 So, let me ask a Clapham type on the bus, a type on the Clapham bus in London as we would say, kind of question, right, okay, so Joe blocks on the bus, you know, so listening to you, it is a, well, with qualifications, a reassuring message, so would you think your data are strong enough to say DBP for the human is totally harmless, no worries. I think that the one reason why we couldn't say that is that if we said that we would be presuming that the data which we've generated which we think is convincing that that's also representative of what you would find in the first trimester, but that's based on presumption, not evidence, so I don't think you could therefore make a statement as, you could make a statement that was that we would probably, or sorry, I can't speak, I would probably be reasonably confident in that remark, assuming that our results are also are equally applicable to first trimester fetuses, but you would like to, you would like to see the direct evidence for that, so, and I don't know what stage Rene Haber's work is in, I've tried to find out from Ben Argegu, but you can't ask Rene, he doesn't, he doesn't let on about what's happening, so. Also, you didn't actually qualify your question with, in terms of fetal human, you were answering with that presumption. Joe blocks on that bus wouldn't be able to do so, but. So, you know, at least, you know, I think the work we presented is in the fetal period and restricted to that in terms of our, yeah. So, so in other words, for to be, to be more certain about the, the regulatory implications of your work, do I understand you both correctly, you would require data from fetuses, from a much earlier period, in addition to what you've already researched. Yeah, I, I think similar data to what we've shown and using similar methods, I think if, if that evidence was there, then the only reservation you would then have is whether the Xenograph system is completely unrepresentative of the fetal, fetal testis in situ. And I think we've, we've no, we've no evidence that, that that would apply and the Marmoset data would suggest that it's a reasonable assumption. Yeah, I'd agree with that. I, you know, I think the small amount of data that we do have with regard to the earlier first trimester window is consistent with what we see in the second trimester as well, but there's a lot less data there as a bottom line. So you've done a little bit there, we have, you know, a couple samples from there. So it's consistent with low response at that time period as well. But we just don't have as much certainty, as much information there. And it is clearly limited to the model that we have. Based on your data, both of your data, would you therefore advise to reconsider the current RFDs or TDIs for the respective delates, the HP? You're really asking then the risk assessment question around what kinds of allowable exposures are reasonable in that time period based on extrapolation, current extrapolation from known response in rat as a bottom line. Should we reconsider that? And those risk assessments now are driven predominantly by the light Excel testosterone response, because that seems to be the most sensitive endpoint in the rat model. Is that, is that correct statement? In the US it's different, but some of the European TDIs are based on these facts. So Richard wouldn't currently be based on his expertise. He himself in the position of advising the respective committees to change the TDIs. You're telling him that? I think what I would say is that for all the relevant studies that we've done, they've only been using a single high exposure dose. So I don't think you can really draw any conclusions on that other than the fact that we don't see anything with that dose. So, but I'm not so sure that I would say that you should use that dose to actually work out your TDIs. I don't know, but that's, I'm getting out of my realms of expertise there. So other people need to be making those decisions on me. We've, we have looked at a range of doses and have not seen any, any responses in the human tissue either. I, you know, go back to that. I think what's kind of striking about the two systems of xenografting that have been presented here is that they really are quite different and yet end up at the same point in terms of observation of effect or lack thereof. You know, so a model of six weeks with human chorionic anatotropin exposure and then a very acute model that we've developed. And it's kind of satisfying that you get the same response or lack thereof given those two very different approaches. That's somewhat reassuring to me. How strongly you bring that into the risk assessment process, I don't think there's any precedent for it as a bottom line. So you get to pave the way for that yourselves and think it through yourselves. You know, there's a weight of evidence approach that has been generally applied to how you use information from different species and you bring that to bear. And, you know, the xenograft model has never been given a weight and, you know, sort of experimental human studies have never been given much, you know, have never been awaited in that regard. And so it's your sort, you know, it's your task to bring that in, you know, as you see fit. But that's actually a very complicated in general, how you weigh in epidemiologic results from human with animal studies, you know, becomes really quite complicated. And it's an art, I'd say, at this point in an uncharted territory for you. Still not answering your question. Because we're whatever we do with the data that you've given us today, we're going to have to defend. And so one of you, I can't remember which one now said, a question you have is, is the xenograft system representative. What caveats do you have in terms of the system? In other words, when you submit your data to for publication, what sorts of things do you say in your publications to head off criticisms that you know might come from your peers about the system? Because it's not, it's an artificial system, obviously. It's not what a test is normally sees. So what sort of things do you concern you as an investigator using that system? The great question I'll start off and then I'll let Richard weigh in. So in the model that we've used, it's very acute. And so that creates problems right away. You're moving a tissue from, you know, an intact setting into a model and looking and doing things to it very quickly. So there are some advantages to that. So we can compare actually the response in rodents where things happen very quickly to humans where they happen slowly. But the result is that we're looking at only a very short time window, where adaptation to that new environment may be coloring the response that we're seeing. So that's a concern. The hormonal environment in the host is obviously different than what one would experience in utero in an intact system, whether it be rodent or human. So that environmental setting is, you know, a concern as a caveat for the system. You know, those are, you know, and I specifically mentioned, you know, we have not measured testosterone production in our human transplants. And that, you know, so we're working on that. But that's a deficiency in our model. You know, I think Richard does not share that deficiency in his model, which is reassuring. So you know, those I think are the main caveats that we have. Yeah, I guess that I think it is when I maybe I said it, but it's just a general caveat. Because I think that you know, what we were doing when initially when we were setting up the system was to validate it in terms of normality in so far as we could demonstrate it so that the cells that you expect to be proliferating or proliferating by functional measures that we have, the cells appear to be functioning normally. And particularly, as far as we were concerned, that the germ cells are differentiating as they should be, because the primary remit was as as model for the origins of testis cancer. And if the germ cells are not differentiating normally, then you can't begin to intervene to make things go abnormal. So I think all those sorts of things, all the boxes were ticked. But I'm not so stupid as to think that means the system is perfect, because it obviously is a model system and therefore by definition is imperfect. And I think the reason why I would have a general caveat is that the more we use the system, the more we get to know, then I guess, the more likely we are to uncover the deficiencies, its limitations. But at the moment, we don't really have a handle on those probably because it's too early days. So at this point, vascularization is not an issue for your system words, which is more long term. Is that correct? I mean, we've not specifically looked as Kim has done at the vascularization. But clearly, there are blood, there's a blood supply, and the testis are growing. And as I say, they're behaving at least semi normally, as far as we can tell. So there don't appear to be any problems on that front. But how normal that is, I don't know, I don't think we could say you don't ever observe any increase in appetite excels, for example, which would be an indication that they weren't receiving appropriate nutrition and oxygenation. I'm trying to think, I can't recall that we do, because we will be a bit alarmed if we did. But I wouldn't like to say categorically that we've never seen it. I just can't remember anything a concern like that being raised at any stage. So, you know, we've looked for that specifically. And we do see in the center of the transplants in the early time period. So day one, day two, apatotic cells, and presumably ischemia related, you know, perfusion related problems. And that really does go away with time. So it's probably vascularizing during that time course. The vulnerable areas have died off, and then you get proliferation replacement. So that is an issue. That's part of the reason that we were doing the time course is you have to look at what the changes are throughout that time. But it is restricted to, you know, sort of the middle of those tissues. Yeah, I may be the only one here who doesn't know what many puberty is. But I would benefit from knowing more of what you meant by that. And what does it imply for vulnerability or lack of vulnerability? And does it go across species? So it's it's something that's generally looked upon as being primate specific. But I think that's maybe not strictly correct. I think that all male animals have some sort of period like this. But I think that's only in primates that it's an extended period that you can sort of clearly define. So for example, I think in rodents, you know, you get a literally a burst for in the first 24 hours after birth, that might be the equivalent that seems to play some sort of role certainly in brain programming. But it's at a different stage in development really than the would be equivalent for the for the human at that stage. I think in some of the domestic animals in sheep and cattle, there's there's slightly more evidence for period. But it's, again, it's not prolonged. And it's not as well defined as in the human primate, where it's something that's very, in terms of steroid production, genital activity is male specific, you get elevation again, out of trophins in both sexes. But you only really get the the gonad responding hormone production in the male. And it's so you get testosterone levels that are into the adult range in humans. In I always sort of like this idea of this, this little baby being breastfed. And yet it's testosterone levels are probably as high as its dad's. But the it's been a real mystery as to what the what the role of that hormone is, because people have done experiments where they've obliterated it in primates. And in one or two speeds, it's been done, I think, in about three or four different primates. In some it seems to have some sort of effect on sexual behavior and adulthood. And the others not. So there's some sort of bits and pieces of data that might affect immune cell development. But I think overall, sorry, there are, I think, well defined effects now on penis growth, and so totally cell proliferation, which are sort of quite obvious. But I think there's always been the suspicion that there's another purpose for it. And that we just haven't been looking for it. We don't know what to look for. So if we knew what that was, and it was something you could clearly measure, then maybe you could be, you could begin to investigate it. But nobody has any clear idea at the moment. So, Burn, I'd add to that. You aren't the only one who's ignorant about that period of time. I think it is relatively understudied. And little is relatively known about it, particularly in humans. So I got interested in this a number of years ago and tried to find out how much information there was about what the testis response is during that time period in humans. And there's very little. There's some hints of initiated spermatogenesis occurring in the early postnatal period that gets aborted and testosterone levels being elevated. But the implications of that overall, in terms of physiology, I don't think we have a very good idea about, as Richard said. I think now we moved away a bit from the risk to the hazard. So would you still consider the phdelaids a reproductive toxicant of relevance for humans? Or would you still consider the phdelaids an endocrine disruptor of relevance for humans? Andreas? I guess all I would say in that regard is that, you know, when we had no data, the default assumption is that the animal results are relevant to humans. That's the default assumption. As we are learning more, the certainty of that default assumption becomes less. I think that's all we can say. I'm not asking these questions because I'm particularly mean, but because we have to answer questions that are particularly mean. So Richard, is this your opinion? Yeah, I think that's a sort of a fair summary. I think it would be difficult to put it stronger than that. What is the summary precisely? Well, that the default position, as Kim was saying, that the rat data tells us what will happen in the human to that is that's become more suspect and therefore we would no longer think that that default position should be accepted completely. It should be looked upon, if you like, with a little more suspicion. The idea of actually trying to get the information that would allow you to remove it completely perhaps. I think also maybe that there is the additional caveat that I am concerned now that that there may be that we may be looking at the wrong age for the effects, which I think would have been something that we simply wouldn't have thought about because all along the assumption has been that it's fetal effects that are going the biggest concern. I don't like to be the most irreversible in which the rat data, of course, said were there or likely to be there in the human. Maybe I can try another summary from taking a slightly different perspective. What am I right in thinking the new findings you presented would suggest that the action with one thalite is a little earlier before the male programming window starts by mechanisms which were very unsure about number one. And secondly, the action is also much later than we originally thought, i.e. in neonatal life. Also by mechanisms we are very unsure about, but phenomenologically the neonatal effects are clear. It's a suppression of testosterone synthesis. So in short, the old thinking was it's all happening in fetal life inside of what you refer to as male programming window. And I think that is still true for a lot of other and the androgens, but maybe not for certain thalites. So your results show it's happening slightly earlier than that or something is happening, DBP, and something is definitely also happening during many puberty in neonatal life. Well, I guess that that's not strictly correct because there are, we're showing evidence for effects on germ cells earlier than the programming window in the rat and we're finding similar effects in the human. They're not in the programming window, but they're affecting germ cells in a similar way. And then, but at the same time, what Kim is finding, talking about, is that you're finding also germ cell effects that occur later in gestation in the rat. So I'm not sure that that would, those two bits of data would allow you to say that we're finding effects earlier than the programming window, as well as later in the neonatal period. I think there are, you know, there are effects on germ cells or whether they're on cell cells or germ cells, we don't really know, but we don't quite know when they are. We don't know if they're more than one mechanism, but they're clearly independent of the stereogenic effects. I think that much is clear. So if you've seen effects neonately on stereogenesis, there's maybe no relationship between those effects and the other ones we're talking about. And I'd just make two comments on that. The effects on the germ cells, you know, through work that Richard's done over the years, the persistence of those effects seems to be transient in many settings. So you just, you know, the germ cells are made to be multi-nucleated, then they dilate apoptosis, then they get replaced by proliferation. And so the persistent consequences of that, those effects on seminephrous cords or totally cells, germ cells, I think are unknown. But they don't have the implications of the concern around the endocrine modulation T levels where you're programming in, let's say, hypospadias or cryptorchizidism, and you can't reverse that once that happens. So there's that question and concern. I guess in terms of the neonatal period, I, you know, there's very little data in that period. There's epidemiologic suggestions, there's the marmoset data, but there's very little information. So I think the certainty of an effect of phthalates in that period is low at this point because of the absence of data. And it hasn't been something that's been modeled, you know, and can be modeled in the well-studied rodent, you know, rodent models that are out there. Is that fair? Question, but just to add, is in humans they're exposed gestationally and neonatally, whereas I think in these models, it's Richard Jersewer either or right. Yeah, we have done routes where we've exposed prenatally and postnatally. And if you only, for some of the effects anyway, not the consequences of suppressing steroid genesis in the programming window, but some of the other effects, such as those on cetone cell proliferation, they get compensated for if exposure stops, but if exposure of the mother continues after birth, then you prevent that compensation to an extent. You can do it to completely. So I think, you know, that it's an important point that really hasn't been sort of considered. There may be there may be effects before and after birth and there is the potential that they could reinforce each other to some extent. And I guess that would be the expected situation in the human, the way you are going to get similar exposure after as well as before. More questions? Well, on behalf of the chat, I would like to extend our thanks to our speakers. Really appreciated you coming here. We've learned a lot and have a safe trip back to your home institutions. And also, thank you on behalf of the CPSC. We appreciate it very much. It's been a pleasure to be here and I wish you all the best of luck in bringing together this really large volume of information and with your report. Good luck. I also wish you the very best of luck. I think we got the easy task. Well, I can only say I hope we don't have to rely on luck, you know. OK. Re-commend the committee, please. And what I'd like to do this afternoon before we break for the day is to set our agenda for the rest of our time on this project and set some dates for our meetings for the rest of the time that we're going to meet. And so I'm going to start at the back. Well, assuming that we submit our final report to CPSC on or about April 30th, Bert and I got together and said, well, then on April 15th, chat members would submit revised draft reports to the chair and the vice chair that we based on an April 5th conference call to discuss reviewers major comments. Remember, we're going to have the outside review. And we would receive those comments on or about March 31st, because we're going to submit a draft report to the outside reviewers on March 1st. We're going to give them four weeks, read the report and submit their review. So that means this is the first of November. We have five months, which to complete our deliberations and write our report. March 1st, four months. Okay. So we don't have a whole lot of time, less than I thought. Okay. So March 1st, we submit our draft report to the outside reviewers. March 15th, I hope we can schedule a meeting in which we would discuss, we had discussion to finalize our report. I say, February 15th, can't read. We would like very much to have a December meeting if we can, at which time we would have a read through of the draft report. And we would also at that time finalize our recommendations for each of the 14 thalates and the six thalate substitutes. Okay. I'll get back to that in a second. Here's what we're, our November meeting, we had our guest speakers. One of the major expectations for this meeting is the progress report for exposure scenarios, which we will be getting into tomorrow. What I want to do after we complete this is to finalize the outline for our report, identify missing section slash topics. And then tomorrow and part of Friday, I'd like to do a read through and critique of all the available report sections that we have and do complete, complete initial run through of the recommendations for each thalate and thalate substitute. I think we, at this meeting, we start, we need to start talking about how we're going to arrive at those recommendations. Don't have a whole lot of time to do that. Make use of the time we have here now going. That's why I think we need to have a December meeting in order to facilitate getting this report done in the time frame that we have left. I'd like to open that up for discussion to see whether what you think and what your time, what your schedules are like for a December meeting. We had a conference call scheduled. Can I just clarify this? I have sort of in my notes a January meeting face to face, but not December. Is this changing? Yes, we talked about, Phil and I talked about that. Phil isn't going to be available for a January meeting. So it would be good, in my opinion, if we can move that back for a week or two and get it late in December. Well, we have another sit down meeting to go as far as we can in getting a document ready for the peer reviewers. Then in February, have the next sit down meeting and be prepared to finalize the document that we have, including the recommendations to go to the reviewers by the middle of February. What we've tried to do is sandwich another meeting in here, and rather than have it in January, have one in late December and one in the middle of early February. Now, the reason for getting this out is if somebody can see a shorter way to get to our goal, we'd be happy to entertain it. We also don't want to end up in the middle of February with nothing to send out to the peer reviewers. And that's what drove this idea of having a meeting in December and another one in February. We thought we needed that to get a draft manuscript ready for March 1st. We had a meeting in January, middle of January. We didn't think that was going to be enough to have a draft manuscript ready in March 1st. In particular, for those of you coming from outside of the U.S., that makes a lot of travel. Yeah. But on the other hand, I think it'll take the same number of meetings, whether we compress it between now and April or if we end up in April having to beg for an extension. I see the intentions and I hear what you're saying, but shall we delay a final decision about that schedule until we face some of the crucial issues today or tomorrow? I think we'll know by Friday morning more to be able to do just that. Yeah. So I agree with you. I think that's I wanted to bring this up because I wanted you to see what we're facing. And I think you're right that that we need to go through the scenario exposure scenario information and data that we have or don't have and factor that into our discussion. And we can do that Friday morning. Yes, exactly. OK, so now I'd like to to go over the outline for our report. I I took what I had as an outline and what I see from Mike, who I think incorporated suggestions that were made at our last meeting. And I wanted to make sure that these were the suggestions that that people agreed upon. And in addition, I want us to talk about other sections that we might want to put in here that aren't yet here. And I and the burn and I both have some some suggestions that we want to talk about. So let's go through the outline as it stands right now. So it starts off with the introduction and background, and that consists of a charge to chap the regulatory history and status of phthalates, chemical properties of phthalates and phthalate substitutes. And Mike, this one is is new. I hadn't seen that before. Would you brief me on what is in there? I and and how does that relate to the section that you've provide some information on before? It could be part of the introduction or it could be a separate section. There's your lease. This is all yeah. Oh, OK. OK. And the C is just a you know, a little bit about phthalates. There are so many commercial ones in generally just general information about the uses, the chemical properties, that sort of thing. It's it's really just background information. So it wouldn't have information on on metabolism that wouldn't go there? Probably not. Like Pekin properties, uses that kind of thing. OK. And just to give a sense of, you know, there are lots of phthalates. There's this many commercial ones and, you know, these are the big ones and these are the ones that chap is looking at. OK. OK. Mike, is this point to broaden after our last discussion about low molecular high molecular weight phthalates? Well, I mean, I could say something about that, but it doesn't have to because that's a. It's an artificial distinction and the definitions kind of vary. So, you know, just some general general information instead of it's in some of the other chapters, but just, you know, they're used in these kinds of products and very, very general stuff. Like you see in the first couple paragraphs of a. I arc report or something, you know, because it'll be a very heterogeneous paragraph. It will be a very boring heterogeneous paragraph spanning from the dimethyl that laid up to right, but very, very general. OK. Just basic information, you know, the structures or molecular weights or whatever point points. But he has a question as we go along, just chime in at any time. So that's that's all we want to have in the introduction and background. Everybody's happy with that. Yeah, and there's a as far as what's in there goes, I think I can add a little bit to section B. The previous reports have things like, you know, the chap met this many times in, you know, stuff like how many meetings they had and that kind of thing. And A. Are we also going to include technical things like cut of date for literature considered, et cetera, et cetera? I mean, it could be in there. It that certainly could be in there. Such strategies. So then we go into the toxicology and burn, as you know, has done the non reproductive and the reproductive toxicity parts looking at these three sections. And you have copies of his most recent draft issues you want to raise with respect to these three sections. Anything else that you think ought to be. Yeah, something that. In some of the sort of writing. Do we need to look back at what Ira says, what other what the EPA has used for. In smart doses or. Reference doses. Are we changing or our tables? You know, the cases we've considered, are they different than what the EPA has used in the past? I don't have a sense of that. And I and if we are, I'm thinking we should probably address why they would be different particular values. I mean, we can easily get those values. I think they're probably different because EPA is in the process of redoing them because they're out of date. And so, you know, certainly we could summarize them. But knowing that, you know, probably within a year of this report being done, EPA will be coming out with new ones anyway. I would assume that that would just be dependent on the literature that they use. Find those. And we've we're using 2011 literature. So right. And there's are probably, you know, well due for. An update. That's what they're doing. The update necessarily go in one direction or another. Or is it just improved data because it's more recent data? Yeah, it's more more recent data. Yeah, definitely. As long as we define, you know, where we're getting our numbers, which we do, I think that's yeah, I mean, the iris databases. You know, every one. Is familiar with that has access to it. So we probably have those numbers written down somewhere. Not hard to get. There's a. Brief section in mind that belongs someplace else and that is that I put some information in here about metabolism and some information about the mode of action. It's not unique to reproductive studies. It is. It's under the larger umbrella of toxicology. And it's in that section in that discussion of species comparisons that we should be talking about. Human versus. Nonhuman primates versus rodents, so on. So even though it's here, it's not. This is not a complete coverage of that. We need to have. We need to figure out where on this report do we want that to be after all of the toxic data after the recommendations we have been front someplace. That's something we can decide as we go through the pieces. Yeah, and as you can see here, I also have a section on mechanisms of action that relate to in utero exposures and mechanisms of action. So. I want to filter it out. Those that related to in utero exposures. So we could very well have a mechanism of action section in multiple areas related specifically to the topic. I don't see any problem with that or we could bring it all out and make it a standalone section. We might as well discuss this while we have it on the table rather than just let it go and forget about it. So what do people think? Because one of the things that came up, Mike had indicated that he had changed my organization and added in here a section on metabolism and one on. Species differences in metabolism and pharmacokinetics and pharmacodynamics. I don't know if there's anything that out there that I'm aware of that relates to. In utero exposures that relate to those. So. But I think there is information out there about that obviously. And that should probably go somewhere else. I'm not sure where. But that's another issue we should discuss. So. Yeah. Can I suggest I mean these things would not mix up with the chapter start deal with effects either reproductive or developmental. I would suggest to pull this out and have a separate chapter called something like toxicokinetics and metabolism of phthalates. Because it's generic. So that could go I don't know if we can scroll back. That could be it could be after C. And metabolism. But when you do you started numbering Roman one or Arabic one and then a B.C.D. Does this imply a B.C.D. belong under introduction. Then it's to then it would be to toxicokinetic and metabolism. You go back again. The exposure section you know where I mean I know we'll come to it but I'm almost thinking that that should be far up front in the report even maybe before the toxicology. One would be introduction background to be tough. Toxicokinetics and metabolism yeah to me basically. Yeah. So the mechanisms of action we didn't deal with. I want to keep that. I have two questions again. It would imply that one to three four five part of an introduction. But this is what but then follows after and then what's in the main part what's left for the main part. OK I'm with you. Yeah OK. OK my other question relates to point number five cumulative exposure. Did you mean really exposures i.e. what Paul is going to work on or do you mean the effect of cumulative exposure. All right then in animals can we call it that then to. Add clarity. So it's. What you mean is experimental evidence of combined effects. Something like that don't you. But there's also a question of how should we handle the human data. For example that I've included in my section on reproduction and Mike you pointed out you questioned whether that should be folded in with other human data as opposed to being there within the heading of the animal data. Yeah. Well I'm trying to recall the exact data. And I mean cross cross referencing is OK. But I think there it was had to do with more like clinical reports or clinical studies or not to mention in vitro studies. Do you put that in the section or. Or do you put it in. Leave it where it is. Would we would we be better off. We can ask this again after we've reviewed my section. But the question will be is it better off left there with the. It's chemical by chemical to leave it there with the corresponding animal studies or move it to the animal to the human. Part where it would be folded in with the epidemiology considerations. Epi studies or their clinical reports some of them because because the difficulty with doing that chemical by chemicals the you know the epi studies are going to look at you know six or eight. So it. You can't really. At least the way I've structured the epi part you can't really do it chemical by chemical because they've measured you know these six or eight metabolites. I did it more by outcome. And these reports are reported mostly by chemical. So they've got hormone levels on a chemical in its metabolites not on phthalates in general or four or five phthalates. Why me that maybe that could be handled by cross referencing to specific sections of your report if it fits. When we go through your section we'll look at. Then I'll look at it this evening you know the specific OK citations and references and what you've written. My section here this introductory section. I need to highlight introduce. Well what we. All this morning I mean. Inter species comparisons. Could go on the three. There yeah yeah OK yep sorry. And I've already I already have the marmoset data. So that do we want to need to discuss and probably this isn't the right time. How we're going to deal with unpublished data. Data is public. No I mean the more in the graph. But speaking about the marmoset data in the neonatal period. I have that in there already. OK. As a developmental stage yeah OK. I think I think some of us should write a narrative of of this what what we heard this morning and in in the introduction right at the beginning under a the charge and chat etc. We should we should also. In the context of literature search and how we dealt with literature come include a. A paragraph there how we dealt with unpublished data if at all that be a viable way forward. You agree with that. Thinking of something else. All right. Tell me again. Make no run. If we would need in the introduction right at the beginning under a where we deal with search strategy literature census date for publications to be that have been considered here we would need a little section on how we deal dealt with unpublished evidence unpublished trying scientific data. And then secondly under C this point number three Thalite syndrome in other species. Some of us would have to write a narrative. Of what we heard. Today but the direction of that narrative would be this is work that's ongoing. It's not reproduced. It's not published. Yeah. And we would we would have to have a. Some some where we would have to reveal how whether or not this is actually. Made an impact on our views or the views which we enunciate. It may come in one of the sections at the end. I think will be appropriate place for that. In some place we need to make it clear that for a lot of these chemicals that we're talking about and it's some 60 chemicals. You know the phthalates and the non phthalates. A lot of them have no data and we need to address how we took that into account and determining risk when there are no data. First of all then it has to be very clear become very clear at some point in the report that actually are no data and then the next step is how we dealt with it. Yeah. Okay. And here's a section. I also deal with the developmental toxicity of phthalate substitutes which I just listed them here. But this section C. I have prenatal phthalate exposures and neuro behavioral effects. So I have summarized the the animal studies on neuro behavioral effects which I think parallels your section on the human studies very nicely so we can go back and forth if we need to and tie those together. That leads us into to Russ's section and what I had before you go and can I just so in in that section maybe in what you've sent us there you know there's text written and then there's some tables. You've sent us tables maybe the two of you guys together. I've sent us a table with some no else listed is that it's such a table going to be part of those chapters. I mean I think it would be nice to have a summary place. I mean for the noel. Yeah. Yes. Yes that could that could easily go in summary table for maybe across the bottom of somewhere that then we could refer to in our chapter as being our case three but it's based on your table. I think it should that be an easy way to reference it. So then we had this section here which will no longer be D but human exposure slash epidemiology I think is what we decided to title it non reproductive reproductive evidence for a phthalate syndrome in humans ontological considerations sensitive windows mechanistic considerations morphological structural evidence. Look about that last time in terms of the phthalate syndrome and TDS that's a religious genesis syndrome I added but you know nowhere near what this would imply you know in terms of based on the human evidence and the relationship between the two because the the epi data is not going to really shed light on mechanistic considerations maybe a little bit on sensitive windows but not to the same extent that animal data does. Okay so how would you how would you want one I was just wondering first off if we would want to have a separate exposure chapter and then a separate epi chapter and if you want epi to I think epi should follow talks then maybe have exposure stand alone chapter after the epi which then would lead into the hazard chapters or that's that's how it is I mean this is after talks right but I I don't know to me it just makes sense to break them into two separate chapters break break one into two epidemiology and the human exposure but they are here's human exposure down here pathway analysis that would yeah I guess I would just call D epidemiology and E human exposure pathway analysis. As the will not have the human exposure can I also suggest to what what begins to where I get lost is we have now three we have Roman numbers then we have ABCs yeah we'll sort that out okay that that'll can I then within the existing framework of can I suggest that D human epidemiology Bracket of Mauser brackets closed becomes Roman for we pull it out at the moment it would suggest it's part of the Roman three toxicology chapter would you agree with that yeah that that yeah I didn't mean it to be part of toxicology it's not he would be five yeah that's you know that's the way it's intended to be so do you do you not want exposure to be in yours is that what you just want to be out epidemiology epidemiology because last meeting we argued for this but you don't want it that way right well because it's not going to include exposure data I mean it will as part of the epi study but not in the same sense that the way Paul's described okay I'm happy and would you want me to you can just put epi because all that these humans yeah the way I structured it now I started off with the reproductive first just because that's the primary focus but that's easy to move around what we can think about that whether you know it makes sense to start with our and so to would be and of the non reproductive which primarily would be the the neuro should we make it neural yeah we can we can use the I mean is it anything else structured I can't remember and then the tables I've embedded but they can definitely be pulled out so the first section was well after a short intro was reproductive track and genital development so reproductive yeah and then the next was the neuro developmental outcomes main section and actually this I should probably move this was reproductive hormones in infants you know the main and the study which I would move into the repro and then there's some studies on pubertal development and gynecomastia which could come under reproductive and so development and reproductive structure those and then and then there was the adult exposures the semen quality studies which you know basically we're mostly just referenced and not described in detail but I think that would also be the repro and developmental section okay would within the reproductive developmental section there could be a you know general tract development there yeah carve that up yeah there could be subsections yeah so I'd say yes there'd be just two repro development and three you want to just do away with I think so because it's in there but it's it's discussed in the reproductive section yeah towards the end in terms of making a conclusion and references the talk section phthalate syndrome and rats see talk section and we thought of as a sub phenotype of TDS which we can discuss tomorrow so there's Paul's section and we just have two sections that phthalates and phthalates substitutes limited to children's products and I guess this would be the Paul's section because I was just wondering if there was more before you flip the slide but so here he's going to try to put in perspective human exposures childhood and pregnancy or is that something in your section Chris we're doing we've we've reorganized to include a bio monitoring exposure section but this could be the modeling exposure section and my question is is it going to be pages and pages of tables or is he going to have text well we know yet there's there's going to be some text I don't know how much text versus it may be more tables in the text I don't know but we're trying to mimic what you're doing so we're doing various populations the first is women of reproductive age then infants and then I think older children and then I don't know general population but we'll see how it works out if that's even much different from adult women and adult adults in general you know we'll see but that plan right now is to have those four groups and the set of allates is probably includes the same ones that you see in the bio monitoring there may be an extra one or something I don't know because oh yeah I think it includes diethyl just because they're well there's a lot of data on diethyl but the I mean structure-wise I'm not sure if we could do the same I mean looking at I mean we're looking basically looking Thallite by Thallite looking at the cumulative exposure in the way you do I don't think that's going to be practical I mean because we're not looking at people and saying you know you know how one person may be exposed mostly to the EHP and another one a little bit of everything I mean I don't know that we're going to be able to get down to that level the biomonitoring section embedded in your chapter could be taken out and we pulled it to the front focus mainly on the exposure and we have a table now that has the biomonitoring sort of point estimates of using population weights diesters and then we had included a table I mean I just took some subsets of some of the one of the Excel spreadsheets you guys sent but it didn't seem complete yet so I'm not sure I chose the right model or the right whatever we're still working we're still working on it so I think the idea was by the time it got to our chapter was to have some sort of comparisons about you know here's if you do a biomonitoring approach these are sort of the estimates that we would get for like the median or the 95th or whatever and and then if you compare that to what they did you know what are those numbers what is the swan data look like compared to the NHANES what are you know and you would make that comparison in your chapter because yours follows Paul's so that's what we were thinking is because then we kind of draws together the whole exposure you know are the exposure values that we're using through our modeling similar to other approaches of getting estimates or ask the other way or the other approaches similar to the biomonitoring yes yeah well I mean it's first are they roughly similar and second I mean if they are roughly similar then can you say anything about what are the relative contributions from different exposure pathways or whatever which may actually suggest some of the exposure sort of writing be even after our chapter yeah I mean I think it could be done done either way yeah I mean that's that's kind of what I was thinking getting at but it seems like the biomonitoring and the rest of your chapter need to be together you can't kind of biomonitoring and then have Paul's piece and then your that that wouldn't work and then to put Paul's at the end after it's a nice comparison to see point estimates you know relative to and Haines population and then the swan data what are those other approaches are they in the ballpark I think we could introduce comparison paragraph after the daily intakes we calculate based on biomonitoring data with comparing it from the external exposure estimates and then we could go on to the hazard index segment of our work so that would fit so that that's the way we intended it that we do the biomonitoring exposure estimates as a first part in our paragraph then switch to the hazard index calculations and in between we could discuss different roots relevance saying we can actually make ours into a couple of chapters in the end it will probably profit from it if we separate it slice it up what would be six apparently we agreed on a section called mixture effects slash experimental evidence Andreas was going to write that I have written it but did we not did we not discuss last time to put it to put it into the section of developmental talks and the toxicology notes notes that we may have I don't remember we could yeah under this section C in the introduction one so you want you'd want to put that really around where the Earl Gray's data are is that what you're thinking yes and at the end of your and some of our own yeah that's a cumulative exposure yes exactly the fine make it make it section six no make it that's what's going to go under section five yeah well we have to rethink think carefully about this because there's also which I haven't written yet but which will come some considerations relevant to broader issues of risk assessment which also will impact on what organ Chris are doing this I'm going to write as well and but they sit well there I don't know that may be a nice introduction so if we break our chapter up into an exposure part that could go with Paul section and then you could write a little introduction about hazard index risk assessment whatever and then go into our hazard index approach my thinking at last time was you know to support your hazard index considerations you can only support this if there's experimental evidence that indeed those and it's work together according to those addition so this evidence I will provide for this point number five and then you know you can then refer to it or take it forward you get my drift yeah so I've added add section from Andreas yeah okay I haven't written a whole lot there so that can either be taken out or can be integrated I'll do that okay back down here so then seven selection of toxicity end points and sensitive life stages basis for prediction of human risk not sure what's going to go in there but I've apparently agreed to write it we can make this section number six disappear yes that's right that's right are absolutely right and it's really easy to do on a computer and these numbers will change but then assessment of exposures to thalates and then this is going to be your section older and this is what I came away with from what Mike supplied me chemical biochemical assessment cumulative assessment hazard index approach method application assumptions I think that's all I had oh now then there's results of hazard index evaluation should be up on the previous slide so I think what one thing that we're doing that's different than what's come before is to focus on the biomonitoring data the risk assessment of exposure to thalates but the approach that we're using is based on biomonitoring estimates of exposure that's where we were trying to set the stage for how similar the comparison is between the approach of using biomonitoring data with the exposure you know modeling so how would you like to change this well I think I don't know maybe I'm so used to thinking about mixtures it's hard for me to go back and think of it on a chemical biochemical basis because the biomonitoring suggests that they don't you know it's clear it's not just one chemical at a time but in your analysis you did do it chemical by chemical right first not really I mean we've got we've got estimates of hazard quotients that would be like a chemical at a time yeah but it's not done it's it's a part of the overall approach not a standalone a standalone do you want to eliminate that because you don't make conclusions chemical by chemical and it's it's part of your I mean I mean yeah the way we've been thinking about I think is just on a as a cumulative set not as a individual has it so clear that they're together from the biomonitoring data well you you said you separated out the biomonitoring the exposure part of it exposure part is that also cumulative or is that chemical by chemical well I mean there's a table now that has it you know one chemical at a time comparing the different point estimates but it's all in one table it's not you know well but it is chemical by chemical yeah I mean each chemical is in is across the the top of the column labels or the chemicals and then we have you know median effects and 99th percentile estimates from the in Haynes from the swan data and then comparing to the Wormarth or whatever exposure modeling and then to what Cortencamp and Faust used in their paper I don't know if you consider that really chemical by chemical is just all in one table well I think that's that's all it's all the basic information you need here so but in terms of organization I think we're trying to make this day make make the exposure sort of seem relevant based on different approaches you know incomparable and then go into the the cumulative assessment using the hazard index approach I think now that we've gone through most of this what each of us needs to do we now written a good bit of our sections know what our sub headings are I think translate that into something I can use for an outline just to help me organize this and make sure that we haven't left any holes that that's all I'm using this for I think our part is less complicated than it might look like so first as we already said we we try to do exposure estimation based on bio monitoring data this is not a risk assessment per se in the beginning so we just try to do exposure assessment by human bio monitoring and that is chemical by chemical you can that we have individual data for each of the late then we agree to introduce a paragraph on comparing external exposure estimates with by a monitoring approach exposure estimates and then the next step would be to switch over to the cumulative hazard index approach that's that's not too different no you have here but it would mean that somewhere between six and eight we would insert something like closure assessment based on human bio monitoring so we don't start with risk assessment we start with exposure assessment want to have a section seven that would be something else exposure what I called it here was estimating exposure from by a monitoring data and pregnant women and infants by the assessing estimating exposure from by a monitoring data and this paragraph would include a comparison with the external exposure estimates but this would be something like a seven B and that would be a common paragraph you all right so that's you Paul me whoever wants to take part but it's like an evaluation of the different approaches if there's some commonality there it kind of qualitative valuation miss something in one of the other approach other results consistent but I think the important part of this is the bio monitoring is going to have to be all of the chemicals to gather from all exposure routes right exposure modeling is going to be able to attribute certain exposures I guess a certain percentage of exposures to different types of yeah I mean that's probably the easiest way to I mean this gets to the I think the point of what we're trying to do in terms of the chap I mean our mission are we really just focusing on toys and personal care products and in the sense of a real risk assessment going to be difficult to separate that agency by agency we need to do it according to real human exposure I would think it's the most important thing to do so is that a concluding thing that we say at the end you know go back to our mission or I think it depends on how yeah I mean you look at the the chap's mandate I mean you you're looking at cumulative risks and that's part of the mandate but in the end the decision that the commission has to make is on a net is essentially children's well toys and child care articles is the ultimate decision the commission has to make so sure the total exposure the cumulative risks from all the sources is an appropriate measure of the effects on human health well aren't making a comment on personal care products for for pregnant women or for women well the exposures are coming I mean the chap has to include exposure from all sources and that's certainly part of the assessment includes personal care products I guess my question is our products under your jurisdiction or products under well personal care products what I call cosmetics are not under our jurisdiction that doesn't mean I mean I I think you're supposed to look at the overall risk and including all sources and say whatever you want in the end the commission has a narrow a narrower jurisdiction but that's sort of for the I guess that's more for the commission to worry about you know it's like first you define the problem and then how do you approach it well the commission could only regulate certain products I mean it goes beyond the children's products but it's does not include cosmetics so you know I think you're you're assessing total exposure and total risk but I think for the risk managers down the road the commissioners it's useful to know where that exposure is coming from you know who's just which products and whose jurisdiction are they is that sort of taking the exposure modeling data at the end maybe in a discussion of what we're going to say at the end but yeah okay yeah this comes a certain our best guess is a certain percentage comes from yeah products or this dude or this whatever yeah not to divert too much but so so section seven then will essentially just be at this point overall comparison not based on percentages of I mean the the route of exposure look right because I think we got a table from from Mike you and Paul that sort of summarized it together yeah all the exposure routes or whatever you guys were modeling yet that's a total what I sent was total well if it's buried in those spreadsheets is everything but the summary I sent was just total exposure couple of things one is I think of what this report might look like I'm getting a vision of a report that might be two to three hundred pages long and it's only in section 14 only one or two pages of that are the recommendations that seems overbalanced out of balance that people would look through this outline because there will be a lot of people who will only read the recommendations and we're going to make them plow through 200 pages of technical materials before they get to the recommendations as opposed to having a report that section one is the introduction in charge section two is background and methods materials kind of stuff and section three is the report is the recommendations in section four is the references and so on but it makes it that would give a message that we focused our attention a lot on the recommendations as opposed to 200 pages of background material and all of a sudden it fell into place here's one page of recommendations I'm not sure I like the way that sounds now it may look different from that or the solution that occurs to me is that are there sections of this that are highly technical information that should go in a series of appendices to shorten all of that stuff before we come to the guts of it which is the recommendations and if people want to go through to find out how much of which the allied is in their favorite hand cream they can go to an appendix to get that not have that way up front as something that they will wonder when am I getting to the substance of this that is in the important part of getting this group of experts together as opposed to pulling together other available information that didn't require scrutiny of the experts except to decide where to put it that's one thing that we might might think about and Mike I'm even ashamed to ask this question but better late than never to have asked it who is the audience for this report but this be written for CPSC should it be written for the general public should it be written for people who are engaged in phthalates as a livelihood industry scientists so on we write it at an eighth grade reading level which is as much as it should be if the general public is going to read it they're going to stumble over eighth grade reading level well our approach has been the body of the report is written as as a scientific publication now when you get into the recommendations or and especially the the executive summary we tend to make it for a more general audience the audience in this case the the narrow audience is the is the commission we're not scientists but who have to make a regulatory decision so but the I mean the technical pick parts of the report definitely should be written as a any other scientific publication now the idea of putting things in the appendix is you know certainly that can be done in the I'm thinking that the exposure scenarios part will be especially amenable to that otherwise it may end up way too big but I think you know the the chapters and so on as I've read I mean it's not just presenting information I mean there's a lot of analysis in there so you know I think it's going to be a good report but I mean you're right so well some people will only read the executive summary anyway but that's we have no control over that for example my chapter on the human and animal reproductive talks what's up front could be just the summary of the no ales that gives these studies that we considered and at least the no ale and the endpoint that was affected but the description of the study by study could be an appendix I don't know if that's too sparse in the front or not yeah I mean it's I guess it's well it's up to the chat but it's I guess it's a matter of finding the right balance of giving enough detail so people could follow the reasonings and why you got to your conclusions I would totally agree with Bernie's ideas the what we've detailed now in terms of structure could easily be an appendix and we could write a much shorter report which in fact would be the core consist of the core of recommendations and the function of that more detailed material would be then to be able to refer to relevant sections in the annex supporting recommendations so we you know what I visualize is something like a maybe 35 page document which but crucially contain things like you know considerations philosophy la da da on which we base our recommendations I mean this we haven't yet covered but that that's key and I actually think that what you're getting at on Andre Sanburn both I mean I think the one of the most important things we're going to do is to figure out what it what our recommendations are and what it's based on I mean we've got exposures that are going to change with time and you know a lot of very difficult things to work with I think the important part is how we dealt with those things and some of the port of that could be elsewhere but the in I mean I'm thinking in terms of not just all this information and then conclusions but probably a discussion section where you talk about all those things exactly how you interpret the information and get from point A to point B would it be more digestible if it was like Andre is saying a 30 page like a like a paper in itself here sounds these are the just these are the difficult things we had to think about how we chose to do that the supporting evidence sounds okay to me you know my section on developmental talks where I've gone through I don't know how many developmental talk studies and summarize them you know when when they were exposed to what the doses were I mean that for some of the way through that I mean it would just it would yeah put people to sleep put me to sleep well I find it thrilling it doesn't put me asleep at all well so I'm wondering how long is the bibliography going to be I mean that may be the biggest part of the report I appreciate the discussion of this not that we need to make a decision now I think this could also be revisited after we've gone through the four sections that we have and see if it makes sense to talk about it more or drop it but it might be a very novel thing about what we're going to do is to figure out how we're going to make those decisions and just even outlining that 30 page paper of this is how we did that I think would be really very very important well I think a 30 some page overview of the strategy that we considered and how we approached this would make this more useful to people who do this in the future whether it's the highlights or not but a lot of these reports go on the shelf forever I mean somebody takes it off their desk and puts it on the shelf I've got a lot of those that I've never read just because when would I find the time to read a 300 page report when I might have read a 30 page one I'm just going to say as a reader of reports to have something you know if there's too much detail you don't see the big picture and yeah I kind of like the idea of having a shorter paper with backup sections so you can see the forest and the trees and these are other these I think are the crux of what will be document we are talking about now the impact of variabilities and uncertainties our discussions conclusions and recommendations executive summary that's going to be the heart of what we're going to be putting together we have an executive summary at the front end the back end oh I think we may hopefully we can get by with just one yeah well I think I think it should be up front so I'll delete the one at the back who had some topics that you wanted to talk about burn well I think we have folded those in have we I had made a list of what I had made a list of things we need to find authors for one of them is this broader section on mechanisms and mode of action and I think that would be up front in the 35 pages of the report metabolism as it relates to toxicity and as it as it defines species differences in sensitivity then dealing with the broader issue of the absence of data and how how we determine risk what did what assumptions did we make about risk when there are no data a lot of these chemicals are in that category I think what we need now is another another outline for this 30 page paper I think you and I need to bump heads come up with a draft that we can put before the committee what about something along the lines of just a shorter version of I mean it would be very interesting to start with even just the of that of that situation that there these all of these chemicals they're in some products and but we have some in some talks information about some of them but many of them we don't and so what do you do with the things there's exposure we don't have any talks data just because we don't have any data doesn't say they're safe so what do we do about that I mean that is a very important question but I don't think we should just kick down the road well I think it's important that there should be up front it should perhaps be a statement in the executive summary it should be in the introduction and charge and it could be one of our recommendations and not all of our recommendations have to be either to ban or to to restrict there could be recommendations for other things as well and that could be one of them Mike were you you put together this introduction before that we've seen and I still think that's this standing introduction to this document that the 35 page one yeah well it's the yeah I think it's supposed to be part where is it in which tab but it's it needs to be expanded a little bit but that's a yeah it's it's it's it's supposed to be in tab five well but it isn't well I it's not in mind but well that's for the I put that I think I just get to tab but it's it needs to be expanded a little bit but these other things certainly can be added yeah Mike another semantics question and I know I've talked with you a little bit about this before maybe it was the whole group but it's the distinction between banning and restricting yeah and the interim ban what does that really mean well you know it's it's one of those the statute uses the term interim ban in but in for us CPSC a ban means a mandatory regulation so that's something that doesn't meet the requirements is banned you know it doesn't mean you ban the chemical entirely or a product entirely it just you know it says if you don't if you don't pass the test whatever it is then you're banned so I could try to get with the lawyers and come up with the you know worry about the wording of these that kind of thing if you want to try to put it in plain language for the time being and I'll get together I'll get the the right verbiage to use for that I agree with the suggestion that under us made earlier today that at this meeting we should have some time where we would talk about what does ban mean what does interim ban mean and what does no action mean I assume those are the three things that we can do and for silent that means no action but we were going to have to either come up in order to meet our charge we're either have to we either have to say that the ban should be continued or the interim ban should be expanded to a ban or released from that ban category so I think in order to have that discussion of what are the criteria that we're going to use for making that distinction when we get the hazard index information we get the rest of the exposure information in front of us and then we have to go through these chemicals one by one and make a statement about each one and we need to know what the distinction is between a ban and an interim ban or if we could not use that term at all and talk about because it would seem to me we we may recommend that it not be banned but there would be no more than a tenth percent in these children's products by way something right and well that's what the ban really is you can't have more than 0.1 percent and I call I try to use the word prohibition okay so a ban isn't a ban either right when he talks about a ban doesn't that mean that you shall stop distribution right right that's not what it means here well it well it it's a condition you know it's a conditional if you don't meet certain requirements in your band it sounds scarier than it really is when we talk about criteria I think we need to finish this discussion yeah any other questions or comments like do you have any thing you want to discuss before we adjourn well let me just give you a brief update on what we've been doing we have as far as the the final lit search that is I'm actually finishing it up right now I hope to have that before we all leave on Friday and we finalize some documents you you've seen drafts of the you know the last 10 talks reviews from verse are in the little piece on possible natural sources of phthalates those have all been finalized so what I want to do is get this last literature search in these documents and I was able to get some of the publications in the literature search not all of them but whatever we have on a CD so you can all take it with you when you leave no first first hour is going to be here after lunch or by one o'clock so can I can I be a little provocative and suggest a change in agenda that we put as first item on the agenda a brief discussion or a brainstorming about our recommendations for example I mean the risk assessment of mixtures what what I will have to say I can say in a nano second I forgot you missed it you missed it I saw it I'm hypersensitive to my name really it's terrible brilliant recommendations we probably want to hear from Holger and Chris I think that's where I was going to be my comment and then talk about recommendations yeah I'm happy with that yeah so conclude you better make sure you have a strong impact on our recommendations although I am reluctant that our approach should be the sole point for the recommendations we have for this morning oh that was to me we that okay okay we did what we did today that not hearing any comments or questions we'll adjourn and meet again at 9 a.m. tomorrow