 All right welcome back This morning what I thought we would do is Chris has some Analysis that she'd like to go over that we can discuss and then I Think the next step would be to finalize the list of phthalates phthalate substitutes and anti androgens that are going to be the focus of our report and then I'd like to start with a general outline in terms of our report and begin to Make assignments in terms of who's going to write what so Chris you want to start off? So I don't know if these are really analyses or just plots, but just to give you a sense of some stuff that we did So I'm going to just show you it's it's interesting to me that how log normal the daily intakes are And I hadn't looked at these plots until this morning So what you're looking at I'm going to go through the seven different phthalates that we're looking at and Or six seven whatever And what you'll see is on the on the horizontal axis is log base 10 But you see so you just to remind you if you exponentiate if you put the the unit on the Y on the x-axis raise it 10 to that power that'll be the value. Okay, so Oh, these are micrograms per kilogram per day. Sorry. I should have that on the plot. Sorry Okay, so this is dbp, and I guess I'm just showing you this just to get a sense of the data. It's always good to plot Dibp Be HP The INP Yeah, IDP So so that was you know, I don't know if those are helpful, but just to give you a sense of it's I Think we were talking last night I think there are places where we're over estimating and underestimating we can talk more about that So I think that's what the bell shapes are showing us on the log scale Okay, so now talking about fasting So this is a the total length of food fast It's a variable I found in in Haines this morning. So I'm assuming this is the right variable But I think it's the same variable that Matt used yesterday. So I think it's the same thing What you see here is that so this is for only children less than 19 years old There were some that didn't have fasting guys because we had 950 before we're down to 885 but you see two or three people have fasting levels up around 60 hours, which I Don't think we need to you know, but the rest of the plots. I just said 24 hours or less. I whether or not those are important So what you're looking at here is the Fasting hours on the horizontal axis the vertical axis is the same Estimated daily intake for each of the chemicals again in micrograms per kilogram per day The the line there is not a it's not a regression line. I fit. It's just a smooth the locally smooth line Okay, so it's going to curve with the data or not When we get into it more if we're interested in what the slope estimates are and things I can fit things with more Peace wise models, but I haven't done that yet So Dbp, I don't know if we consider maybe we could flip through them and then come back and decide which ones we think may be food based Okay, so this is dbp Di Bp Now we're starting to bend a little bit dhp dinp But maybe these last three are the ones that are more food based Where these are flatter and you help me understand the basis for the line And since it isn't the straight line there isn't a consideration of goodness of fit Right. This is what I've done. It's a it's a smooth line. So it's it's like locally Estimating what's going on and then sort of averaging locally and changing so goodness of fit. It's not a selected parametric model It I Guess if I change the degree of smoothing it would be more wiggly, but I think it it fits as best you can So so I guess the thing that we could think about in terms of goodness of fit is How smooth do you want it If you want it really wiggly we could fit that but that's I don't think I think this gives you an indication of how There may be some data sets that are so scattered that they don't warrant the line How would you where's the threshold for deciding that the data are smooth enough or? Collective enough that warrants drawing a line through it as opposed to scattered all over the place And you don't know what the line would look like I think I would consider something that looked pretty flat as being just scattered But there's no indication up or down. I would say this that looks like there's more systematic Effects now, that's not as that's not with a p-value, but that's But this was maybe a first indication. I can try to fit models that do this Where is it flat? Where does it start to bend and actually ask is that slope? Significant and what's the joint point? I mean so we can drill in a little more It was 800 and what was it 85? 885 so this is only children less than 19 years old with fasting values less than 24 hours They're all so be 883 or 882 or some but the data points are clustered around 12 hours give or take so There aren't that many data points at the low times right right looks like the Most of them are about I can't tell about 10 hours fasting is that what? Me the mean and medium or is 11 hours. Okay, so if you if you took that group out and just look at them with that changed things Right, which group out the the lower group biggest group So go back to the the histogram so the one that makes up about 70% of the Sample just take those and do your plots Take those values 70% on the lower side or in the upper side. I'm not sure where you're headed Yeah, I'm just that been in the histogram if you went back and you just took out You know the third. Yeah take out the In there you can't do that Are you say again breath? I think that's what Phil's asked That's right. He's can't say underneath these can't do what I'm asking you to do Sorry, I'm not I'm not understanding the motivation of what you're asking Yeah, the smooth the smooth here So DHP there's a little curve there I guess I mean we could we could have a criterion that we have to have some significance or not I know I don't know how formal you want to be about this We also don't know even if these are Significantly influenced by diet we still don't really know is it you know 90% diet and so on and or is it you know? 50% I mean it may be if it were diet you might see only diet You might see a steeper Is that steep? Well, what's steep? Yeah you know Matt Matt mentioned it yesterday, but Pharmacokinetic models might be a way jet not to interpret the data, but just to Do think through the process of if it's all from food Yet something that looks like that But you know is that enough to worry about and that now this is on the log scale, but that's still relatively flat that worth worrying about lack of a linear relationship or even a lot even a some kind of R squared or R to the one-half power relationship Hence to make me look at this is something that you know it's an interesting observation, but where does it take me? Right, so with some more time. I mean I could find some R squared values and things What is it what's the point yeah, was it due to help us do what we have to do and I really don't think it does much Gets at the question doesn't it whether or not you're going to correct for fasting, right? Yes, at this point in time. It's it tells me no, I don't think I Don't know would you would you draw that conclusion Chris? They know the expert yesterday. I've drawn a totally different conclusion. I think we should stick to what the expert said Where's the data to prove it in front of us? Relationship how would how would we analyze these data Chris to tell us whether or not we should And if you're gonna be if you want to base it on statistical significance I could try to fit models that are like piecewise models where there's a left-hand slope and a right-hand slope And I bet the left-hand slope is going to be a slope of zero I won't force that but I could let it estimate that then the question is is the right-hand slope is It's significant significantly different and if it's if it's do we want to be that formal if it's significant Then we would adjust if it's not significant. We'd leave it. I think that would Exactly, would you do the adjustment? I mean, I you know, I don't know one suggestion might be to use the predicted line and Based on the fasting hour just increased by that increment So people that fasted 18 hours would have a on this case would have a increase of 0.1 log But at 12 hours it'd be much smaller than that So you you would pick a time In normalize them or correct them all to a certain right, right? You're looking at data at the far end In a skill compared to the amount of data that you have for the other part. I you're You're drawing conclusions based on small amount of information. I Can't I can't I can't understand how you can do that all the minute data You have is dragged in the middle and then you have a few points out here Which are moving the slope down a little bit as I said without more data in the fasting hours farther out I don't see how you can draw a conclusion. Well, and if it's not significant, we wouldn't do anything I agree with that that that I think is a reasonable plan, but I'm still a little bit leery Because of the numbers. I think we should go with what Tom Burke said yesterday We know that and Haines data is collected after fasting We know that fasting will have an influence on metabolite levels in urine and Therefore on the daily intake calculation We know how hazy the data is in terms of how long is the fasting time and so on It was Rick and also Matt who proposed to Introduce some kind of factor to take account of this fasting issue Which in I have the same opinion as you it's not worth to get deeper into the problem Because I don't know what we would distill out of it So just as Tom Burke said no matter if it's an adjustment factor or a factor of uncertainty I would implement the factor because we have to take account of the fact that in Haines data is collected after fasting I would set this factor to be two or three We communicate this correctly. I think there's no problem Oh, how long in your experiments with the fasting And then they had a meal or were dosed or years or I'm not sure who else's From the time you ingest The phthalates how long where's the peak Urinary concentration 95% of the dose would be out after 12 hours and the peak would be around four hours So if you have a mean fasting time of 11 hours, we are in the area where most of the metabolites should have been excreted Even more than a factor of two and that's that's fairly common with a lot of chemicals You have done PAH experiments with fasting and I mean what what I'm asking is it maybe there is a peak there around Where you would predict it to be at four hours? It looks a little bit later here as as You said it's it's so little data to the left. I think there's nothing really to make out of it. I Think this is a third Proof that there's in some kind of influence of fasting There is some influence. We see some influence, but I would I would not try to Calculate it to the last digit. Yeah, I Could totally agree with that point There's a there's a lot of Additional variability that we know know about here because in Holger's experiment you can assume that the you know the intake Here everybody has a different intake So you take these 800 points and some people know if you back extrapolated, you know based on their fasting time some people took in a high amount medium low, you know very little and then you're collapsing all that data together and trying to come up with a Fasting line, but they're all starting at different points to begin with right a miss misclassification of exposure Other I guess the other Question I had a lot of these are morning Sessions, I think the data are dominated by morning sessions Speaker said yesterday for a lot of us the big meal comes at the end of the day And that may be your biggest exposure and That I don't know is if that's he might even be a bigger error, but worry about but Is it know as long as is there's a if there's a reasonable way to do this? It seems like a strength of the approach that we've been talking about yesterday and today is that we don't have to be We don't have to speculate on the significance of this You can run the models and look at the at the impact That you get from one line one curvature to the next So it seems like doing a sophisticated statistical determination of is this significant or not? Isn't that very helpful? Because it isn't what we're really focusing on you can run the models and we'll get the answer But you're saying go ahead and run in a statistical test to see if these are significant. Are you saying no no use these lines to determine what the size of the adjustment is and then run the models based on that adjustment or no adjustment and See what impact that adjustment makes and if it's trivial then we've lost nothing on the hazard index your time. Yes. Yes, sorry But it might be at the end of the day. We say we looked into it Ain't no difference. We're so then do we just not continue with it? I think We discussed it yesterday that and Haines is only one Fragment of the puzzle we'll have to get the data from the other studies Their fasting is no issue Russ, I think the Fasting is no issue with the pregnant women and the Well, the fasting time is unknown. Yeah, but they weren't asked to they weren't asked to fast But some of the samples may have been two hours after the last meal, but that's okay That's a steady-state exposure or a step shut off the population Yeah, but they were not particularly asked to fast right, so I think That will solve the problem anyway What several of you have asked that we we finalize is our list of Thalates thalate substitutes and Any anti-androgens that we feel ought to be plugged into your hazard index assessment so based on our Teleconference we all agreed that the permanently banned one should be included. So that's DHP DNBP and BPP and the interim ban DINP DIDP and DNOP and in terms of Other thalates and substitutes I think we need a little bit of discussion. So depending on exposure and toxicity profiles. So The IBP DPHP DEP and maybe DMP were mentioned. So let's let's make a decision on include any of those and if so why the the last four DID DIBP EPHP EEP DEP and DMP. I think Holger you made Several these as we might want to look at as I recall you want I think we have to include all of these in our considerations and Why it won't be that difficult because they are major thalates in use and In children's Children's material or child care article or at least cosmetics or body care products that might Cost-contact as long as you feel strongly that they're gonna cover the targets of opportunity. It's targets. We have to deal with I Have no injections. Yeah, I include those four Okay We'll step up there. I just want to make sure you're gonna type to me. Okay. So starting from the banned ones DEHP interim banned Other thalates DIBP or the substitutes are well, oh, excuse me the on the the second line The DP HP I guess DIBP is in the NHANES data is it in The I be that diisobutyl Okay, but but DP HP is not going to be in there we can do it as a scenario It is a C10th delayed. Yeah, so it'll certainly be detected When analyzing DI DP exposure, right? Hogger, do you mean it's included then in that measurement when it will be detected? It could overlap it's gonna Underline it because it's not specifically tabulated in the NHANES Thank you for the information. I have different information in terms of biomonitoring Okay for the the substitutes then we we had listed ATBC MP what am I gonna measure DMP? It may it may not be that we're gonna run these all through your Hazard index, okay, but there are things that we feel we have to address in the text Because as far as I know none of the substitutes are we're gonna find in NHANES either, but those are on our list ATBC DHA Didn't know DHA didn't show up in the articles that we tested so there's no we have no migration data Okay, so I mean let's put them up. Okay, then we'll we'll talk about whether we want to keep them on the list Okay, ditch HTSlash DOTP and TOTM Then the other one that we did find was Right, okay. I think we should include that So let's talk about whether we want to keep all these on the list or Eliminate some well We don't have to necessarily eliminate them, but we DHA and the TOTM weren't in the samples the toy samples that we tested so that makes it hard to do the scenario based Exposure assessment doesn't mean it's impossible but And And they're also they're not I think they're not in NHANES data I don't think DHA is in there so Which eliminates that approach? So I think we could Put them in parentheses and The thing about You know the scenarios is you can always if you get data you can always go back and put the data in It add a chemical later But we'll we can I think we have three different Reasons for having something on this list one is that we've got NHANES data and we're going to run it through the hazard index assessment To we don't have data, but There are other reasons why we should consider and say something about it in the text in other words if it's High-volume production and it's it's in everything, but we don't have any data then I think we can make Recommendations that we need more information on that and what was the third? Those are the two. I think major reasons why we want to have things on the list not that we're going to Deal with them each analytically, but we're going to address them in the in the report somewhere somehow Can I just say that the other limiting factor? In addition to presence are otherwise in the NHANES database the other limiting factor which will prevent Inclusion in the hazard index approach is Data data about the profile for example DEP According to Paul Foster and Earl Gray is not one of those satellites with the right chemical structure to Influence under an action in fetal life Thought of the third reason For the substitutes at least We want to be able to make the point. I think that if these are going to be substituted We need to know More about them to see whether we're putting something in that's worse than what we're taking out so yeah, and I mean we can Also treat DPHP as a potential substitute even though it's not in the products. I Think it it seems like a logical substitute because it's I think the use of it would overlap DIDP and DINP concerning other anti-androgen Can we briefly reflect in terms of the wording of the charge to what degree we need to do this? As you know, I'm not against it, but I Think we need I need a bit more clarity in terms of What what really needs to be done into what? Well, yeah, I mean I think it's they're beyond the scope of what we're doing I'm not opposed to Having some discussion of that Especially if there may be a significant public health Concern or if they Significantly contribute to the effects of the phthalates But they're not the our reason for being here and I guess my Main concern would be is first we should do what we're what we need to do and I one thing I would not want to do is say no don't include something that the chap thinks is important Doesn't it Add to the background effect so that if we're you know, if we if we know we have exposures to these other anti-androgens And that gets to the point that Tom was making about just because we don't measure it It's not zero. So at least if we had a subset that we could Sort of evaluate us and that's why I wouldn't say yeah, don't do it I think that's a good reason to do it in your model But do the I I also agree it's it will influence I mean the silver book has outlined various In the framework of a unified approach to those response analysis, they've outlined various Possibilities depending on background exposure to other chemicals, etc. Etc. So I think to the degree that matters We would have to consider exposure to other Anti-androgens button I would also think like Mike That it is probably not required to Push the analysis to a level Which we have to do with the lights and I think if you Think of it as a a core project And then you can always say and then if you add these other Compounds it increases the risk this much and I think Think Chris even showed that in some in some of your slides. So Yeah, definitely it doesn't have to be comprehensive, but it could be enough to say by the way more work on these other compounds needs to be done and Partly because there a lot as far as I can tell there they may not be in our Jurisdiction they may be in someone else's But in that regard Andres you may be able to help with this So I've been maybe limiting myself in the thinking about this approach and that we needed the data in in Haines but if we actually had external data for other anti-androgens that are in You know high levels that with high hazard values or low hat whatever, you know where they would be concerned We could actually add a hazard quotient to our Calculation just as a constant perhaps Right, so I mean it might be that we could think about the anti-androgens Based on not just what's in in Haines, but based on what are are there other anti-androgens? That we would be worried about if they were if they were considered in addition to the phthalates Yes, I agree. I think I in my opinion we would have to consider in which direction our analysis is influenced by consideration of other anti-androgens, but that's not to say we can Conduct an analysis to the level of detail that is possible and required for phthalates. I know already I mean it's simply not possible looking at the in Haines database there There's simply large chunks of chemicals missing which would be relevant or and often our information about the profile of In use pesticides is so fragmentary the data are just not there not even in vitro data So there are serious data gaps But it is that a Sort of livable compromise for you So sort of a discussion of what other anti-androgens are out there that we would be concerned about No in yeah, if possible. Yes, but rather in what direction our analysis will be moving if we Were able to consider anti-androgens to the full detail Yeah Well, the risk estimates go up down stay the same that sort of qualitative estimation but without Already we can acknowledge that the data will not be set there to to extensively Quantified the contribution of other anti-androgens I think I was looking at this little bit differently and not a question of what other anti-androgens are out there that we would be worried about I look at it as a theoretical question that if you had other products or other chemicals out there They've worked by the same mechanism of action in our anti-androgens Is there any possible enhancement of the effects of the phthalates as Opposed to trying to make a case that bin clauselin is in trouble because it's an anti-androgen I Don't think that's our intent. It's more of a theoretical question that any chemical We just happen to know a couple of them because of their biological activity But it doesn't mean that they represent a real hazard or that they Represent a serious concern that CPSC would be weighing in on see I actually have a slightly different approach They're thinking and that is that the way you describe that it makes me think that you're asking the question of interaction Is there a synergistic effect from these other chemicals with the phthalates? And I'm actually more more concerned about the additive effect. I mean, you know, the fact that there's so many chemicals The background is Yeah, a little bit of each one. That's why I use the word enhanced Which means that allows for a small additive increment or it could be potentiation any any form of synergy That would be greater than no effect One on the other. So I think if it allows us to answer a question. Is it possible to enhance the effect of phthalates by other materials To which people or infants might be exposed. I think that's a good question and the thinking it seems to me is similar to what we're going to be talking about in terms of food-based Phthalates as well I mean, we're saying we can't just look at the products in these toys in isolation because the phthalates are coming from a Lot of different sources. So we're not going to isolate them and just look at the toys We're going to look at it based in the universe of phthalates, but then there's a broader universe of Antiandrogens, which is also a background sort of right So that's why I would put this as a theoretical question because it doesn't matter if the other antiandrogen comes from dust or comes from some other route we're simply Asking regardless of the source of exposure regardless of which anti-androgen it is is there Should there be concern about potential enhancement of the effects of the phthalates? Yeah, I would agree with that. That was what forced us into Considering scientific evidence in the literature's experimental studies. If they're there we note them But not necessarily then Quantifying quantifying the additional contribution of anti-androgens other anti-androgens to Pactate effects of phthalates mixtures Do that we would need a really good data set So we would end up with statements like this is our best estimate for phthalate combinations However, we note that this estimate will move in this or that direction if we consider Exposure to other anti-androgens Do we know which direction But if I look back at a paper by Subjects I could if I look back at a paper by Courtney camp in Faust There are some nice table five and table six that actually shows the added hazard quotients based on each chemical and There are a lot of you know a half dozen or so here that are other than phthalates I mean it would be relatively simple to add That kind of a additional quotient to I'm not saying only do that but in the discussion of here we go, you know with a now And assuming that they're all affecting the same endpoint, which is testosterone production or which is what his activity Then it's going to enhance It's going to shift that curve to the right on your Octane plots It's also possible that Chemicals in combination would have more than one effect So there could be an effect on testosterone, but there could see it beat There could be some other effect of the interaction between the two chemicals that might neutralize that So there are a lot of ways chemicals can interact not just based on hormonal activity. Yeah, but do we have examples? Also theoretical you're saying the theoretical point is that you're assuming that these other anti angiogens are going to be Combined with more than one or two of the above to cause a shift in background When you're doing pesticides You're dealing with a specific segment of the population Whereas we should be dealing with the sphenyl a you're dealing more generally like you're dealing with with phthalates So one is to be careful in terms of deciding how to frame the question I think about these other anti angiogens and whether or not They are a significant burden beyond the burden of phthalates under the conditions that you would be Ascribing for the population that's part of the and Haynes or some of the other groups that we're going to be looking at I Think from what you've said and what Andrea's has said I think all we can do is to say that it Has the potential to enhance And and we have to leave it at that I mean you could make statements like Byrne would like to say that it could also Mitigate And I wouldn't suggest we'd get into that but for example if some substitute came into play for one of the phthalates But there were other phthalates remaining in these products that had anti-antidrogenic activity Now you're going to add one that structurally you don't think is going to be the same as a phthalate But it has anti-antidrogenic activity. I think manufacturers should consider that in the future When they select substitutes or additional chemicals in products so that They can look back and see how they they kind of Answered this question when they did their modeling and we need to be careful here So I see a value to the future not just about what's out there today Then we are in agreement that we're not going to list a specific or a specific and anti-androgen's correct We're going to address it in in a theoretical sense that we know they're They're out there They're potentially We could use those the court and camp and Faust and I don't know Andres how you chose those particular chemicals Was it based on any exposure issues or was it based on anti-antidrogen knowledge or what were the criteria to two criteria do we we We had to have information about exposures which Proves to be a bottleneck for a large number of chemicals and secondly We had to have information about in vivo anti-antidrogenic effects, which is another big bottleneck. Mm-hmm that Limited severely the number of chemicals we could look at. Okay. Yeah Bit to differing degrees of detail All right, so are we proposing then to include those on our list of anti-androgens? I'll leave it theoretical like we were discussing before Do you want to put the list in? When we put the list in do we do we sort of buy it? I think I see we're saying that you could use that information to modify your equations to take into account those Was I misunderstanding you? Yeah, no the way I'm suggesting is that we would have The approach that I've that we described so far that has the distribution of everybody's different However to say there is an effect that could be this background thing that kids are exposed to me We don't know the exposure. It's it's a hypothetical situation, but we have these hazard quotients from This paper that says these are anti-androgen anti-androgens chemicals with potential exposure So we could just add those quotients so it's just going to be like adding a sum We think it's a hazard index for this child of you know point six, but instead with this background It's additional point three and it moves it to the right and that add the same thing to everybody so it's it's it's just a And I think it's just to make the point that There are background things that we probably should think about to me It's murky because again, you don't know that you'll have a combination of all these other materials in with the phallides I Mean that that's that's the murkiness It's it's not the fact that you cannot develop scenarios that are hypothetical cases saying this is in Greece of the background But do you have some scientific basis from which to derive that development of that? Case or are you or are you doing what we used to do in? Superfund risk assessments, you know putting yourself out on a limb because these summations don't really exist under normal circumstances I clarify The the criterion has to be two-fold number one evidence of co-exposure to these chemicals. So That is that we know Although we can't quantify it in all situations and the second Criterion is sort of a biological a degree of biological Closability backed up by experimental evidence that these compounds can indeed act together and that is the case as well. So But at this stage really I think I think we are we're in agreement we can we note We should note the presence of these chemicals But at this stage, I would be reluctant to agree on a list because mainly well for two reasons number one, I don't really think that's required in terms of the charge and number two because the Situation in terms of our knowledge base is a little fluent and we're likely to see improvements of this in the future. So in order to allow flexibility, I would leave it as At that without agreeing on a list at this stage Go forward could I use the court and camp fast list? With the with the idea that it is murky it is adding something that may not be we don't it's not as clean as the other approach Where we know these are children with these levels, but to me it's back to the the traditional hazard index approach Where we we know nobody's at a point, you know at a median level of all chemicals or a 95th percentile of all chemicals it's just a It's a it's a point to make that there is additional hazards to things that aren't accounted for there And the list is not complete the list is thoughtfully chosen, but it makes the point and then that's it. I mean Okay They're in agreement on that sense. Thank you Just two questions. I have what is the reason for the brackets? Yeah It's because right now we don't have we did haven't seen products with DEHA so we don't have data Actually, we might have some older data but Totem, I don't think we we've seen so Because product wise it's not yeah, I mean product. We don't have migration data from the products Just for matter of completeness. I would include as a must all of the lates of endocrine activity and One of them would be DPP Well, that's the delayed squeezing in between diputal of the late and DHP which is of Known to be stronger endocrine activity than Dipentole Delayed and anything else that's active in that as antiandrogenic activity Further comments on our list. We're all happy with that Just to put something out there not that world would do anything with it, but apart from The biological activity of these chemicals at receptors etc. There's just like with Medications, there's medications that alter the metabolism of other medications and there can lead therefore lead to toxicity So it's not something we know a lot about But it may be something we may want to just mention that there could potentially be other chemicals that may Decrease or increase the metabolism of phthalates for instance glucuronidation and may therefore modify Their response, you know, not something we would do anything with in a Risk assessment, but I think just to be aware that A chem another chemical it may not be an anti-intrigio won't be an anti-intrigium, but it could lead to decreased metabolism of Phthalates by for instance inhibiting glucuronidation or one of the oxidative steps They're an example that I Don't know of Real specific examples we had published a paper telling Andrea's about it about five years ago where we looked at PCBs and phthalates And we looked at additive Interactions and our hypothesis were that the phthalate or that the PCBs were Affecting the glucuronidation of phthalates in there for Potentiating their half-life for instance that was an environmental health perspectives. We didn't look at mechanism You know, it was a human epi study, but we did see Basically greater than additive if Seaman quality But we use something called a relative excess risk index Which is basically looking at additive interaction rather than multiplicative You know, I can send that but I mean that's just why I think about it because You know even the chemical another chemical may not be an anti-androgen it may not have Really endocrine activity, but if it locks or slows down the metabolism of another chemical In the end what the cell what the biological system sees is a Potentially increased response inhibit the metabolism of this other medication you're on and you'll become toxic and You know and I think this is a very very important point to make because You know, it would be nice to just package this up in a really nice little box and say here's the phthalates And let's just do that but in reality There's so much uncertainty and so much concern about all of the chemicals that are out there I think to leave the sense that you know, here's what we can do in the workable thing that we're working on however Or to worry about I think that's something that we can raise in the section on uncertainty and variability Because clearly that accounts for some of that. I guess I have a fundamental question When's toxicology going to take the turn to look at these things and mixtures and do the type right kind of experiments to understand these problems because toxicology is a very difficult time dealing with Multichemical interactions even with the same biological endpoint in the same math study or mouse study So are we just preaching godmotherhood and apple pie or are we doing something that's going to be meaningful if somebody's going to pick up on? I mean clearly I understand totally that there are chemicals out there that exist in Combination in various environments The fact of the matter is is it for me to try to ascribe a risk? Always reverts back to the single chemical risk assessment with that additivity when we know there could be Synergism there can be antagonism there could be a titty there could be all kinds of the stuff So are we really going down a path where we feel that there's gonna be a realistic approach a realistic? Conclusion that people can take away and work it with beyond what we're going to do I mean is or is this a theoretical exercise? Paul one way To get some pressure is through the National Toxicology program Because we did studies on individual phthalates But there haven't I don't think there have been any new NTP studies on phthalates for some time CPSC could recommend through the NTP channels that there would be some mixtures studies done And I I think that would be legitimate As long as we don't leave those a theoretical argument I'll be fine, but knowing full well that there's an extremely Extremely difficult hill to climb to achieve these kinds of ends especially with chemicals that are Not from the same type of source like pesticides and Anthallites But Paul there's already experimental evidence about mixtures of such chemicals in the peer-reviewed literature That's number one number two As far as I know NTP are anyway actively considering To conduct various mixture experiments with precisely the chemicals we are We're interested in but it would help a lot if they got a little Additional nudge well either either that or if if there were you know something concrete one thing NTP is Interested in is not just straight tox tests, but anything like mechanistic type of experiment so Yeah, we can certainly do that Andreas, I mean you've done a great mouse study, right? Right, I'm sorry So you could conceivably redo that study with another exposure to something that you knew affected metabolism of phthalates I'd say and Then look at the results. Could you not? That's not so easy, but I mean it could be done. It's feasible, but funds would need to be provided. We have ongoing experiments, but it's There are concepts available to to address this so it's a little more than pie in the sky really oh Your point is my point that if we're going to do this It's got to be more than pie in the sky or a theoretical construct. It has to be defined reason why and the issue and in the issue has to be built upon the fact that These anti-antigens build upon each other and you have a weight of material in your body that is for multiple sources with multiple chemicals, but have similar endpoints and that Clearly in the future where if we're going to attack this in a holistic way we have to reconsider how we do these experiments and Because I've you know, I've heard this people have written about this for years I mean they've been major environmental health perspectives Reviews on the need to look at mixtures, but in the end On far short of where we want to go Well cannot take pleasure in sending you a couple of key papers than just you see for yourself Key papers are wonderful, and I'm very happy for them But the point is that the overall approach does not necessarily blend into that concept You have to see a change in philosophy to make that work It's not theoretical. It's realism We've got Andreas's paper. We've got Earl Gray's paper on mixtures So I mean I think there has been a change that's been reflected in in research and publication So I mean not everybody's jumping in and doing mixture studies, but at least that's now out there, and I think people are saying that that's What we need more of so I don't understand where you're coming from in terms of There isn't this shift in in toxicology thinking. I think there already has been a shift Okay So I think we've we've ended this with uncertainty. That's probably appropriate So what I'd like to do now is as you all know we have to prepare a report and So I think it's it's time now that we start in in a broad outline of Who is going to do what and so if you would permit me and Mike's gonna put it on the screen to? provide a very broad outline which we can then discuss In terms of how we're gonna do this so in terms of an introduction I Think that would be burn and and my responsibility to put that together and that would include such things as that the charge The the history of of phthalate discussions in terms of the other Chap and etc in addition I think that I Burn and I ought to summarize and and and perhaps Andreas can help us with this the the animal studies and why we're focusing on the reproductive toxicity as as the endpoint so that Again, if you put names so okay, so But and and mercus and the same for animal toxicity and I think that would then I mean not necessarily in the way We would would put this together, but in terms of Information that we need would lead into a Discussion of the Human phthalate syndrome And I would think that that would be I was distracting him Sure, you say that again. Yeah So the the next not next section, but the next piece of information that we need would be the human phthalate syndrome But you know all the background that it's available on that Because that's how we're going to relate this to to humans, and I think Russ you would be Yeah, I mean as we put more details on this related to the Primary animal endpoints or all of the human Well, I think I think you would start broad, but come down and then more details on what's relevant to the endpoints in the report Exactly, okay exactly. Yep How much can we actually use what's in the NRC report? Can we hold off on that until we go through this? So that would be Another big component is going to be what I've listed here is is biomonitoring in phthalates and and clearly I Think this is a section that that Holger can do in its sleep And it sort of leads up to another section that we're going to have which is the hazard index Assessment approach, but so Holger would Do that Another section that we have to address is Exposure scenarios and phthalates even though We're not going to Do that in detail in terms of our hazard index assessment. We need to Discuss that so exposure scenarios and phthalates, and I think Paul that's clearly a section that that you can write Well, but I'd like to have it done independently and then Submitted to the group. We'll put it together and then we'll look at it And then we can I mean it's not that that's going to be the final document then we'll Decide how we're going to actually put this all together and that I'm thinking I'm hoping that that can be the Part of the main discussion in March, but then the next I have down here as Risk assessment related to individual phthalates and then the cumulative risk assessment And that would be again using your your approach the hazard index approach and So this I would I would think perhaps has to be a collaborative Writing Chris Holger and Andreas and Burn and I were talking that there are a couple of other things that we came up with and I I'm not sure exactly who will will write it And I don't think that probably needs to be done before we meet in March But we'll need to have a section where we relate your data analysis to our charge And I think that may may be done by committee relating data to Charge and then we'll need to have a one or two sections on variability and uncertainty and I think Rather than assign someone to do that now, I think That will I think fall out of the sections one through through six And then we will come up with another list of what those are and we'll decide who's best to deal with those Maybe we add to point eight also the point adjustment Yes, we come up with so how does that? Look for a first approach number six following the hazard assessment is a tool yes to the risk assessment right Just like that would be a matter section just like the biomonitoring is a tool to the risk assessment and scenarios I Look at the risk assessment is the combination of all those different tools including So I think there should be a separate section for the hazard index. That's one of the crucial Components of the risk assessment rather than introducing it within the risk assessment you need To fundamentally lay it out show what the results are show the conclusion to gain from results just from that analysis Yeah, I mean I didn't want to dictate The individuals how to do this I would think They have to come up with how they're going to do this in other words some kind of introduction to risk assessment in general and then focusing down to their hazard index approach and what that tells us How they did it that's not all risk I Take you maybe I have the wrong I take your point Paul But I in my mind it would sit very well under number six so number six could be further Fine structured into you know there we have to take up what the preceding chapters have said about exposures We also have to take up what the preceding chapters have in mind number two and three say about effects the spectrum of toxicological effects, so Therefore I agree with you Paul hazard index should be explained But really essentially is part of risk assessment where you aggregate information about exposures and and hazards As long as there's a separate section somewhere where it explains what its role is I'm not going to argue about it, but I think for each section individuals that are Responsible have to develop an outline and and you know what what it is they're going to do But this is a crucial point that we made yesterday is a crucial point in our analysis and it has and it's not just a section it's really a Defining clearly of information and and the final documents got to reflect that and that's going to be you know Earned in my charge to to put that together in a way that that highlights that Just another question for clarification under number two summary of animal toxicity would that include a Summary of experimental evidence for mixture effects Yeah, yes, okay, then put my name down as well under number two And overlaying Overlying all of this is that this relates to phthalates and phthalates substitutes with some Search for impact of other anti androgens That's the other part of the focus. I mean, that's that's what's behind this whole outline They're appropriate every section should deal with those three categories What do you what do you mean by the individual? but Number six, so are we going to address each chemical by itself or do we focus? Didn't you do that in your analysis first? Or was it not sure really what you're looking for there for in another way there. I mean we could certainly show I Mean this morning. I showed distributions Demonstrating exposure effect of biomonitoring data demonstrating exposure Do we need to link each individual also to some hazard By itself even though we know that always a mixture when one of the eight factors says, you know the phthalates and so on individually and In combination with the others and I think For the individual ones One interpretation is that it's the interim band ones is where you we might want to do individually as well as Call them out individually. I mean, that's one way to interpret the language something something we discussed about Discussed at the last meaning probably both meetings But if you were gonna do an individual risk assessment, I mean it would be There on the interim band ones and maybe on the substitutes That largely what you guys gave us yesterday. Can we take things like what I really know what to I don't think they mean. Yeah, individually all 29 no just our list. Yeah, but even then as far as individually You know going back to the eight points of the charge, you know Does that mean the Just the three interim band ones because the Permanently band ones are gone. There's not really any need to do that But the interim band ones are the ones that issue and the substitutes I would look at this That we have to include enough information on The interim band and the substitutes to justify why we're including them in this analysis in the report And then we simply make a statement that we recognize there are dozens of other Palliates that for one reason or another didn't reach the threshold of needing to be included in this report That doesn't get back to the form of the analysis that Chris is worried about Do we do this a list? Do we do the hazard index for each chemical? Or do we do it in and list them individually or do we do them as a mix? Well, you know, I Then depending upon with their products, but it's also it's a matter of partly interpretation of the charge and I think that for let's see or certain ones like If you do call it individual ones, it would I would only do the three Interim band ones I Wouldn't do try attempt to do it for all of them and Probably also the the substitutes To the extent that That they aren't known to have this anti androgenic activity So you wouldn't do the cumulative risk assessment for them Well with the substitutes Wouldn't matter wouldn't deter wouldn't be also the point of determining what products they're going to be in right right If the products are not going to provide exposure scenarios that lead to children's Contact right what would that? Well, yeah, yes, but I mean go actually going back to I'm getting off track Chris's question is about four numbers applies to number six and Say individual and cumulative. Well, we definitely want to do cumulative Individually you might do dinp dnop in Didp maybe that's if I want you mean by do well Calculate the hazard indices the distribution of hazard indices and you know chemical by itself in a maybe But maybe it should be Can I intervene I think it's very clear from the charge that we have to do both we have to do Individual chemical risk assessment traditional approach, you know considering exposure considering reference doses then deciding What what is the ratio if we take that approach the other approaches? You know, there's a there's a variety of approaches possible We need to consult the silver book and they unread the book maybe Whatever and on the basis of and I would also agree with Mike that this should be done definitely for for the intermediate band thalates and If we can for for substitutes Yeah, and of course as far as we can for substitutes and I foresee great great great big data gaps there And then on the basis of this Also then bringing in the band we can then do a cumulative Risk assessment along the lines of what you've and Holger presented yesterday Yeah Is that actually better broken into two parts here's the individual parts and here's the combined parts I we're just saying we're gonna start writing logically and then we'll organize it when we see it all written down, right? The Just it requires I did an analysis of the charge yesterday we did this together and The from what I can see this charge definitely requires us to do hazard assessments for all these Nalites, that's very clear But we have to do risk assessments For each of the individuals is not so clear to me, but we can do it in in what we do For all these chemicals on our list We won't be able to do all of those steps for all of these chemicals Either be if they're not in the in Haines data. We can't do Modeling from the in Haines data But for the ones that aren't covered by in Haines, we can probably do some sort of scenarios So I'm assuming in this package we have the Issues discussed about anti-androgenicity for each of the chemicals either there's evidence or there's not evidence Or is it just not in and I suspect that in most cases there's no evidence one way or the other For those chemicals just get back to the whole point then I Mean we're focusing on anti-androgenicity for our overall approach if we don't have evidence of that from some of the chemicals Are there other things that we need to think about? In terms of the hazard of those chemicals, I would say in that We don't have to reinvent the wheel where we can go back to what the NRC have done Yeah, where it was considered that these Anti-androgenic effects are the critical ones and not other endpoints and and then yeah work from there We don't have to reinvent the wheel. I don't think so. Yeah, I think in our Section on the animal studies. We Can make it clear that these chemicals aren't known for their carcinogenicity in animals and Hepatotoxicity and other endpoints But as we reviewed the data that would allow us to make the judgment that we needed to in the charge From CPSC we focused on the anti-androgenic effect It goes across species and there is this part of the syndrome is recognized in humans and as a result the whole report is going to focus on that one endpoint of toxicity and I don't think we need to get into the carcinogenicity and all the other concerns about phthalates My point is I agree with you completely in terms of the phthalates. I'm thinking about the substitutes But the right endpoint for the sub do we need to address? I think for the substitutes That's a good point in and I think for the substitutes. It's generally going to be other endpoints And I think it's going to be a case-by-case thing where each chemical is going to have a You can calculate a a reference dose, but it's probably be on different endpoints and It most likely there won't be a need to do a cumulative risk assessment on the substitutes Have as your stat put together a document like this Reference to the the substitutes. Yeah, well, what there's a document Going back to the first meeting that Versar did on five of the substitutes We're working on TXIB That'll be done soon And then we also have the six of Phthalates covered by the CPSIA So those are are well-covered Some of the ones diisobutyl DPHP are Coming in dipental Are coming they're not Covered in this report here, but they are on their way as well But in terms of this Getting started we will do what we can with what we have and then as we get more information We'll plug that in Yeah, but I think you're right. I think that the substitutes are going to be a Handled more individually and in More of a separate compartment of the whole in fact I'm wondering if we should even have a separate section on the substitutes We would certainly Include that in in the animal studies that yeah, whatever we could find what's there In terms of biomonitoring Would include that so I I think that would be included in Different sections it could be But the other sections are going to focus on anti androgenicity and they won't In the stand out from that number six is going to be by definition Going to be different for the substitutes Than it is for the phthalates and we may yeah We may find when we put these different sections together That it makes sense to break the substitutes out Treat them separately We can do that, but we'll have the information from the individual sections that we can put together Mike we're in this report. Do we acknowledge that we? Listened to a number of invited outside experts and what it's not what they told us But what why we've invited them. What did we expect to hear from them? I I think the Good place to do that is the in the introduction Mainly but then throughout all the sections In and up to and including the discussion and conclusions we could certainly refer to What we learned from those speakers for example in your Case to situation where you got the Points of departure from Earl Gray that would be a place where you would insert that Okay, so any Additions to this outline we missed so if we get Data from somebody else from pregnant women and children infants, right? Would that actually be discussed in section three and in section six I Would think so section four I can hold with that shift May also be in three Would probably be discussed in three as part of the health effects in those studies. I Assumed that the problem formulation step will be part of the introduction I Guess we need a problem formulation Section somewhere subsection in that context would it be Appropriate and maybe helpful to recognize that we're following the gray book Silver book and including that problem that problem formulation aspect, but we're preserving the red book approach As was recommended in the I think we can acknowledge that it's probably it makes our report timely I would envision the history piece of the introduction being History of the regulatory handling not a history of phthalates I mean that there are books written on that That's certainly something I would help with those that's build them Mike I think we're getting down to the et cetera is now and yeah, this is I would raise one that is in that category, but most reports Now make some kind of a statement about conflicts of interest of the authors Well, they're whether well, you know, well, I think we could include Something about the chap selection process and which would cover that any other comments not hearing any I Would like to propose that We Individuals have a draft document Prepare that we could begin to look at at the March meeting. Is that reasonable and that we would cancel the January meeting Unless there's some reason that we need to meet I Think it's unlikely that we're gonna have enough time to to write anything substantial between now and January 18th given the holidays so then then the next meeting would would be primarily focused on Two things hopefully by that time you will have been able to do some more scenarios with the data that you Provided with and we will talk about what we've written March 30th and 31st Yes, so is there any time I know you guys haven't spoken to whoever you're gonna speak to about additional data But is it reasonable to expect that could be We're timely than not Well, we we we can we can ask them and it's I Guess up to them if they have a lot of questions or if they just say oh sure. I'll email it And I think Russ is gonna give me a name a list of names to contact and I'll also If you happen to know the key studies I Mean I have them, but if you have method to be your yeah I can I can mention a few now. I was actually thinking probably the one you could get the quickest Would be from Shauna Swann's study You know Rick who was here yesterday as part of that and Shauna was here and is Very involved. I think she probably has data maybe on I'm guessing three or four hundred pregnant women And I would think given the criteria that we need she could probably share that relatively quickly And the other would be the group at Columbia University Robin Wyatt who I know WHYATT But I think Ricky Pereira is probably the PI on that and then at Mount Sinai School of Medicine Mary Wolfe WOL WOL FF in terms of children though or Infants with a zero to three-year age group I'm not as familiar with Datasets well, do any of those studies include the infants to small children. They're all taken during pregnancy maternal and I Don't think any have really collected Urans at least within that 3d 3 0 to 3 year age window They may have when the child was 6 or 8, but that wouldn't be as helpful I'll Look through the literature and see what there is other than blunt Or since if there's anything since Brock or Brock John Brock That was an old paper like the bulletin of yeah, remember the chair. Well, it was I Mean they only measured the mono Wester's yeah, but wasn't there hog our paper a kindergartner's from Germany? or daycare centers Only 35 But it's the one with the long name beginning with us Oh Set the anorama. Yeah, which I think yeah, was she with We'll do a thorough scan. Yeah, I'll do that right away I think Shana Swann's group is is where you could get some of this data relatively quickly I'd be happy to you know, Mike if when you email her you want to CC me or bring me Yeah, whatever you prefer, I'll probably Well, the other thing is to you know exactly what parameters we need so I'll run it by you and Holger at least in Chris before I sent something off The only thing when I mean I agree that January meeting should should be canceled I'm just wondering if if needed we should reserve an hour block for a phone call During that time if we need it if we don't need it just yeah, it's it's not a bad idea Just do a stash questions that arises people start getting into this The status of the data would be where we are well all of these things burn brought up the point that on March 30th and 31st were meeting on a Wednesday and a Thursday We typically you know stop at noon or or two on the second day So people can make their flights is that going to provide us enough time since hopefully we will have a lot of documents to go through Plus any data analysis that Chris has done. Do we want to? Think about the idea of expanding the meeting on either side Starting on a Tuesday rather than a Wednesday or going to Friday And well when we chose the date, I think There was at least one person Who couldn't make the day before or the day after so? We won't have any outside presentations either. I mean we'll much probably not eight to five or whatever Day if we're going to keep it on the 30th and 31st Is there a way that we could start at 8 o'clock on the morning of the 31st of the 30th? Get a full day in on Wednesday And at least a half day on on Thursday because if we start 10 11 o'clock on Monday Or on the first day and we quit by one o'clock on the second day. We're really only talking one day. I Have no problem Extending either way But let me check the calendars Let me find them Might force me into having to travel back on April fools day okay for Column C is Russ Said he couldn't make it on Couldn't make it on the 29th in burn Said he he could if he had to okay. Yeah, and I Yeah, I come in I could come in the the night of the 29th too so that I'm Here at 8 and not to you know 9 whatever Is but we're gonna start at 8 o'clock. Is that correct? Yes For me, that's the only way to get back to the west coast Without spending another night Is there anything else we talk about before Would would we plan to share this with each other like two weeks before three or a week or yeah Dides of March we'll share Will be done by April fools day Well our last our first meeting was on tax day taxes from I I think that was a sticking point um In in the paperwork somehow I think to get Something to do with reimbursing them You need a social security number I'll I'll send her an email. Um, let's see In in the meantime one one question before we move on is that is there a member of your staff that I can talk to about the products that we have to consider for the kids for the substitutes and the partially man well we can You and I can talk. I need to have talk to somebody on staff. Yeah, and then And then get the get the information so that I can use that as the basis for these scenarios. Yeah, I mean That's all I'll really need. Yeah, and if If I can't answer all your questions I'll get to the people who did the the actual studies the lab people or the The statistician reports that you have that I can yeah, well, I'll start by sending all of Sending all of that. That's fine. Okay And then if you have any more questions we can follow up Sooner you get it to me the better. Yeah, you've got Should if you have the cds from the first meeting I'll send it send it. It's so much easier. Yeah For me trying to find cds. Yeah, okay. That'll work any other items for discussion Mike are you Um, I think you're good. I I think I'm good. Thank you very much. Okay Well, very good. We're earlier than we uh, we thought so we're adjourned. We're adjourned