 Welcome to everyone. Good morning. I'd like to have everybody here. The chair fell as at home. And we'll not be here because of a travel glitch that occurred too late to be able to resolve it. So I'm feeling beyond my telephone probably from about 11 o'clock on and I'll be chairing the meeting. So Mike, what do you have for us to start out with? Well, welcome to our fourth meeting. And let me just remind everyone that today's meeting is being recorded. It's not being webcast live, but it is being recorded. And this is a public meeting. And we will have a sign-in sheet. So we would like people to at some point during a break make sure that they sign in so that we know that they're here. We do have copies of the agenda on the table by the door. So with that, I think that covers it. Byrne, do you want to take over? Why don't we introduce ourselves then we'll have the audience introduce themselves. I'm Byrne Schwartz, the vice chair for CHAP, and I'll be chairing today. I'm Chris Jennings from Virginia Commonwealth University, biostatistics. Holger Koch from Royal University in Bochum, Germany. You will buy a monitoring exposure assessment. Russ Hauser from Harvard School of Public Health, Environmental Epidemiology. Stan Barone, U.S. EPA, assistant sub-director for human health risk assessment. Let's finish the rest of the chair first. Paul. Paul, Leo, Robert Woodjarts from Medical School and the Environmental Occupational Health Sciences to New Jersey. Did you switch on? No, I didn't switch on. Thank you. It's very faint. Is it? Yes, sir. I'm faint as well. I'm Andreas Gottkamp from the School of Pharmacy University of London. In London. United Kingdom. Mike Babbage from CPSC. Steve Rosano, American Chemistry Council, Valley District. Brenda Hallow, Ferro Corporation. John Butale, I'm representing Ferro. Ann Clawson, Leitham and Walkins. Angela Collins, ExxonMobil Chemical Company. Amy Bakling, ExxonMobil Biomedical Sciences. Pat Marvin, BASF. Laurie Keller, ExxonMobil Corporation, Public and Government Affairs. Quinn Dodd, Minnesota, representing ExxonMobil. Sean Oberli, Product Safety Letter. Sarah Garland, CPSC and Science Mission. Tommy Williams, CPSC and Health Sciences. Leslie Patton, CPSC Health Sciences. Ken Carlson, CPSC Health Sciences. Well, thank you all. Apology for being here. We have members and no choice if you have a choice. Thanks for coming. Mike, did you have other things that you wanted to follow up on before I talk a little bit about what we hope to accomplish today in the department? Yes, thank you. I just wanted to give a brief update on what CPSC has been doing. We have, we're still working on toxicity reviews of the phthalates. We started with the six phthalates that are subject to the regulation. We gave, recently presented the CHAP with a list of, I think it's 17 additional phthalates. And we have 10 more coming from the, coming from Versar that are starting to trickle in. So by the end of next month or soon after, we hope to have at least drafts of the remaining ones. So that'll give us a total of 30-some toxicity reviews. And let's see. We're also working on, or I think we just completed an update of the literature review for phthalates. So we'll be able to get that to the CHAP shortly. This is to cover the last couple of years worth of literature since our reviews and some of the other materials we've given you have been completed. Those are, I guess, the main primary activities. We also continue to coordinate with the other agencies. We're still awaiting some information from the Food and Drug Administration on phthalates and pharmaceuticals. And we're also planning on putting together some chemical information, chemical use information. Once we've completed the tox reviews on the 30-plus chemicals, 30-plus phthalates, we're going to pull together some of the information on usage and how they're used and what the relative production is and so on. So we get a better handle on which ones might be more significant or more important to human exposures. You forgot about the exposure assessment? Well, we're continuing to pull together some of the exposure data. Most of it's covered in the Versaure review, but we're just pulling out the actual numbers and getting that into a form where Paul can use it for a scenario-based exposure assessment. In addition, our human factor staff are pulling together some of the use information, frequency of use, that sort of thing, frequencies and durations and consumer use patterns. So we're pulling all of that together. And I guess we also recently, along with the 17 tox reviews, had included a review for one additional phthalate substitute. We had an original list of five, so now we've got toxicity reviews on six of them. And I think that sums up where keeping in touch with EPA and Health Canada. Health Canada has got some. Well, in California, it has biomonitoring programs underway. There probably won't be data in time to benefit the chat but we're keeping close tabs on those other activities. And I think that about covers it. Are you aware of any other, either US agency or non-US government, that's about to come out with some document that is spread to potentially significantly impact what we do? No, I mean, the other agency working on this right now is EPA and actually a couple of different programs. But we expect to be done before them, although they may have some external review drafts of some of the reports that we can look at as soon as they're ready. That may likely happen before we're done. But I think our work will be completed well before the EPA. Speaking of being done, can you remind us of when we're supposed to be done? The deadline is from the time that you were officially appointed a day before the first meeting or whenever we started traveling. So that would make it about April 13th. So our deadline would be sometime in April, around that time in 2012. So we've got, we're about halfway there. And I think we're making good progress. We're at a stage in developing work product now where there will be an increasing interest from the media and other people who are wanting to see what we're doing. Can you remind us of the policies that you have for us being contacted by the media or wanting copies of our work product, either as individuals or as a committee? Yeah, and well, all our meetings, of course, are open to the public. And in fact, you can view them on the website. There are even transcripts of a sort available. It's actually closed captioning, so they're a little, they're not edited, but they're also available. We held a public meeting in last July. There'll be her testimony from the public, including non-governmental organizations and industry people. And we continue to receive comments periodically from interested parties. In fact, we just received a lengthy package from the Valedester's panel along with some other information. So the overall, our goal is to be transparent. However, the drafts are for the CHAP, and they are not, the drafts are not released. There won't be any, as far as I know, no opportunities for external peer review, that sort of thing. And as far as communicating outside parties with the CHAP, first off, anything that comes into the CHAP is public information, gets posted on our website. So I'd like to remind you, remind everyone of that. And we prefer that all communications come through to us, that people on the outside who want to submit information submit it to me or the commission and we'll see that the CHAP receives it. The CHAP is, you know, not obligated to speak to people on the outside. They're certainly not obligated to speak to the media at any time. So, you know, generally, the purpose of all, well, everything should be in the open. All the incoming information is, yeah, in the open, open to the public. But the CHAP report itself is confidential until it's ready to be released. But someone from the media contacts us. Yeah. And we say we're not free to release information, and they say, but just this one question. The best thing to do is to contact either me or our public affairs office, Scott Wilson or Patty Davis, and I will get their phone numbers and keep them handy. Because all, at CPSC, all media requests have to go through them anyway. So we should offer a response to a media question as to talk to Mike? Yes. At this point. And I will tell them to talk to Scott or Patty. But as we develop written components of the eventual report, that's all protected as a work product of CHAP. Yeah. I think the lawyers call it pre-decisional or something like that. It's incomplete work. And that incomplete work can go right up until we have a document that will roll out. Until it's all done and it's released to the public and the commission at the same time. The commissioners see at the same time the public does. So none of us should feel pressured by anybody, whether it's a different federal agency or a manufacturer or some researcher who shouldn't feel pressured to share with them our work product. Because it's pretty, it's pretty harmful to a committee activity when that happens. When somebody else is out there doing steps just ahead of you because they got a copy of what you were doing. Right. And, you know, part of the, I guess, part of the reason for it is so that there's no, you know, any, there's no influence. I mean, everything is done. The idea, CPSC operates under the Sunshine Act. So the idea is to keep things public, all interactions outside communications public. Which means when we're ready to show somebody, we're ready to show everybody. Right, right. Not an individual. Right. Okay. It's why, well, it's why this meeting is open. It might, when if some of the people sitting here want to meet with us, it has to be a public meeting and it has to be in the public calendar in a week or so in advance of the meeting. Thank you, Mike. That's helpful clarification. Any comments from any of the chat members? Questions or comments about this? Good. Let's say a few words about what I think we need to do today and tomorrow. We have now committed a fair amount of effort in these past months to begin to document what our assignments would look like. So we have written materials, we have calculations, we have analyses, we're gathering information based on assignments that were made a few months ago. And I think the purpose of this meeting would be to see that what we are starting on puts us on the right track to be able to answer the questions that were assigned to chat because there are interesting things that we might do, but if they are tangential to what our assignment is, they may not be helpful and in fact it may be distracting because it seems a lot of time and energy on things that we may not have a place for in the report. So I think it's a critical time for us to find out if our individual contributions begin to fit together in a way that's going to be helpful to us in meeting the charge. So because each of our contributions is slightly different from each other, there isn't one criterion that we can use, but I think it's important to know about the content of what we have produced. Is it right? Is it the right thing? For example, with Phil and I summarizing the literature on reproduction and development from animal studies, is that what you're going to need when, because we have to have documented in a literature review what you're going to use, for example in the hazard index analyses, so that you're not counting on data that came from nowhere as far as the report is concerned, and we, in order to do a broad review of the literature, we may have to include, and will include things that you're not going to use, but it would be noteworthy if you were counting on calculations, numbers, that Phil and I have provided a reference for in our section. So we need to see that we have the correct balance of information to support each other. To some extent, we need to begin to think about style. So the report when it's done doesn't look like it was authored by eight different people. We wanted to look like there was one common style that we use, and it's too early to worry about that seriously yet, that we can work on as we go, but just one example is how we're going to handle bibliographic citations. Are we going to have one bibliography for the whole report, or are we going to have bibliographies after each section? You'd have references specific to what that person's assignment was, which has some sense for it, but on the other hand, other people will use the list of references for a different purpose, and they will want them all to be together in one place at the end of the document, and they don't want to have to go and look through eight different places in the report to find citations, and also then to find out that in three or four of those sets of references, there's about a 50% duplication of references. So that's a style kind of thing that we need to talk about as we go to make the job easier to bring together at the end. As we talk today and tomorrow, we need to identify other ending areas that we haven't assigned coverage. Things that we still need to have that we haven't included in the earlier assignments, and we need to find out if that information is available and who's going to take that assignment and what's the product of that assignment. So we need to make sure that we don't end up in another few months realizing that there was a hole in the assignments, and it's very difficult for somebody to proceed because it's some other piece of information not having been pulled together. If we have meetings, Mike, I'm thinking a lot, and that's always dangerous, but I'm just trying to think about how many more meetings we might have. If we continued to meet at three-month intervals, we would have three or four more meetings, and that gives you a kind of a feel for the pace at which we have to go. I would think by the time we meet again in a few months, and we'll talk about this at the end of tomorrow, but by the time we have our next meeting, we should have a pretty good rough draft to begin to look at because it would take a couple of meetings of polishing and filling in the remaining holes and deciding, do we really want that as a conclusion or not? Do we want that as a recommendation? So if we consume very many more meetings on mechanics, we're not going to have much time to discuss recommendations. So I would say we need at least two meetings to talk about recommendations and sort that out, and maybe one more meeting, and I consider this meeting today to be one on mechanics, one more meeting on mechanics so that we have enough of a draft that we can all go back and then think before that second meeting out, think about what we personally feel the recommendations should look like and have a draft of recommendations before that second meeting out so that we come prepared knowing that this would be the first time that we're really forced to declare what we're thinking. And I don't take a meeting to just reach agreement on what we really meant by those recommendations and whether it's responsive and whether we can reach agreement. Like, I'm not sure what rules we are under. If we want to make some specific recommendations, are we going to vote on them one by one? Or how do we reach consensus on recommendations? Maybe we don't have to answer that today, but that's the kind of thing we need to be thinking about for that meeting when we talk about it. So we have three or four meetings left, that's all. Anyhow, those are the kinds of... So what I haven't said yet is that we don't intend to go through our work products today line by line to do wordsmithing or anything of that kind. If we started that, we could be here for several days. And that was, from my standpoint, that wasn't the intent of today. But instead to look at content and whether or not what one of us is doing is useful to everybody else and to begin to think about how it's going to fit together and look as a report. I would welcome your comments and thoughts about whether or not that that's a clear enough mission for today and tomorrow and whether or not you agree with it. I don't think we're going to be done in a couple of hours, but I also don't think we're going to be struggling at three o'clock tomorrow wondering how we're going to get the other half of the meeting done. Anybody else? Any thoughts about what we want to accomplish today and whether or not we can? I think I agree with what you meant, Tom. Thanks, Andrews. I think it's a good plan. I think you should meet as often as you need to, but not necessarily more often. In terms of style things, one thing that we might want to do well at some point might be easier to do it sooner rather than later, but to agree on some abbreviations and that sort of thing, are we going to call them valet esters for short or alcohol diesters or whatever, that kind of thing just, whether we do it now or at the end, it doesn't matter, but we're going to have to agree on that, you know, agree on a style for the citations and again, you know, that can be done at the end. But it would be more efficient. More efficient, but just do it well. Put it this way, it'll make my job easier at the end. That's important. Well, for one thing, we need to agree on one of the chemicals that we're going to cover and the agreement about the nomenclature is important because we're going to have those words in tables, we're going to have them in text, we're going to use them widely and it's more efficient for us to agree on some of those definitions and terms now than to try to retrofit things after the report is 90% done. That's a good point. And how we're going to pull the other references. So if you can give us an example of what several different kinds of references should be, whether they're peer-reviewed journals or whether they're government documents or whatever, if you can give us some examples there, then as we write our sections, we can begin to modify it now to adapt to that. Well, I can do that, but you don't necessarily have to follow that style. I mean, we have to have a consistent style. But you're saying that if we wanted to do it in a different format as a report, they're all in that same format. Right. That's not a problem. Right. But if we had an example that we could start from, if we wanted to argue for a different one, we can. Okay. Well, in order to keep us focused for the discussion for the rest of today and tomorrow, I thought it would be helpful to review and to lay out what are the questions that we are really trying that we should be looking at as we talk about the hazard index approach and we talk about the animal data, as we talk about the human data. So at the third tab in your book is the list of questions that you've seen from an email earlier. So first on being out of the hazard profiles of the temporarily banned phthalates compared to those of the banned phthalates, I think you need to have an answer to that because we are being asked for recommendations specific to what to do about the ones that are currently banned or those that are restricted. Is the mode of action of any of the temporarily banned phthalates the same as the mode of action for the banned phthalates? I think we need to be able to answer that and know what we're going to do with those that are restricted. And based on human exposures, what are the risks of human exposure to any of the temporarily banned phthalates? Now that is something to which we will only have a general idea at this point that we don't have that fixed yet from any discussions or analyses, but as we look at whether or not we're on the right track, we at some point have to answer that question. And do any of the phthalate substitutes reviewed in this report have similar toxicologic properties to the banned ones? We have to be able to answer that to know if there are others that we should ban, recommend banning. We don't have any authority to ban anything, but would we recommend banning based on that profile? And do any of the phthalate substitutes reviewed have a mode of action similar to those of banned phthalates? And based on human exposures, what are the risks of human exposure to any of the phthalate substitutes? In order to know whether or not we have some things out there that may be as bad or worse than some of the phthalates that we're worried about, we need to have that information. And then we added one more that goes beyond the charge, the specific charge to CHAP. It lies underneath a lot of our discussions. And as we've, at least for me, as I read more and more of the literature in the current discussions that you've put forward, it's important for us to have a really good handle on metabolism so that we know, I mean, first of all, it's a question of the combinations of the contributing factors that account for the toxicity that we see. It isn't just a pair of materials. It's a pair of material plus the metabolites. Some metabolites are sufficient in themselves. So it makes it a more complex picture. I think we have to have some goal here for clarifying to the best of our knowledge what role do the metabolites of these materials contribute to what we see as the toxicity of phthalates? Because we would be remiss with the amount of knowledge out there if we simply talk about the diastros. So I think that's a set, we need to be working toward answering that question even though I don't think that was a specific charge to CHAP. But our, I think our colleagues out there would expect that we would address that in the same way that we would have a special section on motive action as it relates to the toxicity and risk. And a few other broader questions of that kind. Thoughts, thoughts about, does this create a framework for us to go forward through the day knowing that these are the things that we want to be able to address not every one of these, by every section that we're talking about, but collectively we need to cover these. Am I missing something here? Do you disagree with some of these? Or is this enough to keep in the back of our mind that as we consider the contributions of individual people, if it doesn't fit one of these, why aren't we doing that on that track? Richard? Can I just add something? Sort of thinking back to the NRC report on phthalates and the idea of looking at common adverse outcomes as a way of grouping chemicals. I think that we've been talking about sort of common adverse outcomes being related to anti-androgenicity. It's certainly the case that my understanding is that phthalates aren't the only group of chemicals in that group. I think before we've talked about the fact that we don't start at zero, we have background exposures to chemicals outside of phthalates that might be considered similar enough to phthalates. So I think that's a really important question and I think it adds a lot of complexity to what we're doing, but I think it may be worth stepping into that. Responses to Chris coming? I'm worried about that. We have enough complexity to do better. We have enough complexity with phthalates and phthalate substitutes in their own right and to broaden this question to other chemicals really requires an incredible amount of work. I'm not sure that we have the time or effort available to us to prioritize how this set of chemicals relates to other sets of chemicals that may in fact need to be outcomes to be described. I guess I'm kind of thinking not that we would spend as much time on these other sets of chemicals, but to have enough of a background review in the report that would provide evidence of how similar other chemicals may be in terms of that they well could be in a grouping. It is a tough problem because it's hard to know where the boundary is, but I don't know that that means we shouldn't even address the question in whatever limited way or... I'm not even sure yet how we address the question of either additivity, taganism, or synergism among phthalates or phthalate-like compounds in our own analysis that deals with the issue and the exposure in the real world that it does in fact lead to a whole new set of questions that we have to consider and I'm not sure we're going to be able to do that. Andreas? Can I observe that we're going over the same ground repeatedly? We discussed that at the previous meeting and the meeting before and I think there's kind of a consensus here number one, we cannot ignore combination effects between several phthalates. Yeah, I agree. Number two, there is repeatedly mapped out in the literature and here in the panel, so there shouldn't be a problem. Number three, there's also empirical evidence of combination effects between phthalates and other chemicals and we've also discussed this number four, we've agreed here in this panel that these effects cannot be ignored they have to take them into account in some way. However, it may be a discussion how this can be achieved precisely but I think it should well, we've discussed it last time I feel there was a consensus there. And I guess that's the reason I brought it up that's been in my mind and I didn't see that as part of these questions If you point about these questions is to limit to these questions then that seems to be not part of that and that's why I brought it up. Thank you for raising it I think you're right we have this discuss and I think there was a general agreement about it as an issue how to get there from here is as an issue, I have no problem with it it's an issue, we all know it's an issue it's what degree of how far it rises in our analysis that takes us away from some of the central points that we're going to have to deal with do we ban you know, dallas from children's toys and dallas like compound you know, that's our basic you know that's our basic question and you have to be very careful that we don't get sidetracked from something that we all know is important to discuss that I just want to make sure we hit the target when we're finished I I realize that you're concerned about that 30 degree mine as well and maybe we can answer this I wanted to bring to the table an issue related to that which is at the end of the day we need to well, the charge the remit of this panel is fairly wide and this is defined and laid down in the legislation and many aspects which we need to address but I think the key point is we're being asked to say whether or not the existing ban should continue and whether the intermediate ban should be made permanent or not and I think that's the number of issues, there are other issues which we need to address as well but I feel we began this discussion last time already and I feel we need to get a little clearer in our minds in terms of what evidence is needed what criteria are needed in order to enable us to make this decision for example do we need an exporter assessment data for this decision or not is it based on hazard assessment only I think the questions tables are very helpful in sorting this out but this is where I feel we need a bit more clarity so let's talk about that more Mike a question for you in terms of the things that chat should be addressing if we get into areas that involve chemicals over which CPSC has no regulatory authority then are we wasting our time well, you know the way I look at it is our goal is to look at the fallow and that is a huge job in itself if we can do that, that will be fantastic anything beyond that is okay you know, I'd never say don't do it because you know, if it's relevant to public health but it's not our main focus and I think what I gathered from the last time we discussed this was a sense that this is something that would be part of the discussion but you know, maybe a illustrative example or two but not the focus of the risk assessment but certainly to point out that this is by the way there are these other compounds that may also be important certainly wouldn't say don't put that in the report I think there are colleagues who are not members of CHAP who understand very well that there are some obvious things that we have to put our finger on besides just the phthalates to understand the risk of phthalates and if we don't do that they will accuse us in one way or another falling short of the mark of having not addressed the ghost out there that's just beyond the margin so I think we have to consider that and we would be remiss if we didn't but for us to go about searching for all the possible interactive chemicals out there with the phthalates is impossible and we would first of all it would be hard to know what they are and it would be hard to measure data on them so that would be a waste of exercise in power time however there are some obvious examples and you've already approached that in the hazard index work that you've done to look at an example or two where we have reason to believe that there could be an interaction and part of the concern that might appear to be a phthalate might be the combination of that and something else so I think we have to have and they might be real world examples or theoretical examples of the chemicals that we should be worried about beyond the list of phthalates in front of us that would account for the real risk of those phthalates so perhaps there's a way that we can do that without getting stuck in the swamp of all of those chemicals and all of the exposures but have some theoretical examples of this is the kind of motive action that we would worry about if we're worried about anything enhancing the apparent toxicity of phthalates so I think we could handle that by example and not get married in the swamp, Paul our book doesn't have our original charge in it is it toward the end? I usually find it third to the end so thank you it's 12 but I'm sorry I have a problem is this the prohibition? yes so just adding to what Ron said and maybe while Andreas is getting to as well when he starts talking about hazard evaluation you know looking at what's going to be in the background chapters if we're interested in anti-androgenicity just some review of I'll remember there being some sections of that in the phthalates NRC report about some in vitro testing or something you know it doesn't have to be in detail but something like that in the toxicity section might be helpful what what I can see as a relevant point for this panel is to consider the question whether for example, hypothetically we come to the view that phthalate X is relatively harmless then we would have to consider the question does this alter in any way in light of the published evidence about the combination of phthalates in various other chemicals for example but to that degree without venturing into what you might have burning having to look at each and every combination that's rather futile anyway without having to reflect on quantitative implications of such evidence I don't think that would be possible in view of the lack of data but I think what is feasible is to reflect in what way any view of decision and recommendation may be altered taking into account exposure to these other chemicals quantitative rather than quantitative it makes sense but doesn't quite make sense with the charge I think about relationship because most of the discussion is basically on health effects of phthalate alternatives other than fourth phthalate other chemicals that may in fact have similar health effects to phthalates that's where our question becomes because it doesn't say that explicitly well in fact in the NRC report EPA asked for a study report on phthalates the committee insisted on mentioning these other chemicals you know we've got to answer the charge questions first but on the other hand I think the panel might be remiss if they don't at least mention these other chemicals but I think that's not my point and not to mention it's the degree of evidence that we're going to be searching for for these other chemicals in our analysis which may in fact be a level of an analysis that's not warranted at this point may be warranted by another committee when you're looking at synergies in the back I think the key word is another committee I mean that's the way I look at it it's not ignoring it I mean how much time and effort can we put into it based upon the charge questions we have to answer at the beginning of anyway which are quite complex I agree with you Paul there's another aspect of this that I have considered in looking beyond the phthalates if we give too much attention to some chemicals or classes of chemicals beyond the phthalates that are maybe by mode of action or by structure whatever it might be and the readers of the report pick up that this is really a report on those say anti-androgens and they use that as the focus to argue about the strength or weakness of our report and they ignore our contribution on the phthalates then we have given it too much attention I totally agree so the we have to be able to let the readers know that we're aware of this as a concern and why but not get into it to the extent that it becomes something that the proponents of another issue use instead of phthalates I had no problem with that let's keep that kind of as a rule of thumb when we handle this that we don't have to ignore it we just don't want it to become the focus of the report for somebody else is that reasonable? reasonable? I think we can again discuss this when we are talking about our hazard index approach because there we also add other anti-androgens into the calculation formula that only adds on I would say the problem I have is that while I've been trying to construct the scenarios with my exposure if we haven't done a calculation then who's doing that? is that going to be Bursar who's going to do that for the calculations? we have to decide I want to make sure that we hit the right targets as to what we do the calculations for and how they relate to the hazard index in the end because exposure calculations will lead to an intake for each one of the scenarios and therefore we'll probably have lots and lots of information from these analysis the degree to which we do sensitivity analysis on two will warrant further consideration but we've got to keep our target straight because if I start adding on the arrow of the chemicals then we've got a problem I think it's on now it's changing direction from what we were talking about in terms of the other chemicals but in terms of what Paul brought up in terms of the concern with assessing exposure from children's products toys which would be the main peer view of the CPSC but in the public law it does in section 4 specifically mentioned as well as from other sources of exposure so I don't think we should really refer to children's exposures just from child care products because specifically says from other sources such as cosmetic products etc so even though the recommendations would be in reference to children's products and toys I think we need to consider other sources of phthalate exposure and just making that explicit rather than to ease your mind we actually do have household products personal care products and diets I'm just not sure how far we can get with it because of the lack of data but it is in there the critical issue which I thought that Paul and I agreed upon last meeting is that if we do these calculations and look at children's toys and we find there's minuscule or large contributions to a daily dose that they calculate from biomonitoring data then we can say infer other sources you either have insured contributions or no contributions and that will lead to a whole set of other questions of what do you do now it's not it's something where at least we'll be able to infer whether or not this is a big issue a little issue and if it's a little issue well there's a whole lot of work that has to be done to figure out where the real source of this value has to come about by issue you mean the contribution from children's toys and products to proportionally how much that individual is supposed to do that may be the best we can do which is pretty far advanced considering what other people are talking about if we are able to do that I'm not sure that we have the data we'll see what we have I think there is some benefit to having the report cover information areas a little bit bigger than what the minimum charge is because there will be a lot of people who will look at the report and of course silent on something they will wonder well did they look at it or not and maybe if they have looked at it they would have drawn a conclusion on it they didn't say anything so if there are things that we look at that we don't have enough data I think that's important to have in the report I agree it's important to say what you looked for but didn't find or something to that effect that we consider certain things Russ did you have more what might just maybe think that probably would be a chapter on gaps or limitations in the report maybe would appear within chapters but as a chapter I'm not sure it's listed in the outline or not but when Mike was mentioning that it would be rare if researchers would review an area and not have recommendations for further research or very specific gaps of what we were visiting or those recommendations would reflect what the gaps are so that's a list that we should be keeping in mind that we can recall and pull into a chapter at the end because that's complementary to the rest of the report because it helps to understand the uncertainty of some of the things that we did talk about if we come back and make a recommendation to gather more information about this that suggests that there was some element uncertainty or they wouldn't have recommended gathering more information so I agree and although it might be full of gaps your task of compiling the importance of all external exposure sources is very important even if it's full of gaps kind of crazy feel for the next chapter to work at Mike's looking forward to the chapter number three well the commissions only had a three four chaps I think and this is the third one on fall 8s well I think we had one on formaldehyde but this is the third on fall 8s Paul one thing I hope Chris I'd like you to think about I hope you will is that you're doing the biomonitoring component of this I just think it's spot measurements and full of uncertainties and I really think that there's got to be some recommendations to how we reduce some uncertainties I know you're going through a very thorough discussion of limitations and at least where you're going to be able to take the data and how much uncertainty around it but I think that's an incredibly powerful recommendation about what we really need for biomonitoring to be able to make it worthwhile as a tool that can be used subsequently rather than in a way that we used to use air pollution data to manufacture information on air pollution exposure alone really think about it as a really big area where you have a chance to make an impact I think there's no it's no shame to point out the variabilities that actually we have to be aware that biomonitoring just gives you a picture on the variability of exposure that's actually taking place so it's not the biomonitoring data in my research that is variable in itself but it's the exposure so you from a lot of publications that for certain for certain dates we have rhythmic exposure in the morning using body care products for other the ladies have exposures through certain types of contaminated food stuff so we have only exposure peaks on two days during the week but biomonitoring mirrorly pictures what's going on yeah I agree the key thing is how does one expand the design of biomonitoring studies do something more fruitful in terms of understanding variability understanding mean better so that when you do these calculations the uncertainty is reduced because you understand the variability better I think it was when Earl and Earl Gray called Foster were here that we started discussion on what is important what is the key important finding on the toxicity of delights is it peak exposure sets of importance or is it the area of the curve we have to relate all our knowledge to these modes of action to relate it there Chris thank you for raising your point to stay with some good discussion are there any other big picture issues? you know I think there are studies that address the variability of biomonitoring in the spot versus all day samples and so on so it's just that the biggest data set is spot neurons so I think that I think we'll have some sense of uncertainty variability Earl Gray do you think that's enough for the frequency of sampling has to change to really reduce the uncertainty and variability? that's exactly what I try to point out if we have five measurements of an individual and one of it is high and the other ones are low what does it tell us? it tells us that one of the measurements was high so that this individual had a high exposure maybe one time high exposure or over a week but can we connect and neglect it or do we have to make a mean over out of it? I think that's not the case because all the key toxicology data shows us it's peak exposures over a short period of time that are important so maybe the 24 hour events reduce variability to a certain extent but they do not really picture the actual free time exposure that's taking place it's full of peaks and bases and lows that's a hard that's a complicated question to address for many developmental abnormalities the peak exposure is much more important than the time we would average because the window of sensitivity is narrow so you can have a time we had an average that shows no problem but there could have been an exposure on Wednesday morning that was high and a vulnerable time for that woman working in that lab and there will be an affirmation even though she worked below the TOV all the time now whether or not that's the case for the components of this syndrome is a little less likely in my mind because if you're looking at changes in testosterone production as the basis for them fluctuate during hours during time for hours or during critical time periods but it may well be a combination of the peak level that's achieved plus an overall level of exposure that's enough to depress the testosterone so it's a little more complicated than maybe a cleft palate or some other malformation for which there's a very narrow window and there's resistance away from the window I would suspect the window here is wider especially for all components of the syndrome but very often it's just one of those or two of those components of this syndrome that are more visible than the others as well any other bigger picture Chris so back to your original question are those issues then going to be discussed this window of opportunity or windows of whatever going to be discussed in the toxicity section we need to have that's in Phil's assignment but yes we need to revisit that because it's important for us to understand that but even though we understand it in the rat doesn't mean that we understand it in the human we don't we move a lot when we get there understand it to the same extent so even though we can narrow it down to a particular morning of gestation or after the end of gestation it's vulnerable for the rat it doesn't mean that it will be an over two for the human but let's come back to that so getting back to this complex you were doing exposure assessment which I have to define some things more clearly for Mike and his crew are we going to be looking at a cumulative exposure for the woman during the entire pregnancy using do we focus on what we could propose to be the peak concentration that's under inhale or absorb to the skin during a vulnerable period of pregnancy in terms of the children's toys do we deal with the frequency at which a child uses products that they may able to titrate the material out over a one year period a one week period all those questions really provide a different set of data in terms of the 50s, 70s, 50s, 90s potential of exposure based upon the outcome of concern how do we have that discussion to make this real I'm not anxious to see somebody say we'll plug in in the night or seven 365 day exposure to you and give us an answer they'll probably give us meaningless information I think maybe the best we can do is a daily you know, an exposure averaged over a day unless we identify a specific source like a cosmetic or something and you could do some you know, pharmacokinetics or something like that I think a day is probably the best and it wouldn't be terrible that's what I was leaning toward based upon the hazard index that they're developing which becomes the daily hazard index correct the daily index based upon daily index in that case you know, if we think about this we can agree upon that then we don't have as many problems in terms of assessing what the data is going to look like but before we just brought up about the periodicity and the peak exposure where some part of pregnancy does in fact don't worry me because the daily intake does not necessarily reflect the highest level of woman's vulnerability and how does one describe that in an assessment something to think about so do you think we might underestimate or overestimate exposure in this way in terms of a specific effect I think what we're talking about here is partly underestimating correct that's my opinion so actually the spot urine samples that you know we prefer to have 24 hour samples with longer averaging samples may actually in some ways be preferred because they're giving you a shorter window in a snapshot of exposure and showing you more of the variability whereas if Ed Haynes used 24 hour urine samples I would think the distribution would be much narrower and you know wouldn't give us that much of possible exposures so I think you know spot urine samples in a way provide different and potentially in this setting more useful information an example that we had with 5 samples having been taken over a day and one was high and 4 were low you only have a 20% chance of hitting one of those that is really a concern right but if you have a 24 hour urine sample you have a 0% chance of hitting it so if you have several thousand individuals you'll likely capture it well if you have if that 24 hour if it's samples throughout the day as opposed to one you don't want a composite sample if you had 5 individual samples analyze them independently so you knew that if there was one there that might look like an upire but might also be the one that took the turn from the individual then you have a choice looking at the peak or the average these may seem like some of these but I think they are very important things to recapture as we're going forward Chris did you have something else? No I was just going to point out the value of having large sample sizes enough to kind of pick it up I think that's Russ's point across different kinds of exposure Stunning back to the bigger picture of what we might get out of looking at the documents that we've each produced a couple of things for example that we might look at and especially from our area where we've reviewed a lot of literature the value of having some summary tables to go beyond just our textual description of what's out there in the literature so that they can look at in a tabular form what we consider to be the key studies and the know-hills that they had the dose levels that they tested the species so on the information to dovetail again so that when somebody looks at a hazard index piece of information and it came from a particular study they can go back and see what the conditions were in that study maybe in a tabular form and find it pretty easily so we might consider and keep in mind when you would recommend that we would have some tables to make the usefulness of the report better and also the decision that's made in some reports is what kind of information to have up in the text as opposed to a more detailed description back in an appendix and if we encounter situations where it would be nice to have the detail but we don't want it up there for somebody to have to plow through five pages of single-spaced details on something while they wanted a paragraph we might keep in mind when is it something back in an appendix where there's a lot of detail at every amount that you want as opposed to up in the text where it would be summarized a summary of a summary kind of thing and wouldn't satisfy somebody who wants the details but we don't want to have five pages of a line by line discussion of something up in the front people may not read any of them so keep that kind of thing in mind clearly as we go forward on this topic before we turn to Russ Can I just point out I think this discussion has been very helpful about talking about the importance of properly evaluating the exposure that is the exposure across subjects maybe across time or whatever but it's not just from children's toys it's from all sources and then we can go back and figure out you know where things may come from but I think we I don't want to start that again but I think this discussion makes me feel better about this idea of an overall assessment evaluating exposure not just from certain sources My observation having been on a number of advisory committees of this kind is that generally you start out by casting the net pretty broadly for fear that you're going to miss where the fish is you cast the net broadly and then you narrow it down but you give the reader the view that we've already looked at this area and now we're going to focus on this one and this might be the children's exposures but it's in the context of what the broader net has on it if there isn't anything else on this part let me just say what the rest of the morning might look like because it's just about 10 o'clock the next thing on the agenda is to talk about the sections that Russ and Phil and I put together on the background information on toxicity and epidemiology and for the animal discussion I would like to have Phil on the forum and we talked about bringing Phil in at 11 so if we could talk about the start with you Russ and talk about the human exposure and take a break and by 11 o'clock be sure that we're ready to go with Phil on water then we can talk about the cannibal reproduction and development information Russ? That sounds fine and just to clarify this would be the epidemiology not the human exposure sorry so where is your section I don't know four or five the fifth maybe it would be good for us to take a minute and write down the numbers on all the tabs seven sorry to resist the uncertainty in the future it's seven let's say kind of a lot of the numbers I apologize for not having Michael you need to steer this so that we're for sure putting the right numbers on the right tab there's a there is a table of contents in the front there is so this is one is this called summary of epidemiologic studies about that? yes which actually precedes the toxicology so the contents epidemiology should be five and then it should go to animal toxicity and six and seven so I guess starting big picture what I tried to do here was begin to look at the epidemiologic evidence and provide summaries that haven't included any of the data in tables yet but in putting this together you'll notice really the first sentence of what I wrote is the scope and what I did as a starting point was to really restrict this to epidemiologic studies in which exposure was prenatal or during childhood and whether we defined age 12 or 18 so I focused for this draft on those studies there are other studies which I wanted to discuss today whether it was within the charge of the committee or something that should be looked at for instance studies in which there's adult exposure and looking at end points like semen quality for instance or endometriosis and there's other studies in which the exposure was measured during the adult period and I felt as a starting point not to include these and to focus on the epidemiologic literature that included the exposure windows prenatal and childhood so I didn't want to do more work than was necessary until we met as a committee to agree to that approach so I don't know if we want to stop and talk about that or I can go on I agree this is the right focus ok so we're all in agreement that reduces the literature but I think it makes the review of the epidemiologic literature much more relevant to what our task is and then what I've done and I won't go through I don't think it's necessary to go through the details of the studies etc. unless you want me to mention some of them but basically broadly they were focused on neurodevelopmental endpoints studies by swan for instance and angle then there were the other studies the groups of studies on the reproductive tract development which would include intergenital distance or general malformations so those were really the two broad classes of endpoints that they looked at with prenatal primarily prenatal but there are some childhood studies as well in writing this I tried to approach it as an epidemiologist would in terms of looking at strengths and limitations of the studies trying to summarize the information qualitatively not doing anything quantitative and trying to prioritize in a way in which studies are stronger or weaker based on study design confounders that were assessed etc. so that's all in the report I'd say it's probably 60 or 70% of the way there in terms of the literature there are some papers that I have not included and then there would be more but I would want to discuss about the papers that are already there so it's maybe half way a little over half way there in terms of the epidemiologic studies the other piece of this which ties into which probably would require a broader discussion when we get to the toxicological literature phthalate syndrome in rodents versus trying to tie it to statistical genesis syndrome in humans the hypothesis the TDS hypothesis and I wrote a little bit about that but very little probably a few sentences or so in this draft because I felt that after today discussing with Bill and Bernie in particular the toxicological literature we could then come to an agreement in terms of the depth and range of the discussion in relation to the human data so that's kind of a three or four minute overview of what I've done I don't know if you want me to go into more depth or take questions point it out that you focused your study on the prenatal phase is the how much data is out there on adults or as you said effects on human quality and so on can we really neglect it or how much work would it be to compile all these relevant publications just an estimate I would say the prenatal and childhood exposure data probably represents a third at the most of the epidemiologic data there's a variety of studies that have been done looking at adult exposures in adults and points I mean there we probably don't want to completely ignore that they exist in terms of the report but then again we don't want to the same way we were talking about other co-exposures but put too much detail in because then I think it would detract from the focus but potentially a table or a list or a few paragraphs on what's out there that's what you're suggesting in terms of some of these other studies and why we didn't include them in the depth that we did or the prenatal and the childhood exposures because of the relevant exposure wound up but there are these studies on semen quality or endometriosis or even respiratory effects or asthma so I'm blanking on the first author's name but I think it was a Mount Sinai paper that talked about the temporal variability of using a spot urine and I think they referenced some of your work with Susan Tidalbaum and we have done some work on that and Jennifer D.B. with myself and Columbia as well but my if I remember correctly from those papers I mean I got a pretty secure feeling that a spot urine was pretty reproducible from time to time in terms of if you're at one point in time you tend to be high at other points in time is that right so what we had done is looked at to see whether a spot urine sample would predict the category that someone would fall into in terms of tertile of exposure because as epidemiologists a lot of times we categorize people in tertiles, quartiles, etc and it performed pretty well I remember writing sensitivity and specificity around 60-70% in what I've written here that does not include any of the exposure which would include the Tidalbaum paper our paper a few other papers I think Holger's work as well so that would be separate but important part of I think the exposure section that I think Paul, myself and maybe Holger was but that data does there is some data I'd say about four or five studies what's the characterization of the pallate syndrome became gelled enough in rat studies a lot of the studies that Paul looked at was an effort to find out if this pallate or that pallate caused the same thing so it kind of focused the endpoint on the pieces of the pallate syndrome a concern might be are there other reproductive effects beyond those malformations that might be seen as part of the syndrome that are also important that we haven't looked for very hard just because we were focusing on the malformations that are part of the syndrome is there any evidence from the human studies to look at for example the impact of prenatal exposure to pallates on the timing of maturity of the reproductive functions in adults or changes later on that are not occupational in relation but from a prenatal exposure in humans are there other consequences that might occur that are in reality more important than just the elements of the syndrome I agree with you that those are potentially important endpoints to studies so I think pubertal development fertility later adult function is what you're asking right are there studies that have looked at prenatal exposure or early life exposure in these endpoints well two things that are out there that are concerned to a lot of people one is the early onset of puberty in females the other one is the decrease in splinocom in adult men so taking the second one first the sperm count there's been some studies we've done some and a few other groups have but that's measuring adult exposure so it's really cross sectional data probably missing the relevant exposure window if it's prenatal or early in childhood in terms of puberty there's two studies that I'm aware of there's the cologne study that was done in Puerto Rico probably about seven or eight years ago it's a small study there's quite a few limitations in the study ranging from the way they measured the exposure they measured the diester to the selection of the control girls but they looked at the hierarchy early breast development it's not included in what I wrote but basically and can be they looked at very precocious breast development in girls that were three or four or five years of age because Puerto Rico apparently has an outbreak or high incidence of premature cancer so that's one of the puberty studies and the other one is very small also not in here I think the author is by rain they looked at children it was very small I think 20 or 30 children that they assess their pubertal status I think when they were able to say between just estimating 14 or so to look for delay in puberty and these were children that were in intensive care units and basically received I think a remembering right ECMO and other procedures that would have exposed them to high levels of DEHP during neonatal life when they were in the NICUs and this study concluded really that they did not see a difference as compared to a remember right 20 or so controlled children but it's a very small study the assessment of exposure was really NICU or not but those are the only two pubertal studies basically going later in life that I'm aware of so the data is very limited I'd like to follow on the line of argumentation with which Bernie the scene being linking it to evidence of a phthalate syndrome in animals and part of that as we all know is suppression of fetal under synthesis that's been observed in animal studies but there's also some epidemiological evidence that there might be something to it also some studies in the occupational arena I'm sure you're aware of these would you think it would be worthy including those so there are some look where serum 3 testosterone levels were measured or the LH3 testosterone ratio et cetera et cetera with varying success of course so I think you're referring to two groups of studies one is done in adults where you're measuring phthalates and then looking at reproductive hormone profiles right so some of the occupational settings so that's an adult exposure it could provide insights for earlier life exposures there's a few studies I know there's the main study where they did look at I think it was levels of breast milk it's actually not included in here yet and looked at I think it was T-L-H ratios testosterone L-H ratios so that should be definitely included whether we I think we should definitely mention the adult exposure studies but again the same way we would treat some of the other endpoints like semen quality where there's only adult assessment of exposure we would mention that they exist that they either are consistent with maybe what has been seen in the main study or not but I wouldn't go into a lot of detail unless after the discussions today we felt it was necessary you know a lot of a lot of people cite the the clone study and the main study you know in Bornhawk you know the asthma so you know I think they need to be mentioned and as far as the adult exposures go I mean even the animals the adults are sensitive they're just way they're less sensitive than neonatal prenatal but you know so if there's an effect in the adult studies it's not necessarily reflecting just early life exposures I mean it could be effects in adults too it's from exposure as an adult right and through a different mechanism than the in user or well I think it may be you know inhibition of testosterone but the adults aren't immune they're just less sensitive so I think what you're suggesting is you know to include it in the report at some level of yeah I mean it's not the you know obviously we're zeroing in on the phthalate syndrome but I wouldn't want to ignore those and especially because the the endpoint is relevant yeah whereas if we were looking at another adult exposure in a non-reproductive endpoint it's much less relevant to the report but again I would be very careful interpreting colon data at least this one this is I would just mention it but really say that it's very unreliable in terms of exposures as a measurement of parent phthalate but as you said it's an important endpoint and a lot of people know inside this study still yeah I mean I think at the time people were thinking it was an estrogen phthalates were estrogenic as opposed to anti-indrogenic but yeah I agree I would definitely mention it back in 2005 when I reviewed Antonio Califat we included in the report but you know basically didn't really give it very much weight because of what you're saying but we need to recognize it another point about what you wrote and about what we are writing later on too you make the distinction between low molecular weight and high molecular weight phthalates what do you consider as low molecular and what do you consider as high molecular weight phthalates well just to clarify I don't use the categorization at least in my work the low and high this is it's in the report and it's been used by several groups the low molecular weight basically and I wrote in the report here is really driven by MEP basically if you use low molecular weight or MEP you probably get the same statistical association because it's such a big driver of the low molecular weight phthalates and then the other ones would be the high molecular weight which again in the report are really driven by the DEHP metabolites so do we have the consensus among us that DEHP is a high molecular weight phthalate I think some people call it a transitional that in fact we just got a submission on that related to that I'm not sure the different definitions are 100% in agreement I think if you're going to use that terminology in the report we might that might be one of those things where we decide this is what DEHP is in this category or that and just to be more specific for the low molecular weight then I study the MMP MEP M-B-P and M-B-P at least the way they classify them for their analysis and of course the metabolites are the oxidized metabolites are very confusing we definitely have to agree on a way to describe them but that's for you to decide can I ask your learned opinion about what I see as a bit of a conundrum and it vexed me a little and that relates to the low molecular weight high molecular weight from animal studies we know that there are structural activity relationships and it appears that phthalates with an ester site chain of between C4 and C6 induce the phthalate syndrome and low molecular weight phthalates such as DEP for example fail to induce this effect yet on the other hand there are indications that in humans low molecular weight phthalates may not be less present like this without risk or without effect there's for example one study among hair sprayers that's been carried out in Europe they found associations with upstages and cryptocutism if I remember correctly and there are more recent studies pointing in similar directions how do we how do you interpret this it's the difficult as you mentioned the difficult issue the exposure say among hairdressers is more likely to DEP but that's a mixture exposure those papers they didn't assess specific chemicals they're exposed to DEP as well as other chemicals so it could be the DEP it could be something else that they're exposed to or lifestyle differences etc depending on the comparison group etc but you're probably referring specifically to like the swan paper where they found associations with AGD DEP and then also some of their developmental studies as well yeah so the first of all in people college they did this study among hairdressers there are others now recently other studies have appeared so I think what you're asking is my interpretation it could be one of two or at least two explanations that in humans MEP is associated potentially with some of these endpoints or MEP could be a surrogate marker or another exposure a lifestyle characteristic so depending on how well done the study is the comparison group or controls or chosen confounders measured could be users of DEP differ in different respects that in part risk or it could be the DEP itself that's in part risk in epidemiology we always like to see replication we do see it in different cohorts or studies then we tend to think the association is real yeah I'm referring specifically to the work by Ormond to tell that's among hairdressers then an EHP and then we'll recently paper by Jordano that's a Dutch group they use job exposure matrices to classify jobs in terms of likely EDC exposure what they found was an increase in hyper-spadia when mothers were engaged in jobs with exposure to phthalates bifinolic compounds etc it's this kind of evidence I totally take your point in all these studies there were no attempts made to really measure DEP but there are hints in this direction maybe we should consider this critically yeah I think they should be included I think the Ormond I think I'm familiar with the other one or not but included as part of the report but probably as a second level of evidence because of the non-specificity of the exposure but that would be that out that this is what they found but there are potential other explanations and I think Swan or somebody suggested correlations among the different phthalates that were exposed to might explain that so I don't know if there's anything from NHANES that would suggest that people who are exposed to one phthalate are also exposed to another that might be something to look to consider I'm just trying to figure out at least a whole bunch of things that are being added on to what you start out to be as very direct and concise statement as to what studies relate to where we're heading and it seems like it's almost like a tiered set of studies to work with ones which are really directly relevant ones that may have a little bit more, have some quasi-relevancy because of the endpoints and others which are on the march and maybe if you focus on the ones that you've done, the key ones first I think that's the most important and the rest of it if you can put it in as a summary of a table would be easier of other things that may be of importance that might work out best but focus on your main stuff main studies first because I hope that was very well done Thanks and I agree and I started really with the ones that I felt were the strongest studies, the most relevant studies, but then to bring in the other ones which for instance if there was papers in which they measure DEP metabolite MEP in urine associated with hypospedias and then you have one or two hairdresser studies if it lends some support to the study that has the biomarker in it but like you said a tiered approach really focusing on the stronger studies relevant windows specificity of exposure but then also bringing in the other ones which I was going to do secondarily I could definitely talk down from this but is it important to also include some overall sense of how common these outcomes are without any link necessarily to phallics I don't know You mean kind of background information really I mean I'm thinking of the IOM reports you know like I'm actually on the Vietnam Veterans and Agent Orange Committee now where you know each health outcome will start with a paragraph or two about the prevalence or incidence of this condition or disease that I don't know how to do it I mean some of them are endpoints for which that data doesn't exist so for instance the AGD which is really an anatomical marker and a range there's not population data for some of the neurodevelopmental endpoints there's some of that data and I did it in the report a little bit more I'm trying to put it in perspective in terms of whether it's clinically relevant endpoint or sometimes with these sensitive survey instruments you're really looking at changes in population means rather than moving the child into a clinically relevant endpoint so for instance symptoms that are part of the ADHD but the child would not be really classified as having ADHD even though on the evaluation they may have some of those characteristics so for some of the endpoints I think it could be done for others it would be more difficult and definitely would not want to be misleading in terms of that you know let's say the swan and anal studies are looking at some of these subtle changes not applying that these children have ADHD or have any other psychological disorders I say that because after EPA workshop on phallics back in December I can't remember the woman's name but the epidemiologist presented them I think she said 3% of males have or maybe in the United States have unassented testes which was kind of striking to me I had no idea it depends on what age at birth maybe it's 3% because a large proportion will descend but it's somewhere around 1% and that's something we can consider as I put this together more whether there would be a paragraph or two in the beginning of each health endpoint for which it's relevant to put it in perspective and I don't need to add more work and I don't know that the committee would agree that it needs to be there it was just interesting well it has to do with easy detecting an effect of another agent because if it's at the 1% or 10% level there's a difference in being able to detect the effect of any environmental agent compared to if it's 50% in the background so I think it's a relevant addition for the the end points just relevant for it there's that data well, cryptorchidism and hypospady is there's people there's a registry data there must be CDC data I want to come back just for a minute to a variation perhaps of my earlier question in some cases we have an observation in humans and it drives a whole bunch of animal work to try to find out if it's feasible for that particular exposure or the levels of exposure but in this case my understanding would be that the animal findings have driven the question is this happening in humans and one of the impacts of that is that it narrows the search to those end points that we've seen in the rat for the phthalate syndrome as an epidemiologist and a physician do you have any concern that the question isn't broad enough in humans that there may be concern from phthalate exposure that has concern beyond the phthalate syndrome and we're not looking for it I mean it's a theoretical question just wondering if this is a surprise out there waiting for it I agree with that potential concern I think more recently the phthalate research in humans has expanded more broadly in terms of end points that are apart from anti androgenic effects there's a lot of worn hags a lot of respiratory there's other studies that have looked at you know body mass index and others have done that that's using NHANES data at adult exposure levels so I think in the beginning it was relatively narrow but I think more recently it's expanded I sometimes have the other concern is that sometimes people have data sets where they may have end points biologically may not at least from the animal data be relevant in terms of phthalate exposure or whatever the exposure may be and then they look for associations and they don't really are not able to tie it to a mechanism or underlying toxicity data but I think for the at least with the phthalate research is now I think it's been too broad end to that point and sometimes it may be too broad but I think it's I'm not reasoning just to recommend that we change the scope of what we're worried about in humans it's just whether or not there's a surprise out there that might become evident by the time we get the report done I think that the biggest difficulty with the human studies is looking at for childhood exposure and trying to look at adult end points just because of the time frame so if there was a potential surprise that's where I think it would be whether as epidemiologists we'd be able to design such a study where we can characterize exposure during pregnancy and then look at that child's fertility let's say when they're an adult or look at risk of adult disease it's difficult to near impossible with the exposure techniques we have where we can't look retrospectively so that's where I would think cross-sectionally I think the range is fairly wide in terms of the warming systems that we're looking at whether it's pulmonary reproductive some of the metabolic end points have been looked at but I really think it's the latency of the later life effects for which we lack data and probably will continue to lack data that's a limitation for any exposure especially for the valleys the exposures with short half-lives for some of the other ones with much longer half-lives so you can get a not a perfect handle on it for vaccines for instance yeah how are you going to totally agree I think your point is well taken we just can't look at the light under the lamp post for some of these things we have to be really critical about saying that syndrome may in fact work humans but it may not be the only one just in a recent example when air pollution is PM for 50 years we thought PM was primarily associated with lung disease in the last 10-15 years we realized that with the elderly which is a group that's more sensitive and they have less ability to cope with the PM it's cardiovascular end points that are of major concern and is it a lifetime accumulation or is it the peaks that lead to the severity of the effects we're only beginning to understand that mechanism whereas before you were we were not quite dealing with that as being a major point of concern so I think your point is well taken and we just cannot look like we just cannot let people say that this is where we should end our investigation yeah no I agree and I think it kind of ties in a little bit with it with Andreas was saying you know sometimes it's kind of a different different level it's different but where you use the animal data you're saying to kind of drive the end points but using it to drive which phthalates you think would be relevant and Andreas question was well the animal data you don't see these effects with DEP but you do in a limited number of epi studies so then what do you do with that data and then how do you use it potentially you know in a risk assessment it's you're not seeing it in the animals but you are in a limited subset of human studies how do you use it so it's I guess my feeling has always been if I see it in human studies I'm going to go out and do some more studies and aggressively deal with it because of the fact that there are these possibilities that the effects in animals and the effects in humans are not always transferable and I think that's what we seriously think about again going back to PM research a lot of our research the standard was based on the cardiovascular was based upon non-mechanistic studies in animals based upon the epidemiology which drove the process for part of a few years until people began to do the mechanistically based studies to try to address the issue why it's happening because it was done at concentrations which are much lower than normally seen in traditional toxicology studies so again if there is something that I would recommend if we see stuff that is going on in humans I think the first thing to do is to say we need more tox and we need more human studies to validate distance that is much most relevant to our human condition yeah I agree completely and then the I think humans is very different than what's done in tox studies it's basically episodic but continuous in a way which is different than in a tox study so it potentially could account for for some differences in the facts that you see any other comments for Russ Christopher sorry Russ I was just looking at some of what you wrote here and this little paragraph about page 3 you're talking about the phthalate score so you're actually addressing the issue of a combination of fact of these phthalates and I think you have something about that the odds ratios were stronger for I thought I saw that for the summary score then for the individuals so one question is in your reviewing of the papers do you see people addressing the summary scores or something about a combination effect which makes me think you know just to point out when they do that I think it might be interesting to see we may be underestimating what the potential effect could be if we just look at one chemical at a time yeah so it's a few studies have well the swan has used the summary score the wolf papers use kind of the sum of the low and molecular weight and then some of the high molecular weights as in a way a summary so it has been used in a few studies but not a lot and where it has been used I've pointed it out I haven't very explicitly tend to basically a Keegler risk assessment or a way of looking at negativity I've really presented what they've done and how they've used it but I could interpret it further or you could when you're use it you know if you wanted for your section or we can have a kind of a back and forth in terms of making sure it's consistent is the level of detail here I mean fairly detailed you know I don't know maybe six or eight papers I've gone through already at the level that we were expecting for these reports because I really didn't have a guide in terms of you know sometimes like ILM committees you may have a paragraph on a paper here I spend you know several paragraphs or a page or two sometimes on a paper to go into detail and then of course the synthesis which is most important to get a sense of if the level of detail is where we were expecting it or not or as the day goes on we can kind of compare across sections I've just meant to raise that too because the level of detail that I went into for the animal studies is much less ours is much more of a brief summary and it's my conclusion for us is that the level of detail that you have in here is warranted and it's appropriate it's not like reading the manuscript but it's more than reading just an abstract so I'm comfortable with the level of detail that you have in this and as you add more information to it to proceed with that same level of detail especially for the key studies just wanted to be sure before I did too much or too little work but what about the rest of you I'm comfortable with that level of detail but still thinking about from the tiering point of view for the more important studies the less important studies don't need to go into it in terms of I think Mike was saying it's about a year from now or so when the report is due to the CPSC right in terms of cut off literature because there are papers that continually come out would we make a deadline of August October or when would we want or later there's not a lot that comes out but there are new papers on the horizon that I know will be coming out in the next few months or in the fall good question do we try to write the virtual fifth again can we have a page that says papers, key papers published important papers published too late you know I think that it's a judgment we can wait a little while before we set a cut off date but it also depends on the study if it's significant or might have an impact we might you know tolerate a later deadline I think we should agree on a cut off date for everything it's relevant to your study but shall we say September 2011 well that's one meeting after we've had a chance to look at everything that's true so I think that's a good time because we're not we're several months from the end but by that time if there is a study that comes out that impacts our conclusions I think we need to deal with I like September as a time that we're all shooting for that we're going to capture prior papers until September and from then on it's a judgment kind of a provisional is that reasonable of course you might finish early but we could we could so okay for Russ that was a good discussion Russ thank you and if there are other papers like Andreas you mentioned a few or others that you know of because that's another question that I had my experience with sitting on IOM committees extensive literature searches et cetera and thousands of abstracts we pretty much within our own areas we kind of know the studies but there's a possibility that I don't or definitely don't know all of them is there kind of a formal mechanism or way in which we should describe how we identified these studies is that something that would be done up front or at the back or how are we going to present that identifying the kind of the universe of the studies that are there I mean I could do searches I mean it's up to the panel I just received an updated literature search that I will send to all of you we search to medline, toxline you know it's up to the panel if you want to go beyond that or how you want to deal with that in my experience it's good to do that to say to make precise statements about such strategy et cetera cut up dates and the like makes it more transparent for everyone it's good for us as well will you bring that question back after going a little bit further through the rest of the speakers because then it will have additional dimensions that's an important question bring it back okay are we ready to take a break can we order lunch let's reconvene in 15 minutes we'll be ready hi Phil this is Mike Babbage hi Mike we're all here and we're ready to begin the discussion on on animal toxicity okay so I'll turn them the way over to Berm morning Phil the first thing is to find out if you can hear us as we talk to you from our other table say good morning morning Phil can you hear us okay Phil can you hear us okay just barely just barely we'll do our best to speak loud enough so that you can hear us if you lose us speak up quickly we have gone through the earlier discussion about the seven questions and we've gone through the discussion of the contribution of Russ on the epidemiology data and that was a very helpful discussion about the epidemiology data but also questions of format and content and so on so I'm not sure that we need to go through some of those things again but we need to talk about the specific ways they apply to the contributions that you and I have put together so for example the group endorsed that the level of detail that Russ has gone into for the epidemiology studies is appropriate for the epidemiology studies and the importance of them to the overall contribution of the report but that I think the same question is still there for the section that you and I were on so we again we're not going through this line by line but we're trying to find out for sure if there's enough information in our sections to support the discussion of the hazard index evaluations and the other components that go with this that we have to connect to so we're up to the contribution of you and me and you're welcome to start first or I will, your choice what are you going on with this for the discussion in a second okay so I was assigned the task of reviewing the developmental toxicology part of it but I started out with some broader information that may not necessarily be best to leave right here where it is and it may be better replaced with some by somebody else's writing so it may well be best for example to talk about the this isn't the best place to have the discussion about what were the permanent bands and the the interim band chemicals but I did that here to make sure that at least I had a list to work from of the chemicals that I would include in my part and I think we need to have that in an earlier stage of the report so that we all know what are the chemicals that we are looking at so like I would ask for someone coming back to something we talked about earlier this morning I would come back to that and ask if you could have somebody put together a list of the chemicals there is kind of the official list for all of this and then I could take this out of here but then when I went through the section on the reproductive toxicity of these one of the things that existed on these chemicals on many of these chemicals but not all was a review by an NTP component as the center for evaluation of human health risks human reproductive risks and this was an advisory committee that met under the umbrella of the national toxicology program and NIHS to review chemicals that have been nominated by the public for a review for reproductive health endpoints so they reviewed many of the phthalates as a group many of the more visible ones for which there was a lot of information and they wrote a series of reports dating from what the late 90s until 2006 so one of the things that I've done in my in my review is that every time there was a CERHR report I used that rather than plow the same ground all over again by myself I referenced the information that was in that report and their recommendations so that there wasn't a question of me paraphrasing what the recommendations were from the CERHR and in the process of them doing their job the next step after they have written a report is that the National Toxicology Program asked its Board of Scientific Counselors to comment on the recommendations the conclusions of the CERHR so that becomes a non-regulatory comment because the NTP doesn't have any regulatory authority but this is another level of review of the CERHR recommendations that I thought was worth quoting generally the NTP was in agreement with what the CERHR recommended but not always, not always in the same strength so what I did then was to review these chemicals and paraphrase what was in the CERHR report and then the literature reviews that have been provided to us had studies that were reported since the CERHR report was written in today so then I separated those out and reviewed those by myself without the benefit of another review group so that makes mine a little bit different than Russ where there was no you didn't use the CERHR reports in the same way that I did but my question to you as a group is whether you think it is satisfactory to use the reviews that have already been done by that body and there's only one of those bodies out there, I didn't go to IRC or any other group for their comments because this is the most targeted groups specific for reproductive effects in animals and humans so is that an adequate approach does that make this report of the animal reproductive studies too difficult to look at Henry's I think right I'm on now I think this is very well done and very appropriate and also I feel it doesn't contradict the brief in the law the charge which says that we should conduct our examinations de novo it means we can rely on previous reviews but there shouldn't be determinative and I don't think that's the case here and other than that it's just common sense I would think it's very well done and fully in support of that I'm not going to go through these chemical by chemical but what I want to know particularly those of you who are working on the hazard index is the information that's in here sufficient to help detail into what you're doing or other pieces that I need to pull out yet to put in here I may not have captured every no ale but the authors talked about in their manuscripts or in the earlier reviews I can go back and make that complete but what what do you need other than the no ale then to help your work where do you get the point of departure and is that something that I need to pull out of here different from the no ale well if you remember we have two cases that we're looking at and one case is largely drawn from the Quinton camp in Faust 2010 paper and I think many of those reference doses were based on some in Haynes or some American studies but largely European studies what about that Andreas? You are so we all European and then the other assumptions that we're making are based on some work of oral Graham I haven't looked at this close enough to know if you're reflecting I see a lot of grays but yes so are you saying that maybe it would be helpful to actually construct a table that would sort of bring it all together I've included already in a discussion that I had earlier with Mike and Phil that for sure I need to ask the tables in here to summarize it otherwise it's just text and not very interesting to read all that much text about studies after studies after studies so yes I will prepare some tables and it would be helpful for me to know I don't want to prepare a table that summarizes every study that's summarized in here I need to know what would be the critical entries in that table chemical wise and what data do I need to have in the table that allows people to go from your section to mine or from mine to yours and the information is complementary and then I'll put those tables together and Phil will do the same Phil will do the same Phil comes down to this with studies that you use well so again I mean if you look at the Court and Chapter and Bounce paper I think it's very specific there are a lot of references there to this noel came from here this was a B and a benchmark dose you know a lower limit or whatever so are you saying that the direction of your chapter could be to actually get to the point of all of these studies now from that body of literature what do we think is a good reference dose suggestive file yes well one of the criteria for considering an animal study to be a key study is whether or not it contributes needed to go beyond that study and if for example they don't calculate or they have uncertainty about a noel it may be an important study to report but it's not a key study so I will make the cut based on some of the animal findings as well some of the studies are just plain poorly designed to look at those responses or even the breadth of the end points or maybe the right days of exposure so even though they might be in there they may not be key studies for some of those reasons but what I want to be able to do is have people easily crosswalk from our two sections and not wonder why you didn't do this or not wonder why I didn't include that one thing that might be helpful is to look at either the court can't pay for our little report and just start from these are the noels or the references whatever that we're using do you see anything any reason why these aren't the right I can do that that's how I was looking for could I add to that there's a lot of studies out there that provide those response information but often in terms of numbers of animals that those group used there would be question marks basing any points of departure or noels or benchmark doses on those would it be possible to highlight that or to give your opinion, argue of the opinion that this study is suitable to derive points of departure that would help the hazard index story a lot I can do that informally it doesn't mean it would be part of the report but I can do that just as a way of checking to be sure that we're on the same page I was wondering why not also it makes it transparent this leads me on to a related point there's often studies reported where they failed to see any effect and I would think in particular in those cases we need to be developing a sense of power was the power of those studies sufficient to be rather confident and could that information also be added in particular with those studies some information about number of animals produced etcetera etcetera but there's another variable in these studies and that is how the chemicals were actually given in some cases they're given by gabbash right and that's usually a short term study and if there's a repeated exposure over several months there are some labs that mix the chemical in with the feed and they give that same concentration throughout the whole study so then the dose keeps changing every day and there are other labs that every time they weigh the animals like at least once a month if not once a week they readjust the concentration in the diet to provide the same number of milligrams per kilogram per day throughout the study if you pick a time the doses when they just add it in the diet and give it as a fixed concentration throughout a multi generation reproductive study the actual dose in milligrams per kilogram per day might vary as much as two fold so what time do you pick then do you pick the time during lactation or do you pick the time when they're in the first 90 days 60 days of the study or do you pick during mating what days do you pick to express the dose and that's something over which the toxicology community has never gotten control some labs run through a long way other labs do it a different way it's a lot more work to adjust it every time you weigh them but it makes the data much more meaningful so there are some of these key studies are in any one of those three categories and I need somehow you need to be alert that when I say that the animals got 913 milligrams per kilogram per day you have to ask me more for more information than that in order to know how much variation that really had in the study if we threw all the studies that didn't change the concentration on a weekly basis the rainy ones would be a small group that's right so let me see if I can get my understanding do you have Andreas's paper in which you took most of your information on the dose per day say animals and then translated that to a human I'm trying to understand you didn't use the full body of literature you took the summary from his paper but why are we discussing this now we're discussing the I'm trying to understand the basis for their work and whether or not they're including the body of evidence so why do we bother talking about the studies in one way when we're focusing on your work for the basis of the hazardous sense I'm trying to focus my attention to what again our purpose is in respect to development of the hazardous sense not to discount the work that's been done because I think it was fabulous now I don't understand how the two connect do you see my point there's got to be a point of connection why we summarize all the studies but we're focusing on X there seems to be no rationale for that at this point and by the time there's no rationale for the point the two levels the studies summarized by Phil and Byrne for how I'm inspecting them I'm knowing a little to myself a little in two broad categories number one studies which are good enough for example to answer questions does this and that thalite induce features parts of the thalite syndrome or not but these studies are because of their design and intention often not suitable to derive any estimates for so-called safe exposures in the human form so there would not be sufficient for what we call points of departure on the other hand there are other studies which are in terms of their design their intention the number of animals they use for a dose group and the number of doses they examined well suited for such purpose and what this discussion was about and what I think that was Cruz's point was to separate these out because that would help later on with the discussion for risk assessment hazard index etc to have markers put in here in examining the animal evidence which say okay that study is suitable for deriving a point of departure but that isn't etc or when there's lack of evidence this is for example what I myself did in this paper often there is no other evidence there are some studies that would allow you to make some assumptions or estimates about points of departure but because the number of animals used was too small then that has an impact on the choice of uncertainty factor so this kind of information would be really helpful and could then be taken up later in the risk assessment chapter what you just said is not captured it's not captured as what we've written there's no preamble that's really necessary because when I go from here to there I find no connection yeah but that's because these things to me that's a very important what you just said now is a very important thing to put in right in the beginning because then everybody gets a real contextual framework from which to operate in terms of understanding why all these reviews were occurring and why you were able to select what you did to do the next step that's good the data on the endpoints are S, 11, 3, U, S they are relevant for us so we should all agree on this approach and as Bernadette said most of the studies are very heterogeneous and we have to find a common approach to distill the TDIs or the ADIs or the reference dose however you might call them out of it and we all have to be aware that in our approach the reference doses we name are not the reference doses of the U.S. EPA so these are our reference doses which distil from from various studies and that's why we also use the case 2 approach for grace work which has the advantage that it is based on the same study protocol for almost all of the substances but has the drawback that it's not designed really to distill a no effect level out of it so we we might have to discuss also with your knowledge parent if our case 2 approach is valid if we can distill it out of the data or a great percentage at the second CHAP meeting if this isn't a valid alternative the approach so we might discuss that too good I feel more again because it's such a great analysis it may have to be in the end you should be able to jump from and it should be the same and the same point of purchase but again for completeness to suggest to the reader that we did a complete job of reviewing and that the papers that we cite or the data that we select for doing more extensive evaluation wasn't just the first 10 papers we read we read them all but there may be 10 papers out of there on the basis for the calculations that we made but these comments are very helpful I'll follow up with a table that does what hopefully the chair will look at and the text that describes this distinction between what one study provides versus another one versus another one for this normal process that should be and it may also be helpful there's some discrepancy potentially one or more chemicals where you're not quite sure if one value is the right or we can do sensitivity analyses in our work I think largely which we'll show it doesn't matter too much we don't need to split-hit hairs is it 30 or 40 is it 100 or 1000 maybe that would matter at some point we don't need to be too fine tuned about it the other thing I might point out it seems to me we're kind of thinking about by monitoring data for pregnant women and then also for infants so I don't know in terms of reference doses selection do we need to make a distinction there do we need to choose the more sensitive values do we need to think about the animal data from top exposure and paternal exposure I don't know what the toxicologist would think about that I think we need to revisit that point later on when we discuss your contribution another question for those of you who have already been down this trail there may be world design studies in terms of dose response we need to but the end points to set the no-ail are not part of the family syndrome there is a different higher no-ail perhaps for those effects then which one is the one that is relevant for your evaluation if the most sensitive no-ail is body weight but has nothing to do with normal effects then is that what it is for that study this is a tricky question in our paper we've used what we call reference doses for anti-andronicity in order to make the comparison in order to avoid the trap of comparing apples with pairs but so part of the answer to your point would be yet we could continue doing this but there is often I think from memory there is a couple of highlights there are ADIs or other ADIs but points of departure are based not on anti-andronicity but on other effects and sometimes they are lower anti-andronicity now right the public might say why are they basing hazard index or risk assessment on points of departure that are higher than the official one used by other regulatory agencies I think that's an important point which we need to discuss I think there would be a case to argue of course if available we should use the ADIs or TDIs used by regulatory authorities otherwise we are potentially ending up in a big sort of trouble there will be questions asked why have we used the reference doses that are higher than the recommended ADIs but then there would be a couple of answers to that question but then there would be another group of people who are saying that the whole emphasis here is the fact that these cause a syndrome of effects at least on hormonal activity and now you are using field body weight that is totally independent of hormonal status to define to make these risk decisions that's a disconnect as well I think you have to do both evaluations for all the end points because in the hazard index approach with the cumulative assessment we need a single end point or a single syndrome of end point area but for the individual evaluation of the chemical you need to state also the other end points which might be lower I think that is especially true for some of the substitutes the valiant substitutes where the developmental end point may not be important but something else might be simplifying what we are saying is that there is going to be a constellation of intake doses that we are going to be working from versus one or another that we are supposed to be selecting before what are we where are we getting with this depending on the end point you have different reference doses depending on the end point and the reference doses will be based upon your best judgment versus EPAs versus somebody else's I am trying to figure out where the regulatory agency values come in versus what you are proposing I made the point that these are not regulatory reference doses I understand that which is fine with me but I think the point with being made is that if we don't reference them with the regulatory doses we will get criticized we should reference them I think that is the task of you in the combination of the data to compile the regulatory reference doses and so well also the section 108 charge doesn't specify phallide syndrome or anti-under any effects or whatever so I think we should keep an eye on regulatory ADIs often to a degree this problem will be probably academic because most times they are simply not available but for some they are I guess the more we talk about what we do with respect to other agency values and comparability the reason why we chose something versus them even though there are people that are complaining at least it is based upon science and judgment and we put out before them this is what it actually is and why and then we stand on our own two feet which is fine can I also a little addition I keep switching myself on a little addition to the hazard index I think we did this in our paper and you did this in your text as well based the hazard index on endpoints all related to anti-undernicity but there is of course a precedent for deliberately comparing apples with pairs especially with the hazard index approach ATSDR is routinely doing this for superfund assessments they integrate over all sorts of endpoints so if there are different ADIs available for certain phthalates we might just use this as well and see where we end up or have to do it I don't know my understanding of that is that it's a place to start with like a superfund and if you're so far below one by making the assumption just put it all together with apples in pairs then you just stop because it's not an issue but if you are up in an area where you're concerned then you can go back in and focus it more yeah I think we are discussing that later but we should for the hazard index do a tiered analysis sort of moving from a data pose situation to data rich we are preempting a discussion so a table in this section though that would have the most conservative the lowest estimate for reference does and then the one associated with anti-undernicity I think set us up nicely for the next and some issue about uncertainty whether that we want to derive an uncertainty factor in this chapter or at least some sense of that and could you also tabulate regulatory ADIs with their points of departure and uncertainty factors so that one can see whether they're different from points of departure's relates to anti-undernicity I've made it real to myself to do that yeah a lot of that Holger asked us to compile a list of published TDIs, ADIs, whatever and we did that so that could be a starting point for that Russell? Yes, Phil Yes, Phil Just following that discussion and we just received from Mike tables that give us the TDIs, ADIs, RFDs for various regulatory agencies couldn't we add to that several columns that relate to the references that we agree upon at the committee Yes, Phil We just agreed to that before I think we were trying to get on the phone Okay, we said that that is a starting place for exactly what you said Russell, I have a question for you when I extracted information from the CERHRO reports there was a section there on humans and when I did the literature review there was another section in the literature review on human studies but now it looks like we have human epidemiology data in two different places and I would defer to you which is easy for those for which the CERHRO has no report I could go through and take out all of the references to their human studies, their human reviews and just make note that you are capturing those but how do you all feel is the best way to do that I guess my preference would be to include it all in the human chapter given the amount of talk studies versus human I would go back to each of the original human papers and write my own summary of it or include it rather than using what the CERH had done before for the human studies But you can at least use that as a starting place Yes, I think to identify the studies I will assume that you are going to take those out of my section and when I write a revision I will just systematically take that out While we were just talking I was going through and circling the ones the reference less than them to them For more recent studies from the literature reviews that we received there is no CERHRO report reference is to human studies I am assuming you will take those as well and I will take a lot of mine I am more comfortable with that and then you can have them in as much you can put them in yours in as much detail as you want good that's how they make the report cleaner I just want to point out that EIP is missing here ok yes we mentioned that in our discussion film I missed that but what was that over EIP is missing oh yes I think that's one of the ones we are still waiting for the detox review I am hoping so ok, anything else on this reproductive part another variable in here is that there are many different kinds of reproductive studies the protocols and some of them are much more useful than others in terms of completeness and standardization of design but there are some that are unusual designs that still contribute information so I am not attempting to just pick out those that meet the OECD or the EPA guidelines for protocol and sometimes they are the best ones and sometimes they are not and sometimes the NTP ones are the best ones but if there is a continuous breeding protocol that is a whole different kind of study than a two or three generation reproductive study in some ways it is better in some ways it is not so I haven't attempted to flag all of those variations in there but some of them are important like the diet the way of preparing the diet for dose about the design of the study if there was only one design or study that detected these effects then we are wasting an awful lot of energy coming up with alternative designs so I have kind of accepted a variety of studies anything else on the poker I think the NRC report on flood aids had a nice chapter on the significance of the different study designs in terms of finding the relevant endpoints for the flood aids that the old OECD protocols wouldn't be within the window of sustainability and so on so I think there is a lot we can learn from the NRC report on flood aids okay that is all very helpful don't keep me busy for a while yeah Bill I think we are up to you okay I think you have already covered in your section a lot of the relevant points related to my section does the committee have any specific comments or requests about the way I put it together and the next one just a comment on thoughts to get your reaction to that I sorted out the CDRHR report more distinctly separate from the rest of it then built it and not that we have to be identical in how we do that but I sort of saw your approach in a sense that I started with I gave a summary of the NTP CDRHR report and Infantime was just taking points directly from that text and I followed that by studies that have been published since that report was issued I think the only big difference between yours and mine is the number of some headings I think the content is very similar yes I have given relevant references that both the NTP study has and then the references have been published since that report and I would like to ensure that I have been all-inclusive in terms of the studies and that he has agreed to do that and I will include any other studies that I have missed what I haven't done is give any critique of an individual study which there has been some discussion today about doing that I think Bernie you and I need to sit down and discuss how we might do that in a consistent way I agree Phil, in addition to a consistent way whether or not it is appropriate for us to do that there are some who is the benefit of having a group like CDRHR where you have 6, 7, 8, 9, 10 people sitting around where all experts in slightly different areas so they can go through a series of papers and somebody is an expert on SPURT somebody else is an expert on OVA somebody else is an expert on growth so you probably get comments on the value of a study from a broader base of experience than I could bring to the table for reviewing a wide range of manuscripts so I was okay with put bringing forward something that CDRH CDRHR concluded about the weakness of a study I was a little bit more cautious of doing that on my own judgment I think that Andreas made a critical point relative to the suitability of individual studies for determining points of departure and you know I need to have a lot of discussion about what constitutes an adequate study for determining a point of departure if we're going to say that we should or I should evaluate each of the publications that was produced subsequent to the NTP report I think that gives to be a really tricky issue of what constitutes an adequate study unless we can take that another step for if a study for the developmental toxicity area if a study is designed to meet FDA regulations and they meet EPA regulations and they follow an accepted OECD protocol can you get a point of departure out of there? Absolutely and a noel it's expected that you would have a noel that helps answer part of the question I think so yes but wouldn't that point the route of exposure be important for that? Yeah I think if a study is in the literature that's by an irrelevant route of exposure I wouldn't even consider I wouldn't ask is there a point of departure here for an irrelevant route of exposure I would just not use that study that's my own back field would it be helpful to know that there was that there was a different point of departure, a different noel for giving phthalates intraparent to neiling? So what would be a route of exposure to neiling? Eliminate hand to hand? Well intraparent to neiling That would be about it You might be interested in elation and diet Those are all somewhat relevant What about installation versus just direct elimination? Not relevant I don't think for phthalates Yeah I take your point but I don't think we come across a phthalate study where they instilled into the lamb or something Would that make a difference because I know in some cases it does Tell us what else Well one of the things that I had done it's not part of the document that I submitted but it actually put together some cables where I'm summarizing the studies particularly those that were published since the NTP report in terms of the endpoints were monitored whether there were significant increases and decreases and I've also put together another table that summarizes studies that have been completed with regard to motive action so looking at testosterone production gene expression etc Those aren't complete yet I'm still working on those but those are two tables that will be as well as others that we deem necessary Well if you can send me a copy of the format for the table for summarizing studies not the motive action one but the other one then I won't reinvent a new table Yeah they might not Well we can talk about that But then the point of the tables I think after the brief descriptions of the studies was to eventually get to the point of saying this is a reference table that seems to be related to the most sensitive endpoint that's what I was trying to get at and maybe that's not where we want to go Well I guess when you're ready they might be best to send them to Mike and let him distribute them to all of us A variety of input would be helpful on the design of tables so that we cruise tables and allow us to crosswalk from one part to another One of the things I was trying to do was to I looked at a paper by Robert Benson I don't know whether the other members of the committee have looked at that Yeah But they do a nice job for many of the fellows that we're interested in in terms of summarizing the data and then they have a table of brief data in which they cite specific papers which they use to then take the NOAA, LOL, or whatever and come up with the reference dose Following that approach in my section is that appropriate Phil, I think that's appropriate Yeah, I think that's sort of what you've done in your paper isn't that right, Andreas? Yeah, that's right I've actually put together a table comparing reference doses obtained by different groups and they're not that different But I might just add when you say the most sensitive endpoint you might have your table have the most sensitive endpoint, but then also maybe the most sensitive anti-androgen endpoint If there's anything... No, they can do that. What other comments are there for Phil? I guess It's not a comment for Phil or you but it's more of a general question about the diphenyl pallate how that will be handled to what what data exists There was the recent paper showing that it was and whether I haven't looked in terms of what Hogar and Chris have done in terms of including that or not I don't think there is biomonitoring data Well, because it is more potent than the others, we agree that as Phil and I and I think Mike have talked about this we agree that it needs to be in there someplace We need to make reference to the fact that here's one that isn't to which exposure probably isn't widespread but if, for example, that were brought in to be a substitute that there would be a reason enough to do that so we need to mention that here's someplace in the report but here's another pallate that's even more toxic than the other ones that we worry about but what we do beyond that we have to figure out but we agree it should be included I agree it should be included but I was asking what we do with it beyond that That paper is provocative in two ways first of all the of DPP and the other point in that paper is that the strain used the Harlem spragdoli seems to be more sensitive to thyroid syndrome like effects than the previously used child's liver spragdoli previously used by a great lab for example so there's another point there which we need to address so maybe it's necessary to judge or evaluate a little with an eye on that the previously published evidence Do you know of anybody who is now doing the kinds of testing that we've done in the other strains of rats are they testing this pallate in other strains to see how much strain difference and sensitivity there is I'm not sure I think that might well happen but they switched for some reason NTP switched to the Harlem spragdoli I think because everyone else does I have no idea but I think that we certainly need to discuss this further how we're going to use whatever information is available on DPP that's something that Chad has to discuss Mike, can you remember what I'm sure you can if you've ever seen it, you remember it the data that you have within your CPSC exposure factor on this particular phthalate well we haven't seen it as far as I know it's not a product but it's potency I mean it's right in the middle of structure activity range so you know I think it's appropriate to include it in some way in the report you don't have to answer for EPA and FDA but do you suspect their search for phthalates would include this one well I don't have EPA's list in front of me of the ones they're looking at it's a pental it would have been reported if it was found because it was looked for well they're looking including it in their hazard review and you know reference notes so on but as far as exposure I don't know but if FDA doesn't analyze for it then it's not in any of the reports it would be I don't know anyone who's analyze for any sort of products I measure in our HBM studies for a couple years now and I have never seen it it's a good stuff would you repeat that Holder says they looked for a couple of years and haven't found it okay we think we're not sure about whether or not EPA and FDA look for it so that they haven't found it and the report is that they analyze for it and it wasn't there or the possibility that FDA isn't looking for it Dan just reminded me I forget where we heard this but I think there's a paper coming out from Califat where you will find it in a large percentage of the samples they measure the levels are very low but you can at low detection limits you can detect it in some individuals they actually have positive detects but at very low levels and we are right now discussing where it is coming from fight product or degradation product or highly fall is your work in multiple tests or just for a single measurement of a person just a single measurement you have no idea it's fair in the NHANES your data or NHANES they've looked for it and not detected in previous has it not been measured but is it in the newest I don't know about the newest but normally they had tested for it that's the latest CDC paper that was referred to in our workshop that was pre-publication I think it's out now it's worth checking into but are they going to be included in bio-minority studies or was this just a research published research publication do we need I think we need to take this another step further we'll meet again in three months and have the same discussion who could be asked to pull together what's known about this particular cell so the next time before next time we have a report what the thinking is of where it's coming from what is the limit of detection compared to other that we're looking for I think people haven't looked for it because it's not a commercial product but as far as the data I think that's one of the touch reviews that's coming good so then one more anything else for Phil? thank you Phil okay thank you hi Phil it may not be the last time that Joe plays but it is here no it's not that I haven't had breakfast yet oh I think we're ready to adjourn for lunch here let's reconvene in 45 minutes walk on good thank you Joe bye we'll call you back Phil