…and you thought more is always better

It’s a truism that most complex life on earth requires oxygen (O2) for its existence. We breathe in oxygen and flush out carbon dioxide (CO2) formed during energy metabolism. But here is the dilemma – oxygen is a highly potent molecule that can cause damage by producing reactive oxygen species like hydrogen peroxide (H2O2) and superoxide (O2) in the body.

Formation of reactive oxygen species is a natural process and part of our normal metabolism. At low levels they have important roles in maintaining basic activities of individual cells as well as optimal functioning of the overall body. However, due to stress, cigarette smoking, alcohol, sunlight, pollution and other factors they can increase dramatically and cause significant damage to cell structures, known as oxidative stress.

The body balance

As life on Earth evolved in the presence of oxygen and its potential negative effects, it was necessary for life to adapt by the evolution of a battery of internal antioxidant systems. Three of those are superoxide dismutase that help in converting superoxide into hydrogen peroxide and oxygen, as well as catalase and gluthation peroxidase that both further degrade hydrogen peroxide to water and oxygen to finish detoxification.

There are also a range of external antioxidants available often associated with so called super foods. Such antioxidants include vitamins A, C and E, and the minerals copper, zinc and selenium. Other dietary food compounds, such as phytochemicals in plants, have even greater antioxidant effects. These include lycopene in tomatoes and anthocyanins found in cranberries among many others.

A diet high in antioxidants may reduce the risk of many diseases, including heart disease and certain cancers. Pulled together oxygen and antioxidants provide an intricate balance supporting life and maintaining health.

Overdoing a good thing

Along comes the chemicals industry. If antioxidants in food are a good thing why not produce them in pure concentrations in the form of a pill to supplement antioxidants from the rest of the diet? As a result there are now a huge range of food supplements available promoted for their antioxidant activities. And sales of antioxidant supplements, including vitamins and minerals, have increased dramatically with the hope that they may prevent premature ageing and promote overall health.

However, studies of antioxidant vitamins and minerals taken as supplements have been disappointing and it appears that the complex array of antioxidants present naturally in plants as well as those the body produces in reaction to stress may be more important.

And there is more. A scientific study published in 2016 showed that excessive antioxidant use may actually have a harmful effect on the normal cell stress response. It might influence a protein called IRE-1, which is located on the outside of the endoplasmic reticulum, a cell structure that makes proteins like insulin. IRE-1 monitors the endoplasmic reticulum, flagging up any abnormal proteins that are created and alerting the cell to apply corrective measures or create a new protein.

Disrupting the natural cell processes can cause irreparable damage.

So what can we learn?

In short, excessive intake of antioxidants, as can happen when taking food supplements, is increasingly bad for you. Blindly consuming large doses of antioxidants is not the best idea, because while your intent would be to protect yourself from damage, you’re potentially interfering with normal cell signals that are helpful and important.

On the other hand there is increasing evidence that the more moderate levels of antioxidants found in whole foods are more effective than when isolated and presented at higher levels in pill form.

A well-balanced diet, which includes consuming antioxidants from whole foods, is best. If you still take supplements, seek supplements that contain all nutrients only at recommended levels. 

As more is not always better.

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‘Whiter than white’ – titanium dioxide nanoparticles

‘Whiter than white’ is a claim often used by washing powder manufacturers to describe the superior effects of their products. Equally, ‘whiter than white’ is a product attribute strived for by some food manufacturers although rarely boasted about as such as it might have been achieved through a now questionable food colourant, titanium dioxide.

Titanium dioxide in any form can be identified through the number E171 on the product label. It is commonly used in high quantities in food, chewing gum, toothpaste and some medicines as a whitening agent.

A proportion of this colourant most likely comprise of titanium dioxide nanoparticles.

What are nanoparticles?

Nanoparticles are particles between 1 and 100 nanometres (nm) in size, a thousand times smaller than the width of a strand of hair. Although substances that make up the nanoparticles are not necessarily regarded as toxic, nanoparticles are so small that their behaviour can be quite different from what we see for larger particles of the same substance. This is a new challenge for toxicologists.

While nanoparticles have been commonly used in medicines, food, clothing, and other applications, the possible impacts of nanoparticles, especially their long term effects, are still poorly understood. Nanoparticles in sunscreens and cosmetics can penetrate the skin, and this raises questions about what they can do in the body. Ingested nanoparticles can, and do, get into the body in places where larger particles cannot.

Nanoparticles of titanium dioxide in food

Titanium dioxide has been used in a range of foods, from sweets to processed cheese as consumers are more likely to buy and eat foods that are brighter or more vibrant in colour, as they look fresher. It gives a natural whiteness and opacity to foods, such as ice cream and the icing on cakes, helping to create great-looking food.

Food-grade titanium dioxide has a long history in helping make our meals and snacks aesthetically appealing. Food manufacturers have been using it presumably safely in approved uses for more than 50 years. It is assumed that titanium dioxide doesn’t enter the bloodstream as it passes through the digestive system unchanged and unabsorbed. But what about when the colourant contains nanoparticles?

In the past there has been little understanding of the size of any food-grade titanium dioxide particles, but this is changing with a recent focus on the health impact of nanoparticles in general. To provide the characteristic white colour of titanium dioxide, a large part of the particles must be between 200 and 300 nanometres in size. Particles of this size are not considered nanoparticles. However, the titanium dioxide production process results in a small fraction of the particles being nanoparticles.

The food industry claim that there has been no significant change in the particle size of titanium dioxide supplied to the food industry over the years, but acknowledge that there is a variation allowing for between 11% to 39% of the particles to be of nano size. As they are smaller this would equate to about 3.2% of the mass of any supplied titanium dioxide.

Is titanium dioxide still safe to eat?

The Joint FAO/WHO Expert Committee on Food Additives in 1970 considered it unnecessary to establish an acceptable daily intake (ADI) for titanium dioxide in food. This decision was taken on the basis of the low solubility, poor absorption into internal organs like liver and the absence of acute toxic effects.

In the USA, the FDA considers titanium dioxide as safe for use as a colouring agent in food and in 1966 allowed its addition to food up to a level of one percent. 

In Europe, titanium dioxide has been allowed for use as a food colourant for decades at a level required by food manufacturers to achieve desired effects. In 2016, the European Food Safety Authority (EFSA) published a re-evaluation of titanium dioxide including the potential risks of titanium dioxide nanoparticles to human health. EFSA concluded that, based on the information available, it was no reason for concern.

In Australia, titanium dioxide is an approved food additive and has been used in consumer products for many years. In 2016, Food Standards Australia New Zealand (FSANZ) published a review into the oral ingestion of titanium dioxide, including in nanoscale form, finding that there was not strong evidence to support claims of significant health risks.

In Japan, titanium dioxide is used without limitations other than for certain food categories in which it is not permitted.

In India, titanium dioxide is only authorised for use in chewing gum and bubble gum at not more than one percent, and in powdered concentrate mixes for fruit drinks at not more than 100 mg/kg.

But that is not the end of the matter as more scientific information is published.

What are the new findings?

In 2010, the International Agency for Research on Cancer (IARC) found that there were sufficient evidence in experimental animals for the carcinogenicity of titanium dioxide but not in humans. It thus placed titanium dioxide in a lower category as “possibly carcinogenic to humans” (Group 2B).

In 2016, the Dutch National Institute for Public Health and the Environment (RIVM) estimated likely human exposure to titanium dioxide nanoparticles from food, food supplements and toothpaste and concluded that toxic effects on the liver cannot be excluded. Previous studies with laboratory animals had indicated that the ingestion of very large quantities of titanium dioxide can cause damage to various organs, including the liver.

In 2017, the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) published an expert appraisal of a study on the oral toxicity of titanium dioxide showing potential carcinogenesis-promoting effects in rats. At that time, the Agency stressed the need to conduct new toxicological studies in order to confirm or refute the effects reported in that study.

In 2018, RIVM and the RIKILT research institutes detected titanium dioxide particles in the liver and spleen of humans. At least 24% of the titanium dioxide particles were found to be nanoparticles. The concentration of titanium dioxide particles found in the human liver did not yet result in adverse health effects in laboratory animals, but it exceeded the level that RIVM considers safe for humans.

In 2018, US and Serbian researchers published findings from a study that exposed the fruit fly, Drosophila melanogaster, a common model species in human health research, to an estimated daily human titanium dioxide consumption level for 20 generations. They noticed a change in normal developmental and reproductive dynamics, and an increased genotoxicity. The larval stages were at a higher risk of sustaining damage and this was particularly worrisome, since children tend to consume higher daily concentrations of titanium dioxide than adults.

In 2019, University of Sydney research provided further evidence that nanoparticles may have a substantial and harmful influence on human health. Their mice study found that consumption of food containing titanium dioxide has an impact on the gut microbiota which could trigger diseases such as inflammatory bowel diseases and colorectal cancer.

Titanium dioxide did not change the composition of the gut microbiota, but instead it affected bacterial activity and promoted the formation of biofilms. Biofilms are bacteria that stick together and the formation of biofilm has been reported in diseases such as colorectal cancer.

So what now?

The above results confirm the possibility that the use of titanium dioxide may lead to adverse human health effects. Therefore, it might be that the safety of the present use cannot be fully guaranteed. In response, the European Commission has repeatedly requested EFSA to further re-examine the use of titanium dioxide in food.

EFSA in a reply of June 2018 evaluated four new studies and concluded that their findings highlighted some concerns but with uncertainties, therefore their relevance for the risk assessment was considered limited. Further research would be needed to decrease the level of uncertainties.

In a further statement of May 2019 EFSA claimed it could not identify any major new findings that would overrule its previous conclusions on the safety of titanium dioxide. However, it reiterated the importance of addressing previously identified uncertainties and data gaps, as well as further investigation of in vivo genotoxicity but only after the physico-chemical characterisation of food grade titanium dioxide had been completed.

What can you do?

Well, the answer is not much. Titanium dioxide can be found in more than 3,500 food products and is consumed in a high proportion everyday by the general population.

The highest concentrations are expected in chewing gum (up to 16,000 mg/kg), food supplements delivered in a solid form (up to 12,000 mg/kg), processed nuts (up to 7,000 mg/kg) and ready-to-use salads and sandwich spreads (up to 3,000 mg/kg).

Chewing a single piece of bubblegum can result in an intake of over 5 mg of titanium dioxide. The estimated daily maximum consumption of titanium dioxide by children is up to 32.4 mg/kg body weight.

To put those dietary intake levels into perspective hypothetical upper safe levels for dietary intake of between 0.4 and 5 mg/kg body weight per day have been calculated from rodent studies.

You could stop chewing gum but it would not help much. The best hope is that studies currently under way will produce conclusive results so that authorities can either fully clear titanium dioxide for use in food, limit its use or fully ban it from food.

Most of us have to wait and see. However, if you live in France you might benefit from the French government decision to ban the addition of titanium dioxide in food from 1 January 2020.

Food fraud – milk

Food fraud is nothing new, but the intensity and frequency have been on the rise. From counterfeit extra-virgin olive oil to intentional adulteration of spices and the manufacturing of fake honey, food fraud has been estimated to be a $US40 billion a year industry. In a series of posts we will cover a range of recent issues.

Milk is the third in our series on fraudulent food

Next to prostitution, historians consider counterfeiting the world’s second oldest profession. Similar to fraudulent honey and olive oil, which we covered in previous posts, food fraud involving milk has been around for centuries and is actually to my surprise number one on the list of food tampering issues worldwide, due in particular to current cheating in the developing world.

But the Western world has had its problems too. It was common in the old German Empire to dilute milk by 50 per cent and to restore the original consistency by adding a range of substances like sugar, flour, chalk or gypsum. Spoiled or otherwise contaminated milk was sold without hesitation.

In the mid-19th century, New York’s dairy farmers increased their profits by feeding their cows with cheap waste from distilleries. This resulted in watery and blue-tinted milk that farmers mixed with starch, plaster, chalk and eggs to improve texture and colour, then diluted further with water.

Milk fraud has now spread to the developing world due to an increased demand for milk.

Increased milk consumption

Milk in its natural form has a high food value, since it is comprised of a wide variety of nutrients which are essential for proper growth and maintenance of the human body. In recent decades, there has been an upsurge in milk consumption worldwide, especially in developing countries, and it is now forming a significant part of the diet for a high proportion of the global population.

As a result of the increased demand, some unscrupulous producers are indulging in milk fraud. This malpractice has become a common problem in the developing countries, which might lack strict vigilance by food safety authorities.

One of the oldest and simplest forms of milk fraud is through the addition of variable volumes of water to artificially increase its volume for greater profit. This can substantially decrease the nutritional value of milk, and if the added water is contaminated there is a risk to human health because of potential waterborne diseases. For infants and children this may be a serious concern as they are more vulnerable, at a critical stage of growth and development and are dependent on milk products for supplies of vital nutrients. Babies fed fraudulent milk are at risk of malnutrition and even death.

Adulterants added to milk

Although the vast majority of food fraud incidents do not pose a public health risk, there have been fraud cases that have caused extensive illness. Perhaps the most widely cited, high-profile case involved the addition of melamine to milk-based products to artificially inflate protein values. In 2008, it was reported that melamine-contaminated baby formula had sickened an estimated 300,000 Chinese children with symptoms of irritability, dysuria, urination difficulties, renal colic, hematuria, or kidney stone passage. Hypertension, edema, or oliguria also occurred in more severe cases, killing a reported 6 infants. 

A range of other inferior cheaper materials may be added to diluted milk to increase the thickness and viscosity of the milk, to maintain the composition of fat, carbohydrate, and/or protein and to increase shelf-life. They include reconstituted milk powder, urea, rice flour, salt, starch, glucose, vegetable oil, animal fat, and whey powder, or even more hazardous chemicals including formalin, hydrogen peroxide, caustic soda, and detergents.

Some of these additions have the potential to cause serious health-related problems.

Toxic effects caused by some milk adulterants

The presence of urea in milk may cause severe human health problems such as impaired vision, diarrhea, and malfunctioning of the kidneys. It may also lead to swollen limbs, irregular heartbeat, muscle cramps, chills and shivering fever, and cancers, though these are less likely with the concentrations present in the adulterated milk.

Formalin is highly toxic to humans in small amounts and is classified as a carcinogen. Its ingestion is known to cause irritation, often leading to dry skin, dermatitis, headaches, dizziness, tearing eyes, sneezing and coughing, and even the development of allergic asthma.

Hydrogen peroxide damages the gastrointestinal cells which can lead to gastritis, inflammation of the intestine, and bloody diarrhea.

Detergents have been shown to cause food poisoning and gastrointestinal complications. Some detergents also contain the toxic ingredient dioxane, which is carcinogenic in nature.

Difficult to quantify food fraud

It is not known how widespread milk fraud is as those who commit fraud want to avoid detection and do not necessarily intend to cause physical harm. Thus, most incidents go undetected since they usually do not result in a food safety risk and consumers often do not notice a quality problem.

The full scale of food fraud is not known, as the number of documented incidents may be a small fraction of the true number of incidents. However, some researchers contend that food adulteration is not necessarily more common now, but reputational repercussions are certainly more far-reaching with today’s worldwide media coverage.

Detecting food fraud relies on testing. As new tests are developed we get better at detecting frauds, but the fraudsters will always be looking for new ways to cheat those tests. 

Newer technology will help fight food fraud in the future. These include tracers and edible inks that can be used to tag foods, biomarkers, and DNA fingerprinting. 

While it might seem alarming to hear reports of fake and adulterated foods, this might actually be a good thing, because it means testing and surveillance is working.

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.

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.

Related articles

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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