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.

Red hot findings indicate new dangers with bisphenol A

Hormon disturbing chemicals (Photo: Sooz)

Hormon disturbing chemicals can be dangerous (Photo: Sooz).

Endocrine disruptors interfere with our bodies’ finely tuned hormonal regulation systems. Unfortunately, human exposure to endocrine disruptors, and particularly to bisphenol A commonly found in food packaging materials, is omnipresent in our daily lives. The potential risks to consumer health of such chemical contaminants have been the subject of many contradictory reports with science divided over how to handle the findings. Now there seems to be a link between bisphenol A exposure and food intolerance. More than 20% of the global population suffer from food allergy or intolerance making this an important issue.

Scientific controversy

The French are hellbent on proving that bisphenol A is a dangerous chemical that should not even come close to food of any sort. And they might be right. In the USA it is the opposite situation with federal agencies protecting the use of bisphenol A in food applications at any cost. They cannot both be right though. The arbiter is sitting on the fence. This is the European Food Safety Authority that recently completed a new draft assessment of bisphenol A but decided to consult extensively with external stakeholders before making a final decision. It is not going to be easy.

To start in France,  the French Agency for Food, Environmental and Occupational Health and Safety (ANSES) published an opinion on bisphenol A in April 2013 which recommended limiting exposure to this substance and lowering the toxicological thresholds on which risk evaluations were based. This resulted in the French government deciding to ban the use of bisphenol A in all food packaging from 2015. And new research findings are accumulating showing new dangers.

New scientific results published

Using female rats exposed to bisphenol A at low doses during pregnancy and early suckling, scientists at INRA’s Joint Research Unit for Food Toxicology in Toulouse demonstrated that it affected development of the immune system in the off-spring of the exposed rats and predisposed their progeny to food intolerance in adulthood. The scientists tested different doses (0, 0.5, 5 and 50 μg/kg body weight per day) and demonstrated a non-linear relationship between the bisphenol A doses and the undesirable effects observed. In particular, the most marked disturbances were observed at a dose of 5 μg/kg body weight per day. This is of course confusing but in line with the low dose hypothesis suggesting that there can be different reactions at different dose levels. At the low-dose level the scientists found that when challenged with ovalbumin, an egg white protein not previously included in their diet, an immune reaction was seen directed against ovalbumin which induced colonic inflammation that testified to a food intolerance. However, rats descending from the control group developed a food tolerance to ovalbumin, which resulted in a lack of immune response.

This is the same dose of 5 µg/kg body weight per day that is proposed by EFSA to be safe. The new findings highlight the problem of determining a safe and tolerable dose for bisphenol A. EFSA is still to make up their mind but has so far used the expression “as likely as not” for many negative findings to indicate an uncertainty around the real health impact of current human exposure levels.

Laboratory findings questioned

Laboratory findings questioned because of contamination.

Americans have been more gung ho about the safety of bisphenol A. To be fair there is an ambitious ongoing U.S. research project known as “CLARITY-BPA” into the safety of bisphenol A funded to the tune of US$32 million. But scientists from the National Center for Toxicological Research in Arkansas preempted this research by publishing interim findings in Oxford Journals’ Toxicological Sciences claiming that only very high doses of bisphenol A are dangerous, and that the “low levels” in common circulation through plastic bottles, thermal paper receipts, tin can linings and other sources are not a threat. These findings have since been heavily criticised because of bisphenol A contamination also of the control group.

Is there a safe level?

So what to believe? It seems pretty clear that not even 5 µg/kg body weight per day is a safe level. But actual exposure might be much less than this according to EFSA’s new exposure calculations as long as you don’t live exclusively on canned food. We have to wait until the end of 2014 until we can get access to EFSA’s conclusions. Agony for us and for the scientists grappling with the final opinion.

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Eat less plastic with your food

Bisphenol A can be found in soup can linings (Photo: Robert Couse-Baker)

Bisphenol A can be found in soup-can linings (Photo: Robert Couse-Baker)

We have covered the issue once before in case you wonder. All the extra things you get with your food. You can read the previous blog on ink migrating from the colourful outer box into your breakfast cereal as an example. But there is also phthalates used as plasticiser in plastic wrapping that can find their way into cheese. And the topic of this blog: bisphenol A used in the protective lining of food-cans moving into canned soup. So it is obvious that we eat a lot of unintended components even if not chewing directly on the plastic cover.

Are you with me so far?

Plastic component tolerance lowered

Now the European Food Safety Authority (EFSA) has published a long anticipated further review of the potential dangers of bisphenol A. Bisphenol A is used as a component in polycarbonate plastic drink-bottles, epoxy resins used as food-can linings, and in thermal paper used as cash register receipts. There are two ways, oral (eating the soup) and dermal (holding the receipt), that we can get exposed to bisphenol A, with the oral route clearly dominating.

In reviewing past and current research literature, EFSA concluded that the tolerable daily intake (TDI) for bisphenol A should be lowered from its current level of 50 µg/kg bodyweight per day to 5 µg/kg bodyweight per day and be set on a temporary basis because of uncertain scientific results. This is a huge change, lowering the tolerable limit by a factor of ten, but of course it is not going all the way to proposing that bisphenol A should be banned from food contact materials.

Is this conclusion a good or bad thing?

EFSA experts reviewed 450 scientific reports (Photo: J Brew)

EFSA experts reviewed 450 scientific reports on bisphenol A (Photo: J Brew)

Well, not that easy to say.

After diligently reviewing another 450 scientific publications on top of what they covered in a previous opinion, the EFSA experts are clearly still confused. They rightly claim that some reported adverse findings are obscure and not scientifically rigorous enough to be fully trusted. But they also note that these findings get repeated by other scientists, a sign of increasing validity. Although too early to rely on, the EFSA experts are sufficiently worried to lower by a factor of ten the levels of bisphenol A intake humans can tolerate on a daily basis without showing adverse effects. And they also claim that this is only a temporary recommendation while awaiting new scientific results in the pipeline that might require more serious action.

Industry, in its usual fashion, has been quick to interpret the new opinion as supporting the continued use of bisphenol A in food contact materials without restrictions. They base this conclusion on the fact that the new suggested tolerable limit is higher than the highest exposure levels calculated by EFSA by a factor close to five.

So the good thing is that even with the lower tolerable daily intake proposed by the EFSA experts, the safety margin to the actual levels of bisphenol A consumed is sufficiently large to not be of concern.

But the bad thing is that adverse scientific findings are accumulating using much lower doses. As a consequence, the EFSA experts only set the new tolerable level on a temporary basis and flagged that they will need to review the situation again in the near future.

What are the concerns?

This is going to be a bit technical but hang in there. You see, you have an opportunity to influence the final wording in the EFSA opinion. It is just a draft and open for consultation until 13 March 2014.

The dual mountain peak (or non-monotonic) effect (Photo: Frank Kovalchek)

The dual mountain peak (or non-monotonic) effect (Photo: Frank Kovalchek)

The final view will depend on how to interpret findings of low dose and non-monotonic effects. So far EFSA has based its opinion on changes in male mouse kidney weight as the critical endpoint. This is a straight linear effect, that is the higher the dose of bisphenol A the more serious the results. This is the way toxicologists like to see their results as they have tools to transform such results into dose levels relevant to humans. Unfortunately, the scientific debate is currently focussed on the endocrine effects of bisphenol A, which might adversely impact physical, neurological and behavioural developments. And those effects might be seen at very low doses only or even increase again with a diminishing dose. The low dose or the non-monotonic (the dual mountain) effects.

Doesn’t make sense?

Let me explain with a hypothetical scenario.

You have your first cup of coffee of the day. The caffeine will pass the blood-brain barrier and the initial high levels will saturate your adenosine receptors in the brain. As a result you will feel alert and can get on with the job of the day. But a couple of hours later you also start to feel happy. Not because of your work accomplishments but because the lower levels of the remaining caffeine has now activated dopamine that was previously blocked by the higher levels.

This outcome will be different depending on the connections between the two reactions. It might simply be that you unmask a new effect only at low doses. Or you could see the dual mountain effect in that you actually have two dose peaks, one low and one high with a valley in between. This is difficult to test for in animal experiments but very important in case it is the low doses that have the adverse effect.

Don’t worry, it is confusing scientists too!

This is currently confusing scientists with no clear guidance so far on how to handle such situations. Should you wait and see or take immediate action even if you believe the results look a bit suspicious?

The EFSA experts selected the wait and see approach which makes sense as they believe new results will soon be available. However, there is no guarantee that the new results will be clearcut and we will be back at square one.

Experts at the French agency responsible for food safety, ANSES, took the opposite approach, suggesting immediate action. They reached the conclusion that bisphenol A exposure was associated with proven effects in animals and suspected effects in humans, also at levels of exposure below currently suggested thresholds. Specific risk situations were considered for pregnant women and their unborn children. The ANSES experts believed that there were potential links between low level bisphenol A exposure in the womb and later mammary gland tumours, dysfunctional behaviour, metabolism changes, and obesity. This also makes sense considering that bisphenol A is an endocrine disruptor and could reasonably be expected to act in this manner.

So who is right?

Don’t look at me, I have no idea. But I do believe that the dual mountain effect is real. It is not easy to break away from a consensus view among food safety agencies as the ANSES experts did. We can only hope that new scientific results will be timely and unambiguous to break the deadlock.

In the meantime you can make your own soup and avoid plastic water bottles. That’s good for the environment, if nothing else.

Bisphenol A – half of the story

Bisphenol A might be contributing to obesity (Photo: Malingering)

Bisphenol A might be contributing to obesity (Photo: Malingering)

We have written about bisphenol A before. Bisphenol A is mainly used in combination with other chemicals to manufacture polycarbonate plastics and resins used as food contact materials but can also be found in carbonless copy paper and thermal point-of-sale receipt paper. It is clear that bisphenol A is an endocrine disruptor at high doses but there are also some indications that it might be equally effective at very low doses. It has been proposed that the latter might even be one explanation of many to the obesity epidemic. According to this theory exposure to bisphenol A might induce epigenetic changes turning on obesity genes. Question is do we need to take action to remove bisphenol A from the food supply?

Let’s look at the process to arrive at a plausible answer to that question.

When assessing potential risks to public health posed by a food hazard it is necessary to have detailed knowledge of the expected toxicological effects of the hazard, the amount needed to be consumed to cause such effects and the expected population exposure to the hazard. There might also be other sources than the diet to be considered when calculating exposure. It might sound a bit complex and of course in most cases a lot of scientific data need to be gathered and assessed to draw reliable conclusions. But at the end it is still only a straight forward mathematical calculation using the critical dose and the estimated exposure as inputs.

But what inputs to use? Scientific facts evolve over time both on the toxicological side and the exposure side. A range of new scientific findings have been or are about to be published covering low-dose effects of bisphenol A. They are currently being evaluated by the European Food Safety Authority (EFSA) so this side of the equation is still uncertain. In the meantime, EFSA has published a revised exposure assessment providing half of the story needed to complete a risk assessment of bisphenol A.

EFSA previously calculated exposure to bisphenol A in 2006 using rough estimates of its presence in food and very basic food consumption information. This might be acceptable in case such conservative estimates are far lower than the expected dose of  toxicological concern. However, it didn’t include attempts to estimate exposure from non-food sources that could have been considerable. Now EFSA has published a refined exposure assessment using accurate data on the amount of bisphenol A present in food and detailed food consumption information provided by many European Union member countries. On top of that, EFSA also included exposure from non-food sources, thus combining data from oral, inhalation and dermal routes in the final results. Exposure modelling involved the assessment of chronic exposure to bisphenol A through diet, thermal paper, air, dust, toys, cosmetics, and dental sealants.

The new exposure estimates were much lower than the estimates of 2006. In the previous assessment, high exposure was up to 5,300 ng/kg bodyweight per day in toddlers and up to 11,000 ng/kg bodyweight per day in infants aged 3 months. This should be compared with the current estimates of up to 857 ng/kg bodyweight per day for toddlers and up to 495 ng/kg bodyweight per day for infants of 1-5 days.

Thermal paper not considered before was the second highest contributor to exposure in all population groups above 3 years of age. However, diet was found to be the major source of bisphenol A exposure in all population groups so this was not an important shortcoming of the previous exposure assessment.

Cashier a risk group still to be considered (Photo: Dan Goorevitch)

Cashiers a risk group still to be considered (Photo: Dan Goorevitch)

To check the accuracy of the calculations, total exposure to bisphenol A was also estimated using urinary biomonitoring data. Biomonitoring estimates based on urinary bisphenol A concentrations were in good agreement with modelled bisphenol A exposures from all sources, suggesting that no major exposure sources had been missed for the modelled exposure assessment.

There is a slight caveat in the presented data. Estimates of dermal exposure to bisphenol A were associated with considerable uncertainty and didn’t include cashiers as a particular group at risk because of lack of data. This might be rectified when an ongoing study on dermal exposure in cashiers sponsored by the National Institute of Environmental Health Sciences in the USA under the National Toxicology Program is published.

And of course, despite the considerable lowering of the exposure estimates for bisphenol A, we will not know if those levels still pose a risk to public health until the toxicological evaluation has been completed.

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Judgement day for bisphenol A

Judgement (Photo: walknboston)

Judgement over bisphenol A (Photo: walknboston)

Scientific efforts to prove or disprove harmful effects of bisphenol A, a chemical that is mainly used in combination with other chemicals to manufacture plastics and resins used as food contact materials, are gathering momentum. But have we reached the critical mass yet to draw the right conclusions. Let me explain.

Science is all about the exciting exploration of new findings or the more mundane task of other scientists trying to verify the new findings so that they can become established truths, or is it? To be honest, scientists can be a very conservative lot sticking to what they already believe they know. The more revolutionary the findings, the less is the likelihood that they will be accepted. Deviating from accepted thinking can be a dangerous thing and risk your career.

Here are three examples of how the scientific community initially refused to listen.

Environment influencing the genetic make-up

In a previous blog, the importance of epigenetics in understanding gene expression was covered. It was the heretic proposal that environmental factors could influence your genetic make-up and become hereditary. This was revolution and not easily accepted by the scientific community. During the 1940s and 1950s, Barbara McClintock discovered transposition and used it to show how genes are responsible for turning physical characteristics on or off. She developed theories to explain the repression or expression of genetic information from one generation of maize plants to the next. Encountering skepticism of her research and its implications, she stopped publishing her data in 1953.

Barbara McClintock was a dogged scientist believing that her findings were true despite ridicule from other scientists. It took her close to 40 years to prove the concept under constant threat to her position. It is now the hottest topic in biology and will have a major impact on future toxicological research. Barbara McClintock finally got full vindication by being awarded the Nobel Prize in Physiology or Medicine in 1983.

The low-dose theory

Equally important is the low-dose theory of chemical interaction with our bodily processes. According to conventional thinking the dose makes the poison and this is the basis for current chemical risk assessments. The higher the dose the more severe the effect is the accepted mantra, which makes sense to most of us. And here some scientists proposed that low doses of certain chemicals can have different and more pronounced effects than high doses, can that really be trusted?

Actually, there is an extensive body of research that purports to demonstrate such a phenomenon. Recently Edward Calabrese revived the theory through his research on peppermint plants giving rise to a scientific debate that has been gaining prominence over the last 20 years. Much research has focused on endocrine active substances or endocrine disruptors where the conventional relationship (more exposure equals higher risk) has been particularly challenged. Such substances have been shown to have fundamentally different (and harmful) effects on the body at low doses than at high doses. As seems to be the case for most scientific findings that challenge conventional thinking it took a long time for the scientific community to accept the low-dose theory and still there are some lingering doubts. In 2009, Calabrese was awarded the Marie Curie Prize for “outstanding achievements in research on the effects of low and very low doses of ionizing radiation on human health and biotopes”.

The contagious protein

Who has not heard about mad cow disease? It is the animal equivalent of Creutzfeldt-Jakobs Disease in humans, a debilitating brain disorder, the cause of which long was a mystery. And along came scientists proposing that the culprit was a misfolding protein that was contagious and thus could spread between individuals. Stanley Prusiner called it a prion, just a simple protein without any genetic material. The scientific community was astonished. This was just not possible.

It took years of experimentation to prove the theory. Now, of course, with the publicity of the mad cow disease many of us have heard about the prion. Whether prions are the agent which causes disease or merely a symptom caused by a different agent is still debated by a minority of researchers. However, the matter should be considered settled when Prusiner won the Nobel Prize in Physiology or Medicine in 1997 for his research into prions.

And what about new findings for bisphenol A?

The lesson from all of this? It is simply that it takes a lot of time and convincing arguments for scientists to change their mind. And now we have 21 scientists in the EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids pondering about the fate of bisphenol A for the sixth time. Will the judgement be different on this occasion? One panel member already previously expressed a dissenting view, an unusual event in the short history of EFSA. But the peer pressure from the scientific community is high for status quo.

Yes, there are indications that bisphenol A might be an endocrine disruptor effective at very low doses. The effect might even be one explanation of many to the obesity epidemic. According to this theory exposure to bisphenol A might induce epigenetic changes turning on obesity genes. Changes that will be inherited by your off-spring. We will see in May 2013 when the new opinion is published if the new scientific findings are convincing enough. French scientists already believe they are and politicians in several countries have bowed for public pressure and as a precautionary measure banned bisphenol A from baby bottles. Endocrine disruptors are particularly dangerous during early life with rapid development easily influenced.

EFSA preparing the ground work for a decision

EFSA preparing the groundwork for a decision

EFSA has been doing the groundwork by organising a scientific meeting to discuss low-dose effects. It met with French scientists in 2011 to discuss their conclusions. It further organised a Member State meeting in 2012 to air the views of European scientists. Finally, in co-operation with other European scientific advisory bodies, EFSA’s Scientific Committee is undertaking a review of all the current scientific information on endocrine active substances with the view of publishing an opinion in March 2013.

The pot is being stirred.

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BPA-induced juvenile anxiety

BPA-induced behavioural changes

A scientific report published in September 2012 noted that emerging studies had associated prenatal bisphenol A (BPA) exposure with elevated hyperactivity and anxiety in young girls. This suggested a possibility that developmental exposure to endocrine disruptors like BPA might contribute to the growing prevalence of behavioural and mood-related disorders in children. To explore this further the scientists used rodents as an experimental model in trying to establish how chronic, low dose oral exposure to BPA throughout development might impact affective behaviour during adolescence and adulthood. They further studied the underlying molecular changes to the nervous system related to such effects and looked at the potential for dietary intervention with a soy-rich diet to mitigate BPA effects.

Assessment of serum BPA confirmed that the internal dose was within the human range of 2 ng/ml of unconjugated BPA reported in several studies. At this level BPA was shown to induce anxiogenic behaviour in juveniles and loss of sexual dimorphisms in adult exploratory behaviour, but only in the animals reared on the soy-free diet. Changes were identified in the amygdala region of the brain. Expression analysis revealed a number of genes associated with BPA-induced juvenile anxiety in rats, including a subset known to mediate sociosexual behaviour. Overall, the results showed that behavioural impacts of BPA can manifest during adolescence, but wane in adulthood, and may be mitigated by diet. The data also revealed that receptors linked to oxytocin/vasopressin signalling pathways, previously associated with human affective disorders, might have been involved in the behavioural changes.

Reference

Patisaul et al. (2012). Anxiogenic Effects of Developmental Bisphenol A Exposure Are Associated with Gene Expression Changes in the Juvenile Rat Amygdala and Mitigated by Soy. PLoS ONE 7(9): e43890. doi:10.1371/journal.pone.0043890