Genesis of Eden
Deborah Cadbury
1997 The Feminization of Nature,
Hamish Hamilton (Penguin), London ISBN 0-14-026205-9
Foreword
The world is in the grip of the ultimate epidemic. Infertility has spread like the plague. The ending has come with dramatic suddenness. Almost ovemight, it seems, the human race has lost its ability to breed. After a global search, biologists have confirmed, nowhere in the world is there a pregnant woman. For 25 years no one has heard the cry of a newbom on the planet. The voices of children can only be heard on archive tape or television. Children's playgrounds have been dismantled. Schools have become centres of adult education. All over the world Nation States are storing their records for posterity, in some vain hope that some fomi of intelligent life wifl follow us. Without hope of a future for our species, each spring brings us closer to an ending no one could have foreseen a generation ago. It's impossible to view the horse-chestnut trees in fufl bloom, the sunlight moving on stone walls, without pain. We know there will be centuries of springs to come, unseen by the human eye.
In this vision of the future depicted by the novelist P. D. James, in her book Thee Children of Men, she envisages that what might enrage and demoralize us the most is not the impending end of our species, not even our inability to prevent it, but our failure to discover the cause. 'Western medicine and Western science,' she wrote, 'have not prepared us for the magnitude and humiliation of this ultimate failure . . . Western science has been our god.' It is hard to believe that it wouldn't still provide for us: 'the anaesthetic for the pain, the spare heart, the new lung, the antibiotic, the moving wheels, the moving pictures. Now we face the universal disillusionment of those whose god has died." Such a scenario from science fiction may seem beyond behef now. Yet it was recent strands of scientific evidence that provided the background for the novel. This book examines that evidence and follows the true scieiltific detective story as some of the world's leading fertility experts uncover adverse changes to human reproduction. A dramatic fall in sperm counts has been reported. A Danish study found a 50% drop in sperm counts in fifty years; in Edinburgh, a 25% drop in the last twenty years; in Paris, a similar decline. Although some of the data has been challenged, other studies confirm worrying changes to human reproduction. There has also been a startling increase in testicular cancer and sex organ abnormalities of baby boys. Some scientists argue that if the decline continues at the same rate, it will not be too long before human reproduction will be under threat. This change to human reproduction is mirrored by extraordinary changes to wildlife. There are species showing signs of 'feminization', their phalluses severely reduced in size, and others are mysteriously 'changing sex', the males producing eggs just like females. Cancer, too, has been brought into the debate: the increased incidence of breast cancer and prostate cancer. It has been argued that all these changes have one thing in common. They can all be affected by exposure to the female hormone oestrogen. Recently it has been discovered that many man-made chemicals can act like 'weak oestrogens', imitating the female hormone and other hormones. Hormones are the most potent chemical messengers in the body because they act directly on the genes, instructing our cells how to behave and controlling critical body functions. There is evidence that some chemicals used in plastics, pesticides and many industrial products can mimic them, and may randomly create havoc with our reproduction and sex development, and may even play a part in some cancers. More frightening still, these are chemcals which we are eating, drinking, breathing and bathing in' They are chemicals which no human infant escapes, sometimes even from before birth.
Could these be worrying clues to our future? Or in the words of the chemical industry, is this no more than a collection of data which 'generally fails to confirm the claim that industrial chemicals are causing widespread harm to health or the environment by hormonally mediated mechanisms?" Some scientists point out that the field is fraught with uncertainties and there is insufficient data available to confimi what is causing these changes to man. They argue that certain studies even show that sperm counts are not falling and that scientists have yet to agree on this. Without hard evidence, they argue, it would be irresponsible to restrict or ban the use of a large number of man-made chemicals which are used to make many of the products that we need and take for granted. The costs are too great. But for others the cost of not taking action could be even higher and we ignore the growing body of evidence at our peril. 'Imagine if for the last fifty years we had sprayed the whole earth with a nerve gas which had very potent effects. Well, we've done that, not with a nerve gas, but with chemicals which act like hormone disrupters. We've released chemicals throughout the world that are having fundamental effects on the reproductive system and the immune system in wildlife and in humans. Should we change policy? Should we be upset? Yes, I think we should be fundamentally upset. I think we should be screaming in the streets,' says Professor Louis Guiflette of the University of Florida. 'We have unwittingly entered the ultimate Faustian bargain,' argues Dr Devra Lee Davis, former deputy health policy adviser to the American govemment. 'In return for all the benefits of our modem society, and all the amazing products of modem life, we have more testicular cancer and more breast cancer. We may also affect the ability of the species to reproduce. I don't accept that bargain. The stakes are too high here. We cannot afford to take a course of action that will affect the ability of the species to persevere.' This book is an attempt to unravel the complexities behind these differing views; to tell the true story of how the new scientific ideas were uncovered; and to assess their possible significance for human health and public policy.
From: The Human Price
Hormone-disrupting chemicals can undermine neurological and behavioural development and the subsequent potential of individuals exposed in the womb ... The developing brain exhibits specific and often narrow windows during which exposure to hormone disrupters can produce permanent changes in its structure and function ... A variety of chemical challenges in humans and animals early in life can lead to profound and irreversible abnormalities in brain development at exposure levels that do not produce permanent effects in an adult ... This may be expressed as reduced intellectual capacity and social adaptability, as impaired responsiveness to environmental demands or in a variety of other functional guises. Widespread loss of this nature can change the character of human societies . . ."
'What we fear most immediately is not extinction, but the insidious erosion of the human species,'argue Colborn, Dumanoski and Myers in Our Stolen Future. 'We worry about an invisible loss of human potential. We worry about the power of hormone-disrupting chemicals to undermine and alter the characteristics that make us uniquely human. Our behaviour, intelligence and capacity for social organization . . . "at could be at stake is not simply a matter of change to some individual destinies, or impacts on the most sensitive Of us, but widespread erosion of human potential."'
'A Universe of Chemicals'
North Carolina, USA
'If we just focus on the chenicals that mimic oestrogen, we run a serious risk of missing the broader picture,' warns Linda Birnbaum, head of the experimental toxicology division of the EPA's Health Effects Laboratory. 'It is important to realize that there is a universe of chemicals out there that may interfere with other hormone systems. There is evidence that the adrenal glands are one of the most affected and there is evidence of other hormonal effects as wefl. The entire endocrine, or hormone, system is so finely balanced, if you affect one part, it is likely to have an effect elsewhere in the system." For years, scientists had concentrated their efforts on developmental effects of oestrogens because of the tragic cases of the DES-exposed women who developed rare vaginal cancer around puberty. However, pioneering studies by Dr Earl Gray and others at the EPA labs in North Carolina were revealing that some chemicals might interfere with male hormones and even other hormones in the body. The endocrine system comprises several main organs which secrete the chemical messengers, or hormones, into our bloodstream. These are transported to target organs in other parts of the body, with che@cal instructions directing the cells how to behave. In effect they choreograph the delicate and finely tuned process which regulates the levels of substances within the body, a process ten-ned 'homeostasis'. Everything is maintained in perfect balance. For instance, insulin, secreted by the pancreas, regulates levels of sugars in the blood and adapts them so they can be absorbed by muscles and other tissues that need to convert sugar into energy. Lack of insulin can lead to diabetes. Growth hormones regulate what happens to fats, carbohydrates and proteins in the body. The sex hormones, or steroids, control sex development and maturation. There are several main organs involved in the endocrine system. The pituitary gland, at the base of the brain, is seen as the conductor of the entire orchestra. It has a great number of secretions which can influence the other key players, such as growth hormone. The thyroid gland, in the front of the neck, secretes thyroxine, which regulates the general metabolism of the body. Just above the kidneys are the adrenal glands which produce the stress hormones adrenaline or noradrenaline. Adrenaline is the 'flight or fight' hormone, produced when the body is under stress, to dilate the arteries, increase blood sugar and give energy for a speedy getaway. The adrenal glands also produce cortisone and hydrocortisone, which are essential for life. The ovaries and testes produce the sex hormones oestrogen, progesterone and testosterone. 'There is real cause for concern,' says Dr Earl Gray. 'Our studies suggest that it is not just the oestrogen receptor that is targeted, but other hormone systems as well ... I think we need to rethink the whole issue. 12 Dr Gray's studies were to shed light on the mechanism of action of one of the most infamous molecules of the century: DDT.
Scrambling the male hormone
As a reproductive toxicologist, Dr Earl Gray had detailed knowledge of how cherriicals could alter reproduction. For many years his research centred on the mechanism of action of the familiar oestrogenic pesticides and PCBS. But by chance, in the early iggos, he came across studies which alerted him to the possibility that chemicals were disrupting male hormone messages as well. During the pesticide registration process, the Environmental Protection Agency had received a curious set ofdata from a company that manufactures a fungicide called vinclozolin, which is sprayed on fruit and vegetables. Their animal studies showed that the fiingicide had an unusual effect on the male foetus. Male rats exposed to vinclozohn appeared to demonstrate typical effects of oestrogen exposure. But the females were completely unaffected. This result was odd and the data was sent on to Earl Gray to see if he could make any sense of what was going on. 'Their data was a big surprise,' recalls Gray. 'It clearly suggested we were dealing with some sort of "anti-androgen" syndrome, which was "demasculinizing" the males but leaving the females unaffected. Somehow the action of male hormones or androgens appearedto beblocked.'Furtherstudies confimied thatmalerodents exposed to vinclozolin in the womb did indeed show delayed puberty and malformed reproductive organs, including undescended testes. Some males even developed a 'vaginal pouch' and breasts more characteristic of the female, whereas the females suffered no oestrogen-like alterations at all, such as effects on cyclicity or fertility.' In laboratory studies, Earl Gray and his colleague Bill Kelce, together with Elizabeth Wilson at the University of North Carolina, were able to show that the fungicide had exerted its effect by interfering with the male hormone receptor, or androgen receptor. When they added testosterone to the male hormone receptor, it would, as expected, bind to it and activate the genes. But when they added testosterone and vinclozolin, the fungicide would compete with testosterone for the male homione receptor sites and block them. Consequently, it reduced the activity of the male hormone, testosterone, by literallyjamming the receptor sites. just as oestrogen mimics target the oestrogen receptor and can fit it like a lock and key, this chemical was doing exactly the same with the male hormone receptor. The animal was feminized, says Gray, not by overexposure to female hormones, but by underexposure to male hormones. It was a different form of fen-linization. 'We conclude,' they wamed in their article summarizing this study, 'that similar alterations are likely to occur in humans if the foetus is exposed during sex differentiation to active metabolites of vinclozolin at levels equal to or near the tissue levels attained in our rodent studies. ' This work was soon to provide unexpected insights into the insecticide DDT. 'The first studies showing DDT could have reproductive effects were in 195o, and for over forty years since then, no one really had a clue exactly how it exerted its effects,' says Gray. It was presumed, since it had feminizing effects, that it was somehow acting like an oestrogen, although the precise mechanism of action remained elusive. In the spring Of 1994, just as Gray's team had completed their study on vinclozolin, they were invited to a scientific symposium where Professor Louis Guillette of the University of Flon'da was also giving a talk. Guillette was presenting details of his remarkable findings on the alligators at Lake Apopka. 'As the slides went up,' recalls Gray, 'showing the strange alterations to the testes, the reduced phallus and the altered hormone levels, including the near absence of testosterone, I suddenly thought, his alligators looked just like our rats exposed to vinclozolin!' If this was correct, it would suggest that rather than the alligators being feminized by overexposure to oestrogens, it was possible that they were being demasculinized by having their male hormones blocked in some way. The same thought had also occurred to Louis Guillette. It had already been shown that the main contaminant to which the alligators had been exposed was DDE, a breakdown product of DDT. Some of the alhgator eggs had high levels, up to 5,800 ppb, of DDE. This would sulizest that DDE was not interfering with the action of the female hormone, oestrogen, at afl, but with the male hormone. Earl Gray and Bill Kelce began to discuss these ideas. 'It was really a complete stab in the dark,' Gray was to recall later. But if it was true, it would solve a long-standing scientific puzzle. Since Gray was due to give the next talk at the meeting on the effects of vinclozolin, they were forced to wait. 'We gave the last talk, and then we literally ran out of there and back to the lab. We were in a hurry, really keen to test this. We thought it was a real, viable hypothesis that DDE was in fact an anti-androgen.'
They tested DDE in a male receptor binding assay, just as they had for vinclozolin. Within a few days, they had preli@nary results. 'It was a pretty exciting moment,' recalls Gray. 'DDE did bind with the male hon-none receptor. It was blocking the action of the male hon-none.' This result showed that the action of DDT is much more complex than was previously thought. Commercial DDT is really a mixture of two chemicals, Gray explains. 'About 15% of DDT is a chemical called "op'-DDT" which is oestrogenic in its action. The remaining 85% is "Pp'-DDT", which has one chlorine in a different position. This confers very different properties, almost like a different chemical.' pp'-DDT degrades into pp'-DDE, which they now knew could act like an anti-androgen. So, in effect, DDT has a double action on the sex hormones. One of its component ingredients can act like an oestrogen; the other is an anti-androgen, and blocks the action of the male hormone. Further tests confirmed their preliminary findings. They were able to show that DDE prevents the male hon-nones from tuming on the genes they non-nally activate. What is more, they found that DDE is a potent androgen blocker. 'This is pretty extraordinary for a chemical that we used to spread in pounds per acre,' says Gray. 'We felt this was very important, because DDT has been used all around the world and bioaccumulates. It is persistent in many environments, and there is a lot of wildlife and human exposure. A few weeks later they showed their results to Guillette. 'He was giving a seminar at the labs across the street and we brought him over,' Gray recalls. 'Bill Kelce had plotted out graphs showing our results. He put these things out on the table for Louis to have a look at. Louis was just kind of "holy cow!" I think all three of us looked like we had just swallowed canaries; we were really pleased. It was pretty exciting. It's not that often that you have a hypothesis which works just as you thought it would.' With Louis Guillette as 'mentor', says Gray, they continued further studies and reported their findings in a letter to Nature in June 1995.-' They were also invited to present the details of the studies at the American Zoological Society annual meeting. This work received a great deal of attention. 'Now I can explain what I am seeing,'Guillette told reporters from Science later,'DDE should be viewed as an endocrine disrupter.' Gray and his team soon found that many synthetic chemicals with oestrogenic activity can bind also to the androgen receptor, including some fungicides, DDT metabolites and other oestrogenic chemicals. 'The androgen receptor is extremely promiscuous in what it will bind to, even more so than the oestrogen receptor,' he says. 'We're very concemed about these results, especially given the levels of DDE in human tissues. It has been reported to reach levels in human tissues that are equivalent to the levels that bind to the androgen receptor in our studies: between 60 ppb and 1 ppm. And there are plenty of studies of human nilk where levels of DDT exceed these levels of i ppm. There may be all sorts of health effects from this.' What is more, it wasn'tjust interference with the male and female hormones that they were worried about. Evidence was mounting that the action of other hormones may be disrupted as well. The clues for this perspective came from studies of one of the deadliest poisons known to man: dioxin.
The legacy of dioxin
It is perhaps hardly surprising that dioxin should have a particular hold over public imagination. Laboratory studies have shown dioxin to be one of the most dangerous chemicals ever produced. It can be a thousand times more deadly than arsenic. Less than a millionth of a gram will kill a guinea pig.' Scientists discovered its unwelcome presence as a widespread contaminant through a series of unfortunate accidents. The first clues about dioxin poisoning arose in the 1930s and 1940s among sailors. They developed a rare and very disfiguring skin disease called chloracne. A severe rash, like an 'angry kind of acne' could cover the whole body and last for years and years. It was common practice for sailors to scrub the decks of the beautiful battleships with special waxes called 'halowaxes'. Unknown to anyone at the time, these were sometimes contaminated with trace amounts of dioxin-like compounds. During the 1950s and 1960s a number of industrial accidents, often in herbicide plants, led to outbreaks of the same mysterious skin disease. Investigators began to examine the chemicals to which workers had been exposed. They identified one minor, but very toxic contaminant: 2,3,7,8-tetrachlorodibenzodioxin, other-wise known as TCDD or dioxin. But still its pervasiveness as a contaminant was not recognized. Then the tragedy really took off. At the height of the Vietnam war, the American government sprayed millions of gallons ofherbicides over the lush tropical vegetation of Vietnam. The aim was to defoliate the rain forest and expose the enemy. 'Agent Orange' was the key herbicide used, a potent mixture containing two herbicides, 2,4-D and 2,4,5-T. At the time, public concern centred on the use of napalm, which was used to bum villages and torch whole areas. The horrific injuries resulting from this were immediately apparent. Nobody realized that one of the herbicides in Agent Orange, 2,4,5-T, was contaminated with dioxin. But when the veterans retumed from the war, they began to report a number of serious medical problems, including cancer and deformities in their children. Then dioxins were measured in the soil of Vietnam where Agent Orange had been sprayed. Finally, it was discovered that 2,4,5-T could be contaminated with dioxin during its manufacture. The levels of contamination varied depending on the manufacturing process, but there was nearly always some dioxin present. People began to question whether dioxin exposure had contributed to the veterans' medical problems. Laboratory tests were beginning to revealjust how dangerous dioxin could be. At the Environmental Protection Agency, studies revealed that dioxin was the most potent carcinogen that had ever been tested .7 After a decade of debate, 2,4,5-T was suspended as a herbicide by the EPA. 'In the mid-seventies, we were just waking up to how dangerous dioxin could be,' recalls Linda Bimbaum. 'There are more toxic biological agents, such as botulinum toxin, but as far as man-made chemicals go, this was the most toxic.' Papers were produced confirming the han-n it could do. In laboratory animals it could damage the thymus, spleen and testes, enlarge the liver, and cause cancer and birth defects. Then, in july 1976, there was another accident. An explosion at a chemical factory in northern Italy created a cloud of dioxin over the city of Seveso. Thousands of people were exposed. Almost immediately there was a severe outbreak of the skin disease, chloracne. Further studies were started. These revealed very high levels of dioxin in some of the exposed residents, up to 56,ooo parts per trillion.' By now, advances in chemical detection made it possible to detect dioxin at extremely low levels: even less than one molecule in a trillion molecules of water. Suddenly, just as with PCBs and DDT, it became apparent that dioxins were everywhere. They were in industrial wastes and landfill sites. They could be detected around incinerators. Then they were found in our food, in the air, soil and water, and even in mother's milk. One health scare after another emerged as they turned up in a growling list of domestic products, even disposable nappies. Gradually it was realized that dioxins and their chemical cousins are the unwelcome by-products of many industrial -and manufacturing processes. They have been found as a contaminant in the manufacture of certain herbicides and other chemicals such as PCBs and chlorinated benzenes and phenyls. They can be found in effluents and industrial wastes, such as those from the pulp and paper industry, the bleaching industry, and others. Most especially they are found as the by-product of combustion. They have been identified in fly ash and emissions from municipal, hospital and hazardous waste incinerators.' They have been detected in car exhausts and spent motor oils; levels are higher over cities. Then it was realized that there has always been a natural background level of dioxins, which can form whenever things burn. 'However these levels were barely detectable prior to the 1920S,' explains Linda Birnbaum. 'In the last fifty years, as the chemical industry has developed, there has been a dramatic increase in the amount of dioxin present in the environment.' As chemical analysis improved, it was found that there are 75 different cworinated dioxins and I35 chlorinated dibenzofurans, a close chemical cousin. Other related compounds include 209 chlorinated biphenyls, as well as many chlorinated diphenyl ethers, naphthalenes, azobenzenes and azoxybenzenes. Some estimates suggest there are potentially some 5,ooo related compounds if all the chlorinated and brominated forms are counted. 10 However, not all ofthem are toxic. The most dangerous is 2,3,7,8-tetrachlorodibenzop-dioxin, known as 2,3,7,8-TCDD. Next in line are 1,2,3,7,8-PCDD and 2,3,4,7,8-PCDF, which are estimated to have half the potency of TCDD." Several of the other closely related compounds have dioxin-like activity. Like PCBs and DDT, dioxins are very persistent and lipophihc', or fat soluble, so they can be easily stored in body fat. As a result they can accumulate up the food chain, so that species at the top of the food chain, such as man, have higher levels. The British Ministry of Agriculture has been monitoring levels in food and breast milk. They have confirmed that dioxins are present in low concentrations in all foods, especially fatty foods such as cow's milk. Like PCBs and DDT, they are passed through the placenta and are excreted in breast milk, resulting in exposure of the foetus and nursing infant to this class of chemicals as well. Because different dioxins have different potencies, the measurements are weighted in terms of 'toxic equivalents' or TEQ. In a recent study MAFF found the TEQ for human breast milk is 0.7 nanograms per kilogram. They found the infant receives its highest dose early on in nursing: estimated intakes from human milk are over four times higher at two months compared to ten months, due to an increased body weight in the baby and a move to a mixed diet. They report that the 'mother's body burdens of dioxins wiu decrease during several months of breast feeding. The concentrations of dioxins in the mother's milk will also decrease over this period by about 12% a month.' Not surprisingly, since women pass on their body burden of these persistent chemicals during breast feeding, levels of dioxin from breast milk in mothers nursing their second child are as much as 20-30% lower.
The ministry report concludes that although dioxin levels appear to be falling, 'the estimated dietary intakes of breast-fed infants found in the current survey exceeded the recommended tolerable daily intake (TDI) and the Committee on Toxicity of Che@cals in Food, Consumer Products and Environment has considered at length the implications of this erosion of safety margins inherent in the TDl .'14 Tolerable daily intake for dioxin was recommended by a WHO committee in 1990 at no more than io picograms per kilogram of body weight per day. The Ministry of Agriculture data indicate that a breast-fed infant at two months could be consuming ten times more than this, at 110 picograms TEQ per kilogram of body weight per day. Despite this, the Ministry of Agriculture experts, along with many other health officials, still strongly recommend that breast feeding should be encouraged because the balance of evidence suggests that the considerable benefits it confers in 'immunological protection, nutrition and mother-infant bonding' far outweigh the risks." Amazingly, recent studies investigating the mechanism of action of dioxin have revealed that it too can function as an 'endocrine disrupter'. Linda Bimbaum from the EPA's Health Effects Research Laboratory explains that among the first clues were the studies showing that dioxin could dramatically alter the effects of other chemicals in our bodies. 'One of our first thoughts was that dioxin could in some way affect the thyroid gland,' she recalls. 'It is not like cyanide poisoning, where the animals die almost instantly. Dioxin causes delayed lethality. First there is wasting, just as in cancer; the organism may lose up to half its body weight. Now if someone has too much thyroid hormone you can also get very similar wasting syndrome.' Furthermore dioxin could increase the incidence of cleft palate, a birth defect which can also arise with too much thyroid hormone. It was as if dioxin was somehow exaggerating the effects of thyroid hormone, But there were signs that dioxin might also affect other hormones. Multigeneration studies showed dioxin affected reproduction and fertility. High doses suggested it could damage the testes and cause atrophy. Laboratory studies showed it could alter the levels of oestrogen and progesterone." Soon it was discovered it could modify concentrations of thyroid hormone in several tissues as well.1' Then it was found to have effects on testosterone too." The possibilities were endless. To add to the puzzle, it also had some anti-oestrogenic action. Some research even suggested it might reduce the incidence of breast cancer, acting like the drug Tamoxifen, which is used in the treatment of breast cancer. 'It really wasn't clear cut,' explains Linda Bimbaum. 'There were some effects that reminded us of too much of a hormone. Other effects appeared more like too little of a hormone. Sometimes it looked like too much thyroid hormone, sometimes too little, sometimes it was oestrogenic and sometimes anti-oestrogenic in its effects. Sometimes the hormonal effects were only in certain tissues in the body. And we began to think, wait a minute, dioxin messes things up entirely. It scrambles the hormone messages in several ways. Dioxins, Gray explains, have been shown to exert their effects not by binding to the oestrogen receptor, but to another crucial molecule, called the 'Ah receptor'. No one really knows what the Ah receptor does in the body. Although scientific understanding of the endocrine system is considerable, there are stin vast gaps in our knowledge. Recently, scientists have identified several receptors, including the aryl hydrocarbon, or Ah, receptor, for which the nomial chemical messenger or hormone has never been discovered. They are known as the 'orphan receptors'. Evidence is mounting that 'tist as oestrogen binds to the oestrogen receptor and this enables it to activate the genetic material in the cell, in the sanie way dioxin binds to the 'Ah receptor', which enables it to switch on or off several genes. Quite how dioxin disrupts the activity of so many hormones has remained elusive. It is likely, however, that once it has bound to the Ah receptor, it can then send out several signals which niay alter the expression of many different hormones, argues Linda Birnbaum.2, 'Dioxin is unlike anything we've seen in the literature,' explains Gray. 'It disrupts multiple endocrine systems. We're really quite concemed with some of the recent findings on dioxins. What is more, the foetus is especially primed to respond to dioxin. These Ah receptors can be found in the foetus and they have a different distribution to those in the adult. We think it plays a critical role in development and growth.' This is exactly what has been found. Recent studies have revealed that dioxin can exert its effects in the developing foetus at an incredibly tiny single dose. Much of the early work investigating the effect of dioxin on the reproductive system was carried out at high dose levels. Recently, Richard Peterson and his team at the University of Wisconsin tried something different. Their results caught everyone by surprise. In the Peterson study, pregnant rats were given one small dose of dioxin on the isth day of the pregnancy. This is the day that is critical for male reproductive development, when the male reproductive tract begins to form. As adults, they found the male offspring exposed to dioxin had sperm counts that were up to 56% lower than in the controls.
'Peterson's study showed the extremely dramatic effects at low doses,' says Gray. Since dioxin risks were being reassessed by the Environmental Protection Agency at the time, this study caused quite a stir. Earl Gray and his team immediately set about reproducing the study and their research confirmed the Wisconsin result. Dioxin could have profound consequences on the developing embryo at one dose of less than a microgram per kilogram of the mother's body weight. This dose was too low to have any apparent toxic effects on the mothers. Yet the majority of the offspring showed permanent malformations in their reproductive tract that interfered with normal reproduction. It was a constellation ofeffects, including sharp reductions in sperm counts. Gray wamed in his article describing these results that exposure to relatively low levels of toxic substances that disrupt the hormone system during critical periods in development can permanently alter reproduction and produce pseudohermaphroditism.
Apart from reproductive effects, studies of dioxins have linked it with several human diseases. In addition to the disfiguring skin disease chloracne, which is the definite tell-tale sign of dioxin overexposure, it has also been linked to cancer. Studies by Pier Alberto Bertazzi of the University of Milan in a follow-up to the Seveso accident have shown higher than normal rates of several types of cancer. Liver cancer incidence was about three times higher than in the control population. There were also higher rates of leukaemia, myeloma and soft tissue sarcoma. Dioxins have also been linked in animal studies to endometriosis. 'This is an extremely painful condition that develops in women,' explains Dr Audrey Cummings from the EPA's Reproductive Toxicology Division in North Carolina. 'Tissue from inside the uterus, called endometrium, finds its way outside the uterus to the abdominal cavity. In effect, uterine tissue grows where it shouldn't be, on the ovaries, bladder, bowel, or a number of other sites.' Over 10% of all women are estimated to be affected at some time in their lives. The first evidence that dioxin might promote this disease was found by chance. 'More than ten years ago a primate study was set up for another reason: to find out if dioxin affected reproduction. Monkeys were fed very low doses of dioxin for a while. Several years later, the researchers found that many of the monkeys had developed endometriosis. The severity and incidence of the disease was greater in those monkeys that had received the highest dose."' In rodent studies at the EPA's labs, Cummings and her team confirmed that dioxin exposure promoted the development of this disease .26 'I am very confident that endocrine disrupters, such as dioxin, could be associated with human diseases,' she says. Her recent work is investigating how dioxins and other endocrine disrupters can affect pregnancy, especially disrupting the processes necessary for successful implantation of the egg. Although scientists do not yet have a clear picture of how dioxin can have such a diversity of effects, studies such as these highlight a problem which Earl Gray and others have been arguing about for some years. Exposure to chemical pollutants may result in a myriad of subtle changes that can alter the balance of the hormone system through a variety of pathways. A single chemical, he points out, can alter the 'endocrine milieu' through multiple mechanisms, to say nothing of the complex alterations induced by a mixture of compounds. What is more, he wams, 'adult and foetal toxicology are not the same. If adults are insensitive to the effects of some of these compounds, that does not mean the foetus will be too.' In a recent publication Gray compiled a list of endocrine disrupters which highlights the possibility that many toxicants may alter thyroid and adrenal function as well.
Endocrine disrupters
ENVIRONMENTAL OESTROGENS (OESTROGEN RECEPTOR MEDIATED) Methoxychlor; some PCBS; P-isomer of lindane; op'-DDT; bisphenolic compounds, e.g. bisphenol A; octylphenol and nonylphenol/alkylphenol ethoxylates.
CHEMICALS THAT HINDER OESTROGEN ACTION
Dioxin (down regulates oestrogen receptor at high doses); pp'DDT and DDE (increase degradation of oestrogen in birds); endosulfan (inhibits vitellogenesis in fish).
ENVIRONMENTAL ANTI-ANDROGENS AND ANDROGENS (ANDROGEN RECEPTOR MEDIATED) Vinclozolin (binds to the androgen receptor); pp'-DDT.
ANTI-THYROID ENDOCRINE DISRUPTERS
PCBs; dioxin; PCDF; lead; many thiocarbamide and sulfonamide-based pesticides; PBBS; phthalic acid esters; hexachlorobenzene.
ADRENAL ENDOCRINE DISRUPTERS Vinclozolin and related fungicides; aniline dyes; carbon tetrachloride; chloroform; op'-DDT and DDE; dimethylbenzanthracene; methanol and ethanol; nitrogen oxides; PCBs and PBBS; fungicides of the ketoconazole class; toxaphene.
NB The fact that a toxicant is on this list indicates that it may interact with the hormone system in some way, but does not indicate that humans are exposed to toxic dosage levels.
This list, Gray points out, is far from all encompassing. However, he argues that pesticides and toxic substances may attack multiple sites in the reproductive system and may alter thyroid and adrenal function as well. For example, certain PCBS, in addition to being oestrogenic in their action, can also bind to the Ah receptor, 'giving the exact same result as dioxin ... We know from animal studies that some PCBs can produce "hypothyroidism", where there is too little thyroid hormone.' Studies have shown that too little thyroid hormone may have profound effects on human mental development, he explains, and is probably one of the leading causes of mental retardation. 'Because recent studies have linked PCBs to behaviour problems, this seems to me to be important. I think there is considerable cause for concern.'
'Nature is not designed by an engineer,' says Professor Ana Soto. 'We cannot get a clean classification for everything. For example, DDT is neurotoxic and it is also an endocrine disrupter with oestrogenic effects. Yet its metabolites, or breakdown products, are anti-oestrogenic and anti-androgenic and have immunosuppressive effects.' In a recent publication summarizing the data on endocrine disrupters, Colbom, Soto and vom Saal warn: 'Large numbers and large quantities of endocrine-disrupting chemicals have been released into the environment since the Second World War. Many of these chemicals can disturb development of the endocrine system and the organs that respond to endocrine signals in organisms indirectly exposed during prenatal and or early postnatal life ...
Trans-generational exposure can result from the exposure of the mother to a chemical at any time throughout her life before producing offspring due to the persistence of eiidocn'ne-disrupting che@cals in body fat which is mobilized in ... pregnancy and lactation ... Effects of exposure during development are permanent and irreversible."
Reducing exposures
Among the scientists there is general agreement that it is very difficult to take steps to reduce exposure, since many of these chemicals are so fundamental to our way of life. 'I think it is very difficult to reduce exposure,' explains John Sumpter, 'because many of these chemicals are very widely used in a wide range of products. So, for example, if we decide not to buy milk that is in plastic containers because phthalates may be leaching into the milk in their containers and instead you buy it in glass bottles, then it is possible that the glass bottles were cleaned in detergents and these detergents might have contained oestrogenic chemicals. Similarly, if you decide not to use canned vegetables because you are concerned about a possibility that bisphenol A might have leached into the can of vegetables and instead you switch to fresh vegetables, then these may contain oestrogenic pesticides and herbicides. So, because there is a very wide range of chemicals that are oestrogenic and widely used, it is extremely difficult, if not impossible at this stage, to give advice to anybody if they want to reduce their exposure. '
None the less, many of the scientists interviewed in this book were asked if they had modified their lifestyle in the light of their findings. Despite the difficulties in weighing up the significance of different routes of exposure, most of them had inade modifications. The following is a summary of key suggestions.
WATER
At present, whether using filtered, bottled or tap water, it is extremely difficult to know which reduces exposure most effectively. Several scientists, such asjohn Sumpter, have taken the step of filtering their water, although he points out that it is not proven that this reduces contamination. 'We don't know which is the best kind of filter,' says John Sumpter. 'Most filters have a plastic container and we don't know what chemicals are used in the plastic. Then you have these charcoal filters which you have to regularly replace, and I don't know what is in the charcoal that might leach out. I wouldn't be staggered if we leamed in ten years' time that I was adding more chemicals by filtering the water rather than getting rid of them. It is very difficult to win on this issue. None the less, my wife and I chose quite a few years ago to filter our water and we will continue to do so.' Ana Soto has chosen to use bottled @neral waters but she is still concerned about these. 'We use spring water, but spring water comes in containers here that look suspiciously as though they have been niade of polycarbonate ... I wonder when we are going to know. It would be so nice if we knew at least which containers were made ofwhich substances, whether they are leaching bisphenol A or phthalates.' At present this information is not available. Despite all these problems they urge for a balanced perspective. 'Life expectancy has gone up immeasurably this century,' says Sumpter, 'and a fair bit of that is because of improvements in water and food quality. There used to be many water-borne diseases, such as cholera and hepatitis, and now these are gone in the West. Overall, I don't doubt that improvements in water quality this century have saved millions of lives. Somehow, we have to strike a balance between concerns.'
AVOIDING FATS
There is a considerable body of evidence to suggest that reducing consumption of fats, especially animal fats, may help to reduce exposure. A great many of the chemicals which are causing most concem are the 'lipophilic', or fat-loving, compounds which bioaccumulate in fatty tissue. As shown earlier, DDT and other pesticides, PCBS, and dioxins, all accumulate in our own fat stores and may remain for months or years. 'Many of these chemicals travel through the food web infat,'write Theo Colborn and her colleagues Dumanoski and Myers, land become more concentrated as they move upward to the top predators such as polar bears and humans ... Eating less animal fat, found in foods such as butter, cheese, lamb, beef, and other meats will greatly reduce exposure to hormone-disrupting chemiCals.' Because these chemicals accumulate in fatty tissue they have been shown to accumulate in particularly high levels in breast milk and breast milk fat. This raises the vexed question of feeding the newbom, which is discussed in detail in Chapter 8. A number of studies have highlighted the problem that many of these chemicals are transferred to the infant during nursing in high levels close to, or even exceeding, reconnnended levels in the case of dioxins and PCBs.'-' Although cow's milk, from which most formula milk is made, carries a much lower burden of these compounds, other chemicals have been found in formula, such as butylbenzyl phthalate. Most experts continue to recommend breast feeding. Colbom and her colleagues highlight the 'pressing need for more research' on this issue, since, they argue, the transfer of a woman's chemical load built up over her lifetime into her newbom is undesirable. 'It is critical,' they write, 'that we ... make choices that reduce this chemical legacy which is being passed on from one generation to the next ... Children have a right to be bom chemical-free.'
Apart from taking steps to reduce exposure to contaminated foodstuffs, there is also the question of avoiding contaminated packaging. Recent research oudined in Chapter 8 shows that some of the oestrogenic chemicals used in some plastics can leach from packaging into fatty foods. These can include dairy products such as cheeses and butter, and other fatty foods such as chocolates, pies and crisps. Most of the scientists interviewed are avoiding foods wrapped in plastic where possible, or removing it from the packaging as soon as possible. Not all plastics leach chemicals, but at present, in the absence of labelling describing the constituents of the plastic, it is very difficult for the consumer to have any way of knowing. 'We never use plastic-wrapped dinners that you heat in the oven or microwave,' says Professor Sumpter. 'I am concerned about these. People think of molecules as though they are fixed in one place. But they are not; they move about, whether in solids or liquids, and the higher you heat them the faster they move. So I would anticipate that if you heat something up in plastic it is more likely that the transfer of molecules into the food will be greater as the temperature goes up.' 'Certainly, I'm not using plastic as much as I did before,' says Soto. 'I'm not heating anything in a plastic container. Also, if possible, when I'm shopping, I put my vegetables in a paper bag and then in a larger plastic bag to avoid direct contact.' The marketing offood has changed enormously in the last twenty years, with considerable emphasis on packaging which is convenient for transport and storage, and gives appealing presentation. None the less, in the light of concems over the leaching of bisphenol A and phthalates from packaging, there are growing concems that this may need to be tested and labelled, so consumers know exactly what they are eating.
AVOIDING PESTICIDES
Pesticide residues can be detected in many ofthe fruit and vegetables we consume and it is very difficult to know how to reduce exposure to this. 'We've always washed our fruit and vegetables. But if you ask me what is the evidence that washing fruit and vegetables really reduces exposure, I can't produce it,'says Sumpter despairingly. 'We just don't know.' Some of the chemicals used are not water-soluble. Others may be 'systemic' and can penetrate inside the product. Professor Skakkebaek has taken this issue into his own hands. 'To some extent I have altered my lifestyle. I don't use pesticides any more in my garden it's an organic garden and also I'm eating organic butter which you can buy here.'
Colborn points out that many pesticides currently in use have never been tested for hormone-disrupting activity by the Environmental Protection Agency. She cautions against the casual use of pesticides in gardens and points out that studies have found higher rates of cancer in pets such as dogs in households where pesticides are used . Britain has one of the smallest percentages of land under organic production in the European Union, despite a huge increase in demand. Some European countries, such as Austria, now have as much as 11% of the land under cultivation with no chemical pesticides or fertilizers. In America, demand for a 'clean food diet' has increased significantly, fuelled by recent pesticide and BSE scares. The US Food Marketing Institute shows that 42% of mainstream supermarkets carry organic produce and a quarter of all shoppers are buying organic food once a week. lfdemand continues at the same rate, it is estimated that organic food will increase to 20% of all food sales by the turn of the century in America.
PHYTO-OESTROGENS
Dr Richard Sharpe is most concerned about the increasing use of phyto-oestrogens in baby foods until we have further data. 'The evidence for soya having beneficial effects in adults looks quite strong ... but it does contain a lot of potent things, and I'm not happy for children who are still growing to be eating soya. I don't think it is tight that we are giving them food which contains hormones without knowing exactly what effects it has. Phytooestrogens are produced in nature to actually exert reproductive effects on animals and predators, at least that is the thinking ... I'm not saying that it necessarily has an adverse effect, but there are plenty of animal studies which suggest it might. Altematively, it might even have beneficial effects. None the less, I am concemed about our blind use of these substances in baby foods.'When buying for his young family of four, he will try to avoid products with added soya for the children. Other scientists also expressed concerns about soya in the diet for young children, including Professor vom Saal and Dr Pisto Santti. One of the overriding concems expressed by many involved in the research was the difficulty of giving specific advice, since so little is known about routes of exposure. 'I have not been able to alter my lifestyle very much,' explains Skakkebaek, 'because my problem is that I do not know how to alter it. I don't know what should be done. If we are going to be very rational, these chemicals are so widespread we're going to have to wait for more data.' Sumpter, too, highlights the gaps in our knowledge. To date, for example, there has been very little research on cosmetics and health-care products. 'Many face creams will almost certainly have surfactants in them to help them spread,' he says. 'Some shampoos also have surfactants that's how they work.' There are other unknowns too. 'To my knowledge, no one has begun to look in detail at exhaust fumes to check out what hormone-disrupting chemicals may be there. Dioxins have been identified and it would not be surprising if there were related compounds. Some petrol has surfactants in it. These are all complex mixtures which need to be tested ... There is a good argument for carrying out tests on products, rather than individual chemicals, as at present.'
For Ana Soto it is almost like being thrown out of the Garden of Eden. 'It has changed things for me. I've lost the innocence I had before, thinking I could drink what I liked and it wouldn't do any harm. Now that I know all these things, I really wonder, do I have to drink as much water as I'm drinking, or eat what I am eating? If you are doing something that is not strictly necessary, you are just accumulating all this stuff in your body. That has changed me. Now I think that if you don't need it, why would you? Now I know that every time you eat and drink you could be adding to the chemical burden in your system. It's as though afl these products that we've synthesized are out there and getting back to us, no matter what we do.'
The Response
In America in I993, many of the scientists at the forefront of the research were invited to testify before Congress. Panels were convened. The press were invited. Ana Soto, John McLachlan, Louis GuiUette, Theo Colbom and others flew to Washington and assembled in the State buildings on Capitol Hill. Professor John McLachlan, who had been one of the first to warn of possible adverse effects from environmental oestrogens more than twenty years previously, found himself with fifteen minutes to summarize the significance of a lifetime's work. 'I gave my testimony in terms of what environmental oestrogens are, how they work, what a receptor is, and what we knew from experimental evidence in the laboratory and humans,' recalls John McLachlan. 'The Congressional staff and their attendants were not, I thought, overly interested. In fact hardly anyone was there! I don't think the room was completely empty. At all times someone was listening, maybe one or two congressmen and their staff, but they were usually doing something else at the same time. I do remember at some point I diverged from my written testimony to try to explain what an oestrogen was. I was using my hands to explain a lock and key and so on. Suddenly I realized there wasn't anybody paying any attention to what I was saying. All the visual aids were wasted." He stopped, and the recorder clicked to a stop. In the distance, the sound of traffic could be heard, circulating around the State buildings and Capitol Hill. Inside was the hush ofwhispered conversations dealing with the urgent political business of the day. There were no questions just silence as he stepped down from the microphone. 'I don't remember feeling that it accomplished anything,' recalls McLachlan. 'Not much seemed to happen.' But although the response seemed muted at the time, their voices were being heard. In fact, it's difficult to envisage a set of data coming from scarcely a dozen or so independent scientists which was to have such world-wide impact. However, even though the response was eventually considerable, not all of it was necessarily going in the direction the scientists would have wished.
The response: industry
The official response of the chemical industries and other manufacturers involved, is one of care and cooperation. A statement released from the European Chemical Industry Council (CEFIC) said: 'The chemical industry shares public concems and recognizes the importance of addressing any issue related to the safety of its products. Through the European Chemical Industry Council, chemical manufacturers are working with the scientific connnunity and regulatory authorities in Europe and America. Our goal is to detemiine whether there is a deterioration in reproductive health that can be attributed to the influence of man-made cherriicals on the hormonal activities of humans and wilcuife ... An exhaustive review of available research is presently being made. . .'2 A large research progranune has been set up, funded by industry. In America, the Chemical Manufacturers Association, together with other trade associations, is financing numerous studies, including an investigation of the link between DDT and breast cancer. A panel of experts has been convened to evaluate trends in semen quality and a study has been set up 'which win correct for the flaws the expert panel members identified in existing studies on semen quality'. Research is under way to dete@ne if there is an association between PCBs and DDT and endometriosis. Additional studies are in progress on wildlife, dioxins and toxicology, screening programmes, and many other related topics.
'There are people in industry, particularly toxicologists and other research scientists, who take the issue very seriously indeed,' says Professor Sumpter. 'Some of the people I have met through the European Centre for Ecotoxicology and Toxicology of Cherriicals in Europe have been the most balanced and wefl-informed people on the issue that I know of just as in acadeniia, there are people in industry who are for and against the issue.' The Chemical Industries Association in London has a membership Of230 companies, many of which are international, and annual sales Of C35 billion.-' Summing up the considerable research effort on the part of industry, their spokesperson told BBC Horizon: 'Chemical industries across the world, together with leading academics, are pursuing research in this area very, very vigorously. As a scientist, I have not seen such a vigorous attempt to get a clear answer in partnership between academia, government authorities and industry before. This is a very big exercise that is going on and it is being pursued by the world experts. . . There is not a govemment in the developed world that doesn't have a research programme on this. '6 But just how 'vigorous' have all the interested parties been? For those dealing with industry, there is also evidence of a different response behind the scenes. 'Industry doesn't bury its head in the sand,' explains Dr Richard Sharpe. 'They may try that initially, thinking this wiu go away because there is nothing to it. Once it doesn't go away, they become quite proactive. I think what that proaction involves is actually two things. One is to tackle the issue the way I think it should be addressed, which is to fund some research to find out about the problem. But the other is to put into place delaying tactics, because you're tamng about big money. The longer they can delay the solution to the problem, not only does it mean they have saved themselves a lot of money, but it also gives them time to get altematives in place so they don't lose out in the market. An interview with a senior member of the chemical industry in America, who does not wish to be identified, confirmed the significance of delays. He expressed concern and dismay at some of the evidence which has been gathered, and told us: 'Most companies spend a tremendous amount of money on safety and the environment. None the less they do not wish to disturb the smooth running of business. Behind the scenes there is a race going on and very extensive work. But this is all being done very quietly. The real change you don't hear about. The process of change is as follows: industries will nonchalandy agree with regulators that we are not to sell this product or that product at some point in the future and then allow enough time to find altematives which they have tested. The pace of change is not deten-nined by governments or politicians. It is deten-nined by industry. This is the way the system works. Everything is happening very quietly because if the implications of this are that certain chemicals may play a role in the development of cancer, then because of the nature of the law in America, anyone who has cancer may put in a claim and this might open the door to frivolous lawsuits."' So how might such delaying tactics work? 'Industry is actually honest,' Sharpe believes, 'but dealing with them is hke deahng with politicians. They wig answer a question if you ask it, but they wiu never actually volunteer anything. So if they know you are trying to find out something, they will answer each of your questions, but they won't tefl you what the question is you should ask them, to get the answer you are after. For instance, they might tell you about each of the chemicals you ask about, quite accurately. However, they don't tell you that in fact the most important route by which you are exposed to a given chemical is when they are conjugated or metabolized into something else. This is the difficulty, getting around all this . . .' 'To try to give you some idea of how difficult this is for scientists and the scale of the problem,' explains Professor Sumpter, 'if in our group we identify a single new chemical that is oestrogenic, then we need to know several things. Firstly, is this a single chemical, or a member of a chemical famiy? In some instances, the phthalates for example, are a family of about forty or fifty different chemicals, so we need to know what those chemicals are and whether they also are oestrogenic. Secondly, we need to know what those forty or fifty chemicals actually degrade to, because we have to test the degradation products as well as the chemicals themselves. In addition to this, we need to know what products these che@cals are used in, otherwise we cannot derive information about possible exposure levels. So from a scientific point of view, the whole problem is almost insurmountable unless you have help from industry telling you about the chemicals, what related chemicals are in use, how they degrade, how much they are used, and what products they are in. . . As scientists, if we antagonize them, then afl that expertise is lost to us. We simply can't address the issue as academic scientists without industry. We don't know enough about the chemicals. We don't know how they are used, how they are made, how pure they are, the levels of exposure, and so on. But apart from sometimes being less than forthcoming wi ' th relevant information which orily industry can possibly know, manufacturers can also take recourse to 'trade secrets' and simply refuse to give information even when asked. This was Professor Soto's experience, when on the trail of nonylphenol, as outlined in Chapter 7. Some scientists working in the field have been genuinely concemed about co@ng up with results which Will antagonize industry, since this, in some cases, can lead to difficulties with sources of funding. In addition to all these pressures, there is evidence that industry can delay advances in understanding in other ways as well. 'I was surprised to read, in an American industry magazine, information about my work,' says John Sumpter. 'The article said, "Professor Sumpter's work has been replicated in the US and the researchers cannot confirm his findings!" ' Professor Sumpter knew of no such group. 'Later, two people from industry whom I have been dealing with faxed me and said, "Look we are very sorry about this. We don't know how it happened. It wasn't us, basically. . . " Weh, in fact there is no such work in the US and all the research that has been published has supported my findings . . . This kind of thing is not remotely constructive.' Some scientists, such as Dr Theo Colborn, are concemed that the public relations exercise on behalf of industry is considerable and has a significant influence on how these issues are communicated to the public. Her work, both in organizing the Wingspread Conference and her recent book Our Stolen Future, written with Dumanoski and Myers, outlining possible health risks of hormone disruption, has been studied by industry committees. The Endocrine Issues Task Group, in a strategy paper for the Chemical Manufacturers Association, assessed the likely impact of Our Stolen Future prior to publication. 'The book is anticipated to contain an inventory of suspected endocrine-related effects of chemicals in animal species and call for additional research to identify causal agents. Previously published articles by Dr Colborn have contained a hst of approximately forty-eight products or environmental contaminants which she claims cause oestrogenic, anti-oestrogenic, androgenic, antiandrogenic, or other endocrine-mediated effects. Publicity associated with the book is expected to result in renewed media attention to the endocrine issue."O Within industry there is anxiety that such adverse publicity could create widespread fear of chemicals, or 'chemophobia'. Several manufacturers' associations have formed an alliance to work together on the issue of homione disruption. For example, a summary ofagreements ofthe 'Inter-Association meeting on Endocrine Issues' in Washington in September i995 shows that the meeting was attended by representatives of the following associations: the Che@cal Manufacturers Association, the Chlorine Chemistry Council, the American Plastics Council, the Society of the Plastics Industry and the American Crop Protection Association. The agreements include the following:
The existing Endocrine Issues Coalition (EIC) wiu serve as the focal point for developing a coordinated cooperative strategy for our associations on endocrine issues regarding: communications, including a process for coordinating responses to media inquiries; advocacy at the state, federal and intemational levels; scientific research, including when appropriate, joint funding ...
A communications task group will be formed ... The initial task of this group will be to develop a common standby statement, with umbrella messages to be used by all Endocrine Issues Coalition (EIC) members. In addition, more detailed statements addressing issues unique to each association's members wig be developed and shared ... A process for referring media calls to one another will be developed, including contact points within each association ...
A separate advocacy task group will not be formed at this time. Advocacy coordination wig be initially handled within the conununications subconunittee.
At the meeting it was also agreed to set up additional committees, including the Endocrine Issues Coalition steering committee and steering committee coordinating group. Plans were set in place to approach other relevant trade associations to join the coalition." More recently, a memo from the Endocrine Issues Task Group to the Environment Health, Safety and Operations Committee of the Chemical Manufacturers Association has reported on industry's legislative concems. 'In the last Congress, endocrine issues played a pro@nent role in the push for restrictions on chlorinated compounds, and legislative proposals were offered by Senator D'Amato and others to require broad-based testing of chemicals for their oestrogenic potential. Despite the overall focus of this Congress on regulatory reform, endocrine issues have remerged as a legislative priority.' Manufacturers fear that the already substantial data on chemicals which persist in the environment and human tissues will be put together with the new data emerging on hormone disruption to make the need for much tighter legislative controls even more urgent. 'A key trend in regulatory thinking inside and outside the US is the convergence ofendocrine issues with the growing pressure to control persistent toxic bioaccumulators (PTBs),' reports the Endocrine Issues Task Force. 'Internationally, numerous governmental organizations . . . are currently debating PTB policy. The hypothesis that PTBs could accumulate to levels that could cause reproductive and developmental abnormalities via a horynonerelated mechanism is lending urgency to the perceived need of governmental bodies to hmit release of possible PTBs (such as PCBs and dioxins) into the environment.' To tackle this and other issues, among the action plans it was agreed that forming 'global partnerships should be a high priority . . . Global partnering will be of value both to leverage resources in conducting research ... and to take full advantage of an aligned, harmonized approach to risk assessment and data interpretation by the global chemical industry."' American trade associations are now working with their European counterparts on these issues." It is difficult to capture fully the context in which this particular cutting-edge science is being produced, where a few independent scientists are coming up with data which inadvertently unde@nes one of the most powerful economic forces in society today. Most of the scientists involved are working with limited resources and back-up, largely off their own hunches and interests. By contrast the vast enterprise of business can summon highly paid lavryers, public relations experts, and millions for research and development. Dr Colbom and her colleagues point out that the che@cal industry is such a powerful force in the global economy, sales of synthetic chemicals and products derived from them constitute well in excess of a third of the world's gross national product.'
The response: governments
While press releases, position papers, steering committees, coordinating committees, and countless others continued to claim that au was well, faced with mounting public concem, many Western govemments conunissioned their own enquiries into the issue. Of these, the most hard-hitting report came from Denmark. Funded by the Danish Environmental Protection Agency, this independent committee concluded: 'It is now evident that several aspects of male reproductive health have changed dramatically for the worse over the past 30 - 50 years. The most fundamental change has been the striking decline in sperm counts in the ejaculate of normal men ... Many otherwise normal men now have sperm counts so low that their fertility is likely to be impaired. 116 The report also found that, although the causes underlying these apparent changes are currently not clear, 'both clinical and laboratory research suggests that all the described changes in male reproductive health appear interrelated and may have a common origin in foetal life or childhood. This means that the increase in some of the disorders seen today originated 20-40 years ago, and the prevalence of such defects in male babies bom today will not become manifest for another 20-40 years or more.' The role that oestrogens niight play in many, if not all, the reproductive disorders was cited, and it was pointed out that 'the large number ofchemicals in numerous environmental categories suggests adequate availability'." The panel of experts identified many research priorities. In particular, it was found more work was urgently needed to assess: to what chemicals man is exposed; by which routes and to what degree; whether the chemicals get absorbed; the concentrations of these chemicals in man and how they are distributed in the body; whether they are mobilized in certain states such as pregnancy and, if so, how? The report ended rather more pessimistically with: 'Presently, we do not have adequate answers to any of these questions mainly because we do not know what chemicals are ofgreatest concern."" In London, an independent review was also commissioned by the govemment, which was rather more British about the whole thing. Scientists at the Institute for Environment and Health in Leicester prepared the report, which pointed out the lack of proof. They found: 'There is compelling evidence that testicular and female breast cancer rates have been increasing during the last four decades in Westemized countries."' However, they pointed out, 'as yet a causal relationship between exposure to environmental oestrogens and adverse effects on reproductive health has not been established', although such an association must now be regarded as 'plausible'. They did acknowledge that 'proof of a cause and effect relationship between exposure to oestrogens in the environment and adverse effects on human reproductive effects is likely to remain elusive'. They too prepared detailed research recommendations. Apart from Britain and Denmark, the German and Dutch govemments have both recently initiated reviews and a European-wide research effort has now been started through the European Centre for Ecotoxicology and Toxicology of Chemicals. This is investigating screening techniques for hormonally active che@cals and regional differences in adverse health effects and other studies. In America, several govemment agencies are involved. The Environmental Protection Agency has launched extensive research on hormonal effects and identified the issue as a top research priority in its strategic plan. Studies under way include research on breast cancer, screening methods, further testing on hormonally active chemicals and many others. The National Academy of Sciences has convened a panel of experts to assess the data on hormonal effects. Several of the American contributors to this book are taking part, including Professor Ana Soto and Professor Stephen Safe. However, in the absence of definitive proof, as yet all govemments have stopped short of implementing legislation to protect the public from hormonally active chemicals. One of the problems for policy makers is reflected in the British government report: while proof remains elusive, it is very difficult to allocate significant resources to the issue. Some joumalists and environmentalists in Britain have argued that the govemment is not following its own guidelines. Given the difficulties of establishing scientific proof on environmental issues, governments have endorsed the 'precautionary principle' when weighing up scientific uncertainties, in which action may be taken before causality is established beyond doubt. This was outlined in the government's 1990 publication of Britain's Environmental Strategy which stated: 'Where there are significant risks of damage to the Environment, the Government will be prepared to take precautionary action to limit the use of potentially dangerous materials or the spread of potentially dangerous pollutants, even where scientific knowledge is not conclusive, if the balance oflikely costs and benefit justifies it.' Despite the laudable intentions, the precautionary principle has not been applied to protect the public from the potentially adverse effects of hormone-@micking chemicals. Government departments have not specified what evidence they require before they will take action. No comprehensive strategy has been outlined for encouraging businesses to switch to substitute materials or for ensuring that the chemicals that are in commerce are systematically checked. 'The problem is, can we afford the precautionary principle?' asks Dr Richard Sharpe. 'The people who planned it probably never thought through what it might actually mean. It's OK to be doing it prospectively for a new chemical. But it is completely different when you've got a chemical out there and it's part. of the fabric of society and then you say, "Let's apply it to that." . . . Most people's reaction would be, why don't we just simply ban afl these che@cals if they are under suspicion and that is the end of our problem. I wish it were that simple. But the chemicals that we are talking about are used in so many of the products that are part of our modem everyday life that to get rid ofthem would actually introduce a revolution, the like of which we have not seen before in our way of living.' 'Suppose, for example, we were to get rid of phthalates,' says Professorjohn Sumpter. 'You'd lose half the items in your house. The furniture, the PVC plastic, items hke the washing machine, ridge, freezer, and so on, these aD have lots of plastics. Then most of the cosmetics would go, food containers and wrappings. Do we rea,Uy want this? This is not to say we shouldn't be mounting pressure on manufacturers to change and improve and taking action to phase chemicals out if we know we have a genuinely safe altemative. But it needs thinking through.' So despite the flurry of govemment reports, and considerable research efforts, no steps have been taken. Once again, it would appear the public is caught in a catch-22 situation. Governments are unlikely to introduce protective measures in the absence of proof, yet obtaining definitive proof, as stated in the British report, is going to be elusive. 'I think it would be difficult, ifnot impossible, to get absolute proof,' says Sumpter. 'Some philosophers of science argue that you never, ever prove a hypothesis. What you do is accumulate evidence that disproves it. At the moment what we are doing is accumulating the evidence, and most of the evidence supports the hypothesis that exposure to oestrogenic chemicals affects the testes and sperm production, so we're getting closer and closer to being able to say this hypothesis is probably true. But there will always be an argument as to whether you absolutely definitively prove it. So it is a "weight of evidence" argument, and it seems to me that all the evidence is slowly but steadily going in one direction. The question is, what constitutes a 'weight of evidence' and for whom?
The response: the scientists
While for some scientists more research is needed, for many of those at the forefront of the field, the weight of evidence already amassed is overwhelming and fully justifies taking action. 'The problem is how much should we study before we protect,' asks Professor Ana Soto. 'What is our duty as scientists? This issue has already hijacked our lives. How much more evidence does society need?' One of the problems with gathering the evidence is that without concerted govemment action it can be very difficult to tackle key questions for human health quickly. For example, Professor John Sumpter argues a great deal more could be done to identify potential routes of exposure. 'I really would like to get some basic figures on human exposure to chemicals,' he says. 'It is entirely possible that we have missed some chemicals. Up until six months ago we missed phthalates and many of the discoveries have been made by accident. But surely if we got the major chemical manufacturers together with people who formulate the products which we use, it should be possible to draw up what you might can a "hit list" which would allow us to assess to which chemicals we are most likely to be exposed? Senior scientists in the chemical industries could simply be asked to draw up a list of the top ioo che@cals to which there is greatest human exposure. These lists could then be compared to compile a "hit list". Once we had such a list, then we could test these chemicals for their ability to disrupt the endocrine system. We could test the top ioo in six months. We might find a group of chemicals which hasn't crossed anyone's mind yet.' He points out, however, that although this could be carried out very cheaply, it requires govemment support and pressure to ensure industry participation. It would appear even that such basic practical measures as this, to assess human exposures, are not being done. This could be solved, he says, if there was an independent body to bridge the gap between academic scientists and industry, which aimed to tackle the important questions for human health in a systematic way. Sumpter's team at Brunel and Soto and Sonnenschein's group at Tufts are being increasingly approached by industry, who are racing to test substitute chemicals to screen them for hormonal activity. But all the companies who are ahead in this game are American orjapanese. 'It is not in industry's best interests to be left behind,' wams Sumpter. 'Industry may lose out in the long tenn if govemments are overprotective. Government officials are in a difficult position of calculating what information to release. But I think the British govemment still errs too much on the side of caution; it is too secretive and that is not in the best interests of the consumer or industry ... Suppose, for instance, the British govemment said, "We're presently investigating whether we should allow alkylphenols to be used at all." It just so happens they are investigating this, but very quietly. Now if that information was on some kind of public register, the companies that make alkylphenols could effectively see the writing on the wan, and would have time to prepare altematives. Consumers would be applying a bit more pressure and it would encourage these companies to start to move. That pressure doesn't exist in Britain.' Once a company finds a safe altemative, it is likely to move ahead in the market quickly. At present most companies working on altematives are American and business opportunities are being lost in Britain, Sumpter argues.
However, until we are sure we have safer substitutes, he believes it is difficult to move ahead too fast. 'Yes, we should act without definitive proof of cause and effect,' he says, 'if we know we can make a change without introducing something worse. We don't want to replace something that is oestrogenic with something that is carcinogenic. We have to be reasonably convinced that we can move to safer substitutes, and then, yes, we should do this ... history cautions us about assuming the picture we have now is the right picture. As techniques improve and we find out more, problems appear at lower levels of exposure. We really should be concemed now. History wams us to be careful.' This is a widely held view. 'I think in the end we will have to take precautions based on evidence rather than proof,' agrees Professor Niels Skakkebaek. 'It is the same with smoking. There is no proof that smoking causes lung cancer. But there is certainly a lot of evidence.' 'In the case of cigarette smoking and lung cancer, we waited quite a long time before taking any action,' says Dr Devra Lee Davis. 'We waited while scientists had debates about the quality of the data, and while industry, of course, weighed in and assured us that there was no problem; smoking was really associated with other things and didn't really cause poor health. We now know the tragedy of this. Some people have projected that there might be ten million deaths by the year 2000 from tobacco smoke. Now what if we had listened to the scientists who urged that we take action earlier? We would have all been better off.' Several scientists are so concemed at the 'weight of evidence' that they argue our entire approach to regulating the industries involved now needs to be rethought. A legislative framework needs to be put in place which will give humans and wildlife much greater protection. Dr Theo Colbom and her colleagues argue that the contamination of the globe with biologically active and persistent chemicals has sufficiently worrying implications for human health that it requires an intemational treaty to implement global controls. in much the same way that govemments united to deal with the threats posed by ozone-depleting chemicals such as chlorofluorocarbons in the Montreal Protocol of I987, a similar intemational treaty is needed 'to halt the use and dispersal of biologically active persistent compounds such as PCBS, DDT and lindane."' International protocols need to be developed which would 'phase out theproductionanduseofthesecompounclsworld-wideandprovide institutional and financial support for their containment, retrieval and clean-up' . In addition to dais, Dr Theo Colborn argues individual countries can introduce legislative measures to give greater protection. 'In essence what we have to do now is niake sure that we revisit every piece of legislation that is coming up for reauthorizadon, to make sure that we include not only cancer as a risk element, but that we include these trans-generational health effects, the effects on the developing hormone, immune and nervous systems, which are all linked. When we do that, then we can strengthen regulators' roles in controlling these chen-ticals. ' Legislation needs to be redesigned to take account of accumulative exposures, interactions between exposures, and to protect those most vulnerable: the unbom. 'We have too much at stake here, all of us,' says Dr Devra Lee Davis. 'What we have to do is pay better heed to experimental studies, to wildlife studies, and now to the growing body of human evi 'dence that we have, all of which point in the same direction. All these studies suggest that there are widespread exposures to some environmental chemicals that disrupt hormones and that some of these could be behind the increases in breast cancer, the increases in testicular cancer, perhaps the increases in prostate cancer, and I would argue we cannot afford to ignore this evidence. We cannot afford to run the risk that, by ignoring this, we nlay take a course of action that wifl endanger the ability of the species to persevere.' 'The findings demand that there be policy changes,' advises Professor Louis Guillette. 'If it's released into the environment, and you can eat it, breathe it or drink it, then it should be tested, not only for whether it causes an effect in the adult, but whether it affects a developing child as well ... The chemical companies have to realize at this point that many ofthe compounds they are releasing are having an effect on the embryo, the unbom. Is this night? No, I think it ii absolutely, ethically, wrong.' 'Basically we are talking about a matter of survival, not orily of wildlife, but of humans as well,' wams Dr Theo Colbom. 'You can reach a point of no retum, where it is too late and there is nothing you can do. We're going to have to decide how long we want to wait, and how much more evidence we want to collect before we do something. This could determine how successful we are in turning things around." 'At the beginning of the scientific revolution, science was something you did to understand nature, not to transfon-n it,' says Professor Ana Soto. 'But now we think we know enough to go and modify nature because we are going to improve on it or get some other advantage. It is not that this shouldn't be done. It is just that this shouldn't be done so cavalierly. We imagine we have the upper hand and that is the arrogance. At the moment we are doing this as though what we do not know doesn't exist, and that is the sin.' Perhaps by now we should have teamed the lesson. Nature seemed so simple: the flower in the garden, the warmth of the sun, the familiar pattern of the seasons. Yet time and time again, science has revealed an extraordinary complexity that cannot be readily encompassed by the human mind. Who would have thought that the chemicals that transformed our lives, those bright new discoveries that seemed to bring us closer to some tantalizing golden age, could be literally transforming us, biologically, in a mosaic of subde adverse effects. Yet, some highly regarded scientists have produced a growing body of evidence, which surely cannot be swept under the carpet by big business, govemments or our own complacency. Although it is a complex problem, their evidence shows that there is an enormous contamination ofthe environment and possibly a dangerous one. We now know this contamination is in the soil, the rain, the oceans, the food we eat, the water we drink, the air we breathe. Nowhere can you go to escape its touch.
Postscript
Professor John Sumpter took a special interest in keeping up to date with the scientific literature, but as the information on different compounds accumulated, he began to feel more and more uneasy. It wasn't just concem at the random nature of the discoveries and the uncertainties over whether key routes of exposure had been identified. [t was something more fundamental: why was it, he wondered, that we had been using some of these compounds for years and yet basic information about their biological activity had eluded us? Was it possible some of this had been known before? He recollected that a chemist, Charles Dodds, had written to Nature in the I93os about his discovery ofthe first synthetic oestrogen, the notorious diethylstilboestrol, or DES. It was well known that Dodds had arrived at his discovery quite systematically by testing compounds with a similar structure to oestrogen. John Sumpter began to wonder if, in the course of his experiments, Dodds could have tested some of these other oestrogenic chemicals as wefl. Dodds was working on families ofche@cals that appeared similar to oestrogen, chemicals known as the stilbenes and styrenes. Working from labs at the Courtauld Institute of Bioche@stry at Middlesex Hospital, with a team from the Cancer Hospital in Chelsea, at the time their work caused quite a stir. But what was in his letters to Nature? Tracking down the letters was not as straightforward as it might seem, since most computer databases do not go back to the 1930s. Ed Routledge at Brunel University decided to take this further. Eventually the letters were traced and faxed through to the biochemistry labs at Brunel. Some of the terminology used by chemists in the I930s was different from the che@cal names of today, so it took a little while to work out the meaning. Gradually, however, a disturbing picture began to emerge. As early as January 1933, having studied the chemical properties of ovarian hormones, Dodds had foreseen the possibilities: 'It seems likely that a whole group ofsubstances of related chemical constitution will be found to have oestrus-exciting properties [to act hke an oestrogenl,' he wrote. He had then started to search for these counterfeit hormones, realizing they may have some value in medical treatments, checking out all the likely chemica candidates in his laboratories. In the next month's edition of Nature, Dodds was hot on the trail, warning that 'because cell proliferation which characterizes the oestrus state is in some respects reminiscent of the early stages of a malignant growth, we have sought a correlation between substances having oestrogenic action and those having carcinogenic properties'. He then explained how he found that two potent carcinogens had oestrogenic activity as well, a result which he found 'striking' since it was thought unusual that two types of biological activity should be shown by one and the same compound." At the time, he thought a common feature ofthe molecules termed the 'phenanthrene nucleus' was responsible for the oestrogenic properties and he started to investigate further. As he did so, he soon found that molecules which didn't have this particular feature could also act hke oestrogens. This was the breakthrough. In I936 he reported that a completely different class of compounds had oestrogenic activity: he called them: the 'diphenyls'. In fact he published an entire chart of diphenyls which could produce oestrus or heat in a rat .31 Many of the compounds which have subsequently been shown to be a problem have two phenyl groups. Known today as the biphenyls, they include DES, bisphenol A and the oestrogenic PCBS. Couldn't this have been foreseen from Dodds's letter to Nature in I936, thought Sumpter. Seven months later Dodds reported another discovery. He realized that you didn't need two phenyl rings: 'so simple a compound. . . containing only one benzene ring' could produce the oestrogenic response. He then proceeded to characterize the oestrogenic activity of certain alkylphenols. John Sumpter felt almost like a time-traveller, viewing down the decades through the war years and the depression to the tiny office that he knew Dodds had had, marvelling at the man's sheer genius. In the 1930s, the kind of equipment and resources available to him would have been more reminiscent of the last century. Yet despite the limitations, this one man had foreseen that this chemistry was going to be a mixed blessing. Wrapped up in Charles Dodds's scientific letters from the thirties were all the clues needed to unravel the story, Sumpter thought. There theywere: the biphenylic compounds, such as DES and bisphenol A; some ofthe alkylphenols; and many other related compounds. Some were the very same classes of chemicals whose oestrogenic activity was rediscovered by accident in the late eighties when they were contaminating Professor Soto's experiments in Boston and Professor Feldman's research in California. So many of the compounds which now contaminate the environment and ourselves, once created, are not easily destroyed.
Dodds, of course, could not have anticipated this. Yet there it was, the essence of the story set out in black and white, as long ago as the 1930s. What happened to this information in the intervening years remains a mystery. Quite who knew what and when, and whether industrialists were aware of Dodds's research when they began to manufacture products with these and related chemicals, raises another set of questions yet to be answered. Sumpter carefully filed away the old letters to Nature. 'Charles Dodds,' he thought, 'really was quite somebody.'