway showing a barely discernible association between pre-term delivery and artificially sweetened soft drinks but a stronger association with consumption of sugar-sweetened soft drinks.

And the metabolites specifically

Methanol was cleared from any effects after aspartame consumption since it only contributes to a very small part of methanol exposure. Fruit and vegetables play a more important part in methanol exposure and it is also naturally produced by the body. It is only toxic at fairly high levels, such as from consumption of some home-distilled alcoholic spirits.

Neither did aspartic acid raise any human safety concerns. The body can convert aspartic acid into the neurotransmitter glutamate which, at levels very much high than can be derived from aspartame consumption, can have harmful effects on the nervous system.

Phenylalanine is the remaining potential culprit. It is known to be toxic at high intake levels, in particular to the developing foetus in women suffering from the medical condition phenylketonuria (PKU). EFSA considered that it was plausible that phenylalanine could be responsible for some or all of the adverse effects reported for aspartame in rat and rabbit developmental toxicity studies. However, phenylalanine blood levels reached after realistic dietary intake of aspartame were well below conservative estimates of the levels necessary to cause harm.

So all clear for everyone except PKU patients where total control of dietary phenylalanine intake is necessary to manage the risk from elevated phenylalanine blood levels. Fortunately, it is a requirement in many countries that products containing aspartame should indicate through labelling that they contain a source of phenylalanine to protect the small minority unable to metabolise the compound.

And the conclusion?

All-in-all EFSA considered aspartame safe at normal use levels and retained an Acceptable Daily Intake of 40 mg/kg bodyweight. Some dubious results remain but scientific studies are seldom perfect. It seems clear that all doubtful results can be explained without casting a shadow over aspartame. At least according to the EFSA evaluation.

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The food flavouring beef thiophene in doubt

A hazardous substance but a low risk. That is the conclusion of the European Food Safety Authority (EFSA) when assessing the food flavouring called beef thiophene (3-acetyl-2,5-dimethylthiophene). It is a substance that occurs naturally at low levels in cooked beef. As a synthesised food flavouring, beef thiophene is a colourless to yellow liquid that can be used to strengthen the roast and smoked flavour of processed meats but also to give a burnt, nutty flavour to confectionery, baked goods and some other savoury products. So what is the potential danger? Let me explain.

Hazardous or not

Europe reviewing safety of food flavourings (Photo: Xavier Häpe)

Europe reviewing safety of food flavourings (Photo: Xavier Häpe)

The European Union adopted a regulation on flavouring substances in October 2012, with the aim of providing a list of flavouring substances that are deemed safe and thus may be used in food in the EU. At the time of announcing the list, 2100 flavouring substances had already been assessed by EFSA or other equivalent organisations and included in the list. Any flavouring substances not in the list will be prohibited after a phasing out period.

Now the turn came to assess the safety of beef thiophene. Initially there was a lack of genotoxicity information on which to make an appropriate safety assessment. However, EFSA requested additional information from industry. The missing information was provided by the European Flavour Association. The data submitted consisted of a bacterial gene-mutation assay and an in vivo study on mice. The studies were deemed appropriate since they were performed in compliance with Good Laboratory Practice and complied with the OECD Guideline 471 and 488, respectively.

Unfortunately, the bacterial mutation assay showed a dose-dependent positive outcome and it was possible to conclude that the observed mutagenicity indicated that it was due to a metabolite of the substance. Similarly, the in vivo mice study showed dose-related mutations in the liver, with results further supporting the hypothesis that the mutagenicity observed was due to a metabolite of the beef thiophene. Therefore, since the substance was genotoxic (that is, it can damage DNA, the genetic material of cells) both in vitro and in vivo, EFSA considered that its use as a flavouring substance raised safety concerns.

Potential risk

It is clear that genotoxic substances should not be intentionally added to food. However, EFSA found that the overall use of beef thiophene was low with total annual sales in the EU estimated to be 2.3 kg. It is produced as a flavouring by a small number of manufacturers and only used in a limited number of foods. While no exposure assessment was carried out by EFSA, should you have been exposed to this substance in food any risk to your health is expected to be very small. Thus, although it is deemed to be a hazardous substance with genotoxic potential and inappropriate as a food flavouring, public health risk from past use is low.

EU risk managers will now have to decide whether to remove beef thiophene from the EU list of authorised flavoring substances. Other countries might follow. The substance is on the GRAS (generally recognised as safe) list in the USA and, although difficult to get use levels, might be more commonly used there. Since beef thiophene has been approved as a food flavouring by JECFA (the Joint FAO/WHO Expert Committee on Food Additives) it might also be used in many other parts of the world. It’s going to be interesting to see the world-wide reaction to the new findings.

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Aspartame (almost) cleared

The aspartame molecule

The aspartame molecule (Illustration: Wikimedia)

The artificial sweetener aspartame has been associated with some controversy from its initial approval for use in dry food in 1974 by the Food and Drug Administration in the USA. Aspartame has since been deemed safe for human consumption by over 100 regulatory agencies in their respective countries. Although there were some clear irregularities in the initial submission by G.D. Searle, this was not considered detrimental to its approval.

Because of the initial controversy, the safety of aspartame has been studied extensively since its discovery with research that includes animal studies, clinical and epidemiological research, and post-market surveillance. Aspartame is now one of the most rigorously tested food ingredients to date. Comprehensive peer-review studies, as well as independent scrutiny by governmental regulatory bodies, have analysed the published research and deemed aspartame safe for consumption at current levels. This has not silenced the critics.

The ultimate review?

In May, 2011, the European Food Safety Authority (EFSA) was asked by the European Commission to bring forward a full re-evaluation of the safety of aspartame, previously planned for completion by 2020. On January 8, 2013, EFSA released a draft opinion for comment. As part of the evaluation process, EFSA commissioned an external review of the available literature on aspartame. This review was published on 1 March, 2013 and provides an overview of current knowledge regarding the metabolism and toxicity of aspartame. From a database containing 5,023 references the review team identified 1,366 documents of direct or indirect relevance to the risk assessment of aspartame. After scrutiny of those documents, 358 were carried forward for detailed examination.

Review and consultations on aspartame (Photo: ALDEADLE)

Aspartame under review (Photo: ALDEADLE)

The review team noted that aspartame after ingestion is immediately split into three constituents already in the gastrointestinal system and these are consequently absorbed individually. Two of the three components (aspartate and methanol) are cleared rapidly from the body and the only component remaining in the circulation system is phenylalanine. Aspartame itself is normally not absorbed.

The effective potential toxicity of aspartame is therefore only related to the phenylalanine component.

The team reported that:

  • No significant acute or subchronic toxicity had been observed in animal models or in humans even at the highest doses of aspartame which could reasonably be administered, and early concerns that aspartame might cause neurotoxicity in neonates and infants could not be substantiated.
  • There was no evidence to indicate that aspartame is genotoxic. Reported marginally positive results occurred only sporadically and did not indicate any particular cause for concern.
  • Available chronic toxicity studies did not indicate any overt carcinogenic effect in experimental animals due to aspartame, but all the conventional studies were limited in various ways.
  • One epidemiological study addressing possible reproductive effects in humans found an increased risk of preterm delivery in women who frequently consumed either carbonated or (to a lesser extent) non-carbonated diet drinks but did not address aspartame directly and was subject to a number of confounding factors.

The review concluded that there was no consistent evidence that aspartame has adverse effects, either in healthy individuals or in potentially susceptible groups, under normal conditions of use although phenylketonurics do need to regulate their intake of aspartame for health reasons. They are supported in doing this by clear labelling of aspartame-containing products. The review team left some question marks in relation to chronic and reproductive toxicity and supported further research to conclusively exclude any such effects.

Current state of the art

EFSA’s draft opinion now states that aspartame and its metabolites “pose no toxicity concern for consumers at current levels of exposure. The current Acceptable Daily Intake (ADI) is considered to be safe for the general population and consumer exposure to aspartame is below this ADI”. The final opinion is expected to be delivered in May 2013.

If this will be the end of the controversy over the use of aspartame as a food additive is still doubtful. The remaining uncertainty over chronic and reproductive toxicity, although slight, might need to be conclusively resolved to silence all critics. Further unnecessary controversy has been ignited by the dairy industry request to sweeten flavoured milk for children with aspartame without declaring it on the label.

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Ink with your food

Will that be with or without printing ink to your cereal, Madam? What, are you joking, you say? No, it is no joke but probably not much to worry about, although you might like to know.

The great choice of cereals (Photo credit: Alnatura – Wikipedia)

You’re in the supermarket looking at the cereal choices. You want to buy some Swiss style muesli because you believe it is a healthy choice. There is a very attractive brand name package in red, green and gold that you favour and beside it there is an organic version in a bland brown box. Of course you pick the colourful package, that’s what the manufacturer is counting on. Isn’t muesli healthy enough without being organic? And besides, the picture of the muesli looks very appetising.

But what you are not counting on is the potential migration of printing ink components from the outside of the package, through the cardboard and into the plastic inner package. And before you know it the muesli also contains some printing ink. Sounds impossible, but that is what is happening all the time for plenty of packaged food. And this is the reason why printing inks should be safe to use according to the general food legislation in many countries.

So why even raising this? Well, in early February 2009, German authorities found 4-methylbenzophenone (4-MBP) migrated from the outside cardboard packaging at levels of almost 1 mg/kg into certain cereal products. They sent an alarming message to other European authorities because they had never seen this before. Other countries started their testing and Belgian authorities found even higher levels of close to 4 mg/kg in cereals. Problem was there was not enough toxicity data available to say if 4-MBP was safe at the levels found. 4-MBP is used to stabilise printing inks and lacquers applied on the surface of outer packages, mainly cardboard boxes. Since it is very volatile it may easily migrate into the package and contaminate even solid food inside an inner plastic bag. An inner aluminium bag would be safe but is not used that often.

At the end, the European Food Safety Authority (EFSA) issued a statement concluding that short term consumption of contaminated breakfast cereals should not pose a risk to most people. However, EFSA pointed out that should 4-MBP continue to be used with printing inks, more data on occurrence of the substance in foods should be provided as well as appropriate toxicity data corresponding to the level of exposure for a full risk assessment. So the alarm could be called off for this time.

But what do we know about printing inks in general? Are they all safe? Could there be an interaction between different chemicals that we have not yet studied? Maybe you should pick that brown box of muesli anyway, just to be on the safe side for now.