 Okay, given that we've we're gonna be short on time I think this morning and I know that some of you already made reservations for taxis at noon so let's let's get started. Mike just passed around a list and you may have seen his email. Let's go over the work plan make sure that we didn't miss anything and revise the the outline for our report. I will get that to you shortly after I return. On early September Versaurs going to get the exposure estimates for women of childbearing age to to Chris and Bern and I will get the no wells to Chris so she can factor those into her hazard index analysis. In September 20th we're gonna have a conference call 1130 a.m. to 1 p.m. Eastern time. Advised report sections will be due October 20th. I have our next meeting November 2nd, 3rd, and 4th and Mike will invite Kim Vocalhide, Richard Sharp, Earl Gray, and Paul Foster to speak to us. At that next meeting we will discuss exposure scenarios and biomonitoring approaches so the focus will really be on that next meeting and we will also discuss updates of other sections which I don't expect will take much time in that meeting. Yeah that's right they said they could do it in three weeks. I think it won't take it once they get the first one the next one won't take long but I you know I'm not sure exactly how long sometime in September maybe or thus the yeah so we could move to late August say the third week of August yeah the women of childbearing age and then have the infants in early September or mid September maybe but at least before our conference sure I mean if it comes in two days before I'm not gonna yeah I'm sorry put some pressure on that oh yes I agree that's what you want to do totally agree with you would you revise that Mike yeah remembering November I won't be here on the 2nd if you just barely come back from Europe any other additions or corrections okay then on November 12th we have another conference call 11 30 a.m. to 1 p.m. Eastern time and there we're gonna begin talking about recommendations we'll have a meeting January 19th and 20th at which time we're going to begin to put together the final draft or that put together a draft report and parking lot issues inter species differences with respect to phthalate syndrome don't have anyone assigned to that that's something remember I mean I've got some of that in my section that's something you mentioned Andrea's right that we needed to yes I mentioned it but I can't claim to be exactly expert but I refresh my memories in terms of what you were asking beyond what I've already written in my section was that the metabolism no it's it's to do with new findings about how the light excel in the developing test this is set up to do what it does and in relation to that whether there is reduction of fetal Andron synthesis in the rat or the human or any other species I mean we don't do we have to assign anyone to it at this point reason why we're inviting the I'm not I'm not sure because I don't recall the specifics of what we were looking for in that inter species differences so well I think that was part of the reason why we invited want to invite some of them back okay all right we'll just leave that as other entered anti-antrogens new section by Andreas testicular dysentesis syndrome add discussion to epidemiology section and backup updated literature searches and that's something Mike will do correct anything else in our parking lot Mike or a burn something that would save us time later if we can have agreement on it now and we've talked about a couple of times reaching agreement not only on the location of references throughout the document but the style of references because we're going to be adding more and more of those in the next couple of months and it'd be nice to know now what the accepted style for everybody's going to be I think that was one of my assignments was to propose a style or maybe some choices but we can just label tables and figures within actors I think for starters yeah yeah you know again that can be done at the end it's some I mean I find it easier to do the editing first and then take care of that anything else okay then I think we'll move on to we had some discussions left to address in terms of the document I think we were Russ was going to discuss his section I think Mike was gonna talk a little bit about his and Chris and we're gonna discuss there so we've got those to do this morning Mike I think I'll go to you first in case you have to deal with the council okay well in tap 3 I talked about this a little bit yesterday we have actually now 9 of 10 toxicity toxicity reviews completed by Versar so you've got a total well I just emailed one I think Friday so the only one left is diethyl the exposure assessment work is underway we did send an updated literature search but that's something that we can do periodically we that was sent after the last meeting skipping down and it did I have a introductory section that just talks about the the history the CPSIA and all that stuff and then we can add to that something about valet chemistry and physical chemical properties the kind of background stuff that normally goes at the beginning some information about uses and worldwide production we do also have someone who is reviewing some reports there there are reports in the literature claiming that valets are naturally occurring or can be naturally occurring and there's actually maybe a couple dozen papers but a varying quality some of them are not very good and not very convincing some of them are a little bit better so we have someone reviewing them just with the goal of is there credible credible evidence that they can be produced naturally the problem I mean even if it's true there's no way to assess how this might contribute to the our total exposure you know doesn't get into food a lot of these are from claim to be isolated from medicinal herbs and that sort of thing some from microbes so we just want to get a sense of of what's possible or is it plausible that this can happen and then you know give it to the chap and you can do with it handle it however however you want it's just for the sake of completeness and we let's see we are trying to I am trying to put together some tables you know what now that we have talk to reviews on I don't know 40 compounds or something try to sum up that information to make it a little bit easier more usable by the chap and you know we've had some discussions about some industry studies in fact they gave us a handout yesterday that there are some studies new studies that they've done on dinp that they hope to have available by the end of September I think their plan is to submit them for publication and then at that point they would make the actual studies available the manuscripts available to the chap and because we had talked about you know end of September as a a date after which we would not be obligated to review every new paper that comes out so that's about that around that time as far as the introduction section that's in tab four or actually tab five and what I did since the last version what I added was at the very end I added some a series of questions that to try and lay out the sort of the intermediate steps that you could might that would hopefully lead you to the final recommendations and you know you can these aren't really they don't need to be in the in the introduction they're just just to help the thought process they probably should be a separate just a note to the to the panel and you know again this is to try to make your job a little bit easier and you can do with this you could ignore this or change it in any way you want and also yesterday the tables in the back just show you know a list of all the phthalates I highlighted the ones that the chap is interested in will add in some physical chemical properties use information there's a little bit of production information here's to get a sense of you know what the main ones are which ones are high production volume and even though there are some trends as to which ones are increasing and which ones are decreasing so we'll take the information in these tables and try to fold it into a into the background section very handy I think they're excellent yeah and this is you know it's all background information and it's all for the authors the you know I know you and burn want to rewrite it do whatever you want it's just a compiled all this information it's up to you up to the the authors and the panel to you know take or leave what you want but the information is there one question I have is how will we reference the the talks reports I think will reference will I mean in terms of the style will come up with something but there are I guess like you would cite any government report and because these are well actually at the moment moment there some of these haven't been cleared yet clear they're not all cleared yet so they're not all on the website but eventually they will be so you can cite them or but by the time our report comes out they will all be available yes yeah or you can treat them as background documents and you know it the the purpose of them is basically to just get the information for you to use because you and burn have written you know these talk sections so you could just use it as a almost like an annotated literature search order Mike and Phil as we are all writing on our final drafts of each section you pointed out the literature deadline shouldn't we fix a literature deadline or to what publications we accept well I think did we fix it did we fix the literature that we did September but we could revise it well I think it was end of September and I I thought it was kind of a soft you know not a hard deadline but especially if there was a important paper that came out after the deadline we would try to include it but that that was our discussion I guess at the March meeting as I remember but I would I mean we can do that but I think for clarity and in the interest of transparency which we should agree on a census date we can always make exceptions but we could I think it's quite important to fix that now otherwise we block ourselves my fear and if there's a really a bombastic paper appearing after that census deadline then we can always take it into account but I think for clarity we should agree it agree on a date and then stick to it and if there's anything as a block buster we put it in and we say in the introduction are put in and you know up front say this is based upon the evidence that was presented to us and using the evaluation through published through XYZ and that's where you end it and I think it's our intent to to basically have our sections completed when we meet at the November meeting so I think it's reasonable to say and we're going to have a revised reports sections by October 20th so I think it's reasonable to say that the end of September that that's that's the cutoff point in terms of papers that we're going to review and include in our updates think about this way it seems holds true for the exposure assessment that versa is doing I mean you know data can trickle in from now until the end and we just have to stop or else it's just not going to be very valuable making a permanent contribution to what we're going to do Mike would you capture that in the in the minutes so that we have that officially document sure the 30th of September 2011 yep any other questions for Mike I know I just want to add that you know we're just trying to pull the information together you know useful form for the chap to use right we're not trying to write any part of the report yeah and that's that's the information that that Bern and I will pull together in the introduction okay Russ do you want to go through your section please okay so the the epidemiology section this is I think the third version and you probably just saw version two last time but I can go through it broadly and then we can if there are questions and I had a few questions too in terms of the level of detail and the focus so basically I start off describing how I wanted to focus more so not completely restrict to epidemiologic studies investigating health outcomes in relation to gestational or infant childhood exposure because that's consistent with the charge of the chap and then what I've done is I divided the epidemiologic section into smaller sections based on the health outcomes so the first one is phthalates and reproductive tract and genital development and so in this I included a fairly detailed description of the swan studies and the Wang study as well and I've started as we discussed at the last meeting to put the data into tables so some of the tables are more complete others are not but I'd appreciate any suggestions I mean they're they're kind of standard tables in terms of column headings that you'll see in an epidemiologic review where author the study design which of course is important in judging the quality of the study the outcomes exposure measures so the matrices that were used another column for results and then generally there's a column for comments so this is you know fairly fairly standard I could add column or reduce it I think the bare minimum is there though I mean I wouldn't want take anything any of the columns out so that that's the first section on the in a general distance and general development it's probably around five or six pages so I went into a bit of detail here as compared to the other sections because it's so relevant to the phthalate syndrome and then I also try to describe or discuss after describing the studies interpreting and synthesizing across and in this case there's only you know three or four studies on this endpoint but trying to describe some of the potential limitations and then also put it in the context of the phthalate syndrome which I I mentioned relatively briefly with the understanding that that's going to be discussed or is discussed in the toxicology section and the pages don't have numbers on it but it's the page right before the occupational exposure and male reproductive tract anomalies and what I've done here is after describing the results of these studies I raised a few questions including the not so much the clinical significance or the interpretation of a reduced in a general distance in humans and there was a few recently published studies in which they looked at associations between AGD and other reproductive health outcomes she reported associations with hypospadias Mendiola looked at AGD and poor semen quality in men as did Eisenberg so I thought these studies even though they haven't looked at phthalates specifically helps put in perspective what the interpretation may be of a shortened AGD in humans and also brings in the endpoints that are relevant or part of the phthalate syndrome hypospadias and well reduced semen quality could also be considered part of that in terms of looking at adult animals following developmental exposure and then I briefly say and I'm going to expand upon this based on yesterday's discussion that these human studies demonstrate shortened AGD is associated with conditions that comprise the phthalate syndrome support the use of AGD as a relevant measure to assess the anti-antrogenic mode of action of phthalates during fetal development so I then go on to mention the teticulatris genesis syndrome I don't describe it I can then describe it probably in a few sentences I don't think it needs more and in thinking about this further the teticulatris genesis syndrome hypothesis is a hypothesis basically trying to link observations in humans of reduced semen quality well geographic differences potentially temporal differences changes over time increase rates of teticulatrum cell cancer and some data suggesting that some of the male reproductive tract anomalies may have increased over time so it was a hypothesis trying to link these observations to exposure during fetal life to the testis leading to these manifestations either at birth or or later in life so I I view that as in a way different than specifically the phthalate syndrome which basically is observed in rats following gestational exposure and there's specific manifestations that are included in the syndrome and in thinking about it more I almost think of the teticulatris genesis syndrome hypothesis as a broader description of an insult and it could be exposure it could be they also include like IUGR intrauterine growth retardation is leading to teticulatris genesis and these manifestations and then the phthalate syndrome and I'd like to get your thoughts on this could potentially be thought of in a way as a subset or a specific example of the TDS hypothesis because I'm sure there are other examples that that you can think of that would fit under the broad umbrella of teticulatris genesis syndrome so what I'm trying to say is is I don't equate the two as equivalent I think the TDS hypothesis is is much broader and the phthalate syndrome is more potentially an example of the teticulatris genesis syndrome in relation to phthalates important difference though is you don't see increase or you don't see in rats teticular germ cell cancer which you do in humans and that was a large part of the teticulatris genesis syndrome hypothesis the thinking behind it so they they differ in that regard but I see it potentially more as describing the teticulatris genesis syndrome hypothesis and then that the phthalate syndrome potentially is a example of this in rats and then the next step could potentially be what I've done when I try to put in perspective the AGD results from the swan study associations and other studies between AGD and hypospadias semen quality etc as potentially providing a link between what we see in humans with the phthalate syndrome in rats so really making those distinctions TDS really is and phthalate syndrome are really not the same that one is in a way a subset of the other and then trying to link the human data together so I welcome thoughts on on the earth do you think you that you can distill this out in some kind of table because I read a lot about this the comparison between TDS and phthalate syndrome do you think it is manageable to to put all this in a table and compare it in the NAS report but didn't we just have a diagram that kind of helped kind of a Venn diagram so I could modify that haven't looked at that recently so that it may require some changes or the way I'm thinking about it potentially here but but definitely yes so it's so visually either a table or or a figure especially as it has been a topic then and obviously some modifications might have come in it would be valuable to have this in our draft Chris was affected the NAS report what modifications would you see between what you all concluded and what Russ is discussing now it's pretty much consistent yeah I mean I think I don't think there's you've updated though that work I think that that was very good work then it's still good work but yeah I don't is it a different are you saying something different than what was I don't think so I you know I just haven't looked at it in a few months so but I don't think I am I think it's consistent with what should be stated somewhere clearly that there's a consistency between and maybe that's where the Venn diagram comes in you say because that's from that report and you say consistent with previous approach data doesn't lead to a divergence from that conclusion brings in the Venn diagram other quickly you know but I think what I want to be careful about is because as Holger mentioned there's I think a few papers that have come out talking about well there is no data supporting the Tessica just Genesis syndrome hypothesis you know data in humans is be careful not to put an equal sign between the two because then if you know someone basically points to either some of these I think we're editorials mostly or commentaries that you know there's there's no data in humans showing early life exposure to any chemical really or gestational exposure in Tessica just Genesis syndrome and partly that's because it's nearly impossible to do such a study with such a rare cancer that that would then invalidate that equal sign you know basically if the Tessica just Genesis syndrome hypothesis is lacking data and support it doesn't translate to mean that the phthalate syndrome doesn't exist so I wouldn't want to too strongly equate them but I think with a Venn diagram and showing the overlap and then explaining succinctly and probably a few sentences what I what I just said puts it I think in better better perspective and really does separate the two I think you're a very clear writer so I liked what you wrote I one question I have when I read this it seemed like I saw someone speak once talking about how common some of these abnormalities are do you have any have you read that if I remember right this the birth defects that yeah said like 3% of all male births have some kind of reproductive tract anomaly not that it's necessarily due to phthalates right just how common is well for career work it is a month undecended test these there's data suggesting at birth it could be 3% or higher a large percentage will resolve during the first year of life but it's generally considered to have a prevalence of about 1% Crip Orchidism hypospatias is is less so but of birth defects hypospatias and Crip Orchidism are pretty much the most common that you'll see as you compare it to cardiovascular you know other birth defects that are much much rarer I think that might be a nice addition just to place it in context I mean I'm not sure people walking around know that it's not something like from my normal life that I you know I've ever ran against it's only scientists know that yeah I mean but the data in relation to phthalates is on AGD and then the link with hypospatias is a separate study between AGD and hypospatias I mean I could definitely put in a line in terms of what the prevalence of these conditions are but there's there's not a study on phthalates in hypospatias or Crip Orchidism so it's a it's kind of you know an A to B of A and B and then are equal then you know in B and C then potentially A and C are related but I think it's an important here's why you know the whole discussion about it gets back to the evaluation of chemical mixtures and so people have been talking you know let's group chemicals based on adverse outcome and it might be that some motivation of knowing there are these you know incidences of such high alarming rates maybe that is a reason to start thinking about what what is it that could be related to that and group chemicals that broadly not well the data on I think when you said alarming rates is you may really have meant increase increasing rates over time of these conditions and then there's the hypothesis that they may be related to environmental chemicals right nothing really on phthalates there's data on some other chemicals even the data looking at the trends or over time are difficult sometimes to interpret in terms of the diagnosis of these conditions as it's surveillance data is that data from you know hospital setting what's the degree of hypospatias that's recorded because you know some may have not recorded the minor versus severe and if you then change criteria over 30 years what's reported so there's even I think not complete agreement or definitely not agreement in terms of whether there are increases over time there's definitely geographical differences and whether that's partially genetic and or environmental there's some some data but not a lot but I can I can try to I think you had mentioned that last time I remember now you mentioned about yeah what no no but I can definitely add something in so so I can incorporate that into the report in a more of a discussion of TDS but I don't want to go off I don't want to go too deeply down that path because it's relevant but separate in a way from from what we're what we're doing and then I brought in in the next section is occupational exposure or male reproductive tract anomalies and some of these studies were mentioned at the last meeting I think Andrea says had mentioned the Ormont study you know I found a few others so I included these in which they looked at occupational exposure to phthalate with Crip Orchidism hypospadias and described these studies but noting a limitation that they didn't have specific measures of phthalates in these occupational settings usually using usually interviews or job exposure matrices they tried to get at phthalate exposure of course there's other co exposures as well in in some of these settings and this is the Danish national birth cohort one in England by Ormont so I thought I put this in it's about a page as more kind of supporting information and to make the the literature review on on phthalates and these endpoints more complete and then also being objective in terms of the study design limitations which is right in that last paragraph then I moved on to the second section which is actually an endpoint that's growing in terms of the literature the amount of literature on neuro developmental outcomes and phthalates I think there was a paper actually that's not included in here that just came out online in environmental health perspectives that I'll have to include but there's I think about four or five now papers that have looked at neuro developmental outcomes I discussed them in in a fair amount of detail there's two from Mount Sinai School of Medicine angle actually three angle angle and me out of it Nick and the swan study described these in a fair amount of detail started to put them into a table and these were basically pregnancy cohorts in which they assess gestational exposure and then looked at these outcomes in the children when they were when they were young there's also one cross-sectional study from Korea which I put less weight on because as we know a urinary phthalate measures reflecting exposure in the past 12 hours 24 hours at most and if you're looking at an outcome like IQ etc it it's hard to to know how relevant that exposure measure is at the same time that you're measuring your outcome in terms of the relevant exposure window which could be years earlier or even prenatal but wanting to be complete again and then included a second Korean study by by Kim looking at ADHD ADHD symptoms as well and I the table is very incomplete I think partially because at our last meeting I mostly had this section written and now I have to go back to the papers and pull the information from it I'm going to try to keep the table fairly simple especially in outcome because as we know there's some of these studies can have a dozen or more different neuropsych or developmental tests and to start listing every single one in the association with every single one I think would make it a difficult read so I wanted to try to keep it straightforward and simple so question I have is neuro development so many chemicals out there that we've associated with neuro development effects is there enough confidence in the relationship that they're being established that it could not be due to variables like pesticides which are much more ubiquitous in some locations and much higher concentrations lead in non-meric non-us countries I'm a little leery about that issue because of the fact there's so many other kind taking into account organics I mean my goodness they're everywhere so I'm I'm a little leery about neural your concern is with other co-exposures as as confounders you know of course these studies they can measure you know one or two classes of chemicals maybe three but they can't account for for those so you'd have to make the argument that they are covarying the same way as the phthalate exposure is with the outcome so that people that have high the EHP exposure also have high lead exposure or have high mercury exposure or the other issue is that they have low exposure to pesticides or to lead and that this is the variable that exists that you know rises above concentrations of everything else that exposures so that it is a meaningful exposure and its own right I just a little leery out because it becomes it becomes a nightmare when you're dealing with neuro development and the fact that we have so much in terms of pesticides that we deal with and let in burdened some areas that do not not necessarily controlled as well as the United States personal products too for lead well most of the prospective studies were done in the US okay Mount Sinai School of Medicine and Shauna Swan I think it was done it when she was at you you Rochester well the past that's why I worry about the cross-sectional where the Korean cross-sectional for the Korean I worry a little bit about the non American distribution of that with respect to Mount Sinai there still is the issue of pesticides because they've had the urban environment and also PDB ease heading for years to anyway that's I'm just raising a note of caution on that on that area yeah and I was going to raise the question you know in terms of what we focused on in the or what the toxicological literature points to in terms of anti androgenic mode of action of phthalates I don't think in the talks literature we've discussed at all effects of phthalates on neuro development so in terms of the biological plausibility the papers differ and I think that the Swan study looked at play behavior so really trying to look at sexually dimorphic differences which could be related to exposure of the developing brain to you steroid hormones or different levels during development the other studies were we're looking more at executive function or tension deficit hyperactivity disorder etc so I would put those separately but apart from the Swan study I think one of the questions to us in terms of the the talks literature is there anything there in terms of neuro development and then how to frame this because it's it's five six parts pages of the report there's more literature on the neuro developmental outcomes and phthalates than there are on the genital development maybe three versus let's say six or seven studies how will we frame this in terms of our conclusions I know it's not part of the approach that that Hogan you know or not really potentially that relevant to what you were looking at you know in terms of the hazard index anti androgen apart from maybe the Swan study looking at the play behavior that the way it is now it's there if it's part of the report which it should be for completeness how will readers interpret it how will it potentially be used with the gap that we have in the the talks literature or maybe there's literature I'm not familiar with and you know I've only seen the anti-androgenic literature so I don't know if there's a few and I think there are a few animal studies that hint at neuro behavioral effects looking at the structure of the sexually dimorphic nucleus in the brain in some of the behaviors reproductive behaviors in the offspring when they grow up so I'll try to dig up at least the ones I've seen that I came across but could it be approached the same way that we did in the NAS report that we consider the reproductive part just the most sensitive and that of course there could be other end points and then just work is going to focus on the most sensitive but maybe that means there needs to be at least a other end point short description in the top section or well when the NAS report was written like it's probably what the two or three years now so most of these papers the humans were data were not published so at the time I think when we were saying most sensitive it was based on the animal data but at this point even two or three short years later there's now you know five or six of these papers that have come out so not that I'm making this argument but someone could basically say well if you looked at the human data you have really just the swan AGT study but on the neuroscience you have these five or six studies albeit you know there's different end points and I'm not an expert in neurodevelopmental testing to know the overlap you know if you because they're all using different outcome measures but they're all seeing association so at least on the human data side you can say that there's more evidence on the neurodevelopmental facts than there are on the genital effects you know six versus one or two studies but I agree at the time when the NAS report was put together these these studies were not published the swan study was and the animal data was clearly showing that the most sensitive end points would be the anti-androgenic I think it would be risky to attempt to convince anybody that the neuro and the endocrine effects are just totally different considerations they're all connected as well as the immune responses so because these organ systems all talk to each other and are all they all have overlapping control mechanisms there may be species differences in expression of manifestations but probably have underlying mechanisms that are triggered by similar chemicals and just triggered at a slightly different level of sensitivity in different species but I certainly wouldn't deny that there is no relation I would certainly not say that there is no relationship between what appears to be a neural effect in one species and a neural endocrine effect in another species they're just too interconnected to sort them out that way with our level of knowledge today they're you suggesting that we describe that or note that in the report because currently I think in the talks or the animal section that there's Mike said there's some papers that can be added to it but in terms of trying to link the talk studies with the human studies and the human studies across endpoints link as well how should we approach that in the report it may not hurt to make a statement that because it because there's more first of all because there's more literature on the neuro than there is on the endocrine effect in humans doesn't mean that one is more important than the other might mean that one is easier to study than the other or there's more grant money available for one rather than the other so I'm not sure that's a good indicator of the seriousness of the response but I also think it wouldn't hurt for us to have a statement in there that to conclude that there is an effect on one organ system in the human and a different organ system in the rodents it may be premature to draw any conclusions about that because we would expect these are these are related at a lower level of biology I completely agree that you know the number of publications you know it has to do with the the ease of doing the study the data that's available you know there's a lot of pregnancy cohorts that are funded so they they have that neuro data already so I would definitely not use that as a criteria but someone who's not that familiar with the field and looks at the literature will say well you have these studies pointing in this direction but you know you just have one study done in this I think we just need to be very clear in terms of the the link or that they're not potentially not completely separate but also it's important that we have the ability to say that the reference doses we've chosen you know that are based on the reproductive side are the right reference doses I mean if we're worried about neurodevelopment is that something that would be more sensitive it's what that's why I'm saying it makes some comment about what we think may be the most sensitive that's what drives how you choose the reference dose and drinks do you think we should be delving into the neurodevelopment in this analysis as deeply as I think we're heading or do we continue to focus on what we think of the what we think is the major issue for the risk at this particular time and leave it for research to establish whether there is or is not a plausible link I think we should be careful I mean two years ago I agree with everything that was said before two years ago it really looked like the developmental end points by the most sensitive but two years is a long time in research and if there are no indication start other end points either equally sensitive for even more then I think we should note that it is quite a separate question whether the information currently available will enable us to quantitate this in terms of points of departure etc but I think we should note this assess it and if we come to a conclusion that it may be more sensitive than the points of departure based on developmental toxicity we should make a note of that and then exercise more caution in coming to estimates of so-called tolerable of safe doses without being able to quantify it but we should take note I would be surprised if there were developmental talk studies that looked at neural developmental end points for Thales don't you well my we should look like I mentioned a few animal studies I mean they're not I don't think there's a lot but I mean in terms of dose response studies that we can derive a know well from my I we should look but I would be surprised I don't think I don't think the public studies will allow us to to derive new new know well but maybe there are indications in what direction it it points all I'm saying is we we should double check yes look if necessary make cautionary statements good point I'll go on that's the third section and the question is how to integrate this and where are two papers I haven't completed writing this section but reproductive hormones and infants and their association with phthalates so this is the the main study and the Boas study in which they the main study prospective Danish finish study in which they looked at breast milk concentrations of phthalates and serum reproductive hormones male infants at three months of age and in describing the associations it's it's rather complex because you know there are associations with some hormones others not different directions multiple hormones measured so it's it's not a simple outcome and then there was the Boas study which was 845 children four to nine years of age and they measured thyroid hormones IGF one and insulin like growth factor binding protein three and looked at associations with urinary concentrations of phthalates haven't completed writing that so I thought of of these papers as you know really providing in a way background or potential mode of action information in relation to phthalates and some of the hormones and especially trying to focus on the steroid hormones and specifically testosterone so that was discussed quite extensively in the main study in which they looked at measured LH and free testosterone and looked at ratios etc so it's it's now listed as section three potentially may make more sense to maybe follow the general develop genital development section in relation because it's in relation to hormones but if we're going to really include neurodevelopment as under the umbrella of being under also you know endocrine control and that the two may not be separate I'm not sure where to included or at what level of detail at this point I've written you can see that the description of the main study is you know a full page in the Boas will probably be as well is this too much detail where should it be in the report it's not a clinical outcome in the sense that these it's not like these children had you know abnormal levels or clinically would be considered at risk or to have a condition this is looking at these biochemical markers and looking at distributions and shifts and distributions no I think I think the level of details you give is good and it should should stay can I while we're discussing main at our 2005 ask Holger to give us your opinion on analysis of thalates in breast milk and mother's milk I'm aware of all the contamination issues there etc could you give us an opinion Holger as to the reliability of such measurements always problematic to measure the delates and the delayed metabolites in breast milk because of as you said the contamination issues of the mono-aester metabolites and that's what they measured mainly here in in the breast milk so I would be very careful over interpreting especially the breast milk data so despite the fact that they measured metabolites so it's the mono-aester metabolites and they can easily be generated in the breast milk out of the omnipresent parent tell it because the breast milk is high in life is activity and therefore we have especially with breast milk always a contamination problem so this is an abstract from one paper that I was thinking of where they are looking at gene expression changes in a sexually dimorphic portion of the brain in animals in the other papers that I was thinking of are have to do with they're from gray and others they have to do with sexual behavior so you know there's not a lot but there's a hint of something in the animals could you perhaps circulate your collection Mike absolutely fantastic thank you so the moving on the next section for yes coming back to what Andreas pointed out I would really prefer maybe to have the the Boas 2010 publication to be a bit more bit elaborated I haven't finished that yet yeah I I wrote up the main and then I realized if potentially maybe too detailed or I started working on the Boas and then I said I'll stop here and wait see what level of detail but yes you're right there's that's not that's not done and I should then work in what you just mentioned about measuring metabolites and breast milk a sentence or two on that so the next sections pubertal development kind of comastia so I just put a note here need to discuss phthalates are not estrogenic and experimental studies in terms of considering the relevance of these studies on telarki and kind of comastia and we're probably all familiar with the cologne study for from Puerto Rico which was published in 2000 which was probably one of the first human studies looking at phthalates and an endpoint and then there's been a few other studies in which they've tried to look at phthalates and pubertal development or gunna comastia generally very small studies the next one is the dermas and colleagues published 2010 and this is looking at pubertal gunna comastia cases and 21 H match control children and then another study by lowmanic another small study 28 girls with central precursors puberty and 28 match can I just make a comment about the Easter geneticity otherwise of phthalates I think it's not generally true that phthalates are not estrogenic there are bbp for example isn't in vitro estrogenic chemical that the problems with there are problems with reproducibility in in vitro assays which are more to do I think with the complications associated with controlling the phthalate concentrations because they stick to everything but I don't think well it there are certain phthalates that are weakly estrogenic that's not been taken forward as we know with with all the Mary productive developmental toxicity studies because it is viewed there the view is that for those effects other mechanisms play a stronger role than Easter ethnicity so I acknowledge that but I think it is not quite right to say phthalates are devoid of Easter and activities certain phthalates are also in vitro estrogens so that should be reflected in the talk section you could briefly make reference to the relevant studies here or leave it out or what leave it out leave out the human or leave out the no no no yeah but no actually the best would be to make brief reference here to the relevant in vitro studies because this section is really devoid of any description of talk studies it can reference back to what was described but because I haven't done it with the other end points I think this section should still stay in it's valuable it needs to be discussed and quoted and I think all you need to link it to some kind of mechanism is to say there are indications not certain phthalates estrogenic and then put in the relevant references and you have some of those references I do yeah but isn't what the bigger picture rest isn't isn't it that what we really need is some glue that sort of just describes all these different sections but there's certainly things that are going to be locked out and if there's some general discussion maybe in the talk section that describes you know here's they're generally anti-androgens but also estrogenic you know that we're going to focus in this direction right because this is I didn't conduct a full review of every endpoint I mean I tried to choose them based on life stage and exposure and an outcome that I thought would be relevant to what we see in the talks literature I agree I mean I think they're there yeah you definitely have to be aware that a lot of the studies society there are very weak and some are really questionable in terms of approach quality analytical quality yes and I think it's okay to cite them just to so to show that we are aware of them but I would be really careful you know I agree I mean I say all these studies were very small limiting power and several had important limitations and methods used to assess that late exposure but I mean I agree I mean none of them are you know any bigger than 20 or 30 children the other one that I didn't describe was the ECMO study by Raz Barami which had 19 children and they were you know basically using ECMO as a marker for high exposure but it is both the analytical and them and the methodology so on the one hand of course it's a small sample size but on the other hand also for many of the studies the analytical results are very questionable very questionable yeah I would really say unreliable so why do we quote it why why why waste the space I mean you have to be really careful when you put stuff in that maybe unreliable if we discuss that the sample size it's already over accentuating the quality of the work that's right I think our job is to review and assess available evidence we I think we should deal with it and then make these these comments it's no big deal yeah I mean I mean it's mentioned maybe not as strongly as you want like you know there is concern with contamination of blood samples there's so we can make it I mean I'd welcome if you know had in rather than saying it's had important limitations we can say had important analytical limitations or or had we can make it stronger we can make it more more detailed so if it's and I didn't spend it you know for these four or five studies I basically wrote about you page and a half or so which I think reflects the importance of them but I'd welcome you know anything specific you want to add in terms of the analytical limitations or how to describe it I mean I think all of them have that problem apart from the raspberry paper which didn't assess exposure or didn't measure exposure in order letter urine so yeah so as the mate they use blood some of these studies they measure the diester I mean there's and then the so Hogarth I'd welcome any few words or editing whatever you feel it's necessary and then based on the last meeting we talked about whether to include a section on adult exposure and semen quality because of the relevance of the end point and we decided that that would you know basically be very brief and just cite you know the 8 or 10 I don't know how many are here studies and then just conclusion that you know the data seems to be inconsistent you know some studies do find an association some don't and it's about a half a page or so and I this was based on our discussion where we felt it needed to be there but don't put a lot of weight on it or detailed description so those are it's really four or five different end points which I think were chosen to fit in with what our charges and what the tox literature points to one question I have is that the whole issue of spot urine versus 24-hour collection I'm assuming that some of these studies had the 24-hour others had spot urine I didn't really notice too much I think most of them or all of them had spot urine I don't remember any with 24-hour urine so do we need to bring up the limit the potential limitations or my maybe I wouldn't say limitations as much as I do remember I thought I remember if it was your paper or maybe you were referenced in a paper but the talked about the what was the word ubiquitous no the omnipresence of or something like that of the exposure to these chemicals so although you know you may have a spot urine today and then next week the distribution ends up being about the same from even from a spot so that there was a conclusion population so there was a conclusion that from a population perspective a spot urine was reasonable to so would that be worth make that statement was it a Tito on paper that addressed that had the longitudinal versus the we had published we we looked at was small number of individuals that had repeat samples you know let's say nine or ten and then we did a simulation exercise we pretended we took that as the gold standard of what their exposure would have been divide them into turtiles and then do an exercise where you say well if you had only taken the first sample from everyone how well would it have predicted which turtile they're in if you took the second sample how well and then you can get a sensitivity and specificity that's probably yeah we and the sensitivity and specificity about sixty seventy percent which is not awful but it's not great you know it's not fantastic but it's informative yeah yeah but there is a lot of exposure misclassification because taking a spot sample and it's reflecting that individual's exposure and even if you take it a different time of day you're going to have a different measure in the urine or relative to when they ate relative to when they use some of the products that contain phthalates so even within a day a few hour difference can make large differences in their urinary levels I just can't see making that statement too many variables and there's too much uncertainty spot samples are fine but they just don't reflect the day or the reality of what what people are exposed to because there's so much variability from day-to-day hour-to-hour but I think the papers like what what Russ was a part of are helpful to sort of put a frame around that there may be a lot of variability from hour-to-hour but it's still people who were low at one point ended up there's some info I mean Paul you would you would agree that there's some information in that spot urine sample yes there is but not necessarily but it's coherence between that and the 24 hour I mean we'll get shot shot down making sure no not between the but but there is some information in helping classify individuals into quartiles or sure but I wouldn't even come close to trying to equate the two because maybe I misspoke to bring up the 24 hour maybe really what is interest the reason I say that is because in the biomonitoring part of what we're doing we're saying there are people with low levels and people with high levels so so how reproducible if you if somebody ends up being high in a spot urine do they tend to be high later with sensitivity and specificity of whatever you said maybe it's pretty good I mean it's not perfect there are limitations but at least it it evaluates that in could you make that statement and live with it I wouldn't even go that far neither would I I think we can come back to our discussion from yesterday about variability and uncertainty it is not only a question of spot urine samples compared to 24 hour urine samples we all have to be aware that the delayed exposure is high one day low the other day so it is merely a picture of the reality we are seeing it is not only an issue of the spot urine and the 24 hour urine what you have seen and described is important that the ones who are in the upper quartiles are very likely to be possibly at the next measurements also in the upper quartile but it doesn't really mean it doesn't really it isn't really sure that they are not absolute but but there is information there and when you calculate a sensitivity and specificity it's telling you how much information there how much predictive ability there is it's definitely not a hundred percent or anywhere near that but it's you know you're not down at 20 30% so I mean I think statistically you would probably call a 70% sensitivity or specificity is providing some information but yeah within a day the levels are changing so if that person comes in and gives you that sample at 10 in the morning versus 4 in the afternoon there's gonna be differences and then day to day and week to week and and they're real they're real differences yeah I'm gonna call a close to this because we we've got to be finished by 1115 when the council comes back and we still have christen and hold you to can I make one yeah we have a paper actually under review now looking at variability of phthalates over time and I think it's about 120 or 30 women where we have up to 10 or 15 repeat samples and before they're pregnant and during pregnancy and we calculate our interclass correlation coefficients we look at whether there's changes over trimester pregnancy etc so you know hopefully that paper will come come out in the in the fall it's under review now but it could provide some information on variability and also during pregnancy as well yeah so it's much larger than the original paper we published okay so Chris and over you've got the microphone for the last 30 minutes or 25 minutes now this is tab 11 there are some updates that this report here doesn't have namely some of the excretion there's an updated paper that Holger reminded me of that he sent me and I didn't catch the email that so in the table one on page four of the report these some of these excretion factors need to be updated just a bit so it's it's not going to change drastically what's going on but there will be the numbers of what's here will be will be different the other thing is so maybe Holger do you want to talk about this actually this fine tuning we are doing right now and two major publications came to our notice or came out in the recent weeks one was as you said the publication by Anderson et al. in food and chemical toxicology it is now a 20 volunteer study investigating the metabolism of DHP and DINP so this data now puts our assumptions on metabolic conversion factor which we use to extrapolate from urinary metabolite levels to the dose on the more solid ground because the numbers we use have been based on only one single volunteer so these numbers are now based on 20 volunteers and we have minor just to give you an example we assumed the DHP metabolites the the fire the four metabolites you measure to represent approximately 60% of the oral dose and now with the Anderson et al. publication publication it would be 45% of the dose so absolutely this is a difference of 15% so relatively it's it's a difference of 20 to 30% which in the end would increase the doses we calculate from urinary metabolite levels so for the increment of DHP in our hazard index the doses would increase by approximately 20 to 30% using this novel more reliable conversion factors based on 20 volunteers so that that's that is one major development and the second major development is for our relevant for our case two that is the publication by Hanna's et al. that is a publication from the EPA multi-dose program on phthalates from a race group and as I pointed out yesterday this is a good approach to measure the relative potencies of the phthalates by comparing the different dose response curves for the various states investigated and in this Hanna's publication the most important finding is they compare isobutyl phthalate DHP and DINP and while as we have already pointed out in our case to and butyl butyl bansal and DHP are roughly equipotent they now we now have a very reliable potency factor for DINP di-isonol phthalate and they state that regarding testosterone production DINP is less potent by a factor of 2.3 so we use these potency estimations based on the most robust endpoint NOEL for DHP of 5 milligrams per kilogram per day and from this NOEL or TDI we calculate the other TDIs based on the potency estimations from this study in our case to so having a TDI of 50 for DHP multiplying a factor of 2.3 become to a TDI or a reference dose of around 115 for DINP so this is one major development from this study. So what we're proposing is to have three cases that will carry through the first case is based on the quart and camp and fast reference doses the second case will be based on this idea of calculating the reference doses really from the foundation of DEHP and then using real to potency ideas to generate other reference doses and then the third case would be a combination of the work of Bern and Mike or Phil to to up with a repro talk sort of reference dose that we would reference them from internally so the idea would be you know hopefully there'll be a lot different and that will actually we can assess them how sensitive our results might be based on the assumptions of the reference doses my feeling is is that it's not going to matter too much you know I don't think we should split hairs about what anyway so I think there's going to be value to seeing three different case studies that we carry through so as soon as we get those then we'll work work through that so what I was going to do is just sort of talk through what's here now and I know last time people made suggestions some of it we've included it if it's best I remember if there are other things you want to include we can do that but if you don't mind if we could just sort of step through the pages with that okay so they were page but the first page of the results section so the first thing that we're looking at our analysis of data from in Haines 2005 and six pregnant women in that version of in Haines there were 300 and some odd 382 women who were coded as pregnant but only 130 of them actually had phthalates evaluated on them so the analysis is based on those 130 the table three there on on that same page so what I was trying to do there was to give some sense of what if you think about each person then is sort of their own you know it's a different exposure mixture for each woman each pregnant woman so to give some sense of that distribution one way might be to to look at what's the percentage of the contribution for each estimated daily intake value per woman and so what you see in table three is if you add everybody's up and then figure out what the percentages and then take the average of that per phthalate then you see that DEHP with with this calculation anyway is about 37% average of the mixture and that's much well pretty much bigger than than the others dinp comes in second there so of course these numbers will change with the new calculations but so that this sort of way of looking at it and the other thing that I think is helpful is to see the variation there by looking at the minimum and the maximum so for example the DEHP there was one woman who had only 5% of her mixture you know was DEHP and another woman had 99% of her mixture was DEHP and similarly I mean there was one woman who had 87% of her mixture was DIDP so there's a lot of variation in terms of what the exposures are but I think one value of this approach is we're putting all these different mixtures into a distribution from the hazard index so if you think of a better way of combining them and instead of just summing them but what's here is just the sum of the daily intake estimates and again this table three is just the intake not the not the hazard index just the intakes right the relative intakes right table four on the next page is just a question maybe that's just been answered the in table three these percentages there are the percentages of the hazard quotients to the overall hazard index or what this is not hazard index it's just the daily intakes okay so every woman has it the different daily intakes there are some and then it's the average I mean the percent of those and then across the chemicals table four again this was a request from last time which I think it's kind of helpful these are just Pearson correlation coefficients for the different daily intake estimates and Holger pointed out yesterday that it looks like I guess the DBP BBP and the I don't know the DHP there whichever way you put that but there's there's low molecular weight and then higher molecular weight sort of clusters of correlations which might be interesting in terms of exposure and be considered the HP high molecular weight delayed sorry didn't mean to step into anything there because it is right and so so you see along the diagonal there and a little bit off the diagonal that some of that's highly correlated in terms of correlations there the next sections are just the calculations of the hazard index for each of the three cases what's here is all going to change I don't want to spend too much time going going through this but if you just think about it in terms of the approach but the numbers will change you know with these differences that Holger spoke about one thing that we're doing then is with the with the inhanes we have this opportunity to actually try to model some of these hazard indices as a function of various things you all may have ideas of what else to include here so I'm at the top of page nine on the right hand side there I'm actually trying to model the estimated hazard index per subject as a function of body mass index age race poverty index marital status education level I mean there could be other things and maybe you all can think of other things in this sort of model building strategy I ended up with a body mass index being negatively associated with the hazard index and age being positively associated and other things sort of dropped out of the model I don't really have an explanation for that maybe we it's worth some kind of comment there but I if you have other ideas of covariance I mean we could you know in Haines has got a lot of things we could look at but maybe with some thought so and then what but interestingly then I kind of used that same model building strategy for the for the other two cases here in the next couple pages and we end up with about the same thing so that's I think saying that it's not reference dose dependent in terms of these associations body mass index and age coming up may I remind ourselves of the discussions we had yesterday about issues of exposure and users and non-users so looking at the distributions we have here I think very typically we often see some people some individuals really being apart from the others so I think this is something that that we are waiting for from from the external exposure side to give us the info on where might be some highly exposed individuals that we see here also in the biomonitoring extrapolations so this is not a bell shape it's not a bell it is it is certainly or is it by modal I think it's a tail thing but that I think what you're saying then is maybe from the the other exposure analysis important variables will come up and then maybe that will suggest covariates that we could figure out are those the ones that sort of explain these higher levels that would be kind of cool and then sort of this section will be so on the bottom of page 10 right now the summary of sort of the three cases you know that's going to change as the numbers change but we're seeing pretty much some agreement it turns out what was here cases two and three were more similar than case one but they're still pretty pretty close in terms of about what was it I think about 10% yeah I think about 10% of the estimates or above above one that was for case one now that's going to change a little bit with the with the new calculations but but you know we're seeing right on that sort of upper tail for all of these cases which I think is informative again it's not going to be dependent I think in terms of what the assumptions are for the largely speaking for the reference doses so that helps but that discussion up to that point is only looking at the seven the seven phthalates which are summarized at the top of table five the bottom of part of table five is going to those day to come up later but it's just here just to put them all together can I just ask a question yes the in a previous draft you you listed the contribution of the rail satellites to the hazard index and as it varies from case one two and three or three isn't you and I seem to remember that in case one mostly DHP contributed to the hazard index in case two that changed what about case three so that was an earlier version if you like that we can put it back in in this version I I was thinking that that was maybe more succinctly described by that table that was just based on daily intakes and not based on the denominators of the hazard index but if you if you like if you like that I didn't get the feeling everybody liked that last time so I well it's an important piece of information it tells you it tells you whether we're really dealing with a mixture effect or whether just one or a few satellites dominate what's happening in terms of the in terms of the hazard index okay so we can put that put those tables back in so the the next part so this section now in the bottom there's not a page number but the bottom of page 11 this now this little section is written just now for case one it'll be extended to cases two through and two and three as well but largely what we're trying to focus on here is the idea that so we have hazard indices just based on phthalates now what about the other anti-androgen so available in in Haynes are by our monitoring data for bisphenol A and butyl and whatever the other paraben is propyl paraben and so we use the same kind of approach to build up daily intake estimates for those three additional anti-androgens and and then the other thing is the court and camp and Faust paper had I think seven other chemicals that they looked at for anti-androgens and and provided median intakes and higher high-end intakes so what I'm trying to do here is like what you see on page 12 is adding from that say this the seventh allates by themselves you get a certain distribution of the hazard index if you add on top of that the three anti-androgens from the biomonitoring it doesn't shift all that much it shifts a smidge up and that's a scientific term but then the but then the other thing is we can take just the high intake median estimates right the median estimates from the other seven anti-androgens from the court and camp and Faust and the high intake estimates and see how it shifts up and what happens is when in the most conservative case there in case one for the most conservative case of adding the the constant from the high intake estimates you're adding 0.593 units of hazard index to the baseline of the phthalates and the and the three other anti-androgens from the biomonitoring and it goes up from about 10% above the value of 1 the distribution up to about 14% of course those numbers are going to change with the new calculations but I think what you're seeing is the impact of it really matters what the denominator is how many chemicals are you going to look at and the more you know if you're assuming that we have a combination effect the more you add you know potentially though the further that distribution is going to shift so this is kind of an exercise show that so the next the next part there on page 13 so now we switch to the swan and al data so the in Haines data we don't have we only have one value from each pregnant woman in the swan and al data we have pre and post natal that measurements and then measurements on babies up to age three I think now if you look at table seven there on page 13 these are the mono esters that were evaluated we actually decided that instead of seven valleys were here we're going to only look at six because we are we assumed that this mono three carboxy propyl phthalate wasn't specific enough to DNOP and the other metabolite that we used from in Haines wasn't available in the swan data so we're reducing now from seven to six with that but otherwise the calculations are the same as what we saw before so we have 418 pregnant women here 340 women had prenatal measurements 336 had postnatal measurements it turns out that these women the distribution of the age here in this figure of sorry it's not numbered yet but on page 13 that age distribution is a little bit older than the age distribution from in Haines that in Haines distribution was a broader sort of range or p there is a fatter distribution in terms of age but it's about four years or so shifted up and in fact the 25th percent of them in Haines was 21 here the 25th is 27 so at that end it's like six years so it's a this group is a little bit older whatever that helps with okay so in this in this data then a similar analysis on page 14 this is kind of an interesting table this is now a little bit different than what you looked at before this is the Pearson correlation estimates but it's based on prenatal values correlated with postnatal values per woman right pre and post and so the diagonals aren't one this is not just like the usual correlation table and the sample size now reduces because it's we only have 258 women who have both only I shouldn't say only but who have both pre and post values okay but for those two sorry 258 women who have pre and post for for DBP DI BP BBP and DE HP but the sample size reduces to only 18 for DI NP and DI DP where there's both pre and post natal values okay so be careful about the sample sizes there that's what those asterisks need but largely what you're seeing here is very interesting that we actually see correlations between pre and post values I don't have data about you know when these measurements were taken prenatal and postnatal maybe we can look at Sean Sean's papers to find that out I don't I have not tried to do that but I don't know this specific data set but I know in her paper it's around 28 weeks of gestation the prenatal so late in pregnancy and the postnatal I don't know how postnatally that is think the average at least from the AGD papers was about 12 months okay so you know the fact that these are correlated I think may go to the fact that these you know behavior habit whatever it's very similar exposures weekly correlated weekly very weekly being post preimposed yeah so that's very weak that's what you already discussed on okay very weak but still significant okay okay so then what's here is just you know going through the cases again these numbers will change with the new calculations but again I want to point out that the distribution I think for the prenatal distribution and the postnatal distribution you may say it's a weak correlation but the distribution looks similar okay and we'll see if that shows up still with the new calculations but right but look at but look at the similarities from case one though the distributions on pages 14 and 15 they're more similar so there's must maybe there's a chemical there that's throwing that up so we'll see what that looks like with them with the new case yeah yeah we can look at okay so going on then so again those numbers will change with the new calculations but so okay infant data on page 19 so we have 291 infants ages 0 to 37 and you see in that tape in that figure 6 I don't know if it'll stay figure 6 but you can see the age distribution there so it's kind of clunky so one thing that we have made an assumption about was in the in the published use of this method for estimating daily intakes we've used a paper by Raymer et al to calculate the data intakes in children but that paper only was based on data from 2 to 18 years so we made the assumption that for infants less than 90 centimeters long the creatinine excretion rate was assumed to be that for the 90 centimeter child so that is an assumption we've made and I don't know I mean I guess we could kind of figure out how to study that the impact of that but so far I haven't done anything I'm just pointing out that assumption okay so now at the bottom it's sorry about the page break here but the bottom of page 19 and top of page 20 again we're looking at correlation coefficients between now the top part of the table is the prenatal and the the columns are the baby values or the infant values for the different chemicals there were no baby pre-values that have the same sort of mother child combination for dinp and didp there were some values then though for the post natal so that's why the block part there not a very strong association between the prenatal and the baby but for the post natal and the baby I think there is okay you guys decide if it's strong or not but it is significant I can tell you that values about 0.3 between DIBP for for post and baby values DIBP BBP DEHP about 0.3 point 0.38 can I can I express a word of caution to apply this kind of hazard index consideration to infants for the simple reason that the potency estimates or the reference doses which which you use for that are really for fetal life so I'm sorry I don't want to be a party pooper here but perhaps you know that would complicate the the entire analysis and I wonder whether we could well this entire analysis cannot live without analyzing the infant data or is it possible to come up with a consideration of what the reference doses how they should change that that's guesswork there's no data for that very difficult but I think it's enough in my opinion the whole thing can live without doing these considerations for infant data maybe just have the daily intake estimates but not the hazard index for the infants yeah can do the daily intake estimates but then the question is what for show things like this correlation Andy I think we felt obliged of including the infants because it it's one of our tasks within the one of our duties so yes I would feel more comfortable if you wouldn't include the infants but I think we should at least do some exemplatory calculations here because it's our task here yes but the the question then is one can you actually do a risk a risk assessment for for infants you know it has to be it has to be credible and the data as far as I can see I simply not there to do this in a credible fashion our task is to look at toys yeah therefore the infants borns the newborns and the toddlers are both part of this oh it would need a series of of heavily qualifying statements well I think we have to do that but I think we have to do it but I think the point of putting heavily qual heavy qualifiers on this is appropriate but we can't ignore it at all otherwise we know I'm not advocating to ignore it but but I'm I'm putting in provisers here I mean the analysis we do has to be credible really something that the that your chapters could address are there are there talks papers out there for well in the in the animal studies the Jew you know prenatal exposure is the most that's the most sensitive stage juvenile animals are more sensitive than adult animals adult animals you have to really am I so can we derive reference doses from postnatal studies I take some doing largely just to see if it's would would they change that much from what we already have it may not it may not be to actually derive new values as much as just to assess is there any reason to think they would be much different than I think like Mike said they would be different they would I think experience tells us that they would be higher how much higher I know I mean it needs a bit of a biological reality check I mean that the truth of the matter is that the vulnerable period is in fetal life the damage is done in fetal life not in in neonatal life or postnatal life for for the things we are looking at the damage is done in fetal life if there is any damage in reds during the sexual differentiation that takes place in the reds at the end of the first trimester which takes place in humans yeah you're saying that our whole premise is wrong that toys are significant are insignificant no no no no not at all the the damage occurred before they're born not at no no there is further evidence to suggest that the damage done in fetal life mm-hmm you know there's no recovery if you then have postnatal exposure so all right you're saying that you have a initiation yes and then you have a promotion if you want to use these analogies that would be correct because otherwise then the whole analysis is useless for afterwards if there is no postnatal exposures of concern my point is only that for the postnatal period it is difficult to to use say approaches that can quantify it we know qualitatively that if exposure persists in postnatal life you you help the syndrome coming out at least that's the evidence from from rats all right so it makes me feel more comfortable yeah first I was yeah no no no don't don't me as I thought I'm a statement hmm okay fine I'm okay the only problem I'm highlighting here is that for you know for for the postnatal period we we have it is very difficult to quantify the the effect I think I got your point we might very reliably estimate the exposure rather reliably but we shouldn't maybe do the last step of extrapolating to the hazard index but we can say that the exposure of the infants is in the same region as the exposure of the pregnant women for example that that would be that that piece of information would be important to then argue here you know the damage the damage done is is promoted what about what about another approach what about saying the conservatively conservative can I just say though what we could do is use the reference doses that we've got and then do a little sensitivity now since they suppose it's off a factor of 10 multiply each reference dose by 10 and and see what the impact of that is without knowing more I mean I don't think what you're saying is it doesn't matter what the exposure is you're saying we don't we don't know how to quantify it he's saying the opposite he's saying exposure does that's my point is that instead of instead of not having a hazard index let's just say it suppose it's 10 times the reference does a shift by a fact by you know a whole order of magnitude what happens I think you I think you make a good point Chris and I think we just have to play with the numbers once we get some exposure values to see in fact where we come down on this issue because that's going to be important in terms of how we look at this postnatal exposure question which is the relevant question for what we have to do and Andreas would you say that the postnatal exposures in that case the the infants are gonna be no more sensitive than during fetal exposure no more sensitive hmm yeah or would you say we have no idea or would you say that using the prenatal values it you're not gonna underestimate the risk you may overestimate it yeah it's just it's just like comparing apples with pears slightly and you you have to look at it quality qualitatively based on animal evidence and and based on animal evidence we know the damage is done in fetal life but if exposure to phthalates persists postnatally it comes out stronger okay I'm fine where we are it's just a matter of seeing what the exposure data comes up with and what you do then with the relative magnitude of the factor with the discussion we had earlier about there could be neurodevelopmental effects that it could be in the same ballpark of what we're looking at there's you know some epidemiology sort of evidence of something you know I don't think we should I mean I would propose that we keep on with this idea of a hazard index but just with more of flags around it saying with these reference doses are not a set maybe conservatively they are we wouldn't expect it to be more sensitive we just have to be just have to I think as we have to lay out the stuff and put the as just as we're gonna have to put the uncertainties around the exposure issues we're gonna have to put the uncertainties around the dose and hazard index especially for because it's gonna be really different and I think being upfront about it and I don't think we have to bring in the idea that there are other effects at this point I think we just have to be very careful on how we phrase it but and is it reasonable that even because it's children or infants that you'd have another uncertainty factor added anyway ultimately you know your attempt what you're trying to do at this stage is quantify the unquantifiable at this stage because you know you can only argue qualitatively there's no data at least to my knowledge that would help you quantify it I agree totally agree you have to take a step back at this point and see where we we are in September I really do I think we just have to step back but but it's no problem mm-hmm I don't see a problem I agree with it I just have to see where it comes I would like to point out though that what we're seeing is that the with the calculations that done now that the hazard indexes for the babies is bigger than for the than for the pre and post natal values so so if the reference doses I mean they could go up some and still be you know in the same ballpark as the women I agree that you know I just don't want to say we can't do anything I think we can place it with some flags around it in your resume okay so then finally and I know we had a wrap up but just can I just say finally though in the summary of the results it seems to me we need to discuss how we're going to interpret this and so something about you know maybe we could put a summary table about the percentages above one or you know in the neighborhood of one whatever but then have a discussion of you know what this value of one means we're not really hypothesis testing it's more of a you know guide of some more concern the closer the higher the percentage above one so some discussion about that and I guess my final point was based on the discussion Mike had earlier those questions that you had written down it made me think do we want to look at distributions of the hazard indices per component you know actually produce the plots for that instead of just summary values like like I had before you do have the percentages or well I took out the hat yeah yeah we can put those back or put some plots and I which may be helpful as well so one more thing is I think that they're even in spite of the age difference in the women I think they were quite a I look through the daily intake distributions from those shawna swans data and from the in Haynes and they're pretty similar distribution so I think you know it's it's in two different data sets it's pretty similar daily intake estimates you want to invite the council at this time the CPSC general council Cheryl Falvey will join us so I understand that yesterday there was a fair amount discussion about peer review I haven't watched the tape and so I wasn't I don't know everything that you talked about I've gotten a little bit of briefing in between other meetings today and so I thought it would be helpful for us to lay out what the important considerations are if you go down the route of peer review and give you some context as to how we view your work because we view you as an extraordinary super peer review group already peer reviewing prior CHAPs work on DEHP is that right DEHP and DINP that were done in the past and we have a layered process here where we have Congress asking for the formation of a CHAP to go even further than those prior CHAPs looking at a whole host of other issues but relying on section 28 of our statute which is the statutory basis for the CHAPs authority and how you're to do your work so when we put together and convene a CHAP we follow the National Academy of Sciences selection process we get recommendations three times the number of CHAP members you're vetted through an entire process which you may or may not remember where we've looked at everything you've ever written looked at all kinds of financial interests and done an assessment of your qualifications to do chronic health assessment risk assessment and look at chronic health hazards so the CHAP is in the scheme of peer review of our agency's conclusions the most sophisticated process we have to ensure the integrity of the scientific process so that's the guiding principle here is we need to make sure that if we're going to have peer review that we maintain that same integrity we can't have it would absolutely have to be open public and transparent the peer reviewers would have to be vetted through the same rigorous selection process we can't have it be an informal process and I don't know if you've discussed that or I've sort of heard about that but we can't have chapters going out privately to certain people to look at an informal input that cannot be the way that works we look at each of you are writing different sections of this report not chapters but sections and your peer reviewing one another's work with regard to you know with your lens from your scientific expertise that being said if you feel strongly that there's science missing that you need additional peer review you need to make that recommendation to the Commission and if you need additional scientific input now there's no reason to necessarily call that peer review we could get other experts to come in and present more data to you if that's necessary and we could you know schedule another meeting or that kind of thing but any peer review process would need to be open public and transparent with the same rigor applied to how we select the peer reviewers so I wanted to put this in context as well and the way this process works you the Commission's expecting a recommendation piece from the seven chat members vetted by you but that will not represent or contain findings or conclusions that represent the official position of this agency it's just your recommendation and it would need to have a disclaimer that that's that's all it is the Commission would then under the statute go forward with a rulemaking based on those recommendations and there would be opportunities potentially for peer review as well as notice and comment which are two different things different rigor different participants but both of those opportunities are presented here even after you've written your report so just just putting it in context all your writing is a recommendation to the Commission it doesn't represent the Commission's conclusions or findings in any way it would have such a disclaimer on it but if you need peer review if you feel strongly whether that's in a particular area that you feel is underrepresented particular issues the whole report you need to include that as part of your report and if we need to set up a peer review process now to get the right people on that panel that would be something we would need it would be extraordinary I'm not really aware of a separate peer review process occurring in a prior chat we've had prior chaps reports be public and be made and you know public comments on those and that's an option for you as well we could consider so with that I think I'll answer any questions you have about the process to give you a little perspective from our side several of this of the sections of our report will be standard review of areas that are pertinent to our report into the recommendations that we will make and and and those don't really require peer review but in some sections we're going to be breaking new ground and in those sections I think that the panel feels fairly strongly that we would like to have some peer review to have as we would for a research article that breaks new ground that we were going to submit to publication would be peer reviewed and it's in that context so we're and it's it's these two areas that we're breaking new ground that really drive will drive our recommendations that's why I think we feel strongly that we need to have this peer review so there are timing issues here in terms of an options that we can consider we don't need to consider those right now but it's giving me some things to think about I mean do you make the recommendation finalize it with the caveat that these two chapters should be peer reviewed or do we engage in that peer review now do we start with a schedule that has us running out to get those peer reviewers right now so that when those couple sections are done we have the people lined up to look at those later this year it just accelerates the drafting and the process in order to meet the April deadline but there are lots of different options we could pursue you could finalize it with the recommendation that it be peer reviewed so it really depends on you know our scientific team working with you to figure out what makes sense where you are in the process and and how quickly we can get the National Academy of Sciences to make recommendations and that kind of thing but it you know I'm sure if the if you recommend to the Commission that these two sections are breaking ground and we would like to have additional comment or peer review that's something they'll need to consider and we'll go up a level and figure that out may I just add our thinking about peer review was not was not because we feel we need additional expertise it was only adopting good practice for example also from the National Research Council reports as a general rule peer review makes every report better and and our idea to up this here was was really inspired by this insight so let me stress we don't feel we need additional expertise on this panel I feel however that this request of this idea is sort of unprecedented that's what you're saying so in previous chaps this was not common practice it's sparing over the years and I don't have all that history yet but we've put it out for public comment a report when it was final and sometimes we've said that's for scientific peer review and public comment but there are more recent documents that have been issued by the federal government that talk about the fact that when you just put a document out for public comment you don't you're not guaranteed that you get the scientific expertise to actually look at the issue and what I hear you saying is that just like a scientific article would benefit from making sure you have that input I'm not sure just putting it out for public comment even if we put the words for scientific peer review and public comment you'd really get what you want so I want to make sure you get what you want it's also not public comment anyway it's just you see many of us are used to the NRC NAS procedures where peer review is in fact part of the preparation of the report so the when when a piece of work at the NAS enters peer review it is not considered the final product it's part of the preparation of the final product but just describe that process a bit for me because I'm not as familiar as you with that process having been chair of one NRC committee and vice-chair now the second one what you do is you have the deliberations of the committee are basically private there are some public sector analyses that are done it's a little bit different than here where you have open public meetings all the time the products of the committee are not released to anyone we're not allowed to talk about it until after the higher projects over but the reason the point where you have a draft report and that draft report basically is one that's agreed upon by the members of the committee sometimes it's a hundred percent agreement sometimes there's some dissension in the committee report then they have minority opinions that are expressed in the report that is sent out to a series of peer reviewers in NRC reports they take subject matter experts for some sections and they look at integrative overall set of reviewers for for the entire document and then when it happens as you get back to review we get the comments the comments are returned to the committee they are reviewed by the committee they're reviewed by the academy and then we make changes based upon those reviews and again it's all internal it's all private because it's not a final report it's going through the final report then based upon the comments and the of the reviewers the reports revised the reviewers are named in the front of the report but their comments are not released it's basically a peer review a peer review usually means that you are being reviewed with a degree of an amenity although we'll know the names most of the time who do it because we review it because we know the style and the features of these individuals but some people you may not know all right so in the end the final project product is a product of the committee with a agreement or disagreement or some logical compromise on the content of the report by all the committee members and sometimes it'll be a minority report and then there's a publication that publication will in fact be the final report which is what we're looking to provide you in any case the critical point here is that we're not looking for a chapter or two to be reviewed what we're looking is for is the basically the product the integrative product of what we do because it's not just a chapter here chapter here it's the integration and the science with which we achieve the conclusions that we are presenting to you for recommendations we're not asked wouldn't be asking them to validate our recommendations we're asking to say did you we did we do this right so therefore the questions be very specific so to be a charge to the peer reviewers say we want you to look at this we're not we we're not interested in whether or not we've looked at every scientific publication that's come out and whether or not there's a gotcha in the last six months that we didn't get that's not fair that's not what we're about it's basically taking the evidence putting it together and making a strong statement as to why we come to our conclusions that's what we're looking at that's the way we'd be done I think in this particular instance and I think that's what we're having in terms of our thoughts and discussion and as said by film but it's it's a process and it's a process the Academy has it's well established you can get the you know that they have a procedure and it's well in place and I think it's that you can get it from them without any question just like if they select members of committee there are procedures for selecting peer reviewers and how a peer review is conducted and it's usually fairly rapid not allowed to do this over of course the six to nine months there are requests as they you're giving us report you have X number of days to do it because we have a timetable for getting our report out so that's where I sit on this issue what it really provides is another level of insurer assurance in this case for your agency that the report that we give you that the recommendations that we made have been fully vetted and that you're getting the best possible report and recommendations are the peer reviewers that are selected through this process vetted for financial interests and vetted for qualifications absolutely and we'll I think in this particular instance we'll have to define few with the qualifications are since we're not asking somebody who's an expertise in developmental toxicology we're looking at some people who are a much broader higher level of skill sets staying be able to integrate that and look at hazard exposure and risk so that's the kind of people we'd be interested so we can give you criteria and the academy has a slew of individuals that we all know and respect who can or that function oh let me take that back and we'll give it some thought as to where and how that would fit into the timelines you've been talking about over the next day and or the last day and we'll get back to you thank you very much thank you thank you welcome Mike do you have any final comments before we turn let's see I don't I don't think I have any final comments you know as usual I'll be writing up notes in a meeting log and you know our to-do list and that sort of thing so I'll be in touch and I'm assuming that council will will be in touch with you and we will yes and I'll relay whatever you whatever whatever they say to the panel and you know if you have any additional thoughts on it yeah any other comments from the committee hearing none meeting is adjourned thank you everyone