More chemicals in everyday living: Children most at risk

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Over the last 50 years, global chemical production has increased many times over. Today, the world has around 145 000 registered chemicals. Current research now increasingly suggests that chemicals previously considered risk-free and that have been in free circulation are capable of affecting development in the womb and can give rise to long-term effects on health. And it is children who are most at risk.

There are a large number of signs to suggest that something serious is about to happen in our world. One important sign is the increase in disrupted sexual development that takes multiple forms. Registers and studies of new-born boys around the world from the 1960s onwards show an increasing frequency, with inexplicably large regional differences, of cryptorchidism, that is, the testicles have not descended into the scrotum by the time of birth. Likewise, scientific studies are able to demonstrate a steady increase, at least since the 1980s, of hypospadias, that is, the urethra opens on the underside of the penis, or in the worst case as early as at the scrotum.

Through studies of young men from as far back as the 1940s, science can point to a gradual reduction in sperm quality, and the Nordic cancer registers clearly show that all the Nordic countries have seen a steady increase in the incidence of testicular cancer since the 1960s.

Bild på Olle SöderThere are also other signs of disrupted sexual development - such as the number of children born with ambiguous external genitalia or the number of young people who seek help for gender identity problems - but these signs are less well documented scientifically or occur to such a small extent that it is difficult to draw conclusions from the variation that can be seen.

"Most problems of disrupted sexual development affect boys, which is due to the formation of the male sex organs being more complicated and completely hormone-dependent - without the male hormone testosterone, even fetuses with a Y chromosome obtain a primarily female development," says Olle Söder, Professor of Paediatrics at the Department of Women's and Children's Health, Karolinska Institutet and paediatric endocrinologist at the Astrid Lindgren Children's Hospital in Solna.

The testicles are formed at an embryonic age of about six weeks when the embryo is only 1.5 centimetres long, and one to two weeks later, they begin to produce testosterone, which then drives the development of both the internal and external genitalia. Before a fetal age of 20 weeks, everything is fully developed and from that time only needs to grow.

All the conditions just mentioned, where studies of children show a gradual deterioration, could be caused by disruptions to hormone signalling.

"We do not know the reason for this, but one hypothesis is that it is due to endocrine [that is, hormone] disruptors in the environment," says Olle Söder.

This hypothesis is supported both by animal experiments and by observations of animals in the wild that have been affected in a similar way. Among other things, Olle Söder mentions findings from the Everglades in Florida, wetlands where it was found that alligators exposed to emissions of substances that counteract testosterone have a markedly higher extent of deformed genitalia compared with alligators living in the same area, but where there were no emissions. In a Canadian study, researchers instead exposed an entire lake to oestrogens similar to the residues of contraceptive pills discharged from sewage treatment plants, and the fish stock they were studying was eventually knocked out completely due to deformed genitalia and reduced fertility.

"It is true that humans are exposed to much lower concentrations of endocrine disruptors than in these animal situations, but at the same time there are also genetic differences in humans in terms of the receptor that testosterone binds to, which makes some individuals much more sensitive to endocrine disruptors. These sensitive individuals could be affected by, for example, hypospadias or cryptorchidism much more easily with doses that wouldn't affect the population at large," he says.

Earlier onset of puberty

Olle Söder also makes mention of data to suggest that the onset of puberty in girls comes increasingly early, but whether this is linked to chemicals in the environment is much more uncertain. Firstly, researchers do not currently know what it is that triggers puberty, what the trigger signal is or how it could be affected by chemicals. Secondly, the age of the first menstrual bleeding has come down steadily since the early 1700s, when it was 19, to 17 in the early 1800s, 15 in the early 1900s and, since the 1960s, to be at 12-13 years of age. The causes of the change from the 1700s relate to the improved health and psychosocial conditions of children in pace with several centuries of societal development. But researchers are now discussing a seemingly new trend of earlier puberty onset in girls that they have discovered to exist from the 1980s onwards. Maybe chemicals are involved here, but nobody knows.

If chemicals are capable of affecting the fetus via hormone-dependent mechanisms that control the development of the nervous system, the consequences can be very serious. Olle Söder, Professor of Paediatrics

A lot of data also suggests that the occurrence of ADHD, autism and other behavioural disorders as well as depression is increasing in society. "And, purely in terms of mechanisms, this could also be an effect of endocrine-disrupting chemicals," says Sandra Ceccatelli, Professor of Neurotoxicology at Karolinska Institutet. This is because the development of the brain and nervous system is also affected by hormones such as stress hormones, thyroid hormones and oestrogen - and is thus also very sensitive to disruptors.

"This means that if chemicals are capable of affecting the fetus via hormone-dependent mechanisms that control the development of the nervous system, the consequences can be very serious," she says.

She goes on to say that endocrine disruption in the fetal stage may cause a change in the structure of the nervous system and alter connections between various cells in the brain.

Such developmental exposures could affect brain functions resulting in postnatal behavioural alterations, and that is exactly what animal studies have shown," says Sandra Ceccatelli.

These studies analyse suspected substances one at a time in order to make it possible to derive assertions about how dangerous they are. But that is not the situation in real life. In 2004, an environmental organisation in the United States examined umbilical cord blood from ten American new-borns and found an average of 200 industrial chemicals, pollutants and pesticides in each child. Of 413 chemicals that they were looking for, they found a total of 287 substances in the children. These included the long-banned PCB, brominated flame retardants, banned pesticides, combustion residues from oil and waste incineration, plastic residues and mercury; in other words, mainly old and known environmental toxins. But the significance of such a mix of hundreds of chemicals is something that researchers find difficult to assess.

"At present, we don't know that much about the consequences of being exposed to a large number of chemicals," says Sandra Ceccatelli.

Poor state of knowledge on the effects of chemicals

On top of this, the state of knowledge about the harmful effects of chemicals on brain development in fetuses and children is extremely poor. A report published in 2006 in one of the world's most prestigious medical journals, the Lancet, demonstrated that of 80 000 chemicals used around the world, there was scientific evidence of disruption to child development for only five. Many of the others have been insufficiently investigated. Today, seven years later, researchers know of a few more substances, according to Sandra Ceccatelli, but at the same time, the number of chemicals used around the world has increased to about 145 000.

In other words, researchers are lagging far behind the chemical industry. This also means difficulties for the politicians who are responsible for regulating the chemicals market. Without facts, it is difficult to make the right decisions. So it can almost be described as a stroke of genius when the EU, with the help of Margot Wallström as Commissioner for the Environment, pushed through the REACH legislation. REACH stands for "Registration, Evaluation, Authorisation and restriction of Chemicals". The Regulation came into force on 1 July 2007 throughout the EU. Among other things, it stipulates that all chemicals are to be registered and that it is the companies that are responsible for demonstrating that the chemicals are safe.

"REACH is quite a substantial step forward, but it has its weaknesses, and many are working for it to be tightened further," says Annika Hanberg, Professor of Toxicology at the Institute of Environmental Medicine at Karolinska Institutet.

One weakness, for example, is that the stringency of requirements varies depending on the amount of a substance that is produced and imported. Production over one hundred tonnes per year must be thoroughly tested, while substances with an annual production of less than one tonne essentially do not need to be tested at all.

But chemicals that are potent can cause damage in very small amounts. With respect to dioxin, for example, toxic quantities are measured in picograms, or 10-12 grams. So even quantities smaller than one tonne can cause quite a lot of problems.

Another weakness is that the rules are designed on the basis of traditional toxicological principles which identify a toxic dose and then assume a lower dose to be safe, something known as a threshold dose. But for the chemical compounds classified as endocrine disruptors, maybe this principle does not apply. Especially in highly sensitive phases of development, such as in the formation of genitalia or the interconnection of the brain's neurons, only very small amounts may be sufficient to cause damage. At this point, researchers are not quite in agreement.

"Toxicology is based on threshold effects, but endocrinology isn't. There is no threshold effect in an already well regulated, active hormonal system in the in the body," says endocrinologist Olle Söder.

"We have had somewhat different views on the effect of low doses. Toxicologists have long debated whether there may be other effects at low doses that cannot be predicted from the higher doses of animal experiments. This is not consistent with how toxicologists have traditionally arrived at which exposure is safe for humans. And most toxicologists are not experts in endocrinology, so the area of endocrine-disrupting chemicals is one where it's good to have collaboration between different disciplines in order to come a little further," says toxicologist Annika Hanberg.

The effect of this conflict is that there are no international guidelines on how to deal with endocrine disruptors. Instead they are measured by the same standards as for other toxic substances.

"The industry follows the guidelines that exist, and in doing so, they conclude that an endocrine disruptor like bisphenol A is safe, while there are hundreds of studies to suggest that there are negative effects in doses down to a thousand times lower. But all the studies have weaknesses, meaning that they are not taken into account, as per current regulations," explains Annika Hanberg.

No common definition as yet

Despite it being over 20 years since the publication of the first scientific reports on endocrine disruptors, researchers from the different camps have not yet arrived at a common definition of what they mean by an endocrine disruptor.

One definition, developed about ten years ago by the World Health Organisation, WHO, says that for a substance to be classified as endocrine-disrupting, it should have harmful effects for those exposed to it or for their children. The international organisation for endocrinologists, the Endocrine Society, has recently produced another definition that says that it suffices for a substance to have some influence on a hormone effect, regardless of whether it is harmful. The plan for this year is to arrive at a definition acceptable to all and which can work in practice. This is because both definitions have their problems. The first, because there must be solid evidence of harmful effects before a substance can even be classified as an endocrine disruptor, something which can take time. The second, because it includes every substance that affects hormones, including drugs like contraceptive pills and growth hormones and perhaps even grapefruit as well. And this would be a problem for legislators who want to act in line with the principle of caution.

"If you banned all substances meeting the latter definition of an endocrine disruptor, it would have very, very serious ramifications, and I can't see that as being a decision you arrive at lightly," says Annika Hanberg.

For the politicians who have the legislative responsibility, this situation means a balancing act between strong interests from citizens, environmental organisations and the chemical industry. In this unclear situation, it would naturally be wise to adhere to the principle of caution and ban anything that is not proven safe. But the problem is that it is even more difficult to prove that something is absolutely safe than to prove that something is harmful. And a ban on everything suspected of being harmful will result in those chemicals being replaced with others that we know even less about and that are perhaps even worse.

But politicians in the EU and Sweden have nevertheless taken action. Besides pushing through the REACH legislation, they banned certain endocrine-disrupting plasticisers, known as phthalates, in plastic toys in 2007. In addition, in 2011, they banned baby bottles containing bisphenol A, commonly abbreviated as BPA, an endocrine disruptor similar to the female hormone oestrogen. In April 2012, the Swedish government then announced a further ban on bisphenol A in packaging for foods intended for children up to the age of three, which will take effect in July this year.

It is, of course, a very good thing to protect children from these potentially harmful substances, both because they can be more sensitive and be exposed for a longer period, but given that they are most sensitive in the fetal stage, it is perhaps even more important to protect the mothers-to-be.

"Personally, I think that we should be extra cautious when it comes to fetuses because that is where we really know they are extra susceptible," says Annika Hanberg.

And there is data that should make any woman of childbearing age think twice about her lifestyle. In a call to action addressing the world's paediatric endocrinologists, Olle Söder and a number of international researchers wrote two years ago, "Ironically, the most efficient mechanism of reducing the body's load of EDCs (endocrine-disrupting chemicals) may be through pregnancy and breast-feeding, in that the compounds are transferred to the fetus and new-born child via the placenta and breast milk."

As regards persistent environmental contaminants such as PCBs, mercury and lead, there is not much that can be done. These have accumulated in the body throughout life and may have even been transferred from our own mothers. But something that can be avoided is the more short-lived endocrine disruptors, such as bisphenol A. And it is primarily a matter of avoiding tins and cans. This is because the inside of some food tins and beverage cans has a plastic lining that contains bisphenol A, which leaches into the tin or can, to a slightly varying extent depending on the contents.

"These are currently assessed to be perhaps the greatest source of bisphenol A exposure, but here there are still no restrictions at all," says Annika Hanberg.

An interesting experiment demonstrating the effect tins might have was initiated and carried out last year, not by researchers, but by four journalists at the Swedish newspaper Svenska Dagbladet. For two days they stuck to a diet that was extremely high on content from food tins and beverage cans, including tuna, baked beans, pea soup, ravioli and coconut milk washed down with soft drinks and beer or with coffee microwaved in plastic cup. According to them, their consumption the entire time was within reasonable limits and could be equated with a kind of camping diet. The values of bisphenol A measured in their urine went sky-high. There were increases of several thousand per cent, which in fairness does not always say that much if the original level is low, but one of the reporters, a young woman, showed the highest absolute value of bisphenol A ever recorded by any person in Sweden, perhaps in the world. Had she been pregnant, what effect would this have had on the fetus? Nobody knows.

Cell experiments do not give the full picture

But there are also rays of light. Maybe Sandra Ceccatelli has an answer to how knowledge of neurotoxic effects on the fetus can be increased more rapidly in the future. This is due to a model she is developing based on neural stem cells, that is, cells which can develop into brain cells, that she investigates as she exposes them to low concentrations of various chemicals suspected of being developmental neurotoxins. By studying how the development of these cells differs from their normal development, she can determine whether or not the substances could be neurotoxic. But unfortunately, one cell experiment can never give the full picture as there may be other mechanisms in the growing fetus that mean that an effect observed in the test tube will not necessarily occur in real life.

"But we can get an indication of whether or not there is a risk that a substance is neurotoxic, and then we have to flag it up. This can be an important first step in the process of identifying hazardous chemicals," she says.

At the moment, she is in the process of checking the method so that the results really are relevant to animals and humans. In the future, it might even be possible to use the method to quickly screen for a large variety of substances in order to rule out those that are not neurotoxic; and then let the rest go on to animal experiments to investigate how dangerous they are in living organisms.

At the same time, she is developing animal models that differ from traditional rat and mouse models. One idea is to use fish.

"At the moment, we are in the process of evaluating whether chemicals that cause particular behavioural changes in rats or mice induce similar alterations in zebrafish," she says.

The aim of all the work is to derive more knowledge about various substances more quickly without having to use as many animal experiments as today.

"I'm hoping we'll be able to use data from the in vitro cell models for the risk assessment of neurotoxicity within five years. And to see the introduction of a mandatory requirement for all new chemicals to have undergone neurotoxicity testing before being used," she says.

Another ray of light is the plan to transform AstraZeneca's disused toxicology lab in Södertälje into a foundation-owned business, which would test chemicals and drugs for other companies commercially and, through links with universities, contribute to research on such things as test methods. The working name of the company is Swetox.

"Swetox would integrate and strengthen Swedish toxicology research and help Sweden to act within the EU in this field," says Annika Hanberg.

But until researchers know more, what can an ordinary citizen do?

"I usually say that we should be informed consumers," says Olle Söder.

This is easier said than done, however. But there are some rules of thumb to stick to that can actually make a difference. Wiser choices in future purchases can affect our immediate local environment and at the same time send a message about which products are desirable and which are not.

Text: Fredrik Hedlund. Photo: Getty Images. First published in Medicinsk Vetenskap 2/2013

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