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Chemical Contaminants and Human Disease: a Summary of Evidence

March 18, 2004
09:00 am US Eastern Time

Call Transcripts

Moderator: Michael Lerner
We would like to encourage everyone to have the database open for viewing during the call, if at all possible.


1. Introduction: Michael Lerner

I would first like to welcome the new CHE Partners who are on this call. This is a particularly important call. A collaboration of CHE scientists have been working together to create a unique document summarizing the evidence on chemical contaminants and human disease. From solid scientific literature, they pulled together a table of 200 diseases, disorders and conditions in which environmental contaminants are either known or suspected of playing a role. This is something that is attracting a lot of interest. It really serves CHE because it identifies the large number of diseases and conditions where we either know that contaminants play a role or that there is concern that they may, so it's a particularly important call.

 

2. Gina M. Solomon, M.D., M.P.H., Senior Staff Scientist, Natural Resources Defense Council history and co-author of "Chemical Contaminants and Human Disease: a Summary of Evidence"


The history of this database is previous to the first CHE meeting (two years ago). Michael Lerner came up with the idea of creating a spreadsheet in which we would list some of the common diseases that so many of the CHE Partners are working on or facing. The goal was to try to create a list of the environmental contaminants that were related to those diseases. I took a quick stab of doing this for the first CHE meeting. I sat down with two or three occupational and environmental medicine textbooks over a weekend and listed out all the diseases that I could find along with the chemicals and environmental contaminants that were listed as being linked to them. It was pretty quick and dirty, but people seemed to find it useful and there was a call to do something more comprehensive. Since then, it's turned into a two-year project in which we struggled with a lot of scientific and methodological problems that I want to raise as caveats before Sarah gives her presentation.


First of all, the spreadsheet that we produced is by no means comprehensive. There's an enormous amount of scientific literature out there and it's really impossible to go to the primary literature and find everything that's ever been linked to these diseases and even so, to try to list them would take up an enormous amount of space. So there is much that is missing. Since we mostly used review articles and textbooks, certain types of new or cutting edge and emerging issues are not as well reflected in the spreadsheet, as are older more well-established occupational and environmental literature.


Secondly, we were not really able to deal well with the dose. There are certain contaminants that cause diseases at high doses, but at lower doses are not as likely to be associated with those diseases and it was very hard to tease those out from the ones that may be known to cause health affects at lower doses. So, keep in mind the fact that dose is not well reflected in here. Some of these things may be more relevant than others to our day to day exposures. Along those lines, there's also the issue of burden of disease. For example, a chemical that you'll see under lung cancer, called bischloromethylether, is well known to cause lung cancer in humans, but it accounts for a tiny fraction of lung cancer cases only among certain exposed worker populations. Similarly tolulenedisocyanate is listed as known to cause asthma in humans, which is true, but again, most of us aren't exposed to that in a way that it's likely to be a contributor to our asthma. So some of these that are listed are known to cause certain diseases but in only a special subsection of the population, particularly among workers.


There's also the pathway of exposure issue. For example, there are certain chemicals that can cause disease only if they're ingested or inhaled and then others where it's very controversial. An obvious example is asbestos only causes asbestosis if you inhale the asbestos, and not if you get on your skin or if you ingest it. Of course if you ingest it then you're at risk for other disorders such as colon cancer. So, depending on the pathway of exposure there may be different disease contaminant links. Again, it was really difficult, without putting a million footnotes and caveats into the spreadsheet itself which would have made it really bulky. So these are all listed in a section called database limitations which is in the introductory section on the website. Please pay some attention to that, because otherwise there's a risk that you could be misled by just looking through the spreadsheet.


Finally, we had a tough time with the strength of the evidence categories. How do you categorize something as well-known versus suspected or potential? The cutoffs were not always clear cut. So we tried to put things into strong, good or limited evidence categories, but be aware that there's a gray zone in between those. As new science develops chemicals are certainly going to be moving between categories as research comes out.

 

3. Sarah Janssen, M.D., Ph.D., co-author of "Chemical Contaminants and Human Disease: a Summary of Evidence"


There are a total of 182 diseases or health conditions that have been associated with these chemicals. If you open the spreadsheet, in column A are the particular diseases or health conditions. Right now they're organized by organ systems. For example, the first five diseases that are listed are associated with the kidney. The next nine are associated with the cardiovascular system and so on. We've covered all the major organ systems, like respiratory, gastro-intestinal, as well as things like cancer, auto-immune disease, neuro-developmental diseases. I tried to make sure that those categories were associated with each disease, so the next three columns (B-D) are the categories that are associated with the disease. For example if you look at line six, Glomerulonephritis, first that's a renal condition, secondly it's listed as an auto-immune disease, and third, it's associated with pediatric cases.


As Gina explained, we used three major textbooks to form the basis of the spreadsheet. If you look in the lower left-hand corner there are tabs (strength of evidence, references and footnotes). If you click on that tab it will take you to a second sheet, which lists all the references that were used in the sheet. On the very top are three textbooks. Two of them are from occupational and environmental medicine, those were published in the late 1990's. The third is a toxicology textbook that was published in 2001. These texts formed the basis of the spreadsheet. But as we got into it, it became clear that there were certain areas that weren't covered very well in the textbooks. In particular, conditions like neuro-developmental disease, auto-immune disease, reproductive disorders, as well as certain chemical classes like pesticides. These conditions required scientific literature, primarily review articles in the areas where the textbook coverage was weak. So, if you scroll down, you'll see that that blossomed to over 150 additional references. If you click on the strength of evidence spreadsheet and look at column H, that is where these additional references are noted, if a chemical was listed based on one of those references. So, again, using line six, Glomerulonephritis, as an example (in column H), there are references of 23 and 52. Otherwise, the assumption is that the three textbooks were used for all of the other diseases that were listed.


The chemicals are organized by strength of evidence in columns (E-G). The first column (E), contains chemicals that have a strong association with a disease. These are chemicals that have been verified to cause a health condition, either by a large retrospective, or a prospective cohort study. Also listed here are chemicals that are listed as group 1 human carcinogens by the International Agency for Research on Cancer. These chemicals have been determined to have sufficient evidence for causing cancer in humans. The next column (F) is the good evidence column. This category is for associations of chemicals and diseases that come from smaller epidemiological studies, like cross-sectional, case series or case control studies. This is also used for some chemicals that have human evidence for disease, along with strong corroborating animal evidence of an association. It also includes the IARC grouped 2A chemicals.Tthese have limited evidence for causing cancer in humans and sufficient evidence in experimental animals. The last column (G) is for limited or conflicting evidence. In many cases this would be the most prevalent category for some chemicals. These are chemicals that have only weakly been associated with causing disease, usually by reports from a few exposed individuals (case reports), or from a number of studies that were done in humans that gave conflicting or mixed results, or from reports that demonstrated toxicity in animals and human studies haven't been conducted at this time. We didn't do a comprehensive review of animal studies, but they did end up on the spreadsheet if they were included in textbooks or if they were in any of the review articles. Also in this category are the IARC grouped 2B chemicals and the EPA grouped B2 chemicals. These chemicals show limited or inadequate evidence of causing cancer in humans and limited evidence in animal studies. Most of the chemicals that ended up in this column came from the references that were published in the last five years since the textbooks were updated. And finally the last column (I) is for footnotes, where comments can be added about a particular chemical or an association. For example, if a low-dose exposure has been associated with a chemical or if there's something of unique interest about a chemical like a gene-environment interaction that's been shown to cause a disease.


I'd like to emphasize that this spreadsheet is a work in progress. In particular, there's been a new edition of one of the textbooks published since the spreadsheet was compiled. That's certainly going to affect where some of the chemicals fall in the columns. Additionally, new scientific studies are published all the time that are going to affect where things are. The last column (I) is also going to be updated to reflect some of the information about exposures and the caveats that Gina mentioned.

 

4. Ted Schettler, M.D., M.P.H., Science Director, Science and Environmental Health Network and co-author of "Chemical Contaminants and Human Disease: a Summary of Evidence"


I'd like to start by running through a few of the diseases on the spreadsheet and point out some patterns that occurred to me and see if there's a story that emerges from some of them. Some of these are just ideas that would be worthy of discussion at another time.


If you scroll down to rows 51 and 52, asthma, you'll see that this is somewhat of an exception, because you see quite a few contaminants or chemicals in column E, which is the strong evidence category. That is rather exceptional when you compare it to some of the other diseases. I would like to note that some of these come from occupational exposures where the link was made in work groups that could be more easily studied and where exposures could be assessed and where sometimes the people were severely exposed and the outcome was fairly obvious.


If you scroll down to row 98 (bladder cancer), which stuck out to me because it's one of the few cancers that has also a number of contaminants or chemicals in the strong evidence category. Again, many of these are occupational exposures, but you'll notice among them are two more population-wide concerns, both tobacco smoke and disinfection by-products or trihalomethanes, which are the result of chlorinating drinking water.


If you scroll down to line 102 (breast cancer), you'll see quite the opposite pattern. Here we have only three links in the strong evidence category and a long list in the limited or conflicting category. I think there are probably several reasons for this that are interesting to speculate about. One would be that breast cancer is one of the malignancies that has a substantial/heritable component, although it's well less than half the population-wide risk of breast cancer that can be attributed to genetic factors. The twin studies that were done in Sweden suggest that it's probably somewhat less than 25% of the total breast cancer risk that's heritable and it may be as low as 4%. The other point that I wanted to make was that breast cancer and prostate cancer may be malignancies in which an early life exposure is actually quite important. This then creates a methodological problem for studying the link between environmental contaminants and the malignancy, because of the long latent period between the relevant exposure and the outcome of interest. I think that that kind of methodological problem will reflect itself in this chart and will begin to explain some of the patterns that we see.


The other malignancy that I wanted to explain was on row 121 (prostate cancer). Here we didn't have any contaminants in the strong evidence column, although, as Sarah pointed out, some of these are arguable. We do see many more in the limited/conflicting evidence column and I think we could persuasively argue that pesticides ought to be moved up from limited/conflicting to good evidence. Again, this is one where there's increasing evidence that early life exposures may be important and may set the stage for the emergence of the malignancy later in life.


Row 145 (abnormal sperm), again you'll see in the good evidence column, a number of occupational exposures where men who were exposed occupationally to these chemicals, some of which are pesticides, glycol ethers and lead at high levels, really had profound impacts on their sperm counts in some instances. So those links are solid. Then as you move over to the right hand column you'll see some conflicting evidence, which is clearly a result of lower level exposures and the evidence being less persuasive.


Finally, please look at row 172, which is ADD/ADHD or hyperactivity. The only point I want to make here is that although we know about ADHD, it's really a syndrome that consists of a variety of traits which are mixed together in various proportions that include problems with attention and behavior and often mixed learning problems as well. So it's very difficult to study ADHD in an animal, as animals lend themselves better to studying specific traits like hyperactivity and there are validated tests for doing that. So we sort of see a mixture of traits and syndromes listed here and the chemicals that show up in these various columns have been well studied in humans. But the list gets pretty small pretty quickly because most chemicals haven't been studied in humans in terms of what their impact on neurological development might be.


I took a quick look through the entire database and noticed that there were about 15 diseases that had lots of entries in column E compared to the other 2 columns. What stands out for each of these is that they're generally diseases where the exposure and the outcome happens fairly close to one another in time and the outcome is obvious when it occurs and it's acute in many cases. I think what this tells us is that these are easier to study. The challenge of course is going to be identifying those conditions that are associated with environmental exposures where there's either a long latent period between the exposure and the disease, or where the increased risk from the disease is relatively low. Meaning in the range of 1 1/2 to 3 fold increased risk as opposed to something where there might be a 10 or 15 fold increase. Those are going to be the ones that will be difficult to tease out where the relative risk is smaller than the big hitters like cigarette smoking and lung cancer for example.

 

5. Questions and Answers


Toni M. Temple, President, Ohio Network for the Chemically Injured:
I'm disabled with multiple chemical sensitivity but the other three people and one animal, all had different symptoms. I think we need to start taking a look at genetics as well as exposure because different people react based on their genetics as well as prior exposures they've been in.


Anthony J. DeLucia, Ph.D., Volunteer, Kingsport Tomorrow:
I really find this very helpful. I'm wondering when we can update it with things like fine particles and their role with a number of different problems that we have. Fine particles is being discussed right now at the national policy level. This is critical and we could really use the help in an area like this.


Ted Schettler: Fine particles are in a number of places right now. But if anybody has suggestions like this please do send them to me Contact.


Raymond R. Neutra, M.D., Dr.P.H., Chief, Div. of Environmental & Occupational Disease Control, California DHS, EHIB:
Congratulations, this is incredible. I have two comments. First, because I'm an EMF man, I think you're a little more conservative on some of these, particularly on the neurological side. I would say there's some limited evidence with regard to Lou Gehrigs and Alzheimers. Second, I've been trying to think about the issue of dose, particularly with regard to estrogen mimics where we think that the traditional dose response way of thinking may not be appropriate. Are there certain classes of agents where the old Paracelsus dogma about "the dose makes the poison" and other classes where they don’t, or do we just not know?


Gina Solomon: We certainly struggled with that. We have numerous contaminants where we know what they do at high doses and have absolutely no idea at low doses. And we also have diseases which are at least generally thought to be dose related. So, something like irritant bronchitis requires a sufficient dose of an irritant to trigger the symptoms in someone. So there are some cases where a certain dose is implicit, others where we only have high dose data, a few where we have low dose data and we were unable to come up with a way to flag those as being different or unique. You've just pointed out a very important issue, in that we haven't found a way to sort out the dose issues in environmental health very well yet. We often have to just gloss over a lot of that in this table even though it's a very important area of scientific research.


Raymond R. Neutra: There are classes of agents where, aside from what data we have, we suspect that exquisitely small doses are important and maybe higher doses don't necessarily have more of an effect. I'm thinking of some of the estrogen mimic things as an example of that. Have we gotten to the point where we think that kind of dose response pertains to certain classes of agents but not to others?


Ted Schettler: I think that we can't say that it's a feature of certain classes and not others. I think this is an emerging area of toxicology where we're seeing effects at lower doses that may not be the same as the effects at higher doses. I think what's going on in some dose response curves is that we're seeing a mixture of mechanisms that are getting glommed together. I think this is an emerging area of toxicology where it would be too early to say it's true of some classes and not others.


Participant: Are you going to take a position on hormesis?


Michael Lerner: Yes, we are planning on having a partnership call on hormesis. Ted, can you explain hormesis?


Ted Schettler: The word hormesis was actually coined back in the 19th century where it got mixed together with homeopathy, in sort of a social science phenomenon. The notion in homeopathy describes the use of exquisitely small doses of a chemical or an herb, for a possible salutary effect. Because of the social context of the discussion, hormesis has largely been lost to toxicology for a long time, but has recently come into the public eye once again. The term is currently used, as opposed to the way it was used initially, to suggest an effect at a low dose that is different from an effect at a high dose. Many people use it to say that it's a beneficial effect at a low dose, but it need not be that, it's simply a different effect at a low dose, compared to a high dose.


Michael Lerner: This is an area where the chemical industry is very interested in promoting the idea that low doses of these chemicals may be good for our health. At the same time there may be real evidence that there may be some truth to it, although it may be misused by industry. It's certainly an area where CHE wants to put the science before the Partners and it will be the subject of an upcoming call.


Mike Green, Executive Director, Center for Environmental Health:
This is such a great tool. I can see it helping all of us a lot. Is there a way to search this by chemical as well as by disease?


Sarah Janssen: There's not an easy way to search by chemical. You can do a find under the edit menu and enter the name of the chemical and it'll pull them out one at a time for you. But there's currently no easy way to sort by a particular name of a chemical in all three columns and have it pull it up.


Nicole Rogers, M.P.H., R.P.C.V., Special Projects Coordinator, San Antonio Metropolitan Health District, Environmental Health and Wellness Center:
How will we know if the database has been updated? Will you be sending out notices?


Sarah Janssen: When I make updates I will send them to CHE to be posted and we'll also have a date on the website so people will know when the last edition was posted.


Phil Shabecoff: This is a really remarkable document and extremely helpful to journalists such as myself. I wondered if I could have permission to share it with the members of the Society of Environmental Journalists?


Michael Lerner: Absolutely. It's up on the website and it's available for any responsible use. I am delighted that a journalist of your quality finds it useful.


Participant: Along those same lines, do you think this would be equally beneficial for the lay person to know that this exists?


Michael Lerner: We welcome CHE Partners using their discretion to tell people about this. The whole purpose of CHE is to get good science out for the scientific community and the public.


Suellen Lowry, Director, California Interfaith Partnership for Children’s Health and the Environment:
The interfaith partnership I work for works really hard to get this kind of information out. What is the best way for us to look at this wonderful tool and to couple it with how these chemicals are actually delivered? What products are they in? How do we put those together, so when we're standing up in front of an adult education hour at a synagogue or church, we can translate for people?


Ted Schettler: You just have to go to other sources. There are sources that will talk about products and what are in them. But I don't know if a database exists for specific products and the chemicals that are in them.


Toni Temple: The ATSDR has information on disc that are available. They have lists of hundreds of chemicals and how we are exposed to them.


Michael Lerner: The Environmental Working Group's Body Burden website, which was the study of a dozen mostly CHE Partners, looking at the body burdens we carry of over a hundred chemicals, for the most part. I believe that website does tell you the products that contain the chemicals that we were tested for. For a short public version that's a great place to go, because it shows you what's in people just like us.


Tracey Woodruff, Ph.D., MPH, Public Health and Environmental Policy Team, National Center for Environmental Economics, US Environmental Protection Agency:
What are your plans for specific areas that you're going to be updating or looking at in terms of your methodology? I also had a comment related to how you divided up your strong and good evidence. Might you reconsider how you look at animal evidence? I noticed that some of the things in the limited category are based on animal evidence, for example, butadiene and ovarian atrophy. At the EPA that might be in the good category because it has a strong animal basis. It doesn't necessarily need confirmatory, epidemiologic evidence. It seems like from a public health perspective that could be very useful, because it's better if we have animal testing rather than waiting for the epidemiologic evidence to move something up in the category of where we think it is in terms of how it's related to health effects.


Gina Solomon: That was a really tough one for us because since we weren't systematically reviewing the animal literature and weren't using, for example, EPA documents, we didn't feel like we had a very good basis for evaluating the strength of the evidence among the animal studies. So, it was only when something made its way up to the review article level or the text book level, based on animal data to even hit the threshold to get onto our spreadsheet.


Tracey Woodruff: I was wondering if you could think of some other way that's sort of like a review-level-like system that's comparable to what you did? Like maybe putting everything that, for example where they picked the critical effects for the RFD, those could all go in the good category?


Michael Lerner: Tracey, would you be willing to help us think about that? It's a very important point, and if it's good enough for the EPA to be in the good category, in principle, it should be good enough for us.


Tracey Woodruff: I do worry that chemicals will be downgraded. I'd be happy to help you think about that.


Phil Lee, M.D., Professor Emeritus of Social Medicine, UCSF, Institute for Health Policy Studies, Stanford University:
One point has to do with tobacco. In some cases we refer to environmental tobacco smoke, as in Sudden Infant Death Syndrome. In other cases we say tobacco smoke and in still others we say tobacco, as in oral cancer. I think we could be more specific. For example, oral cancer needs to be either chewing tobacco or smoking tobacco, not just tobacco.

My other comment has to do with making the spreadsheet even more useful. That is to have a shorter list of those where the strong evidence is really dominant, and that suggests action. Then others where the evidence is limited or conflicting, which suggests we need more research. I wonder if we could look at additional ways that we might format this material.


Michael Lerner: That's an excellent point Phil. In fact we have had a variant of this. I think it was 20 leading diseases of concern.


Ted Schettler: We took 25 diseases of concern and evidence was mixed. Our plan was to look for different software that would allow us to reorganize it in a variety of ways. One of the ways would be what Phil has suggested, by strength of evidence. That would be very useful.


Phil Lee: Then we could get the Partners with concerns about those different diseases together to move forward.


Michael Lerner: If we were just looking at this for a combination of public health concern and strong or close to strong evidence, what stands out as the leading diseases in that combined category?


Ted Schettler: The ones that stand out in strong evidence are: liver injury, heart disease, contact dermatitis, etc. That list is not the same as the ones that were of major concern to people. There is some overlap. Those of major concern are breast and prostate cancer, for example. So there are a variety of ways to sort this and think about it depending on what your purpose is.


Michael Lerner: Autism and learning and developmental disabilities would be another example. I think you've raised a very good point Phil. We want to be able to get at the strong category, calling for action. But we also want to be able to get at the diseases of deep public and popular concern, where the current evidence may not be strong, but there is a strong patient and scientific constituency concerned about the issue.


Gina Solomon: We might want to even think beyond the strong category when we think about candidates for action. Some of the chemicals in the strong category either don't affect a lot of people or affect almost no one, or may already have extensive regulatory limitations on them. Some of the chemicals in the other categories actually have very widespread exposures. So from a more precautionary approach, we may even want to think about those more seriously.


Michael Lerner: So perhaps this could be a homework assignment for the CHE Science Committee. To take Phil Lee's guidance on this and think about the different ways that we can, not only re-sort the spreadsheet, but look closely through the three different lenses we've been discussing: strength of exposure, breadth of exposure and public concern.


Phil Lee: Can I also suggest that the committee meet with a group of journalists to discuss those lists. The journalists may give a different insight into what's important from a public standpoint.


Michael Lerner: Maybe Phil Shabecoff can help us think about others who might share your interest in this.


Sandra Miller Ross, Ph.D., Health and Habitat:
I hope that we're also looking at the Multiple Chemical Sensitivity's environmental illness aspect of this in that. Before it gets to cancer, we often have these other early warnings.


Michael Lerner: Yes, MCS is definitely a subject of concern and will be the subject of a later partnership call.


Devra Lee Davis, Ph.D., M.P.H., Visiting Professor, H. John Heinz III School of Public Policy and Management, Carnegie Mellon University:
This is a remarkable achievement and my compliments to all of you for doing it. It's a great piece of work and it will be very important for all of us. I want to follow up on what Tracey Woodruff said. I think she's making a very important point with respect to the animal studies and I recognize the limits with what Gina has explained in terms of what the review was so far. So I really want to encourage you to follow up with what Tracey suggested.

The second thing is that the suggestion that was made about ATSDR being a source for information. Unfortunately ATSDR has been subject to some political pressure recently. So, for example, under mercury the ATSDR does not list a lot of low-dose effects on children right now. So we want to be aware that these government sources are not always the best on this sort of information.

Finally, with respect to the breast and prostate cancer, I would respectfully point out that the Veteran's administration lists prostate cancer as a confirmed human carcinogen caused by agent orange and compensates people for that. So I don't know what criteria were used there, and I think it's something to consider. The same with respect to breast cancer and I'd be happy to talk with you off-line.


Richard Denison, Ph.D., Senior Scientist, Environmental Defense Fund:
I wanted to make a comment on an earlier point in terms of sources for linking chemicals with products. The national library of medicine, under NIH, has developed a household product's database that is on line now. It uses MSDS's at least, to try to do that with about 4,000 products.

I also have a question for Gina, who had mentioned the limitations with respect to exposure pathway. I'm wondering if you could elaborate a bit about what the difficulty is there. Is it more a matter of the presentation and the complication, or is it actually discerning exposure routes for the information that's in the table?


Gina Solomon: It was a question in the presentation. When we were trying to decide how to put these up we were wondering if we should specify that, for example under chronic beryllium disease, whether we wanted to specify inhaled as the relevant exposure pathway. We realized that we would be putting ourselves, potentially on a pathway to trouble. If we looked at hexavalent chromium for example, we would have to make a judgment call about whether the data supported that it causes cancer by non-inhalation pathways which is highly controversial right now and is something where we didn't really feel like we wanted to make an opinion on the science. So we decided to just leave out any details about whether it was an inhalation pathway or an oral pathway. So its just information that's missing that folks would have to find elsewhere. When you see things in that table you might have to look beyond it in order to get the whole story.


Richard Clapp, Professor, Department. of Environmental Health, Boston University, School of Public Health:
I see this as a teaching tool. I'm about to give a lecture to first year medical students. This is their only chance to learn about environmental health and I want to use this next week. I'll give you some feedback about how it works.


Michael Lerner: Thank you, that would be wonderful. I have one last comment, if you find this call and if you find CHE useful, this month is CHE's "Tell a Friend about CHE" month. We're doing an experiment, which we described in the newsletter, just asking CHE Partners to let somebody else who might be interested in CHE know about it. We want to see whether this word of mouth networking extends the partnership to the level of quality Partners that we have in a helpful way. So if you have a friend or colleague who would like to be part of these discussions, please let them know and encourage them to join CHE. Let's see what happens this month, and we'll report back to you in the next newsletter.

I'd like to really thank Sarah Janssen, Gina Solomon and Ted Schettler for the extraordinary work in putting this together. You can hear the enthusiasm with which this is being received and we look forward to continuing to develop it. So thanks to the three of you very much.


Jeanette Meyers: Please mark your calendars, the next call will be on April 20 at 9:00am PT/12:00 noon ET. The topic will be Parkinson's. The May call will be May 11 at 9:00am PT/12:00 noon ET.