Article courtesy by Trevor Butterworth | Feb 26th 2013 | Forbes
Professor Richard Sharpe is a leading expert on male reproductive health, directing a research team at the UK’s Medical Research Council (MRC) Centre for Reproductive Health at the University of Edinburgh in Scotland. The MRC, which is celebrating its centenary this year, is one of the world’s oldest medical research institutes, publicly funded and wholly independent of government. Among the discoveries by scientists working under its aegis are penicillin and the structure of DNA. Sharpe’s focus on reproductive problems has put him at the forefront of research into phthalates, a family of chemicals that make plastic flexible, and, more generally, endocrinology, endocrine disruption (how trace exposures to environmental chemicals may adversely effect hormonal function), and the impact of lifestyle effects (such as diet) and other health issues (such as obesity).
Given Sharpe’s key work on chemical risk, and the fact that he is not funded by industry, and that he does not dismiss concerns about the risks of environmental chemicals (“I am not a die-hard ‘chemicals are safe’ man by any means,” he wrote in the UK’s Independent newspaper), it came as a shock to many environmentalists when he denounced the crusade to highlight the risks of another chemical, bisphenol A (BPA), as violating the fundamental principles of scientific inquiry.
The broadside in a 2009 article in Toxicological Sciences. The controversy over BPA lay, he argued, not in the in chemical posing a threat, but in the refusal of a small group of scientists to accept that their basic research, consisting of small studies with questionable methodologies and limited statistical power, could not be replicated by much larger studies using larger sample sizes and more sophisticated and careful methods. This small group (mostly funded by the National Institute of Environmental Health Sciences, and centered around the University of Missouri biologist Frederick vom Saal) had insisted that an industry-funded conspiracy was the reason the larger studies couldn’t be trusted; and yet, as Sharpe pointed out, very careful research by the Environmental Protection Agency and similar, publicly funded, bodies in Europe and Japan couldn’t replicate their findings either. Scientific method obligated them to either design better studies or concede their original findings were wrong. They did neither. As Sharpe wrote:
If an earlier result cannot be reproduced in a huge study conducted in a scientifically rigorous manner, as exemplified by Ryan et al. (2009), then the original result fails one of the golden rules that govern scientific research. When this happens repeatedly, as is the case with bisphenol A, then there can be no logical, scientifically based reason for continuing to espouse that the original results are the only ones that are correct, rather the converse.
Professor Sharpe was a speaker at a symposium on BPA at the recent meeting of the American Association for the Advancement of Science in Boston, where this interview took place (with later follow up by email).
So what has changed in the past three years since publication of your paper in Toxicological Sciences?
Sharpe: I think things have not moved on quite the way that I would have liked them to. There’s still the camp who is ignoring a lot of the evidence, and which remains the most vociferous. One of the issues is that in science nothing is ever absolutely black or white; but if you ignore a lot of the evidence – the bits that don’t fit – you can make something black and white. And I think’s that essentially what’s been happening with bisphenol A. There’s a certain group of people who are convinced that it’s responsible for all manner of ills and when evidence is published that does not fit with that, they find ways of dismissing it. If that doesn’t work, they then try to discredit the people who did it, which is not the way to go about things. I think that is just completely unacceptable.
My involvement in the whole area – because I don’t work on bisphenol A and I don’t even feel I work on endocrine disruptors, they are just one possible explanation for the health problems that I’m interested in – is that I want to see thinking in this area become evidence-based and people start using all of the scientific data to make their interpretations and to move things forward; that’s the way science works after all.
It almost seems that the controversy over BPA can be described as asymmetrical information warfare. The public only seems to hear about observational studies, which tend to make for very simplistic and usually alarmist storylines, while the more complex studies – the multigenerational reproductive toxicity studies, the detailed pharmacokinetic studies – are ignored. Yet in the hierarchy of evidence, these complex studies are designed to give us more definitive answers about whether there is a risk. And, of course, these are the studies that the regulatory agencies rely on to set policy. How can we get beyond this public failure to understand that the regulatory process is actually working to answer their concerns and working well? Is this a media problem?
Sharpe: There are lots of issues, obviously, and one of them is that the public, politicians – people in decision-making positions – don’t understand uncertainty for one thing, and a lot of the issues in science are to do with uncertainty. What is never stressed enough is that scientists work at “the borders of ignorance” – what is in front of us is unknown and we try to find our way forward by making hypotheses based on what is known. This means that we are wrong most of the time, and because of this scientists have to be very cautious about interpretations that are based on our projected ideas about what is on front of us. What decision-makers, politicians and the public want is unequivocal guidance, not uncertainty. So this creates a dilemma for scientists. Those who are more prepared to throw caution to the winds and make unequivocal statements are more likely to be heard, whereas a more cautious scientist saying “we’re not sure” will not be taken notice of. The bisphenol A saga has until recently been a story of such contrasts. Now, in my opinion, it has moved beyond this because the available data now shouts much more clearly that humans in everyday life are not effectively exposed to enough bisphenol A for any effects to occur.
It’s also very much about the type of information and data – if the public can identify with the data, they’ll take a lot more note than if they cant. For example, association studies are usually very simple. The way they are reported in the end is, for example, “an association between higher exposure to BPA and obesity or waist circumference.” So people can identify with that – they understand what obesity is, they see it around them, and therefore, this will grab their attention. Whereas if you say ‘somebody has done this multi-generation study in rats and they used a whole range of doses of BPA and they found no effects’’, they will say, “well that’s in rats, what’s the relevance to humans?” I think it’s quite difficult to put that all together for public consumption, and for sure we obviously have not done this well enough.
One of the features of those who believe BPA is very dangerous is a communicative approach that sensationalizes their findings, such as claiming that allowing your baby to drink out of a plastic bottle is equivalent to giving them a contraceptive pill, or that BPA is the biological equivalent of global warming. These make great headlines – and have been cited by many in the media – but it seems that if a similar statements were made in a different scientific field, there would be no controversy, because they are so outlandish they negate scientific credibility.
Sharpe: I couldn’t agree more. I think the statement about BPA from polycarbonate bottles and oral contraceptives is not only an exaggeration it’s fabrication, a total misrepresentation of the facts. You can see how alarmist it is, because, again, people can identify what it means and because it’s a scientist saying it they assume it’s credible. What they don’t know is just how completely untrue it is. If scientists are going to adopt a position that literally plays loose with the scientific evidence, then, well, what do you do? Well, my reaction was to speak out.
As a scientist who believes in the scientific method, you can’t adopt the same approach of abandoning principles. You can’t play them at their own game. You can’t cut scientific corners, because I think that is completely unacceptable to do. All you can do is to ask people again, to focus on the evidence. That’s all we can do: You’ve got to be able to explain all the evidence via whatever interpretation (or hypothesis) you propose.
You can’t simply – which is what the other faction would do – say “Well, that exposure data must be wrong, because we see these effects in rodent studies and because we see all these associations in epidemiological studies.” I can understand how they will adopt that. But if you sit down and sift through all the evidence, you can’t make if fit together. And as a scientist, you should then be saying, “well, okay, obviously we’ve got something wrong.” And this is what they are not doing.
[toggle title=” One of the reasons why I wrote that piece for Toxicological Sciences ” height=”auto”]
One of the reasons why I wrote that piece for Toxicological Sciences is because it gets me genuinely angry as a scientist when supposedly fellow-scientists not only disregard scientific method and principles, but also discredit the whole field of endocrine disruptors and environmental impacts on human health. These are important areas with lots of unknowns, and with big implications for improving human health (both reproductive and non-reproductive).
If those of us who work in this area are to retain credibility (and therefore attract research funding), we have to become far more evidence-based and self-critical – we need to be far less accepting of any one single piece of evidence, especially where this is in vitro or derived from animal studies that use much higher levels of exposure than are likely to occur in humans. Please note, I’m not saying “ignore evidence;” I’m saying that we need to be looking at it with far more circumspection. If we had done this with bisphenol A, we would not be in the scientific mess we are now in,, because ultimately the truth will win.
You’re not the first scientist to warn that crying wolf on BPA will harm environmental science. I’ve heard the same thing from many regulatory scientists here in the US and in Europe. It will be a gift to the chemical industry, proof that you can’t trust environmentalists. And here in the US, it will almost certainly be used as an excuse by Congress to slash the NIEHS’s funding given general budgetary pressures.
Sharpe: Endocrine disruption will get tarnished by all of this. And people will say well there’s lot of other things that are in the same category as this [BPA]. That’s going to mean that people are going to take their eye off this particular ball for the wrong reasons.
Can you give a brief outline of what you want people to take away from your presentation at the American Association for the Advancement of Science? It could be seen as a call to advance beyond BPA, which is looking increasingly like an innocent bystander in broader story of cause and effect, no?
I had two take-home messages. The first was simple – we should all focus on the evidence and let this do the talking rather than opinion being in the driving seat; opinion is only of value when it is based on all of the evidence.
The second is a little more complex, and is triggered by the complete disparity with two scientifically sound and detailed datasets on bisphenol A. On the one hand, human studies showing a highly consistent association between exposure to bisphenol A and obesity and obesity-related disorders (e.g., type 2 diabetes), and on the other hand the exposure/metabolism studies which show unequivocally that the amount of bisphenol A that actually gets into our bodies in biologically active form is so low as to be unmeasurable. My message was that these ‘complete opposites’ shout out that there is something that is missing that would enable us to account for both of these datasets. I suggested that because eating a modern Western diet has been shown to be important in determining how much bisphenol A we are exposed to, then eating too much of such a diet, which we know is the key cause of obesity, could also explain the association between these disorders and the level of exposure to bisphenol A.
The more you eat, the fatter you get and, at the same time, the more bisphenol A you are exposed to. The latter does not cause the obesity; it’s what causes the obesity (i.e., over-eating) that causes the increase in bisphenol A exposure. The attraction of this explanation is that (a) it is simple, and (b) it is consistent with all of the available evidence. However, it is an interpretation, no more than that, and needs to be tested to tell whether or not it is correct. If it is, we can essentially forget about bisphenol A as a human health problem and focus on the real culprit – overeating.
You did some of the key work on phthalates, which attracted immense attention from the media, and lots of precautionary bans, but seems to have faded somewhat from the news. What does the latest research tell us?
Sharpe: That’s a much more interesting case than BPA, because we are much more exposed to phthalates. The interesting thing is that the effects we’re most concerned about in rodent studies are those that occur via affecting the fetal testis and their production of testosterone. Now we’ve got four or five independent pieces of evidence which show that that doesn’t happen in humans according to the most direct studies that have used fetal human testes tissue in vitro, or after xenografting into immune-compromised mice.
And there’s also primate data showing an absence of adverse phthalate effects when you expose in the appropriate time period of pregnancy. So all of these findings say that there’s a fundamental difference between rodents and humans in the way the fetal testis responds to phthalates. And exactly the same is true, as it turns out, for estrogens. Estrogens have profound suppressive effects on testosterone production by rodent fetal testes, but they have no effect on human fetal testis. So there are differences in the way the testes operate in rodents versus humans and we need to take this on board when we ‘re thinking about what sorts of factors (chemicals, lifestyle) are likely to negatively impact the fetal human testis.
Based on what the results with phthalates and estrogens tell us, we need to be more critical of rodent data and less accepting of it until we have the evidence that it is an appropriate model for the human. I say this as a scientist who specializes in using animal models to understand human disease, not because I think they are no good, far from it; I’m saying that we need to go the extra mile to establish human relevance before we commit to an animal model and extrapolate the findings to man.
Just in case anyone thinks that this is the end of concerns about phthalates, it is not. First, there are effects on germ cells in the fetal testis in both rodents and humans, although we don’t yet know what, if any, human health significance these effects have. Second, testosterone production by the testis does appear to be vulnerable to inhibition by certain phthalates after birth, both during the immediate post-birth period and in adulthood. So I don’t think phthalates have a clean slate, as it were. I think the major concern has been pushed to one side, but there are other concerns that we still need to address.
Given that there is limited money for scientific research, and given that has said we should prioritize research on things that people are most at risk for dying from. What do you see as the future for chemical risk and environmental science? What should we spend money on?
Sharpe: A colleague of mine, John Sumpter, who was involved in endocrine disruption when it took off, says that what we need and what we haven’t invested in is intelligent thinking.
If you ask about how we’re being impacted by environmental and lifestyle factors – let’s say we’re talking about male reproductive health, but it could be any health issue – where would you start to look for impacts, in terms of what’s happened in the last 50 years?
Would you start with environmental chemicals, which we are exposed to at very low levels, and which, by and large, have very weak hormonal and toxic activity? Or would you start with something that was exactly the opposite – something designed to have high biological activity, things like pharmaceuticals – or our diets, which are clearly having a big impact on human health in a range of ways.
I think what we’ve done is that we’ve started looking at the wrong end of the spectrum. We should be going back and looking at the other. My own thinking is that
diet is going to turn out to be much more influential than we thought. It’s not just going to be about diet triggering obesity and its related diseases; there are going to be other impacts, and based on several bits of emerging evidence, this will include male reproductive disorders.
Finally, what could the media do, given their power to create sensational news and panicked policy making over chemical exposures?
Sharpe: I’m not sure I’m in any position to tell the media their business. I recognize that they need stories to make headlines and to make money, so some exaggerated claim about environmental chemicals is always going to be more attractive than a detailed study that shows no effect. My concern is that by feeding the public a continual stream of alarm stories that are poorly based, as with many of the stories about bisphenol A, people will become desensitized; the public is not stupid, people know it cannot all be true, especially when they see that everyone is living longer. But what happens if we discover an environmental chemical (or mixture) that we really do think poses a threat to human health, how are we going to get them to take serious notice of it, rather than filing it away with all the other alarmist stuff?
Ultimately, the problem is not the media it’s how we sell science – not very well is the clear and obvious conclusion. The public, even much of the media, do not know how research operates, how we “stumble from one discovery to another” and never in a straight line. I always tell schoolchildren that if you want to be an explorer, then science is for you. Being involved in scientific research is like reading the best detective novel you’ve ever read, except with far more twists and surprises; it makes for a very exciting life. We need to sell the wonder of it far better than we have done – although Brian Cox has done an excellent job in capturing this. So maybe the media would help if they tried more to capture this aspect rather than spinning out yet another scare story.
There are wonderful science stories out there that show how, over a period of time (usually 10-15 years or more), a seemingly “heretical” finding leads to completely new understanding. It’s the story of how science got there that’s appealing, not the single original finding. Scientific research really does work, given time. The truth, which can be very strange and unexpected, always emerges eventually and, in so doing, repeatedly makes fools of us scientists. But if you care about science, you don’t worry about looking a fool, because there is equal merit in having your own ideas (hypotheses) proved wrong as in having them proved right; either way, science advances and we get closer to the truth.
He writes a weekly column for The Daily, called “The Information Society,” which is about how we produce, consume, and abuse information in our so-called knowledge economy. He is a contributor to the Financial Times, for which he has profiled writers such as Tom Wolfe and the late Louis Auchincloss; and he is a regular book reviewer for the Wall Street Journal.
He wrote a weekly column for Forbes – “Medialand” – which covered all aspects of our mediated environment from style to technology, and has been published in Los Angeles Times, Washington Post and other publications on a wide variety of cultural and scientific topics; and he has appeared on NBC Nightly News, NPR and the BBC. He is editor-at-large at STATS.org, a non-partisan, non-profit project affiliated with George Mason University in Virginia that examines the way statistics and science are used in public policy and the media