 Okay. Now we're at the stage of the process where the panelists will elect a chair and a vice chair. And so I would like to begin by asking the panel if there are are there any nominations to be the chair of the Chappan fallowites. Well that the chair is responsible for the overall conduct of the committee and for organizing it and to see that the the work the various parts of their assessment are done in a timely manner. They will work of course with the support of the CPSC staff. We will give them all the administrative and other support that we can. The chair is a very important critical a critical position. They will help shape the overall assessment that the chap will be doing. The vice chair will be there to assist the chairman and to help them with any of their responsibilities as needed. And the chair once the committee the chair is elected the chair will for example help us to schedule the future meetings and how often to meet and so on and so forth. So the chair is a big big responsibility and very important and of course we all know that the chair of a committee such as this a good chair makes all the difference. So does the panel have any other any other questions? It has to do with the budget. Yes. So you were saying the chair is going to help decide how many meetings there are and things like that. Is there a budget for us to meet on a regular basis? Well I think we needed to see get the panel together brief you and see what the panel in the chair thinks we will need how often we will need to meet. This is because this is so much bigger in scope than our previous chap. We only have that experience to go by. As far as the budget goes you know we plan for a certain number of meetings in terms of travel expenses and so on. There isn't a particular amount of money necessarily set aside for things but whatever the chap needs we will ask for is the process we use here. Okay any other questions? Can we any discussion or should we do what anyone like to make a nomination? Could I nominate Philip Mercus for chair please? Okay we have a second. Okay so we have a nomination. Are there any other nominations to be the chair? Is there any discussion? Dr. Mercus would you like to maybe say something or is there any other discussion? Well this is this is clearly a huge task for anyone to lead up this committee because the charge is quite extensive and so we're going to have to as a committee really define exactly what it is we we think the charge should be and then how we're going to carry it out. I've worked on NRC committees and I've been a director of a center so I have some experience with handling processes like this so I'll do my very best. Thank you. Is there any other discussion? Okay I guess all in favor of Dr. Mercus as the chairman of this chap please raise your hands. Okay so we have one one abstention and now do we have any nominations for vice chair? Would anyone like to make a nomination? I would I'd like to nominate Bernard Schwetz for vice chair. Would anyone like to second the nomination? Okay is there any any discussion? Dr. Schwetz would you like to say something? Well just to say that I'm honored to be on chap to begin with and certainly honored to be nominated to help run run the the process and I've known Phil for a long time and I would be happy to work with him as the vice chair. Thank you any other comments? All in favor of Dr. Schwetz as the co-chair or vice chair? Okay thank you. Well congratulations Dr. Mercus is our chair and our vice chair is Dr. Schwetz and Phil if you would be so kind as to take over the the meeting from now on if this is your meeting you can speak from your chair you can speak from here whatever you prefer. Sure this is the first slide and you know this is a bullet version you all have the actual language in your binders that you can also refer to. What's CPSIA 108. In the description of the chap begins on let's see the third page no no no the bottom actually the middle of the first page is where under number two is chronic hazard advisory panel. I thought that the best way to proceed is just to start with these bullets one at a time and flesh them out decide how we're going to fulfill that bullet. Seed on to the next one it's pretty clear that may not be accomplished at this session or tomorrow but we'll make a good run at it. Question? Chris? What I'm looking at maybe I'm looking the wrong place it looks like this is more description of the panel itself and not so much what's listed here. Is there other language for this? Yeah be exam be examination they're like eight charges right yeah eight charges it's called CPSIA 108 you might be on the so the first charge in in this document is examine all the potential health effects including endocrine disrupting effects of the full range of phthalates so that in by itself could be a book. Who wants to to speak to this in terms of beginning to establish an outline for this particular point? This may actually be in the wrong direction of what you're really interested in but you know from some of the work that we've done previously on the NCR on phthalates it was clear that through some of the discussion that there are other chemicals that may have similar effects to phthalates and our thinking at that time was not to focus too narrowly so even here just to say just to look at phthalates when there are other chemicals that may you know have similar effects are we starting off even from the beginning by focusing too narrowly or well we can all chime in on this but my feeling would be that if if we start off with the universe we're gonna be it be difficult to proceed so we're going to have to limit ourselves in some ways to make this a project that's manageable in two years time I would think but please have your comments now yeah if I could my view of this is that it's a huge task that you have and it would be I'd be happy just to see you accomplish that if you want to broaden the scope even though it's important I mean I wouldn't say no to it but you know just understanding the the breadth of this I think to look at just phthalates would be a wonderful start if you even more than a start I won't say no but I also in my understanding is the other chemicals are mostly pesticides in which case they're again you know not in our jurisdiction and again not that that's not significant but I'd start with what we need to do first but I certainly wouldn't wouldn't rule it out I I see both sides both concerns and maybe I can propose a middle way and I also think it would be too much to broaden the scope and to subject a number of potential other chemicals to the same degree of toxicological examination however I I think Chris is right and this was one of the key points of the NRC report we have to protect ourselves against the danger of examining a totally artificial problem but I think in in only focusing on phthalates when in the real world there are other exposures which may actually exacerbate the effects of phthalates may there's some evidence to suggest that I think to salvage this and to serve both both these opinions the why out of this dilemma would be to focus on phthalates so leave leave the scope here but take the other chemicals into consideration under the rubric of background exposures so with specifically asking the question do we have evidence or reason to believe that co-exposure to other existing chemicals might actually exacerbate the effects of phthalates would that be a compromised proposition which could largely lead to some kind of a factor adjusting for the fact that there are things that we're not accounting for but to address that in our thinking might make it seem more realistic and less I think I think in number seven which we probably won't get to for quite some time I think you could probably bring it in they are where it says in using sufficient safety factors to account for uncertainties regarding exposure susceptibility I mean you could you could think that other co-exposures to chemicals that have similar biological effects could be brought in there that's what I didn't mind yes one thing that I think we're charged with is finding out if there are any phthalates other than those six that have already been reviewed by your staff that warrant further consideration for potential limitations to exposures or inclusion in products so as a minimum I would think we have to have information on the other phthalates beyond those first six and if that convinces us that we should be looking at other chemicals that either potentiate the effect of one of the phthalates or in somehow in some way modifies and makes other phthalates more toxic we can keep our eyes open for that I think if we start searching for those now that would be a major task and make it harder for us to evaluate your first priority of knowing whether or not with those six we need to include that list to more than six and as we look at the other ones I would add to what was just said in addition to the amount of them in the environment or in body tissues that that may identify some that are very that are out there in large amounts but we would also find in that they're not very toxic possibly so we need to look at the amount that's out there but also the inherent toxicity of those that are beyond the six so that we would give specific priority to those that are the most common and those that are the most toxic and see if there is one that's most common that's also most toxic and that would that would be a way of looking at these other phthalates mean outside of the six in addition to the six I think that makes perfect sense I probably should have started there identifying which phthalates we were going to focus on that I think that's a good point burn a question about support then from the CPSC can we get the reviews done on the other phthalates well I mean it's sure do we know what the other phthalates are going to be I mean we need to I think yeah you know of all the phthalates in the universe I think that there's 10 that people have identified in the biomonitoring studies I don't know if that means there we're only exposed to those 10 but at least we know that in somewhere in here in the overview tab the second to last tab I think I give a list of the of the on page 22 of that tab I have a list of the phthalates that have been identified in biomonitoring studies so we can start by looking at that there's a couple others I mean I think doctor well I subdued I know dr. Koch has a might have have some there's another one dphp maybe we could add to the list so that might be a place to start it's to look at the fell and if you want us to look at the dimethyl and diethyl certainly so we could look at essentially anything on this list that we haven't already color covered probably should then spend a few minutes or or whatever it takes to identify pellets that we'd like to have research done on in terms of literature when he wanted we want to include all those in table nine yeah um in you're looking for the tab may add something okay so we have this list of the three phthalates which are banned and the three with the provisional ban so I think that's obligatory for us to focus on then we have on page six of the slides it's slide 18 so I think we should focus on those that have been identified to provoke the late syndrome in in rats so additional to this is diisobutyl delayed as a mandatory one and then of course we have although they're inactive in the in the rats we have some hints for the low molecular ones like the evil and the methyl phthalate those should be included rust correct me if I'm wrong and looking at the higher molecular weight phthalates so that's the di np and di dp we have an additional one that's the propyl heptyl phthalate which is a C10 phthalate which is also on the market now so the lights in the first look just in terms of exposure and toxicity reasonable but still goes Chris's fundamental problem looking at in isolation I don't know how we can look at anything global in terms of other compounds and classes of compounds grab is crazy no it won't because it hasn't driven us crazy on the nrc panel we've done it and we you can you can we can build on that expertise so you want to build on what the nrc panel did to to basically pair away the other chemicals or agents of concern yeah there is a body of knowledge available not only in the nrc report which which would help us to to achieve that so all right if you want to do it that way I'm more than happy to agree to that because I think we have a fundamental agreement that we can't do everything and some other bodies resources to ensure that we can focus on phthalates effectively so I have no problem and and I I would agree and I think that a starting point should be on the phthalates and on the nrc panel that's what we basically did I mean we really started with the phthalates and then I think brought in the other chemicals that may act through similar mechanisms or similar common adverse outcomes so and I mean this report to could be a framework that could be built upon you know other chemicals can be added later too it's you don't have forever and you know you don't have unlimited resources and so on but let me just assure you Paul we're not reinventing wheels here and we are also not starting from zero so there's really a body of knowledge yeah I mean the method the nrc report really is a how to go about doing this yeah it makes our job so much easier even though it's still daunting it makes a little bit easier but still I think we need a consensus on which endpoints we are focusing well that's a good point I think that's the next step before we go there I was a little slow what is our list of phthalates now table nine that we were just looking at right I think page 23 right yeah yeah thanks are there others besides well table nine there's also they're mentioned on on slide 18 but I think they're really the same or maybe not entirely the same it's basically anything in table nine or on slide 18 that isn't already covered by the the first six plus dphp I prople that I to propel heptal but have we in this way answered burns concern that there may be other slides what and do you think this is well take table nine is the things that are identified in human urine I don't know whether there could be others that they just don't measure I don't know that but those are the ones we know that people are are exposed to you know so I mean you're looking at really two different things you're looking at total exposure and you're also looking at the children's products and some people you know this is all subject to interpretation but some people when it says the range of phthalates used in children's products some people take that to mean the mainly the three interim band ones but again you can that's open to interpretation are we getting ahead of ourselves right now sorry let's let's sorry stick on number one yeah so from my notes this morning did you say that there are roughly 30 phthalates well as far as I can tell there are 30 commercial products my understanding is that half of these are high-production volume chemicals I could try to confirm this in the bio monitoring studies there are these you know 10 that they measure and you're talking about like in in Haynes in Haynes in other studies I mean nobody I don't think anyone measures all ten of them at the same time but there's a total of ten that have been measured but my understanding from the in Haynes is that those chemicals were selected for study based on things like production use and also likelihood of effects do we know for sure that those that aren't considered there really I don't know for certain but I can you know I think we know who to ask the list of metabolites analyzes always a state of the art thing so you only can analyze what you have the metabolites for I would propose to our circle here to maybe have a look at table three in the overview on page four and I think this is a good list of all the relevant commercial or irrelevant commercial order of delights so I think this would be a good approach that we can take these delights which are which we think with our knowledge to be relevant which say what we're talking about this one page for this is nothing to do with bio monitoring or it is those that are present or not present as I understand it what we're asking for here is information about what data are available on these right but why just the ortho phthalates well the I mean these are the ones that have a month have the effects from peroxisone proliferation to the male developmental toxicity as a class I mean that's the concern and these are the the plasticizers that have been used for many years and you know yes some of the substitutes are the pterothalates and they're actually covered in the substitutes part it's simply when people talk about phthalates in you know they're really they're usually talking about the ortho phthalates did you want to add to that list of I mean I'm not the person to ask about that I was just trying to make sure that we knew when we said phthalates and this is ortho phthalates but you know maybe if we're if we're starting to talk about what the list is going to be if we could include you know we we got to this list from these assumptions and largely what Michael said just said of things that we could include right we can build that justification from what he just said I mean more than likely this list of 30 you know once you get past those six you're gonna find less and less data anyway actually it'll it's gonna be more than six because you can see the isomers so it'll be approximately 10 in the end the other comments do we know what the universe looks like now it's blue or is it orange the orange just orange so should we go through this list and discuss we could be cans I'll consider all of the ladies there on the list of table three you want to go through it or do we want to think of it like the six and then those that aren't in the six what what other than the six yeah is there anything other than that that we ought to be looking at I mean all we can go straight to table nine as you suggested originally all no no all right well I know table nine was on page what 26 again we're not going to use this list to determine effects of each one of these or in combination but rather just to ask them to prepare information for us what is what is known is that am I correct on that so I think in terms of going through them one by one that's probably for a later date this is just yeah we are discussing now which the lights to focus on and we've agreed to table the 10th our lights list listed in table nine are the ones they're sort of minimum correct I don't agree on anything yet but that sounds like a fair way it's a minimum yes but bio monitoring doesn't cover everything true so well how do we want to proceed do we want to say let's start with those in table nine and then we have to prioritize the rest other than table nine in in one or maybe one or two more there's probably not going to be a lot of but certainly not going to be bio monitoring data in not much in the way of exposure anyway so you know I'm not sure what we would find out about them I mean we can look but you know I don't know how much there's gonna be but still going back you know this just says though that we're supposed to be looking at the full range of phthalates that are used in products yeah well it says the full range of I think the full range of phthalates used in children's products and I mean this is you know this is confusing to say the least and well Mike that can't be totally correct because we're also going to be looking at pregnant women right so that's going to bring in exposures a whole variety right that's right true we can't focus only on phthalates in children's products I totally agree but it seems to me that if we're going to be transparent in terms of the list that we finally come up with that we're going to focus on we need to start off as broadly as we can and just have a literature search and then once we have that we can say well for X through whatever there's just not any information that we can go on so you know we don't discount that they might be a problem but we don't have any way to assess it and then we would focus down on our our shortlist okay that makes sense yes we go especially if there's if there's some explanation of why the others haven't been studied is it because of some structure that makes them not likely to have an effect or you know yep any information that we can we can include in our report yeah good yes go ahead in terms of commercial importance could we get production numbers oh we we can try we can we can try I mean of those 30 you know half of them I believe or high production volume chemicals we can try to get the the latest information from EPA that you know that that might be the only information that we have and in order to judge whether or not to pursue a particular chemical but could could that actually be part of our conclusion at the end is that you know especially and I don't know if the high production chemicals are the ones that have been studied or are there high production chemicals that really aren't studied or haven't been studied and if that's the case you know maybe part of our conclusion at the end of the day is we have to judge based on data and there are data gaps yeah of course and these are the gaps that we find and I assume that's going to be a big part of our final report is what are the data gaps that you know either prevent us from making a judgment or I won't say the alternative okay any other comments on how we're going to proceed in terms of identifying the phthalate family not that I think the next task would be to move to that first bullet and start to talk about what potential effects are we going to be focusing on in requesting information about would that go back to number one the information requesting number one include that because then we yeah I suspect it would if we're going to look at them or we're not going to look at them we're going to have to know what potential effects are from the get-go yeah but would your search I'm just thinking from from my perspective of developmental toxicology since this chap is really focused heavily on exposure to children would your literature search pick up the effects of phthalates on development reproduction well I mean it it would if they're if they're in toxin at you know the National Library of Medicine databases we will pick it up the prop the the thing is most of the the literature on in the especially for the developmental studies it looks at multiple phthalates and so there's probably you know for the phthalates for these other ones we're adding on if there were a lot of data we probably would have seen it anyway it probably would have come up so you know certainly will look but I think that you know if you just do a search on Earl Gray and Paul Foster you'll probably come up with all the relevant data anyway a question to follow up on that the concern that we always have and at this time about unpublished literature that are relevant is in your interactions with those two individuals in the laboratories that they represent are you aware that they have unpublished data that would be important for us to be aware well you know there's always stuff going on I know that that well they're testing more and more compounds to see if they're active active as they call them and I think we can certainly expect to see more in the future we can ask them we can invite them to come add up to a future meeting and present certainly that's a possibility I wasn't thinking so much of ongoing studies as a study that was done 10 years ago and it wasn't exciting so it didn't get published but it had valuable information I mean all we can do is ask yeah a lot of I mean there's unpublished data that submitted to EPA that would come up in us in our searches but other than that that's you know yeah it's hard to account for what what's we don't know and all we could do is talk to as many people as we can am I correct to say that the Paul Foster and Earl Gray would be largely focusing on reproductive chemicals that may have an effect on reproductive well specifically the male developmental effects so if we if we're interested in other health effects oh well we would just search for the chemicals and we'll do that another another issue is having access to ongoing or planned studies I know that we talked about the fact that there are studies ongoing at EPA and and NIHS I think we need to see if we can track that information down just so we know what is going on is get published we can certainly do that what about non-repro and development endpoints cancer for example you know they're there are data absolutely so we look at it definitely comments yes one comment about this cancer endpoint there is a school of thought saying that if you look at which effect is probably the most sensitive or which group of effects turns up fast as you escalate dose it is developmental and reproduction but there may be one or two examples but that's not true yeah I think there's a lot of examples where that's not true I mean for the ones that cause these effects that's often the most sensitive endpoint but there are others that don't cause those effects so it's it's you know clearly people are most concerned about those male developmental effects the phthalate syndrome in the possibility that phthalates cause the human analog of it but not all of the phthalates have those effects so you're you're kind of torn you know do you look at these effects because that's where the concern in it is and because that's where you know that the effects are additive or do you look at other effects like liver toxicity which it may be more common and when you add them all together may be more significant and I meant it in slightly different ways if you look for example at the INP correct me if I'm wrong but I think that would be an example where cancer effects occur at lower doses than reproductive right right should all be captured in in literature we're going to be yeah yeah I just wonder is there any other I'm only aware of developmental reproduction and cancer but I just wonder it's made just my ignorance whether there's another group of effects we should take into consideration the other there's in chronic studies in 90-day studies you see effects in the liver in the kidney are common occasionally you see something else well you see of course testes in certain ones you see occasionally thyroid or something else and but the liver in the kidney are the most common and they're often the sensitivity the doses are very close to the doses where you see the developmental effects in humans there's concern with respiratory effects I don't I'm not that familiar with the tox literature to know if studies have been done looking in inhalation exposure or but there's there's studies I know that are ongoing and have been published where they've looked at you know asthma or wheeze in relation to phthalates yeah there was a couple where well the borne hog looked at asthma rhinitis in eczema I think those they're not real strong studies in you know people have looked at various kinds of immunological endpoints and you know there's some effects here and there but it's not really I mean it's obviously it's a concern people some people would say that that's important I think that the other endpoints are a lot more strongly established I think the same as the case with other effects that have been found based on epidemiologic hints like obesity or diabetes I think we should it's not current few that these effects really are caused by the phthalates so we might keep it in mind but I wouldn't put any focus on it but if you're screen the last two years on phthalates effects I'm based on enhance data and bio monitoring data and epidemiological data you come up with these effects like obesity diabetes the asthma story was a bit before that but I think but I think I mean I think it brings up another point but we probably I agree we shouldn't probably go there but when you say effects on children's health you have effects while the child's child and then potentially you have delayed effects where you know obesity or asthma you know decades later you could think about yeah I think it would probably correct me if I'm wrong but it's important for us to maybe define all the potential effects and then limit ourselves to the ones that that we have data that we can okay yeah in the yeah I mean the reviews that we've done so far cover everything you know almost to a fault do you have a table a table of the effects well effects versus the chemicals of concern really let's see in the page five of the slides yeah there is a slide and there is something in the in the overview if I can find that yeah you haven't on page five for some of them in the overview I'll bring up the slide in the overview document on page nine it gives some of the main endpoints but again it doesn't there's no way to you know you'd need a mile page a mile wide if you put in everything so those are the the highlights the ones that kind of jump out you and I worry about though is I think it's only been more recently that people have started thinking about mixtures in a more systematic way where as if we're looking at papers that are you know somewhat older they may be looking at the facts of a single chemical at a time and saying oh there's no effect on obesity or diabetes or some are respiratory or whatever and it might not show up but if they started looking at it more you know as a combination maybe they would show up I don't know how to get around that except to go back and think about each of those older papers or older and maybe it's not older but just I you know I I think it's it would be possible to miss effects in the literature because things aren't thought about as a combination yeah well that that I think gets us unless we want to say more about the world of phthalates to the next point which is individual versus cumulative risks is number three likely number three is likely levels of children's populations pregnant women's and others closure to phthalates it's others is makes it very broad I mean I'm not sure if that means the general population or other sensitive groups oh I was I was looking at number two there have we talked about that I mean I assume that the literature search that you're going to do is going to pick up both days with individual phthalates as opposed to combinations yeah well we'll get probably all just individuals I mean the combinations are we probably already found those so yeah very few process question about the literature searches is the purpose then that you're going to be giving the panel the original articles or synthesizing the data well I think this is this is what up to the panel I think for starters we're going to look to see what's there because for some of these phthalates and some of the endpoints there will be hundreds of papers okay because I think in rat you know in the toxicological literature yeah yeah but we've you know well we've probably covered the well most of the big ones I mean yes some of them are going to have a lot some of them are going to have very little like DH a DHP will have quite a lot but yeah mm or DMP probably not yeah right and now while we're doing this I mean there is working going on PA and we will see I don't know what exactly what the timing is on all of their work but you know we we can maybe share some resources too but I mean they're not in the they're not in the binder but on your CDs we have the reviews of the of the six plus the well the overview document in the couple of other studies that we did so that's that's on your CDs and we can you know it's too big to put the binder but we can if if you like we'll print those out in in shipping to you if you like if that would help so you don't have to carry them back but we've got that in then we'll we'll start working on expanding the the scope or clarification I would ask what is the purpose in including pregnant women yeah sometimes pregnant women are included not because there's a concern about the physiologic differences between pregnant and non-pregnant women but are included only because of the sensitivity of the concept is yeah in which case the target is not pregnant women it's really the concept is prior to birth I think you know my interpretation is that they're concerned about the concept is then we shouldn't create an expectation that we're going to look for the sensitivity of pregnant females to the phthalates because that's not what we would do okay now it's it's possible that their expo the the pregnant woman's exposure patterns might be a little bit different which would impact the fetus but that's fair game yeah but not just pregnant women because they're pregnant that's that's not a this is not a high priority I think that's what they're getting at the task I see here is what are you gonna be using as the baseline for what levels are we're doing biomarker levels we'll be able to get data from and Haynes to begin differentiating whether or not there is a significant difference between pregnant women exposure and non-pregnant women I mean there's there's limited data on exposure to pregnant women and children under six right oh well these are the likely categories that yeah three yeah are directing our attention to and that's going to be an awfully hard data set to acquire I mean more uncertainties and gaps than anything else that's what it would be really nice if the National Children's study got going really fast because they're gonna get those two populations but there are quite a few studies on pregnant women I know Columbia Mount Sinai there are there are studies there are there are studies just not as extensive as in Haynes right but still the pertinent question is what is meant by level it can mean two things internalized dose or tissue levels it could also mean intake I think in to resolve this we have to focus on both yeah there are attempts in the literature russus the expert there but it is possible and Holger as well it is possible to calculate back what the likely exposure was on the basis of metabolite level so but we need the other dose metric intake as well in order to make valid comparisons with results from animal studies etc so start our understanding then shall we agree level in the sense of intake as well as tissue levels yeah no I would be less I'd be less optimistic about thinking we could go back to where the exposure came from because we don't know what the sources are I mean we can I literally say that a person's been we may be able to characterize the cues in which we can put pregnant women or you know the baseline exposures that may lead to make you where you may have a dose of X in the body but to go extrapolate back to the sources I that's a daunting task and no one's accomplished it for any chemical yet no there is information about that I'd start to do this there is information but it's it's no day once you get back to trying to figure out where the exposures came from you're dealing with you know inhalation dermal ingestion uptake so therefore you have different degrees of assimilation and bioavailability and we don't have that kind of information so I think trying to go backwards at this time it's a little bit more funky than you might think it is but it's something worth pursuing but I think that's a lot of research but I mean it says consider all the available sources but if you have biomonering data and you know what the total exposure is you don't necessarily have to know how much of it is coming from each source you don't necessarily have to do that I mean to look at the children's articles exposure from that you might have to do a ground-up scenario based thing if we if we're going to move from three to four we have to be really careful yeah because four talks about total exposure I just want to be clear that we're not going to get that from going backwards from biomonitoring data we just won't have the capability right right right it's not possible at this point in time well the pharmacokinetics and the data just don't live there maybe we need comments from here going to us here but as far as I know the literature this is what you just said is not state-of-the-art we have further developed than you think we are and that's part of our task I think is to say that where are we and what can we what can't we do but there is there is some data I mean I agree that it's all not there but there is some in terms of that question so in terms of biomonitoring those extrapolation yes there is data but I still have to say yes to what Paul said that we are still on the quest for identifying real point sources sometimes so there is still a lot of things to do especially if one if you want in the future say we should restrict the use in this and that product no no I'm not disputing that I know I know that but we are yes I know but let's say we have broad feeling of what the likely exposure can be in the median and also in the upper percentiles right that's what I meant yeah I mean from the from the urinary metabolites you can say what the person's total exposure is that's right with the reason within reason long as you know it's a single biomarker you have all the biomarkers established right one particular chemical you could probably make an estimate it doesn't mean that it covers the distribution of all populations I I'm just being careful here yeah we can overshoot the you know we can overshoot it and come up with them numbers which are not meaningful when you get to a large population yeah well you're saying here sure there's there's data for whom and for how much can you who can extrapolate to I think I think the data is there to do very good extrapolation I do reconstruction modeling all the time from biomarkers backed exposure none of the chemicals I work with except for lead and that's under very limited circumstances can I get back to what the exposure no I agree with you I mean I think what you're saying is in which I agree with and I think Holger said as well that we don't know the proportional contribution to what's in that individual's body or urine so we don't know our 2% coming from personal care products 20% 3% for me or 30% I would that I agree we I don't think we know that there's been you know a handful of studies but 99% of that we don't know but I think we we do know you know what levels are in different segments of the population in their urine that's fine yeah so I think we're agreeing in terms of the gaps yeah but the proportional contribution in the specific source yes we we don't know what's most important or most relevant and we still have to keep in mind that the population which below three years of age is not very well covered by you and by monitoring data you say not very well covered what do you mean you can't get blood out of them easily or urine that's the problem what about from breast milk turning human by monitoring that's a very difficult parameter right how many you know how many kids are getting 90% of their milk from breast milk infants well infants I mean they're all different ranges of people who use or do not use formula purge but it's not necessarily uniform I just think with bio marching we have to really be careful not to overemphasize certain things that we cannot do with it there are certain things we can do with it but we have to really careful and I and Holger's right about the issue of very tiny very young children because you know we can't get I mean I've tried to take urine samples from from infants and it's a daunting task trying to take all those diapers it just doesn't it's just not an easy thing to do really isn't can we discuss grappa grasshopper we've gone from grasshoppers to diapers with the heck yeah but it is very hard Chris it and then we we tried it and it's it is a it's a real daunting task to get good urine samples from from in that well the back calculation to the intake you can do for adults for infants who knows in the same thing pregnant women you know the physiology and everything who I don't know if you can accurately make do that calculation for those populations okay well I number four is not going to get any easier consider the cumulative effect of total exposure to Thales we get it for us sources no I would like I would like to assure you that it it sounds difficult but we it is possible to do that is an enormous advance of knowledge in this area it has been done before this is topic of ongoing research we're not going to start from zero we can build on something what are we building upon yeah could you summarize what what's out there briefly first of all the NRC report which is a if you like review of all the mixture studies both with phthalates combination of phthalates combinations of other anti-androgen and put briefly the body of knowledge so far tells us that it is possible to fairly accurately anticipate the effect of a combination of any of these chemicals if you know the potency of those chemicals individually so the it is possible to adopt this kind of predictive approach fairly validly that's quite amazing so basically additive mostly dose additive yes there are our own group and configuration in Europe we've thrown a spanner in the works by it's a recent paper where we hit upon a synergism between one salate DHP and a combination of other anti-androgens with respect to one end point and that is hypospadia small formations of the penis in the rat the same mixture produced concentration additive your dose additive effects with respect to all other relevant end points in the rat we currently have no explanation why this particular endpoint should show a synergism but that's one finding but apart from that most other joint effects of been those additive so which is very important because it may open the door now for modeling approaches rather than investigating each and every combination of chemicals again and again we we are now I think at the level where modeling is a real possibility I'm going to look at from the other direction I mean you're looking at in terms of the cumulative effects a total exposure I'm looking at it maybe from the different vantage point accumulative effects of whole exposure on a dose first which is the only way you can link it back to children's products and other sources rather than the effects on the body I mean we have to have a clear definition of what we're looking at because none of everything you said is correct but I don't know how I can basically link in any one of any one of those statements back to children's products for other sources such as personal care products how do I do that I mean we're talking about biological effects here you're talking here you're discussing I'm looking at this as a little bit of a different twist to the question because what we're being asked here in this room is to deal with the issue of whether we're going to ban the use of this chemical in certain products and I don't see we haven't come to that conclusion yet from what you just said it's true what you're saying but I don't think that's what this question is asking you're getting at the central question of extrapolating animal data to humans especially for individual products yes I mean I'm not sure how I can do that this way I mean it's it's I think this is a really tough question I think there's a toughness in two of those three issues that are in that number four and I don't know how it would even begin for us to approach whether it comes from personal care products or something else but even the other two I think there are two different questions here when you talk about exposure and mixtures cumulative exposure is an issue of its own right regardless of individual chemical or mixture and I think there are two separate questions so what is the evidence for cumulative effects from these materials that are absorbed rapidly and eliminated rapidly where you wouldn't expect a cumulative effect because they don't build up for a long period of time so what is the cumulative nature and second what is the difference in toxicity from the mixture versus the individual compounds and one specific question I would have about what you've already looked at it has been my feeling in the past that mixtures don't especially have chemically related structurally related chemicals it's unusual to find a new target organ you find enhancement and existing target organs that you knew before is there any evidence in this Thalite database for the new target organ to come because of mixtures can I just answer this taking your last question first the answer is no I'm not well I should be more careful I'm not aware of anything which doesn't mean it's not there but I'm not aware of anything but your first point cumulative exposure that's I take your point but partly that's semantic cumulative exposure the language of mixed toxicology is funny and not often very clear and sometimes ambiguous cumulative exposure can usually in this specific area of expertise means exposure from multiple chemicals we are multiple routes and pathways that's EPA's definition of what cumulative exposure means you're quite right it could also be interpreted to mean building the building up of levels inside our bodies from exposure to chemicals that just stick around that are highly persistent and cumulative I think to simplify or to clarify point number four I think I would interpret the charge here the text that cumulative exposures or cumulative effects it talks about is meant in the sense of the effects of combined exposure simultaneous or sequential combined exposures to several chemicals well that this discussion brings up a really good point I think that we have to be very careful how we define terms we have to make sure that we define them in either multiple ways and say this is the way we're going to use it or talk about it in different ways but I think it's important that we define our terms it's one of our tasks there's another way to look at cumulative effects of total exposure this is not a constant exposure either this is a this is like an interval exposure it could be a frequency effect so therefore you could have multiple hits of exposure with high concentrations and in other times we're not because especially if you're talking about mouthing a material it's not going to be all day long it may be a kid maybe going on vacation he doesn't see his you know mouthing devices for two weeks but he comes home or may sees it every day when he comes home he doesn't use them anymore because you have no idea how this thing works you're looking at you're looking at something that is absorbed eliminated quickly and it may be absorbed again in another time at high concentrations this is a very ambiguous question to answer also in conjunction with point number two where it says consider the potential health effects of such of these phthalates both in isolation and now importantly and in combination with other phthalates so to me I don't know whether I interpret the intention of the legislator here wrongly but I think that means we should look at mixtures that's a good point and that there's an overlap or a link with point number four which we are just discussing so yeah that's I think we need to define it that way yeah another point regarding cumulative effect total exposure phthalates have been described by some people as pseudo cumulative chemicals meaning that often when the rate of input exceeds or comes close to the rate of elimination you have either a build up or at least a building of a steady state so an equilibrium yes so whichever ever why we interpreted I think we should look at that and mixtures I think there's no way out of that as it seems to me that's the intention of the legislator but I don't want to lose I don't want to lose sight of the second half of that statement from children's products and from other sources such as personal care products that is going to be a real nut to crack that may be simply easy to deal with in the sense that we can't but I think we have to just be aware of that and understand that there are going to be limitations and this may be a limitation big one but you know again I one way to interpret it is they want to know children's articles and everything else yeah as long as the everything else includes personal care products that's okay you don't necessarily have to single out the personal care products yeah but does it make sense to think about maybe we're simplifying too quickly but does it make sense to think about having by a monitoring data sort of be the flag and say you know this is where we know we have exposure it's evident here in humans here's the exposure and that exposure evaluation in terms of risk needs to take into account that there are multiple chemicals that actually individually could be at very very low levels right and which so a combination all at individual sub thresholds we really could still have an effect I mean that's the combination effect right so then once once you have sort of that right side by a monitoring data to an effect some kind of a relationship there then go back and say so where did that come from the exposure you know maybe we could explain some from children's toys or whatever but I don't think we have to start with explaining the exposure and then going straight to effects without going through the biomonitoring which is something that evidently wasn't available in the dinp chat work I think we just have to use every sliver of data that's available to try to come up with some understanding of the situation there's going to be no perfect data set and we just have to be careful not to overinterpret anything and use it wisely I think you're absolutely right up to you how long would you like to break break floor okay let's take a 15 minute break we'll be back at three yeah let's reconvene although we have scheduled a fairly extensive break here I noticed from the schedule I didn't oh it's it's at the chairman's discretion I think we're all eager to have more detail here and so let's proceed so are there any other you're going to stand okay comments concerning cumulative effects have we have we defined the major questions that we want to address I think so I think we're just going to have to come back to this and when we start thinking about how to address this charge there may be a variety of different subheadings into this that have to be dealt with and one of the things that burn mentioned at the break was that we really need to define what and and who we might want to have come talk to us providing additional information okay so let's go on to five you all relevant data including the most recent best-available peer-reviewed scientific studies of these phalates and phalator alternatives that employ objective data collection practices or employ other objective methods well that's going to come out of all the information that we've already talked about so we're like god motherhood an apple pie doesn't feel there is a question that we should address I think related to this and that is whether or not we are going to review for use data that are not published but it's peer-reviewed information so are we are we willing to use data and if so what kinds of data analytical data talks data I my instinct would be to restrict it to published peer-reviewed data I would be careful about that because it's the first time we are talking about the late alternatives and if the late alternatives coming onto the market like DINCH or like DPHP or whatsoever I think there's a very little scientific peer-reviewed data well then we get into the Shelby Act United States you know when we make regulations or making recommendations for regulation only information has to be made available for somebody to come and check it to make sure we made the right decision and that's that's a that's an act of Congress so as long as what we use can be made available for somebody to go back and analyze it in the end once we've gone through it that's fine I mean anything that's a work product from a contractor that we hire will actually have to be made available and that's that will be that's reasonable but if we if we're looking at confidential information that we can't use you know beyond beyond this we can't use it and so we have to be make sure that any gator we use it's not published can actually be released to the public and we're just not going to have confidential information put before us that we cannot touch you know later date because we have to be able to be subjected to the Shelby Act I mean the reality is that there's a lot of data on industrial chemicals that's not published in the peer-reviewed literature but a lot of it is public either because it comes from EPA or through EPA or or it's volunteered by the company so I mean it's the the the chap it's your call how you want to do this but that's the reality if I were doing it I would use the any data as long as it's public now data that's not public is another matter we wouldn't touch that but again it's it's your call I'm sorry I'm I'm very happy to grow backwards here with what I said I mean if if there's public data I'm all for using them even not in the peer-reviewed scientific literature as long as they meet the criteria as long as somebody can go back and take out that data and do another analysis on it which everyone's allowed to do I mean especially when you're dealing with regulation in which we're making a recommendation I think that's fine but if we can't use it in any way if somebody cannot take that data and use it themselves I don't want to touch it at this point in time. What about when we're having people come to talk to us about studies that are ongoing that aren't published yet then it's the matter of time that eventually it would be published can we. If they're willing to let it be released yes the problem is that if it's not been published the data belongs to the investigator and this may be preliminary data and we cannot force them person to give it to us but then again if it's just for information only and we don't go beyond using it for information but don't use it in terms of deliberations we're fine but if somebody wants to give us the data to use they have to recognize that that data in the original form has to be available to anyone and that's basically the basis of their scientific publication which is fine but they have to be informed of that. I'm not sure that will come up it may but I think when we were talking about having someone from EPA or NIE just come talk to us it was more telling us about what is out there in the planning stages. I don't know that we were going to ask anyone to provide preliminary data although that may be possible if there's something out there. I think again the same criterion and be in the public domain. People can tell us anything they want but it's how we use it afterwards. If they're telling us that they have a study and planned or that certain preliminary data fine that goes just so far we just can't use it until it becomes firm so that anyone can have access to it and use it to make calculations which they think we may have done wrong. We could probably refer to that sort of thing in terms of data gaps. We see this data gap and there's this group that's doing experiments that may address it that probably is something we can do. Alright the next criterion to consider the health effects of phthalates not only from ingestion but also as a result of dermal hand to mouth or other exposure say here. Oh you don't like it do you? Oh no it's just a lot of hard work. How much work is out there in terms of inhalation on phthalates? Can't we think about that more as a result of the biomonitoring data we don't know what the exposure is anyway. So I mean if we were limited to only phthalates of a certain exposure route that would limit us worse than saying in terms of biomonitoring right? That would make it easier. I think Paul this is the section you're going to write. Thanks. Well the question we have is where is there enough data in fact maybe part of your literature to find out is the data available for different routes of exposure or basically we're dealing with animal studies from ingestion? I mean there's not a lot. There's a few studies that address very few that address inhalation house dust that sort of thing but very few. I mean there's data on dermal absorption rates and so on so you could do some scenario based type thing. There are risk assessments, exposure assessments but not a lot of data. I'm interpreting that different I think than what you all are speaking about. Thanks. I was reading that more, you're talking about Roman numeral 6? Yes. Consider the health effects of phthalates. But not only it seems to me it's a list of possible exposure routes so we're really just talking about health effects of phthalates is the way I was looking at that. Instead of saying here's what it is from dermal, here's what it is to handle that. In that case there's even fewer. I would agree with you Chris. I think in terms of maybe the way this was framed or written is really they're concerned about phthalates and children's products which may pose a risk but also recognizing that there's other sources of phthalates that may also pose a risk and consider that when you do a cumulative risk assessment or assessment. That still exposes your route isn't it? But I don't think it's prescribing that this would want an assessment to look at what's the risk from Route A, Route B, Route C. I think it's really... That's just the way I'm reading it. Because of what this is embedded in, this is a public law and I think that they were concerned with phthalates and children's products but when you're considering the health risk from those phthalates that the child may be ingesting, also consider that that child's being exposed through potentially dermal inhalation diet and other routes that may then contribute to that child's body burden and potential health risk. You can actually define forward. You can't do it backwards from biomarker but you can define the daily intake dose from inhalation, dermal and ingestion and then figure out if any one of them have any relationship to the final biomarker levels or the levels that you're concerned with in terms of a potential health effect because that's where the rubber meets the road for us where once we say there's a daily intake from inhalation, dermal and ingestion then we can actually start figuring out which types of situations may or may not be in any influence whatsoever and is it still the fact that children's mouthing objects are still most important? I guess I was reading it more generally that this law is in terms of trying to understand the risk but also consider that there's other sources than just from a tether or from a child's toy and not asking us to do a risk assessment for phthalates from dermal exposure, phthalates from air How do we, how do we differ? Like let's say we have, you know, a tent, all right? A what? Tents, all right, a tent. Tent, yeah. All right, for, you know, other kind of things that we use that may have phthalates and the number, the possibility for exposure from that is, you know, X may well be based upon either dermal or ingestion or inhalation from X it may be that from that, from those tents may be so small compared to X prime from, you know, a tether that you don't consider it and again when we're considering banning something you want to consider banning based upon a position of strength that the exposures are de minimis I mean I think they don't want us to ignore as we did in the past, you know, where we said well the exposures coming mainly from malving they want us to also consider not necessarily, well if you're doing a scenario based risk assessment they don't want us to ignore dermal or inhalation that's what I think they're getting at In what sense not ignore, I mean we can document studies that show dermal or inhalation or ingestion exposures, is that where we stop or do we go beyond that and say, you know those roots of exposure in this population are minimal and we're going to disregard I'd rather have a contractor do daily intake dose based upon a few pertinent scenarios for different types of products and use that as the, you know, potential intake from those roots, that's how we define whether or not on a scale of one to ten that root of exposure has any meaning for a health effect I mean that would be a reasonable thing to do when it meets our charge Any other comments on that? I think this is an important point that we have to Are you heading Chris? Yeah, but I'm, maybe, okay maybe I'm in a rut here, but I'm thinking I'm still thinking biomonitoring data is the flag biomonitoring data is telling us what the exposure really is and I know there are caveats of, you know what levels we're measuring and maybe in children it's more difficult or whatever but it's clear there's exposure that has taken place you can't explain what the exposure is perhaps but you can say there's exposure here so given those levels of exposures those numbers of chemicals what's the health effect side of that and then go back and say, okay so for that level of exposure we would expect, you know, these teething products or these, whatever We're saying the same thing we just have to do the calculation separately because there's no way For exposure to explain the That's right, you have to do those separately and what you have to do is you have to come up with realistic assumptions about what the kind of context will be so that you can make meaningful judgments as to defining what the intake dose would be and then maybe we can actually do some modeling to have somebody do some modeling to figure out whether those levels can actually lead to a level of metabolite in the body through pharmacokinetics we can do the forward, we can't do the backward the backward's impossible right now but the forward you can do and you can do some calculations that can help maybe explain that within this particular situation that if you have X contribution from inhalation the amount that you would see in the biomarker meaning the metabolite would be so minuscule it wouldn't be picked up but if you have something worse from ingestion you could actually do a pharmacokinetic analysis and say, yeah, from the standpoint of this bioparticle biomarker this particular metabolite you may actually be able to see within the range of detection that level Chris? I guess you are after weighing the relative importance of various routes of exposure am I right? Well that's the question I think that we're... My reading of this charge is that we have to take into consideration all routes and I think that's really important but I don't think we're required to weigh the relative importance How do we make a judgment? Then we get into definitions what do you mean by take into consideration different routes? For example, you know, we have the feeling and there's data to suggest that uptake via food is very important and that point is taken however we are... I interpret this text to mean that we're not supposed to just look at food but we should consider other routes as well for example dermal uptake from personal capital etc etc But just document that those can or do occur is what you're saying, that's the level of... Or another way of putting it would be that let's say di-synonal or DH one of the phthalates there's a 2 microgram per kilogram per day exposure but we also know that that child may be exposed to 5 micrograms from personal care products I'm just making up numbers, 8 from AR etc keep that into account that that child's body burden is 20 micrograms and they're getting 18 from other sources and 2 from the toys when you consider the potential health effects of that phthalate I mean that's the way I would... That's exactly what I said we had to do Well, I think we have to weigh it but I don't think we have to then determine the risk Read number 7 and then you'll know why I'm not going to back down Yeah Well number 7 I think is very far reaching and I think would require a lot of discussion in terms of We're going to have to quantify at some point and it's either for 6 or for 7 I'd rather do it for 6 because then I don't have to do as many of 7s as I would have to if I quantified for 6 If I can do exactly what you say Russ If I can discount X, discount Y discount Z and only deal with Q I'll be happy But I'm wondering in number 7 maybe Andreas and Chris I mean does that seem accomplishable? Number 7? I mean it's a very ambitious To me there's a lot in the semantics you know there is reasonable certainty et cetera et cetera I think something will be accomplishable I'm sure I still have to say the whole concept of no harm has to be defined what we mean by that is it one in a billion, one in a million, one in a thousand You have in there children and pregnant women so you have a very different potential risk to a fetus versus a child Well I did it for arsenic and drinking water I guess we can do it for phthalates and whatever I mean again depending on the end point are you going to have a an estimate of risk or are you going to have a you know we're above a certain level of concern or below it This is something that developmental toxicologists are very sensitive to because you know pteridogens get in to the fetus or embryo and different roots and some of them are less of a problem depending on the chemical some of them are more of a problem and so it seems to me that at least when we're talking about pregnant women that the root of exposure is going to be an important consideration and what that contributes to the possible burden and especially since in seven we're supposed to make a risk assessment right I don't know how you do that without We need some intake doses and if we are able to prioritize them based upon some quantitative estimates with various realistic scenarios for six we're in much better shape I think we can calculate intakes from two ways one way is from biomonitoring data which is an integral measure of all roots and sources of exposure we can get a pretty good estimate on what is the exposure for different populations based on biomonitoring data but I go along with you too that if we see that for some populations and some phthalates or the phthalates cumulative taken together there's a problem because we reach doses which are close to or over the tolerable daily intakes we still have to investigate the roots and this can only be done with the models for the products, for the toys for application of personal care products and so on Looking back over this why do I have the thinking that we're focusing just on children if I just review this quickly I don't think it says anything about children it's talking about children's toys but it's not talking about just limiting it to children or other that's me I hope they're not meaning genetically susceptible that would be tough are we really talking about exposure to humans not with particular thought on children or is it wrong to say let's just focus on children including fetuses infants all the way through adolescence also says or other susceptible individuals in their offspring so I think they're still kind of coming back to the child or the fetus at least my reading of it of the child because then it says or other susceptible individuals in their offspring I don't know women that may be more susceptible I'm not sure what that means only pregnant women have offspring as far as I know no well then at the end it says and other potentially susceptible individuals so it doesn't I think it's a catch all for you know to cover their backs but is this a point where we want to focus are we going to focus on children are we going to say we're interested in phthalates on humans they are human too I think it's sort of the legislator wants us to think very hard that every eventuality is covered that's how I interpret it that's a good point I agree I think this is another instance in which we have to define what we mean by potentially susceptible individuals and we may say we don't know what this population is I would say based on animal data we can reasonably predict which are susceptible subpopulations and for me in the end it's all women in their reproductive age and it's all children until they are until their puberty so all mechanisms that are regulated by anti-androgen and disrupted by phthalates possibly so in the end in the beginning the window seems pretty tiny from the animal studies gestational day 15 to 17 but in the end it is from that is true if we think reproduction and development but that's probably not true if we think cancer yes is there enough data on the cancer issue to have that as a meaningful endpoint for our discussions well that's not an option for us to decide the legislator said you look at everything we discussed that already but are we going to prioritize the effects also at some point yeah we discussed already that very likely developmental effects and reproduction is important in cancer probably others too but these two definitely cancer is it's mainly the liver cancer and for some phthalates they cause liver cancer in rodents the problem is that they're caused by this mode of action which probably most people would say is not relevant to humans although there's one paper just came out that sort of reopens the question but but you know there's a good chance that they're not relevant to humans those tumors so I'm not sure depending on your perspective that might not be a high priority endpoint this seems like kind of a last minute catchall thing that was thrown in here after the priority questions were already established I don't think this changes the focus of this review from children I think instead this is kind of looking 90 degrees and saying are there any other populations that are even more sensitive than children generally where this what do they call it yeah but the level at which there's a reasonable certainty of no harm I think they're looking to see if they may have missed something that they would want to follow up on at some later time or if it's sufficient just to focus this all on children and the next question is we have looked at phthalates now look at things other than phthalates look at the substitutes so I see those two as kind of cleaning up the whole thing here and bringing those two last questions in after they've already addressed the priority ones that relate to children that's how I look at both of these I think you're right but I think eight actually says that they came back to their senses because they only talking about children's toys and children's care articles rather than these other sensitive subgroups so maybe they went off target in seven but they at least came back toward the target they came back to the real world but I think I think if we attempted to do the whole picture it would detract from our ability to look at children and that's what I see as the primary focus I agree so the pregnant women is there just for the fetus and whatever different exposure levels maybe that I think that's my opinion and unless we see more specific recommendations that say look specifically to see if non-pregnant women are different from pregnant women then I think it's a different question but I don't see that in here one of the other susceptible populations could be adult males correct and so we could you know say that and give a paragraph to that but have the main focus be on children from the embryo fetus through I don't know where we'll have to define that young children, adolescents I don't know where does it end for females or for males that's the question I have for males it doesn't end but the fetus is more susceptible than the juvenile which is more susceptible more sensitive than the adult we need a higher dose Paul it ultimately ends with death no thanks I agree okay well obviously we're going to have to still sort some things up with respect to six or seven and eight Bern do we want to turn now to the point that you brought up that might be a good time to do it now a strategy I think a question we need to deal with a strategy on how we would approach this whole task so that we don't choke on it at some point and that there are maybe more options than these two but in just in terms of my thinking this is as far as I got one approach is for us to proceed chemical by chemical and address the questions that there are to describe the potential risks of these phthalates and the substitutes relative for that or for that one specific chemical at a time approaching whether we would make recommendations for either continuing the ban or for creating a ban or for changing the ban that does exist and that there is a rationale for doing that but the other approach is to not start our discussions chemical by chemical but concept by concept and the one that I think we're most likely to stumble over is what is this threshold for acceptable risk and to some extent that's independent chemical but if we start out chemical by chemical we are certainly going to end up with the first chemical trying to decide what is acceptable risk and then the possibility is that we would have to go through that discussion each time because now the scenario is different there are different kinds of data different kinds of exposures etc and I think we've all been on committees where that discussion consumed a huge amount of time compared to everything else if you let it go too late so the possibility is that we would approach this from the standpoint of looking at some kind of rules of operation of thinking that we would agree to before we have DEHP in front of us or before we have one of the phthalates where there is very little information and the approach then becomes skewed because there is no other DEHP here so those are two scenarios that we might consider as we approach how are we going to most efficiently use our time and not have to revisit issues because we didn't take certain things into consideration when we discussed this earlier so I would pose to you for discussion whether we might approach these what would seem like a sensible way going chemical by chemical or do we delay that and talk first about some concepts of doing risk assessment and then apply them to the chemicals in the orderly way or do it all phthalates at a time however you would want to do that comments my instinct would be to go for the second approach which you outlined for a simple straightforward reason the charge is to look at not only phthalates in isolation we have to do that as well but to consider them in combination if we pursue the first approach chemical by chemical and then discuss chemical by chemical whether continuation of the ban should be recommended or not I think we are missing a great chunk of the spirit and the intention of the legislator so I would favor your second approach I totally agree I think that's the only wise way of doing it we have agreement anybody else I think we should define the basis for our risk assessment approach in terms of tolerable daily intakes what is tolerable what is not do we scoop out these intake levels to a certain degree for one phthalate what do we do with a bunch of phthalates what's the definition of the risk assessment approach we choose hearing no other comments I think that's the approach we should take is have the general discussion the obvious question is how do we proceed to do that do we do that using our own expertise outside of this body what do we need for the risk assessment we need end points we need effect levels we need as a basis for discussion the tolerable daily intake levels for all of the phthalates and possibly later on replacement products I think we need this basic data from the beginning on there is an interesting report also from the National Academy of Sciences about risk assessment in the 21st century and there's a very thought provoking chapter in there which is very critical of these numbers these quantities that usually come out of toxicological risk assessment and instead calls for focusing rather on action before we take those numbers too seriously and then they begin to assume a life of their own and etc etc so I wonder if we go down your route number 2 whether it would be timely and appropriate to perhaps ask a panel member from that report to come to visit us and explain this a little further and that's a good suggestion and coming back to your question do we bring in outside people to talk to us or do we start through my suggestion and my feeling is that we have enough experience around the table that if we invite other people in for a day to talk about this all we're going to do is delay our own discussion to see if we reach agreement and I think our time is more than discussing this within this group instead of bringing in outside people early on and I would bet that we could reach a discussion about a strategy for doing a risk assessment of a phthalate that will be beneficial to CPSC in the future for other phthalates and I'm not sure we need to bring in other experts to tell if we fail if we try this and fail and bring somebody else in very much like your approach Andreas but if we want to add up exposures to risks to a certain extent need the numbers to do this addition but if we encounter problems on this way maybe then we might need the advice of other people in this field I listened to a talk by Joe Rodericks who I think he shared this no he didn't but he was on the panel and he actually very eloquently explained this I took what he said to mean that numbers of course are not unimportant of course we need them but his emphasis was to focus on risk assessment as a decision support tool rather than emphasizing too much the mechanics and the quantitative outcomes which I think is a very important point but I don't know we can the book is out it's the silver book Science and Decision came out in 2009 we can all read it maybe then it's a good report it's gonna help us do the framing but it's still when it comes down to doing the work we're gonna have to have some contractors do these calculations for us and we just have to decide how we're gonna do it in such a way that it's meaningful for prioritization of both the potential effects we want to consider in long term and the potential exposures we want to evaluate in the nearer term I think the first course event in this whole process is to get all this background information for us and maybe having somebody assimilate some of it in such a way that we don't have to go looking at disparate locations for information I'm mostly concerned in terms of starting off with the end points that are the most crucial and where are we gonna go from there because that's gonna define a lot of the things that are gonna cascade out from that both in terms of market data and in with work with respect to intake doses that we're gonna have to do later on Mike how are we going to do this you are going to search and provide us with all the data but at least in some areas that's gonna be huge are you going to then expect that we will look at that and sort out what we think is important and put together and present to the panel at a future meeting or is there some way that your staff can summarize literature in different areas and provide in terms of the literature we can start by doing a search and get a handle on what there is for these other compounds and from there we might either ourselves or possibly a contractor do some kind of a summary and it's a matter of do you simply want a summary of what's available for starters are you gonna do you want us to derive ADIs or whatever or lay out the data it's a matter of how much you want and how much what you need and what the how much data there is whether we can do it or whether we're gonna need help and it's I think I would say suggest doing it sort of stepwise first see what's there see how bad how big the problem is then get a little more detail about of exactly what you need do you want us to pick out particular endpoints or whatever it is because I know some of these data there's gonna be typically you'll get a couple thousand pages of LD50s like over and over LD50 on Tuesday and on guess what next week it was the same and you know a few of these chemicals there's gonna be data rich but a lot of them I think it's gonna be data poor and it's also we don't know for so many of these we don't know what the exposures are gonna be anyway so I mean yeah we'll think about this before we invest to exactly what we're doing before we invest too much other than that you know certainly we can gather data we can you know depending again depending on the amount of the task of the size of the task we can oh do some sort of analysis get together the what no effect levels or whatever it is dose response data whatever we can find as much as you want to do but in the I guess in the end we would want to know exactly what you you know you want you want to just to identify the endpoints or and then do the you know look for quantitative data whatever it is I'm still a little unclear on you know for all of these chemicals you know there's only 10 where there's bio monitoring data so we have no idea what the exposure to these others are so I'm a little hesitant to there's some chemicals like isobutyl that we want to add others I'm not so sure we need to do all of that but the first course we can see how much data there are and there are there are other reviews too the Australian government has 21 reviews so they've actually done that I mean they're very concise reports very matter of fact they sum up the data this is what we have you know this is what's available this is what the studies say and I have a feeling anything beyond those chemicals you're not going to find much but you know definitely I would we need to expand the list at least a little bit and also a lot I think maybe some of this you know there's a point where you just you're looking at the phthalates as a class mm-hmm and you know maybe some of these can be consolidated to some of these chemicals can be consolidated into groups because some of them are closely related can anyone on the panel give Mike any guidance in terms of what they'd like to see in this data search you know I think this is obviously a very huge task I think that if at the end of the day we end up with a list of a bunch of chemicals and a list across the top of a bunch of endpoints we're still not addressing the issue of you know overall effect and the effect of the mixtures of the combinations mm-hmm I don't know and it might be that if we start saying you know I'd like to look at it this way that then you're starting to get contractors involved or things like that and I don't know at what point it becomes out of the scope but it seems to me at the end of the day if you know you're talking about reproductive developmental effects even just designating yes or no there was an environment and there was a reproductive developmental effect of things but there was on this animal yes there was and combining effects that that way and of course if you're talking specifically about you know phthalate syndrome the structure activity relationship is fairly clear so we could you know look at the structure and have a pretty good idea whether it's going to be active or not of course other things are a little bit you know it depends on the end point but the other thing is what do you need to do the risk assessment I mean I don't see how you can do it without a TDI or an ED-50 or some other measure of potency you know there's just no other way to do it and for example for a given end point you know even if you look at the even if you look at the phthalate syndrome effects there's a range of effects from the continuous drop in testosterone how much before you consider it an adverse effect you know AGD up to the malformations and so on so you know do you want to consider the same end point for all of these you want to pick one, you want to look at a number of them I suspect that the dose responses are different Earl Gray showed a slide had no data points just lines but it looked like some of the AGD testosterone production had a very linear dose response the malformations cryptorchidism looked very non-linear so but I mean it comes down to what do you want what do you need to do the cumulative risk assessment do you need ADIs TDIs do you want ED-somethings or a slope or you know I think at some point we need to know what the the current the denominator is going to be for that for doing that and you know not just is it repro developmental but what the end point is that you that you want to use I guess the decision what is needed in terms of data input data for cumulative risk assessment is a task in its own right so this we can't just decide right now but maybe we should isolate that as an issue already to set aside and to be considered separately because I I mean this is this is not something you can do in events the afternoon right I mean there were obviously just a question data requirement that certainly was discussed in the NRC report ways to do that but that might not necessarily be the only way and it might not necessarily apply to all the end points but you know eventually to get to the question of I mean there has to be a number I don't see any other way way around it but does this get us back to Burns point is if we and I think Holger made the point if we come up with a a method of an approach you know if we the details of the approach that we're going to take and then back out and say okay so what kind of data do we need for that approach as opposed you know I hate to just task you all with go find all of this without any real boundary that at the end would just be a lot of stuff we couldn't there wouldn't be specific to the things that we needed yeah and you know you don't maybe you don't know until you see the data you know it's a matter of this one's better now that I have the data this is the only way to do it or something I mean you know we'll do what we can we'll see what's available what if I ask it this way what about finding the most complete data set or the data set with the most with the best endpoints or something some quality stuff let us do analyses or do whatever we want with that and then ask the question is there anything out there that would have informed this differently than what we have at the end as opposed to just going out and finding okay yeah I mean that works this can be you know a continuous thing you know hit the get the most important the most glaring deficiencies first isobutyl and so on but yeah we can do that but if we've already decided we favor approach number two driven by risk assessment concepts but my and I really like that the advantage of this is also that a lot then resolves itself in terms of data requirements this is the organizing principle that will help us to decide what kind of data we need just to make sure I have this in my own mind in a correct way we're really looking for two different things one is the question of the additivity or lack of additivity of effects from a mixture but there still remains the question of if we review the data on the individual chemicals and find out that the permissible level in a product is too high based on the migration and the sensitivity that's independent of the mixture question true so we need data on both of those in order to be able to do the risk assessment and from the standpoint of looking at the effects of the mixture it seemed to make sense to not cast the net as wide as we possibly could for an effect that was seen in one phthalate in one study as opposed to looking at what are the small number of responses that are common across phthalates and where we have data that it's a repeatable observation not unique to one study by one person and if we can't find useful information coming out of that kind of an exercise with a change with a biological effect that is common across phthalates the likelihood that we would find it for an observation in one study one phthalate is even smaller so in terms of the endpoints that we would want to have data on I think we could narrow that down based on what we already know what you've told us it's up here is to some extent I think the approach as the list of chemicals gets longer would be to go not chemical by chemical but end point by end point this is the end point these are the chemicals that might be the best way to organize the data to organize that slide I'm still struck with the idea though that although there could be a cut off of an individual chemical that I think what you're saying it's the combination effect that I think we still need to think about I can't imagine that there would be a cut off for a single chemical if there are chemicals that are acting in a similar way in some sense that by considering the mixture it actually is a lower level than an individual chemical if it's an additive effect we don't know if it's additive there could be inhibitory effects too where a phthalate would occupy a receptor and the other one that you normally see as a testicular toxicant now doesn't have access to that receptor so it is less toxic than it was before so the effects of mixtures are not always predictable I mean I know it's a it's theoretically but for other chemicals for phthalates it's you know they seem to I mean it's almost amazing that you don't see inhibition and so on but for phthalates it seems to well phthalates for the particular endpoints it's additive everything else I'm not aware of any actual data I mean it's any assessments you do would be based on just assumptions I would think I would start it simple those additivity we would restrict to a certain point to do this calculation we need the individual information on the phthalates so it all starts with looking at the end point for the individual phthalates and then we can speculate on those additive effects in terms of doses exactly I agree with you totally I mean we have to start simple we have to start with what we can learn and until we do that the exposure part you guys have to give us some ideas to what you're looking at as your biological endpoints and the meaningfulness of various compounds to reach that endpoints either additively, singular or synergistically because without it we'll be lost because we can't make any kind of exposure and then dose estimates without it so I think that's the fundamentally where we have to start keeping it as simple as possible because if we start looking at various trees we're going to lose sight of the goal I'm a little bit unclear though how that gets back to what you suggested that we had the expertise to do here in this committee have we done that in this discussion or no we haven't I think the issue of what is acceptable what is an acceptable risk level for chemicals that have a high environmental background level in existence that we're not going to be able to reset to zero is a discussion that we need to have because that's the real world for the phthalates so I would propose that perhaps tomorrow we could start a discussion about acceptable risk for an environmental chemical for which there is an existing background level that is going to be there for a long time yet because it's against that reality that we have to decide what is an acceptable risk above what's created by the normal background and are we already I mean I don't know if we're at a risk level for phthalates or not that was your question earlier we don't know for sure but I think that's a discussion that we still need to have do we need anything provided to support that discussion or is this something we can well yes but I think it's around the table and the discussion it would be great if for those of us who haven't read this other report that you were talking about Andrea it would be helpful if we could have a few minutes of assistance from people who have read insightful documents that some of the rest of us haven't looked at yet that would be a place to start this discussion and update us on current thinking from the Joe Rodericks of the world for whom I have a lot of respect and then we can see how do we how do we use that current thinking to address the question of acceptable risk to a phthalate I mean Bob you can go Andrea you were going to answer his question so I'll defer to you go go go I could tell a joke about Iranian twin pregnancies now we need a joke I think yes we need a joke they're the longest in the world did you know this because when it comes to birth the one twin goes after you after you go first you go first and so on just reminded anyway what in answer to the issue here we could do that in addition for example I could we've just published a first attempt at cumulative risk assessment for these chemicals and related agents and if you wish I could give a brief presentation about this tomorrow it might help good I think we need to make all this more concrete at least for someone coming from my perspective where I don't do this sort of thing never happened are you talking about the paper the paper with the synergism no not that one that would feed in there a little but it's another one yeah cotton-compant Faust cumulative risk assessment on phthalates and other antihandrogens I mean is it in print yet it's published okay but only just 2010 what journal international journal of andrology okay I don't know if I can get it by tomorrow but I'll see what I can do see if we can get a copy of it for the if you get the PDF could you pass it on to me as well I only have one for for uncorrected proofs yeah it's a it's a matter of how soon I can get it oh gosh I know it's a tough okay so we've got our agenda set for can I have one question to I guess take the point of burns a little bit farther do you guys have the data that CDC has published on phthalates in biomarkers biomarkers for phthalates because it'd be really interesting I think for us to get a perspective of what the range values are right now because we're going to establish a baseline somewhere the only way baseline we're going to be able to start with or baseline levels that are biomarker data to at least understand where we're sitting some of this I don't even know whether all these are above non-detect or not I haven't looked at it in the last couple of years it's more like 90% detects but but I think it's important for us to understand what's out there right now in terms of they've had three reports I believe right and I'd like to see those data in terms of the three reports separated by percent frequency and by French percent frequency by age because I think that's important for us to consideration I think that's a reasonable amount of data we need to at least start with Bern's idea of what's background and what's above background just want to add to the enhanced data which is very valuable but I think there's one point that has been overlooked all the time in interpreting enhanced data in terms of exposure enhanced data is data after fasting yeah and when calculating back to exposures this has always been neglected so this might be an issue to discuss that's an important detail but just to get an idea of what's out there I mean you're gonna see there's a large amount of data really low and there's a few they're really high and I think just to give ourselves a perspective that's all I'm looking at at this point not the analysis of it I can I think you have it the paper I have together with Antonio well it's on the CD I mean I have the last report the summary data sitting out on my desk the data we can get you can download the raw data and do all sorts of analyses and we may want to do that later on but yeah I can pull up the I mean there's just some simple graphs that everyone can see from the oldest to the newest I think it's useful for our people to understand what it is that we're dealing with and I think it's important consideration Chris has brought up the idea of biomarkers a number of times today and it's good to at least get some feel for what they look like another another thing I always pointed out is that most of the enhanced data that has been published not the data sets the data sets that you can download now but the most published data is cut off at the 95th percentile so you don't see the up of 5 percentiles you don't see what can happen you don't see the maximum exposures that could happen when you chew on something or something that's why I want to see the distribution of data until the end right I think that's another request before tomorrow's meeting we may have time to discuss our expectations for visitors coming into the meeting next time and presenting information to us if there are specific things that we want and we think they could address it would be helpful if we could identify those at this time rather than just take our chances of getting in that's useful if there are things that we can specifically ask for it would be good to be able to identify those today and tomorrow and then we can make those specific requests of the people who are asking for time and if people want to present information that's outside of our list of what we want as a high priority one thing we'll do is there'll be a federal register notice and then post it on our website what we want people to present in as much or a little detail as the panel wants and it's something we can talk with the chair and the co-chair when we prepare it is what are the specific questions you want to ask of the presenters that definitely we can do tomorrow's discussion we really need to outline those kinds of questions potentially who can provide or at least to get a good start on them well I do think at lunch we said we want to see E.P.I. and we want to see NIEHS at our next meeting E.P.I. for what they're doing on modeling or data analysis and NIEHS for what they're planning to do on more Thallite studies so I think those two at a minimum I think are priorities for this group as soon before we leave tomorrow you're going to want to talk about the next time we gather well we'd like to do that just because it's so difficult to get seven people find an open date it might be easier to do when we're all here sitting around the table bring your calendars tomorrow and so that's something in the past what we've done had actually a three day meeting it doesn't have to be but one day was the testimony and then two days to meet in person but again it's up to the panel in the chair how often, how long and so on but it's the kind of thing we'd want to give say people would want at least 45 days notice something like that before to prepare for the testimony and so on so you know we're talking maybe a couple months from now two or three months bring us into August never again August in Washington I don't think you know I think we're talking June June or July they could do late June okay we could try for that August Washington kind of shuts down although we'd probably have the place to ourselves it's also hot late June sounds good to me any other issues that we want to cover today Mike, any suggestions we might I don't have anything specific yet for today I think we've got an awful lot done and I think we've got a great start it's up to the chair if you think we've done enough for today and if you want to take a break the plan was to reconvene at nine o'clock but again you know that can be changed we can probably do it a little bit earlier if that's what you want to do I have to leave at 2.30 tomorrow so do I yeah that's right I mean we do have people leaving a little bit earlier so if you want to start a little early that's good and that's fine and let's see other than that you know I think we're good just if you tell me what time what do people think about starting at eight rather than nine is that okay with me okay start at 8 o'clock so tomorrow we'll start at 8 breakfast well do you want to we can still still bring in some breakfast for the panel I know that earlier or started at you know 8 o'clock at that at 8 we could still bring in some food do you want to bring it in at 8 okay okay one thing well we'll think about tomorrow we don't have this room because there's going to be another meeting going we're going to have to use a room upstairs we'll have to I'll have to actually there one of us will take you up it's just a couple floors up but we'll have to take you up there I think we'll just bring you bring us up there we'll I'll try to be there a little bit early yeah the shuttle will pick up people at oh we'll okay we had scheduled for a that should be fine okay short ride over here yeah yeah and that way be bulk anyway we can walk and be here by 8 o'clock okay I mean if that's what you want to do the weather's good okay so the agenda tomorrow then we'll be to discuss Burns proposition others who want to that's right okay and yeah I'll see if I can dig up a copy of that paper and and Haynes data I'm not sure if I can get have it in a form that you know I've got these I have in the report is a like a page well this is the wrong not on the right page but it's you know basically a page or two per per phthalate so I'm not sure I can get it by tomorrow into a a useful form the most important you know I think that I think what we're talking about here is baseline so you're talking about the most important phthalates for us to consider things as we go along there's a 2008 report on the environment by the EPA that's actually uses 2001-2002 in Haynes data that has it pretty well summarized I have a PDF copy of that or at least of that chapter if you want to but there's a later there's much later than that but if you I mean it gives you some indication are we going to go out tonight oh yes that's the last thing yeah we're going to go for dinner yeah be up for that for these discussions or go on to other things whatever is there a way of getting us reservations at a decent restaurant what I need is the list of restaurants from