 Okay, what I'd like to try to accomplish in the last hour that we have before we break for dinner is I think Chris would really like more information about what we would like her to do with the model she's developed. We talked about getting data for exposure in young children and that will be provided to her, data relevant to exposures in pregnant women. What other issues would members of the CHAP like her to explore? I think we kind of agreed that the points of departure and the reference doses that are in those two scenarios is sufficient. We don't, at this point, need to use other values. What else would we like her to do? Besides the data you showed for children's tethers and stuff like that, is there any other data you've collected on things like children's shampoos and things of that sort? Yeah, we didn't look at cosmetics because they're not in our jurisdiction. Okay. Well, they weren't covered and they aren't covered by the rule, but we did look at childcare articles and trying to think what does this include things like cups? I need to bring up the list. Well, whenever you select a few, not a laundry list and add it to the ones that you have, you're going to be giving us the data for already and I think that can be used effectively to help give the, you might say, the ground truth to some of the values that we see in data. Okay, okay. And I think Holger and I also, and just to let everybody know, we ended our debate pretty quickly. We decided we were going to ignore all the human data and just go with the model data because there's uncertainties also in all the biological data and the moment you start looking to define uncertainties with greater and greater detail in one set of data you got to do in the other and I think we'll just loss, we'll get, we'll do exactly what Phil didn't want us to do, get lost in the weeds because the uncertainties will just overlap. We're going to, we're going to leave it just with the model data. Sort of playing on that, do we want Chris to do things like what if 75% of the exposure is dietary? If so, what specific, what ifs would we like her to, to explore? And so that percent, those percentages are some I need to give me reasonable values for which chemicals and what, what percentages. So we need to, we need to get some specifics here so we can make assignments either to, to Mike and the staff or to members of the panel that will actually come up with the information that we need. So if we, since we can calculate at least estimates of daily intake in micrograms per kilogram per day units, since Mike can give us values at least for some of these toys, at least on average or whatever kind of distribution, then if we also on the other end have percentage of some of the chemicals that are, that we think at least on average might come from food. And we're kind of wiggling our way down to figure out, are those values, are they going to overlap or are they sort of telling the same story? I mean, so it's somewhat. It brings us closer to closure on it. And I think that was what I was trying to achieve and I think that's what Bernard wanted us to achieve this morning so that we knew we're in the same bull park for both down up from bottom up and up down. That works because then we can have scenarios where how many times a child drank out of a cup per day and what the migration rate is based upon things of that, that sort, and you can have it over a course of a year. Those kinds of items will help you determine how much of the urinary component for different chemicals. And I think we have to select three or four or five. I think that was one of the things that was being suggested to see where we sit on the scale. So at least we know, you know, still probably 90% or 80% diet. But I think let the data from the exposure scenarios drive that final decision. And I think that would be reasonable. I think we have to select the agents we want to look at. And I defer to toxicologists to give me a little bit of guidance on which ones you think are the lowest hanging fruit or the most important hanging fruit. If we can put that off just temporarily, that's one of the things I'd like to get back to. But in terms of helping Chris with a list, Chris, in terms of where the exposures are coming from and how much is coming from different exposures, maybe we can just leave that as something we would like you to do. When you start thinking about this, when you go back home, you're probably going to come up with questions on how am I going to do this and what information you'll need, then you could get back to Mike and or members of the committee and get help with that. Well, also, I think me and Holger will be able to help you out in terms of, once Mike gives you some data, we can then help you expect to how to use that data appropriately to make a scenario. So I'll be involved with that with you. And perhaps maybe we should get into what Paul was talking about in terms of what agents are we going to be focusing on, because one of the things I think we might like you to do is what other anti-androgens might we want to look at using your scenario and maybe different combinations of phthalates and other anti-androgens based on some logic that I'm not aware of, but that sort of thing. So I think maybe we need to talk right now about what phthalates, what phthalate substitutes and what other anti-androgens are we interested in plugging into this hazard index analysis. The requirement would be that there'd have to be metabolites or exposure levels and or concentration levels in children and in teens. So I mean, as long as that was the case, they could be added. Or whether there were other databases that had that information. I mean, I don't really know, Russ, what other... Are you saying, and Haynes, because that's where you think they would be found, or you would want it to come from the same database as the phthalates? I think it's difficult to get raw data from people who feel like they have ownership of their data, even if it's nationally funded. I mean, I know we're going to request data from people, whether or not they'd let us actually use it in the way we want to. So I know I can get to Haynes in a timely way. I don't know that I can actually get into somebody else's data. I hope so. I don't want to be a naysayer, but it's more difficult than this potential that people won't agree to it. So we know we have access to Haynes is the reason I'm saying. What about the stuff from Columbia? I mean, it's going to be hard to get. Well, we haven't asked yet. I mean, Columbia would be a fairly... I don't think so. Robin Wyatt and Perera. Pardon me? Robin Wyatt and Ricky Perera. I would think that Robin would want to... Yeah, if it's released anonymously, just with maybe the phthalate levels and a few covariates. So maybe you might want to ask them, because they've got a really good database. That's six, seven hundred pregnant women, I think. Does Mary Wolf also have a set of data? Yes, yeah. Oh, I think from Mount Sinai, Mary Wolf might be another person to... Bruce Lamphere, who's... Bruce, yes. Who's in Vancouver. He's in Cincinnati, but it's in Vancouver now. He has phthalates in his data set. So those are three good... This is related to pregnant women, so yeah. So let's get back to the list of phthalates and anti-androgens. Are there any out there that either there is... We know of compelling databases where we could extract the information and use it, or some other reason why we should look to see if there are data. If we look at the data from individuals, I think there is no better data set than in Haynes. And I don't think that with the pregnant women and newborns, we have any other data than phthalate data. Do we have... Did they analyze any anti-androgens or any other chemicals, maybe except BPA? I don't think that... Some of the pesticides, the non-persistent. Some of the pesticides, yeah. So we have to be aware that as soon as we leave the secure and Haynes track, we are getting on tricky surface, or let's say not so robust or... But that shouldn't preclude us from venturing out into the forest and see what we can find. If we can trap some good data, well then we should use it. Question then becomes how do we do that? How do we step out into the forest or into the forest to see what's there? Is that something... Well, and to ask if we can use it... Can we publish it? Can we... What are the parameters around using somebody else's data? Mike, do you have criteria that you can... A letter to or a discussion with an investigator saying you'd like this data and this is what we'd like to use it for? I mean, we'll do that. I mean, I don't have any... No process, but we'll ask... We'll explain what the data are for, how they will be used. You know, exactly what information we need. Now, if I remember under the Shelby Act, anything that's funded with federal dollars has been published in the scientific literature they have to hand over. Good. They don't. They have this, I think they do. If it's been published in a scientific article, not if it's something that's in draft, but it's actually been signed and it's being used in the process for discussion of a federal regulation. And if they decide they want to be participant, then the raw data can be ours. I remember because that's what happened with the Harvard...the whole Harvard scenario in the late 1990s and that's what ended up requiring the Shelby Act. Because it's all federal dollars, it's tax dollars. So, you know, I think they'll be more than happy to participate, but this is kind of important for us to have more data than we have now. Going back to Phil's question about other anti-androgens and then hands. I mean, I'm trying to remember what else is there. I don't think they measure Vinclozolin or I don't recall. If the panel is all right, I might volunteer myself to join forces with Chris and Volga to look at these other anti-androgens. I think there might be a few polyborominate flame retardants and compounds like this, but well, we have to go through the NHANES database. I would suggest that's the first port of call and then see whether the other databases that are informative in that respect. Perhaps something might come up at the meeting that's going to occur early next week at the EPA meeting. Do you know what the real agenda is? Because I'm going for the first day. I haven't seen an agenda yet. Neither have I. I was just wondering if you had an insight. No, but I'm supposed to talk with them before the meeting, like the day before I think so. Or next week sometime prior to the meeting. So I'll see if they have anything. I'm actually presenting on the second day. Okay, but so at least we'll be covered both days. I'm curious if you can have reasonable discussions with the EPA if there's some way of them perusing their databases to see if there's anything to help augment what we're doing. I think you should broach that subject. I will, but I figured since Mike's going to talk to him first. Yeah, well I mean what you're thinking in terms of pesticides or okay. Pesticides primarily. That might be a big can of worms or something. Sure. Pardon me? In terms of what? The concentrations in urine and all that material? There are. There are a lot of data on. In fact, if you look at it, because of the passage of the Food Quality Protection Act in 1990s, the EPA has done an incredibly good job in terms of characterizing multi exposure and the partitioning of the urine levels of the various pesticides based upon food, dust and other things. So they have a wealth of information in that regard. It's a matter of what portion of it would be useful for us that we should be thinking about, but they've done a very good job. Yeah, I mean is it proprietary? No, these are all published. Okay. In fact, they published a gigantic summer report I think a couple of years ago. Okay, well definitely. Sheldon is the lead. She's their lead person in neural who headed the pesticide research program down there. Yeah. A valuable resource at least to find out if they've got data that would be useful to us. So, but are we limiting ourselves to anti-androgen chemicals with the reference doses that are published that are measured where metabolites are measured in inhanes? I mean, unless we go to another data set, but the data set that we have now. I will certainly explore in Haines, but I think Paul is saying that there may be some database information at EPA as well on pesticides. As far as I can see there are no pesticide metabolites or urinary levels of blood levels in inhanes. But what we need is information about exposure to pesticides from any other source and what Paul said with EPA may indeed be very helpful. I just want to point out the complexity of the task, like with Winklosolin. Winklosolin is metabolized to an aromatic amine and aromatic amines are not measured in inhanes. And it's broken down to an aromatic amine that can be metabolized if other substances too, so it's, it's, yeah. But that we can put in the text as to why we're not going to consider it. Right. So what we need to do is to find out what is available for what pesticides and we'll use the data we can and for what we can't, we will say why we can't. And if there's something in there that's really important for the future, we can say that in any reconsideration in the future that people should be considered, should be beginning to plan on how to fill these data gaps. For example, measuring the amine. Right. That's a recommendation we can make. So are we, are we saying this as a way of correcting for any, any approach that we use for the data that we've got? Or because of the requirement for the data, for the approach that we're, that we're talking about is the same levels, you know, one year in value, all these values coming out of it. If we, if we go to EPA data, I mean, we could say there are additional risks due to blah, blah, blah. It's, unless it's. Before we, before we go any further down that road, can I make another plea for perhaps going through the charge and then so I think at this stage we really need an impression what the good work Chris and Holger has have done really helps us in addressing that. Yes, that's what I wanted to get to. But I do think that we do have to consider before we leave tomorrow, what are the agents honing on? Because there's a laundry list that we had the first meeting that took my breath away. And I think, I think all of you were clear in saying that we have to focus more, more specifically on the ones that we think are critical. Okay, so Mike has put up the relevant information. And so I'd like to go to point number one under the second half of that slide. So we are to complete an examination of the full range of phthalates that are used in products for children, including one, all the potential health effects, including endocrine disrupting effects of the full range of phthalates. So to my mind, most of that is going to be done in writing. And then Mike's I think already put together some information that summarizes all the potential health effects. We're going to ultimately focus on male reproductive effects and we'll give our rationale for why we're going to do that. So I think we can handle point number one fairly easily. Any comments? And number two, consider the potential health effects of each of these phthalates both in isolation and in combination with other phthalates. And I think that's the beauty of what you have done that allows us to do that in spades. I mean, make any kind of combinations we want. But that I think does come to the point of what are the phthalates that we're going to consider and other substitutes, other antihandrogens. And I require a little point of clarification here. All of the potential health effects, we need to be clear what this means or how this should be read. There's one, I mean, when I first read this I thought potential health effects, there's an emphasis on hazard assessment. The text in the law is not very clear about this. They say scope of the risk assessment without. But if we apply the terminology or the framework in the red or unread book and now the silver book, we have to distinguish between exposure assessment, hazard assessment and risk assessment. Now, I'd like us to be clear about this point number one. Does this, for example, require an aggregation of information about exposures with information about hazards to come to any risk characterization risk assessment? In my mind, actually, it doesn't because it says all of the potential health effects, the emphasis on potential. So I think we are required to look at the range of adverse effects that are likely to arise from exposure to phthalates but independent of specific exposure levels. Or am I reading this wrongly? I mean, that's how I would interpret that. We would do essentially a laundry list. I agree. To me, that's a selection based upon hazard and how we then partition it depends upon the exposures and other issues. For clarity though, the wording in the statute doesn't say scope of the risk assessment. It describes it as an exam, the CHAPS examination is supposed to cover all these things. So this is my summary. So you can cross out risk assessment and put in examination. Point two is where we then go from our laundry list down to male reproductive developmental effects or what we're going to use as our end points in the hazard index assessment. Everybody agree with that, I assume? We talked about that in the conference call. Then getting to point three, examine the likely levels of children's, pregnant women's and others' exposures to phthalates based on a reasonable estimation of normal and foreseeable use and abuse of such products. What does that mean? I think the same thing that the laundry list means for the hazards. We have to define them, our list, and then we focus on what's most important, which we base someone on the data we'll be getting as examples of what we have to consider noting that the background will be dominated by diet. The point is to lay that out very specifically, that the dietary issue is a confounder, and what we're going to try to do is lay out the scenarios that are most important in terms of children's exposures based upon the relevance of the background for each one of those chemicals we select. But essentially that point is that's exposure assessment. Yes. Exposure assessment. Yes. Point number three. Is that one of the work that we do for estimating daily intake? I imagine showing the distribution of the daily intake for each of the chemicals. Yeah, of course, that's part of it. That's just totally part of it. The biomarkers are not divorced from exposure assessment. They are a component of it. And what you're doing is basically probably the most firmly based science that we have in this whole process. So clearly that is a significant contributor to that, to number three. Just to be clear, so the second part of number three is referring to use of such products, right? So really making conclusions based on toys and children's articles or, yeah. Thanks for that. Well, yeah. I mean, I assume that means products for children. Well, pregnant women, so it's just meeting cosmetics, I would think. Oh, okay, okay. Yeah, well, exactly. Completed examination of the full range of phthalates used in products for children. I would think we want limited to children. Yeah. You don't have regulations over cosmetics. Well, we don't have. Yeah, right. We don't have authority over cosmetics. Right. Or food. But food will be used as a baseline, the background. Yeah. Because children and pregnant women eat old food. So, but when we're talking about the actual children's products, I think we're talking about plastic toys. We're talking about plastic utensils, things that they use daily or periodically. And presumably, or things in our jurisdiction. Right. Well, of course. Yeah. You have to lay that out for us, too. Yeah. Then that doesn't make sense because examine the likely levels. Pregnant women's exposure to phthalates in toys. They're not going to be exposed through toys. Not a whole lot. Back to almost nothing. I mean, that makes that. It's an incongruous statement. Yes. Absolutely. It's totally incongruous. There should be two totally separate statements. One about children and toys and products. And then there should be one about pregnant women or women of childbearing age and their products. That's an incongruous statement right there. Plus the abuse of such products. Yes. So we have close to circle. So it's all products. And again, I think we're going to talk about this in a laundry list way. And then what data we have with pregnant women that might inform us we'll use. But that's all we'll have. I mean, is it possible to separate statement three into one that relates to kids and one relates to pregnant women or women of childbearing age? So it is not an incongruous statement. I think it's within the CHAPS purview to make that distinction. Let's do it. Yeah. Otherwise it is nonsensical. We want to try to simulate a scenario that could be representative of exposure levels or at least concentration estimates for daily intake for children less than six years old. So if we're going to. So if we if we so we've got in Haines, we may be able to get other data, but we have in Haines that goes from six to 18. And we can use Mike is going to give you data that would be from zero to 36 months. Well, we're going to try to get by a month. We're going to ask for biomonitoring data from the study authors. What I'm going to what I have is is data that could be used to estimate those exposures. Toys toys and children's things. I think I'm just trying to say that, you know, if we don't get data, at least in a timely fashion or whatever, I mean, I'm just. Gonna have to use you have to use whatever you have from in Haines as your baseline and based upon exposure scenarios that can be constructed. Or the kind of products that can be used from zero to six. Again, you'll get a fairly good idea of what the intake would be. On those products. So therefore, even if it's four or six to 18. You not do not necessarily think that it's going to be there's going to be an overwhelming disconnect there. Unless you find it in the products that they have for children, very young children, the numbers come up real high. And you say that the in Haines data are not applicable, but the levels here are much higher than we find in Haines from six to 18. So therefore it is an issue. The worst that it can be is at least a rough point at which to assess the exposure or intake that we're going to estimate for very young children. So my question is, do we want to try to simulate it based on, I mean, Holger and I did a simple case where we just said DEHP is 50% higher. Do we want to try to improve on that with additional chemicals? Toys that have different kinds of other than the, I mean, I don't even know if DEHP is the right chemical that these toys are made from. But can we make that simulation a little bit more based on real options over? I'm not sure what assumption you make. So maybe you can give me a little bit of clarity there so I can say yes, no, or maybe I think the most important. Approaches to get the urinary data for these children. So that will kick out most of the assumption part and then we'll have to modify the calculation formula. Okay. The more the better. Yeah. Okay. We could also down extrapolate from the enhance data, but I would prefer to base the calculations on on actual data from these studies. I think four kind of answers some of the discussion we were having relative to three because it says, consider the cumulative effect of total exposure to thallies both from children's products and from other sources such as personal care. So I think if we break out the two groups that kind of takes care of that. Yeah. I mean the pregnant or child, a child bearing women versus the children will have a natural segue to personal care products. Yes. And five review all relevant data, including the most recent best available peer reviewed scientific studies of these thallies and thallied alternatives that employ objective data collection practices or employ other objective methods. And we will. Yes. Take a deep breath, right? Six, consider the health effects of thallies not only from ingestion, but also as a result of dermal hand to mouth or other exposure. And I think to the extent that we can do that, we're already talked about that a lot today. I don't see where this is anything different than what? Anything different than number one. Number one, why would we expect the health effects to be modified based on whether you get the material by dermal hand to mouth or inhalation? Unless it's cytotoxic or something. I'm just not sure what that means there. Well, it probably means that for some chemicals, the toxic effect you can expect depend on route of exposure or route of administration. And I think we are asked here to consider that whether that matters. And if we find it doesn't matter, we just say so. Because I think we're focusing on male reproductive, right? Yes. Focus. Would you anticipate this to be driven by route of entry into the body by deposition? There are issues concerning allergies and let's say, what do you say? That our primary focus, right? No, it isn't. It isn't, so I think we can... I think it could also, number six could also mean that when we do the scenarios, don't just do mouthing but include dermal contact and so on. Fine. If we can't. I think that's what they meant, but I don't know. That's the way we interpret it. And all the biomonitoring data do that. They take into account by definition. Sources and routes. Okay. And seven, consider the level at which there is a reasonable certainty of no harm to children, pregnant women or other susceptible individuals and their offspring. And is that something that can be readily done with your hazard index assessment approach? Again, this is six and seven are, again, typical hazard assessment subjects. While they go, they determine the, which was it, the denominator of the hazard quotient. But you don't need any exposure information to address these points. Right. I mean, I think a level of no harm is something like a reference dose, which you calculated and I think that's what they're getting at. The reference dose and then the amount of risk is based upon the amount of exposure. For someone who doesn't do this sort of thing. So how do, how do we accomplish that? We take information from the literature and make statements about whether there's no harm at a certain level. Is that what you're saying? Those values have been published. I mean, the Andreas has published the one set. We have other estimates of them from Earl Gray. Right. So those are our cases, right? That needs to be critically examined to the best scientific standard. Is any of the EPA or are these associated with that too? I think the EPA ones are out of date. That's what the meeting next week is about. Right. Updating those. But I think, you know, Would they have some relevance to seven? I think the, I'm just asking them. I'm wondering how far apart we are. I'm just inquiring. I think the published levels are old and they're updating them. Okay. But I think, you know, you have reference doses. You can calculate your own if you want to. It's up to, you can call them TDIs or something else if you want to. There are some of these data in the Irish, Iris database. Sorry, slip of the tongue. Nothing to do with Ireland. Iris. But the criticism of the NRC panel was that a lot of these data are not suitable for examining, say, effects related to antiretronicity, et cetera, et cetera. So that needs to be looked at, oh, that's EPA's job, but we have to go back to the literature. No, because I was looking at this also. So is this the latest view of the 17? Yeah. So is that part of seven? And for part of the defining, having to the criteria. Well, that was inside. That's a review of the toxicity data that could contribute to seven. To start to come up with a number for seven. Yeah. But we don't necessarily have to come up with the, I don't think we don't necessarily have to come up with a number for all 17 or all 29 or whatever. Back for some of those, the data are from sparse to practically nonexistent. Will that be part of our selection process for the way to use as the chemicals that should be focused on? I mean, the staff came up with a list of phthalates and prioritized them. And those 17 are the bottom two tiers. Perhaps one of the assignments that we should take back to the room tonight is to look through this document so that tomorrow we can go through and say, okay, this is what's out there. Which of these are we going to put into your assessment? Well, I mean, Chris and Holger can only, in terms of their assessment, are limited to what's measured in NPAs. That's true. Now, for the other, the ground up, the limitation isn't there. But on the other hand, if you need to know what products there, I don't think those are high priority ones. I think it's a question of toxicity, usage, and exposure. So if we take, for example, dipental phthalates, it's one of the strongest phthalates that even the industry is not using it. So we might have to talk about it in terms of toxicity, but exposure-wise it's not an issue. So actually one of the strongest phthalates is not hit by the ban. You need to say that. Yeah. Okay, then the final one is consider possible similar health effects of phthalate alternatives used in children's toys and childcare articles. I'm not sure why other products fall out here, but does the... We're not used in the same way. Well, I think it's because the ban, the prohibition applies to toys and childcare articles, and these are the substitutes, because one of the questions, obviously, if you take out the phthalates, what do you put in their place? This is simply to see whether these... to look at the substitutes. And they're saying, in particular, similar health effects. I think for our purposes that means anti-androgenicity. But then that says that if these are anti-androgens that are drugs or pesticides, but they're not used in children's toys and childcare articles, then we don't need to include them. We wouldn't reach out to those groups to reach defined other anti-androgens unless they're phthalates or phthalate substitutes. Yeah. Well, I think eight is specifically to what's going into the toys to replace the phthalates that were removed. I mean, the other anti-androgens that we've discussed is separate. Other comments, Mike, do you have anything else to accomplish? I think we've accomplished a lot today. And I guess I would just... on the subject of the other anti-androgens, our focus is the phthalates and the substitutes. And certainly, we can't ignore that or shouldn't ignore it, those other things, but they're not our primary purpose. Well, that's what we said. Right. So hearing no further discussion, we'll adjourn for today and reconvene tomorrow at 8 a.m. Thank you all. Thank you.