Toxic Inheritance

by Sarah Barnett / 05 May, 2007
We must head the grim warnings from the animal kingdom about the dangers of environmental chemicals.
It's not easy, being a frog. Their numbers have fallen worldwide by about a third since the 1950s, due to a combination of environmental impacts, but the worst problems they face - the result of sometimes swimming in a chemical soup that makes them voiceless, sterile or even hermaphrodites - could be really bad news for humans, too.

Biologist Jared Diamond has already raised the alarm about the rapid increase in human infertility in the western world. "The average sperm count of an American college student today is 80 or 90 percent below what it was 50 years ago ... It is quite remarkable, and there must be a reason for it. And the reason is almost surely environmental chemicals."

"People will introduce a chemical technology and think there's no problem," explains Professor Terry Collins, "then 10-20 years later they'll start to see things in the animal record saying there is a problem."

Collins is an Auckland University alumnus who directs the Carnegie Mellon Institute for Green Oxidation Chemistry in the US. He was recently back home as one of the university's "distinguished alumni" to deliver a series of lectures.

The trouble with evidence in the animal record, he says, is that the industries producing the chemicals, and the governments regulating them, usually demand human health evidence before taking action, which is almost impossible to produce.

You can't pour herbicide over a baby, then wait and see what happens. "From my point of view," he says, "I think frogs are enough."

Professor Tyrone Hayes has the frogs. In his University of California Berkeley lab - part of the Department of Integrative Biology - he researches the endocrine-disrupting properties of the US's second most popular herbicide, Atrazine, also used in New Zealand.

The endocrine system is essentially the series of glands that secrete and regulate hormones in the body. Endocrine disrupters mimic oestrogen, leading to feminisation of males and a heightened risk of hormone-related cancers in both sexes, particularly breast and prostate cancers.

Hayes began the research in 1998 for Novartis, the Swiss-owned company that developed Atrazine - banned in Switzerland - by putting trace amounts in tanks where he was raising leopard frogs.

The males, once fully grown, developed problems after exposure to concentrations as exquisite as 0.1 parts per billion - one-30th of the US Environmental Protection Agency's (EPA) "safe" level for Atrazine contamination of drinking water. Some had multiple sex organs, some had traces of egg yolk in their testes, some were hermaphrodites and still others had shrunken larynges, rendering them unable to make mating calls.

Hayes left Novartis shortly after the results became apparent.

"That's the short version of it, yeah. What happened was I became very uncomfortable," Hayes claims.

Novartis later became Syngenta, which continues to deny the validity of Hayes's research.

However, Hayes's follow-up studies, published in the peer-reviewed journals Proceedings of the National Academy of Science and Nature, found similar results in more lab frogs, as well as in wild frogs that had been collected from areas with Atrazine. Forty percent of the males were feminised - chemically castrated - and 80 percent had shrunken larynges - again, after a single exposure to low concentrations of Atrazine.

In 2003, a group of workers at a plant in Louisiana where Atrazine is manufactured sued Syngenta over a rate of prostate cancer shown to be almost nine times that of the general population. The case is pending.

Last year, the European Union banned Atrazine as part of an initiative to put the onus onto chemical manufacturers to prove their products' safety, as new science like Hayes's comes to light.

His current research looks beyond reproductive difficulties and into broader areas like immune function.

The EPA still maintains that the science is insufficient to ban Atrazine, although it has now asked Syngenta to monitor water in areas where Atrazine is sprayed.

You only have to look at lead contamination to see how influential industry can be, Collins says. Lead paint was banned first in Austria in 1909, but it wasn't until 1979 that the US was fully rid of it. "Crazy. We never needed it. Could have used zinc, could have used titanium."

Instead, paint in the 1930s was 50 percent lead by weight - "a lethal dose for a child was a square two inches either side ... And people writing papers about how it was bad for kids were oppressed."

Tens of thousands of children died in those decades, he says, and "the whole country suffered IQ deficits from lead. There's absolutely no question."

He's not kidding - IQ loss can be measured exactly by how much lead is in the blood. "Purely so that a small group of people could make some more money."

On the other hand, industrial and governmental action was swift when the damage to the ozone layer from CFCs was made apparent - there was only a two-year gap between the UN's Montreal Protocol in 1987 to phase out CFCs and its enforcement in 1989. Although Collins is quick to say that he doesn't want to diminish that major accomplishment at all, "one of the major producers [of CFCs] had the patents on the next generation of products that would replace it. That was also critical to it."

Endocrine disruption puts the stakes, he emphasises, "infinitely higher" than even the historical lead contamination in the US.

So, if Atrazine is banned in Switzerland and on the EU's list of known endocrine disrupters, surely New Zealand is taking a precautionary approach?

In fact, almost 50 tonnes of Atrazine are used here each year. The Food Safety Authority's most recent Total Diet Survey (2003-04) found no Atrazine among the agricultural residues they tested, but Atrazine has been found here in groundwater at "safe" concentrations since 1993. Safety levels are based on lifetime exposure.

Andrea Eng, the group manager for hazardous substances at the Environmental Risk Management Authority (ERMA) NZ, says that ERMA carries out regular reviews of hazardous substances, as proposed by either the chief executive or public submissions. At the last consultation early this year, it was proposed that Atrazine be added to the list of candidates to be reassessed at the next review at the end of this year. ERMA is considering its inclusion.

Hayes, who may be travelling to Tasmania soon to testify for Atrazine's removal there, says "maybe I'll see you in New Zealand!"

You have to wonder whether he is worried for his own health, handling Atrazine - "I am and I'm not. I think one of the most important aspects of this is that early exposure is very important.

So if you look at compounds like DES [Diethylstilbestrol, a compound that was found in the 70s to cause a rare vaginal cancer in the female children of women who took it while pregnant] - it wasn't their exposure as an adult, it was exposure in the womb. And now even their granddaughters can show the effects. That's one of the reasons I take this very seriously.

"Even if we stopped using Atrazine today, it'll still be around in 20 years, so my grandchildren will likely be exposed. And if you look at DES as a model, where the granddaughters of exposed women show effects, my granddaughters' granddaughters will be affected by Atrazine, even if we stop using it today."

"When a baby is developing in the womb," Collins explains, "it's not just what's locked into the DNA that determines the outcome. So, for example, the mother's hormones are released into the blood and these chemicals - at exquisitely low concentrations - control what happens to cell development.

"If you do anything to jumble that message, if another chemical comes in that looks like a hormone, or that alters the biosynthesis of the hormone, or that blocks the way the hormone is picked up by proteins and transported through the blood ... there's an immensely complicated series of events going on. And it's exquisitely timed. When you get into this area, it's bone-chilling."

But Atrazine is just one of a host of environmental chemicals causing concern - often because they seem safe at first, as Collins explains, or at least seem safe in isolation. You could expose cohorts of frogs to each of the nine major agricultural chemicals in a US cornfield, he says, and nothing might happen. But expose them to a cocktail of those nine chemicals, "in just infinitesimal concentrations, and they're messed up".

Hayes explains that "mixtures of pesticides actually have greater than additive effects.

"So, for example, animals are, in addition to having retarded growth and development, experiencing immune suppression. And we think that happens through the so-called stress response, where there's an increased load of stress hormones. And those stress hormones lower immune function both in the lab and in the field and make animals more susceptible to disease pathogens."

Dr Ninja Reineke, of the World Wide Fund for Nature's (WWF) toxics programme, says from her Brussels office that she only started looking at environmental toxicology during her post-grad studies, through her chosen specialty. The lack of training in environmental properties (see box, right) could be seen as astounding, she agrees, "but all in all, this is still quite a new science".

You could trace the beginning of it back, she says, to the publication of Rachel Carson's Silent Spring in 1962, which brought to light the effects that the pesticide DDT had in the environment, and on birds in particular.

Though the book was met with huge suspicion at first, DDT was banned in 1972 in the US and in 1984 in the UK, some time after the rest of Europe. Still, Reineke says, "Everyone thought perhaps this was only a problem with DDT ... It's only in the past 20 years that people have realised this is really something more."

In that time, an entirely new breed of chemist has sprung up: the green chemist, of which Collins was one of the first. Their aim, Collins explains, is first to get pathogens out of the environment by developing and patenting non-toxic replacement technology and, second, to talk about it.

"People like me who have the security of a tenured position from which I can't be fired - unless I do something ridiculous - have to talk about it."

It would be easy to play the blame game, he says, and "say it's all chemistry's fault, we need to get rid of chemicals. That's not very reasonable, and often it's not chemistry's fault - we just didn't know. And it's how you behave when you find out, that determines fault."

But, because of endocrine disruption, he's quick to warn that "we're talking about the highest stakes imaginable here ... we cannot have multi-decade periods go by while we dither about thinking about whether or not to deal with these problems".

But if industrial chemistry is relatively new and green chemistry is in its infancy, the science of endocrine disruption is younger still, dating back just 16 years to the publication of Theo Colborn's Our Stolen Future: How We Are Threatening Our Fertility, Intelligence and Survival, which the New York Times Review of Books described as "so important and its story so powerful that it deserves to be read by the widest possible audience".

Colborn - now retired - received her PhD in zoology in her fifties, after raising her family, and in the 80s went to work at the WWF in Washington DC, where her job was to scan the papers for stories about environmental impacts on wildlife. She began to find evidence of animals with reproductive difficulties in and around the US Great Lakes, which, at the time, were laced with industrial waste.

For example, at mink farms around the lakes the animals that were fed local fish were developing high rates of miscarriage, or birthing pups that simply wasted away. If they were fed ocean fish, they were fine. In Florida, meanwhile, alligator farmers were having trouble finding eggs at Lake Apopka, and when a local zoologist, Lou Gillette, went to investigate, he found that the male alligators in the area "were simply not up to the job", as Collins puts it, of inseminating the females.

Colborn, looking for a cancer connection, began to wonder whether the endocrine system - the system that controls our hormones - was being affected by industrial waste in the waterways, and discovered that it emphatically was.

In terms of the correlation between animal results and human health, Tyrone Hayes says, "a lot of the underlying mechanisms are the same. For example, the induction of the enzyme aromatase in frogs -aromatase is the machinery for converting testosterone into oestrogen - that mechanism exists in humans as well. So in the same way that Atrazine can cause a hormone imbalance in frogs, it can cause a hormone imbalance in humans.

"In frogs, excess oestrogen means you develop as a hermaphrodite - if you're a genetic male, you grow eggs in your testes. In humans, excess oestrogen and the absence of testosterone means you experience infertility if you're a male, you have low testosterone and sperm, but what's more important is that you develop breast and prostate cancer."

So although "safe" limits are set for exposure to chemicals in the environment, this new science means that level of exposure could be almost irrelevant, because instead it becomes about timing, particularly with the most vulnerable: babies developing in utero, as Hayes pointed out with DES.

One of the first major studies on humans in this area was to do with exposure to phthalates, one of the most ubiquitous classes of chemicals in everyday life. Phthalates (pronounced "tha-lates") are found in any PVC product. Although grown adults are probably fine with exposure to these plastics, Collins says that pregnant women should be cautious. "If on the day that they hit the blood and some particular part of the anatomy is being put together, it might not come out as it's meant to come out."

In 2005, Shanna Swann, an obstetrician at the University of Rochester, tested 250 of her patients for levels of phthalates in their urine and compared the levels with the development of their babies.

She found that those women in the top 25th percentile for phthalate levels - one woman in four, hardly off the scale - were more likely to have baby boys with a shortened "AG index" - the distance between the anus and scrotum.

They're still babies, so clearly the implications for their reproductive years are far down the track, but a short AG index is normally indicative of a wide variety of reproductive issues, from undescended testes to infertility.

"Of course," Reineke cautions, "we need to be quite careful at this moment to make any direct links to health effects, but we can say that these chemicals, in the lab, have been linked to really problematic things like diseases - not only allergies, but also up to cancer and the endocrine system - and the relationship there with the potential breast cancer increases is also a very important issue."

Dr Philippa Darbre echoes this. "It must also be remembered that no xenoestrogen [synthetic oestrogen] has ever been proved to be linked to breast cancer incidence." But the Leeds University breast cancer specialist, whose research has centred on the effects of underarm deodorants and cosmetics on breast cancer, continues, "the presence of such chemicals in the breast and the ability of such chemicals to mimic oestrogen are indeed pieces of evidence which make me concerned, but there is no definitive evidence for any direct link".

But, she says, "It remains true that lung cancer cannot be proved to have been caused in any one case by smoking.

"I am not sure any longer why we need to plaster so many chemicals under the arms every day - people have lived for hundreds of years without and it is a massive experiment to ask every man, woman, child, and increasingly younger children and babies to use these products every day for an entire lifetime."

Still, the majority of evidence remains in the animal record, "and the link to humans," Reineke says, "is not quite so apparent. We basically decided to generate part of that data ourselves, to convince European decision-makers that this is an issue that concerns us all."

The WWF tested three generations of women from families in 12 countries in Europe. They found that all of them had DDT and PCBs (polychlorinated biphenols, see box, right) in their blood, despite these chemicals having been banned for decades in the EU. The younger generations were more likely to be contaminated with newer chemicals, like brominated flame retardants used in carpets, clothes and non-stick cooking pans.

These were banned more recently, after being found to cause immune suppression and loss of vitamin A and bone density in polar bears - living hundreds of miles away from where any of these chemicals are produced or used.

Alternative products are available: Reineke says that there'd be no need for flame retardants if we weren't using synthetic material in the first place. Syngenta manufactures alternative herbicides that are now used in the countries that ban Atrazine.

Collins says, when it comes to PVC and phthalates, "We do not need them. That's a half-trillion-dollar statement on PVC probably if you were to go right through the economy and see where it is. We don't need it. We should get rid of it. It is bad news at every level. We should restrict polycarbonates [part of the group of plastics labelled with the number 7], and keep them away from food."

Reineke says that a precautionary approach is the only way to go, and Gillian Woods of the Breast Cancer Network (BCN) believes it's time that we took the same attitude in New Zealand.

The BCN presented a petition to Parlia-ment last November, calling for a breast-cancer strategy that, among other things, would "ensure that this strategy recognises and includes the role of synthetic environmental chemicals in breast cancer; ensure that this strategy includes testing of New Zealand women for body residues of chemicals linked to breast cancer; and adopt a precautionary approach with chemicals for which there is evidence of a link with breast cancer, and ensure their replacement with safer, non-persistent alternatives".

Green MP Sue Kedgley says "there's a policy vacuum" when it comes to environmental pollutants in New Zealand, but Woods acknowledges that the science, especially around plastics, "is cutting-edge ... and it's a really difficult area because breast cancer is such a complex disease. You can't say it's like smoking and lung cancer because it's nowhere near so clear-cut. And there's familial factors - even though you may not have the breast cancer gene, and most people don't - you may still have some tendency there."

In fact, Dr Meriel Watts, a long-time campaigner against pesticides, says that "familial risk relates to the fact that some of us inherit a gene that increases our sensitivity to carcinogens and endocrine disrupters. It doesn't cause breast cancer, it just makes us more susceptible to other factors."

"It could be simply that the same DNA-damaging chemicals," adds Darbre, "could cause breast cancer in everyone, but those with loss of BRCA1 or BRCA2 function [the breast cancer genes] are simply more susceptible because they cannot repair damage as easily."

Whatever part endocrine disrupters play in the many factors surrounding breast (and, for that matter, prostate) cancer, Woods says she believes their case is strong enough for the government to implement new policies. The Ministry of Health's Cancer Control Strategy states its first aim is to "reduce the incidence of cancer through primary prevention", and it lists those areas as cancers related to tobacco smoke; physical inactivity and obesity; nutrition; UV exposure; alcohol; infectious diseases; and workplace-related cancers - in other words, those people exposed to carcinogenic compounds in the workplace.

"What about the rest of us?" asks Watts.

The Cancer Control Strategy, now two years into its first five-year phase, comes up for review in 2010, and Dame Cath Tizard, chair of the Cancer Control Council, says that at that stage, "the council will be pleased to receive and consider new evidence on environmental carcinogens that can be linked to the development of specific cancers in New Zealand".

Woods is hopeful that if we look to the EU example, where known endocrine disrupters are being phased out, "There are a lot of things that other countries have started to do, that we could copy. There are initiatives overseas and the information is starting to build about how they're working. I think there's good cause to work for this."

Just ask a frog.

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