Thank you, Dr. Mori.

It is an honor to be with this group again. This is my 4th year at the International Scientific Symposium on Endocrine Disruption in Japan. I am very pleased to see how much progress we are seeing made with every year, with every addition of new scientific results.

What I would like to do in my allotted time is to ask you to rise above the very tight focus we have had on specific details, to, instead of looking at the trees, look at the forest of the issues that we have been discussing. What I would argue is that as you think about endocrine disruption and children’s health, we are in scientific heaven but regulatory hell.

What do I mean by that?

We are living midstream in a scientific revolution that is radically changing our understanding of the links between contamination and health. The papers presented at this meeting are carrying us forward in that revolution; just in the last presentation we learned new things about hypospadias and Bisphenol A. It is truly astounding.

If you go to an academic library today, and carry out a search in one of the computer databases on how many publications have there been within the last year on one substance, on Bisphenol A, for example, it is quite remarkable from how many different laboratories, on how many different endpoints, how many different methods people are now using around the world to look at these links between contamination and health.

You will find publications on aggression and behavior, findings from Japan on concentrations in human biological fluids, and some really remarkable results looking at the interference of Bisphenol A with the standard treatment for prostate cancer.

Another fascinating study from Ehime University examines possible involvement of Bisphenol A in increasing the conversion rate of pre-adipocytes to adipocytes, raising the possibility that Bisphenol A is involved in the epidemic of obesity that the world is now experiencing.

New results like these are being published virtually every week, making it difficult even for specialists to keep up with this torrent of science. It is truly extraordinary to see what is happening.

But it leads us to regulatory hell. I can imagine the regulators who are trying to keep track of just this one compound, Bisphenol A. It must be like the Dutch boy and the dam, where there is one leak in the dam over here, and there is another leak over here, a 3rd one over here, a 5th one over here, but all of the sudden in a completely unexpected direction the dam breaks because we have completely new results coming from a completely unexpected direction.

We have heard a lot today and over the last couple of days about some deep issues related to this regulatory hell. One of them was an issue that Fred vom Saal touched on earlier, which is the inadvertent contamination of experiments through endocrine disruptors in food that is not yet understood or endocrine disruptors in some of the lab equipment that are giving us false controls and leading us to a literature that is probably now polluted with many false negatives.

More deeply, we are also seeing data from multiple studies of endocrine disrupting compounds that are repeatedly falsifying the operating assumptions at the heart of risk assessment process as it is currently practiced. I am going to summarize what some of those core operating assumptions are for you.

First, the dose makes the poison. The simplistic application of this assumption is now clearly falsified by a whole host of data showing low dose effects with non-monotonic dose response curves. In fact, at the Yokohama conference we had a panel of scientists including industry spokesperson Dr. Jim Lamb agree that this is no longer a valid assumption. So that is out.

We have seen some elegant work looking at thresholds of effects. Dr. Daniel Sheehan, David Crews, and others have shown that for systems in which hormonal systems are already activated, there is no practical threshold for effect in that system. So that one is out.

We heard an elegant paper by Andreas Kortenkamp this morning rejecting the notion that you can derive useful regulatory guidelines by basing your work only on single chemicals at a time. This is just no longer adequate in this modern era. So that is out.

We also have an assumption, increasingly prevalent, that you have to demonstrate adverse effects in order to start regulating. But when you look at what we really understand between changes in biological systems and the ultimate developmental processes, you can see that we would be incredibly arrogant to assume that we can predict adverse effects based on our current understanding of what those changes actually mean. So that is out.

Finally, if you listened to Dr. Elizabeth Guillette earlier this afternoon you heard an absolutely spectacular discussion demonstrating that the animal studies that prevail throughout regulatory science, as important as they are, are probably not sufficiently sensitive to get to the endpoints that parents really care about.

There has been some work trying to employ operant conditioning techniques and behavioral studies with animals to get at more sublte behavioural effects, but they do not play a very large role in the regulatory process and they do not get us to the sorts of endpoints that Dr. Guillette was talking about in her work.

So we have got to be looking for other sources of guidance. Is epidemiology a good source? Epidemiology has some real problems in dealing with endocrine disrupting compounds, also.

First, nonmonotonic dose response curves are deeply challenging to human epidemiology as it is currently practiced. So is the fact that as development unfolds in the womb, the same compound at different times in development can lead to completely different disruptive patterns. How does epidemiology currently cope with that? Not at all, at least in in utero studies.

The converse is also true: disruption of the same developmental process in that same developmental window by different compounds can lead to the same effect, dramatically increasing the statistical noise in epidemiological work, unless at the same time you are able to monitor all the relevant compounds that might be interfering with that developmental process.

Finally, as Dr. Mori mentioned, long latencies can intercede between cause and effect, decades sometimes between exposure and impact.

So what is the regulatory answer here? First of all, we have to acknowledge that the current process is fatally flawed by its dependence upon falsified assumptions and polluted literature. We have got to start over.

We have got to build a new science-based approach, not one that is based on false assumptions, but is based on real data, that begins with models that are incorporating some of the factors that I mentioned: incorporating the low-dose non-monotonic response curves, incorporating the fact that there can be no threshold, incorporating a focus on mixtures at the core, and demonstration that if we find an effect in regulatory research, we find an effect in a developing organism, we should then reverse the burden of proof so it is not incumbent upon us to demonstrate an adverse effect, it is instead incumbent upon those who would wish to use the product to demonstrate that an effect is not adverse. This will require a compete reversal of the burden of proof.