 Good morning everybody, we have our chairman here this morning who would like to welcome us all to the beginning of this convening of this important CHAP. I think Mike has just left the area, but he'll be back in a moment, but please let me introduce the chairman of the CPSC, Inez Tenenbaum. Good morning chairman. Well welcome everyone, this is very exciting time for us here at the CPSC. We have not convened a CHAP in many years, so we are just delighted that all of you have agreed to serve on this very important committee and we just want you to know how much we appreciate the time and effort that we'll take to devote the serious science to this issue. The work you're undertaking is extremely important to this agency and to Congress, you in the CPSIA, which is how we refer to the Consumer Product Safety Improvement Act, ask us to impanel this esteemed group of experts to study the effects on children's health on all phthalate and phthalate alternatives. Our agency's current phthalate limits apply to children's toys and children's child care articles. There are nuances in the statutes that you will become much more familiar with in your work here, and what is important for you to recognize about your charge from Congress is that you are to look broader in thinking about the risk and likely exposure scenarios. The work this panel has been charged with by Congress goes beyond the exposure that might occur when children play with toys or sleep in their cribs. You have been asked to examine the range of exposures, including the exposures that could occur before birth. You've also been asked what exposures can occur from things such as personal care products, which may not even be in our jurisdiction. The goal is to get the best scientific evaluation about the uncertainties regarding exposure and the particular susceptibility of children and pregnant women. We can't think of a better group of people who are assembled here to evaluate the best available science and advise us on how to protect America's children. So we look forward to working with you over the course of the next year, and we hope that you will enjoy your work as much as we appreciate your being here. Also, feel free to call me at any time. My office is on the seventh floor, and if you have any questions or need assistance, you know I'm here to help you in any way. So thank you for serving. Thank you very much, Chairman Tenenbaum. And let me second Chairman Sentiments that we appreciate very much your efforts, the efforts of the CHAP in the work that you will be doing in the coming months. And we look forward to working with you. Let me welcome you all to the first meeting of the Chronic Hazard Advisory Panel on Phthalates. I'm Michael Babich. I'm the Project Manager for Phthalates at CPSC. And it's my honor to introduce to you the members of the CHAP on Phthalates. If perhaps if the members wouldn't mind introducing themselves, starting with Dr. Koch? Yeah, please. Well, I'm Holger Koch from Germany. I'm working for the German Social Accident Insurance, which is also an Institute for Occupational and Prevention. It's a university institute at the Royal University, Bochumheim. I have done a lot of work on Phthalates, regulating exposure, bio-monitoring, exposure assessment in some parts, also risk assessment. Maybe some of you know some of my publications in this field. I think that should be it. My name is Phil Merkis, and I've been retired since 2008. But prior to that, I spent most of my career at the University of Washington in the Department of Pediatrics. And I'm a developmental toxicologist. Hi, I'm Russ Hauser, and I'm from the Harvard School of Public Health and Harvard Medical School. I'm trained as a physician and epidemiologist. And Bern? My name is Bernard Schwetz. My primary training and experience background is as a toxicologist. And within that, primarily reproductive and developmental toxicology, two years ago, I retired after 25 years in the US Public Health Service. And I have worked for industry. I've worked within NIH. I worked within the FDA. And more recently, before I retired, I was the director of the Office for Human Research protections within the Department of Health and Human Services. And that's the office that is responsible for oversight of all research involving human subjects that is either conducted or are sponsored by HHS. I'm Chris Jennings. I'm a professor of biostatistics at Virginia Commonwealth University in Richmond, Virginia. And I've been interested in the development of methods and design issues for studies of chemical mixtures for quite a while. I'm Andreas Kortenkamp. I'm a professor in toxicology at the School of Pharmacy in University of London. I'm mainly concerned with endocrine disruptors, and in particular with the mixture effects of endocrine disruptors. I've surfed on the National Research Council Committee, which produced the report, Thalates the Tasks, ahead. Really, my expertise is in assessing and evaluating the effects of multiple chemicals. Oh, good morning. My name is. Hey, thank you. And I'd like to also introduce some of the Thalates team members. Dominique, would you? Yes, I'm Dominique Williams. And I'm one of the toxicologists here at CPSC. Ken Carlson. I'm also a toxicologist here at CPSC. And Cheryl Osterhout. I'm a pharmacologist. Thank you. Michael Green. I'm a statistician. Thank you. And my colleagues at CPSC have helped prepare some of the documents that were prepared in advance for the CHAP to assist them in their duties. Let me talk a little bit about today's agenda. First, I'm going to give a little bit of the background and history of this project, of the work on Thalates that's been done at CPSC for a couple of decades. There also will be an overview of Thalates, a very quick and brief overview of the chemistry of Thalates in some of the important toxicological issues. And we will also talk about the charge of this CHAP, the scope of the work that is outlined in the Consumer Product Safety Improvement Act of 2008. When the staff is done briefing the CHAP, providing the background information, and so on, we will take a break. It'll probably be lunchtime by then. But when we reconvene, the CHAP will elect a chair and a vice chair. And at that point, the chair will take over the meeting and the CHAP will begin its deliberations and outlining its work. Let me just say that we appreciate the work, the willingness of the CHAP members to serve in where extremely impressed by the knowledge and experience and ability that they bring to this panel. So a little bit of the background, the sort of institutional history on Thalates at CPSC. In the 1980s, DEHP was the principal Thalate that was used in children's products, things like tether, soft plastic toys, and so on. But then the National Toxicology Program reported that DEHP caused liver tumors in mice and rats. So the CPSC initiated a rulemaking process. We conducted a risk assessment, did some research on exposure, and convened a chronic hazard advisory panel. Eventually, however, the manufacturers simply removed DEHP from tethers, rattles, and pacifiers. These are the children's articles that they considered intended to be placed in a child's mouth. That voluntary ban was later incorporated into an AST standard known commonly as the toy safety standard. And so eventually, because of the voluntary ban, the rulemaking proceeding was terminated. And for the most part, DEHP was replaced by another Thalate, DINP. In about 1998, we were petitioned to ban PVC in children's products, not just Thalates, but actually PVC. The petitioners Greenpeace and others, actually 10 different groups, mentioned Thalates lead in other heavy metals as the potential health risks associated with PVC. And so we began to investigate. At that time, the manufacturers voluntarily removed all Thalates from tethers and rattles. By that time, there were no Thalates and pacifiers that we were aware of. And they did this while we conducted our examination. To assess the potential DINP risk, we did three things. First, we convened a CHAP. The purpose of the CHAP was to consider the potential chronic hazards from DINP in these children's products. But especially at the time, the concern was about the liver tumors that DEHP and DINP produce in rodents. These liver tumors are associated with a process called peroxisome proliferation. And there was a question as to whether these tumors were relevant to humans, because the question is there was no evidence of that peroxisome proliferation would occur in humans. So that was actually our primary motivation in convening the CHAP. We also conducted a study of children's mouthing activity. We observed children, about 200 children up to three years of age, looked at what they put in their mouths, how frequently and how often. And one of the findings of that study is that children's mouthing activity, it's a very intermittent process. A toy or a teether will go in and out of the child's mouth many times during the course of a day. But the actual time it's in their mouth was much less than we expected. Before this, we and others had assumed that children had teethers in their mouth for hours and pacifiers in their mouth for many hours a day. And we found that that wasn't true, that in fact the most common thing that children mouth is their fingers. And they mouth just about everything that they can get their hands on. But most of those things it's very infrequent. We also worked on laboratory methods for measuring DINP migration to estimate oral exposure from children mouthing these articles. There was a method developed in Europe and it was actually validated with volunteers, adult human volunteers to measure the amount of DINP that can migrate into saliva. So the CHAP concluded, they published their report in 2001. They concluded that the cancer risk was negligible or non-existent. They said that the process of peroxisone proliferation is not easily inducible at the least, is not easily inducible in humans. And therefore there was little or no cancer risk from that process and therefore the liver tumors were not considered relevant. They also concluded that DINP exposure from mouthing teethers, rattles and soft plastic toys posed a minimal to non-existent risk. And the critical endpoint, the most sensitive endpoint for DINP in the absence of the liver tumors became chronic liver toxicity. DINP, of course some people are concerned about endocrine disruption or developmental effects. DINP is less potent than some of the other phthalates in inducing those kinds of effects. So in that case the liver was the most sensitive endpoint and therefore was used for that risk assessment. Later on when all the other work was completed, the observation study and the laboratory work, the staff, we had a little more data to work with and we also concluded that soft plastic toys, teethers and rattles were not hazardous to children. I think we had a little more data, so a little more confidence in our conclusions. So the petition to ban PVC was denied partly because of this work and some other work that was done. The main limitation of the work on DINP is that it was one phthalate in one class of products. Of course, even in 1998 and 2000, people were concerned about the, aware that we were exposed to multiple phthalates and concerned about the cumulative risks, but we just didn't have the tools to do a cumulative risk assessment that we have today. A lot of the key papers, Earl Gray's, some of Earl Gray's papers and some of the early biomonering studies were just published as we were finishing up the work. And the work, How to Shell's paper on the Mixed Year and the NRC report, Swan's paper were all published since then. So in 2008, kind of the work of Congress passed the Consumer Product Safety Improvement Act and one section of this act applies to phthalates, section 108, and it does a number of things. First, it bans the use of three phthalates, dibutal phthalate, butylbenzal and DEHP at a level of more than 0.1% in children's toys and childcare articles. It also bans on an interim basis three additional phthalates, DINP, DIDP and NOP. These are banned from children's toys that can be placed in a child's mouth and childcare articles. Now the act defines children's toy as a product that's marketed and intended for use by a child while playing. It's a broad definition. And in fact, the staff is right now working on clarifying that definition. Exactly what does, you know, does that include, obviously it includes dolls and action figures and so on, rubber duckies. But does it include things like, you know, tricycles and bicycles and sporting sports equipment? The staff is working on clarifying these definitions right now, but it's important to note that the definition of children's toy and the childcare articles, the scope of the CPSIA is much broader than the risk assessments that we have done previously. They also define childcare article somewhat in a somewhat narrow way. They limit it to articles for use, marketed and intended for use by children three and under that facilitate feeding, mouthing. What is it? Sleeping, feeding and teething. So it would not necessarily include children's clothing, for example, or things for bathing childcare products not necessarily include the whole scope of what people might consider a childcare product. Also, the interim ban in the case of toys, it's only toys that can be placed in a child's mouth and they have a definition if there's a certain size, I forget how many centimeters in one dimension, then it's small enough to fit in a child's mouth. Also, we'd like to point out the European Union passed a very similar regulation several years ago and that involves the same six thalates, but if you're familiar with that regulation, the details, the scope and so on, the products that are covered, there are differences between the CPSIA regulation and the European regulation and I know that causes some confusion because that regulation has been in existence for a while and a lot of people assume it's the same, but some of the details differ and in fact we're still working out what some of those details will be. And it also calls on us the CPSC to convene a CHAP on thalates and thalate substitutes. This is to address the cumulative risks from exposure to thalates in children's products as well as all other sources of exposure and potential thalate substitutes. So, let me just take a little break here and ask the panel if there are any questions. Okay. Continuing on, I'd like to give a very brief and not very detailed overview of thalates, both the chemistry and the toxicology of the potential health effects. And of course in doing so, I realize that some of the people on the CHAP, some of the people in the audience know a lot more about this than I do. I also realize that there's so much information that I can't possibly cover everything. I'm bound to omit some details that may be important to the risk assessment and depending on your expertise, you may feel is I'm leaving out something critical and I don't want anyone to have the impression that I'm trying to leave something out or glossing over something. Just because of the short time I need to talk in generalities. And I want to do this because I know some of the CHAP members in their work are very much focused on thalates per se, have a lot of experience with thalates. Others may not. So I just wanted to take an opportunity to give a brief overview so that we have sort of a common starting point. When we're talking about thalates, we're really talking about dialkyl esters of ortho-thalate as shown in the general structure here. Based on information from EPA, I estimate that there's about 30 commercial products known as thalates. In the literature you could actually find there's probably a couple hundred thalates at least. Of these 30 thalates, maybe half of them are high production volume chemicals. And metabolites of at least 10 of these have been detected in human urine and other human or blood or other fluids. Now, 90% of the thalate production or maybe more is used as plasticizers for PVC. The Dave Barry, the writer says that the four building blocks of the universe are fire, water, gravel, and vinyl. So it's no doubt that, I mean, this is why we're here. This is why thalates are so ubiquitous, why there are so many, why they are such important commercial products. The other 10% of plasticizer production has uses that you might call all of the above. They're solvents, they can be plasticizers, and they tend to show up, you can't, it's hard for me to get a handle on all the uses. They tend to show up in places where I don't expect them to be. Anyway, these are viscous-less liquids. They're hydrophobic. Some of them are extreme hydrophobes. They have log K values, eight or nine. Generally, low vapor pressures, they're semi-volatile. And their physical chemical properties are determined in part by the carbon backbone, both the length of the carbon backbone and the branching. And that this, in turn, affects how a particular thalate is used in products, what it's used for, it affects exposure, and it can even affect the toxicology of the thalates, as we'll see in a little bit. The industry classifies thalates into three types. There are the shorter chain or low molecular weight thalates like dimethylthalate and diethylthalate are used mainly as solvents. They're plasticizers for cellulosic plastics. They're used in fragrance products. There's some sort of a carrier or fixative or something that's mixed in with fragrances. Skipping down to the long chain or high weight ones, diisononthalate, diisodesselthalate, these are used exclusively as PVC plasticizers that in between ones, the transitional ones, dibutyl, butylbenzyl, are used for a little bit of everything. They can be solvents, they can be plasticizers. A little puzzled why they consider DEHP to be a transitional thalate. I thought it was more like DINP and DIDP. Perhaps there are other schemes that classify it just a little bit differently. Also, when we're talking about thalates, there are some things we need to keep in mind. There are branched and linear thalates. The alcohol groups or the alcohol groups, the side chains of course determine the different thalates. Now, unlike what we learned in organic chemistry, for the alcohols that have more than six carbon atoms, the prefix iso doesn't mean a methyl group at the second to last carbon atom in an otherwise straight chain. It means that these are mixtures of isomers with different branching. And so the iso-alcohols and the isothalates, di-isodenol, di-isodesyl, are complex substances. They consist of a mixture of many different isomers with different branching patterns. Not only that, they can be made by different processes. So, DINP and DIDP have at least two cast numbers each, corresponding to different processes. The product made by the different processes is considered interchangeable. They can be used for all the same things. But the mix of isomers is a little bit different. You can even have different chain lengths. One form of DINP is described as C9 rich. In other words, it's mostly known, but there's some eight carbons and 10 carbon chains that are present as well. So, we need to keep in mind that DINP is not one chemical. It's a mixture. Also, the commercial products might not be pure. The linear alcohols, for example, or the linear thalates could have significant amounts of branched chain. Impurities, 10, 20% or something, and vice versa. So, it's helpful to keep in mind that these aren't pure compounds that we're necessarily used to working in a research lab. Now, by and large, the thalates are metabolized, metabolized, absorbed and metabolized and excreted fairly rapidly. Within about a day, the metabolites in your body fluids probably represent the last day's worth of exposure, something like that. The first step is the diester is cleaved, actually in the gut, when you take it orally, it's cleaved to the monowester. The monowester is the putative, monowester is the putative active metabolite or toxic metabolite. And this happens very rapidly. This can be cleaved further to give phallic acid. For the longer chain phalates, things like more than four carbon atoms can also be oxidized either at the second to last carbon or the last carbon. So you can have carboxy, hydroxy in oxometabolites. And finally, these oxidized metabolites can be glucuronidated. There's some mixture of glucuronidated in free metabolite. And depending on the molecular weight, they're excreted in the urine and the feces, but the mix depends on the molecular weight. The higher ones tend to be excreted more in the feces. The oxidative metabolites are important for biomonitoring studies. In the first biomonitoring studies, people measured the monowesters and that's great for the lower molecular weight phalates, but for some of the higher molecular weight ones like DEHP, DINP, these are the most abundant metabolites that are found in urine, which is the preferred method for biomonitoring studies. And so some of the early studies lacked sensitivity because they weren't considering these. Now, this kind of sums up the toxicology of phalates in a slide. By and large, they're not acutely toxic. Most of them have LD50s over 5,000 milligrams per kilogram. They're mild to non-skin and eye irritants, generally not a lot of sensitization, although there have been some reports, I suppose. And they're not genotoxic in any conventional bio-assay in vivo, in vitro, bacteria, or eukaryotes. So we're generally concerned about the effects from chronic health effects, from chronic and sub-chronic studies. In sub-chronic and chronic studies, the liver and the kidney are the most common targets. One target organs, the testes is actually, it's very much dependent on the structure of the phalate. One of the common results of phalate exposure is the activation of PPAR-alpha. PPAR-alpha is a nuclear receptor and transcription regulator, among other things. It induces in rodents, peroxisone proliferation in the liver, cell proliferation, and ultimately, liver tumors. Now, PPAR-alpha may be required for some of the toxic, some of the other toxic effects of phalates. In studies with PPAR-alpha, no mice, some of these effects, like liver and kidney toxicity, occurred, but they occurred later with less severity. However, it does not appear that PPAR-alpha is necessary for some of the developmental effects that we're gonna talk about. One of the, PPAR-alpha is significant because humans have PPAR-alpha and phalates activate it, but in humans, PPAR-alpha induces a different set of genes than it does in the rodents. There are actually relatively few other tumor sites than the liver. Of course, you always see mononuclear cell leukemia in fissure rats, or almost always. For some, very strong peroxisone proliferators are associated with the so-called tumor triad, which is the liver, pancreas, and testicular germ cells. And you do see, the phalates are actually very weak peroxisone proliferators compared to other compounds. And you do see occasionally some benign testicular tumors, latex cell tumors, not germ cell tumors. There were a few pancreatic carcinomas and a couple of the bioassays. But for the most part, you don't see the triad. And there were, with DINP at least, there were some kidney tumors in male rats, which were attributed to alpha-2 microglobulin, or 2-Uglobulin. And if you look at the studies hard enough, I mean, there's an occasional site where you see some tumors or some hyperplasia. But for the most part, it's the liver tumors that are the most common, but by no means seen with all of the phalates. And what people are most concerned about and what has gotten the most attention is the reproductive and developmental effects. And this includes various kinds of effects, variations, malformations in the skeleton in the viscera, as well as effects on the male development, depending on the time of exposure, the window during prenatal exposure. This slide shows the, sums up the data for the six phalates that are mentioned in the CPSIA, plus dimethyl and diethyl, two low molecular weight ones. And just the point I wanna make here is, the liver is a common to all of these. The kidney is the next most common. And this may be significant from the standpoint of a accumulative risk assessment. The testes are a target only for particular ones. Paroxysone proliferation is also not universal. There are reproductive effects have been shown for some, but not all of them, developmental effects. And in this case, I'm lumping everything together, all the kinds of developmental effects. They are common, but we'll talk a little bit more about this later. The diethyl here, the little plus or minus, I think there was some reduced pup weights or something. This was not the kind of malformations you see with some of the other phalates. None of them is genotoxic. And actually, on this list only two, of course they all haven't been tested, but I was a little bit surprised that only two of them had tumors associated with them. I expected to see more carcinogenicity, I think. I'm gonna skip this and this is just to illustrate. This is paroxysone proliferation in vivo. And for various phalates, this is increasing molecular weight. So is dibutal phalate, benzalbutyl phalate are pretty weak. Pretty weak, DEHP, DINP, branched ones in DIDP, which are branched phalates are relatively strong. 610, 711 and diandesil, these are linear phalates. And they're pretty weak. 610 means six to 10 carbon atoms, like a mixture of six, eight and 10. This is like a mixture of seven, nine and 11. And this is diandesil, so 11 carbon atoms. And they're relatively weak. So not everything is a paroxysone proliferator. Not everything causes liver tumors. And of course, this is the real reason why we're here, why people are so concerned about phalates because of what some people call endocrine disruption. You can call it developmental toxicity or in so on. But this is the phalate syndrome, which is described in rodents. Certain phalates inhibit testosterone production. And this has a number of effects. The most profound effects are in male pups exposed during late gestation, what some people have termed perinatal exposure. They expose from late gestation into lactation. And the results or the effects of this include reduced analgenital distance, nipple retention, undescended testes, and hypospadia. So there's a range from subtle effects to frank malformations. And while the male fetus is the most sensitive, they are juvenile males are also sensitive, more sensitive than adult males. But enough exposure, even adult males are sensitive, high enough exposure for a long enough period of time. And there are effects in the female fetus as well. There can be malformations. There can be at least one study when they mature, there were behavioral effects. So, but the point here is that the male pups are the most profoundly affected. The structure activity relationship is pretty specific. This is caused by phalates, linear phalates having three to six carbon atoms. Or, and there's a number of branching branched ones like DEHP, so the conclusion, whether it means it's because it's branching at the C2 position or maybe it's because of the branching, it looks like a butyl or a hexal as opposed to an octal. And of course, what really has us concerned is that if you expose the animals to multiple phalates, multiple active ones, the effects are additive. I mean, one report they're even synergistic, but the point is there's a cumulative risk from exposure to these phalates. And it's not even just the phalates, cumulative exposure to other compounds that inhibit testosterone production, even if they have a different mode of action. The phalates are anti-androgen. Some people think they're synthetic estrogens, they're not. They block the ability of the testes to produce, they block the synthesis of testosterone. There are some other compounds of glutamide and so on that have a different, they block, actually block the receptor. They have a different mode of action but these other compounds are still acting concert with the phalates. And this is just a summary of the active and inactive compounds. Active ones, propyl, butyl, pentalanhexyl, also some of the isomeric ones, butylbenzol, DEHP, diisononal is active but it's less potent than the others. It's a mixture of, presumably it's because it's a mixture of isomers and some of the isomers are active. Probably some aren't. Inactive, anything, dimethyl, diethyl, too short, dienheptyl is too long, di-T butyl is not active. Apparently doesn't fit the receptor, whatever the receptor is. And fortunately, the other phthalates, the other isomers, the terra or paraisomer, the isothalates are not active as well. There have been a few epidemiological studies on phthalates that have been published. Most of these involve some comparing the health effects to some sort of biomonitoring data. They've looked at a variety of endpoints like effects on semen, quality, swan, of course looked at reduced enogenital distance in male infants. And so on. People have looked at main, looked at hormone levels in males that were exposed of vial lactation. There's one on reduced birth weight. And I think there's since been at least one that looked at exposures, excuse me, that looked at behavior. And finally, I guess there is one that I forgot to put in. That's not here on the slide, but it's looked at the ability of phthalates like DEHP and DINP and house dust, the association with asthma. Now, most of these studies, they're looking at correlations between exposures in certain health effects. One of the problems, one of the confounding factors is, well, A, we're all exposed and we're all exposed to multiple phthalates. So not to mention, we're exposed to lots of other chemicals, some of which may also have similar effects. So generally what you're seeing in these studies is some correlations. They're very suggestive, but there's no causal link as yet. In one of the puzzling factors about these studies is, sometimes the strongest associations are seen with diethyl and dimethyl. And they are the ones that are not active in the animals. I mean, maybe people are different, I don't know. But that's a little bit of a puzzle and sometimes you don't see an association with the active ones like DEHP or DINP. But the work continues, I understand that some, Dr. Hauser and some of his colleagues are working on alternate study designs, case control type designs that might be able to shed more light on this. One of the important developments in the last 10 years has been the availability of biomonitoring data. Urinary metabolites are preferred, are the preferred method for a couple of reasons. One, it's not invasive, it's relatively inexpensive. And also because you're measuring metabolites in phthalates are ubiquitous, they're present in lab wear and flooring and so on. So that reduces your concern about contamination by if you're measuring the phthalate as opposed to the parent compound. We have pretty good data for the general population and there are methods for estimating exposure from the metabolite levels. Unfortunately, the data for infants, children three and under and expectant mothers are limited. There are some data, there's not a great deal. And as Paul alluded to the Dr. Loy, the National Children's Study is, among other things, will obtain data, biomonitoring data, urinary metabolites from children and our mothers basically from conception through childhood. And some of the people involved with the study have told me that there's a chance that some of those data will be available in time for the CHAP to take advantage of. That remains to be seen, but we're hopeful. Anyway, so far 10, the metabolites from 10 different phthalates have been identified and that includes I think 21 or 22 metabolites at least. The NHANES is ongoing, there's a new set of data that's out that needs to be analyzed and so on. And there are biomonitoring studies going on in a lot of other countries, including Canada and Europe and probably others. As far as sources of exposure, identifying the particular sources and pathways is a little more difficult. I mean biomonitoring tells you it is very good for telling you what the total exposure is. For the most part, people have thought that food is the major source of exposure for most phthalates. But I think the more I look at the exposure data, I think the harder it is to really pin this down. Phthalates in food, they could be in the food itself during growth. They're mostly in fatty foods, meat, and dairy products. It can come from processing, it can come from packaging. The people at the FDA and the people who make phthalates, the manufacturers, say that in the United States, PVC and phthalates are not used a lot in food packaging. So that leaves background, general background exposure and perhaps food processing as the major sources, but really food can be contaminated at almost any stage. It can be contaminated sitting on your table at home. Personal care products can have lower molecular weight of phthalates, mainly ethyl and butyl. There are medical devices that contain DEHP and this affects, can affect a narrow subpopulation of people. People undergoing major medical procedures and or kidney disease, there's a lot of vial in automobile interiors. They're in consumer products, home furnishings, fragrance products, children's products, although obviously that's changing. We can also be exposed from the environment. That includes household dust. Household dust is a magnet for semi-volatile compounds and other pollutants. That can be a significant source of exposure or pathway of exposure, especially for children. It's not entirely clear how it gets from the products to the dust and what the factors are that affect that. So about 10 o'clock and I'm wondering if we might want to pause to take a little break. Byrne, you have a question? Well, the presence of phthalates and their metabolites in here? Well, they're present everywhere. I mean, they're present in human milk and cow's milk. In milk, you sometimes see not just the metabolites, I'm not sure why. You see metabolites and you see some parent compound. So I'm not sure what's happening there if that's because of some source of contamination because you would expect, at least from oral exposure, the mother, for example, you would expect it to be metabolized first. So that's a little bit of a puzzle. Primarily looking for is whether or not secretion into milk and therefore you might have more in milk lipids than you would have in other foods that don't have milk in them. Well, I think you... I'm not sure. I mean, they're hydrophobics or they definitely have an affinity for fatty foods. As far as I can tell, that's the main determining factor. I don't know if there's any other kind of facility to transport. I know some people have looked at pharmacokinetics. There may be an answer in the literature, but I'm not aware of it. Paul? Since I'm a novice to this area, I did a lot of background reading and I'm a little puzzled by your summary talk because a lot of the things that you were worried about has been the issue of behavior and activities and the uncertainties associated with it. And I see nothing here discussing it. I see the same old stuff, sources, epidemiology and toxicology, where in this particular instance as well as other instances, the behavior of the child is so important in terms of where they're contacting the material and how they're contacting it. And I would like to at least hear at some point a little bit of discussion about where you are, what you learned and what some of the uncertainties are because it's clear to me at least that you have some of it right, but there are some other issues that remain. And on the household dust, the issue of sources, Charlie Wessler of our place and myself, Charlie could give you a really good summary of the fact that it's the grasshopper effect in the house that moves the phthalates from the toys and whatever to the dust and then goes back to the air, back to the dust over time. But I'm mostly concerned about this fact that there's a disconnect still with behavior and activities because to me that's crucial in terms of getting the exposure which leads to the dose and whatever biomarker levels we're going to be measuring. Well, I think that in terms of the children's behavior, mouthing behavior, we have done some work on that. And I could, after the break, bring up a few more slides and talk a little bit more about that. Sure. To me that's important because I don't want to lose that because it's clear that you recognize it. I want to make sure we don't lose that as part of the discussion. Okay, I'll expand on that a little bit after the break. Any other questions or comments? No, I'm not worried. Why don't we break for about 15 minutes and come back at about 10.25, reconvene then? Thank you. Okay, welcome back. Dr. Loy had asked for a little more detail on some of the exposure assessment work that we had done in the past. So I'm going to insert a few slides here from some earlier talks to give a little bit more detail and then we'll get back to our agenda. We're doing pretty well time-wise. This is the work that we had done to assess children's exposure to DINP in products like tethers and soft plastic toys. I've already seen this. Our approach to the exposure assessment was this. We surveyed soft plastic tethers and toys for DINP prevalence in content. We measured the DINP migration rates using a laboratory method. It's a lab method that was calibrated with adult volunteers. And I'll explain this in a little more detail in a minute. We also did an observation study with 169 children up to 36 months old. And we did a probabilistic analysis of oral exposure stratified by the child's age and the type of product. This is the apparatus that was used in the laboratory method. This was first developed by the Dutch RIVM, their EPA. They refer to this as the head over heels method because it basically tumbled the sample. The way it works is you cut a little disc of plastic from the toy or the article. You put it in a bottle with a certain amount of what could be a synthetic saliva or even just a saline, normal saline, whatever. I think we used phosphate buffered saline. It's rotated, spun around here for, I think it's 30 minutes at 60 RPMs. You collect the liquid, you put fresh liquid in, do it for another 30 minutes. Then when you're all done, you combine the two liquid samples. You measure the amount of DINP. Or other phthalate and you calculate a migration rate which is in dimensions of micrograms per square centimeter per hour or sometimes we express it as micrograms per 10 square centimeters per hour because 10 square centimeters is the size of the disc. It's also the size that most people assume the surface area that's in the child's mouth. That's based on the surface area of a pacifier. This just shows the products that we tested. This is the percent of DINP and this is the migration rate, micrograms per 10 square centimeters, this is per minute. What this shows is there's a lot of noise. You can't really predict the migration rate just based on the DINP content. Regardless of fixed law, I think that there are just other factors such as there are different methods for making the products, molding and spinning and all this stuff, there are sheets, there are other compounds present, colorants and so on. So there are just probably other factors that we're not controlling for. The hope was that you'd be able to say, look, if you're below a certain percentage, you're at an acceptable dose. But it didn't work out that way. The method was developed by the Dutch and actually what they did is they first did some studies with adult volunteers and then they developed a method that would give the same migration rate in vitro as the one with the volunteer studies. Now, when we started this in 1998, people, every country's EPA or CPSC laboratory had their own method for measuring migration. There were widely different results, but no one tested the same product. And when we tried, you couldn't replicate the other guy's results. And people tried all sorts of crazy things, usually a combination of a liquid extraction and some mechanical action. We actually had a pneumatic piston that basically chewed the sample. We found out later that that was badly underestimating exposure. Then Canada had actually false teeth chewing on it. In the UK, they tried putting steel balls in while they shook it around in a flask, but the steel balls went through the side of the flask. But the judge came up with this and it closely matched the rates that they saw with the adult volunteers. The only problem is they didn't have a big range of products and a big range of rates, but at least that average, the correlation for the average kind of product was there. And so that's the one that everyone adopted. And anyway, these were calibrated with the adult volunteers in a typical study. You have 10 people, you get a 10 square centimeter PVC disc, mow that for a total of an hour. That's four 15-minute sessions where you collect all your saliva. And most people had in there a 15-minute exposure to a blank. There was a standard disc that the people in Europe had made up that contained 40% DINP. Or you could use a sample cut from a toy. Anyway, you collect the saliva, analyze for DINP, and calculate the migration rate. Let's see. What do we have here? These are the results from a number of different studies. This is a frequency distribution. This is the relative migration rate. I divided by the migration rate for individuals by the average migration rate. So all the studies would be on the same scale. They're really not that uniform. And this is the percentage of the people in the study. They had ends of either 10 or 20. And this just happens. We have three from the Dutch because they shared their raw data with us in one of our own studies, which was a sample, actually a rubber ducky. And as you can see, it looks pretty much log-normal. And it's definitely skewed. And there's always one person who's way out there. But these are adults. Their instructions were to gently mouth, suck, and chew. So there's always someone who, like, you don't get a sample back at the end. But for the most part, it approximated what children do. And of course, you worry about things like, well, they're adults. They could probably apply more pressure than a child. But there's nothing we can do about that. And I'm not convinced that that's true. Also, some DINP could be absorbed through the lining in the mouth. We did some calculations to convince ourselves that that was not significant. We also, I mean, there's a possibility that they could swallow some of it. But anyway, this was important to us because the method we had been using and the one we used in the DEHP CHAP was way underestimating exposure. So to have this kind of validation is we were very fortunate to have this. So what did we find? 42% of the toys that we tested contained DINP. Now remember, in 1998, the manufacturers voluntarily took phthalates out of tethers and they weren't in tethers and rattles. They weren't in pacifiers. And in fact, by then, instead of 90% of the toys having DINP, we were down to less than half. We had a migration rate. The migration rate didn't depend very well on the DINP content. From the Dutch study, because they had good data, with the PVC standard disc, we took their data. They had an N of 19. And we also had that same standard disc measured in a laboratory. And what we did is we calibrated it this way. When they designed the method, they were actually calibrating the lab method so that it would correspond to a 90th percentile migration rate. We wanted to do the actual average, but then include all the variability. So what we had was 19 measurements or measurements from 19 volunteers, measurements in the lab with five standard discs. And so we had an average ratio of 0.28 plus or minus all this variability. The observation study, 169 children, three to 36 months old, they were randomly selected in Chicago and Houston. This was some sort of random dialing thing. And it's not easy to recruit infants into a study by just getting on the phone and calling people. We had trained observers. Actually, the Dutch had done a study like this where they had the parents collect the data. We had trained observers. We thought that that was better because mothers are busy multitasking. We had 12, 20-minute sessions over a two-day period wherever the child was at home or daycare, whatever. We wrote down everything they mouthed, the frequency and the duration of mouthing. We did have, because our observers weren't there the whole time, the parents recorded the time that the child was awake and not eating, because that way you can extrapolate from the observations, the samples, to a whole day's worth of mouthing activity. And this was very much dependent on the child's age and months, as you could imagine. And of course, for some of these kids, they're only awake maybe half the day. Very briefly what we found, average daily mouthing time, this is in minutes per day. Four, all except pacifiers, 70 minutes per day in the youngest group and slowly declining with age. The window for mouthing is pretty much peaks in this age range. Over 36 months it starts to decline. Soft plastic teethers and rattles, here less than two minutes a day, here a fraction of a minute per day. Soft plastic toys on the order of a minute per day. The way they did the study, I mean we have a database, if I understand it correctly, Michael, where you can go through and arrange the data and sample it in all different kinds of ways. If you want to look at blue toys versus green toys, you could probably do that, I don't know. But what we found is that mouthing is intermittent. These totals are short, they actually may represent many events. And we considered mouthing to be anytime the toy touches the child's lips, not necessarily even in the mouth. Another thing that we did a little bit different from other studies, some people use very broad categories like non-pacifiers. I mean they looked at things like all except pacifiers. We tried to be a little bit more specific to get at the products that we were interested in. So that's one reason why some people's mouthing times may be longer than ours, because they're actually looking at toys as opposed to soft plastic toys. And this is some more summary data. This is for soft plastic toys, the rubber duckies, the tub toys, squeaky toys. And you can see the mean daily mouthing time goes from, actually in this case, peaks at the one to two year olds, and then declines in the older children, and 95th percentiles here still under 10 minutes. The medians are actually zero, because on a given day a child might not mouth a soft plastic toy, mouthing something else. So to estimate the exposure, we took all of these data. Exposure is the product migration rate determined in the laboratory with the sample of the product. This is the calibration factor. This is the migration rate of the standard disc with humans divided by the standard disc in the lab. This is the number of hours per day that the child is awake and not eating, and this is, or do I have it backwards? This is the mouthing time in minutes per hour that the child mouths a particular kind of toy, and this is the time the child is awake and not eating divided by the body weight. All of these things are sets of data. We have multiple measurements with the product. In fact, for the basic case, because we know that 40 percent of the toys had DINP, we actually included a number of zeros to account for that. We had all, you know, 19 migration rates with the humans, five from the lab, and of course all these represent all the subjects in the study except that they're stratified by the age of the child, and these are stratified by the... Well, not really. The mouthing times are stratified by the age of the child, these things, and the type, the product category you're looking at. And that's the body weight. We had essentially distributions of all of these things. So you go through this Monte Carlo type of thing, which is, you know, random except where it depends on the age, the exposure time, the mouthing time, and so on, body weight. And so this is what we got. DINP exposures from soft plastic toys, very low on the order of a microgram, not even a microgram per kilogram per day. These are means, upper bounds, the errors, the ranges here, confidence intervals represent the repeated sampling of the data. This is the 95th percentile, and we even did the 99th percentile just because we could. And these were all lower than our acceptable daily intake. So let's see. And this represents soft plastic toys where 42% of them contain DINP, since we call this the hypothetical case because tethers, rattles, and so on no longer contained any phthalates. So we just used the migration rates from soft plastic toys and applied them to tethers and rattles. There was no reason to think they would be different in assuming that they all contained DINP. So this is basically if the industry went back and put DINP back into all of these toys, which they voluntarily removed, and still even the upper bound exposures were low. And I think that was the best highlights. We applied migration rates from toys to other products. I think that's not much of a stretch. Assume that absorption through the oral mucosa is negligible. We didn't, in this case, we didn't look at dermal, although that's, you know, dermal is, we think it's low. It's not zero limitations. There's lots of variability. And of course, the bottom line is we looked at one phthalate, one class of products. But let's see. Well, this is where we are today. We have the chronic advisory panel to take us one step further. And I think that sums up the exposure assessment that we did for DINP as relates to the children's mouthing behavior. Yes. Just a quick question. How does that intact compare to intact via food? Well, I mean, we didn't do that compare it. You know, we only looked at one root. The food, it's not so easy to determine, as we learned in Berlin a few, about a month ago. You know, there are lots of different foods. You test all these things and you get non-detects. It's hard to go from like a market basket survey to estimate an exposure. I mean, you know, there are people who do this and are experts at this. You know, we think that this is low compared to total exposure. And we think that food is where most of your phthalate exposure comes from. But I don't know. Well, see, we've been focused on, you know, DINP and DEHP in just these few products. It's only since a year or two ago that we've broadened this scope. But the more I look at the literature, the less convinced I am that the generalizations, like most of our exposure comes from food. I'm not so sure about that. And one aspect of that is the fact that it may be incidental contact with the food on counters, which also would indicate to me that that's incidental contact with the children's hands on counters. Because it's not just during food preparation. It's also the fact that you have children waltzing around the house and with the grasshopper effect totally in play, you can end up with kids mouthing a lot of stuff from a lot of different places. It doesn't mean that the exposures are high. It's just that I don't think at this point it would be reasonable to discount any roots because I don't think we know a good answer. Could you just explain those grasshoppers in UK and US houses to us non-US members on the panel? What is the grasshopper effect? Well, it actually was created in Canada, but that was for outdoors. Basically what happens in a home, you have sources of all kinds of semi-volta materials. And the first time we really looked at it was with pesticides. Pesticides, when they're sprayed on the floor, for the semi-volta, you spray it, and it used to be the raid commercials, and it'll follow the bugs to where they live. Meaning that once it's sprayed, it's semi-volta, or at the temperatures that the house is in, material is going to evaporate, and it's going to stay around a while and it's going to follow the bugs. So the grasshopper effect is that when it's sprayed, it goes in a certain spot. But because of the temperatures of the room, there'll be semi-volta-lization. If the room cools, or the air currents are being what they are, and you have absorbable material like this, it acts like a sink for the pesticide or other semi-volta, so it'll go here. It doesn't mean it was sprayed there initially, but it'll come there. And then as time goes on, it'll evaporate, go into other parts of the house, and eventually go out the window. Over time everything goes down. Grasshopper's landed. Yes, and so when you think about it in terms of any semi-volta, that is an issue. And when you're thinking about anything that gets sprayed in the house and lands on this kitchen table, well, that could be, you know, something. It's the same sort of thing. It's not just phthalates. It's anything that's semi-volta. Anything that you use can be transport. The question is how much, how long, and what it has to deal with, what the issue is in terms of the dose that leads to the associated toxicity. Because you just can't assume, because it accumulates, you're going to get sufficient amount for a dose that's meaningful for a particular toxic effect. It's just that putting that all into the equation gives you a better understanding of what the issue is. Thanks for that. And to expand a little bit, all sorts of flame retardants, all sorts of pollutants, you find them on surfaces. They find them on window film. They find them in the dust particles. And I look at the dust particles are a pathway. They're not a source, really, because they get there from a variety of different sources. It's called approximate source. Approximate source. And so, you know, that also complicates, you know, there's some publications, a warm-up where they try to break down. You get this percentage from food, this percentage from toys. And the problem is when you get the dust, I mean, that's coming from everywhere. So these aren't all mutually exclusive sources. So that further complicates the issue. Could I ask another question? So I realize that on these studies you were doing, you were focusing on the DINP part. Yes. How representative is the DINP for other phthalates? So when you say it's a low level of DINP, but there are multiple phthalates, is it a reasonable approximation to multiply that by the number of phthalates? I think that's hard to do because the potencies aren't the same. I mean, toxicologically, the potencies aren't the same. DINP is one of the less volatile, more hydrophobic ones. So the exposure is going to be a little bit different. It's probably behaves very comparably to DIDP, maybe even DEHP, but the lower molecular weight ones are, I think, a whole different ballgame. The exposure patterns are going to be different. And the data, well, with the biomonitoring, the first studies didn't detect much DINP because they were only looking for the monowester. I'm not sure. I mean, DINP exposures were thought to be relatively low compared to some of the other phthalates, but this can change over time. One of the important things, there are two things to keep in mind about when you look at exposures. One is things change over time. DINP is slowly replacing DEHP worldwide. So things change, and the products change. Obviously, they're taking phthalates out of children's products. They may be reformulating some of the drugs that have phthalates in the time-release formulas, I suspect, and so on. The other thing is that things can vary by region. The phthalates that are used in a particular kind of product in Europe might not be entirely the same as the U.S. The overall exposures are fairly comparable, but I don't think they're the same. So those are my two caveats for looking at exposure data. What about personal care products in children? So that's something we don't know a lot about. There's been some studies, a couple reports in the literature where people obviously, the phthalates are there. It's surprising. The FDA says that they're not all that common. A, they're not all that common. And B, that they're already reformulating. Personal care products, things like skin lotions, baby lotion, and that sort of thing. Colognes have some of the lower molecular phthalates. FDA says that they're already encouraging the manufacturers and the manufacturers are reformulating these things. The low molecular phthalates are in a lot of fragranced products. They can be in air fresheners. They might even be, I've heard laundry detergent. The problem is we don't really know. I mean, if it's a consumer product, manufacturers don't have to tell us what's in it. Even for cosmetics, it's not like a drug. FDA has less control over that. So we will get whatever kind of information they have. We will get that for the chat. I don't think it's going to be as comprehensive as you might expect. While we're at various exposure sources, what about drugs? Phthalates are used surprisingly widely in the formulation of drugs. Yeah. Well, again, I'm not sure the FDA says not so widely. And also, but they are used in some drugs. And again, that's something that may change. But we will get whatever information the FDA can provide on that. Now, it's an issue where, you know, maybe an issue where the inert materials, maybe, I don't know if they have to just fully disclose that. We will all get the bottom line from them. I wasn't aware they were that widely used, but I don't know. Diabutyl phthalate is an inactive ingredient in the medications. And the second question is widely used. Well, currently in Germany, that's what I can say. There are 25 medications which still have diabutyl phthalate in it. In the past, it has been around 65. Unluckily, one of the most widely used medications did use diabutyl phthalate. It was used by over 5 million people per year, including pregnant women. So you have to get away from these relative numbers and really have to look at what is the real use. I would like to come back to your slide, number 12 and 14. In slide number 12, I didn't really... So all except pacifiers means that the children's... children mouth 70 minutes. Yeah, that includes everything, including their fingers. Yes. So we have a gap of 68 minutes, which where they use mouth something different than soft plastic, heathers and soft plastic toys. And if the order is, I think fingers were most, then pacifiers, and then heathers. And then this unintentional use for the kids, like mouthing cables. Those things are, I mean, they're scattered around. They're there, but you see one here, one there. It's not consistent. The average for mouthing on a chair leg is probably infinitesimal. Children also mouth toys that were not made out of soft plastic, wooden toys, metal toys, that sort of thing. Just about everything. So in slide 14, this factor, does it mean that the machinery overestimates exposure or underestimates exposure? This factor of 4.28. Yeah, the Dutch who developed it, and then later the JRC, designed it in such a way that it would overestimate the average. They were aiming for the un-upper bound migration rate in the human studies. We decided to calculate the average, but then, through the Monte Carlo modeling, look at the range of values. Did you correct for lipase activity in the human saliva, like degradation of the di-isonomol phthalates? No, we didn't. Because there's lipase activity in human saliva. You would have a degradation in the saliva, so this would lead to an underestimation, although you still have the active compound in saliva. Well, I need to look at exactly what the lab did and whether they would have detected that. They may likely thought of that, but... Never can be sure of. Yeah, but we can go back and look. Can I ask another question? Maybe we're getting too far off the track. No, no. Just in terms of inhalation, I mean, you start talking about house dust. It seems like if I, Russ may know a paper, I thought I read about a paper that had, I think it was PBDEs and breast milk, and based on the rate of the times the houses were vacuumed or something. So it seems like exposure could increase... I think if you do anything to stir up the dust, like cleaning, ironically, you could have a short term. I think we're, you know, I guess we're talking about chronic effects. We're mostly talking about long-term exposures. But... But I mean, have there been studies about inhalation exposure to phthalates? Well, the problem is the vapor pressure is so low. There are a few measurements of levels in ambient and indoor air, but the vapor pressure is so low. Most of it's bound to particles, and most of those particles probably settled on the floor. So, yes, there's inhalation exposure. No, we don't think it's that high. Well, it's unquantified. It's unquantified. That's better to describe it, because the rug rats love the floor, and they, when they move along, they stir up dust that is maybe four times the average level of re-suspended dust in the room when you're just sitting there. These are studies that have been done recently with a robot that mimics children's behavior on the floor. And so, you know, I think the best thing to say is it's unquantified, and it's a good point that if we're going to do this right, we really have to think about what the different exposures are. Yeah, and in fact, with the dust, even if it's inhaled, I mean, it probably ends up in the gut anyway, as opposed to in the lungs, or most of it. But, you know, this is why we have the experts, because I add a loss for something that's so non-volatile. You know, that's not easy to estimate, so certainly those are points well taken. But is part of our charge to think about this in terms of products like toys, are we thinking about this more generally in terms of just general exposures that could come from all kinds of products but exposures? Yeah, well, you know, the charge is next on our agenda. And I think the way I see it, you're focusing on children's products, the toys and other childcare things. But you also, doing that, knowing that children and everybody else are exposed from all these other sources. And in fact, it's the cumulative exposure that is going to determine the risk. Right. So, we have to do a little bit of both. We can get back on, let's see, talk here. Move on to, let's talk about the charge and scope of this CHAP. In general, the sort of, the rules for conducting a CHAP are outlined in the Consumer Product Safety Act. We're required, in fact, to convene a CHAP. Normally, we have to convene a CHAP if we want to issue a regulation that's based on a risk of cancer birth defects or gene mutations. This is, you could call this an extraordinary CHAP that's mandated by Congress. A CHAP consists, by law consists of seven independent scientists. The commission selects them from a list of nominees that comes from the president of the National Academy of Sciences. In addition to possessing the required expertise, they have to be people who are not employed by the federal government, except NIH, the National Toxicology Program or the National Center for Toxicological Research. Also, they can't be associated with the manufacturer. So in this case, manufacturer of mainly phthalates or children's products. And that the members of the panel select a chair and a vice chair. In this particular CHAP to sum up the charge, the mandate from Congress is that you conduct a risk assessment looking at all phthalates used in children's products. And that include, in that you are to include all potential health effects on children's health, specifically including endocrine disruption, that you are to consider individual and cumulative risks. In other words, I think the individual phthalates, as well as cumulative risks. You're supposed to estimate exposure to children, pregnant women and others. I think others means if there are any other sensitive subpopulations. I'm not aware of any. You're supposed to look at total phthalate exposure from children's products, personal care products, and all other sources. And you are to consider all routes of exposure, in other words, not just mouthing, thermal inhalation, whatever. And as part of this examination, you're supposed to determine a level of no harm to children, pregnant women, other susceptible individuals, their offspring, and to do this using appropriate safety factors. You're also to consider alternatives used in children's, phthalate alternatives used in children's products. Obviously phthalates, when manufacturers take phthalates of a product, they have two options. One is to use another plastic that doesn't need a plasticizer. Some of them do that. The other option is to replace the phthalate with another plasticizer, like an adipate or something like that. So you're looking at the phthalate alternatives, which I interpret as the other plasticizers. And that your examination is to be conducted de novo using all available information and objective methods. Part of the language, the specific language about de novo says that you can consider work done by previous chaps and other bodies, but you're not restricted. You don't have to accept those conclusions. You're free to go back and revisit anything that you want to do. And your report will include a recommendation whether to ban any additional phthalates or phthalate alternatives. Once that report is issued, the staff will evaluate your report and recommend to the commission whether to ban any other phthalates or phthalate alternatives and also whether to make the interim ban permanent, the three phthalates that are banned on an interim basis, DIN, PDIDP and DNOP. The timeline is such. The way it's written, you have 18 months to complete your examination, but you have another six months to repair a final report. Please see this as essentially you have two years to complete a final report, the two, the examination and the report kind of blend together. And once the final report is complete, we have six months to brief the commission with our recommendations. Now, to prepare for the CHAP, this is such a large job in such a broad scope. We did toxicity reviews of the six phthalates mentioned in the act. Of course, there are other phthalates that are important, too. We thought this would be a good start. And these were prepared by the staff, by the people sitting at the table and myself, and these have been peer-reviewed by outside scientists. Our contractor, Versar, has done a report on the toxicity of five phthalate alternatives. These include acetyltributyl citrate, diethylhexyl adipate, something called DINCH, DEHT, which is an isomer of DEHP, and this tri-melotate, tri-octal tri-melotate. And most of these are, in fact, being used in children's products. Versar also did a very comprehensive review of the published exposure data. And I saw there, I had no idea that there was that much. I knew there was. It's a very extensive report. We also did a laboratory study on the plasticizers in children's toys. We collected some toys last December, November, December. We specifically did it before the requirements the ban actually went into effect. So these were from late 2008, I think. Is that correct? And what we found is that, in fact, even before the ban was in effect, very few of these children's toys and childcare articles had any phthalates at all. The one that did would be actually comply with the new regulation. We identified the plasticizers, the concentrations, and measured migration rates by that head-over-heels method. We also measured, did some wipes, some to get an estimate of exposure as it would relate to dermal exposure from handling the products. We're also, part of our job is to coordinate with the other federal agencies to get whatever information we can get for you from FDA, information on drugs and cosmetics, CDC, the NHANES. EPA is doing some of their own work on phthalates, and we're going to keep close eye on that. Try not to duplicate things too much. Try to take advantage of what we do and what they do and vice versa, some of the EPA staff are here today. Of course, we're anxiously looking forward to the National Children's Study. As far as the phthalates go, of course, the universe of possible phthalates is huge. It could include any of the 30 phthalates that are not mentioned in the Act, specifically mentioned. It could also include phthalates, and in fact it does. The toxicity review for these five, we arrived at these five by a process that's described in the report. First, we considered the entire universe of substitutes that we could identify. There were 20, 30, something like that. We chose these five because they had a high likelihood of being used, which means they probably already were, and also because there were data, tox data available. Now the data, if you look at these, the citrate's been around for a while. The adipate has been around for a while. You might notice it's got the same ethylhexyl, the same alcohol group as DEHP. This, the terephthalate, is the isomer of DEHP. Fortunately, the terephthalates don't seem to have the developmental effects that the ortho phthalates have. This guy, Dinch, diisononal, it's actually made from DINP. The aromatic ring is reduced so that instead of the aromatic ring, you have a cyclohexane group, and this is in fact being used. As far as the database goes on the toxicity database, it's a little bit uneven. I'm not sure any one of them is as well studied as DINP, for example. This one is interesting. The manufacturer has a lot of toxicity data. They've done a number of studies. Those studies are considered, they consider them to be proprietary, and they don't want those studies to be released to the public. All we have are their summaries of their own studies. This is something we can talk about, how we want to deal with this. The others, well, they're summarized in the report, and we have actually, for most of these, if not all of them, we have migration rates from the laboratory study. In terms of interagency coordination, well, since you're looking at total exposure, this crosses jurisdiction, EPA, I mean FDA, EPA. Of course, we've got jurisdiction over certain of these products. We don't have jurisdiction over automobile interiors. We will certainly monitor everything we can find, data, some of the biomonering studies that are going on, and we will request all the available data from the other federal agencies. My job is to stay in touch with them, and with that, I think our job here as the staff is to give you administrative support, interagency coordination, as much support as we can in terms of staff time, toxicology, whether it's statistics or the lab, mostly my time, our resources are limited, but there is also a possibility, depending on what your needs are of some contractor support, what I wanted to do is we have the studies that we prepared for you. Some of them, they're too big to include in your binders. The lab report is in your binders. Along with, I did just a quick overview of phallates, chemistry and toxicity that's in there. You have a set of CDs that contain all the staff documents that we prepared, plus other existing information, the previous CHAP reports, the NTP reports and so on, a lot of background information. For the people in the audience, the staff reports will be posted on our website very soon. The old CHAP reports are already there. If you have any questions, give me a call. But let's pause just for a minute and ask the panel, do you have any questions about the scope and so on? I think the scope is obviously very broad and very demanding and it's a challenge. Yes, regarding the scope. I understand that we're charged with coming up with a recommendation whether or not to ban any additional phallates. Yes. Ban is sort of the final tool. Does this charge and rather rough maybe, does this charge mean to consider alternative regulatory activities or is it really ban yes or no? Well, you know, we think of, I mean you're right, if we were doing, if the staff were doing an ordinary rulemaking activity, the ban is the most we can do. It's the death sentence, whatever. I mean, it's the most severe. And in fact, we would have to exhaust all of it. We would have to, in order for us to do that, we would have to say nothing else would do. In various other findings. You have a little more, under the, because of the CPSIA, you have a little more freedom than that. I think you could recommend anything you want. If you could recommend something less than a ban or, you know, additional information, research is needed to make a determination. You know, I don't think you're limited to just that. And for us, you know, we don't ban the chemical per se. We're not EPA. We can't ban it from existence. What we do is we put a limit on its use in particular products. So some people call it a partial ban, whatever you want to call it. It's not a complete and total act. So that means that when we consider things like bicycles and, you know, camping products, that's in a different category than mouthing of a teether. Because clearly there are a lot of differences in terms of contact and potential for exposure. Absolutely. And I also think that when you get beyond, you know, if you think of the teethers and soft plastic toys as the sort of core products, other childcare products, I think as the scope of that regulation gets, if you broaden it, looking at things like sporting goods and so on, there's probably less exposure to phthalates as you expand anyway. This is something that, you know, it's not going to be easy when you broaden it. You know, again, when we knew that this rule was coming, we didn't anticipate the scope of it. We were focused on, you know, rubber duckies and so on. And that definitely broadens it. But on the other hand, I think the potential exposure from some of these products is much lower. And that helps me because it's the idea of the contact frequency, the contact intensity, which will lead to a dose of meaningful meaning. Because I think we have to prioritize that rather clearly because not all exposures are equal. I think prioritize is the key word. And when you look at, I mean, when you try to estimate exposure for, I mean, these broad categories, it's got to be, it's not going to look like what we did for DINP. It's going to be a different approach, a much broader approach. I would think. Question. So on the slide, you were talking about looking for level of no harm to certain individuals. Can I put quotes around the word no? Well, absolutely, I think that we, I call it an acceptable daily intake. EPA calls it a reference dose. It's a level of where you think the risk is negligible. And we get to define what negligible means. I mean, it's the kind of thing that a toxicologist, as a toxicologist would define it, because you can't know everything. It's more about what you don't know than what you know. I mean, you can't set a level based on what you don't know. What I'm thinking about, though, is it seemed that one point one of my graduate students was working on something about sort of acceptable levels of risk. Yeah. And there are actually Supreme Court cases that have considered what acceptable might mean. I don't remember the case, but where people actually talk about society's risk. Right, in fact. I mean, are those kinds of reports could be made available? We could try to find it. I'm not aware of a Supreme Court. I mean, this is the kind of thing for cancer risk was what was a topic discussed a number of years ago. I mean, what's an acceptable risk for something like cancer where there is no dose where the risk is zero, or at least you believe that. You know, it's not just a scientific question. It's a societal question. Something for us, the commission would decide. We would say, suppose there's a cancer risk, we would say the cancer risk from using this product is something in a million, and then they would decide what's acceptable. You know, in that answer might vary depending on if it's children or if it's adults and so on. You know, right now, looking at the NRC report, we're talking about setting up something like a more akin to an acceptable daily intake or a reference concentration. I mean, I don't know what methodology you're ultimately going to use, but it's going to be you're either above or below. And if you're below, then you assume that the risk is negligible. I don't know if you're going to get into calculating actual risks. I mean, it would be, we'd of course like to do that, but we'll deal with that acceptable risk question when we come to it, I guess. That's partly clarifying the question I'm going to ask now. Are we really in the business here with establishing, say whatever you want to call it, acceptable daily intakes, et cetera? Or is the emphasis rather on estimating or judging margins of exposure, which is very different? Well, I mean, those are two different approaches. I will make a lot of work for that. The former, I think, this is all subject to interpretation. I read that as a regulatory scientist looked at that and said, oh, they mean an ADI or an RFC. I mean, margin of exposure is a valid approach. That works. It works for me. It may make it easier. You mean to talk in here about exposures and if we can prioritize and systematically eliminate some of them, that may make life a lot easier. Yeah. Okay, that's reassuring to hear. So we would be free in that. I'm asking because deriving an ADI is a lot of work. Yeah. Right. That's true. I mean, actually, well, not that you're bound by them. In our touch reviews, we derive sort of provisional ADIs for a variety of endpoints for each chemical. I mean, you don't have to use them, but they're there. The information is, the basic information is there. I think, you know, you're, as a group, you're here for your expertise. And if you're, you know, want to, if your judgment is to take a certain approach to this, I think that's fine. As long as, you know, we're addressing the concern. What this band date has, it's really, they're concerned about cumulative risks and sensitive populations and so on and so forth. And I think as long as we address the spirit of these things, the methodology. I don't think matters because you're going to use the best methodology that you can. I'm sorry, I'm firing a lot of questions. That's okay. And one other question also of enormous relevance to our work. There's in Europe a route to dealing with these, which is called the substitution route. Meaning that in cases where you have for a certain chemical in a certain product already a substitute, which can be used. You, if you like short circuit all this time consuming and arduous toxicological risk assessment and say, right, we're not doing this, there is a substitute, that's it. Use it. And then the decision is make to restrict or ban the use of that certain chemical in a product. But without going through the labors of of a toxicological risk assessment. Do you see what I mean? Well, this is sort of a pragmatism, which is emerging in Europe. The alternative would be to say the trigger value or the trigger for a ban would have to be a toxicological risk assessment where the margin of exposure or whatever you want to call it. It just is judged to narrow and then you you make the decision. Yeah, well, I'm not sure I follow, but I think there's a certain economy of of effort here. Once you have a framework of how you're going to assess exposure, you can substitute one chemical for another. If you know the migration rate or the vapor pressure or whatever it is you need. I think that will help to simplify things and obviously they want us to look at substitutes. So I, you know, I think there's got to be a way to just simplify that this as much as to that extent. I may be becoming more confused rather than less because I begin to wonder with this family of chemicals and alternatives. Is what's what's most important for us to make recommendations on the approach that we would take so that as new phthalates or new substitutes, new alternatives become available on the market. There's an approach that has been recommended that can be followed for the next one as opposed to calling another chap. Right. Because of one more alternative. Or is it specifically recommendations on these 11 chemicals? Well, what they're asking for the bottom line is they want to know. Do we continue the interim ban of those three? Do we need to regulate any other phthalates or substitutes? That's the bottom line of what they want. If you in doing so if we if you come up with a methodology and approach, obviously that's a big benefit because it can be applied as new alternatives become available. You know, you're you're not limiting you're not limited to just saying, you know, yay or nay on some of these chemicals in that list of five substitutes. I mean, it turned out to be a pretty good guess, but you know, we didn't really know that they were going to be the ones when we started. Are there are there precedents that have served as the basis for this threshold for negligible risk that would be helpful to us? So that I mean, there are some people who feel that because there is no benefit to be considered here, there is no balancing it's strictly risk and any exposure represents risk. Therefore, there is no accept no acceptable exposure. And we're talking about chemicals for which some 90% of us have body burdens. So it's a meaningless statement to say that there is no safe level that doesn't help you as an agency. So are there precedents that would help us to have a better feel for what you've already accepted as this threshold for negligible risk? Well, let me thank you. An RFC, for example, an ADI is generally defined as a level of exposure on for up to a lifetime. That is to believe to be without significant harm. So if you can identify a level, you know, it comes down to is it, you know, risk versus an ADI. I think if you follow a traditional approach like an ADI or a reference concentration, applying uncertainty factors, however you get there, however you do the details don't matter. But if you follow that general approach, I think that would be generally recognized as a negligible risk level or whatever. I don't think that's a problem. But your point about the fact that we all have a body burden of this, of these chemicals is well taken. I mean, I guess in a way that's the point of this. And I feel like to some extent, maybe the tail's wagging the dog. If the exposure from these products turns out to be small compared to those other exposures, then, you know, maybe the answer is for another agency to do the regulating. I don't know, but or it may be that we can limit the use of these products and children's products, but someone else has to worry about the other exposures. But I think that we'll have to see where this leads us. And if that's the case, I think your recommendations, you know, you have latitude. And if banning the chemical in children's products is not going to do much good, then, you know, you could say that. Unfortunately, banning something that's used as a plasticizer drives the use of something else, which we know less. That's true. And that's probably why the substitutes are in here, because someone raised that question. And it'll be interesting to see in five or ten years in the NHANES data whether the, you know, phthalates go way down in the adipates and citrates go way up in what the implications of that are. So do you know for sure that NHANES is monitoring these alternatives? I wasn't aware of that. No, I don't think they are, but maybe they will. I mean, I pose that question to the national children's study people, and they say, you know, there are ways they have provisions so that as things change, if they see that need to look at some other phthalates, there are ways to adapt that within certain limitations. But yes, it would be nice to see some biomonitoring data on some of these other compounds. Okay, so one more question. So when you say the word ban, what you're thinking about is ban in children's products, children's toys. It's not banning, like you said, you're not the EPA. Right. So we're not talking about banning these plasticizers, period. I mean, our recommendation is we may do an exposure assessment or whatever and find, you know, a very small percentage actually comes from certain products, which may be, you know, a little bitty part of overall exposure. So your word ban really is just for these sorts of products, particularly children's toys. Well, and you can recommend, you know, you can recommend anything. I mean, you can recommend that chemical B-band. I mean, we couldn't do it, but you can make that recommendation. You could also recommend is that, you know, the scope of the ban is broad or narrow as you see fit. Usually there's a level because nowadays there's no such thing as zero of anything. So, you know, you come up with some practical level. But I think you have a lot of latitude into what you can recommend. And I mean, you know, again, it's your experts and it's your scientific judgment that we're interested in. We don't want to limit you. I mean, we want to answer the charge questions, but we don't want to box you in to, like, yes, no answers. But again, I see this as a, among other things, a matter of prioritizing, you know, out of all these things that we can do, what are the ones that will give us the best answers? And I think if there's any housekeeping things that we need to say, we're coming up on the noon hour. And I think we'll break for lunch from noon to about one. For the, those of you in the audience, there is a cafe downstairs in the south tower, one of the other buildings on the ground floor. Just take the elevator to the ground floor and walk. You can walk over there. If you walk that way toward the metro, you can find lots of, in lots of restaurants in Bethesda. And we'll reconvene here at one o'clock. Thank you.