 In the interest of time, I think we'll go to the final speaker, Dr. Peters. Is it on now? There you go. Okay. So I took a little bit of a different tact from my presentation to my predecessors, and I guess I was given the task of putting the rest of you guys to sleep since you've now eaten. So I should be able to do a pretty good job of that. But what I did was I actually just took the questions that you asked me and I answered them. So I'm going to go through a series of slides. I thought I'd just go that route rather than I saw Pauls and Shaunas and Earls and I was, jeez, where are their questions? You answered them indirectly, so I'm going to just go straight through this thing. Here's a real simple slide right here. What's that? Yeah. Well, I guess I'm one of these people that like to, I'm very, I like to have things just this way, and so it's good scientists. You would know this right, Andreas. So the first question was, was there any new evidence that since the publication of the Clonic Review that would suggest that PPR alpha agonists or proxumpliferation will lead to carcinogenesis in humans and my answer to that is there's really nothing compelling that goes down that road. And correct me if someone thinks that I'm wrong, I'd be glad to discuss that with them in greater detail. The second question was, what is there any new evidence since that publication to support the conclusion that PPR alpha agonists are not likely to pose a cancerous to humans? The findings from Frank's lab with the humanized mouse lines and the mechanism that they propose is probably something that might be a reference of relevance to this question. So I'll elaborate on this a little bit more later. On the third question posed to me and now I'm going to get into a little more detail on these slides. And so what I did here was I kind of, you guys, I'm not sure who put these together, but they were multiple, these questions had lots of questions within them. So I tried to just underline the question that I'm answering in this one here. It relates to the ETO paper in 2007 that the National Academy of Science panel addressed as well. And that was that the DEHP caused liver tumors in PPR alpha nome mice. And the question was whether or not these authors suggest that PPR alpha independent mode of action and how do these findings affect the conclusion from the Klonig review that PPR alpha agonists are not likely to pose a cancerous to humans. And so my interpretation of the ETO paper, or the answer to this question is, it raises questions that's for certain. And it definitely raises questions about whether or not this is an independent mode of action for DEHP. I think there's limitations to the paper, and I'm not going to go into a little bit to too much detail there, but I'm a little bit concerned about the lack of dose response and that there's no consistent dose-dependent changes in liver tumors in particular in the wild-type mice. And I bring that to your attention because they really only found those effects primarily in the nome mice. And we've had this discussion a little bit, and I'm going to elaborate a little bit more on this right now. And that is that the phenotype of the PPR alpha nome mouse may not be relevant to humans in the sense that there are no known polymorphisms in PPR alpha that make a protein or code for a protein that has no activity, but there are no polymorphism PPR alpha that lead to an enhanced activity of a receptor. And the functional significance of that polymorphism in terms of what it does and why people might that have that might be different than others that don't is uncertain. Some papers report different activities associated with, but it's never been a clearly determined. And what that has to do with cancer risk has never been examined as well. But for sure, there's no example of a PPR alpha protein that has no activity. So the knockout mouse model really lacks expression of this protein. And it serves a function, a very important functional role in mice as well as in humans. So the phenotype that they found in that DHP model, I'm trying to get to the point here, is that the knockout mice develop liver tumors with age. That's known, Chris Corten reported that a number of years ago and a couple of other groups have it as well. It's likely the fact that there is lipid accumulation in the liver. And we know that a paddock lipid accumulation is known to be negatively associated with liver cancer. It's a causal risk factor for liver cancer, independent. So that's something that happens as well. And there's also known to be enhanced inflammation due to the fact that PPR alpha has epigenic activities that interacts with NFKappa B, for example, and it prevents inflammation from progressing. And so coupled with this increased lipid accumulation and the enhanced inflammatory anti-inflammatory activity, I should say increased inflammation, the trend for more liver tumors in the null mouse model could reflect an entirely different mode of action. And it may not be relevant to humans in the sense that we all have PPR alpha, and it does what it's supposed to do because we just ate. You gotta burn fat when you eat. So I shouldn't say right now, actually, you're gonna be using your PPR alpha in about three hours from now when you're starving, and you need to mobilize fat and burn it for energy. So we all have it for a reason. In that sense, this model may not be relevant. This is not found when PPR alpha is present. So in the wild type mouse model in the DEHP study from Ito, there was really no consistent increases in liver tumors found in those mice. So I draw the question, I mean, you could interpret those findings, it was never been interpreted that PPR alpha could actually protect against liver cancer in this situation. So it's kind of a, you have to think about what they're talking about there, whether or not this is independent mode of action for DEHP. So it remains possible, though, we're getting to another question, that there is more than one MOA for DEHP, including the PPR alpha mode of action, which I'll talk about in just a little bit. But keep in mind that if that were true, I would argue that it's perhaps, well, it's probably linked to the fact that there is no PPR alpha expressed in those no mice, and therefore the MOA in that particular model may be entirely different. And you guys can wrestle with that when you go to interpret your findings there. Second part of this question was, is it plausible that some PPR alpha agonists may induce tumor genesis by PPR alpha independent mode of action as proposed by Chris Corten's group, I believe this paper was? And the answer to that one is yes, it's definitely plausible. But it doesn't rule out the possibility that the established PPR alpha mode of action can also be a central mode of action for any given chemical. So, and I put up there that it's difficult to reconcile how a PPR alpha knockout mouse does not develop liver tumors in response to long-term exposure to PPR alpha agonists without accepting the notion that PPR alpha is required to meet the hepatic carcinogenic effect of these chemicals. I mean, it's impossible to reconcile that. I mean, PPR alpha is clearly required, some seminal work by some pretty famous guy back in the decades ago, or centuries ago, sorry, did some studies that showed that. And I think that it's something to keep in mind. So, can there be an independent mode of action? I think there can be for some of these chemicals. And DEHP may or may not fall into that category, and it may have something to do with the fact, getting back to the ETO paper, that you have no PPR alpha present, in which case then some other mode of action might kick in. Now, one of the things that Chris has postulated that is that whether or not, a car is involved. And that's, I mean, Kurt Almichinsky is actually the first to show that ethylate could actually activate cars. It's actually, it's one of the car variants. It's a molecular pharmacology paper. It came out a couple of things about a year or two ago. And so there's been some speculation that DEHP may be functioning through car. And I thought I'd show this slide up here that yeah, car is involved in hyperplasia. It's known to be required to mediate the, some of these carcinogenic effects of some compounds like phenobarb and TC-bobot. But what this slide shows is that, in the knockout mice, you don't, I think this thing, oh, here we go. In the knockout mice here, you don't get hyperplasia in response to these car agonists where you do in the wild type mice, but I also draw your attention to the fact that it's also well known that car activity is also known to exhibit species differences. So you can have great differences in the response. So for example, TC-bobot, where you get enhanced activity here for the mouse car analog, you don't get so much activity for the human. Phenobarb is kind of about the same. And interestingly here you actually see the exact opposite of that. So you need to keep that in mind as well, that if you're gonna think and wrestle with the idea that cars involve with DEHP type activities, you also have to figure that there could be some species differences there as well. Okay, question 4A was, and you talked about the humanized mouse model, and you actually asked about the yang paper. That's actually, I wanted to clarify something from this long question that you asked, was the yang paper was actually the second of, it was the third paper of three papers that have come out. The first two are actually much earlier than that, and that was the 2004 paper in the 2006. The 2004 was the initial characterization of the humanized mouse model that was for the liver-specific expression of the human receptor. And then the Morimora paper in Carson Genesis in 2006, that was the liver-specific, that's the liver cancer paper. That's the only one that's been done with liver cancer. The yang paper really dealt more with hyperplasia instead of things like that. It did nothing to do with the liver cancer. So I believe you were talking about the former paper here in the middle of the Morimora paper when you asked these questions. So, and they're kind of all related. So what your question was is that, since you get, you get, what you end up getting is you end up getting lipid catabolism being regulated inside what we call the humanized mouse model, but you don't get changes in self-proliferation occurring. And what does that mean? And so that's what those two studies, or that's what those studies could be. So, the question here was, how do these studies support the conclusion of Clonig that P-perialpha agonists are not likely to pose a cancer risk to humans? So probably the most important thing to take home from those studies is that they demonstrate that the human P-perialpha in a mouse model modulates lipid catabolism. That is the basis for the ongoing therapeutic use of fibrates, which had been used for many, many years. That demonstrates functionality of this receptor in vivo model. And so I think that you can take home that that receptor is functioning very quite similarly to what you would see in a human and the fact that you get regulation of lipid catabolism, you get changes in lipids that are beneficial in humans, and you see the same thing in a mouse model. Demonstrating that the activity in the human P-perialpha in a mouse that does not cause liver cancer after chronic treatment with one P-perialpha agonist, which is known to cause liver cancers to these P-perialpha dependent mechanisms, that's actually a fairly important observation. And so the most likely explanation for this is differences in activity that could be differences in molecular targets, as well as differences in transcriptional cofactor recruitment. So the mechanism that was worked out for the species difference that Yatrik Shah did when he was at the NIH, we'll show him by this slide here. So you all know that we don't really know how you get mutations in DNA in response to prox-impliferators. They're non-genotoxic carcinogens, and this has been a big gray area for a number of years, but we do know that there has to be some mutation or some mutational event that occurs that leads to cancer. So what Yatrik found was that using this humanized mouse model, actually the first thing he did is he actually discovered that these let's seven C microRNA cluster here, which in turn regulates proteins like the myc oncogene. When this is down-regulated in response to activation of this receptor, P-pair alpha, you get down-regulation of this let's seven C microRNA, which leads to an up-regulation of C-mick expression, which drives expression of the cell cycle. And through that mechanism, you get increases in tumors. And so that's the postulated mechanism. So in mouse model, mouse P-pair alpha regulates lipid catabolism as well as cell proliferation. And this was a fairly convincing argument this is what's causing it. We knew that cell cycle was progressing in mouse models for years. We knew that proteins like cyclins and CDKs were all up regularly. We could not figure out for the life of us what, we knew that they weren't direct P-pair alpha. Target genes, we went down all these things looking, we could never figure out what was driving it. And it turns out it was a microRNA or a microRNA cluster that was actually regulating expression of these oncogenes. And that's what was driving progression. So that paper, this was a secondary paper to the humanized study. This also used humanized mice here as well. Kind of set up the framework for what the working hypothesis is to explain the differences between humans. Because if you look at this mechanism in the humanized mouse model, they found that you do not get this change in let7c microRNAs and you do not get the liver tumors. And so this is putatively the mechanism for the species difference between mice and humans or between rodents and humans. Now I would argue though that you still need to check this out in other human models. But this is clearly where people are moving in this direction trying to validate that this is what's going on in other human models. And once that's done, I think that you can establish fairly conclusively that this is what potentially could explain why humans appear to be refractory. I mean, fibrates have been used for many, many, many years and they're just, if they were causing liver cancer, by now you'd think 40, 50 years later that people would be taking these things at the market and that's really not the case. So there's a pretty strong case that there is a species difference, at least for fibrates. So can these studies be interpreted as evidence for PPR-alpha-independent cancer modes of action in humans, as suggested by the Guyton review in 2009? So the arguments presented by Guyton suggest that the Moray-Murray study was limited because the number of mice were only exposed for 38 weeks, there was mortality in the wild type mice, there was a small number of animal study and the human PPR-alpha may not function the same in the mouse due to differences in transcriptional cofactor recruitment. You gotta, these are legitimate potential arguments of why there's differences between them. But you gotta get down to the bottom line and that is how does one explain the lack of tumors in humanized mice expressing, that responds to ligand activation by regulating lipid catabolism. So you recognize that you are getting one functional role of this receptor to occur in these animals. So these are reasonable criticisms one can point out, but you still have to kinda come to grips with why these mice don't get liver tumors and that receptor does appear to function. So the humanized mice don't really comprise compelling evidence of a PPR-alpha-independent mode of action in humans, but more importantly, their argument for the PPR-alpha-independent mode of action was really based on two papers and one of them was the Ito paper, which we just described, so I'm not gonna go into details on that one, but more importantly it was this paper from Qin Yang in Frank's lab and that was published in 2007. And what they did there is they showed that there was a lack of change in hepatic cell proliferation despite increased expression of lipid catabolizing enzymes in a transgenic mouse that expressed a VP16 PPR-alpha fusion protein. So the conclusion that Guyton drew from that was that PPR-alpha activation by this fusion protein is not sufficient to induce hepatic carcinogenesis, so these data therefore are inconsistent with the hypothesis that the effects mediated through PPR-alpha activation constitute a complete MOA for carcinogenesis. There's a major problem with this interpretation and I'll point that out in the next slide. So PPRs are ligand-activated transcription factors that respond to ligands by undergoing conformational changes in the protein structure. They dissociate from co-opressors, they recruit co-activators, scaffolding proteins, RNA polymerase, and they sit down on target genes and they increase expression of target genes. So these interactions with other proteins and the folding of the protein itself are major factors dictating how these PPRs are going to function. So for example, the ligand has a major role in modulation of receptor function. I put up here Triglitazone or Resilin as many of you remember which caused liver failure and it killed a number of people. That was the first glidazone, the PPR-gamma agonist on the market versus PO-glidazone which is Actos, the good one that you've been reading about in the newspaper not Rosie which you've been hearing so much bad stuff about. And so here you see an example of two ligands that elicit significantly different biological responses but and part of the reason they think is that because there are differences in the recruitment of different co-activators. So you have to think about ligands interacting with the receptor. These are the kinds of things that are going on. So the argument that was put forth by Guyton was the fact that those mice don't get increases in cell proliferation, the VP16 fusion protein mice tells you that this receptor is not causing increases in cell proliferation. There's something wrong with that MOA. There's a major problem with that and here on the next two slides I can illustrate this pretty nicely for you I think. So the fusion protein does not equal and dodges PPR-alpha. So this was the protein that Frank's lab made. They took a viral VP16 trans-activation domain. Forget about that response element up there. It doesn't really matter. I mean it's there, but what's more important is they fused it to the PPR-alpha CDNA. Well this trans-activation domain of the VP16 is entirely different with the way it works. And so I'm not gonna get into this description here what they do, but basically there are a number of proteins that interact with it. The VP16 trans-activation domain relies on to activate transcription. It's totally different than what you see in response to a ligand interacting with a receptor. That protein's totally different. You don't have the conformational changes. There's some things that go on there. So the lack of change in cell proliferation in the VP16 fusion PPR-alpha transgenic mice could simply reflect differences in the ability of this protein to modulate targets that can regulate cell proliferation. It made us not be able to target the Let's 7C microRNAs. That could be a key step. But more importantly, this is a classic example we use in one of the classes we teach of a Penn State. It's a good example for biochemists to understand that you cannot take a protein and draw these two conclusions. You're comparing apples and oranges. The viral VP16 trans-activation domain was used to make a fusion protein with the MyOD transcription factor. The MyOD transcription factor is a muscle transcription factor that modulates differentiation. It has a trans-activation domain similar to PPR. It's not the same one, but it basically functions the same way. What this group did is they actually took the VP16 trans-activation domain, fused it to MyOD, kind of the same analogy they did with PPR-alpha. And they took this protein. They said, well, what does it do? So they replaced this. It turns out that that fusion protein, oops, it trans-activates MyOD reporters. It turns on target genes, okay? But it doesn't induce myogenesis. So what it shows you is the fusion protein transcription factor doesn't act like endogenous transcription factor. Here you have another, it's the same exact thing where you have an analogous system set up before with the trans-activation domain and fusion protein where you get modulation of some targets, but when you actually look at the end product, the terminal differentiation of the skeletal target genes, you don't. So you have two different comparisons. So to draw the comparison by saying that the VP16 fusion protein doesn't, in the PPR-alpha mouse, doesn't cause increases in self-liferation, therefore it diminishes the MOA for PPR-alpha. You can't do that. You cannot make that comparison because it's comparing apples and oranges. And until you could work those things out, you can't do that. So that's a problem with that interpretation. So getting back to the question at hand is kind of a long drawn out. Can you take the humanized studies and argue that they demonstrate for a PPR-alpha independent mode of action? My answer to that question is no. They certainly draw some questions about it, but they don't definitively demonstrate that there is no functional MOA. So that argument really doesn't hold water. Question number five was many phthalates are capable of activating both murine and human, PPR-alpha and PPR-gamma. Are PPR-alpha and PPR-gamma required for contributing to the toxic effect of phthalates and rodents, including, and they went down this laundry list. So what I tried to do here was I split it into two different things. And I'm gonna talk about PPR-gamma first. You asked about cancer. I'll tell you it's highly unlikely. There are ongoing chemo preventive and chemo therapeutic studies in humans. These things have been going on for years because we know that targeting PPR-gamma prevents tumor genesis. The efficacy is a little bit dubious, but in fact, there are ongoing clinical trials right now to this day examining this. So whether or not PPR-gamma causes cancer, highly unlikely. Liver toxicity, that's uncertain. It's never really been examined in no mice. There is some evidence that you get increased lipid accumulation with PPR-gamma agonists. But PPR-gamma is actually usually typically very low in the liver. And there's also some evidence of hado-protective effects due to anti-inflammatory activities of PPR-gamma and the agonists themselves. Kidney toxicity, again, uncertain. There's never been examined in no mice. Reproductive and developmental effects. There was some work done down at NIHS. The name's slipping my mind right now, but it was a woman's group that she showed that MEHP and some PPR-gamma agonists could actually inhibit aromatase activity in rat granulosa cells and that an antagonist mitigates this effect. But there's no evidence to date of developmental toxicity due to PPR-gamma agonists in the literature that I'm aware of. So I don't know if that's gonna be a problem. Other health endpoints, I'm gonna address that later on another slide. And then for PPR-alpha, the question's same kind of tumor endpoints. You talked about PPR-alpha with cancer. I think there's a clear role for PPR-alpha in liver cancer, but other mechanisms can't be clearly ruled out for all compounds. But clearly, there is data for that. For pancreatic acinar cell tumors and latex cell tumors, I think there's an unclear role. I'm not gonna get into the details there, but whether or not PPR-alpha is involved that's been kind of all over the place here. Other tumors that's really never been examined, particularly in great detail. For liver toxicity, and here's just another slide. This is a slide I'll use some data from Jerry Ward's paper where he looked at liver toxicity and there's really just hyperplasia or I should say hepatocyte of megalae, where if you look in the wild type mice, you get enlarged hepatocytes and proxumpliferation. You don't get these effects. It's similarly treated PPR-alpha knockout mice. These mice were treated with DEHP. So there is some evidence for DEHP that liver toxicity is mediated through this receptor. Kidney toxicity, it gets a little bit more grainy here. You got yes and no. So this study was done, Jerry hit him with a whopping dose of DEHP and essentially what happened in the study is most of the wild type mice died after, I think it was about somewhere after 16 weeks. They didn't live very long. So in this study, he kept the knockout mice around longer. I'm quite sure why, but he did. And he looked at the tissues, looked at the sympathology. So if you look at kidney toxicity, after four weeks of DEHP feeding, he finds nephropathy, focal tubular degeneration, atrophy. He sees a number of things that are found only in wild type mice, but not in knockout mice. So after short term treatment with DEHP, there's clearly PPR-alpha dependent changes in the kidney. Then as you go on, after eight to 16 weeks, you get these things cystic renal tubules and this effect was diminished in PPR-alpha knockout mice as well. So you still have these early events that are occurring that are clearly a component of PPR-alpha dependent. But then after 24 weeks, you get severe nephropathy in the PPR-alpha knockout mice, but he wasn't able to compare this with the wild type because they had all died. So there's something there going on where you are getting a pathology that's independent of the receptor and this has been seen in other tissues as well. So I'll show you in the next couple of slides. So these are reproductive and developmental effects. Again, getting back to Paul's talk, these doses are really, really high, but if you look inside the mice, after eight weeks of feeding, you basically have no spermatogenesis in most tubules in the wild type mice. And after eight weeks, in only a few tubules where you get normal spermatogenesis is not found in PPR-alpha knockout mice. But if you look way down the road 24 weeks later, you get a distinct pathology here in the tubules inside the knockout mice that was, again, indicative that there are effects of phthalates that are not dependent on this receptor. And that's essentially the title of this paper is that we're talking about independent effects of the receptor. So Jerry was like, and this is a paper again that was done about another century ago when I was a wild postdoc trying, just dreaming up things to look at, and we were trying to look at whether or not the receptor was required for the developmental toxicity of phthalates. And again here, we found that DEHP-induced developmental toxicity was essentially similar in wild type and knockout mice. This was presented at the teratology meeting a number of years ago, and there was really no difference. The thing to take them from this one though is that the dose that we treated them with was somewhere between 500 to, I think it might have been a 1,000 milligrams per kilogram, so it was very, very high. And it was associated with maternal toxicity as well, just as Paul pointed out. But there again, so there was no dependent effect here in terms of PPR-alpha and that phenotype. Okay, so, and then that question, I think I might under question six now, yep, so here's question six, and this was a tough one, so I'm getting more and more vague with the tougher ones because I really didn't know how to quite handle some of these questions here. Whether PPR-alpha or PPR-gamma induce a different, so what are the implications of interspecies differences in PPR function regarding human health risk? I mean, that's a question that, I wish I could just say, oh, this is what it is, but we really can't get to that right now. So, whether PPR-alpha though and PPR-gamma induce a different suite of genes, as you guys suggested, in humans versus rodents, that may be overstated. I mean, you have to think about that too because there's also differences that probably do exist and there are probably differences that exist for different agonists, but there's also very many similarities. For example, the basis for modulating lipid metabolism by fibrates occurs in both species. And similarly, you get modulation of glucose homeostasis, which is the basis of thiozolidine diones, which is the basis of the PPR-gamma agonist. So, there is clearly overlap as well. So, is there overlap? Are they totally diametrically different? It's possible. So, I think you're gonna have to deal with interspecies differences that are due to a number of different things that could have to do with the receptor itself, which may be the case for PPR-alpha liver cancer, distribution of the receptor, cofactors in different tissues, response elements, and then epigenetic differences, which we don't know about, which you don't, I mean, that's a clear thing. And in fact, there is examples of PPR-alpha agonists modulating epigenetic activities. Yvonne Racine, and I'm trying to remember the other guy there at Duke, the epigenetic guy. You must know. Randy Journal, yeah, I mean, classic stuff like that. So, he's shown this as well. So, there's clear examples that these things kind of things might take effect. So, you have to keep this in mind. So, I didn't answer your question very good, but I can tell you that that's something you should think about. Are adverse effects in rodents mediated by PPR-alpha and PPR-gamma relevant to humans? Again, it's gonna be context dependent. You minimally require data sets from either knockout or knockdown experiments, and you need to demonstrate the requirement of the receptor, as well as you need to have strong data sets for comparative purposes. So, I used the example of fib rates because you have a fairly strong weight of evidence that at least some PPR-alpha agonists, the fib rates, that liver cancer is observed at rodents is probably not relevant in humans, okay? Other examples are a little bit less clear, like for pancreatic acid cell tumors, latex cell tumors are not gonna go down that road. PPR-gamma dependent increase in osteoclast activity is found in mice, and that correlates very well with decreased bone mass observed in some humans that are treated with PPR-gamma agonists. So, some toxicity, so that's another example of one where you've got toxicity that does correlate pretty well with humans. Some toxicities are found in humans following exposure to PPR-agonists they're not always seen in rodent models. So congestive heart failure is something that's associated with PPR-gamma agonists. It is not necessarily modeled well in rodent models, so those are examples. So you go all the way across the board where you've got them, yes, no, maybe so, and you can take it from there. Okay, and then you asked me what, what's that? You asked me what's known about the function of PPR-gamma in humans? This was an easy one, because I like to give history lessons. So, Peter Tauntono from Bruce Spiegelman's group was the first one to show what this receptor does. He showed that activating PPR-gamma causes fibroblasts of differentiation to adipocytes. That was the first evidence to demonstrate that PPR-gamma actually promotes terminal differentiation of adipocytes. I mean, I can take you back even further and tell you how they identified that receptor, but it wasn't a stretch for them to go down this road because they clone it from a gene that was involved in adipogenesis. So that's what it does. What they do know is that the regulation of a number of targets in adipose, they think, and I'm not gonna go into the list of these target genes, but when you activate PPR-gamma and you up-regulate expression of these target genes, these changes in gene expression are thought to be the basis for the hypoglycemic effect induced by thiozolidine diones. And so if you delete the receptor in adipose, you diminish this response. So adipose is thought to be one of the primary targets, but again, I can tell you that this is very much a gray area. They know that gamma agonists work to reduce serum glucose levels, but really the specific mechanisms in which tissues it's working on, because skeletal muscles probably gonna be something else where it functions, they really don't know the answer to that, but they do know what it does. There are, as I mentioned earlier, ongoing clinical trials looking at the efficacy of chemo prevention, and that's due to the fact that if you turn on PPR-gamma in cancer cells, you can induce terminal differentiation, you can inhibit cell proliferation, you can increase apoptotic signaling, some of these through PPR-gamma, I should say receptor-dependent as well as receptor-independent activities. So that's known to occur. PPR-gamma, like most of all the PPRs, they have potent anti-inflammatory activities through a mechanism called transrepression. Be glad to talk about that in greater detail as well. That's another known function for PPR-gamma. It's been shown to inhibit differentiation of a number of T cells, and that's the reference down here at the bottom. This reference is for that paper right there. Might be used to inhibit autoimmune diseases such as multiple sclerosis. There's a number of functional roles for PPR-gamma described in literature, but one of the things that's also associated with our adverse side effects, the toxicities, which you asked me about as well. So I mentioned hepatotoxicity with Resulin earlier. That's one of the known side effects with one particular PPR-gamma agonist. Fluid retention, which may occur through a regulation of a kidney-specific epithelial sodium channel transporter, which may contribute to the edema, which is also associated with these compounds. Weight gains also might be due to some of these things here, as well as the adipogenic potential of these compounds. A congestive heart failure is a big one that you all have heard about what's happened to rosyglutazone in the last few weeks. And bone fractures, which maybe some of you hadn't heard about, and that's due to increased osteoclast activity. So these are known adverse side effects associated with thiazolidine diones, or PPR-gamma agonist, and they really don't know. I mean, aside from, I'd say that they used to think that this edema and the fluid retention and weight gain might have been due to this regulation of this protein, but it turns out that that study may be not so reproducible, and so people aren't so, they're not so convinced that they've got that mechanism worked out either. Are there any, and I'm getting down here the last couple of slides here, and these are pretty easy, because I didn't really have to answer these questions very well for you. Previous, you asked, are there other cancer sites that the CHAP should consider a risk assessment of phthalates, such as pancreas or testes? We used, I was on this CHAP 10 years ago, we used mononuclear cell leukemia for DINP, I believe, and you're welcome to look at that literature. I don't know that you're gonna be looking at PACTS or LCTs. I mean, there's been arguments put forward that P-pure alpha activity is associated with the generation of these tumor types, but I'm not really quite sure if that species difference has been demonstrated conclusively. I probably yield that question to Paul, who probably has a little bit better experience with all of his bioasses that he's been looking at this thing for the last century. He probably knows more about the different tumor types that are found with all the different phthalates than I do, because you know, as you can see, I'm a little bit younger than Paul, but, and then lastly, are you aware of any ongoing studies that might be helpful to the CHAP? We have an ongoing bioassay in my lab going on right now that you might be interested in hearing about real quickly in that we're using this super-duper PPR alpha agonist that's highly specific for the human receptor, not the mouse. So Wyeth has greater affinity for the mouse receptor than the human, so we've got this one compound that has a very, it's nanomolar affinity for the human receptor, and we have a bioassay going on, and we're using the wild type to knock out the humanized mice for this, and we're also doing it kind of as an aside in the same experiment. We're dosing neonates when they're first born to see if there's a difference in sensitivity between young versus old, because there's some interest in that as well. I've heard that there's also long-term bioassays going on with DEHP, but I'm not really quite sure about the specifics of that one as well. And with that, I've taken up my half an hour of time. I'll leave it to questions. Thank you. Questions from the committee? Well, first of all, most of the, or I'm to blame for a lot of the questions, especially the ones directed to you. In, I think the question about number six, where, you know, the human relevance, I guess my question is, or what I was really thinking is, if some of the effects in rodents are mediated by PPA or alpha, that doesn't necessarily mean that they're not relevant to humans. Just because, you know, if the liver tumors are not likely relevant to humans, doesn't necessarily mean that any other effects are not relevant. Yeah, I mean, I don't, I'm not sure if we can answer that question right here today. I mean, but there's no, I mean, you can't automatically apply the same logic without knowing a whole lot more. Yeah, I mean, I think that you can and you can, I think that you can take the logic that, I mean, what's been applied to that globally, I think it was tried, we tried to do that with PACT and LCT as way back when too. And I think the problem with that was that the database for the mechanistic information we had at the time was minimal. And that was the problem. And I think that's the problem you're gonna kind of grapple with here, is that you don't have a data, see with liver cancer, it's pretty rich. And in particular, like with the fibrates, for example, we got a huge human population. We've got tons of studies done in human cells and even humans. We've got good human, relatively decent human data, even better than what Shauna can get because they get liver weight and things like that. I think that you have, there there's a little bit better potential, but so I don't think that you can. So to answer your question then, I understand the logic behind that and you probably could do that if you had a stronger data set. Yeah. I guess my other question, Shauna earlier mentioned a study that implicated phthalates or associated phthalates with metabolic syndrome in humans. On the other hand, you have PPA or gamma agonists that are used to treat type two diabetes. So are those two conflicting? Yeah, that didn't, yeah, absolutely. Actually all the PPR agonists, PPR alpha, PPR beta delta, and PPR gamma agonists, all of them are targeted for metabolic syndrome for various aspects of them. So PPR alpha is the dyslipidemia, PPR beta delta is for the glucose regulation as well as the fat burning potential and PPR gamma is the glucose regulation as well. And all three of them for their anti-inflammatory activities, which has also been shown to have effects in the macrophages and the adipose of people that suffer from metabolic syndrome. There's a relationship with that activity. So the fact that phthalates may or may not be associated, I would say that they were associated with metabolic syndrome would not be consistent with the notion that it's functioning through a PPR-dependent mechanism. Well, thank you very much for a great talk. Any other questions? Lily. So it was actually really on the pancreatic acid cell tumors and the latex cell tumors. And, you know, as you know, Jeff, you don't get those in mice, right? And that's a real problem with regard to the knockout kind of thing that you see them in rats. And so I think I would absolutely agree with you. You know, the evidence that that's PPR alpha-mediate is fluffy, to say the least, in terms of the mechanistic information. I think the other thing is the only time you ever see latex cell tumors in mice is usually due to an estrogen activity. And I think as Earl mentioned earlier, the way you actually diagnose latex cell tumors in rodents compared to humans uses very different diagnostic criteria. So in rodents it's based on seminiferous tubular diameters. It's either one or three diameters. Actually, it doesn't really matter because they're usually that big that you can see them. In humans, they don't do it. And so when you actually go and look at, as Earl alluded to, some of the data that's come out of testicular biopsies in subfertil men in Denmark, they actually have what they call latex cell micronodules in a lot of these men. And if that was in a rodent, it'll be a latex adenoma. In other words, if you applied the rodent diagnostic criteria, you would be called an adenoma, but that's not what's used by the pathologists of human disease. So there's a... At one time, we thought latex cell tumors were very, very rare in humans. And actually, it seems that it's really the malignant tumors that are very, very rare in humans as they are in rodents. I've only ever seen two in 25 years. And also, they're not necessarily associated with any endocrinopathy. And that's true in both rats and humans. So I think those tumor types are not quite as different as we once thought. And also, the DHP bioassays, yeah, the NTPs do in one, but starting with a utero exposure. Oh, you guys are. Yeah. Okay, good. I thought there was one going on. Yeah. It must have been you that told me that. I probably was. I remember it, but... Any other comments, questions? Not hearing any. We have some time before we're scheduled to go on with the next presentations. Does the committee want to delve into other issues while we still have these three speakers with us? Do we wanna just quickly review our critical issues and see if that prompts any more questions? You obviously have it there. Why don't you go ahead and go through those? Okay, well, this won't take too long. And I guess the first question was, what are the really important endpoints? I mean, is it the male developmental effects or should we be also looking at cancers and other chronic organ toxicities and so on? I don't, does anyone wanna comment on that? Paul said, yes. I mean, I think we feel that the developmental alterations in the male rat from the androgen alteration are the sort of the low dose effects. But I think it's important to consider all of the other effects as well. Effects in the female during pregnancy and the F1 female in the cancer. I mean, if one decides for some reason that the male reproductive effects or an androgen pathway is irrelevant, you still have all these other effects that are clearly not mediated to that pathway. And I think it also puts in perspective the fact of the mechanism of toxicity that thaliates is not a simple inhibition of steroidogenesis. So I would, I mean, I would see the male endpoints now as critical unless they're deemed irrelevant and then important to consider too. Okay. I think you also have to consider the exposure as well, because I think we'll be trying to say that you could induce these effects on reproductive development, fairly narrow critical window development and that's not necessarily gonna be true for the other toxicities. So, you know, are you talking about, you know, low dose long-term chronic exposure where some of those other endpoints might become more important? One question along those lines is, I guess, what do we think is the window in human, the susceptible window in humans? I mean, is it, could it be that as short as one day can have an effect? Or, you know, do we have to assume that that may be the case? Well, we certainly can get malformations with one day exposure in a rodent. But as I tried to illustrate, you don't get the complete sweep of effects. So, you know, and we know the period of sexual differentiation in humans, it's first trimester, maybe just over into the second. So I think it's from like week eight to 15 or something like that. So that's the, that will be the critical window in a human for if those effects were to occur in humans. I guess number two, what are the relevant populations we should be looking at? I mean, we know obviously the fetus is a sensitive target, the infant and so on. And because of the fetus, we want to estimate exposure to the mothers. Are there any other susceptible populations that we're overlooking? Or other than the general population? Any others that we know of or you know of? Either are no, well, for example, no, P-P-A-R, allotypes, whatever, that have no activity, for example. So there really aren't any populations that we know of that might be extra sensitive to phthalates. One's really looked at that. That's the one mutation, the L162V. I don't know that, I don't know that that would increase sensitivity of liver cancer or not. I think that's something that we've mentioned in our reviews before, but I think that the question though about the low dose, I think you have to be very careful about, I think there's really clear evidence that if you go back to the literature, that there are P-P-R-alpha-dependent effects in the liver that occur at higher concentrations, that the ETO paper suggests that there's independent events and keep that into context with that, that there are no mutations in P-P-R-alpha that have a protein that doesn't function so that low dose exposure, in my opinion, the relevance of that to the human population may be less so than at the higher doses where you would go to a P-P-R-alpha MOA and the lower doses may be independent, but it may not be even relevant. I guess, let's see. As far as the phthalates, which ones are essential that we need to look at in our cumulative risk assessment, obviously the active ones, do you think that should include methyl and ethyl or? Based on our rodent data there, we haven't seen anything, but you're gonna have to come to terms with some of that human data about whether those associations really were more a surrogate for exposure because the diethyl is so prevalent in humans or whether it really is positive. Yeah, yeah. And our plan, I think, is to rely heavily on the NRC report. And is there any, I mean, it was Taylor made for this exercise, but are there any things that we ought to, any reason not to not do that? Not that there's any conflict. Excellent panel item. Okay. That panel was okay. No, I think I failed charm school. I think that the evidence that exists is generated since that meeting is consistent with the report. And I don't think that there's evidence studies to the contrary, but there's not a lot of publications or studies. Yeah. And I think one thing that we did want to ask, are there any critical studies bioassays? One or two that could be done in a short period of time that would make a significant impact on what we're doing. Well, there's some of the phthalates that if you're going to consider all the active ones, there's some of the ones that we found to be active. There's very little data on. So the diheptal phthalate, I think there's what one study of his? Hexyls, no. And Hexyl, there's not many of the dipental phthalate. There's, you know, a lot of these, there are no developmental multi-generational studies. Okay, yeah. And so there's a large database on phthalate reproductive toxicity, and I just guess 95% of it is to do with phthalates. So there are a lot that we don't know much about. I know that, I think EPA was, may not, when it gets to the program office, it may not consider phthalates that are very, very minor use or no obvious apparent use at all. I think there was some question about if anybody even uses dipental. Yeah, yeah. So it's an exciting chemical from our perspective because of its potency to validate the question, but it might not be too relevant for cumulative risks. Well, looking at the database, you know, all the different endpoints, it's not always clear to me, do we have data on common endpoints for the, say, the handful six or eight chemicals that are probably the most important? If we have to say, you know, you have effects on variations, malformations on one chemical, you have testosterone production data on another, are we gonna have problems combining different endpoints for some of the different phthalates? Are we gonna be faced with that? If for the postnatal studies, I mean, what I looked at, you compare across the studies and there's some endpoints that you can't really compare like hypospatias because it's not reported in a lot of the papers. And some of the things that we've begun to measure that people didn't measure in many of those studies. So that anal genital distance or gubernacular changes won't be there. But we did find in most of the postnatal studies that we looked at that there were also five or six common endpoints that I had graphed. So almost all of them had testicular and epididymal alterations and sometimes in histopath alterations. And most of them have organ weights and things like that. So it's likely a sufficiently robust database to... There are some endpoints common to all the papers, even the older ones. I think you also have to be careful about, you might have confidence in ascribing that an effect may have occurred. But I don't think you'd necessarily have as much confidence in when an effect didn't occur or at what dose level. Okay, okay, yeah. And well, the other part of that is the dose response. Exactly, yeah. And do we have adequate dose responses for a lot of these? I guess, well, let's see. We heard a lot about other anti-androgens. And I guess some of, one of them, there was a question whether people are commonly exposed to it. But if we were to, not that we're necessarily gonna do it, but if the chap we're gonna consider other anti-androgens, what should we consider on the basis of what people are likely to be exposed to? Do you know that? Well, I think for the U.S. population, you'd probably exclude prosimidon because it's only imported in expensive French wines. As long as the pregnant women are consuming large children and are not consuming large quantities of that. So there's, then some of the others are food use pesticides. You'd have to look at the exposure information there. So there may be selected populations that have higher exposures, but I wouldn't, based on that information, you might end up excluding all of them. So we'd have to get exposure data. But you do have, from the risk assessments, the RFDs, and they also estimate margin of exposures. And a lot of those, like for Vinclosal, and I'm more familiar with, they estimate the top 95% of exposure you could. Oh, as Andreas had talked about, sort of simulate the worst case exposure situation for some of these, and see if it would contribute anything at all. Okay. Remember, some of the weak anti-androgens are like Para-Para-DDE, which probably we've all got in our fat as well. So some of them are more likely to be co-exposure than others. Yeah, which actually of all the things that we have in our bodies and in our fat, I don't know how many chemicals. I mean, there must be others or some that have, that are potentially interact with the phthalates. Or can contribute to the effects, the cumulative effects. I think that's all I have. Any other comments? Chris? Some of that discussion, and maybe I oversimplify what you all were talking about, but so we were thinking about reproductive effects, so exposures to pregnant moms and fetuses. But what about toddlers? Are we worried about exposure to toddlers? Well, some of the highest exposures recorded are actually to NICU infants. But I'm talking about effects, not exposure. Well, I think in, I don't think that the NICU kids, you have kids that have health problems and I don't know that they're monitored for very long and you wouldn't have an inadequate control population. I think for neonatal exposures, only in rodents might be the appropriate exposure period for the toys. I think there are two studies, two, three studies published where there's only that exposure. And I said, one of them's Laurie Dostal and Byrne Schwetz. The other was a Baxter chemical study with oral and Jectin studies and they were single dose, single dose or two high dose and the DEHP was positive with oral sub-Q exposure in those with permanent testicular effects. But it was, you know, it's Jectin or oral six, three, I think it was three and 600 milligrams per kilogram. So there's really a paucity of data there. I think that most of our studies have included in utero exposure and uterine lactational exposure, looking at fetal development and its interference with androgen signaling and other pathways. I guess the question you have to sort of extrapolate is the androgen signaling or those pathways important in the human infant, you know, and there is that neonatal infant testosterone surge in humans that Ruskin, you can all discuss. And I think it's believed to be important in some processes with its role in humans is less certain. That's differentiation in you. I think there's not a lot of information there either. There have been some effects on puberty as well, which would be later. Right, yeah. Concerning other chemicals to take into account sort of via background exposures according to our charge, I thought earlier data, which you showed today about combinations of TCDD and DBP were, shall we say, a little provocative. How can I put it? I think in my mind there are now these data indicate to me that background exposure to dioxins might modulate. Let's put it this way in some serious way, the effects of thalite exposure, but my impression also is that it's probably too early to come to move this into some sort of quantitative assessment. Could you comment on that? Well, I would agree it's too early to put it into a quantitative assessment to say if the cumulative effects were a response or dose additive. I mean, we're talking about a limited published data set where I wouldn't even go out on a limb and definitely say that there was a cumulative effect that appeared that way from the pilot study and we're repeating it. So it's been to me an intriguing hypothesis, but I wouldn't make a regulatory decision on it now. Even though it's my own wonderful data. Well, it shows how modest you are and how responsible. But let's put this mixture effect aside. I'm also rather interested in the connection between dioxin and these endpoints you looked at, TCDD and PICNAR. Can we just looking at TCDD as a single chemical for a moment on the basis of some data that are published maybe or by you come to a quantitation of the effects? Oh, well, from the rat studies, there's a lot of dose response data from exposures to dioxin. And I think probably the lowest dose exposures are from multi-gen study done with Murray. And are you on that one too, Dr. Schwetz? Yeah, where they were giving nanogram quantities per day and have clear adverse effects in the animal. So the things that all of us have done since then are one exposure and pregnancy to microgram quantities and you see rather reproducible, reproductive effects in the offspring, the males and in the females. And those can be quantified. Based on what you understand or surmise about the mechanisms of action in operation there with respect to these effects, what about all the other dioxins and polychlorinated abends of furans? Can they, is this perhaps an AH receptor mediated contribution and should the others be taken into account as well along those lines of what's your comment? I think that's the general hypothesis, but EPA has had a dioxin risk assessment ongoing for 20 years, a long time. And it's just in draft form now. So I don't think the agency has a consensus that's accepted, peer reviewed yet on the adverse effects from the rat literature, it's clear. And you get similar effects in the rat from some of the dioxin-like PCBs as you get with the dioxin. Okay, thank you. Let's take a break and we'll reconvene at three. Hello? Hello? Your call cannot be completed or dialed. Please check. Welcome to the conference calling center. 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Calling in, but let me check with her. Let me see if she's in her office. Well, let me start. This afternoon, we have some of our federal partners in to speak with us from EPA and FDA. And I have asked them to tell us about any phthalates activities that are ongoing at their agencies or specifically in their program offices. And to tell us if they have any information or knowledge they have that might be helpful to the chap because as we're acutely aware, not all of our exposure comes from consumer products. Much of it comes from other sources, the environment, from foods, drugs, cosmetics and medical devices to name a few. So we do have, well with us here today, Peter Gimlin from EPA, Office of Pollution Prevention and Toxics, Jamie Strong from the National Center for Environmental Assessment, Ron Brown from FDA, the Center for Devices and Radiological Health. On the line, we have Steven Chang and Laura Gubbernelli from the FDA Office of Drugs. And has Abby joined yet? Okay, well, we're expecting Abby Jacobs also to call in. So, okay, welcome Abby. So, Peter, would you like to start and tell us a little bit about what's going on at OPPT? Whichever you like, just press the button. I don't have a slide show, so I'll just talk here. What I'm really mostly gonna talk about is a regulatory action plan. We've developed EPA, I'll just pass some copies out to the group here if they're not familiar with it already. Peter Gimlin, I'm an OPPT, that's really, it's our regulatory control office dealing with toxic issues. I think Jamie's gonna talk about some of the research in a few minutes. And I was the working chair to help develop that plan, so that's why I've been invited here. This document and this effort stems out of an effort that started last summer with a new administration to try to revitalize our approach to TOSCA. This toxic statute, toxic substance control actions from 1976, and some parts have worked well, but with the control of existing chemicals all over the market, not a lot's happened. Some things have been regulated, but in a lot of cases it's been very slow and we haven't done much to control things. And so there is, well, there's various legislation on the Hill right now about reforms to TOSCA, which there's a lot of interest in, but in the meantime we've got the existing TOSCA. And one of the efforts is to try to revitalize, try to put some more effort into what we're doing and seeing if we make the existing law work as best it can. Out of that effort, we released in December several so-called action plans, which are really road maps or just in public announcements and laying out what we intend to do to control some existing chemicals and our reasons for doing it. One of these is the phthalates action plan, I just handed out. This plan, for purposes of this plan we've identified eight phthalates that we're going to take action on, at least that we've identified in this plan. It's possible as we get into more further along in regulation or research, we find that some of them don't warrant full-scale, additional regulatory controls, we find that some we've left out need to be brought in. But we started out with this group. It's the six that are specifically mentioned in the CIPSEA legislation and two additional ones, DIBP and DNPP that are being studied by Jamie's group that came out of National Academy of Science report. And we've got some research underway on those, so we included those as well. By way of background, one of the questions you pose was the relationship of the EPA control to the FDA. And that, this issue really goes back to the language in the TOSCA statute itself. It's not a regulatory matter, so much as a statutory issue. When TOSCA was passed by Congress, the language in the definitions of section three of TOSCA they define the term chemical substance to mean broadly any organic or inorganic substance, combination, elements and radicals. But then they go on to say such term does not include and they list various things. And one of those is any food, food additive drug, cosmetic or device, such as terms, as such terms are defined in section 201 of the Federal Food Drug and Custom Med Act when manufactured process are distributed in commerce for use as a food, food additive drug, cosmetic or device. So in giving us our authority under TOSCA to regulate toxic substances, they specifically exempted any of those devices or products that are already being regulated by FDA. So pretty much there's a very clear bright line from with our basic statutory authority that whatever FDA is regulating under their authority, we don't regulate under TOSCA. So we need to coordinate what we're doing but there won't be overlap. It's a little different situation than we have with the consumer product, consumer products where theoretically both, if they have consumer product with phthalates in theory, we could also provide it's not an FDA yet and we could also regulate it. In many cases it wouldn't make sense but we can work on who would be best suited to maybe go after certain items. But with FDA, if it falls into their categorization then it's up to them and we're not gonna be able to do anything about it under TOSCA. Now briefly, the steps in the plan we've laid out, we've listed some intended actions and these are mostly actions we can take with our authority under TOSCA. One is to put them on a list of chemicals of concern. This is an existing authority that we've actually never used at the EPA. So this is a bit of an experiment to try to make use of this and see what advantage it produces. It doesn't, it's basically essentially a list of chemicals. It's a public list to let public know we have concerns about these chemicals and it doesn't have too many immediate effects in the regulations about controls or restrictions that are like it. It's really just a primary list. We do, we currently right now attract to publish a proposed rule in September and at that point I'll be open for public comment. We don't have a fixed date for final rule sometime next year, maybe perhaps by the summer depending on the extent of public comments we get. The other action, second action we're taking and this is actually under different statutes to start rulemaking to put all these eight phthalates on the TRI list for public reporting. Right now only two of them are on the list. Dbp and Dehp and if we get these others on the list we'll get some more reporting data in a few years from the public about uses and releases, well releases but it'll give us some more information and hopefully we can get a better idea of exposures from that data. We've started the rulemaking process to some fixed date for the proposal. I imagine sometime next year we might have a proposal out. We have to go through rulemaking on that as well. So it'll take a little time to get a final rule out and then there's the reporting cycle under to get the data back in. So it'll be a few years before we get any new data from that effort. We also begun on one of the chemicals that DNPP and looking at the data there's an inventory update reporting requirement under TOSCA. It has certain thresholds of I think in these cases it's 25,000 pounds of production has to be reported periodically to EPA. We didn't get any reports on this chemical in the last couple of cycles. So we're gonna try to impose a restriction on it called a SNR or significant new use rule. Essentially the idea is under TOSCA if you come up with a new chemical that's not in the marketplace. You have to come into EPA to get approval. There's a screening process, a 90 day review. If we issue this significant new use rule on this chemical then that requirement will be imposed on DNPP. And if anybody were to reintroduce it into the marketplace they would have to come in through this review screening by EPA. So that'll give us a little advance notice if it's gonna be reintroduced in the market and a chance to consider if there are any restrictions or requirements or additional information we might want to see from that. We're gonna come out in a scheduled to propose something early next year. At this point we're not certain if there could be smaller manufacturers, smaller importers or uses. We're doing a little background investigation on that right now and if we don't get anything solid on that the proposal would have an opportunity for public comment and then that would be people's chance to basically raise their hand if they're actually using it. If that's the case then we'll have to assess how much is being used and if it can proceed with some modified version is or not. We've also begun an assessment under our design for the environment program to basically look at phthalates, how they're being used, if and primarily what they're being used for, what kind of substitutes are available or they're better safer substitutes. Talk to the industry, see if they have any interest in using these. Basically it's a voluntary program looking into it seeing if they're safer greener ways to handle chemicals, try to enlist the cooperation of industry and working on the project. That project, the scope of that's being set out this summer, exactly the details of that. It will be completed sometime in 2012 and we'll be interested particularly in this to see, well obviously what can be worked out with industry before we get to any kind of rulemaking and also to see what's developed in substitutes. I think it's one of the issues we're dealing with in terms of regulating this safe and commercially available substitutes, what's out there. And finally the last part of the plan is to consider rulemaking under section six of TOSCA. This is the part of TOSCA that gives us our broadest authority to regulate chemicals. Anything up into including a full blown band of the chemical but there can be lots of partial bands or restrictions, marking requirements, pretty much you name it. There's anything up into including a full band of chemicals possible, depending on various findings we have to make in the statute about the risk involved. I have to make basically what's called a no and reasonable risk finding. And it has to be, pretty much our controls have to be matched to what we find in terms of the relative risk of the chemical and what the controls would accomplish. We've got that down at the moment basically as something targeted for initiating in 2012. When we got into looking at phthalates last summer, what we quickly realized is that what you're dealing with here is the cumulative risks are really gonna drive a lot of this and that a lot of work was being done on it right now. Not only your panel and your panel's report would inform this, but the research we're doing right now at EPA for IRIS and that it was basically premature to try to attempt to move forward of any regulations looking at phthalates on a case-by-case basis. They're using the existing individual assessments and maybe just trying to take an additive approach that whatever case we developed for rulemaking would basically be surpassed by the information that comes out of your project in the IRIS project. There's also an endocrine disruptor review going on at EPS as well. So in this case, it was really necessary to wait until we get this information and we can use it to support the rulemaking. I think you had asked the question too about just generally on data gaps and issues. Again, we haven't got into this hard building a rulemaking record issue yet so we can't lay out specifics. I couldn't lay out specifics that we need this piece and that piece. But in general, we're missing some ecotoxicity data and particularly on DNPP and DNOP there's some missing data. I guess it's a general. On some chemicals, we've got a pretty good case like an NDHP seems to be pretty well studied. Other ones, it's a somewhat spotier record. The information on generally on release and worker exposure could be a little better. I think we've got certain data but we would like more certainly for doing a rule. More information on human exposure sources particularly for DEINP, DIDP and DNOP. The exposure data we have varies. Again, we've got pretty good data for DEHP but for those three I listed and some of the others we could use more. Also the issue of trying to, we don't have a good sense right now where we're looking at the data where particularly sources come from. We know there's human exposure. We know it's out in the environment and some of the sources but trying to piece together the picture of these particular uses are attributable to this component of the human exposure. It's the details of that. I haven't been able to piece that together yet. Particularly the adult data we would like to look at and I know you're focused on the children's data and actually a lot of the data right now seems to be focused on the children's exposure issue but some of the adult data is getting a bit dated. Some of it's 10 years or more older and a lot of the data comes from Europe and Canada and we didn't find much data on US exposures in particular. One of the bigger issues I think we'll need to try to get a better handle on is the mechanism of the migration of the phthalates from the PVC plastic. A great deal it's being used in PVC and this is potentially a large reservoir of phthalates in the environment and a means for spreading phthalates throughout the environment globally but a better handle on how fast these phthalates migrate out of PCBs and what circumstances to get back, to get free back into the environment. And then finally mentioned earlier the whole issue of substitutes. There seems to be quite a number of potential substitutes out there. Some pretty well developed. I heard you mentioned Dinch earlier today that's been developed and has actually got on the market. A few others on the market but the whole issue of how many are they suitable for all the various applications of phthalates are used for which ones would be suitable for which application. The cost as a substitute or the economically viable and also the risk. We're looking to move people to safer substitutes and make sure that we're not just pushing the market from one set of risks to another set of risks. That's it. Does the panel have any questions for Peter? I'm not all that familiar with the task of requirements but we're comparing sort of the limits based on here's the FDA and here's the EPA sort of purview. So my question is thinking about the FDA has requirements of certain products being listed on food items and what's in the ingredient. That's not the case for products or their products and things like that. Is that something that the EPA could actually try to impose that here are these phthalates. We don't know where they are. What products, does it have the ability to actually require those things being listed? Yeah, it does. Under the section six of TASCA we could require labeling. That's one of provisions specifically mentioned. So that could be an outcome of a rulemaking instead of a ban or some of the controls simply labeling requirement that if your product has phthalates it would be listed. It could be done. How long would it take for you to arrive at such a decision? Unfortunately, it takes a while. Plan is to start rulemaking in 2012. There's a process of a proposed, we have to propose a rule, take public comment and issue a final rule. So in practice it tends to drag out and it can take several years to get a final rule out. So starting in 2012 and several years from then. So it's a slow process. For the different actions, for example, the chemicals of concern list, the TRI list, are they hazard based? What kind of information do you need to support those regulations? They have different standards and they're less than the section six. The section six, which is the most restrictive is the most burdensome. We have to make a finding that the chemical may present an unreasonable risk. So we have to look at the exposure and toxicity and make an assessment. The chemical concern list is based on a lesser standard of it may present an unreasonable risk. So we really just have to basically make a basic finding that there's some exposure and there's some toxicity. We don't have to approve the level. But you have to basically lay the groundwork that there may be an unreasonable risk here. So that's a much lower burden of proof. The significant new use rule, there are certain criteria laid out in the statute. Most of them deal really pertain to exposure. So it's mostly making an exposure finding for a SNAR. The TRI listing, they have their own standard and I'm good to say I can't tell you what that is off-hand because it's a different statute. I believe it's mostly an exposure-based finding for a TRI listing, but it's certainly a lesser standard. I guess what I'm getting at is are there any opportunities where we're gonna overlap? Where are the CHAPS activities and your activities may be the same? And I'm thinking actually the DFE activity looks like the most significant overlap. Is there anything else? Are you gonna be doing an exposure assessment or not before 2012 or looking at exposure data, anything like that? There will be some background reporting reports study to support the TRI listing. Believes those will be ready. They'll be basically a report on each one of the six chemicals. Those should be ready next spring. I'm not sure if that's publicly available at that point that be made publicly available with a proposed rule. I'm not sure that's gonna go into enough detail that to be as much, it's probably covered ground that you've already covered in your preliminary technical reports. We could certainly try to share them with you as soon as we can get them and make them available. Hopefully before their public release and you get some clearance to send them to you, but that's still looking at early next year. I'm not sure that will have that much new in it for you. It's basically, usually they just get contracted out and it's probably background, probably mostly a literature review, I would imagine. I'm not sure how much new assessment would be in those. For the significant new use rule on DNPP, we'll be doing an economic analysis to support that, which we'll basically be looking at uses, how much we think is being used and what the uses would be at this point. We're hopefully come back with nothing, but if there's anything then it'll basically assess that. That also would be part of the public record. I'm not sure when that would be available later this year. I can see if there's something we can get to you in advance or not. I'm not sure again how much use that would be. But yeah, I agree. The design for the environment assessment may be the most useful thing we can cooperate on at the moment. It's again, it's getting scoped out this summer. I'm not sure at one point we'll have useful information to share, okay? Okay, so we'll keep you posted. Yeah, I think that if we knew, well, if you couldn't find anyone making a di-pental, then I think that would be one less thing that we have to worry about. Okay, we'll keep you informed of that. The question that I think is a follow-up to Mike's, your overview statement of the action plan says that recent scientific attention is focusing on evaluating the cumulative effects of mixtures of phthalates in an exposed organism. In view of the timing of this plan, is that cumulative risk assessment likely to be something that's done before all of the rest of the announcement of your planned activities, or is this saying that this would eventually become part of what happens after an advanced notice of proposed rulemaking? It's at the end of the second paragraph of the overview. Let's see. Last sentence. That's just a broad statement about scientific attention, not specifically laying out something we're doing to support the action plan. It's just talking about the fact that the NSA study had come out looking at that. What's going on generally? Congress and tasks, this group to look at it, are ORDs looking at the issue as well. It's just a general statement. We've discussed that also. So what I'm wondering is whether you have already decided which phthalates would be the ones and which endpoints and which age groups should be modeling? No. No, we haven't got there. I think Jamie may talk about that. Any more questions? Thank you, Peter. Next is Jamie Strong from NCIA, National Center for Environmental Assessment. Okay, thank you very much. I am glad to be here to tell you a little bit about what's going on at the Integrative Risk Information System program within the National Center for Environmental Assessment at ORD at EPA. So just Mike asked me to give a little bit of background. EPA's IRIS program is a human health assessment program that evaluates qualitative and quantitative health risk information for different chemicals in the environment. And currently we have information on over 540 substances on our database. We address chronic exposures typically. The assessments include many high-profile first applications of risk assessment guidelines and science policy. We do non-cancer and cancer hazard characterization. We do the hazard identification and dose response part of the risk assessment paradigm. We include a mode of action analysis for both non-cancer and cancer effects where the data are available and we derive reference doses and oral slope factors for effects resulting from oral exposure and reference concentrations and inhalation unit risks for that inhalation exposure. On May 21st, 2009, the administrator of EPA released a new IRIS process, and this has led to increased improvements in transparency, consistency, and public participation in the process. And you can find the process at our website at epa.gov.backslashiris. So currently on the IRIS database, we have several individual assessments for several individual phthalates, including DbP, dibutyl phthalate, ethylhexyl phthalate, DEHP, butylbenzyl phthalate, BbP, diethyl phthalate, DEP, and dimethyl phthalate, DMP. Now, these assessments were done throughout the 80s, so, and are based on effects, RFDs are developed based on effects such as mortality, liver weight, and decreased growth rates and alterations in growth. Only RFDs were developed for these because of the lack of inhalation data at the time these assessments were done. And then these are the cancer assessments for those five phthalates that I mentioned. The only one that has a quantitative cancer assessment is diethylhexyl phthalate, and again, these were done in the 80s. So I just wanted to let you know what was currently available on the IRIS database. IRIS assesses chemicals on an individual basis and has, that's been the way that we have done things in the past, so the concept of cumulative risk for hazard and dose response represents a paradigm shift for our program, but the science of risk assessment is increasingly complex and more data are available that lead to questions on how to address issues of multiple exposures, multiple risks, and susceptibility in populations. As part of this ever-growing database, we took on, asked the NAS to go ahead and look at cumulative risk, particularly for the phthalates based on the following rationale. The phthalate assesses, I'm sure, Earl and Paul Foster told you this morning are a group of chemicals that are used in the manufacture of various products, they're in personal care products, pharmaceuticals, detergents, medical tubing, et cetera. And then humans are exposed to various phthalates and their metabolites in the environment, including through direct contact with these various products. Multiple phthalates have been detected in saliva, urine, amniotic fluid, and breast milk in humans. And the human epi studies have demonstrated a possible association between exposure to some phthalates and their metabolites and indicators of potential effects on the male reproductive system and these studies mirror those effects that are seen in animal studies also. So as I said, in 2008, we elicited external expert consultation from the national academies. Many of you served on that panel or spoke to that panel. In the evaluations of issues and approaches related to conducting a cumulative risk assessment for the phthalates. So this was our charge to the committee. We asked them to identify and prioritize data gaps and research needs related to the phthalates and to doing a cumulative risk assessment for the phthalates. We also asked them to identify issues related to cumulative hazard and disresponse assessment for the phthalates and to provide recommendations on the relevant phthalates for consideration in a cumulative assessment. And then finally, discussion of the data that would be required to perform a cumulative assessment for this class of chemicals. And in December of 2008, the national academies released their report, phthalates and cumulative risks, the tasks ahead. And this is just a very brief summary of their conclusions, but the main one was to include phthalates and other chemicals. For example, agents that cause androgen insufficiency or block the androgen receptor singling pathway in a cumulative risk assessment. And to base this cumulative risk assessment on common adverse outcome, not to focus exclusively on similar modes of action. And that although a variety of mechanisms are clearly involved, dose addition did provide adequately predictive methods when the committee evaluated the available data for the phthalates. The bottom line was that a focus solely on the phthalates to the exclusion of other anti-androgens would be artificial and could seriously underestimate risk. Now, the report's implications are far reaching and potentially impact the entire agency. Our plan that we've put into action is to evaluate the underlying science behind the recommendations and to consider the implications for the actual IRS assessment. We are evaluating the options for performing a cumulative risk assessment for the phthalates presented in the report. And we'll talk a little bit about that in the next couple of slides. Particularly, we're planning a workshop for this fall on the specific recommendations related to the methods for conducting cumulative risk assessment. The recommendations from the panel, and as I said, that's scheduled for October, November timeframe of this fall. Though we have initiated an IRS human health assessment for selected phthalates, which includes the following six phthalates. Prior to the NAS convening to evaluate cumulative risk assessment, we currently, we had on the agenda, on the IRS agenda, dibutal phthalate, diethylhexyl phthalate, and butylbenzal phthalate, and following the release of the report and consideration of the recommendations, we've gone ahead and added diisonomal phthalate, dipental, and diisobutal phthalate to this assessment. The assessment will include non-cancer and cancer qualitative and quantitative health effects information and where the data are available for each of the phthalates. The assessment will also include the cumulative hazard and dose response assessment for these six phthalates. The cumulative assessment that IRS has undertaken may serve as a framework for extension to other phthalates and to compounds that affect similar adverse outcomes in the future. An external peer review of this assessment is anticipated to begin in 2011, and you can follow this schedule at the IRS website on our IRS track system. Some general issues related to cumulative risk assessment for the phthalates that we're currently dealing with and hopefully will address at our workshop are toxicoconetic issues, exposure issues, identification and selection of the data to serve as the basis for the cumulative risk assessment. For example, recognizing that the induction of any of the phthalate syndrome effects is representative versus focusing on the effects common to the six or the most sensitive outcome. We're gonna ask at the workshop, are there other non-reproductive non-cancer endpoints and what should we do about cancer endpoints? As I said, the methods for conducting a cumulative risk assessment and then the inclusion and exclusion of other anti-androgenic chemicals and what that means. The primary goal of the workshop is to discuss and evaluate the NAS's recommendations, specifically methods for performing a cumulative risk assessment. And the purpose is to facilitate discussion of which options for conducting the cumulative risk assessment should be included in the assessment and the strengths and limitations of each of these options. And CIA recognizes the importance of the recommendations related to the inclusion of other anti-androgens in addition to phthalates and the possibility that exclusion could lead to an underestimation of risk. So as I mentioned before, we hope that this will serve as a framework that can be extended to other compounds and possibly other phthalates as data becomes available that indicates that they affect common adverse outcomes. Potential objectives is the identification of which method should be used. NAS recommended two approaches for aggregation of cumulative risk. One was a hazard index and one was a point of departure index that Dr. Cortenkamp has probably presented or discussed with you. We wanna look at any other methods that could possibly be beneficial for the assessment. We also wanna talk about data sets. The presentation of cumulative risk based on mixtures data or should we be looking at the human versus the animal mixtures data. Presentation of cumulative risk based on individual phthalates data. Again, human versus animal. And are there other data sets that we should be considering? And finally, identification of sensitive effects to serve as the basis for this determination of the points of departure. As I mentioned in the previous slide, looking at the phthalate syndrome as a whole versus the most sensitive or an individual effect that is common among them. And then are there other endpoints that we should be looking at outside of the male reproductive tract system? Going on at Iris, I don't know if I have any questions. Are there any questions from the panel? Well, just an observation that issues that you've highlighted on your slide, the exact issues that we've highlighted as issues that we need to address. Have you at this point identified those individuals who are going to participate in the workshop? We've just initiated a contract with a contractor. And so we're currently looking at a work plan and we're gonna work with a contractor to develop a list of experts, a recommended list of experts to include in the discussion. And you plan on starting your deliberations this fall? Yes. Something we obviously need since we're doing things in parallel need to be involved with. And I've talked to Micah and we've had coordination and communication and I definitely hope that some of you or some can either attend or participate as part of the panel. I'm wondering if maybe we could schedule our meeting to back up to that or something. I know that would be a long time commitment, but do you have or will you have a rationale for why you chose the six valates that you did? Part of it is that the recommendations of the NAS panel. And we are looking at common adverse outcome and as Earl and Paul indicated, it seems that the male reproductive tract is the primary target of toxicity. But as Earl and Paul also mentioned before and as we're starting to realize as we get farther into the assessment, there's new data emerging on other phthalates that may cause similar adverse outcomes. So do we just continue to add phthalates to the assessment or can this serve as a framework? That's one of the issues that we hope to discuss at the workshop also. This is a first step though. Question about selecting a non phthalate anti antigen. First of all, how many would be enough to make this kind of accumulative evaluation better? Is one enough, is two, is three? Because this is an EPA activity, would it have to be a pesticide? I don't know the answer to that. The list that was presented as part of the recommendations from the NAS is quite a long list and includes PBDEs, dioxins, PCBs, some pesticides. We have talked to OPP and they're aware of what we're doing in our assessment and we continue to keep in communication with the different program offices but I don't have an answer for that right now. I mean, at this point what we're doing is the six phthalates and accumulative assessment for those six. There's also a question of how widespread would the exposure have to be to that particular material to really be in addition to the cumulative risk assessment because if it's a pesticide to which a very small number of applicators or users are exposed, would that be relevant as opposed to a PCB or a dioxin where everybody might be exposed? We're trying to scope out the extent of the exposure information that we're going to include. Obviously, we're going to have to with doing the cumulative risk assessment for these six but with regards to the pesticides, it's interesting that you say that because for a lot of pesticides, phthalates are inert ingredients so you may not even have a measure of exposure. So are we overlooking, so phthalates like DET are common components of pesticides? I would have to refer to somebody in OPP but after my discussions with them last time, it was evident that they are inert ingredients and pesticides. So I'm wondering, I don't know which phthalate. If I was remiss in not inviting OPP to the meeting or maybe we can have them at a future meeting. Does the panel have any other? Thank you, Jamie. Look forward to the fall meeting and before I introduce the next speaker, I am collected to introduce Donald Havery from FDA, the Office of Cosmetics and Colors. Our next speaker from FDA Center for Devices and Radiological Health, it's Ron Brown. Good afternoon. So I'm going to discuss our experience with phthalates and medical devices. DEHP is the primary plasticizer in PVC medical devices. We did have some knowledge that DEP and maybe DBP were used as solvents and inks on IV bags but that's really a minority of the exposure. Really the main actor is DEHP. So in 2001, we conducted a safety assessment of DEHP released from medical device materials and that report was put on the website and that's readily available to the chap. In fact, Dr. Schwach, you may remember when you were the acting principal deputy where you had included a summary of that study on the update of FDA activities and the JAMA notification that you had. So that's been out there for a while. But we did recognize that there's some new studies coming down the pike and I'm sure you've heard about some of those today and yesterday. So we are updating that risk assessment under the auspices of the International Organization for Standardization. But it was the earlier safety assessment that served as the scientific basis for a public health notification that we issued that provided healthcare providers with guidelines on what types of phthalate containing devices to use in what patient populations. So just briefly, some of the recommendations were don't alter a medical procedure just because you're worried about exposing the patient to phthalates. That gets involved in a recent benefit decision. So really the main decision was a medical one not necessarily worried about exposure to phthalates. But if there were alternatives available for certain procedures that you should consider them for high risk groups like male neonates. One of the challenges though is that the labeling is such that healthcare providers now have a difficult time determining which PVC devices are plasticized and not and that's something that we're working on possibly with labeling guidance. So in that safety assessment there were really three parts. One was an exposure assessment specific to devices. The other was an effort to derive a tolerable intake for DEHP. So conceptually the tolerable intake is similar to the EPA's RFD or maybe an acceptable daily intake. One of the differences though is that we can derive a tolerable intake for different routes of exposure and even different durations of exposure. And the process to derive those tolerable intakes is really based on an international consensus standard that was developed through ISO. So we can get international buy in on the methodology. We base the parenteral TI actually the intravenous TI on the data in the Comek et al 2002 study. So that was a study in which they administered DEHP solubilized an intralipid intravenously to three to five day old rat pups. So technically it was not a trivial undertaking. They exposed the animals continuously for 21 days and sacrificed them. They had one group that they did the necropsy on and another group they carried out to a recovery phase in 90 days. So we thought that was a particularly strong study to base the TI on at least for medical device related exposures. One, it was using a clinically relevant route of exposure. Used a clinically relevant vehicle. We are probably familiar with some of the vehicle effects with DEHP, whether it's from DMSO or ethanol, maybe affecting lung morphology and what have you. We knew that patients do get this intralipid solution as part of an IV feeding regimen. So we thought that was clinically relevant. Certainly the animal model or the age at least was a sensitive subpopulation. And we knew that it covered that very vulnerable period where the male reproductive tract is developing that gestational day 15 to 17. I think we heard Paul talk about that earlier this morning. So we think that that's a especially good study to base the TI on. My colleagues at the National Center for Toxicological Research or NCTR did a similar study. And they reported the results at the SOT meeting last year. And we were very pleased to see that the NOEL and LOEL tracked very well with the values in the COMAC study. So we have high confidence that that's a good study to base the parental TI on. So that's really one of the things that makes our safety assessment unique. We've heard about the activities ongoing or forthcoming in iris. And certainly the NTP has been very active in this area. But we really focused on effects after parenteral exposure. So what are we doing now? I mentioned briefly that we're revising the safety assessment under the auspices of ISO. Taking a look at the whole range of data, but we found that at least for parenteral exposures, that although there are a number of new oral toxicity studies, there really aren't any parenteral studies that would change our earlier assessment for the derivation of the TI. But we are including inhalation in this draft, which makes it somewhat unique. We're also going to include a section on how to evaluate the significance of the TI, how to compare the dose to the TI. How much above the TI do we have to go before we start worrying about the potential for adverse effects? So really putting that into context in a risk characterization framework. The other thing we're doing is we're revising our exposure assessment. And in fact, I have a student working on that right now. So there are a number of new and important studies in the literature. So we're updating that component of the safety assessment. We're also conducting some of our own exposure assessment studies. And I'd like to describe three of those to you based on the data gaps that we identified when we did our first exposure assessment, the first of which we found that there were very poor data on oral exposure to DEHP from internal feeding tubes. So critically ill patients, particularly critically on neonates, who were receiving internal feeding, we found that there was a gap there. And we knew the potential existed for relatively high dose of DEHP to be administered to these patients, only because many of the feeding solutions, the baby formulas, had fat in them that would result in the migration of the DEHP from the tubing. So we've done that study. I'm embarrassed to say that's been sitting on my desk and needs to get out as a manuscript. We're ready to send that in. But we've just started to study literally this week. I was just down talking to our collaborators looking at DEHP exposure and critically ill patients who are getting cardiopulmonary bypass. So there have been one or two other studies in the literature. Japanese investigators have looked at exposure of patients on cardiopulmonary bypass. But we had plasma levels of DEHP. So it was harder to back extrapolate what the dose was that would have resulted in those plasma levels. In this study, we're going to look at urinary and metabolite levels. And we're going to back extrapolate based on the pharmacokinetic models that Dr. Koch and others have developed. I think that'll give us a better handle on what the actual doses are. So that study is being done with investigators at the Children's National Medical Center here in DC. So in addition to those patients, we're going to have 30 patients on cardiopulmonary bypass. We're also going to have 30 critically ill patients who are in the pediatric ICU who are being treated with PVC medical devices, but who will not have cardiopulmonary bypass or extracorporeal membrane oxygenation. And then there's a third control group of relatively healthy patients who present to the cardiology clinic for various reasons, but there's no reason to expect that they would be exposed to PVC medical devices. So that study is just starting now and hopefully we'll have some preliminary results by the end of the summer. We hope to move quickly on that. We also have a study looking at DEHP release from hemodialysis circuits and that's being done in conjunction with investigators at the University of Michigan. And again, that study is just starting as well. So based on our earlier exposure study, we recognize there were some gaps in the literature, especially for patients who are exposed to fairly high doses of DEHP. So relative to a general population exposure, maybe this isn't significant in terms of size, but it certainly is significant in terms of the magnitude of the dose. So we felt it was important to do those studies. And then finally, we're at the very early stages looking at aggregate risk of exposure to DEHP and MEHP. So we typically think of MEHP as the endogenous breakdown product, metabolite of DEHP, but as Dr. Strong showed in her slides, patients can be exposed to not only the parent compound but metabolite from exogenous sources. So for example, with PVC, if it undergoes gamma radiation for sterilization, you can have breakdown of the DEHP to MEHP. It's also true in stored blood in the blood bank if you have esterases in the plasma, it's gonna break down the DEHP release from the bag into the MEHP metabolite. So we've got patients exposed to not only DEHP, but exogenously formed MEHP. So we've had some early thoughts about how to do a cumulative risk assessment for those two. But at least from a device perspective, we have very few exposures to phthalates other than DEHP. So it really gives an overview of where we are with the safety assessment and the new exposure assessment and just some of the new exposure studies that we're doing in the Center for Devices and Radiological Health. So I'll be glad to try to answer any questions if I could. Thank you, Ron. Has the device industry moved away from DEHP as the main plasticizer? We're finding that's true for some devices. For example, I talked about those interal feeding tubes. I would say almost universally they've gone to silicone tubing. It's more of a challenge for other devices. And we were talking about cardiopulmonary bypass. I think because of the unique properties that DEHP imparts to that type of tubing. And also I think it's well known in terms of its hemocompatibility profile. It's thrombogenicity. In those devices they have not moved away from DEHP. Although I do know there's some interest in looking at alternatives like citrate-based plasticizers, TOTM, and there's some discussion about moving to DINCH as well. But we haven't seen those devices yet. What long-term studies are there on these infants that have been benefited from some device that has a high level of DEHP that gets transferred into them? What are the long, at least out through adolescence? Only one study that I'm aware of and it's actually a very small study. So I know that Dr. Swan talked about many of the general population studies that have been conducted or studies in which the primary round of exposure was oral exposure. It's actually a very small study done at Children's Hospital. Dr. Rice Barami looked at 16 patients who had been exposed in relatively high levels of DEHP while they were being treated on extracorporeal membrane oxygenation and then followed them into adolescence. The problem, of course, is that there are so many factors that could result in ultra-reproductive endpoints. In fact, in these 16 patients, they found no difference between those patients and controls. But the sample size was too small to draw any definitive conclusions. I just want to point out that in the Rice Barami study, no exposure was assessed. That is very important. And of course, that's always a challenge in exposure studies. And even if it had been assessed, it's difficult to know what exposure as a neonate means 16 or 18 years later when those patients are exposed to thallies for multiple sources throughout that time period. Just a question out of personal interest. How do you handle the risk-benefit equation for voluntary medical patients like voluntary blood product donors? Plasmapheresis. Plasmapheresis, atheresis, trombot, platelet pharesis. How do you handle this equation for these voluntary patients? That's really done on a device-by-device basis based on that patient profile. And I don't want to make it seem like I'm sidestepping the question, but those devices are regulated by our Center for Biologics. So I haven't been as involved in those types of devices, but it's an important consideration if the exposure is voluntary as opposed to life-saving measures like cardiopulmonary bypass. We have not differentiated, or we have not taken risk-benefit into account in the derivation of the tolerable intake value. That's strictly a science-based and science-policy-based value, science-policy to the extent that we used uncertainty factors. But it's really up to the risk managers to use that number in making risk-based decisions on individual products. Are you aware of any phthalite exposure from other medical devices other than tubing, et cetera, et cetera? Yes. There are some dental devices that will expose patients orally to phthalates, primarily DEHP, but there may be some others as well. Tubing really, though, is overwhelmingly the major contributor of exposure, especially tubing that's in contact with lipophilic substances like blood or plasma. I probably didn't express myself correctly. Medical devices is one thing, but then drug and drug formulation, drug delivery, vehicles, et cetera, et cetera. Are you aware of any of this? Actually, I'll defer to my colleagues in the Center for Drugs, but of course, when you have drug formulation vehicles, especially if their intent is to emulsify or solubilize a lipophilic drug, the potential does exist for those agents to extract phthalates from the tubing and bag. Well, I'm thinking in particular of capsules, of which I'll show you a quite enlarged version here. Do you have any idea what exposure via these routes is? I don't, and we have not investigated that. Don't you think that's a dangerous omission? Well, most of the implanted devices are actually using fairly hard plastic, so it's our understanding that phthalate plasticized PVC is not typically used in implanted devices. No, no, no, this is not implanted. This is an enlarged version, you just swallow it. It's a pill. Oh, okay, then I am not personally aware of those devices. We have someone from the drugs on the line. Yeah, I'll address it when I speak. Thank you, Abby. We've heard a lot though about that one of the primary exposures can also be from food. Is the FDA involved in all and looking at phthalates and food? I'm gonna defer to my colleagues from the Center for Foods to answer that. In terms of the exposure study, what are your goals there? I mean, is it to define range of exposure, the highest exposures? Because I know there are such studies in the literature. And then the second part of that question is, would you be collecting any potential health outcome information, such as a blood sample to look at liver function tests in the neonates or bilirubin, something like that in the plans as well. So the goal of the study is to not look at health endpoints, but we are gonna look at liver enzymes just to make sure there are no, there's no underlying liver disease that might affect the metabolism of DEHP. We're also looking at Bisphenol A as well. I didn't wanna necessarily raise that to this committee, but we're trying to catch a cast a wider net. In terms of the goals are both to characterize the range of exposures as well as the upper bounds to the extent that we can with 30 patients. They will have, they won't be entirely homogeneous in terms of the procedures, but for the most part, the patients on cardiopulmonary bypass to go through a certain regimen or procedure. So there'll be some variability, but maybe not much, but we're gonna try to capture that to the extent that we can, similar to what Dr. Califat did in looking at bending the patients into medium, low, medium, and high exposures based on device use other than cardiopulmonary bypass. And you, excuse me. Yeah, the NICU study. Of course, you were the primary. And we actually have, well, we have samples now from about 50 NICU babies that we're gonna be looking at, in addition, you know, the separate study, looking at phthalates and BPA as well. So we're hoping, you know, whenever we get the data, it'll be published relatively soon. So your studies, obviously, have been very useful in the design of the study and really serve as a roadmap for our efforts. And it was, if I remember, you did not look at kids with cardiopulmonary bypass. So we wanted to address that, yeah. Yeah, correct. We did not. And the other thing that we did in our study too, the recent one that's not published yet is trying to determine if the exposures are coming primarily from the medical devices, the feedings, et cetera, because a lot of the NICU babies, you know, are receiving supplementation, formula or extra nutrition, which, you know, basically they could be getting their exposures through other sources. So how are you considering that or just are you collecting that information as well? We are. And we've, we think we've been fairly comprehensive in developing a database, a priority to look at some of the factors. Although it's a challenge for DEHP, it's maybe even more of a challenge for Bisphenol A in trying to keep track of, you know, what baby bottles do they use, those types of things, what kind of formula. So, yeah, we tried to build on your work as a basis for this study. Any other questions? Thank you, Ron. Next we have Don Havery from the Center for or the Office of Cosmetics and Colors. Where did you find that slots on this side? Thank you. There we go. Oh, okay, hold on. This one? Yeah, thank you. Thank you this afternoon. Just for a few minutes, I'm gonna describe for you the information that we have collected on phthalates in cosmetic products since our, we started working on this in 2002. I'll talk just briefly about our regulatory authority because that has an impact on the information that we have on cosmetics. I'll talk about the phthalates that are used and then I'll focus primarily on the surveys that we've conducted since 2002. I'll talk briefly about exposure assessment and finally our conclusions and our future plans. First off, our regulatory authority. We have no pre-market approval for cosmetic products. There's no mandatory safety testing. There's no mandatory submission of any safety testing and no mandatory reporting of those safety tests to FDA. We can ask for it during an inspection but a manufacturer's not required to give us that information. So as a result of the regulations that we operate under, the regulation of cosmetics is entirely post-market. We have as much information on what is on the market as you do when you go to your grocery store and look at the foods or the cosmetic aisle in the food store. That being said, however, manufacturers are responsible to assure that their products are safe. They are responsible for conducting tests although the FDA does not tell them what tests to conduct and of course then they have to conduct any additional research that they think is necessary in order to assure that the products are safe. These are the phthalates that we know are used in cosmetics, the dimethyl, diethyl, dibutyl, benzoyl butyl and I raise another point just for your information. There is about 25 other phthalate derivatives that are listed in the International Cosmetic Ingredient Dictionary. I listed a few there just as an example. These are higher molecular weight phthalates so I don't know if they impact on what you're doing but just so you know, they're out there. In cosmetics, phthalates function either as a fragrance, solvent, primarily the diethyl phthalate is the best-known solvent, a plasticizer, the dibutyl phthalate is the best plasticizer in cosmetics and occasionally as a denaturant. The FDA does have a voluntary cosmetic registration program. We don't really know what part of the market this program captures. We estimate right now it's about one-third but we don't really know since there's no pre-market approval and we don't know what's on the market but just to give you an idea of the distribution of phthalates that we have filed in our program, we have only three products and they're all hair products with dimethyl phthalate. The bulk of the products are diethyl phthalate and these are in a variety of different types of products. The dibutyl phthalate is almost exclusively in nail products and we currently have no products filed with benzoyl butyl phthalate. Now I'll talk a little bit about our surveys and I can tell you that at least this survey is published and I can give you a reference for that. The second survey has been submitted for publication. We've done three surveys. The first survey was in 2002 and 2003 where we surveyed 48 products and 67% of those products had at least one phthalate in it and I should tell you that it's gonna be hard to remember the numbers so when I'm done here I'll show you some trends that we've seen over the years. As you might expect, the diethyl phthalate is found most frequently, it being an effective fragrance solvent and we think it's there primarily because of the fragrance. It's found in just about all products. I'm not sure why we didn't see it in shampoo, probably just because of the random draw of picking a product or two from the market that didn't have it. You can see that the range is quite substantial going up to almost 4% with an average of about 3,000 parts per million. The dibutyl phthalate was found in a number of different products, typically nail polish, hairspray, mousse, any place where you would want some kind of a plastic effect either on the hair or on your nails. The range in nail polish was also quite variable and it was found up to 6%, which is not surprising, that's typical for a nail polish. The dimethyl phthalate was found in three products, all nail polish and the benzyl butyl phthalate was found in one hairspray. We conducted a similar survey a couple years later in collecting products that were on the market between 06 and 08. We surveyed 60 products, this time we decided to include baby products since that became the focus in the literature of an issue. We found 52% of the products had at least one phthalate. Again, ethyl phthalate was found most frequently, but this time only in 35% of the products. Similar to the previous survey, we found nearly 4% in the fragrance, so there wasn't much reformulation going on in the fragrance products. Dibutyl phthalate was only found in nail polishes in the second survey. Again, there had been some reformulation going on, but again, levels as high as roughly 6%. In the second survey, we could not find dimethyl phthalate or benzyl butyl phthalate. In that second survey, the baby products we looked at, 24 products of a variety of shampoos, body washes, creams, lotions, and oils. We found diethyl phthalate in five of those, the highest up to 274 parts per million diethyl phthalate, most likely there because of fragrance. Our last survey, which we just completed, was done under contract, so these data are preliminary. We tried to maximize the contract by doing single point analyses, so we need to go back and re-run some of these samples in our own laboratory to confirm them before we're certain of the data and before we can publish it. But this is our preliminary data. We surveyed nearly 200 products in this survey and we also included baby and children's products. In this last survey, 23% of the products had at least one phthalate. Again, diethyl phthalate was found most frequently, this time in 18% of the products, and dibutyl phthalate was only found in 14% of the nail products. There's clearly been some reformulating going on. In the baby and children's products, we included 49 products of a variety of products you can see there. Diethyl phthalate was found in only five of them at levels up to 390 parts per million. Now I'll try to put it all together a little bit in focus. The trends that we've seen since 2002, if you look at products with at least one phthalate, it's pretty clear that the trend is down. The cosmetic industry has been reformulating phthalates out of their products. The percentage of dibutyl phthalate in nail enamels has almost gone to zero. If you look at those numbers, the highest we found was seven parts per million in a nail enamel. And I have to throw in one caveat here. Cosmetic products have a shelf life of two to three years. So when we go out and buy products for surveys, we don't really know how long they've been on the shelf. So for these trend date on this last slide here, they may have been on the market, no seven. So some of these higher numbers, if we were to run out and buy samples today, they might not be that high. It's a little bit difficult to know exactly what's on the market at any particular point in time because of that shelf life issue. For that reason, we intend to have to run another survey two years down the road to see if the trend continues. And I make that point primarily for the fragrance products. If you look at the trend, it's clearly down, only half of the products that we looked at had diethyl phthalate. And these are fragrance products like perfume, not a fragrance cosmetic product. So the high that we saw still of about 4% in the products we just looked at may have been a product that was put on the market two years ago and may have been reformulated at this point in time. So a summary of our observations in our surveys, certainly the frequency of use of phthalates in cosmetics is declining. The use of dibutyl phthalate in nail products has significantly declined. Frequency of use of diethyl phthalate has also declined and who knows in two years time, it also may be nonexistent. The diethyl phthalate concentration, however, in some products may be still high, but we don't know. We don't really know what those pieces of data mean until we conduct another survey and confirm it. Just a point of information, two exposure assessments that we're aware of. You probably are familiar with the cosmetic ingredient review. This is an industry supported group of scientists and physicians who review the safety of cosmetic ingredients. They reviewed the safety of phthalates in 2003 and this is published by the way. As part of that review, they did an exposure estimate to dibutyl phthalate and they assumed four cosmetic products were used at one time, nail polish, hairspray, deodorant and perfume. They used a dibutyl phthalate concentration of 15% which is way out of sight now compared to what appears to be on the market nowadays. They used a skin absorption of 5% which is data from a Mint publication in 94 and nail absorption of 8.5% which was obtained from the cosmetic industry. And they calculated a total exposure of about nine micrograms per kilogram per day. So that number though based on our current survey data is gonna be a whole lot lower because a good deal of that exposure comes from the nail product. We also calculated exposure from cosmetic, from fragrance product, again a perfume in 2005. We had measured 3.9% of diethyl phthalate and the fragrance so we used that number. We also knew that the skin absorption was about 4.7% again from the Mint paper and we calculated about 16 micrograms per kilogram per day. So our conclusions based on our work since 02, there's been a significant reduction in both the frequency of use and the concentration of use in phthalates in cosmetics. Diabutyl phthalate appears to have been removed from most nail products. So exposure from cosmetics now is extremely low. The diethyl phthalate frequency of use is declining. We are not quite sure yet if the concentration of use, clearly it's going down in most products. Again, because we don't know what that data point meant and whether it was a current market product, it's a little bit hard to say exactly if all fragrance manufacturers have removed the diethyl phthalate or reduced it in their products. We plan to continue to monitor the research on health effects of phthalates and we're certainly gonna need to conduct another survey, at least one more in two years time to find out what current levels are and to see if the downward trend continues. Thank you. Thank you. Any questions from the panel? I have two questions. Thank you for your comments. My first question is when you talk about serving products, how do you select the products for the survey? Is it in some way a random sample or are they chosen by market share? It's completely random. So you go to your local CDS and say. Just start pulling. Start pulling. It's unfortunate again because of our regulatory authority and our lack of knowledge of what's out there. We really don't know so we just pull them randomly. That's our only option. And also when you say that the products are being reduced in their uses for certain things like fragrance or something, do you have a sense of what's been used to replace them or have you looked into that at all? A couple of years ago when we met at a meeting with some fragrance industry folks, they told me the diethyl phthalate was a perfect fragrance solvent and they were very reluctant to remove it. But they did say that they were studying two alternatives. We haven't looked to see if those are the two that have replaced the diethyl phthalate. No, they're not phthalates. Off the top of my head I can't even remember what they were but they were not phthalates. Okay, well, Michael, they list ingredients on cosmetics. Is that strictly voluntary? And since I never see phthalates listed, is that because they're generally part of the fragrance or consider part of the fragrance? Yeah, that's exactly right. By regulation, fragrance ingredients can be listed as fragrance. That's because there could be 300 or 400 chemicals in a fragrance and you wouldn't be able to fit it on a bottle. So when the labeling regulations were created, that was the argument made for just using that word fragrance in place of all those other names which wouldn't mean anything to anybody anyway. Yeah, well, most of the ingredients in shampoo are, don't mean much either. But okay, so it's, because even though it's not a fragrance itself, but it is part of the fragrance. If it's part of the fragrance, yes. But if, for example, they were using di-butyl phthalate in a nail enamel, that would have to be listed on the labeling label as an ingredient. You would see that. Okay. Yes. Thanks. But there's no chance of changing that. That regulation, not unless you want to buy a 10 gallon bottle of shampoo so they'd have enough room. You know, even just with an asterisk, you know, in this list of fragments it could include or it does include phthalates that blah, blah, blah. I can't imagine, well, I imagine they, I suppose they could do that, but I've never heard anyone suggest that, no. It appears that they want to take it out based on our survey, so. Order, I mean, I thought it would, was more because the fragrances were a trade secret, but. Certainly that was probably part of it. When those regulations were being developed, the fragrance industry did not want it to divulge that information. Any more questions? Holger? You only analyzed the low molecular weight phthalates. Did you also analyze the EHP, DINP in those products? Well, those other, those phthalates that I listed are the only ones that would be in a cosmetic product. As with a certain purpose in it, yes. But we know from wood stuff that some phthalates can accumulate in the fatty fraction. So if I would assume that during the production of chapstick lipstick solution, some creams, there might be an accumulation of other phthalates like the EHP, a known phthalate during the process. So I would be interested in the content of these products because if you assume you use chapstick lipstick every day, there might be significant oral uptake this way. So that would be interesting. That's a good question. A chapstick would be a drug, however, but lipstick would be a cosmetic, but you're right. It would not be listed on the label because it was part of the manufacturing process. We could look at our data. We have the specter just to see if there was any other phthalates there. It's probably a good idea to do that. In the surveys, you said they're published. Is that in the literature or on your website? It's not on our website. The first survey's already been published. That's in the Journal of Cosmetic Science. The second survey was submitted to the same journal. So it will probably come out next year. Okay, can you send us a site for the first one? I can give you a copy of that paper. Okay, great. Thank you. Abby, are you still with us? I'm still with you. Could you please tell us what's going on in the Center for Drug Evaluation? Yes, okay. I will ask if we could make some kind of an estimate of what the exposure is to phthalates through pharmaceuticals. For pharmaceuticals, none of them have DEHP. One still has diabetes phthalates being reformulated. However, quite a few have diethylphthalates as part of sustained release and delayed release products. However, these parts were not thought to have toxicity at the amounts being used, so there's been no effort to make suggested people reformulate them, although they can reformulate them on their own. Other phthalates used are not alkyl phthalates. Actually, most of the phthalates currently used are cellulose esters, such as hypromelos phthalate. The interest from CTSC seemed to be for the alkyl phthalates, so we focused on the diethylphthalates for which we have a number of products. We'll actually know exactly how much of what phthalates are in all prescription products. It's not publicly available. We identified all prescription drugs that contain phthalates, and we know the exact amounts. So one idea is to determine the number of prescriptions written for these 20 or so drugs that contain amounts of about one milligram or more per unit dose of phthalate, and with knowing the prescription numbers and the amounts in a drug, you can get an estimate of the exposure. This information could also be stratified by age or any other way that people making this estimate would like it to be stratified. So this has been our plan. We hadn't really done anything before because it hadn't been considered to be a safety issue. So are there any questions or suggestions about what kind of information you would like us to derive from what we have? Questions from the panel? Yes. Any questions? I mean, I figure out the 20 or so drugs that have the diethylphthalate in it at a level that would be of interest, and we can determine the number of prescriptions written and that information could be stratified. Would you like it stratified by age, any other way you would like it to be stratified when we get this information? It doesn't take a year to get it either. Well, I'm thinking, do we need diethyl? Do you need it at all? Okay, I see a yes. Okay, go ahead. Just wanting to confirm that there's just one medication left with dibutylphthalate in it. Yes. What has been the situation, let's say, five years ago? There are just a couple more. That would be highly interesting because that's the current biomonitoring data from the fourth report. So that would be interesting to know the situation in the year three in 2004. The enzymes that children with cystic fibrosis have to take large amount of enzymes for digestion. And so it's given slow release and protected from immediate digestion, but they take lots of it. So a number of those had dibutylphthalate in them. They've pretty much been all reformulated. There's one product left, and it's in the process of being reformulated. Do you tell us which product? No, that's confidential. Can you tell us the class of drug or any, give us a hint? It's for the GI. Okay. When I give the 20 or so drugs, I can tell you if it's in for neurology, indication cardioleno, because the exact amounts for a particular drug is confidential information. Can I ask specifically about those capsules for release in the stomach? I don't know, look at this situation from a European perspective. Are you sure these capsules don't contain any high molecular weight phthalates? I mean, the hypermellows, phthalates, those cellulose esters of phthalates, they do, yes. They're not considered alkyl phthalates. But like DEHP, DINP? No, none of them do. And they would have to report this to you if they did? We'll have the exact composition of every composition. Okay. Both components, all of the ingredients. Including the inert ingredients. Yes, absolutely. Okay. And, oh, go ahead. I was gonna ask, you mentioned the cellulose, and I think there's the vinyl acetate and... Yeah, there's a cellulose acetate phthalate to a right. We have the original request was to look at alkyl phthalates. Are alkyl phthalates used to make those in their manufacturer? I don't know. In manufacturing? I haven't looked into the manufacturing. I'm just wondering if they were, then they may be present in the polymer. I'm not sure that they are, I don't know. I'm just asking. Well, by the way, I'm sure you're gonna be small compared to the amount of phthalate you actually have from these 20 drugs. We're talking about a milligram per unit dose or more. And when these drugs are reformulated, I mean, is that a process that takes months or years or? Depends on how much trouble we're having. It can be compatibility issues. Depends on the product. And does it go through formal review? I don't know the process. Absolutely, it goes through formal review. Well, I would think that if these are mainly like time release or entericotid, then they would have to at least do some kind of bioavailability. Well, I have to make sure that it really gives the claims to be, and it has to be equivalent to what they had before, so that they don't have to do new clinical study. Yeah, and I guess we can ask the same question as we did for cosmetics. Do you know what the substitutes are? And there's other phthalates, but they were replacing methacrylates afters before, a lot of... So if they're taking out dibutyl or diethyl, what are they replacing them with? The hypermellophthalates. Okay. And we can have methacrylate polymers, which have their own set of taxisities. They're replacing them with polymers. I like polymers. Yes, it's always going to be a polymer for the delayed release, sustained release. Okay, now the polymeric ones, the polymeric phthalates, do you know, are they designed to hydrolyze that part of the release mechanism, or are they supposed to stay intact? Do you know that? Well, they're supposed to stay intact, depending on what the product is. Usually, the sustained release needs its little by little release, and then there's those that you want to get all the way through the stomach to the intestine. You don't want any degradation at all in the stomach. Yeah, I'm just wondering what happens to the conjugate, the cellulose phthalate? Yeah. Does it lose phthalate groups or something? I'm sure. Well, phthalose itself isn't degraded very well in the human. Right. But the phthalate, I mean, there can be esterases. Yeah, well, I'm wondering if it can release phthalates as it slowly releases the drug. I'm wondering if these compounds... They're a big phylic acid. Well, if that's what it is, that wouldn't be so bad, I guess. Are you discussing both over-the-counter and prescription? This... Um, at times of prescription, originally, I did a search in a literature suggesting that there were some patents for using phthalates for aspirin-I-vuprofen, but when I looked up the actual composition of the large suppliers of it, they were not using the diapophthalate. They had other Walgreens. I looked up Walgreens. I looked up Walmart. I looked at bottles in the store. I didn't see any. They had the composition. They had other compositions. There was no diapophthalate. How about supplements and nutraceuticals? Is that included in that? That's regulated by drugs. That would be regulated by foods. Sit down. You don't have anybody from foods. You just had the cosmetics person. I don't know why we're being a dietary supplement. I don't... Well, I guess for the same reasons it might be in a drug to slow release or delay release. We don't regulate those, so I didn't look it up. Let's see. But if we were to pursue the exposure data on diapophthalate, asking the panel what kind of form would we want those data stratified or how to stratify it? Or is this something we need to maybe think about for a few days? I actually have somebody. There's somebody on the phone. Hi, Abby. This is Steven Chang. Yeah, he's on the phone. Please, we can do any search you want. Okay. All right, panel. I guess we're just trying to figure out if there's some age groups, if you're looking more for adults versus pediatrics, or you're looking for gender or an ages, there's many couple of ways that you can sort of acquire this information. So there's also some other things you can look at too, but I just wanted to see what kind of about your staff. Well, this is Mike. I think that there are probably more than one way that the panel would be interested in because we likely will be looking at general population as well as women and neonates or pediatric uses. So maybe we'll get back to you on the specifics. Well, neonates would not be having sustainably, slow release, they'd be getting IV formulation. Right, right, yeah. So. Less than one years of age, if you still need it that broken out, that would be useful. Okay, well, I mean, it's right now, it's useful to know that you have the data and that you can do this. And I think when we'll spend a little more time deciding exactly what it is that we need before we ask you to do the analysis. But I didn't know if you were thinking about duration or how long people use these for as well. I didn't know if that would be useful too. Yeah, we're thinking about that and have to think up what other things we might want to consider. Would your list also include things like inhalers? Are you used by asthmatics? They don't have any phallates in them. To deliver. If you want some products, well, we can look into that. But if there were products that included, you know, we could look up asthmatics and inhalers. Or the delivery system, because I know there's some data that hasn't been published showing that asthmatics have higher urinary MEHP. They can get things from the mouthpiece of the inhaler. Yeah, that's what I'm asking. That would be a hard plastic, not a soft plastic. Well, there's a ring in there. Yes. But it's within your jurisdiction. We did a search of all products that contained phthalates and no inhalation products came up. We have an internal database that lists all products and all excipients and the amounts of all excipients. Okay, so would these inert ingredients be listed in the PDR? Yes. Or the package inserts? Yes. So if something had a phallate, it would be listed there? Yes. Doesn't tell you the amount. It has it in the order of how much is there, but not what it is. Run for Mr. Mayor if you don't find it in the PDR with the composition. I have a general question back. I asked a few minutes ago, but I may be on the wrong track myself, and Holger, maybe this is a question to you, is in my head, I keep thinking that we've heard that food is an important source of exposure to phthalates. And if that's the case, maybe we need a food person from the FDA to speak to us. Because I don't have a good sense of. Yeah. When you say food, where does it- Well, FDA or the other option would be to try and find someone at agriculture, just to see if there's anyone there who has data or interest in this. Because we're taking food as different than medicine. I mean, this is food as in usual use of food, right? Well, the amounts are gonna be small compared to pharmaceuticals, actually. What particular food would you think you would be exposed to phthalates? I think we think that mostly fatty foods, but we've seen study after study suggesting that the diet is the major source of exposure for many of the phthalates. And it's not clear how it gets in the food, whether it's packaging or processing or environmental, but that seems to be the way it gets into our bodies. Do we have an idea of who we could talk to, maybe at another meeting about that? Yeah, we can try. The foods people weren't able to be here today, but we can certainly get in touch with them and we could try agriculture, although I don't know if they necessarily would have someone, but we can certainly ask. One other question I had. I would say that the FDA foods are not agriculture because they actually look at indirect additive and what comes out of packaging. Okay, although it's not entirely clear that it's just from the packaging. So anyway, I guess the other question I had is do we need, should we be talking to someone from Biologicals or are there any other federal agencies we should have on the phone? I mean, we've had conversations between the staff and CDC. We haven't spoken to OSHA or NIOSH, but that's something to think about for maybe future meetings is other potential sources of information. Well, biologic, the blood products could be in contact with soft plastic. That would be in CBER. Vaccines are there, but other biologics are in Center for Drugs. And you're certainly welcome to contact representatives of the Center for Biologics. We have, in our exposure assessment, we've incorporated those devices into outlets, but we can still give you some. Well, I think that's probably, well, it's up to the chat. Any other questions or the panel? Thank you very much for making your way here on a day without the benefit of traffic lights. And thank you, Abby. Abby's on the phone because she just came from another meeting and wouldn't have been able to drive over here. But thank you very much. But someone let us know if you want more information. Yeah, we'll let you know before we send you off doing something and then change our minds. Okay. Is there anything else you want to be looked up? I think for now we're good. Okay, just let us know, for me, no. Thank you. Well. Again, I want to thank everyone for their contributions. This has been really quite helpful. And I think we're saturated now with input. And my brain is rebelling. So it's, and it's also 5 p.m. So I think we ought to, unless there's some other business, we ought to adjourn. Okay, and we'll reconvene at 8 a.m. Tomorrow. Yes. Again, thank you all.