Advisory Board & Committees
Transcript - December 6, 2007 BSC meeting
This transcript was generated automatically and has not been reviewed. Typically, automated transcripts will contain words that were not recognized properly by the software.
Event ID: 901749
Event Started: 12/06/2007 8:19:26 AM ET
Can I ask everyone to take their seats. Good morning. My name is [ indiscernible ]. I will be chairing today's meeting. The first order of business is to be [ indiscernible ]. A reminder to turn your microphone on for your introduction and for your comments. What do we start on the far end.
Mark Torson from the National Institute for Occupational Safety and Health.
[ indiscernible ]
Tim Carney.
Jim Rivera, North Carolina. National Toxicology Program.
Bill Janzen.
Sam Wilson.
Sean Broker.
By -- Bobby [ indiscernible ].
Cathy.
Harish Sikka.
Mary [ indiscernible ].
Jack Bishop.
Bill Stokes.
Larry Wright.
Kathy Price.
Rich Shoemaker.
Merry Gant.
Ken Hudnell.
[ indiscernible ]
Robin Makkar.
Nigel Walker.
Bill Jamieson.
Paul Foster.
Dave Malarkey.
Ruth Lund.
Michele Hagan.
Michael White.
Bill Kelley.
[ indiscernible ]
Christine.
Ray Thais.
Diane Perkin.
Thank you very much. I would like to extend a special welcome to our new board members and also mentioned Dr. Baden who is not here. There are also several members who will be leaving us. Do with like to thank them for their service. Those are Dr. Sikka, [ indiscernible ], and Dr. Walker. We have several people joining us by webcast. A reminder port our ad hoc members, we welcome your comment on any topic including not only the 1 year review, but any topic, but he will not be able to make motions or vote. An announcement for all board members, it is our custom and we will be taking a photograph at the morning break. Texas that is we ask that everyone gather in the foyer immediately upon return said that we can get that done and still have time for coffee. Are there any announcements?
I have a few announcements. First of all, I just want to note that the security desk needs everyone on the board and add hearts to sign in and get a bad. The desk sergeant did not have the and this morning when you came in. I am sorry for that inconvenience. So now let me get down to the meeting. In but the folder you will find the latest agenda, the roster, the list of written comments and hard copies of these, it is all [ indiscernible ] and a form to fill out for reimbursement retreat with like to get back as soon as possible. Please be sure that you signed in and be sure to use the microphone and identify yourself whenever you make a comment since the meeting is being taped and a transcript is being prepared. It is being videocast and conference. The meeting is being videocast, and if your making a public comment, please register at the table outside. The photograph will be taken at the morning break. The draft treaties and nominations up to a preliminary comments will not be included in the minutes. The board and ad hoc members must realize any comments a wish to be incorporated into the minutes. I'm going to read a conflict of interest statement. The members of the NTP board service individual scientists and do not serve as representatives of any specific organization. Anxious as the temperature in the meeting as to whether a potential conflict of interest might exist relative to the topics for discussion by the board. To to your occupational affiliation activity or financial interest of yourself, your spouse are outside organization for which you are negotiating or arranging for future developing. Should there be a potential conflict of interest you can not participate in the decision or vote on any action. As far as I no there is no one with a conflict of interest. Thank you.
Thank you. We will now begin with the agenda. Is in your notebook under tab three. The first order of business is to hear from Sam Wilson, the acting director.
Let me Harish Cale and welcoming you to the institute's today. I would also like to express our gratitude. We met Texan time out of your busy schedules to compound and lend assistance to the National toxicology program. I thought that for the retiring members that we would not release the you around the table much anymore. But it is a pleasure to welcome you back even after we said goodbye last time and gave you this nice certificates to put up on your wall. We really appreciate your help over the years. For those new members, we welcome you to the board and hope that your experience with us will be valuable and enlightening. We want to allow you to do more effective research and the Environmental Health sciences arena. I thought that I would just make brief remarks this morning. One point that I but like to make is to all come bill as the acting deputy director. Bill joins us after a long to near in the extra mural division here at the institute. And in particular his work on the Superfund basic research program which just over the past few days here in the Research triangle Park area enjoyed its 20th anniversary celebration. Bill was instrumental in founding the program back in the late 1980's and he fostered the program through many years of interesting developments and the research seems and also the budget wars that occurred over time. I think I will stop for a minute and see if Bill would like to make any comments.
Thank you. First of all, I want to thank you all for the opportunity to attend this meeting and to participate. I am looking forward to an interesting day, an informative tape. I know some of view were sort of -- from my involvement and the extra route Division I am Christopher Bradfield -- looking for to get to know you all. Again, I just want to thank you and to reiterate what cents a for all your hard work and efforts on this board of scientific councils. I am also looking forward to a good day. Thank you.
As you all know this is a very active time in the environmental health sciences. I would increase you to interact. She is keeping us all posted on a mad by minute basis on the stories and the media and the important themes that are emerging in the environmental health sciences. The BP a topic, as you know, is very much on that front pages these days. It it is receiving coverage in the most popular and available media that we have in this country. Other similar topics such as the fact of environmental lead and the topics surrounding heavy metal to human health effects are all over the media and certainly some of the disease advocacy groups are extremely active and concerned about the environment or exposures. And when does of susceptibility. Indeed it is a very active time in this field of hours. I do hope you will have a chance to interact with Robin and also with Mary get here is located in our Bethesda office concerning any of these ongoing legislative activities. Of course that is that area of focus for her work. I thought I would spend a few minutes talking about the NIEHS budget. Of course, the National toxicology Program is funded through the budget in part. In fact, substantial part. But at the present time we and the other agencies are on a continuing resolution that is in force through mid December. And the prospect of receiving a budget actually for the institute and the NIH overall for the next year first is a continuing resolution through the entire year is unknown, up in the air. We are hearing reports all the time about the difficulty of achieving the budget. Indeed we look forward to a favorable budget. The process is very complicated with the issues surrounding though or and the concerns about domestic spending that we all know about. So at the present time we are operating on a continuing resolution which means spending at the rate of the previous fiscal year budget. And basically we are looking forward to budget activities sometime during the next year. The weather is favorable or any different from the 07 budget -- I just wanted to give you that very general review of of the budget process. Of course is a very important topic for all of us here in the leadership of NIEHS. I wanted to move to another thing, and that is to give you a chance to ask any questions that he might have about that as did our the National toxicology pram. I think we have plenty of time in this schedule here to take questions that you might like to direct to the scene near the ship. Okay. If not then I will close with just one other point. That is to welcome our federal agency colleagues to this board and to tell you specifically how much we appreciate your participation and your consistency. There are [ indiscernible ].
Thank you very much. Next we are going to hear the NTP update. In addition, what he is kind to the podium, members can find written material in tab four of your notebook.
Thank you very much. Last time we were here in share and one of the topics that I spent a as a bit of time on was the proposed realignment of the National toxicology Program within the division of Lynch Real research. And I would like to update you on that and give you an outline of how the program is outlined such that you can see how we carry out our business. Realignment of the program was accomplished on October 28 of this year. And we are not composed of the program office and five branches. I would like to announce and congratulate Dr. Rick Wolff who is going to be appointed or is appointed as the deputy program director for policy and up with like to introduce Nigel Walker. Nigel, would you stand up? He is hard to the deputy director for science. You will see much more of them are the next few years. The program office is comprised of a number of different offices and a series and in the office of nomination and selection. We also have the office of the a sound policy and review headed by a very old. The report I carcinogens is headed up by Bill Jameson. You will hear from him later today. The interagency Center for toxicology lab This is the portion of our program that supports our interactions with the toxicology activities. The Center for the evaluation of risk in human repression. You will be hearing from Dr. Mike shall be as well. The five branches are the toxicology branch. Every knows Paul I'm sure. Cellular and molecular pathology. The chief is Robert sells who took over for Bob recently. Would you like to stand up? Program operations branch, the acting chief is -- I think Cynthia is stuck in Wisconsin because that is where she was yesterday. The stability branch. The Act to achieve is Jeff who is ill today and not able to attend. The by molecular screening branch is Dr. Rate -- appraiser. Thank you. So I've would like to just walk through briefly some of these activities. The function of statements, I won't read them to you, but the tax policy branch was created to pull together all the toxicology efforts within the program concerning those and scientists involved in designing studies with any a toxicology. They're is a specific focus on integrating activities of the toxicology Program of the reports and analysis functions with the Texaco Canada can't new efforts and toxic gudgeon Nomex and modeling. So to emphasize this we have actually placed it in to their functional statement to remind them that this is an important part of their activity. The toxicology branch activities, but like to point out that Dr. Ron Melnick received the award for efficacy in public health from the American Public Health Association in November of this year. This is a great honor for Ron and the SEC itself. Dr.Frank Johnson was co author with a number of other offers -- authors are in the paper it is reporting the outcome of the 15 not strained a sequencing project which was published just earlier this year. This is quite an achievement and I encourage you to look at this paper. But make sure you get this reference. Some significant activities include inter agency agreements. We have reassigned some of the point people involved. Nigel is taking over, and I am very happy to relinquish that activity. [ indiscernible ] is taking over for Dan Morgan. Many of you may -- many of you may not have remembered, but many years ago there was a concept nomination for radio frequency radiation that came to the program. And this has been an extraordinarily complicated and difficult project put together, but we are finally achieving -- we are putting this up off the ground and moving. Has been about three years in the making, but you can see here that we are making progress. This is a -- the online Institute of Technology Research Institute is read these studies are being carried out. You can see there is a crane pulled up in the building lists some big boxes on the back. Inside these are the actual redecoration chambers that are being -- that were manufactured in Switzerland and brought on a boat. There were shipped up the rivers and various likes to Chicago and are being placed in a facility that was actually where the end to be carried out its election of magnetic fields activities. You can see the chambers are being dropped down into a subbasement area where the studies are being put together. You can see these are some of the -- this picture seems to be odd to me. It did not look like the perspective when I put it in here. There are 21 of these that have been assembled and will be used for the exposure to radio frequency radiation. You can see another set of them going down the other hallway. So just showing you this. We are making progress and getting ready to the shakedown of these. The people are in Jakarta today. Ron is in Jakarta today. Several other folks were supposed to try to get to Chicago today. They are probably not there today, but the pilot studies are about to begin, and we anticipate during our pre chronic and chronic studies starting next year. The program operations branch, this is a collection of activities related see the initial aspects of how we do our studies. Nominations are reviewed by this group and other groups and are given to the toxicology prank for the initial study designs. And the actual work involved in putting these studies to get there is handed over to the program's operations branch. So chemistry activities, studies related to [ indiscernible ], Quality assurance, maintenance. The project officers that actually take the designs and put them into the contract laboratories, all of this activity is done in the program operations branch. Cellular and molecular pathology branch. This is in essence and the same branch that was called the laboratory experiments of biology and environmental toxicology. You can read through this. Many aspects of support for policy and the program archives and [ indiscernible ] archives. This group also provides all but those is support for the investigators within-digit. New areas of emphasis. Respired is placing -- he is challenging his staff to become more expert in non neoclassic lesions, interpreting and understand the mechanisms involved in that generation of those lesions. And with regard to that there is scheduled to me no pathology workshops coming up over the next couple of days. We will be looking at the reproductive and developmental Leeson's as well planned for 2008. Robert is wanted to have his group put together and out list on background with their plastic lesions and rodents. I would point out that one of the other achievements last year was that Susan and other colleagues in several groups participated in a paper that was considered the best paper in 2006 and toxicology pathology. The out a host susceptibility branch is setting up this effort responsible for the planning, conduct an assessment of chemical toxicity in multiples trains. And the other function of this group is to try to put together collaborations' with investigators that will allow their to be and interaction between the National toxicology Program an intramural the investigators, potentially even private partnerships with private companies to examine the relationship between the genetic underpinnings of response to diseases and the fans of the exposures and responses that occurred in relation to those diseases. In terms of putting together this program Jeff has issued a request for information. You can read the title of it. Basically it is to get input from the academic community as to how exactly a program of this nature can best be structured such that we could take addresses of the ideas generated in the academic to Nancy picking out those exposures that might be best approach and might give us information related to chain environment interactions. So we have 29 responses, very detailed responses from a number of different individuals. And most of these are from existing grantees. They express strong support for this program. Although there are many details that need to be worked out in relation to putting together a public-private partnerships we are moving forward with this. That is the function of this branch. We met with program staff responsible, which is a program at NIH that is focused on developing new drugs for cancer, chemotherapy and particular and other diseases. And it uses a model where there is a cooperative agreement, in essence, between private individuals who provide the ideas are particular drug that must be evaluated in preclinical and other toxicity and efficacy tests with the resources of the NCI and NIH to cooperatively work together and get the stars into a place where they could be put and with the Food and Drug administration. So we are looking at that as a model. We are also going to be asking some of you to participate in a subcommittee related to providing some advice and counsel as we go forward with this. Then Jeff has already made a number of attempts to communicate the program plans and goals at a number of meetings. And there will be a workshop on this particular susceptibility activity at the [ indiscernible ] in Seattle and March. The pilot to a screening branch. This is the branch that is responsible for implementing the portion of the road map related to the development of screening activities. For rapid detection of a body like cities we are working with the talks cast program and the chemical genetics center and their molecular libraries as it did. What do some of these the activities and interests as last time, but we are in the process of working with these groups to put together programs to evaluate and actually perform high throughput screening assays on the chemicals of contrast to the program. This also carries out the automated screening essays which is done in a laboratory at [ indiscernible ] under the direction of Harish Friedman. This group is also charged with developing analysis tools and approaches to allow the integrated Assessment of the high throughput screening and points with the findings from our standard toxicology studies. So the activities of this grant so far, these high throughput screening interactions are accomplished in little barks of 1408 Quapaw. We have made available one the Senate to vote chemicals that which has been screened. The second set of chemicals is being selected currently. We are looking to continue to select new as this to put into this program. We have had discussions with commercial suppliers. We are looking to primarily evaluate and place [ indiscernible ] into this program which target what has been turned toxicity pathways that have been proposed as a concept for moving this field for. In a report recently that came out in August called toxicity testing in the 21st century Dan and a number of very distinguished scientists worked on this effort for a number of years and have come up with the concept of moving forward in the area of trying to push in vitro approaches towards creating toxicity information that could ultimately be used for regulation. Said the targets we are looking at are the same kind of targets they are outlining in this book. And I actually brought a copy and forgot to bring it up to the podium. I have it if anyone would like to see it. We have it established in [ indiscernible ] and have found this to the tune of $1 million. We plan to try to do that again. We are also putting together a memorandum of understanding to formalize the interactions that we have and make a very concrete document and interactions so that we can understand each other's roles and how we can move this field forward. Moving to the activities, I would like to point out that the supporting agency which is the into the portion is now 10 years old and will be having a 10-year anniversary symposium in Bethesda in February. The activities of this group and the topic of this meeting will include the five-year plan which this group look that in some detail at the last meeting in San. We will have a talk on the evolution and future of toxicity testing. Dan who I mentioned headed up the effort on toxicology testing in the 21st century will be presenting at that meeting as well and there will be roundtable discussions and other discussions from various agencies discussing how these new activities will be moving forward in light of the requirements to get regulatory evaluation and validation of new systems. And the days following that workshop there will be another workshop which has a very interesting topic and Col. This workshop is on the acute chemical safety testing, investing in these zero approaches lines for Texas the valuations. But we are trying to do here is address issues that have been difficult to address through the evaluations that have been done up to this point in terms of coming up with in vitro alter access to toxicity testing in points. The idea here is to begin to look at the toxicity pathway and see if there are not be more humane and points that could be understood in the responses of animals pearly an acute toxicity testing paradigms' that might be understood to allow us to create a better way of evaluating acute toxicity and knowing when to stop a steady and also identifying some and points that might ultimately be used and a person in in vitro testing methods. Since this is a concept that I don't think has been approached in other workshops. It is a difficult concept to get your hands around and it has been a very exciting concept that a lot of people have shown interesting. And finally I would like to mention clearly the poster child of the animal rights movement has been the rabbit eye test. I would like to mention -- let you know that we have for did test method evaluation reports to their agencies in October of this year concerning for in vitro methods that could be used piece. So this is a significant achievement. If positive findings are coming up in these tests. There is no need to go on. So this is progress. Moving on to the Center for the evaluation of risk those of you who were here in CNN have a fairly good introduction into this situation. Dr.Wilson just talked about this briefly in his comments as well. Again this site survey is an analysis activity and of the program office. The product of this activity is something called the [ indiscernible ]. There have been done put out on a personally 20 chemicals so far. We are working now on completing the review and evaluation. There were obviously problems that were encountered during the review. There were allegations of potential conflict of interest with the support contractor being used to help assemble some of the background documents and some of the information that went into the early Travis of the expert panel working group report. We had a first expert panel meeting in March. In April there was an inch round draft panel report released for public comment. This all steps beyond the March meeting carried out beyond. There was a separate panel meeting in August. Just last week the final expert panel report was released for public comment. We plan to the brain -- you will not be allowed to but not participate in our joy over the review. We plan to bring the brief, which you will hear about later from Dr. Shall be in his comments to the board of Scientific Council is meeting scheduled in May. Maybe we can make it sound. So the steps of the program has taken briefly in response to issues led to conflict of interest them up during the review include the following. As you know, we have reviewed all contracts for potential for conflict of interest and developed language that has been incorporated into the contracts. We have also conducted an audit of the draft panel reports. This activity was carried out after the June meeting site. That is why I am bringing the findings to your attention at this point. We ought the tip -- audit said the search strategies and the Fidelity and the December and March versions. I won't bore you with details, but I can't go over details with you if you wish. The audit provided assurance that the expert panel reports did include consideration in our estimation of all the relevant references and included changes that were requested by the panel members. We concluded that the draft of expert panel reports used to print the panel to the states that message earlier was useful for this evaluation process. The next steps will be receiving public comments on the final expert panel report. And those are due by the end of January. The brief which is a short synopsis of the opinion about the potential for a particular chemical to cause repetitive or development of the facts were risks to human health will be prepared by the staff, and reviewed by an interagency Court committee and released for public comment before the meeting. Fiske there will be a review of this draft brief carried at the meeting, and we will be supplementing this with several experts. And then [ indiscernible ] will be finalized and released. I showed you this slide at the end of my last presentation. This has not changed. The program expectations are to continue to provide basic toxicology and increase the emphasis item [ indiscernible ]. [ indiscernible ] with our existing testing information. Continue to work to develop new methods for toxicological [ indiscernible ]. And very importantly we should provide guidance I would like to stop there and take any questions. Asked I did --
Do you have a target date for when studies will be started in this program?
Well, we should begin the pilot studies and September of 07. We are about four months behind. We are looking at January. That is a quick study and we will probably do -- these are perinatal. So we are starting exposures to pregnant animals treated they will be starting in probably February for the pre cryonics.
Any other questions? If not. Thank you. Our next agenda item is on the study plans for malls. This is not an action item for the board. This is an informational advise item only. However, this is a departure from the usual steadies'. It is a very difficult area of work. Therefore the advice of the entire board has been requested. We will ask for comment and advice. Following approval zero that group met and made recommendations. But from that we have a study plan that will be presented to us.
Good morning. Thank you for allowing me to update you on this exciting and challenging project that the NTP has undertaken. So, you will hear me refer to the malls sort of interchangeably during the talk. You are really focusing your studies on balls. As you probably experience in your kitchens are perhaps sometime in your home fungi are very ubiquitous from the penicillin the you see. This is particularly in water-damaged buildings. This is found commonly and both indoor and outdoor environments. And this is a good illustration that in the environment and what people encounter are various different life stages of fun bad. So you can see, we have stores. And these last stages -- what the organism produces carries with love life States. Sorry. So why study mauled? Well, this is an extreme example. I want to point out that when you see mold like this is really a combination of the number of different things. It would be a number of different strains of fungal organisms. It will also have bacteria as well as [ indiscernible ] growing in it. So I referred to it as malt I acknowledge that there are a number of different organisms that are essentially co cultures. When he sees something growing on the water damaged building this is actually the home of a collaborative. This was her home tennis and heard think the trend. And yet I shall see a picture of her letters. So exposure to the malls or thoughts levels of months -- molts has been assisted with a whole concept of sentence. Some are neurologic and some are pulmonary and respiratory. You can see exacerbation of as not. There are all kinds of cotton to difficulties reported, vision problems, memory loss. And so it is a considerable public health concern. It is so important that the Institute of Medicine did an analysis of data. In 2004 they came out with the report on indoor spaces and health that was published by the National Academy. In this report they found a significant evidence of exposure to damp environments and some environments. There was a suggestion of an association between damp indoor environments and respiratory illness in otherwise healthy children, but it was unclear what the stimulus of this respiratory illness was, whether it was specifically mauled or whether there are other common and/or elements such as dust mite, a cockroach, animal dander. There was insufficient evidence to determine whether damper environments are related to a number of other health outcomes. One of the things that is been in the public attention is [ indiscernible ]. It is a very visible. It's black and of the looking. It has been reported and the popular press as toxic mold. So much of the press that has been associated with looking at health effects have been associated with [ indiscernible ]. So the Institute of Medicine felt in particular that it was important to point out that there had not been associations. However, there were very many data gaps identified in particular with areas of narrow talks. There have been some association with imine diseases, reproductive effects and cardiopulmonary. Again, many uncertainties remain. So there have been Betjeman's of exposure to fumble Ellison's, but they are limited to a very small number. The potential for the different components of the orgasm to end these health effects is also unclear. In the relationship with fungal exposures and many of the neurologic manifestations is also unclear. Upswept. The molds were nominated to the toxicology Program by a private individual. That nomination did not include any specific organisms, and points or health effects. It came up with before the board of Scientific counselors and the board endorsed the study and suggested that the program consider studying not only steady but just the other organisms commonly found in such as penicillin. We had an internal cost of reviews similar to what you will be seeing the results of the ledger on today. In 2006 and the entire concept review committee suggested to primary things. One was that we solicit expert input on how to conduct large-scale real life exposures scenario rodent toxicology studies and to seek advice on the end points that we should measure. And the second point was to explore the feasibility of conducting studies of real life exposures. So this is a very significant departure from these traditional study reviews a well characterized compound. We have a good idea of the metabolites, where it goes. This is a great leap forward. Even early in the process want to point out that there was quite a lot of debate on what to study. I already talked about Secchi and some of the other malls and how to study them. So we convened a group of scientists who had significant expertise in studying malts to talk about the design and conduct of an all types of policy studies. This meeting took place in March of 2007 and the report is included in your folders. And we informs their group of scientists that came that we wanted to implore -- employee exposures scenarios and that our focus was to identify potential hazards to human health. We mentioned that this is a departure from a normal study. The first thing we think about is the chemical to be tested. There are well over 1 million species of fungi that exists. Only 80,000 of them have been described. In terms of care transition of things like that spores and the potential mycotoxins or vault so organic components that these things produce, this field is a very much in its infancy. When we look at the King's Lycra of exposure we still -- lesson that most of the exposure will be in violation. Score ever there is also significant in Justin exposure. There is mold -- mold on the food we eat. There are also significant turmoil exposure as well. We have the considerations of a species, strength, and gender. We talked about susceptibility and potential susceptible sub populations. So this is something that we wanted to at least consider addressing with the information group that met. I wanted to point out some of the key issues and complexity of studying these organisms. There are a number of studies that have looked at isolated might retard cents or they have looked at different fractionated portions of these organisms. When you think about doing a real lead exposure scenario one of the things we are then talking about is using whole organisms bursas well described talks and. The growing conditions were conducting a broad toxicology study may be different from the growing conditions that are up the mall for malls. So in terms of temperature, humidity and the substrate we select these are important things we need to consider and the design. I have already mentioned that led states in terms of sports and the age of culture thaw is not only important in the different things that you find in a real life culture but also because these toxins vary depending upon the live stage, temperature and humidity conditions. So again, a consideration. So there is a summary in your report of the recommendations. We felt it was important if you're trying to emulate a real lesson are at the weaker of the organisms on building materials. We wanted to simulate a high humidity scenario which would be at damp building where an air-conditioner is producing some condensate and you get a little bit of mold growing. Also a century since the Mariel would be more like a water damaged building, a hurricane could train at type home where there have been a sense in saturation on the carpet and wallboard. We should use fresh isolates rather than art of cultures because some of the Arkwright cultures have lost their potency or a lot of their ability to produce toxins. We suggest redefined the goes States and harvest material for use for the entire study. They gave us an extensive list of materials we should characterize samples for including micro toxins, potential Allison's. We will look at particle size, activity, colony farming units and these boards produced and the sport count in the material. We are working to evaluate bio markers appropriate for the fund had been used. Some of these are available in literature. We partner with NIOSH. [ indiscernible ]. Protein and some of the metabolites. We ought to look at tissue burden and distribution of some of these products. The group felt that our current models were appropriate for these studies, but the ancillary studies could also be included that would address issues like susceptible populations or specific and points such as some of the amino respiratory and points or some of the Ottoman diseases. And just to release some of up, everyone that came thought that exposing animals to a real life mall the Environment was not a good thing to do and would provide important information to help protect the public health. So where are we going with these studies? Our research program needs to integrate the results from toxicology studies, a clinical partnerships and bio marker and exposure data provided through the studies as well as through other agencies to produce sort of as for the picture as we can on the health effects of mold. I talk for a little bit now about the road and toxicology studies we are proposing to conduct. Our specific aims are to assess taxes see. We will evaluate the currently available markers as well as develop new markers. We hope to evaluate the contribution of different organisms by not only studying "cultures of malt but individual estimates as well. We will start by conducting stop chronic studies of rats using insulation. We are quite a test to make shoes to simulate real live exposure shares. We will obtain a mixed culture of mold from the home I showed you the picture of earlier. And we will also obtain a mixed cultural malls with reporting health effects. It is the sick building syndrome we will obtain that culture from EPA. We are also going to test for us lots of individual organisms. We will test to different Islip's of stacte bought shares. The two types produced two different types of mucker toxins. So we will be looking at one Isolette that produces each of the different human types. Study is that greenish black fungus to see. Is known for colonizing high sales building materials, particularly in affirmance of excessive watering humidity. We are also going to look at aspergillus. That is common in indoor air as well as on dips and board and furniture materials and wallboard. And finally we are right to look at [ indiscernible ] which is common in indoor and outdoor. It is one of the most important fun guy in terms of elegy, infection, and as the severity. During the studies will be looking at neurotoxin plants. We will be conducting a functional operation battery. We helped a partner with an individual at NIOSH and Michigan State to work on old factory sensing and points and we will be during target to testing of animals. We will be looking at impact on particular target organ systems including the cardiovascular system, the pulmonary track, GIs system and immune system. We anticipate that these studies will get less significant information on which organisms may be the causes divisions for command of. We are looking at potential organs for toxicity, does dependency as well as the utility up by a markers which is primarily what is being used now for frontal exposures. We hope to use our roads studies in our clinical partnerships to bridge gaps. We suggest that the recess will provide information on additional clinical measures that should be looked at in epidemiologic studies and we felt that information from our clinical cooperations can be used to develop airmobile markers of exposure and the fact that we can use in the Russian studies. I want to take my last few minutes to talk to you about the clinical partnerships we are doing. This collaboration is part of the Hill study. It is setting off and violence all asthma on a Louisiana. If this is being primarily conducted through two lanes University and been funded by a number of different government agencies as well as private foundations. It's primary objective is to implement and test and asthma program to get the impact of Hurricane Katrina our kids with asthma and your odds. Some of the questions they're asking this was there is an increase in how adjusted to the excessive moisture after Hurricane Katrina. They're looking at mold, Park Ridge, dust mites, then there, except for. Is there an impact on the destructive health-care system. Of assistive few details about the study design. It is beyond the scope of this presentation, but in order to help you understand our part in it there will be for ordered 50 kids enrolled. They need to have a prior diagnosis of moderate-severe asthma. They will look at a variety of and points including symptoms such as wheezing, days with symptoms, your typical as of measures. There will look at biological measures of lung function clinic or emergency room visits. And they are going to do a number of the virus of measures in collaboration with the EPA. They are looking at baseline levels of mold as well as a number of other religions and looking at moister and humidity in the home. They are pointed to a very a extensive clinical evaluation of these individuals including questionnaire. There are going to to halogen testing and the individuals including an expanded molt panel and will do a blood drop. Using the information obtained we are going to look at -- and this is highlighted in red because this is the partnership or collaboration. We are going to look at total [ indiscernible ] intelligence Pacific focusing particularly on both. And again they're going to do extensive environmental evaluations as well. Such a focus and we will be looking at total I see and allies in specific. So we will be running a whole panel adjust their rates intelligence that people look at, testified, cat, dark, rat, Miles, a cockroach scurried to will be doing it makes small panel and will look at a number of faults commonly found. How is it in red are the ones we are doing in the road steadies'. My pleasure want to turn off. We also have some Katrina specific mold evaluations. So we will be using the makes small screen panel as well as six have been identified with increased prevalence. That includes stacte buttress and aspergillus which are to that we are quite to be looking at in our rodent studies. So all of the positive and the jewels will be tested for the Trans Pacific mall evaluation. We are also quite to look at 50 individuals that are negative. And of those 25 will be individuals that have high levels. Suppose would be individuals reconsider allergic but are not allergic. And then 25 of those will be true negligence. Velocipede looking at specific waltz. And this is because kids that are hyper reactive, report be able to skins prick test. This would give us additional information. 45percent of those had a positive test to the mold mixture. We are conducting some Pacific mold evaluations. Of the 39 positives there have been great duty to eight of the malls. That was very high. [ indiscernible ] is common in indoor air. One of the things we were studying it was included in this this kind of fell in between. So with that I will come back to why we are studying mold. This is a house in New Orleans not being torn down repeated. If this is most that is growing behind a wall board. This is not from New Orleans but small drawing. You can see here that you could not see the mold underneath all port. Same here. One of the concerns is that in addition, to people -- in addition, to the exposures that routinely occur there are exposures and homes that you cannot see. And so we help to provide public health information so that people will feel or comfortable or at least now about the hazards they cannot see. This is our collaborators at Tulane. Was her home that I should you pictures of. We hope we can provide information so that people with mold and their homes don't feel they need to walk around like this. I'm happy to take any questions.
Thank you. Questions or comments around the table?
Despite the collaboration I really don't know anything about this study. That is beside the point. Considering we're two years out can you talk a little bit about the experimental design where you can actually show that this is Katrina related? How does that work?
We are using a mixture of mold and will be obtaining a culture from a house that was saturated during Hurricane Katrina. So what we hope to provide information then would be on exposures to make shoes of organisms that might be commonly found in homes falling in the event like Hurricane Katrina.
I am new to the panel and not familiar with previous discussions, but this -- I had some questions regarding these studies with the mixed culture of mold and the individual organisms. Have you already demonstrated that these mixed mold cultures from the house in New Orleans and the sick building syndrome, did they actually contain the same organisms that could be looked at, the as / of organisms? It seems to me to be able to sort out -- you need to be testing the same things individually.
We will characterize those cultures before and. The individualize a let's will be isolated from those cultures. We -- we will have a very good handle on that. O We are going to obtain has been very well characterized with what organized -- organisms are in it, but we will grow it and characterize it before we use it in our cities.
Other questions?
This is a very ambitious and important program. And I'm sure I preach to the choir when I say very complicated and hard to interpret. This is painfully relevant to me because I discovered a leak in the roof over my career I ask very recently. We took out a ceiling that looked very much like the wall. The Hinckley nobody lives there. But this is nationwide. Even in San Francisco we have this problem. A couple things come to mind. When I read to the document and then when we were talking here, I'm sure you have thought of this, but things that kind of -- there is a preference to saying that it says it will be done under space permit conditions. The guide is 30-70%. Every facility in the country will tight that 30 percent which is nothing like the conditions that people are living in. New bonds and North Carolina even. 95percent timidity. I don't know how you're going to bad -- balance the animal Welfare and care issues. I don't have an answer. It is just something to consider. When you get into studies we all know the important component is the analytical chemists the characterization. I have done some work with a natural product extracts which are roads of the sample. You're going to need marker compounds to show the does you're giving is we think you're giving. If you work with posters of multiple malts couple not sure how you're right to do that. I'm a little concerned about the idea you will take samples and calls to them and then test them and have it be the same as what is growing in the walls. I think back. Years ago when we did work with complex mixtures or you go out and take diesel exhaust and say there are 80 chemicals and then you reconstruct that you never got the same results as the actual complex mixture. Particle size, mixed-race and a whole bunch of other things. That will be hard. And my final point is we have some fine see our arose during work with you. I doubt any of them have any experience in anything like this. You have to build capability from the ground up before you even start doing studies. People have tipped have experience handling these things is it misters of spores and finance and live organisms.
I will try to address those. We talked extensively -- [ indiscernible ]. If we end up doing to cut one of these scenarios for doing these exposures is the Crow the material. Would be grown. Phew it will be tried down as dust. And this scenario -- so you are exposing to a real-life Mr. Come about the exposure scenario. You have your material and test article. So that was discussed extensively. The information group really felt like in terms of animal exposures that they needed to focus on the conditions that were optimum for the health and safety of the animals rushes the organisms. If we used organisms that works right down and harvested, that would address that consideration. There is that point. I will say -- and I realize that this is a massive undertaking. And this is different from a traditional study in that we are not necessarily going to be able to say that this is exactly what be exposed, and this is exactly what happens because of this individual component that be exposed. That is a significant departure from the study. We will be able to provide important information of what the end points are in terms of target organs following exposure to the multi of looking at and some real-life mixtures. We would characterize to the best of our ability and note that this is going to require some novel context and strategies to approach both exposure and data interpretation. I see that Don and Greg are over there. We are currently already doing market research we need to do a study. If it is done as a dry dust then it can perhaps be done similar to how we do other traditional studies. We know of at least one organization that can probably do this from their previous experience. And that is all I will get into in terms of the function because I don't want to get in trouble with the Contract folks.
Just to follow on that, what I think I am hearing you say is that you believe that the dry particles will in fact have the same pathogenesis potential as particles in a dead environment? RS Mike gearing you say you aren't so sure that is true, but this is what is feasible?
It is a little bit of a combination. People are exposed to dry dust and mold. When you are enable the house and the fan comes on for air conditioning then you get dry dust that is spread around. You get that inhalation exposures. So we are simulating that aspect of a real live exposure scenario. We aren't going to simulate in the Russian studies 90 percent humidity and inhaling this stuff off wallboards. So one of the considerations is that when we drive down this material will we be isolating the things? Did was pointed out that as we grow this stuff would be to make sure it is [ indiscernible ] because we are going to be doing inhalation exposures. Och there are probably bacteria as well as other things in these cultures. So people are exposed to dry dust. So and that aspect we are mimicking a real-life exposes scenario. But clearly if you step into five different houses the exposures will be different in all five of those. So what we will be doing is dividing the exposure as well as we can and knowing that this is the exposure. So this is going to be very might set a, this is what we studied. This is what we characterize from that study and these are the conclusions that we can trot. I think that we need to be Terri careful when interpreting this data that is necessarily globally acceptable to Albany mold situations. We know that isn't the case but we can provide information on and point and bio markers were specific exposures.
I a agree with all that. I would have some concern that in different human environments organisms be -- may be more pathogenic. Negative results may actually underestimated risk. But that is what they've got to be it one other question and I'll turn it back to some other board members. I did notice and written documentation provided estimates that you intended to do pulmonary function testing court challenge testing. Is that included in the tests?
If we saw health effects it would be ancillary studies and they would be collaboration's with investigators are the folks and the extra rock community. So we have the capabilities of doing this test. We are working with Michelle in the laboratory of predatory biology. They are actually on the design team that will work on these studies. So we have the expertise to do that, but it will not be part of the Hazard identification portion of these studies.
From the cult perfective I encourage you to the as the population, that would be a key issue.
Thank you. I am just sitting here. I am getting a wrong with what you're going to do with the data when we are all done. I'm trying to put it into that reasonable box that this is really the hazard ID. Because it is like, we are trying to amass all this data. What are we going to do with it? How will that help the real world. Now we don't want people living in mold infected homeless. If we think about this hazard it like that does response steady I am having a hard time with that as being the very meaningful in the long run. I am sure you had a lot of discussions about this. Can you just give me insights? This is going to be a huge investment. I think we also officially go, what a great idea. But then, what are we going to do with this? Will it cause more problems than it will solve?
Well, the short answer is yes. It will cause more problems. But I think -- I seeking a number of things out of these studies. One will be additional places. Right now after all the exposure is Barry much focused on their respiratory system. Asthma and other pulmonary and points. There have been fairly -- the next thing is the neurotoxin, the comet to issues. There had been accused of these on some of the other potential target organs. And when piece where I see we are quite to make an important contribution is looking at the potential target organs for this. For example, if we see immunologic effects there has been suspicion of all the minutes your suspicions of association with are the minutes tick. Without doing these has identification studies I would not know which model to put it in from step one. And so I think that we need to get some information about other potential target organs. I think that we need to actually have a mechanism for trying to figure out, once these things get and what happens? What happens to the toxins? Where did they go? We know some of the very important marker toxins, but we don't know it for very many. There are not a lot of by a markers of exposure or a fact. So this will make a very important contribution in terms of developing those as well. So those are some of the things I can see coming out of it. If we see a constellation of health effects with a mold Mr. -- I don't think that is quite a surprise anybody. The OTC clinical effects in people following exposure to mold, but we'll at least have some quantitative measures of the amounts of particles were supporters or-that cause these health effects. So we will get an idea. So those are the places where I think we can make a contribution.
This is just a comment. The concern I had when I looked at this -- and I realize it is a problem with the exposure, but that is not the exposure conditions. Is not a problem of low humidity or temperature. And even from the terminal area exposure of normal skin and humidity are entirely different scenarios. So I really -- this just adds more scope. You really need to consider that susceptibility, we know that will be stressing. You might get an entirely different type of scenario.
Before you respond to Dr. Walker wanted to make a comment.
I would disagree for the following reason. Let's take your sick building scenario. We typically have -- there are reasons for the mall to be there. But people who are being exposed, you were in a normal humidity temperature environment. You're being bombarded from these point sources. It is more or less what they are talking about doing here. They are trying to set reproduce what is happening worries still have the moisture. And I agree with you there, but there will reproduce by having this which I is 75 you're calling it particles, but you're talking about different parts of the mall. You're still going to have intact sports which is what you experience in a situation if you get away from the trend.
I agree. Even people moving back thaw, the committee will be high. I'm just -- it is that interpretation following up on your point. When you finally get this data you will have mulled under different conditions that may not all the -- be applicable.
If I could just comment, once you move into a tree house you have air-conditioning and temperature control. People are focusing on going in and renovating a house. If one of the concerns is everyone does there house tested for malls when you buy a new house. It is those sports and things that probably are the long term out comes.
IP think [ indiscernible ].
Of glad this is not an FDA issue. I think this is it. Important undertaking. This is going to be a public health issue. To buy -- okay.
Think one of the issues that comes up is coincidental or co exposure. If I remember it was added to the ends looking homes thaw or other complications that allowed them to be sensitized. That is what resulted and Co, the filly or distress which argues that it is a co exposure for a compromise of the health system which leads to the infections, at least in that population. That is a long explanation to get to the point made on page nine. What do we know about animal and their productivity of human respiratory small disability?
Some we know that animals can desensitize.
I think we have good examples. You can sense that animals to test might and to some of the Concord halogens. So you need specific conditions. I think those kinds of studies are a little bit outside of the Hazard identification studies that we'll do. In terms of co exposures, when we do that mixed cultures we truly will have a co exposure in terms of not only fungal organisms, but again there will be material from the bacteria that is in there as well as anything that gets harvested off the wallboard. I mean, there has -- it has been a longtime and I joke with this. I really see sometimes that exposure scenario for this, just big sheets of wallboard with mold growing on it and sand blowing across it in animal cages. I really think -- again, that simulates a really live exposuresSo there have been a lot of studies with molds, but generally using individual Mike owe toxins, versus, or fungal fragments, doing work with A leverageis desinsitization, different fungal fractions, as well as spores, looking at fragments, spores as well.
We can sensitize animal models. I think we have some aspects of the culture covered. We are not going to be able to take interest account, at least in these studies, currently designed, other environmental factors, liking environmental tobacco smoke. There were discussions about host susceptibility, looking potentially at different strains of mights later on. These are ancillary, clearly genetic components to as many as well.
I think clearly, for the hazard identification phase of this study, we need to be at least somewhat focused on sled exposures and not worry so much about some of the other co-exposures.
I will curtail discussion at this moment, come back for more discussion. We have two individuals in the audience for public comment.
Dr. Shoemaker and doctor huh old. While they are coming up, we have numerous written comments, comments by Mrs. Susan Break man, school mold help, Sharon Kramer, public citizen, Lisa Nagy, American academy, center for research on biotoxin and associated illness, and Dr. Singer, professional association.
We will move to public comments, then board comments, then if you will stay with us, we may have more questions to come back to you. Our first public individual is Dr. Shumacher, from the center on biotoxin and related illness. I am going to ask you take the 7 minutes normally allotted so we can give individuals time to make comments on your presentation.
We want Dr. Hud kneel to precede.
private citizen speaking on behalf of Sharon Kramer, private citizen not able to attend.
Good morning. I am very grateful to have the opportunity to address the NTP this morning on the topic of mold and human health. I commend you for taking on the role, there's long been a need for leadership on the area, very slow coming. Hasn't come from CDC, from EPA, you just heard how they are looking at A jerjic aspects of mold, allergic, but it's important to look at the toxic aspects of mold. I have been a neuro toxicologist for 23 years at EPA studying human health effects related to a variety of compound exposure, air borne metals, pesticides, and the last 10 years I have focused on mold or biotoxin associated illness.
Most recently I led an interagency effort to address the issue -- single cell organisms that make multipole and highly ponent toxins, much like mold does here. I have addressed reports on that issue, and the editor, coauthor of a 1000 page book about to come out on the -- state of the science and research needs. I am glad to be able to address you today about mold, you can see I am pretty excited about having left EPA, Tuesday was my last day at EPA, have now joined a company that the best solution to fresh-water blooms. Before I address the risk management aspect of clinical intervention, now addressing the risk management aspect of preventing molds.
I want to make a few brief points, leading to what we call biotoxin -- a contentious area, as you have heard, inappropriate position papers misleading the public. This problem will ultimately be resolved when someone like the NTP takes leadership, and was so well expressed today in earlier talks, will combine what can be learned from human and animal research.
It's a highly-complex mixture to which humans are exposed when in water-damaged buildings. Many types, as well as fragments released to air and humans breathe in a very complex mixture that can involve, if you if you various compounds, and toxins. This is an example that it's important to do what you are doing, look at mixtures. This is not a simple -- this paper gives example, one if you think fungi, one -- fungi, one -- a variety of mechanisms to which they -- they often verge on one common pathway, the induction of an inflammatory response, primarily governed by the immune system.
So, with Dr. Schumacher and others, I looked at illness for a long time, starting with fister ya, and human mold illness, we have -- bacteria, Lyme disease, a toxic illness that follows the disruption of the bacteria. Biotoxin-associated illness is very frequent characterized by a variety of symptoms, due largely to inflammatory responses being initiated, can vary in people from day-to-day. We found a useful indicator of neurological effects by looking at visual contrast sensitivity; a process through which visual patterns are detected. We found in biotoxin-associated illness, a large, maybe 60% loss of ability to detect patterns, and we can see recovery of this, along with symptom abatement when we treat people with coul owe stire owe mean, a compound that vastly increases toxin elimination rates. I encourage you to think about using some of this intervention aspects in your studies, the coul owe sire owe mean is shown to vastly increase the elimination rate of a wide variety of toxic ins, including some micro toxins.
Some of the main things we see in -- the abnormalities of the -- pathway, increases in -- probably due to damage to -- receptors, and the result of low levels of MSH, markers of damage, all coming about due to inflammation caused by cytokines, and the -- complement factors.
As we mentioned, it's a contentious area. I was really shocked when the ACOM came out with a position paper authored by a few people that basically reached what they claimed to be a definitive conclusion, that it's highly unlikely that humans are ever going to get sick from this complex mixture of things found in water-damaged buildings. What did they base this on? One single mouse study, exposed three weeks to one stipe type of spore. They also used literature showing this level at which effects were seen is unlikely to be found in indoor air because they looked at a survey of building concentrations of mold in buildings where people weren't sick.
They really failed to address a lot of issues. This study did not show -- other studies indicated the Noelle is quite a bit lower than the level their study had. They failed to realize that people aren't just exposed to spores, but there are many times more fragments, loaded with toxic substances that people were exposed to when they inhaled air in these buildings. They tested the least susceptible population in this rodent study. Three weeks of exposure doesn't come close to what human experience. Most humans get sick after months of exposure.
Most shocking to me is that you make, they would make a statement on human health risk assessment without doing a risk assessment. There was no taking into being the account all the things -- no susceptible populations, short-term rather than chronic exposure, no information on developmental effects, cars no gistity, disregarding the need for need assessment.
You have two minutes remaining.
As we said, it's a very complex mixture. The NTP has the tune the to opportunity to really take a leadership role by partnering with people to do the human research, do complementary work together with NIEHS or together with -- that's it, thank you very much.
Thank you, express our thanks to Mrs. Kramer.
Next speaker is Richard Shumacher.
Good morning. I thank you for the opportunity to talk to you about my passion. I've been a private practice physician for many years, practice started in 97 where blooms of an organism, fister ya, made people ill, and there was no one to help me with what to do, how to evaluate patients with s with these illnesses. I I am pleased to here the NTP recognizes the number of illnesses that need to be evaluated and specifickyally the roster of organisms ever increasing. I wouldn't have last year put micro bacteria on the list, now I will. Proteins made by stacky boit rise, excellent paper from Dr. Dearborn, hem a lice ins, materials inflam owe Jens identified identified in -- found in organism and buildings. These are real, we know them now. I don't know what the list will be next year. I would emphasize the spore counting is, in my opinion, now, not a very useful exercise. Focusing on spores ignores the very large part of the iceberg.
Specifically, I have over 4500 patients in Excel data sets I have looked at over the years. We know there's a very strong genetic basis to the illness. 40% of the population will have -- associated with the increased relative riff being in illness acquisition. That means 76% don't. A sick patient and non-sick, with the same exposure need to be looked at, and separating cases in controls when looking at genetic aspects. We know full well if we follow not acquired immunity, cases are no different than I GE controls. I hear you focusing on I GE, that has merit, but not the same as focusing on innate immune elements. The final pathway of deficiency -- critically important. I hope the FDA guy will help me figure out how to get exemption, they are all deficient, all needed. Specifically what we have done in my office, take patients who willingly need to know if a given environment makes them sick. They come in ill, fortunately we can treat them, reduce the very many biomarkers we control, stop interventions, let them go to other environments other than potentially water-damaged buildings we think might be making them sick, we document, no change in symptoms. Put them back in the affected building, measure biomarkers on day one, two, three. That ability to see prospective change of illness presentation without any other confounders in time gives us a chance to assess causation. Also gives a chance to create a health index -- innate immune -- that's all on the printed material. Specifically treatment, not the focus of your discussion today, but I will tell you coul owe stire owe mean is your first step. We need to look at these very unusual bio-- deep nasal spaces, hardly ever found in controls, these organisms make toxins that cleave -- and must be removed to have treatment follow. Must be down-regulated, comment about abnormalities and -- T-cell abnormalities are common, and these patients in children especially compared to adults, 58% of kids will have -- antibodies without cell ciliac disease -- walking around
A huge issue, we worry about angiogenesis, cancer, most have incredibly low veg F, we look at the feck by -- see the delivery of oxygen is down in the range of class 3 and 4 heart failure in these patients. The toxins, activation are hugely important, C 4 A is probably the most important marker we look now. We published a paper and have one coming forward.
You have two minutes.
The cognitive issues have dominated my practice the last half year. Where do these come from? We are doing -- in patients with a 1.5 tees la coil in Salisbury and can show in cases compared to controls extremely high elevated levels of lactate compared to glutamate, ratios, high levels of C 4 A and many coggingative symptoms. We selectively treat for high C 4 A, not enough to make clotting occur, we see symptoms disappear, resolution of lactate elevation and normalization of --
We don't know if -- is so important why do these illnesses appear only after a -- event. Is there an effective antigen presentation .d recovery, made ill again, markers higher -- you do animal study and --
Looking at the role of innate and immune receptors, we need -- in these patients, and the role of bleeding is well explained with acquired -- disease.
Specifically we don't know if HLA is the same in rats and mice and men. Must look for , absence of -- in patients. It's incredibly important. I have not seen any good studies. Be nice to find -- specific assay with no NOAA, looking at -- inflammatory genes analyzed, hoped to have ready for today, presentation out next week, research is encouraging looking at the behave being mechanism of illness. The real issue I want to leave you with is that there's a pathway in a model for illness acquisition in people that is seen reproducibly. Each of the elements that are abnormal here contribute to the illness and each must be addressed to achieve wellness.
Thank you for your comments and written materials. I will turn back to the board for questions of the speakers or of Dr.
Dr. Walker?
I would like to make one comment. First impression might be this is a problem that's common in areas of moist environment like the southeast or northwest. I would like to point out the state of New Mexico is in the top 10 states where you find production of molds, in spite of the fact we have 8 to 10 inches of rain a year. We get a little moisture and the molds go nuts. If you have a building where you have a water leak, if it rains you have all this mold that enters the air, fragments, microbe rail fragments, spores, buildings in Albuquerque where we have toxic mold problems.
Thank you. I had another question about the design. You mentioned New Mexico's problem, should be recognized hospitals have a problem. Our unit, premature babies, we just had a mold event. Had you looking to characterizing extremely early life exposures. From the model, this probably will not capture that population.
At least initially we will not look, but there has been suggestions to do these in reproductive and in developmental studies, a good potential candidate for per I natal studies, those type, per I natal exposure, neuro, immuno toxicity, and reproductive and developmental issues. One of the issues in terms of developing the next tier of studies is we need more guidance on what to study. We won't be able to look at all of the mixtures, individual components in these types of studies. That's a life-time research study for me. I think we are trying to focus a little bit on the hazards identification aspects at this point, and then we will move on to the more specialized focused types of studies.
That's what I understand from the dossier you provided. I would say you might find the sub-population studies in fact need to be considered more main stream, depending on what we find or not.
Other comments?
Paul Howard. Can I ask a point of clarification? On your NTP project on molds, point two, as far as recommendations, convene an expert panel, is that the one you have or --
That was the panel already convened.
I would like to make a designation you keep that panel together, I would hope you had one or two people concerned about mold ingestion, not only inhalation.
We do, and routinely discuss these studies with all the panel members. I talk with Jim pes cay all the time, he and Tina ra ponen have agreed to serve as ad hoc members of the design study team and we work a lot with Don Bees hold, deet live -- we really have a lot of outside input as well as the internal design team, not only NTP --
Fed almost entirely from a public nomination process. We receive nominations from a number of sources, primarily other federal agencies. We hold a formal review on approximately an annual basis, cycle groups of 10 or 12 nominations through the process each year. The first step is a federal interagency committee review who helps us formulate preliminary -- out for public comment. NTP staff take the nomination, begin to develop research concepts which you have and will be reviewing for us today.
These are also reviewed in house before sending them to you for your comment at a public meeting as we are doing here today as the Board of Scientific Counselors. We will take your comments, consider them, revise the research concepts as appropriate and put these before the NTP Executive Committee for the final step in the review process before the NTP moves forward to design and initiate the studies as needed.
The group of nominations we are finishing up here at this meeting today is group of 10 new study nominations reviewed by our federal interagency committee last December. These nominations and study recommendations went out for public comment in the spring at our June meeting. We asked you to review four of these 10 nominations, and at this meeting today we are finishing up with the remaining six listed at the bottom.
What is it we are going to do here today? What have we asked you to do to prepare, individual staff scientists in consultation with others developed draft research concepts, for fist of five of the six, for one we have no -- I will get to that in a minute. A research concept is meant to be a brief document, the railed rationale behind the nomination, at a high level, not containing experimental design details.
We try with these to address the issues raised during the nomination, the preliminary study recommendations that we heard from our federal agency committee, as well as point out key issues we think need to be addressed or which may pose difficulties, outline the data gaps and try to formulate high hypothesis and specific aims we think we can address. These concepts have been provided to you. Further on this morning you will hear presentations from the project leaders. Gail mentioned each will be followed by questions, general discussion, any public comment, and then ask the Board to vote. The Board will be voting on whether or not the nomination warrants study by the NTP. We have been asking for your comments on the research concept, not asking you to vote on or approve the proposed research program, but merely whether or not the program should pursue the nomination.
In these charge questions in your notebook, we formulated these to try to orient you on the type of review we are looking for. A clear, valid rational for the proposed research program, articulated -- does the program -- as outlined appropriate in scope given the public health importance. Are there other studies we should be considering as part of the overall research program. Finally, does the program merit utilization of resources and what priority would you give it.
Today's session, how are we going to mover through the rest of today's session. Luck I willy you won't have to hear from me. We have presentations from other staff. We will move to the individual research concept presentations, amino Perot dines, Dr. Irwin and after lunch we will move to nano scope -- Dr. Walker, the project leader for -- Dr. Mike Sanders, in the intl interest of time I will make a brief presentation on what we feel is a fairly limited scope of this propose said research program, intels I will as well as I will tell you about the study recommendation for -- the nomination for which we are not recommending study, have not presented a research concept to you. Finally will end with two concepts for that thalides -- not a new nomination, relates to a number of programs we have ongoing or completed, being reported in our toxicology report series, as well as several prior nominations for -- evaluation on risk to human reproduction in the monograph for -- thalide.
I would like to clarify anything about what we are going to do the rest of this morning, early this afternoon. If not, we will move right into the concepts.
Fferz
Thank you.
Is the first compound is amino Perot dines, Dr. June . June Dunnock.
Good more thanking. Today I will go over the research set for the amino perodines, this includes studies for two A mine owe perodine, three, and 4 A mine owe perodine, because of a lack of information suitable to predict chronic toxicity and tox is it for this class of chemicals.
The studies requested were tox Ico logic characterization, including a two-year cancer study of 2 amino perodine, and neuro tox evaluation on the 3.
The production of 2 amino perodine was -- through 2002, it's used as a starting material in drug production. As mentioned, there were no standard tox studies reported in the literature. 3 amino perodine didn't have use production data reported in the literature, it's used an intermediate in pharmaceutical productions and dyes, there's no standard toxicity information reported in the literature.
4 amino perodine, no production information available, also with EPA, checked with them. Used as a pesticide, and intermediate in production of pharmaceuticals and dyes. This spring, [ indiscernible ] obtained approval from FDA to do studies with 4 amino perodine for treatment of MS. While FDA has approved these studies and we have requested additional information if it's available from the company, but there are no standard tox studies reported in the literature.
A few groups have looked at whether the 3 amino perodines cause gene, genetic toxicity in salmonella strains and by and large the studies were negative except for a positive test for 3 amino perodine. One of the interesting biological activities of the amino perodines is they block potassium channels. All 3 amino perodines block channels, studied by a variety of groups over the years, primarily an invit rough cell population with -- they found amino perodines interact with potassium channels by -- when the amino perodines block the blinding site the -- the consequence of blocking the channel, amino perodines are in ward and outward potassium curves, when blocked, the potentials are maintained, nerve signal is increased.
Other characteristics, won the Nobel Prize -- substitution on the molecule necessary for blocking an activity. The proteinated form of amino Perot perodine is the active species blockage of potassium channel -- based on this information many groups supplied, we hypothesize the amino perodines would cause neuro toxicity, cardio toxicity at exposure levels shown to block potassium levels. University of Rochester looked at different serum levels of the amino perodines in humans.
We have reported as part of the NTP series of cancer studies, liver carcinogenissity, and met -- Sim laver to --
Is summary the rationale for study is to provide hazard identification information on this class of chemicals and to provide comparative toxicity information for the three amino perodines. The key issues to address, your input, toxicity studies, special endpoints to tag heart, liver, neurologic, immune logical toxicity, project using rodent studies for the initial screens for toxicity, and the relationship to whatever toxicity we see with the actual potassium blood level of amino perodine.
Our hypothesis would be that these chemicals, because of the potassium blocking activity would cause -- or immuno toxicity.amino perodine has the potential to cause liver toxicities. The proposed research project would be to conduct a series of short-term toxicity studies to identify toxicity to these various systems. We would also include studies in one lab to look at toxicity across the amino perodine, also initiating studies, I guess you heard in previous meetings and today, high through-put screens to look at toxicity. Those are being done in collaborations with a group at NIH, and usually we send a series of 1400 chemicals. The amino perodines will be looked at with other chemicals of known effects, along with other perodine chemicals.
Thank you.
Dr. John -- rough cell.
Generally I am supportive of this program. I was actually a little shocked when I got this, said there was no toxicology data. I was sure that was wrong, began to do search and was astonished. There really is very little in the literature. I found a 1973 review article, data pre-70s that's so old I am not sure of the value of it. So, generally the production values are high. This is a useful, one of the things, spoken with June with about, there's actually a lot of human exposure data to 4 AP. It's been around, clinical reports going back to the early 90s, most not sited in the overview paper, a lot of interesting information, primarily cardiovascular and neurological aspects. That's important to pursue those end points. And to reits rate, neuro toxis and cardiovascular are the key areas that ought to be focused at. I was less convinced with immuno toxicity, I wouldn't recommend charging into immuno, I think you will learn enough from a 90 day study to tell you if there's immuno tox, hold that to -- in vitro studies proposed, of course I don't know the designs of these, not addressed in the concept. I would reel relegate those to lower priority. In vit rough might be useful, not a particularly high priority.
As mentioned, there apparently are some FDA submitted studies, I understand there's freedom of information issues and proprietary information on data, but perhaps if Dr. Howard can help with this to the point we can, there clearly have been good studies done recently if they have an approved IND, it would be useful to try to obtain those. In summary, I think it's a worthwhile program to move forward, significant human exposure, values, very little known, those combined make this worthy of study.
Next, Dr. Russell Thomas.
I am generally supportive as well, testing on this perodine series. A couple of things in addition to the lack of toxicity studies, corroborated to making this a higher priority, ability to leverage the potential pre-clinical studies being done in the testing and forming of perodine. Assuming that approval of the drug, you would have also, as well as the treatment for multiple sclerosis the chronic bioassays performed, the NTP could leverage in trying to do these perodine series. That was another positive. In terms of, given my background in genomics, I focus on alternative studies proposed in the document. There was some genomic studies, high through-put screening, little detail surrounding those, but if you want to focus these studies on understanding mechanism mode of action, perodines, and how the chemical series plays a role in cardio toxicity, neuro toxicity, really encouraging the use of time series data as well as dose response data. As well as, if the ultimate goal is identifying hazards in humans, really cross-species assessments of gene expression changes in more ex vivo type models could go a long way in showing whether the mode of action assessments are actually relevant in human type models. With that, I am supportive of moving on and performing greater assessment of these amino perodine series.
Are there other comments?
The presence of the amino -- in the molecule can potentially lead to toxicity, but there's no mention in the hypothesis about the possibility these compounds could be mute owe Jenic or -- have been shown to be mute be mutogenic --
Thank you for your comments. We have asked to obtain more data they may have on 4 amino perodine -- on
Paul Howard: Basically the FDA cannot compel industry to provide information part of the IND. We cannot say you should publish this. It is up to the spopsor sponsor to publish. Since it's proprietary they cannot release the information without them initiating it. However, we have requested of the product center to see if there's information that can be made available. I will follow-up with the actions of this board, see if the data can be released. About all I can say. We cannot compel release of information.
We do hope to get some mechanistic information from our shorter term studies to be able to better predict cancer outcomes .d . We have quite a bit of program on that, Teddy -- and looked at the, and gene change at two weeks, six week and 13 weeks, they published in, I think Cancer Research.
There are some genes in common among the car sin Jens they ens they looked at car carcinogens, help predict the cancer outcome, and I expect we would be looking at some of these end points with these series of compounds. Once we get this data we will make a better decision on how to design any cancer studies we might do.
Dr. Thomas had asked if we remember were going to look at different end pointeds, and we are collecting data on that, a project where we looked at a series of carcinogens and non-carcinogens, gene toxicity, will hopefully be able to build on some of the knowledge in our collective to understand the cancer potential of this group of chemicals.
Certainly I would appreciate receiving any other comments, now or as we go along with planning this, maybe Dr. Thomas can come over and help us when we get a little further along in the process.
Other comments?
Dr. Janzen?
Bill janzen: I want to comment if you are setting up in vitro studies it would be helpful to have these tested on potassium channels.
They center, Christine Wick is here, Ray, Tice, helping us pick and select the high through put tasks, several investigators are experienced in in vitro tests for ion channels. We expect to be working with these folks at NIH, and I think they will be able to help us look at a series of ion channel blockers, quite knowledgeable in the field.
We have no one registered to make comments at the meeting, but is anyone in the audience who would like to make a comment at this time? Not, further board discussion?
If not, we are ready for a motion on this compound.
John -- I move we accept the nomination.
Second?
Nancy Kirk -- second motion.
Thank you, call the compound for a vote. The vote is for approval for this compound to go forward to study. Have a show of hands to approve.
anyone voting no or abstain?
Anyone voting no?
Anyone abstaining.
Dr. abstaining. Will you make a comment?
I work for a pharmaceutical company with research in neurological diseases.
Thank you very much. Compound passes,
next is 2 meth oxy night row -- that will be presented by nted by Rick Irwin.
2 meth owe oxynitro-- nomination based on, really increasing production of this compound, now up in the million pound per year classification. Because the carcinogenic potential was unknown, toxicity inadequately characterized, significant potential for occupational exposure. Consumer exposure is undocumented. It's used in the synthesis of pigment yellow 74, present in numerous consumer products tattoo Inc. that inks and -- in arngs addition, 2 meth oxynitro-- is structurally similar to two carcinogens, [ indiscernible ] transitional cell carcinomas of the bladder in rats and mice, and -- skin and thyroid neoplasms in mice.
Human exposure is really primarily occupational, and is associated with handling the dry powder during die manufacturing. However, there are no epidemiology studies or other reports dealing specifically with exposure. The estimates are really for workers expose said to pigment yellow 74, no direct exposure data. Again, the possibility that could be present as a contaminant presents the possibility there could be exposure. This is predominantly with workers in the apparel, textile, printing industries, using pigment 74. There are no standards or guidelines set by OSHA or -- no recommendation for a TLB, for 2 meth oxynitro--
This is the structure of pigment yellow 74, and you can see the -- pigment yellio 74 has a number of uses, studies indicate association between tattoos and skin cancer.
There's really very little information in the peer review literature on this compound. There's a preliminary report that indicates there are too major metabolites, 2 mi meth oxy -- reduction, and 2 amino 5 -- actually NTP has done a two-year study of 2 amino 5 methy -- induced an increase in -- cell in the pancreas, in mice and rats, no other effect, some evidence of carcinogen when reported.
A number of preliminary reports indicate 2 meth oxy nit row -- is toxic. Several case reports, accidental exposure, ingestion of para final -- in humans, this leads to -- the release of high levels of myo glob in -- renal failure, a number of cases have actually been fatal. There are cases in the literature, have been studied in rats, nee cro sis of skeletal and cardiac muscle. The nit rough reduced metabolite of -- has also been reported in rats, causes neck nee cro sis of skeletal muscle at scle at doses of -- to the extent you can translate to humans it would appear it could also be more myo toxic in humans.
So, one of the key issues in developing a study plan for this compound is to determine what route or routes of exposure to use. Occupational exPenal Code Section exposure is dermal and -- dermal carcinogens when administered in feed. I put an asterisk, exPenal exposed to the feed, they generally kick quite a bit out in bedding and are exposed dermally also, simply because of contamination of feed in the bedding.
It's interesting to note, studies have been done orally. The specific gain would be to conduct absorption distribution, met am met an limp in orallal -- identify the tify the major metabolites. The purpose of these studies is to evaluate this. The second specific aim would be to conduct pre-chronic toxicity studies. We want to do these by utero exposure. Biomarkers for monitoring damage to skeletal and cardiac muscle. The skin serving as a portal of entry we can use -- we can do these by dermal administration, getting good absorption through the skin. However, if AD ME studies ifnd Kate dermal ab sompgz is minnial, probably the case, studies will be conducted orally, we have to consider skin a target org et based on results of the toxicity and -- studies. We will include studies of reproductive toxicity as a pre-chronic --
Second is DNA reactivity. It's been reported to be a bacterio, we may be able to develop a strong enough case to say we expect this to be a carcinogen avoid having to conduct a two-year study. The third specific aim is to reexamine the bacteria -- Jenisity, to do DNA activity looking at -- assay and look for presence of -- the basic idea here is to try to be able to build a strong enough case to attempt to make some type of prediction of carcinogenic potential. These studies will provide a complete complete characterization of -- try to make a prediction, if we can't build a strong enough case we will have enough data to set doses, initiate a two-year study. Those are all my comments.
Thank you Dr. Ire win. The first board comment is Dr. Michael --
Thank you. The reasons for initiating this research program are clear and valid given the high production --
Yous the positive mute owe Jen sin, and structure activity relationships. the key aim of the research is to assess the toxicologic and potential of the compound, development in it reproduction, appropriate routes of exposure have been considered based on occupational exposure.
I think it's appropriate that, looking at toxicity, special attention be paid to skeleton muscle, heart, especially considering the 28-day study they did see evidence of cardio toxicity.
I am in support of the fact, the decision to perform car Sino gistity studies will be put off until other results are obtained,ed study for DNA formation, based on results of those studies it may not be necessary to form a form a two-year bioassay. I will give this study a moderate -- the potential occupational -- low, noted because of extensive use of the compound in the dying and printing industries there's potential for exposure in the general population, all be it low.
Dr. James --
Several comments. I agree with Dr. Pin owe, that the rational is well stated here and I think it's compelling in terms of going forward based on the Jen owe toxicity and the structurally related molecules. The part that I don't quite totally understand, either from the material or the presentation, the relevance of the production and use of pigment yellow 74. What we learned today, maybe in here, I missed, that the yellow 74 does 74 does not other area of concern, this molecule, actually in yell so 74, because while it's used in the production of it doesn't mean there's any there in the final product. As I go through, see the references to yellow 74, yes in wide use, potential wide exposure to yellow 74, I don't know whether that constitutes any potential exposure to the compound. That needs to be addressed or considered as the program considers this molecule forward. I think the scope of the research program is generally appropriate, based on the current knowledge and the step-wise approach, and making a decision on carcinogenissity studies at some later point, may not be done at all because of information, very appropriate, and I applaud. The focus on identification of mess an lights, I think is certainly appropriate as is in the proposed program. Two additional points, one that I encourage the program to consider animal/human metabolite comparisons, in vit owe systems very early in the program, and other programs, to know whether you're dealing with potential similarities or not. We all know the vag airies of in vitro -- but provides useful information that could impact your future decision-making as to where you prioritize this molecule as well as others to know where to spend your limited resources. As you do early animal studies I encourage you to think about obtaining information on you are inary metabolites, to go forward, know whether to look at your in may be a useful area to a to a to look there -- distribution is important, you identified the skeletal muscles, cardiac, whether potentially due to very very high exposure, localization in the tissue, key importance, I would want to make sure that distribution study got included in this program, included very very early.
I think this program addresses a basic question in terms of toxicity of the compound and the group and I think in terms of structure activity this is a very good series of molecules to be working with. Again, since you already know there's skeletal muscle effects, I think it's worth taking the time now to see, well, what kinds of additional information you might get out of even your very early studies in terms of potential mechanism of skeletal muscle. Doesn't appear to be a fishing trip, in fact it appears the information is already available, that is the skeletal muscles regs targets, why not try to get a, additional information beyond what might be the standard protocols early in the program. This research program merits utilization of NTP resources, I ranked it moderate, primarily on the basis of I am not so confident of the human exposure, particularly if one might determine human exposure from yellow 74 is nil.
Thank you. Other members of the boards would like to comment?
Dr. Howard: I can address some of the issues raised. As far as human exposure to pigment 74 to the -- we did a study in 2004, looked at impact of light of pigment yellow 74. You find it breaks at the bond to give you the compound in the other half. Photo decomposition of pigment yellow 74, not certain it's used this yellow note pad, but you put it in the sun light you have decomposition, so it is a possibility as far as human exposure. The group here, where it breaks apart.
I was encouraged by a study, published 2006 looking at metabolism of yellow 74, the -- you get -- what had he showed as potential for the -- demeth ox lags. The metabolism is consistent with what we know of pigment yellow 74. We have a study, yellow 74, labeled, finally, and seeing things we don't know what they are, if they are perhaps hydrolysis in vivo, but the metabolism studies suggest you don't -- yellow 74.
Were those rodent or human studies?
Rodent studies.
To responded toe to that, it's important in terms of photo degradation. I didn't appreciate that, it's very important information and raises my level of support up.
In this page one of this document you mention the 2 amino -- metabolite of the compound is mutogenic, both with and without -- activation. I think it would be good to mention by what mechanism is it -- [ indiscernible ] appears to me there's some --
I haven't looked into that particular compound. I just reported a result.
I would speculate that it could undergo oxidation to -- react that way, not necessarily need to be metabolic, could be spontaneous oxidation.
My comment, given this 2 for 24 is a metabolite of 25, you already tested for carcinogenissity, does it make sense to -- as a positive control in some of the studies?
I think we need to really take a look at the metabolite profile. The reports that I, the two metabolites are based on a preliminary report, there wasn't quantitative information given, so I would say, certainly be something we would consider, but need to see how much, if it's a major metabolite or not.
You mentioned briefly the 90-day study would start with in utero study. Something specific for the compound or following the general trend? If it's the latter I have concerns about that. It's a fairly big move in that direction. Practical considerations, also considerations that although there's this dogma that kids are always more sensitive, it's really not the point of focusing on development, because they are different. Sometimes they are actually less sensitive. If you are going in that direction, I don't have an issue with, but what we need to do is put comparative data on the table, starting with young adult, need to build a database before we jump into that as a generic approach, that decision based on data.
Well, it's really probably a little bit of both. Our default position is becoming that unless there's a good reason not to do an in utero exposure that would be our default. There was an indication there's a substantial number of female workers in the dye and printing industries. There's concern about exposure in that sense too.
Are there other Board comments?
I have a comment and a question in regards to the -- as I, I think it's important it be done in vivo, I don't know how -- the other thing is, I will like to see the aspect of the high DNA reactivity being a rationale for not going ahead with the study. This seems somewhat of a shift for the NTP, I wonder if you thought through an algorithm of how this data might be used for data assessment.
Would you like to respond?
I think, based on the fact we have three other compounds that we know are carcinogens. We would argue, if this, see DNA -- strong response in the comet assay that we would say chances are this will be a carcinogen also. I am not too sure of how all that decision-making would take place, but I think we at least have to make the attempt to do that.
Dr. would Mike to like to make a comment.
We have in the past had a couple of occasions where we made predictions on short-term data, one that it was a car carcinogen, the other that it wasn't. There's a lot of information that needs to be gathered, as we found out during the first two series of studies, did information taken forward, reasonable anticipated carcinogen. Whether we could reach that level of information with this compound I can't predict at this time. But it is the way we need to go if we're going to create a different type of toxicology in the 21st. Century and use information in ways we aren't used to using it, part of the process of moving us forward.
Dr. Walker?
In your scope of work, in a couple of comments, you want to look for -- adducts and -- slides, DNA and adducts and target tissues, what are you using at this point in time to test target tissues, structure activity relationships or just the finding of the -- tumors in the pancreas of a metabolite -- what are you thinking about here in terms of moving ahead, trying to find adducts, what tissues are you going to look at, and also, if you are going to move forward with using the data you find in your data, I remind you to be careful, adducts are not mutations. There's an EPA document that, commentary, framework for evaluation of Jen owe toxic -- you got the impression that if you had done Dan adducts you had mutations, cell makes the mutations, you will have to think carefully if you are moving to a new paradigm of how you use the DNA --
Do you want to comment?
Studies would give an idea of where the compound would go, as a first guess, as to what our target tissues would be for looking at DNA adducts. Of course it will depend on what else we find with a lot of these studies. There's just so little data available for this compound, it's hard to look too far forward at this point.
Dr. Howard: I am glad Dr. Tor sen brought this issue up. What's been proposed, hazards identification, but in other words for -- to make good decisions we need dose response information on carcinogen sis, and before this study is truncated without a two-year study, the regulatory -- sufficient information available or two-year study available to make a proper risk estimate for this type of compound. May be an excellent study, this truncated, just short of providing adequate information for regulatory agencies. I point out for clarification regs not criticism at all, but page 4, 90 studies showing -- I think that's a bit high, for clarification because this is part of the public record. None of those are epidemiological studies, not a clear association, I want that for the record.
Thank you. Other comments by the Board? No written comments were submitted, no registration for comment, anybody in the audience that would like to make a brief comment? Seeing none, I will ask for a motion, putting forward a motion to vote whether the compound should go forward in study, not the disciple design per say. Could I have a nomination?
I make a nomination this compound move forward for additional studies.
Motion to approve the compound to go forward to study.
John -- I second.
Motion made by Dr. Pin owe for the record. Show of hands those voting yes to move the compound forward.
Thank you very much. Could I have a show of hands, those voting no? Anyone voting to abstain?
If not, the compound carries, move forward to study. Thank you very much. We are going to adjourn now for lunch. And we will return at 1:00.
Double checking with our manager. Yes, 1:00.
Thank you very much.
The next come down for discussion is [ indiscernible ] And the proposal we presented by Dr. Nigel Walker.
Okay. Where are we? I think this is an opportunity to talk to you about this concept. If you remember, this was part of a two-way nomination we receive from the FDA. So this is being used in a wide variety of different areas, particularly in the biomedical field. It is used for target it chemotherapy. You are right in the way. There is nanoscale gold particle right behind his head. It is used for imaging and a whole bunch of different areas. It is also used for electronics, but really the focus was around its use as a platform for biomedical applications. Just to orient you to what nanoscale gold is, you think of gold as an element. This is the classic one that nanometer sized particles. If you have 55 gold atoms together, that is about the size of C60 particle. You can find commercial entities. To put that in perspective again because when I live and that the world is different. This is what Al was just what did a moment ago. There is it as a blue thing. These are upset and I suppose being used as platforms. So we talk about a particle and a 60 because they are all with different. Hopefully this gives you some perspective for that. Some of the background of the effects go when you think of gold itself is one of the most admired metals. The program comes as no surprise. There have been some examples of dermatitis. You can have people get elected corrections to that. There really is little bit dated. They're is a general lack of major keep toxicity in some very high does studies and show some but not really much. There are some studies which tend to be relatively small in scale. The does ranges at a been used all particularly I would like to highlight the study by profs group that looked at such as critical four-60 per you see differential uptake so we know there is something that depends on size depending alterations. There are no toxicity studies with well characterized materials of different sizes and to find coatings. FDA nomination was around the cutting issue on what happens to the bare bold particle First a conjugated particle. These were those recommendations to look at rent based studies, looking particularly at eight, B, and eat. The single and repeat of the 28 states and link if need be. They should at least encompass a multitude of sizes and the range of 10-60 the images with or without cutting still see what the impact of coatings are. Of course we need to make sure these are the really characterized in terms of what size is and what the coatings are and how well they've remained intact. So the rationale, from the Senate is in public health point of view the primary focus of this particular study is to have the properties impacted by the size. In general there is widespread uncertainty about no materials. This is an a identify research need across FDA for no material information for drug delivery vehicles and platforms. Health able to use that is up to the FDA. They will use that within their interpretation of when they get submissions to the agency all products that are based upon this kind of platform. And while these are all and the development Phase and there is no specific drug on the market I'm aware of that have now and the skill as a platform. Those are in development, but clearly there is the potential to increase exposure. The other good rationale is this integrates with that NTP ought to and Research program on a nasty as materials looking at how the physical chemical properties relates to this very broad class of materials. To to give you some idea, we are dealing with the carbon. We have been listed on going with a program developing on data to us. Although oxides were the first things restarted on and now we have the metals. So together we are trying to deal with quite a broad base of different materials so that we can maybe come up with some more generalities towards how to deal with size and cubing issues. One of the key questions for nanoscale gold -- there is a need particularly for zero medals and how ionization affects us. Out the surface modifications affect that. What could things and sizes should we choose? For this particular group of studies this is really a very important question for us. You could have anywhere from one through 100 different sizes and increments of one and an editor with three or four different coatings. Do the math on that and you are up to many potential test articles. So how we choose what we go forward with is important. More importantly to me in terms of interpretation is that those metrics. We live in a metric world where you do mass per kg and those kind about measurements. We know that surface related metrics may be important. So that is why we must do a very good characterization. At the moment we don't know which is the most appropriate metric. So this figure gives you, and a not so, the initial phase of the program recognizing the number of permutations. We are starting small. I will build upon this. Imagine you have a cold particle of this size. We want to characterize the impact. I regret to have at least two sizes. That was one of the key questions. And you have the impact of cutting. Well, that question, that imports and increase in size. So does the overall particle size and there is the cord particle size if you lost the coaching or if the coating is somewhat flexible. So the policies we want to look at our issues of course size and different coatings, Sam Cooke and different size. So that is the fundamental and parts is we want to look at and how those impact on toxicity. We are going to use centra stabilized gold particles for the uncoded and polyethylene coated particles. We realize this is the initial foray into this area. These are the policies I have articulated. There will be applied more effective and visual terms. So we should evaluate the effect of particle size. I can't really see what of said there. Steve is and the way. Time course and to see disposition. I'm looking at my screen here. I don't like looking at the screen, but of course too. Using different materials we have on strength we can evaluate the tissue this position as to put world and IDs to we can get an idea.
Titian and tissues of both the zero valence. Within this respect we have started in Beijing with folks on how to do this and having preliminary discussions. Papilla which materials we choose will be through dialogue with those. Why the important point is that we are just about to release three specific standard reference materials that are DHHS, 32 and 60 nanometers. This release is happening while we are in this concept review phase. So likely as not we will probably use these materials. Because they're gone through a lot of trouble to make these. We will follow on and what we learn from that to evaluate the effects of those different sizes and coatings on the profile of subacute and subscribe with particular reference to the immune system as their system because of concerns about potential uptake into the brain. I think that is the end of it and I'll take any questions you have.
Thank you very much. Our first discussant will be Dr. Ruth year.
The kit. I previously discussed some of these comments. At the we are actually making progress. There is an need to define basic parameters as a function of size and cutting and to define the fundamental toxicology and characterization metrics. There were some public comments about not being able to do these studies if you don't know the characterization metrics. However, you don't know what the proper characterization metric is until you do the biological Studies and find what is actually predicted. Said this because reported. As you mentioned I hope that the information that you actually start cleaning from the other particles and the materials being studied has more knowledge as these things come to final decide. We really don't know what is going on across particle types of all. I have a little bit of concern on three particles because you are confounding some of those comparisons on size and serve as cutting. That is a basic concept. You need to make sure you have enough particles can you can very specifically make sure it is size or a cutting. The characterization, as long as you continue correct rising as he described as crucial. The question that is important how that this research should help define is what you mentioned on -- we are used to taking a pass relationships treated there is more particle distribution . It may be to a distribution of particles. So that demonstrates the need that we must not to do studies with the input is and distribution of particles. Whatever happens if we don't know how to do that is crucial that you characterize it so that we can come back and try to make sense of this. I had a question about using standard particles, but you stop that by using the same particles which should be available to other investigators. Because what is a problem in this field is in studies across particle types. And there is a control issue whether you use a different state had a cold and there for toxicity. And whether in this in studies -- I mentioned this last time, used a control particle, whatever that is. You want to at least get the product work transition. Let's see. It does propose to reserve to address the point? Is a crucial area. It is important that this work done and the basic aspects of toxicology we defined. As a high priority we must in line with the other studies begin to define basic properties.
Would you like to make any comments now?
I wait.
Very good.
Dr. Steven Roberts has joined us through videoconference from the University of Florida. He is the second discussant.
Thank you. Actually, I did not realize I would have such an active role in your presentation. I hope what did not obscure the information too much. I think my views are pretty similar to the Thames. I think that the rationale for this study is quite strong and was well articulated not only in the nomination but and as a presentation. There is plenty of reason for taking a look at these, but in terms of the increasing expanding use of nanoscale gold particularly as a platform, but also other sources of potential exposure to nanoscale gold and the virtual absence were very limited information available. As I look through the literature there are these statements that are almost anecdotal about the biocompatibility of gold and the absence of toxicity. When you try and track those down to a published reports in the literature you really cannot find them. There is just not much out there. So it's pretty important to begin to do well controlled well studied -- well-designed studies on toxicity and began to build the basis for an understanding of where these things go and what they do. On the rationale, one of the things that stem touched on relief and got out too much in the nomination. Nigel touched on it in his presentation. I only do we get information, but there are some real technical issues associated with doing these studies. I think that as NTP tackles those issues for nanoscale gold and other materials they are working with that their ability to find solutions for these will be the viewable information that gives going to be applicable as we began to study other [ indiscernible ]. So at least I consider that to be a strong rationale for doing this study. The devil is in the details in terms of doing these studies. There are a number of challenging aspects touched upon with the century issues. When you are working with these particles you want to actually work with a particle-size distribution and how you factor that into your design and interpretation. Fifth other issues about whether or not the presence of these particles into areas with some of the end points and those kinds of things. So there are many things to be dealt with as NTP starts through these. That will be valuable information indeed. I think just briefly the scope of the issue is very relevant. As I looked at this study by I thought that if you are really going to test a popsies about the of the subsides it would be nice if you have more than two sizes. I understand the cost issue, but if there is any way to work additional materials or other sizes, that will strengthen your ability to gain understanding. Another about the CS, I think he can effectively test using your design which is a very clever in its efficiency. Even then there will be issues. Maybe if you use different pegs you could potentially get different results. These are things that Liza and the other investigators are well aware of. They have done a good job of explaining there are lots and lots of things. You have to start somewhere I would also say that the priority for this should be high. It is an important issue. As we began to get information and learn how to study a, think the National toxicology Program should be indeed. I would endorse the astronomy and give it a high priority.
Thank you for your comments. Are there members of the board to have other comments or questions?
I wanted to just reinforce what the first to viewers at to say about quantifying exposure and distributions of particles. I think it would be a mistake to place our bets all on bass were surface area or any other particular way of quantifying exposure at this point in time. I think it is very important to give a complete characterization of the distribution of sizes and shapes and coatings to give a complete characterization so that perhaps in the future when people have other studies that want to correlate with this they will have this data and can look at any kind of exposure measure there would like to. We want to avoid the mistake that was made with asbestos which is a similar situation I saw the critical early on. People place their bets on microns' with the greater than three to one aspect ratio. That turned out to be the wrong course. So despite all of the studies we have had a lot of the risks are still very uncertain because we don't have a careful characterization and exposure. So we don't want to make that same mistake with no particles.
Thank you. Do you have a comment?
I would like to suggest you consider not having three groups, but for so that you have small and coated particles, small cut the particles, large and cut the particles and large coated particles. That way you are likely to have more information at the end of the day. If such turns out to a better, but not coating then you have a 5050's but. Bill really what the combinations of both of them have an impact.
As, during the internal review process the issue of size and the number of particles was raised as a major issue. We should probably be thinking of going beyond. The advance of the press materials now being so close to release within this month, it is almost certainly will go with the 1030 and 60. Dealing with the particles is going to be more complicated. The discussions I've had with this farce, that is of going to be trivial. How we met the coatings to the standard reference materials -- it can sometimes at 20-30 nanometers. So your actual Dynamics size of your problem would beg maybe more to your for 30 or 60. It might not be exact we may not have a direct comparison. There are intricacies there are just having small credit. They are really more like you're bigger particles. We are aware of those. Nonetheless, the issue of the book address materials, I think it requires us to use this reference materials given the links we have gone to characterize. They are very tightly to the tax distributions on those particular materials.
Just one small point. All the people have already commented on the importance of the pharmacokinetics' and tissue distribution which I certainly endorse. I notice in your document that you have noted that if feasible location within tissue will be determined. I just wondered, have you considered the use of scanning with energy disperse of X-ray analysis?
It should and can work. One thing we have learned for our work is, what you see isn't always what you get. You may see things that may not necessarily be what he think they are. So we have to use a combination of both. There is also the question that has been raised. Was pregnant. We get ionization and that is a key metric. If you actually look at the forms within the tissues, that's something we need to do. And that is one of the issues there.
Other comments by the board? C9 we received no comments or individuals registering to make comments. Any other comments? Seeing none, for the record we did receive written comments on nanoscale gold. Those were forwarded to the board by e-mail and our present in your packet. At this time we are ready for a motion.
I make a motion that we move this forward.
Do I have a second?
I'll second.
Thank you, very much. The motion is that nanoscale gold will be moved forward to be studied. Can I have a show of hands were those individuals who agree with the motion to study this compound? There is a unanimous vote for approval.
You guys had me worried there for a moment.
Can I make a comment? That he is eager to see this move forward. One thing a what the board to recognize is that what NTP has done is brought in NIST and be NCL. Those are very powerful allies. And that is to be commended.
Thank you for pointing that out.
Our next compound is to to pins and allied. We will now hear from the project's leader. We are working to bring in the presenter who will be joining us by video conference.
Hello, I am here.
She will be speaking on this topic. She is a member of the board, but she is joining the beating out. So we will go forward.
I only have three slides.
We would like to give those up if we can.
I could go without them if we have to wait much longer.
There are already here on the computer if you come and gather around.
We are getting there. There we go.
Hello again. As I mentioned this morning -- I am going to present this concept and try and be brief. We elected to do this in the interest of time. I just don't want to leave you with the impression that any last thoughts went to the development of this particular Research concept. This nomination is for [ indiscernible ] which was nominated by the National Cancer Institute based on high production of volume and light of adequate toxicity data and some suspicious -- suspicion of toxicity based on chemical structure. You can see the bottom half of the molecule of there. And it is with the when [ indiscernible ]. The argument how was considerably stronger than for this compound. What we have here is an analyst substructure. This has have some evidence associated with various Texases. It is used, as entirely has a masticating agent. There are certainly other types of products made using this particular compound. Production was 1-2000000 pounds per year. All we really know is just that. Certainly eight Berber industry work report have to handle this compound and could be exposed to an audition. Anytime a rubber products made with this compound got out into the environment there could be some residual exposure. And we have no specific exposure data. This data is very scant. It has fairly low acute toxicity. There are some old but sufficiently convincing studies and the literature. And this is can sensitizes. There is no Agena toxicity or repeat those toxicity studies of any kind some of the data gaps we identified and the key issues, as I mentioned suspicion of toxicity based unstructured. Little or no data describing the extent -- extent of exposure. All the types of data that one would like to see to be able to make those kinds of judgments are pretty much lacking. I speculated that this compound would be converted to biologically active, either in the body or in the environment. By the positive step incentivizes and studies indicate that the chemical is probably reactive or is being metabolized and descant to are reactive compound to shield them positive stance since the position. As we move forward here and and identify potential metabolites you may even think about looking further in terms of Jeanette Texas to the stage for some of these degradation products. So the proposed research program has four parts. First we determined the in vitro. Also the potential for extortion followed by in vitro metabolism studies using the hon. compound in both human and [ indiscernible ] preparations. Then after finishing up those determine whether or not we want to approve further and to an orbit availability study and to a little more extensive characterization which would require some labeled compound. And so that is all I have to present to you. I'm happy to answer questions.
Thank you.
Keith Sober from Merck. I think there is a clear and valid rationale for the proposed research program. The scope is a bridge. Well the toxicity is low there is substantial potential jurors industry workers and small amounts to the public as well to read. The importance of the program will depend a little bet on how much of the compound is likely to the beach out of other rubber gloves or latex gloves to the public or how light -- how much might lead of rubber tubing that would be part of food processing. Without that information we don't know much about what the exposure to the general public would be. More importantly little is known about reacted metabolites. So I think there is brilliant and studying in the absorption of metabolic activation at potential in this compound. Overall I would put the importance of this topic as moderate given the amount of compound that is manufactured. Thank you.
Thank you. Our next discussant is Dr. Pop.
I certainly agree with the opening comments. This is fairly straightforward. I have a couple of comments of the endorsement. I certainly agree that the concepts documents is clearly written and clearly indicates how the results will be utilized to make further decisions. I think that is Gary important. As already pointed out the emphasis in terms of bioavailability and metabolism is a very appropriate. That is where the emphasis should be or at least the major part of the emphasis should be at this stage of the program. So I think the program as outlined is appropriate for the knowledge that exists today. I think this is a well warranted program, and I gave this a priority ranking of high.
Thank you. Are there other comments or questions by other board members?
You mentioned the metabolism of this compound. Ops plan and it proposed to use the eight compounds, but for in vitro studies you are using unlabeled compounds. Why not use and [ indiscernible ] compounds because it would be much more efficient to detect a small amount of metabolites there we have [ indiscernible ].
It could end up being more efficient to do that. The primary reason -- and I know I forgot to mention this, but it is complete with that that disulfide bond that is one of the critical steps. So does first studies would primarily be designed to see if that happens. Again, once we get an idea of that there will be another step where we think about what else to do and perhaps start using regulate the gold compounds.
Nancy correctly. I had Oregon State University. Are you not concerned about sensitization potential? I don't see how these studies are going to address that. I've wondered if maybe you should add something along that line. There seems to be data that says the parent compound could potentially be responsible for sensitization.
Isn't clear if this is a parent compounds. You present this could be a strong dissent the desert. In our first look at this the kind of felt like those reports aren't the literature at least identify it as a sensitizes. We just weren't proposing to do more. We can certainly rethink that based upon the your comments here.
Other comments by the board? We did not receive any requests to speak at the beginning. Is there anyone in the audience to would like to make a comment or ask a question? We also did not receive any written comments on this compound. As such, we are ready to take a motion.
This is Keith. I move we bring in the compound for work.
Is there a second?
I second.
Thank you very much. The motion is to be voted on is whether or not this should be moved toward. All those in favor raise your hand. The vote is unanimous for approval. That you very much.
The next compound is pentathlete at Simeon.
Okay. There we go again.
We need slides back up please.
Is that Tracy on the line? She is board member who could not join us. It is to try she is one of the reviewers. Can you see as?
Yes.
We are waiting for slides ago. You are to videoconference. So you cannot see as. Breaking onslaughts to go up.
Okay. As I said, we do not have a research concept for this because our recommendation is to not pursue any studies at this time. What we are asking of you is bit different in not responding to the form of questions that you saw. But simply whether or not you concur with our decision that this domination does not or study. So the structure up there is totally [ indiscernible ]. This is a molecule with six engines and Ed. It is nominated by the National Cancer Institute based on high production volume and lack of adequate toxicological data and positive [ indiscernible ] data. It is used almost entirely as an intermediate in the production of a number of different resins and lubricating oil which perhaps accounts for its largest use. The U.S. production was 1-10000000 pounds per year. We know very little about potential exposures. Although such a way we presumed they occurred during any of the processes that I dark about in terms of they use, using this chemical to make any of these products could result in potential exposures in the workplace. We have no specific exposure data located. In terms of the ducks waddled data we have moderate to acute world toxicity. It is known to be endured since and corrosive and a sentence desert. Not much published literature here coming. Some of this is growing from material Safety Data sheets. Icahn also presume we have experience with Hughes and the workplace. Some studies indicate that is mutagenic in several salmonella strains. Those were part of these studies requested by the nominator. So our recommendation is not to pursue any studies at this time. A couple reasons are listed here. If you read this you certainly cannot help but be somewhat concerned about the potential hazard. It is a very reactive chemical. You would think exposure would be supplementing. Most of our justification has to do with potential practical difficulties in carrying out taxes that would be of value. Due to its terraces the and expressivity any sort of challenging tax cuts to study could be considered inhumane. We could do studies have lower exposure levels and the supporting document there was some data provided for some lower molecular weight. These have been applied at very low levels. I believe it was the year. Most of these were negative but at low levels because properly you just could not apply to this chemical is a very high levels. There is no occupational exposure guidelines, no hazardous waste regulations for this compound. But there is some information that could -- the documents of skin and eye irritancy. Those regulations should be considered. One of the things was for Texas cities to raise as those being considered were validated. We feel it would be reasonable but not as a whole lot to the existing body of knowledge. It may be a useful chemical for further validation studies were four for these types of in vitro toxicity.
Thank you.
We weren't even asked to prepare comments. Unless we disagreed. I agree with that decision.
You are on the phone with us. Do you have any comments to make?
As I understand it, we will take of Folkestone not studied this compound. Could I have a motion about this compound?
I move that we conclude stuff not studied this compound further.
Is there a second?
I second it.
So the vote on this motion is that we will not move this compound for a word for studies at this time. Can I have a show of hands for all of those who agree with the motion cannot study the compound? Excuse me? We have to have your vote orally. You can't raise your hand obviously. You fared so the motion ought to study the compound. Thank you. The motion carries unanimously. The next compound we will be moving to is [ indiscernible ]. We have Dr. Paul Foster presenting.
Thank you very much.
Did after and. So you are going to it now appeared to presentations. This first one is a new nomination. The second one is not. Hopefully that will become clear as we go through. So that nominations are actually from NIEHS. It is used to double the as a solvent. In fact, the metabolism of most is relatively simple and that basically there is just a simple hydrolysis. And then that can then be [ indiscernible ] to make it more water soluble. This is one of those there bridge compounds. I think it's probably worth providing some extra points about what they're concerns are regarding potential toxicity is. So the first part to make is, this is a fairly large What we mean by that is that a given dose, the fetus is much more sensitive to these compounds. The neonate is much more sensitive. I think the greatest concern for these compounds is the effects in utero. They seem to be the events that are driving the interest in these two agents. Into tickler with regard to these aspects is a number of the agents--the other interest is that as androgens they cannot be picked up until after that exposure. Two good examples is DBP and DEHP. This resembles a syndrome that has been called testicular dissension this Dysgenesis and from. The editing to bear in mind is that there are species differences and susceptibility to the reproductive and anti androgen effect. The wrap is much more efficient at producing these effects than is a mouse. Other reproductive effects, the rat and a guinea pig are about as equally prone. Now, this is a fairly bitter rich environment. There are a fair number of multi generational antwrens generational studies that have been reported. The NTP conducted a study in the mouse. I think this was back in the early 80's. Again, I . out that the mouse is eventually and insensitive species to the facts. This used levels of DEP up to 2.5%. The conclusions were that there were no biological significant defects and the mouse under the conditions of the study. I provided in your package, if you look very closely at the assignable generation data there were some small changes. In the F one animals compared to the zero parental animals. There has also been a recent study in the rat that did not report any effects. That was a fairly robust study. You also have to bear in mind that this did not include some of the endpoints of that we know to be very sensitive to the effects. For example, [ indiscernible ] retention is the end point. It is not mentioned in this study. The other point to bear in mind is that there are some significant questions raised about experiments--To actually detect--I think this is quite an important point as well. The bear in mind that when you are looking at adults that have been exposed in utero and a multi generational study, we take one Mail and one the mail. There in mind that when we look at the development affects, a classic in study, if you like--For example, we take one male and one canal. It is not surprising. I think the other thing to bear in mind is that there have been some other studies, mainly Trans generational studies. The DEP administration to rats. --I think the caveat that goes with these particular studies is that they are very small studies. They only had a single dose level. The reason for doing this is to not look at those responsive relationshipses. Not only do we have all of these defects in animals, but there is some human [ indiscernible ] as well. The critical thing to bear in mind here is that the work that has come out of the work with our partners at the CDC, the National nutritional Health examination study where the CDC currently and has been over the past four or five years been looking at levels of [ indiscernible ] these are fairly large studies that have been reported with yearly. The message is that the DEP concentrations are the highest from the general population. They are also high is depending on different ages as well. It is not just male or female. Almost all of the samples actually had some DEP metabolites present. Chances are that every single person at this table [ indiscernible ] DEP at some point today. The other thing to bear in mind is that there has also been one under study that the CDC has undertaken where it has taken amniotic fluid from women in the general population undergoing an amniocentesis. DEP were found here and were at the highest concentration. There are also two a fairly small epidemiological studies. The first one release correlated DEP concentration and shown that it was a positive--This is work from [ indiscernible ] Group. The second study--In mothers' breast milk and so that this was directly related to the testosterone LH levels in a study that came in from Denmark. There are a couple of caveats. Both of those findings would be consistent with the affects of other [ indiscernible ]. Those are the kind of things that you might have expected to see had it been an anti androgen. You also have to bear in mind that both of these studies, the experimenters also looked at DEHP metabolites and found no correlation. So, these are small studies. It does not fit with the rodent data. One of the conclusions and you can take away is that they might be--Rather than a relationship with the specific one itself. What is our hypophysis? I thought this was going to be straightforward, and I am not sure. DEP does not affect reproduction in rats and some might be to present a risk to humans. How would we go about testing? Well, what we really need is to conduct a robust multi generational study in the erratic. I think robust is critical to this. I think we need to include the end points that we know to be sensitive to the effects of the [ indiscernible ]. I think the study will not be a simple three dose and control. You might want to include something closer to where the exposure levels by the. The study should incorporate an increased number of pubs retain to adulthood for examination. I think it is worth stressing here that this is not extra animals. These are using your animals more efficiently. We are taking them through adulthood. There are no extra animals. I think it is worth pointing out that the NTP has conducted a study with just this kind of design with DEHP. There is a much lower dose level than the conventional multi generational design. This was a fairly large study. The defect level dropped three dose levels just by using this kind of design. [ indiscernible ] dropped 25 old. The other thing that I did is crucial which is we need some percent [ indiscernible ] on the delivery to the fetus. We also need to know what the delivery of this material is to the pups so that we can make direct comparisons to the data that is available. What is the significance? I think the studies would fill critical data gaps for which public health concerns have been raised. One, the high exposure and to we have these two human studies that seem to link maternal exposure. I think the most important is that the EPA has as the National Academy to start looking at A cumulative risk. As received the one has the highest concentration, it will be important to determine whether DEP itself has any contribution to the mixtures for the people in the general public that have been exposed to.
Thank you.
Well, there is certain wide spread exposures to this compound. But think it is important, potentially, for a health issue. I actually gave this particular proposal a low rating in my written statement. I think this proposal is quite different from the ones that we have seen previously. The others were compounds on which there was a little [ indiscernible ] level. As pointed out, this is a compound where a great deal of information is available. In particular, there have been two multi generational studies already conducted on this compound. Onewas in mice by the NTP. One very recent study in rats. Both of these studies were at. The only thing criticism, both studies including the talks logical design, the only 1I have heard of is that it had animals. I did look at the end point--It has been suggested in humans. The thing that strikes me about these studies is that they are at extremely high doses of. In the mouth study it was two and a half%, the high dose and it was negative. In the rat study it was one and a half%. It is also an extremely high dose. They are huge, 20,000 times higher than the average human exposure. Given the negative data that we have seen so far, I would suspect that any defects that you might see, if you see in effects, would be at the high dose and fairly minimal. I guess I do not really see how that finding, itself, would really help us understand the effects in humans in doses 20,000--In particular, any perspectives on the findings we have found in human studies. I am sort of thinking that the emphasis for this is the human study conducted by [ indiscernible ] that showed some relationship between metabolites and the [ indiscernible ] distance. This study has not really been replicated. It did say that it had been replicated, but the study referred to was the study that use the same data, just estimated the exposures to these. I think that my feeling is that this is a problem that is crying out for an epidemiological study, a definitive epidemiological study that will really answer the question that the defects that we are seeing in the earlier, smaller study valid and if so, what is the implications of it? It seems to me that doing a definitive epidemiological study would not create insurmountable problems. You will need some information. You'll need some data on the mother and some serum data. You would need some non-Invasive [ indiscernible ]. If you did confirm the relationship that was seen in the smaller study, you would follow up the children to see if it results in any negative effect later in life, I think a study like that would be-It would go much further in resolving the issue in humans-A multi generational animal study done at 20,000 times the dose and repeating similar studies that have already been conducted. Another concern I have is that it only involves one [ indiscernible ] anything we learn would only tell us something about this one chemical. I guess also, just because it is the one that has the highest exposure, it is not necessarily the one that would be of greatest concern. Then, finally, there is another in a sensible proposal but we are going to hear about. It seems to me that there were some overlaps between this study and what the study is that is going to be proposed. Maybe we should just take one study at a time. It might be possible to get some information that we expect to get from this study. I guess my thought here is that this study should be given a fairly low priority.
Thank you. The next is [ indiscernible ] who is on the video conference with us.
Can you hear me? I think that this proposal has some merit as far as looking at or addressing questions that are raised by the new data showing that there is [ indiscernible ] exposure. It seems like that is the main driving point for this proposal which is to provide additional data that would alleviate concerns related to high human exposure. I gave this proposal a priority of moderate to high. That was based on the human exposure to data. Clearly, there are a lot of animal studies showing that there is low concern for the anti androgen affects of DEP. However, there are deficiencies in the data set that we need to acknowledge. Those are the fact that in the multi generation study, there were a limited number of offspring that were evaluated, which would reduce the power to detect low incidence. It is really the only study that, I think, we have confidence in for making an assessment about anti androgen effects. With that said, it is a robust study and Paul did say that. Clearly, at the dosages that we are using, the multi generational study, one would expect that high dosages would produce some changes. [ indiscernible ] as a class have been shown to produce a variety of effects from changes in retention, which, in fact, do drive the no defect level. As you increase the dosages, you do start to see pathological changes, testicular changes. One would expect when pushing the dosages up to 1 gram or 1 kilogram per day when you do the multi generational study, you would expect to see some testicular changes. So, I think that with that said, doing another multi generational study is probably [ indiscernible ] the next that. If there is a concern about really understanding whether there are defects on the male reproductive development, with the information that we have, we know that it is caused by in utero exposure. We know what kind of defects we are looking for. This question might be better addressed in the first tier by doing a with dose ranging study where exposure would be limited to the In utero. And they would be rather high and we could assess the end points that were mentioned. From that point on, I think we could make a decision about whether further studies are warranted. If that study is negative, I think we would have a clear, comfortable-We would be comfortable with making an assessment of the hazard associated with exposure to DEP at high doses. That is the general, overall opinion I have about this. I do have a few other comments that I want to make. One it is about this human study that looked at LH [ indiscernible ] testosterone ratios and Babies. I think it is very interesting data. It makes me wonder whether that would be something that we would want to look at commentary on the animal studies and looking at the correlation between of this bio marker and toxic and Points to see if we can develop an animal model that we would use to validate this, use is by no marker in the units. My other comment relates to the statement that was made about the rat being more sensitive than the mouse. I guess I have a question and a comment. My question is, do we know why the mouse is less sensitive? If we do not know, is that a question we want to explore, because at this stage, in the development of a database, it seems appropriate to me to start thinking about which animals are--Maybe it is the mouse. Maybe that depends on the basis for the sensitivity. Is it a pharmacokinetics difference? Is it a difference in how the reproductive tract developed in the two species? I think that covers what I wanted to say. I am inclined to say that additional studies would need to be more focused on answering the specific question about in utero exposure. Thank you.
I was asked to address this proposal as well. I certainly--the human epidemiologic study would be a wonderful thing to have. I thought the NTP proposal of multi generational study with a full assessment is both appropriate and scope and required to sufficiently address our back in knowledge. When I looked at the literature in this area, I noted that there were several problems. First is inadequate power. In some cases, very limited sample size. It never could really be used to prove a hypophysis. It is much more difficult to prove a negative than positive. Apparently there were an apparent bias--Suggesting there would be no findings, it was unclear whether there was inappropriate finding in this study. Oneof the concerns about negative data is what happens to us in clinical medicine all the time. Something is started as an office and an obvious that-When I looked at this with literature, I had serious concerns that there were sufficient data that it is truly a negative compound in human exposure. The end points were not as complete as I would like to have seen. In that regard, I have a question that you also raised in your commentary whether we would be looking at alterations in the LH testosterone racial as well as [ indiscernible ]. The questions raised here about the appropriate model is a puppet and does deserve addressing. --Is appropriate and does deserve addressing. The other question is the dose. It is hard to dose at a high level. In that regard, the question is whether we dose not only in in utero but in prenatal and whether there are hormonal changes not only structural changes. Regarding the issues of gene expression changes, there are a negative change and whether it is appropriate to be done. I would suggest that these studies go forward for subsequent analysis. I totally agree with the idea of doing [ indiscernible ] studies. They are essential for invalidating animal models used. Without those, we will not be able to validate the model. Finally, I did not include this in my written comments, but I wanted to ask this. If I understand some of your earlier work in is mechanistic the important here. We are seeing an increased efficiency in the human population. If we did not factor these into the study designs, they could [ indiscernible ] the model correctly and that might explain a rodent model being negative. I guess in summary, I would say that I support this being done. Do not think the data is adequate. [ indiscernible ] of mixtures. If we will include this in the mixtures, we go forward with the mixture studies, we need to know what rules--Necessary for risk assessment. I would support it provoked I will turn it back over to Dr. Foster.
So, which is likely to try and address some of that? Too Do you want to wait and see if we have other comments? We have a lot around the table already. Dr.Howard, I think you were for.
I just want to make a comment that the discussions within the with FDA, DEP was used. There is interest in the FDA. I cannot quantify how high or low, but it is on the radar screen. Thank you.
Studies indicate that [ indiscernible ] receptors--On the other hand, studies suggest that this is not relevant for humans. If this is the case, then why are you proposing this study--In the rodent studies.
That is the second presentation.
That is our next discussion. Hang on to that comment.
I am filling a little ambivalent about this one and listening to all of the comments. Just a point of order, we will have to vote on this before we vote on theinitiative. In hearing the comments and what's really struck me was that the rat is much greater than the mouse. When I saw that slide, which side is the human sitting on? I do not think we know. There are opportunities to do epidemiology data. I agree with the comment that maybe there is more to be gleaned from epidemiology. Again, this is a point of order question probably have to vote on this before knowing--
I will clarify. Which will vote on both of these together after we discuss both.
Okay.
Thank you for bringing that up.
I think that is an important consideration by.
I wonder that you would hear from me. I would agree with several of the comments and get right to the heart of the issue. On the negative side as far as giving it a low priority, I look at it as a practitioner in this field. I do not see that it is likely to get a whole lot out of it. The margin of exposure is dramatic in this case. Even if the low affect level were to pump down even tenfold, is it really going to matter at the end of the Day? That is pretty rare--25 does-You know it is active. You are looking at a pretty sensitive marker. You do not have any signal, really, at the high dose levels. I would be surprised if it moved the no defect level that much. That is one think. As far as the whole issue of sampling, I know we have talked about this for years. Before the board at a benefit, the sampling issue is a good one. We are always thinking about how to best sample. In the [ indiscernible ] study, you said that we only look at one male per ledger. I think we look at more than that. We take three and see if they get any and we take one adult and do it twice because it is a two generation study. We have pretty fair numbers. Do it all seven, say seven males, it would not be 12 or 14. That would only go so far. It would increase some. In the grand scheme of things, maybe not that much. Even in the developmental Studies, there, you are looking only at about seven because half of them are males. This is a fairly decent size. It seems to me like this is a different research approach would to be looked at things like that and know it is a potential outcome and if there are markers that we can have. Our technicians can take those out, no problem. Can we put the effort more into developing the marker of a forward look into development. Finally, if we are talking about a smaller dollar figure are smaller amount of animals, it is easy to say to do it. Here, being fair to animal welfare concerns, if you are doing however many dose levels, you are talking about three or 4,000 animals. To really be genuine to the animal welfare issue, we need to think hard about that one.
Any other comments or questions from the board?
I just want to make one comment. I was put off by the hypophysis. If we did not expect to see anything, you say your hypothesis as what you expect to see. That is a big talent and listening to some of the other comments suggest to me that I really like the focusing in on the developmental. And coming up with some bio markers and maybe doing a species comparison with mouths and and mice and ratses.
Would like to address some of these so far?
What how long do you want me to go? Let me start with [ indiscernible ], because they cost me the most problem, actually. I think you have to bear in mind here that what we are saying is that you cannot really look at the development--To be a sensible. All right? That is why the target organ--You also have to bear in mind that with the high dose levels, you do not always have the same F1 and F2. They are not complete replica. They cannot read. I think that was a bit of a red herring, to be honest with you. But that is another thing. Let me try to go to some of these other ones. First of all, this was really aimed, primarily, at the multi generation--Not the cancer assessment. I think that is why we want to specifically try to do this is to have a and signable that is robust, and really try to nail down what the potential is this. When you look at the data, it is far from perfect. You can always say that the studies are not perfect, but on the other hand, it would be nice to know that this is the highest concentration. Be very careful about assuming what is in the material in humans. That is not proven to be very good for [ indiscernible ] and Credits. In other words, what is present in the maternal urine is not what [ indiscernible ] is getting exposed to. You can have a much lower level of exposure--Then you would get by just comparing maternal urine. Any race, what else do we have here? Could we measure with free T levels? Yes, we could do that. I do not think it would be a problem. What to point out from the Danish study is that they were focusing on the levels in the first six months of young boys. "we were looking for is if that peak is [ indiscernible ]? Would it be the same as the others measured and humans? I do not know. Could we or should we do and epidemiology study? Probably. Would read wait another 20 years-It will take 20 years to get those endpoints of adult reproduction. We could get the initial things that after birth, but we need things like fertility and those other things. Would it the ideal, yes. Is it likely to happen soon? I don't think so. The mouse obverses the rat. I think that is a big thing. To get to [ indiscernible ] point, I thank you, I think it is pharmacodynamics and pharmacokinetics. Neither writes nor humans and exhibit--For example the only time you will see a [ indiscernible ] tumor is in response to estrogen. We now know that some of these modules are relatively normal in humans. I think I would put forth the argument that the rat is closer to the humans then the mouse. I'm sure there are others, but I cannot think what they are.
Paul, can you address the design, the need for a multi generational steady rather than a study where you are exposed during the critical window, which we know is in utero?
I think you could do that. That would not necessarily cover the ability for the animals to reproduce. If you look back to the data that I presented from the mouse study, there were in effect on sperm count, even in the mouse study, the F one. If you would like to look at anti androgen--I would not disagree with you. The in your true exposure would probably the most of it.
I would mention to the board that there is an ongoing study, the National Child study. In that study there will be [ indiscernible ] measured before conception all the way through childhood all the way to adulthood, assuming that the funding is not removed. That will be delayed. They are on our radar screen right now. Any other comments on this topic? We did not receive any written comments. Are there any Members with of the public present that would like to make a comment? Dr.Howard?
Can I ask a question? You are saying that the most proper way to go would be to focus on the epidemiological study. I do not know what you are asking, procedurally.
I understand that this is the National Institute of environment for help studies. Whatever is most appropriate for advancing the science should be used. Is since that the National institutes should fund such a study. That just seems like a very reasonable thing to do.
Your comment is that it would not be funded under the NTP mechanism?
I do not know. From the signs point of view, it seems to me that that is the obvious study that we should do. The results from the studies that we talked about, they were done at doses at 20,000 times higher than what humans are exposed to. Forget the limitations. If there is nothing happening in humans, it is telling me that these animals studies are totally irrelevant. If we do not see anything in animals humans at doses 20,000 or higher. We should do a study to replicate the findings. That would not take 20 years. It could be done quickly. If we do see something and replicate what has been seen, then we can follow those up to see if there are adverse effects. We could follow up and see if there are some adverse effects. I do not see that this study with high doses and animals would answer the question.
I want to reinforce what is being said. I know this came up at the summer meeting with a different chemical where I was really pushing that we should look in the workplace and not go to a basic animal study to try to show that there was an issue. I think the culture of NIEHS has changed enough to where we are moving more and more towards getting human data and we need to balance that much more regularly with what we are seeing in the animal studies and change how we prioritize after we have gotten the basic data down. It will probably have to be a bigger topic of discussion. I do not know, John, if you even wanted to mention, but I just presume that NTP could sponsor it. With.
We have not traditionally, sponsored the study is. There is nothing that would prevent us from working with the epidemiology branch. We do have a one epidemiologist in our program. There are other avenues that could be pursued to address the issues.
I think we will come back to this in the next grouping of compounds because it is a ballot initiative. When I want to go on to that and then discuss this in that area.
I will love to talk to you about that if I know what to do.
We have some slides. This is the second part. This is a research concept placed on DEHP. Here is the structure of DEHP. We already have a number of existing [ indiscernible ]. These have been over a number of years. The go back to the early 1990's. Nominations related to this proposal would be on the [ indiscernible ] initiative which was initiated in the early 1990's and nomination of the DEHP by FDA and the critical data needs from the DEHP needs. The background is-As we all have come to know, I offer the purchase first part is that DEHP is a environmental contaminant that produces adverse reproductive, developmental and cancer as it affects an experimental animals. Based on the NTP--It was then that the IARC delisted DEHP as a carcinogen based on a mode of action criteria. I think we are involved in a lot of that work. The essential idea was that t he--This has limited relevance. There has recently been-This is a true life bioassay. This is for liver to Marks. What it showed was that you could also see it testicular [ indiscernible ] in this particular study, both in terms of the number of cells and multi focal. There is also an interesting piece of information and I have tried to extract this into an one table. This was a 22 month study that was conducted with DEHP. I think what is interesting is when you look down here, which you get more [ indiscernible ] in the tumors with the knockout than you do in the wild type. That is interesting in its own light. It is suggesting that you might have more than one. We have already mentioned some of the phthalate. If I remember right doctor in the sample was one of the authors on that particular paper. We know that DEHP metabolites in a road it. They have been found in rodents and humans from the general population at amniotic fluid. We know that both humans and rodents are already being exposed. The critical thing here is and this is what I was trying to refer to earlier, the margin of exposure between the levels that are found in a rodent compared to what it is found in the maximum in humans was only a factor of 20. That is compared to a dose of 11 milligrams per kilogram. Human exposure data also indicates that people in the general population are exposed to multiple phthalates. Of the many that they are exposed to they can produce developmental defects in rats. What is interesting that has appeared recently is the study that has been done with PFOA, the post natal developmental defects were not seen in the knockout mouse but the prenatal effects are. I think that is quite interesting. You can see that it starts to pose the question--It is likely to be developmentally regulated. What are our hypotheses that we would like to test? First, we would like to say that lifetime, it is a. Natal two your exposure to DEHP what does-I think it is worth adding the pancreas as well. There has been a more recent study that showed an increase in tumors in ratses as well. Also, the [ indiscernible ] is developmentally regulated in the rat. It is unlikely to contribute to the toxicity initiated in neutral after exposure to DEHP. That is a hypothesis that is worth testing. Thirdly, the exposures to mixture of phthalates based on their individual potency would result in [ indiscernible ] addition to counter that might be anti androgen it, for example. So, how would we approach this in a general manner? First of all, I think we would undertake DEHP perinatal cancer bioassay and in the rat. I think we can evaluate, and using this particular strain of rat, targets other than the liver. We can see the actors and and tight estrogenic effects. We might be able to pick up the testes and pancreas. When no that human fetuses are exposed. There is a reason to go with the perinatal group. The other thing we would like to do is to undertake a ontogeny study. When is it first expressed? And see what the target tissues might be. To is also worth understanding that the anti androgen effects and the other positive phthalates are not found in any mouse study. Although there has been some reports that you can see in facts on primordial germ cells, none of them have shown decreasing female antigen and [ indiscernible ]. Using the mouse approach, it is not likely to give us the outcome we want if we cannot induce the kinds of developmental affects that we would like to see. I think we would then like to undertake a perinatal mixture study using the toxic equivalency factor. You would not go into doing that and remember, the NTP does have a history of doing that. I think we all know we would need a fair amount of information on individual chemicals before we undertake an do this study. Some group exposure would be a really important thing to have a. Estimates during pregnancy and lactation---It is quite difficult to control external dozes during pregnancy and lactation due to the amount of food that they eat. The [ indiscernible ] give you a lot more control. I think we would also need some short-term assays on a number of different phthalates the ones we have suggested are a [indiscernible]. This is interesting. In Europe, it is a category two. You cannot use it in Consumer Products. Interestingly, in Europe--[ indiscernible ] is also known to be positive. If we had some good data, we could even consider using an discernable. It has the highest concentration. We need to develop a potency estimate so we know how to take the approach. I think we might end up with different kinds of potency estimates depending on what it is that you want to look at. For in utero exposures, we would base this on testicular testosterone levels. There is some pretty good data out there that this seems to be a very good, quick, short term way of finding out relative potency of phthalates. For the older animals, we could probably use [ indiscernible ] activity as a means of developing the estimates. Haven't gotten these potency quotes, it is anticipated that we probably would not use more than three mixtures to start with. That would be based on a large extent to see what we got based on these. If we go with any of these is specific phthalates, we would need data so that we understood what they would be at the appropriate times. What would be the significance of this? I think that such studies would provide a cancer hazard assessment for lifetime exposure. Since we know that [ indiscernible ]-We can start to address some of the potential impact of light exposure. I think we can provide toxicity data on the other important environmental [ indiscernible ] on lifetime exposures and give critical data to--Based on what we are seeing, it is clear that humans are exposed to multiple phthalates. Moreover, recent data showing that because of a similar mode of action and civil shows were administered in combination. I think it is appropriate to consider the risk because we know that human subjects are exposed to multiple phthalates. I wanted to finish up with one side from a paper illustrating the very point. This is what happens when you put DEHP and DEP together. There is one malformation. You have a zero in DEP and 2% and DEHP and together you get almost 50% when administered in this critical window of exposure. That finishes my comments. I would like to get your input, if at all possible.
Thank you, Dr. Foster.
I will try to move this microphone so that I can see you. Before I forget, I'd like to thank you for that trip down memory lane.
[ Relay event
[ LAUGHING ].
One things as I've read this that I would like to at least say is the take-home message for me is that the focus is cancer risk for this one. In the discussion we had about comparing the DEP, we should keep that in mind. Having said that, I think that this program has a clear rationale and is largely based on the recent findings that was published in 2007. The results had an uncertainty over the role--Carcinogenic potential and mice. I think that coupled with the idea that there are critical exposure windows and development there is a rationale for moving forward and understanding the risk of exposure in developing animals. The first hypophysis influence of developmental a on treatment of DEHP on cancer risk. I think that that's certainly makes sense. I like the concept of comparing in utero versus adult onset of treatment. That design is very appropriate. I am not familiar with previous discussions--Based on the information in the proposal, I would wonder why why a [ indiscernible ] rat might not be appropriate. This kind of the study needs to be carefully designed with additional endpoints and time points that get at exactly what the mechanisms are that we wish to examine and understand as it applies to the developmental window since we do not know what will happen. The second hypophysis is that [ indiscernible ] is developmentally regulated and in the absence we tend to support other mechanistic considerations. I think that it harkens back to the first hypophysis and the approach that we need to make sure that we consider all potential mechanisms and that kind of study. There is a good fit there. My only question is I would like more detail on the strategy for investigating the expression. As you know, there might be very small sum population perhaps that could be responsible for mediating. With out a variety of approaches to studying the expression of this receptor, and I might add, considering looking at other with PPRL and Delta theta at the same time would be a good way to look at this. The third hypophysis looks at the mixture question. I guess I agree with many of the statements about understanding exposure. That is really going to be a very important part. I struggled a little bit with how you pick the end points for calculating the toxic equivalency factors. If you say, for instance, you are going to measure ACP, you are picking a and what that does not have Revlon's. For what ever equivalency factors you have a disconnect there. That one, I think will be a real challenge, to get the right equivalency factors. The other question I have is a vista of the phthalates that were included as a representative examples. I am wondering how many degrees of freedom you will ultimately have for a long-term study. Based on the references I was checking in the proposal, it looks like two of those phthalate were associated with liver tumors and only phthalate were associated with the risk of [ indiscernible ] tumors. There might be other information that I am not privy to or have Miss Somehow that would inform that. At the beginning, you can almost tell which phthalates you will use in that long term study. I am wondering what the other ones add at this point in terms of toxic equivalency factors. I am going to make a few general comments. I think this issue of cancer risk is fairly important. It goes back again to the importance of PPR Alfa and if there are any other [ indiscernible ] mechanisms involved. I think there would be some real body and expanding the [ indiscernible ] to go look at the knock out mice. Part of the reason is that there are non-Phthalate products that do mediate their carcinogenic effects. That is predicted data to that effect. The question is, can we go back and understand more about what happened and really use that and characterized effects of not only DEHP but [ indiscernible ] would be another candidate to consider. There is another model which is the knock out and mouse in which the human receptor has been expressed and. I think if we want to see how this transitions, we might see if that model is available to be used. One think about these models that I really think provides a good opportunity for the NTP to provide some value is the general robust nature in which these studies will be conducted, everything from the genetic background of the animals to the conduct of the study to the evaluation of the end points. I think that there is an opportunity here to provide a lot of high-value information for discussing cancer risk. I think the relevance of phthalates, I do not think we need to say too much. We have already heard a lot about that. In terms of priority, I consider this a high priority. What the mechanism has a significant impact on the use of this information for assessing human health risk. I indicated areas where I think the proposal can be modified.
Thank you. The next is Dr. [ indiscernible ].
I think this is an excellent proposal. It addresses an important issue, which is the affect of prenatal exposure on cancer risk, and of course, the mixture for phthalates as a class is an important question. We need to understand aggregate is exposure to phthalates to understand the cancer risk in humans. When I read this proposal, I read it as if it was being conducted in a tiered manner with hypophysis one being conducted first, etc. That is how I read it. I hope that is right. Keeping that in mind, I think the results of the first hypophysis will influence the design of the mixtures study. Clearly, if there is no increase in tumor incidence in the DEHP perinatal due to the prenatal exposure to DEHP, but I think it would reduce our concern for--
[ LAUGHING ].
Go ahead.
Where was I? So, if there is no increase in tumor incidence with prenatal exposure to the DEHP, DEHP being probably one of the more potent phthalates, then I think we would reduce our concern for other phthalates and exposure to mixtures and cancer incidents. So, with maybe that is--
[ LAUGHING ].
Keep pressing forward.
Okay. So, that was my comment about the decision, the tiered decision making in this project. As far as the hypophysis one, I kind of echo some of the comments. I do have an additional comment about the design, which I think is valid to have an adult exposure-Only group. I do question how do we interpret an increased tumor incidence from the Perry --Perinatal does not we are trying to get it taken care of. Please continue.
Throughout the lifetime of that animal, including perinatal exposure, how will you distinguish the role of [ indiscernible ] exposure, the role of that window of exposure in tumor incidence? I do not have anything to offer except adding an additional group where you would look strictly at perinatal exposure and its effect on tumors.
If you are willing, I will press on to the other comments and let you answer them all at one time.
Most people have mentioned most of my comments. I have enthusiasm for it. I am troubled by this whole is rat the right model? Any clarification on that would help a lot. I think as much as we have going on, it would be very good to characterize the experimental animals, as far as that. My one question there is that we did talk about the other PPRs. I did not know this particular receptor, but they have co modulators. Just because you do not see it change in the expression does not mean there is not a change in connectivity. You might need to look to see where what is known about those modulators. Initially, I have quite low enthusiasm for the third, it is because it is fairly broad. It is presented in a null hypothesis and the word--Your data did show a very strong synergistic effect and gave me more enthusiasm for exploring that. That was a big difference.
Are there other board comments that you would like to make before Dr. Foster addresses these?
If it's any consolation, I like this one. I think it is, based on human exposure, it is a good one to look at United expert your. A couple minor points. Maybe stay away from [ indiscernible ], as a label. In terms of [ indiscernible ], the aim of the project would be to test that assumption. I think in addition to the things that you have mentioned, the key question with connectivity is which chemicals are in, and which are out. What is a common signature or common toxic response? Lastly, in keeping with were the mixtures are going, it is real important to stay down on the -- The question is what is going on when you add a bunch of chemicals when they are all below their threshold? On the last slide you s howed,--There are more robust ways of looking at that. The real important question is what is going on and what is happening at lower dose levels.
Would you like to make any comments before we go to the public for any comments?
I have been thinking about this proposal in terms of how it would be used in regulatory and standard settings. When I think of it in that respect, I do not have a lot of enthusiasm for a long term exposure--I am wondering if it is really worth the utilization of the resources. I have a lot more enthusiasm for the third hypothesis, trying to develop some scheme would be very with a hopeful and a regulatory setting and you use whatever scheme you come up with to assess the mixture of phthalates. I am wondering if this proposal is really going to get us all the way where we need to go. We are limited in a number of combinations that we can look at. I am wondering if there is an in vitro test or group of in vitro tests that can be done very quickly, and we can apply all sorts of combinations of exposures very cheaply and come up with some ways of managing the relative potency of these with some pharmacokinetics data and come up with a range of relative potencies, all different combinations of these. Perhaps, we can take some in vivo studies to propose what we are saying on the in vitro studies and to validate what we have with the in vitro studies and comprehensively assess the risk of exposures to mixtures.
Which I like to comment on that?
I think I will go to [ indiscernible ] first. I think that she is right. If we did not see any difference between adults and perinatal, then that does of the a--That is good information to have a. I think we still need [ indiscernible ]. I wish there were some really simple in vitro studies that we could do. I do not think there are. What I tried to suggest where some of the relatively short in vivo that will give us some reasonable potency estimates that we can then select a much more limited number of agents. I have looked fairly hard to see if there are any. I really just do not have any that we can suggest. This now represents a fairly important component. As you know, the National Academy suggests looking at--And has not been able to do so. I think this is quite timing that we are trying to get some of the real information on what those potential risk perhaps my the.
Figure that, very much. We did not receive any written comments on this initiative. Is there anyone who would like to make any comments? Any further board discussion? If not, I would like to call for a motion pergolas to these in the order that we talked about First.
I move that we disapprove it.
The motion is to disapprove the compound or do I have a second?
I second.
All those that are voting in favor of the motion, which is to disapprove [ indiscernible ] for going further in the study, please raise your hand. The approved number is-We have no one person-Are you voting no?
I needed to give me an explanation.
I felt from the discussion that it should be taken forward.
The chair does not bow, as I understand it. The motion is approved that it will not go forward.
I Disney to be sure that I got this down for the record. The next motion to be brought forward is the [ indiscernible ]. Can I have a motion on that initiative?
I would approve that one.
Is there a second?
I second.
We have 22nds on the motion proposed. --I have two seconds on the motion.
We are not scheduled to have the technical reports subcommittee. This is an action item for the board. We are running behind schedule. We will go forward with this piece of it and then take a break. We will take a very short break. We need to get everyone where they need to be this afternoon. This will be an action item with a vote taken at the end whether or not to approve or disapprove the report. I need to call to the committee's attention that there was no one compound left out of the initial minutes. There was a report on that. I believe in the sample was left out of the Minutes.
It is on my screen, but it is not up there.
The sub committee review the technical reports. We reviewed seven reports on the six chemicals. Each of these reportses was discussed. Some suggestions were given to amend some of the text. The conclusions were reviewed very specifically and sometimes were amended. Basically, what I will do is run through each one of these technical reports. These are not my slides, Barbara.
There we go. Great. Okay. So, it was cited in a 2-Year drinking water for that. The subcommittee unanimously approved on a 6 to 0 Boat. The following are the conclusions that there was clear evidence of all test animals, male and female mice and they were oral squamous cell in the rats and in desirable in the small intestines. The second compound was formamide which is a solvent and water softener and an intermediate in organic synthesises. The subcommittee accepted the reports on a 6-0 lote. The evidence as shown here, there was no evidence of the carcinogenic in rats. There was clear evidence in male mines base on and Saddam will soar, in the liver. --In the male rat in the [ indiscernible ] sarcoma in the it liver. The evidence is shown here, based on the combined carcinoma in the kidney and nasal epithelial [ indiscernible ] and a --An e-mail rats there was some evidence of [ indiscernible ]. There was also clear evidence in female mice, based on neoplasms, adenoma and carcinoma combined. For Cresols, accepted--The subcommittee unanimously agree when--Based on renal tubular adenoma and some evidence and female mice's. The next is a chemical intermediate, corrosion inhibitor, solvent stabilizer and polymer modifier. On the basis of the 2-Your installation studies, the subcommittee voted 4-2 to accept the conclusions of the report. The conclusions were that there was some evidence for being carcinogenic in male rats. There was no evidence of carcinogenicity in female rats. In male mice there was some evidence and equivocal evidence--and the female mice, there was some evidence based on nasal epopee epithelial adenoma. The vote of 4-2, the two disagreeing did not agree with the committee's decision to reduce the evidence from clear evidence to some evidence for the nasal epithelial adenoma in mice. Then, the committee review non to the studies on it [ indiscernible ], which is a synthetic steroid estrogen that is used in contraceptive devices and contraceptive pills. Deeper study was a multi generation dosing scheme where they looked at chronic defects over four generations. With just to keep this clear for myself, I do not know if there is a pointer, in the F zero it reflected adult only exposure. The F one was pre and post natal plus adult in comparison to-Excuse me. Does look over there. I knew I would get confused over here. The F one sacrificed at [ indiscernible ] is looking at pre and post natal plus adult exposure. Thank you. Okay. We are looking at is F2. Si F2 generation is a pre and post natal plus adult exposure looking for a cumulative effect across generations. F3 is pre and postnatal only and the F4, there was no direct exposure either pre or post. The defects seen in these studies--The effect--The adverse effect include a decrease by the way that occurred both in female and male during exposure and--increased mammary gland hyperplasia in at the male mice and mild mineralization and delay of a separation in the F two. I can tell you that that is a potential cumulative effect on track effect. That was not seen it in the F1. The second technical Report concern the carcinogenicity results. In this study, we were looking at the exposure ratio of two years. In the F1 generation and the F3 generation. The F1 generation had continuous exposure compared to animals that were only exposed three, Post and early adult. This was allowing time for repair, recovery, or also isolating defects. Then, the F3 generation that was exposed only through day 21, and the results of these steadies, which were accepted by the subcommittee in a 7-0 vote, there was no evidence of carcinogenicity in the F1 generation of the male or female animals. This has been previously classified as a carcinogen when fed to animals at higher doses. In the animals, the F1 animals exposed from conception to 22 weeks, there was evidence in carcinogenicity and the female animals with Paulas and the F3 animals exposed from conception through winning, and the animals--In the females, equivocal evidence as well. I think that is the end of our report.
Thank you, Dr. Kerkvliet. Are there board members that would like to ask questions or make any clarifications? Are there any public comments? If not, I would like to have a motion whether to accept this report or not.
[ AUDIO/SPEAKER NOT CLEAR].
Is there a second?
I second.
Thank you. I'd like to see a show of hands for everyone who votes, yes, to accept the report. The boat is a unanimous. It stands approves. We will take a five minute break. There are coffee and cookies. I will call you back in five minutes. We have business to conduct before people leave.
I will ask people to go ahead and come back to the table.
Can I ask everyone to take their seats, please, the next item of business are the nominations review. This is an action item for the board. In contrast to the usual NTP nominations, we will be discussing it either of the two compounds should be under review for reproductive risks. There are two on the agenda. We will talk about each compound generally. We will take some comments from Dr. Michael Shelby. We are joined by Dr. Michael Collins who wants to discuss Cadmium.
Thank you. Thank you for the introduction and thank you all for being here today, for those of you that have spent extra time reviewing these combinations. I would like to say a few words in the beginning. Just to clarify what these nominations are, this is a process that [ indiscernible ] follows that extends from the nomination of a compound or substance for expert evaluation of all the way through the release of the CERHR process. One is the selection process which is on the panel on the left. The center is the preparation of the expert panel report and the draft of the brief. The end is the final stage in producing the monograph which includes the NTP brief and represents their official position on the reproductive and environmental hazards. Today, we are very early in the process. We had a nomination of Cadmium and Lead. Those nominations have been considered by the CERHR core Committee, which is a group that helped guide the activities of CERHR. It includes representatives with expertise in reproduction and development from the National toxicology Program, the Environmental Protection Agency, the Food and Drug Administration, Consumer Product Safety Commission and the CDC. We meet quarterly to discuss action items, such as nominations. The nomination process is open 24/72 anyone in the world that wants to make a nomination. It is done through our web site. It can be done by telephone, by e-mail, by the U.S. Postal Service, however you want to do it. Every nomination that we receive, we prepare a preliminary dossier which is the first, at understanding how much literature is available, production volume, something about human exposure and the extent of the literature on the reproductive and developmental toxicity studies. If the Court committee feels like there is interest in it at that point, we go back and prepare a final dossier, which is represented by the two documents that you have on your notebook today on Cadmium and Lead. This is the first time under this new policy that we are coming to you to get your advice on whether or not you think these are worthwhile endeavors. I had Lead first in my slides and the chair as that we do Cadmium first. I will skip through a few here first. All right. Cadmium came in through an anonymous nomination in 2000. We changed the process in April of 2001 where we would no longer accept anonymous nominations. We need your name and affiliation and e-mail address or something along those lines, so at least we have a record of who submitted teas nominations. There was no rationale provided. We do not require a rationale in our nominations. When the court committee first reviewed it in August of 2000 and deferred the compound. Last year we went through all of our deferred compounds, the core committee did, trying to see if there was anything that might have moved up the priority list by virtue of new literature or public concern. We needed a bit more information on it. We got that and was reviewed at the next quarterly meeting in January of 2007. At that point it was recommended for evaluation. Very briefly, the rationale was that it is a high production of high-volume chemical, about two and a half million pounds per year in the United States. There is widespread human exposure through a variety of routes, primarily dietary and cigarette smoking. One of the big issues was the increased use and disposal of Cadmium, nickel batteries and all of our personal electronic devices. Looking at the literature on it, it is fairly rich. There are at least 37 studies of developmental toxicity in humans. 94 developmental toxicity studies in animalses. 29 human reproductive studies and over 100 animal reproductive studies. In making a decision, is not of great importance to us what that literature says, whether those studies are all positive or negative or half and half. We want to critically review all of the available literature and come down to a weight of evidence in order to make a decision about the potential hazards to human health. There is public concern. The dossier said that this is probably assumed under a public concern about under a toxic metals, a large number of compounds. There is sufficient concern that fairly strict controls have been imposed in Europe regarding imports of Products that contain Cadmium. It has been in the news several times, the topic that is most often discussed in news and on the Web is e-cycling and that these Cadmium batteries were disposed in waste dumps. Now, it seems that the large part of it--Where this recycling takes place. There is public concern. Based on that rationale, the court committee recommended CERHR undertake thorough evaluations of the potential effects on human health. That is the end of that.
Thanks. The first to discuss this is [ indiscernible ].
I think Michael outline-I will not repeat everything he said, based on the nomination, the drivers here are being human exposure and to add to that [ indiscernible ] who detect Cadmium samples. The one thing I will add, too, is the last part anyone has done a thorough review on this was in 1999. It has been a while. The dossier did a very nice job there of talking about the new studies that have been done since 1999. That was very helpful for me going through it. In terms of the key points, to is more like a potpourri of points, not a real definite signature, where with reproductive toxicology, the majority or the focus area would be on the testees'. Having said that, it did look at some of the studies were quite high dose levels and by--That will be it something for the panel to consider. As Michael indicated, this coming along for the right on the toxic metal concern. Last night in the local newspaper I read about the toys coming over from China with Lead. Cadmium is the second one mentioned. It seems to come along with that. Like I said, I do not think there is anything else that I am aware of, evaluation's--Going on in the near future. This would be it for a new evaluation conducted in the last decade or so. There have been quite a number of newer studies. I do not think any of them jump out as the changing of the game. There is a lot more studies out there. Overall, I was supportive and gave it a moderate priority. I gave it moderate.
Thank you. We have Dr. Collins. With.
Can you hear me?
We can.
Okay. First of all--
I am sorry. We have the wrong person on the screen. Could you hold for just a minute , Dr. Collins? Dr.Collins, are you still with us?
I am still here.
Should we go ahead with your verbal comments?
He looks a lot better than I do anyway.
[ LAUGHING ].
There you go.
I appreciate that comment.
They are saying that we will not fix it. Let's hear your comments and verbally in.
First of all, I would like to state right up front that I have been working on Cadmium in developmental toxicity for the last 10 or 15 years. I am not a very unbiased observer of this overall process. From that perspective, clearly, I think it is an important problem. We have been working on it for many years. Second of all, what I would like to say is, I think that it is very difficult to determine if, in fact, this compound causes human developmental and reproductive toxicity. The exposures to human are in general, a relatively small. From that perspective and from the other ideological perspective, it is very difficult to tease out on the contribution of Cadmium to overall reproductive and developmental toxicity. On the other hand, it is an extremely potent developmental toxins and has been shown to be so in all of the animal species that have been tested. It seems to me that it is only logical that there is a potential for it to be a productive and developmental toxicant in the human. The second thing, I guess, that I would like to say is that the document that we received that looked at Cadmium over all was somewhat incomplete. I think that there were real substantial commissions from that document. It is hard for me to say that. I know one of the authors pretty well. He is a lot smarter than I am. He has not worked with this particular chemical in the past. I think he missed a great deal of the historical literature. Also, some of the literature, at least the review articles on the compound are in relatively small Journals that are not very widely disseminated. I think you could easily miss some of those kinds of issues. I evaluated this compound as high. That is because I have no frame of reference for what sorts of things you evaluate in other circumstances. I have evaluated no other compounds. From my perspective, I have chosen to work on this from a research perspective for the last 10 years, as I have mentioned. Clearly, it has the potential to be very important. It has the potential to be a very important chemical compound. There is lots of other data then what is in the dossier of what we have received. An example of that is that there are no papers in here that are cited by Bill Webster from Australia who has spent over 10 years working on the Cadmium issue in developmental toxicity. None of those papers are cited here. I think that there is, clearly, the need for a more thorough investigation of the compound. How should I proceed. Do you want to ask me questions, or should I just give a statement.
If you just hold on the phone with us, we might have more discussion that you can respond to and we will have some response back from Dr. Shelby and you might want to have some response back and forth. Stay with us. Let me ask the board for general comment and discussion. Let me ask Dr. Shelby if you would like to make any additional comments or respond back to things that he has heard.
The only real criticism I have heard is about the [ indiscernible ]. We do a more thorough job when we start preparing a draft report. Maybe [ indiscernible ] knows.
The issue is not to make a decision about the compound. It is the decision on doing a thorough literature review and case for analysis. This is not a question on whether we study or not. It is whether we assess the literature.
Right.
I do not remember. I think the reference is cited--That is why a lot of the old literature was not cited.
Some of the old stuff is in there. It is focusing on post 1999.
That is right. That is why some of the older stuff might not have been in there.
I did not seek any discussion on exposure--Or an points that you thought were worth mentioning.
I answered no to the first one. [ AUDIO/SPEAKER NOT CLEAR].
Dr. Collins, do you have any comments?
I would think that there are potential susceptible populations. That is based on the work that Dan has published on the CDM gene in mice. He has isolated that particular gene as being SLC39A8 witches a bicarbonate [ indiscernible ]. I do not know if there are, in fact, polymorphous ands in that gene in the human population or not. I do not know whether or not it is worth studying. Clearly, it is considered a gene that is susceptibility or resistance, depending on its categorization in the rodent models. So, in fact, wrote thats are either susceptible to testicular toxicity or not susceptible, depending on what they have in this gene. Different mouse strains are totally susceptible or not susceptible, predicated on the specific gene. We have also, recently, might Babbittry published a paper saying that we think that there is another gene in all in the overall process, and we think it is--In addition to that, I would say that there is a lot of interaction of Cadmium with other [ indiscernible ]. So, the processes that are involved in the transport of all sorts of [ indiscernible ] like iron, calcium, etc., could, in fact, be very important in the overall susceptibility of Cadmium.
Thank you, Dr. Collins. Any other members of the board with comments?
I could just make a small comment, it seems to me what little I know about Cadmium, one of the things that it makes hard to predict susceptibility, etc., is that there are so many diverse mechanistic impacts, also a tremendous debate as to which are the dominant mechanistic impacts on anything that could focus on what the true mechanism pups are behind some of these things and would [ indiscernible ] susceptibility.
We did not receive any other written comments or written comments. I openness to members of the audience.
Dr. Shelby, any other further, perhaps on this?
No, ma'am.
I am asking for votes whether there should be approved.
I move.
I second it.
Thank you, very much. Could I have a show of hands for everyone who agrees that this compound should be on the next review. Unanimous. The compound was approved for review. The next compound will be Lead. Dr. Shelby, are you going to make some comments? When it decides to come back up, maybe. Dr.Collins, thank you. We did get you on video for a while. You are still with us.
That is too bad.
[ LAUGHING ].
I think that a is still with us through ideal.
Yes.
Thank you. The second substance recommended by the court committee is Lead. This came from Dr. Elizabeth and - [ indiscernible ] last year. I have not touch anything except this what. The rationale behind this is an occupational exposure allows blood levels of 4 0 micrograms--This is allowed in workers including women of child-bearing age. This does not mean that those workers have that blood level. In many cases I think there are very good controls. The Association of Occupational environmental clinics has been working with NIOSH on this issue. Levels of 10 to 19 are associated with possible spontaneous abortion and reduced birthweight. Below its 10 is possible adverse population effect suggested by epidemiologic studies. In addition to what a CERHR evaluation could contribute to the overall public health community, it might help-It could help confirm the need to recommend advising exposure limits. The history on this, was that at the July 25th meeting of this year. The core committee recommended evaluation. At what levels below 40 micrograms per [ indiscernible ], if we were to move forward billion pounds.
Your written comments will not be entered into the record otherwise.
I think that Dr. Shelby has been a very nice job. There is not a great deal that I can add to it except to say that it is of high importance that I recapitulate with what Dr. Collins says. We have been working on developmental toxicity for over 15 years. It is extremely portend and an important topic for human health and worldwide. Oneof the things that have been found in a deficiency similar to what Dr. Collins mentioned is that there is very rich literature with the effects of Lead on the brain that is not in the dossier. I have been publishing for 15 years on Lead and there is only one reference. There is quite a bit of effort on that. Other labs that are working in the similar area do not include it. There is a vast amount of literature that needs to be incorporated into the review. It is providing some very exciting results. There are some very specific topic areas that are very recent that would be useful to have in the review. Separate from what has already been said, with the importance, and obviously we see it on the news on a daily basis, the only comment I would add is that we definitely need to look much closer to the literature that is available, that is not included.
Thank you. Are there, perhaps by other board members? Yes. You sure microphone, please.
Just a general question, the criteria for choosing [ indiscernible ], but at the same time there are many other [ indiscernible ] that meet the same criteria. The question of why are these two chemical planned selected initially?
Dr. Shelby, which like to address that question?
They were nominated to us to evaluate. We do not select our own chemicals. We rely on the scientific community, the public at large to provide us with what they think are the chemicals of concern.
Were any [ indiscernible ] nominated?
Yes. John, did you want to say something? We have a list of, perhaps, 400 nominations that are in our files. We have done expert panel evaluations on more than 20 of those. We do not have the capacity to turn things out on an assembly line. We try to choose the ones that are most important to public health.
I believe that these two chemicals receive the highest priority?
From the court committee, yes. From the nominations that we had, yes. You are all welcome, I invite you to go to our web site and make nominations.
Please use your microphone.
In terms of the production and development, I think they[ indiscernible ].
You are certainly welcome. Go to our website and make a nomination. We don't ignore any of them. They are all dealt with by the core committee.
Are there any other comments?
I think it is really a good idea. It is set a date their rich area, both lead and cadmium. And that I think most of you that have been in research for a long time see how things began to attains and the older studies get forgotten. They can really contribute so much to the understanding that it is really great to have expert committees. Some people that are in the field and some people that aren't come together and try to look at the literature and come up with a synthesis of what it all means. I really support this.
Let me tell you that when the panel reports are being prepared and evolving from their first draft to the final draft -- I mean, we do very thorough literature searches. We update them every two weeks or so while this process is going on. We invite the members of the expert panel to identify the richer for us. We go through the to the Hebrides and papers that are being reviewed and see if there is anything there that we might have missed. We invite the public through federal registered notices to comment on these drafts and supply us with literature. We make a substantial effort to cover but the trip the best that we can.
Thank you for that clarification. It is a long process and this is a new process, somewhat, to this board. We did not receive any written comments are was anyone registered. Is there anyone in the public present that would like to make a comment? If not, with no further board comments or questions we are ready to move to a motion. Could a have a motion on whether or not lead to should be moved forward to expert panel review?
I move that we move forward.
Can I have a second?
I second.
All those who approve, can I see a show of hands? The vote is unanimous. Lead will be approved for expert panel review.
Our next agenda item is the report on carcinogens, an update on the process and time lines. This is not an action item. This is an informational items seeking comments from the board. Dr.Jameson will be giving this presentation.
Thank you.
Thank you, Madam. Since we are running behind I will try to the to my presentation as briefly as I can. What I was asked to to or would like to do is bring you up-to-date on the status of the report, where we stand and a timeline for the preparation of the next report. This is show and tell. The report on personages as the last report that was published. As he got the report was mandated by law. It is required to be prepared every two years and submitted by the history of Health and Human services. It's a listing of all the chemicals are a listing of chemicals that are either known to be human carcinogens are reasonably to every single reasonably anticipated to be. This report was published in January of 2005. As I indicated it is supposed to be published every two years. It is currently December of 2007, and we are just starting on the next one. The reason that we are so slow in getting started is because test as the 11th report was being published there was the issuance date quality acts. And the OMB issued bulletins are guidelines for peer review for documents prepared by the federal government. And in order to be compliant with the Data Quality Act and also the peer Review Guidelines issued we went through a series of -- starting with a public meeting in 2004 we had a number of meetings to address the issues outlined in those guidelines and to the modify the process we had for review of nominations that were used for the 11th report to update them if you will to be in compliance with the Data Quality Act and peer review guidelines. And it took until this past April so work out all the details and to get the -- get all that information workout. I put this up here. This is a recent publication which kind of out lines work gives you a little bit of back ground on some of the hassles -- I'm sorry, not hassles. Some of the activities we have had to go through in order to address to the quality issues and to satisfy the Allenby and various other people that our process is as open as it possibly can be. And we are doing the best review of our nominations. I have the side there if anyone is interested. Anyway, what I would like to do is discuss with you very briefly what our current process is and let you know what the nominations are we are working on and a timeline for that. So what I wanted to go over here was the report on carcinogens review process. First we have a nomination process very similar to the other nomination processes that he heard about. And the nominations, we invite nominations from the public, but we also generate our own nominations internally by Motta during literature and reviewing reviews on a particular chemicals or exposures circumstances for Carson sank a fact. Once we identify a list of nominations we published those -- for we list those in a Federal Register notice and ask for public input to identify any issues concerning that nomination that an individual may have come by any concerns they may have a lot the review for their carcinogenicity and also for the 12 report we also are asking for people to nominate experts in the field related to that particular nomination who could assist us, served on an expert panel if you will, to peer review the background document we prepared for that particular nomination. Once we get all the input we identify what we refer to as the candid substances that we will look at for the next report. Then we prepare a dossier on the canted substance. We go to an internal committee for their comment, and we go forward to the director with our recommendation for the candid substances that we propose we look at in the next report. Once the Candida substances are selected we go to the next step which would be the preparation in the release of the background document for each of the nominations. We do a thorough literature search concerning carcinogenicity of the candid substance. We prepare a draft background document. We meet our rosy staff. We have a support contractor who assistance with this. We also go out and try to identify experts who have published on a particular candidate substance and a we are looking at and contact them and ask them if they would be willing to help us draft certain sections of our background document the it expenditures section, animal carcinogenicity or the other relevant data. We get these people to help us, and we draft the background document on the nomination based upon that literature concerning their carcinogenicity and mechanisms for the can to the substance. We then also based on the nominations that we get for people to serve on an expert panel and also individuals that we would then that in ECP identify, we contact these people and we organize and expert panel to a peer review the background document for each candidate substance. And after we have that document and identify the expert panel we publish a Federal Register notice going out and announcing the availability of a draft back ground died here asking comments. And we also indicate that when the expert came the note will be invited the public to attend and make public comment at that meeting. The expert panel meets in a public meeting. They need to appear refused the draft back ground Stockman. Once they have completed that and accept the document as being something that can be used we then asked that same expert panel to make their recommendation based on our criteria for listing status and the report. So from the public meeting we get. You of our background document and a public review and recommendation for listing of that Canada substance and the report on Carson's in St. Was the expert panel meeting is completed we take their recommendations. We finalize the document. We will publish a final version on the web along with their recommendation and solicit comment on both the background document, the final version and their recommendations. Once we have the final background document we go to a series of internal reviews within the government. The first one is referred to as the interagency scientific review group. This is a group made up of agency representatives from in tepee participating agencies and other government agencies. They meet to review the background document and give us their independent recommendation for listing status of the Canada substance and the report. This is a government meeting, and so it is closed. It is not a public meeting. Following that we go to NIEHS, NTP committee and ask them to apply the criteria and make a recommendation for listing status of the Canada substance and the report. Again, this is a government meeting and not a public meeting. Once we have all the recommendations from the expert panel the interagency scientific review group and other review groups the ROC staff prepares a profile which is a write up of the data on the candid substance. And this profile will reflect what we recommend to be the position for the particular material and ultimately will end up as the write up in the report on carcinogens for the Canada is listed in the port. Once we have the draft of that we get to that next step, which is a peer review of the draft substance profiles. Again, as I indicated this profile is what are ultimately would end up in the report on cars and engines for that particular Canada substance. We will take this draft profile. And this is when you step in our review process. We bring that profile to this board and ask you to appear review the profile. The profile should support the opinion of the material to be listed in the report and if so it should be tested -- and also that the profile supports the listing of known or reasonably anticipated carcinogens to read this is done in a public meeting. We take the draft profile and publish it and ask for public comment. We invite them to attend the board meeting where the peer review takes place. As I indicated we ask you tab review this substance profile. Once we have the profile peer reviewed the profile for all the Canada substances reduced we then go to the next step which is preparation of the actual report are carcinogens. We take the profiles and bring them together. In the meantime we have also been updating some of the older profiles that are currently in the report. We prepare a final draft of the next version which would be the 12th. We submit that to the director of the National toxicology program. The director to streets to the executive committee asking all the member agencies to look at the draft of the report to give us their comments before it is submitted to the secretary. Upon getting their input and the approval of the director and making any changes that need to be made based on their reviews the report is submitted to the Secretary of Health and Human Services who alternately has to approve the report. Then you send it to Congress and the report is released. So this is our current process. It is rather involved and link the. These are facts candidate substances that we're currently pumping at. This list is in your book. You can read them. I would just point out that if you look at-related exposures we make one a background document, but it is actually to Canada substances. For this one selected DNA, parents to an editor's, it is one background document but three separate Candace substances. The rest of them are all rather innocuous and probably Candace substances that want generate much interest at all. We got a recommendation to the get this to see if it should be removed based upon earlier refused. Metalworking fluids, certain glass wool fibers. Again, I want go through the list because of time. These are the 13 we are knocking at. Quickly, here is a time line. The entries in red are completed or to be completed. As I indicated in April we are announcing a new review process. Our first notice of the first expert panel meeting was in July. We had our first expert panel meeting in October. It wins for being our first meeting very well. November13th, we had that notice for the second expert panel meeting. In this meeting is scheduled. The expert panel meeting is January 24 and to defense. It is going to be held in Chapel Hill. We invite everyone to come. A good time to be had by all. There is the rest of the time line. February through May we will have the remaining expert panel meetings for that next to Candida substances. June through November is when we will have the expert panel meeting for the remaining seven candidates to it as I go through, there are overlapping things happening. In July will have our first interagency scientific review group meeting for the first seven candidates. In September we hope to have the first review group for the seven candidates. November is when we anticipate we will come to you as the board with a first set up profiles for the first seven candidates. Going on down --
Part in the interruption.
Sure. We also anticipate a have a board meeting in August for the remaining profiles. We are anticipating it will be January of 2010 by the time we get the final report submitted to the secretary. So this is a rather long and involved process. It is something that I think is very workable. At this time on with the two eggnogs the hard work of my staff. Dr.Reed has worked tirelessly to -- tirelessly on getting the process to the point where everybody is happy with it and also in getting these background documents and expert panels identified. See is to be commended for the good and hard work. Sean cheater is a tactical Information specialist who worked on the record and has been keeping things straight for us for a long time. I would also like to think my administrative assistant.
Thank you.
That's it.
Are there any comments or questions?
Can I ask you to back up to slide back there was something on the slides not and I hand out.
The one that starts with -- I can't announce it.
It wasn't on the dust.
You are correct.
I'm sorry, that shouldn't be there. That is a mistake.
That shouldn't be there. Sorry.
So the net book is correct and the slides are off. Other questions by the board?
I think I asked this before. As a chemical moves through the review process work goes to the review group's, what if the tide turns and the recommendation is that it is not listed?
I'm sorry?
As you move through the review groups and these chemicals are to be this did what if other groups conclude that perhaps it should not be listed?
What, we would take that recommendation as always. In the past three take recommendations from all the review groups. We consider them in the making of our file determination of what we recommend to the Secretary to be included in that report.
What if one groups --
No. Let me restate. What if the recommendation is not to list? Traditionally the report on carcinogens only contains chemicals that are listed. So how will you record that you reviewed a chemical but decided not to this to it?
We have had a part of the senses in the past where there have been nominations that have been reviewed and the recommendation was that it not be listed. They eventually end up as not being listed in the report. However, we have an appendix and a report of the nominations that were reviewed for listing but not listed in the report. There should be a short profile in here.
Any other part comments?
We have no one registered. Is there anyone who would like to make a comment?
Could you please identify yourself and your affiliation please?
[ speaker unclear ]
No. Historically to put together an addition of a report on carcinogens is the 3-year process. So there is overlap between when a [ indiscernible ]. Once we get our seed established on the new process going good on the timeline that I put up here just a little while ago, we will start the process of identifying the new nominations. Those will be announced and we will start the ball rolling. So it is staggered, if you will. It is consequential.
Any other comments? If not we will move to our last agenda item. We will have a brief discussion of the implantation of the workshops and retreats recommendations. For those of you who are worried about the airline situation, our goal is to be on the bus by can tell and we will make that deadline. We would like to have you present for this last presentation.
Thank you. This should be a very short recommendation. I have told you already have about some of that changes in the structure and alignment of the program that are going to help us build Ford and hopefully increase our efficiency and provide opportunities for new leadership and fresh approaches to the problems we face. One of the things we did was create a pile molecular screening branch to the implement one of the major activities outlined in 2004. One of the other activities that was called for in this road map was to go back and read look at some of the testing strategies and the way that the toxicology program carries out its work. We carried out a series of three workshops that I will talk to you briefly about. The first one was to examine the strains of animals we need to any use and the toxicology Program Studies which we're the rat and mouse. We evaluated the current rent models and we also wanted to look at a proposal that had been floated for a number of years to increase the genetic coverage of the rodents bioassay. One might want to use multiple strands. This was an approach that had been published by Michael testing a number of years ago. There have been periodic looks at this and recommendations over the years that we look at it in more detail. So we did that. The overall recommendations that I'll go through in some detail here or to discontinue the use of the route from it particular sub colony that we maintained. We wanted to establish eight new [ indiscernible ]. The recommendations were the continued use and to sequence in our recent hunting activities the parental strains of this house. And the multiple strained approach was considered to be a viable option, but there wasn't any real overall recommendation as to whether we should or shouldn't implement this because of the considerable limitations and difficulties in this approach. I should mention that these workshop reports have been published and are in your handout. They are actually very complete and thorough documents. I encourage you to read them for all the details that I will be briefly going over. Within that stocks and strains workshop there were three groups. There was a rat Creek, a mouse group and a multiple strain group. The rat group expressed some support for the use of strains because there was really little data available other than the Fisher 344. And the liabilities that we had been using in our particular studies were recognized as being serious. They suggested that this particular Connie should be discontinued, and we did that. They made a recommendation that we might want to go to a highbred from at different comic. This Rhodesian did not go forward. They did not recommend that we use the additional strains. In other birds, their record to a recommended we keep one strain. If an unrestrained was chosen it should become the default train. The mouse groups, there is a recommendation that we used [ indiscernible ]. The F-1 hybrids were preferable. One of the problems is that there -- it has a background rate of liver tumors. We have looked at this in great detail. The their tumor instances are not that critical. If this was something that was -- this was to be watched. They made a recommendation that said continued use is essential. And this was specifically with regard to the fact that there has been a recommendation to drop the mouse. The group said that this allows utilization at the extent of genetic information. And they recommended that if we did an additional or multiples train approached we should add them only one at time of keeping this as our primary stream. If we do is stick with hybrid strains in particular that we wanted to choose parental strains. The multiple strings group also looked at the issue of recommendations to be seen concerning depth advantages of genetic variation. We looked specifically at the statistical power that one would lose our perhaps gained based upon keeping the same number of animals that we usually use now, but by dividing after Prop. with a number of strains of different animals. We look at the system apart that one could receive if you had a strong response and a variety of different scenarios. And overall the recommendation was that they didn't feel there would be significant power loss. So long as all of the strains were not in the very weak response category. They felt that this could -- using multiple strands could help identify mechanisms. Consisting of added cost for the range finding studies could be very strange treat the increase at all resource cost, production, is part multiple strands, that need to develop the struggle to the and the idea that deprecatory acceptance of this might be questionable because the recommendation was that we would be doing statistics and the incidents isn't and a super strain. Finally there is currently very little information. The second workshop five likes to go over very briefly was held in May after a dozen sex in Raleigh. Hormonally induced her protector terrorists. This address the issues, we have recognized problems in recognizing our more induced cancers. The overall recommendations, we had a group looking at prostate and one at [ indiscernible ]. The overall recommendations were that the experts we brought together were not overly impressed with that we currently use and adequately representing our identify animals that might cause [ indiscernible ]. There was that thought -- although there could be additional and points built and that could use this information to predict outcomes -- they might not results are might result in a tumor in an organ that was or was not relevant. But the pattern of change might be indicative of the response to reedbuck this group also recognized the limitations of the fish or Brad with specifically prepared to the end points at evaluated. They recommended that we discontinue this.
The final workshop was to evaluate new by a markers. This was 2006 and September where we asked a group to help us identify Baia markers for pulmonary cardiovascular and lipid metabolism that we might see with chronic studies. As a result of this workshop we have in fact added to studies in rats with a car near toxic indicator.
We have evaluated as a measure of long-term glucose overload. This doesn't seem to be working out unfortunately. It may be that insolent measures are a better way to go. We also have come under consideration of a panel of information markers. In response to these workshops we will maintain the use of the hybrid pop. The hybrid is favored and the parental strains are genetically diverse. This is about as far apart as you can get. We also have decided to discontinue use of the rat and have selected the on as a default strained. I should say what says. If there is evidence that a particular strain of rat should or should not be accused then we will go had and take that evidence under consideration in a strange election. When there's nothing else that should help us then we would use that.
It has a low incidence of no spontaneous stammers, moderate size. It is a robust -- has a robust for productive capacity and there is a good commercial availability.
I've written from these workshops drafts were asked their reconsider the use of the gang [ indiscernible ] programs. We have in fact decided to go to the perinatal game as the default when there is no other information that would lead us to believe that isn't relevant. Our contact capabilities in regard to toxicology have been restored after a couple year he does. This was a recommendation of the hormonal workshop. There is an increased emphasis on children's temperamental health and regulations. We plan to focus it initially only on bad for this increased consideration. We are using a hybrid mouse. It makes it more difficult to do the parental testing. And the development of a study designs was a process that doctors spent a lot of time on. We in fact gave you a copy of that initial design and a pamphlet that you have for the last meeting. We did not get a chance to go over it in detail, but we are going forward with this and think it is going to be a positive change to the program activities. I'm sorry this was kind of a hurried discussion, but I think I will stop at that.
Thank you. Are there members who have questions or comments?
Comment. I recall someone showed once that in a teepee have been easing of male rats and female mice that we have captured. Most of the carcinogens is have the number of animals. Is any consideration given for that approach?
We consider this routinely. There has been a reluctance among the design teams that look at these. And I can't tell you the specific reasons. They don't come to mind right off hand, but we have looked at that. There is concern that everyone loses response and mouse. If we pick them nice and feel not the ones that respond and we miss that and there is a reliance on the need -- probable or possible carcinogen that we would not want to miss that by picking the wrong side.
We received no public request for comments. Is there anyone and honest who would like to make a comment?
There is no vote and we will consider this completed.
The you have any concluding comments to make?
I've would just like to thank everyone for coming today. We received a lot of really fine information and lots of things that others with be taking back and thinking about very carefully as we go forward. Thank you for your activities today.
We have some announcements aren't getting to the airport.
So the boss will take you to the airport. We will have camps to take some back to the hotel.
Web page last updated on December 27, 2007
