Transcript of BSC Meeting - June 11-12, 2008 - No longer available

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Transcript of Day 1
Transcript of Day 2

Day 1

Event ID: 1024966
Event Started: 6/11/2008 8:16:02 AM ET

Good morning.Good morning. I would like to ask people to take their seats, please.I would like to call the meeting to order. I'm Gayle McCarveer. I'm the member of the faculty from the university of Wisconsin. We will ask everyone to identify yourself. Beginning first at the table. Followed by the audience. We'll start first with Dr. Howard.

Paul Howard.

Ruls cattily.

John mir Sal is.

[ Speaker/Audio Faint or Unclear ]

Katherine Hammond.

Diane [ Indiscernible ]

Mike pino.

Nancy Kirkly.

Ray Novak.

[ Speaker/Audio Faint or Unclear ]

John boo cere.

I'm Sam Wilson. Paul Foster.

Mike Shelby.

Chris [ Indiscernible ]

Kenny crump.

Bill Jansen.

Chris Brad field.

Keith sow per.

Jim Rivera.

[ Speaker/Audio Faint or Unclear ]

Ruth.

Michael bellm.

[ Speaker/Audio Faint or Unclear ]

I think we missed a couple over here.

[ Speaker/Audio Faint or Unclear ]

Steve leader.

I think we're going to need to do that again. Please make sure that your microphone is on.

Dr. Richard sharp.

Steve leader.

Thank you.

Nigel walker.

Matt stout.

[ Indiscernible ]

[ Speaker/Audio Faint or Unclear ]

Gloria.

Ruth.

[ Speaker/Audio Faint or Unclear ]

Bill sook.

David shore.

Diane Spencer.

Christine whit.

Robin Macker.

Eddy ball.

Jonathan.

Steve henchs.

Shelly tile.

Michelle.

Marc Jackson.

[ Speaker/Audio Faint or Unclear ]

Barry.

[ Speaker/Audio Faint or Unclear ]

Dan dor gee.

Tom.

[ Speaker/Audio Faint or Unclear ]

Joseph.

Ray ties.

Laurie white.

[ Speaker/Audio Faint or Unclear ]

Nina baker.

Mary wolf.

I believe that's everybody. As you can tell we have several ad hoc members on behalf of the board I would like to thank you for your work. I would want to remind you that we welcome your comments on any topic, as a matter of procedure you are not allowed to vote or make motions. We will have a photograph today at the morning break, which is our custom. We would like the board members and the ad hoc reviews at the start of the break.

This meeting is being video cast. It is critical that you turn on your mic before you speak. Also that you identify yourself before making a comment. Dr. Shane?

In your folder you will find the most updated agenda and roster. A form to fill out for reimbursement for you to send in. Please make sure that you have signed in. Please use the microphones and identify yourself whenever you make a comment since it's been taped. The meeting is also being video cast. We would like to have the names mentioned each time you mention something. If you are making a public comment please register at the table outside. The photograph will be taken at about 10:45. Thank you. The ad hoc members cannot participate in any votes, but can participate in all of the discussions. I'm going to read a, um, the draft reviews that you sent us, our preliminary comments will not be included in the minutes. [ Speaker/Audio Faint or Unclear ]. The members of board booed serve as individual scientists not as a representative of any any organization. Each is to exercise judgment as to whether a potential conflict might exist relative to the topics for discussion by the board.Should there about be a potential conflict the reviewers is to decline interest and is not to vote. To the best of my knowledge there's no conflicts of interest for today. Thank you.

We'll turn now to the agenda. I will Dr. Sam Wilson, Dr. Wilson.

Thank you, Dr. McCarveer. On behalf of the National Toxicology Program I would like to express our appreciation for your participation in this board meeting. We realize it's at great expense in terms of your time and priority setting. Also in terms of the challenge in getting here this morning. We very much appreciate your participation and look forward to informative and lively discussion these next two days. I will keep thigh comments -- my comments brief this morning. Just reinforce the NTP's position toward full peer review and public input into the peer review process. At the same time the commitment towards full transparency. Our aim is to sort through the science and to come to the best solution possible based on the scientific information. And so with that reinforcement and statement I will conclude my remarks and look forward to the deliberations today and tomorrow. Thank you.

Thank you, Dr. Wilson. Dr. John boo cere will now present the NTP update.

Thank you, Gayle. We've had a busy time since the last time we met in December. I would like to run through a few of the activities that are led to this point. In January we put out an EHP outlining the new initiatives of the NTP within NIEHS. And you will be hearing a little about the progress we've made with the our host [ Indiscernible ] activities tomorrow. With regard to this there's a number of fairly important and significant events that we've had in the last couple of months in relation to the efforts of the program to respond to some of the NRC reports recently that have come out with regard to how we might approach and change toxicology to meet the challenges of the 21 century. On February 14 we announced the signing of a memorandum of understanding between NTH, NIEHS, the NIH chemical Gino Micks center. With regards to putting together a cooperative program to address issues related to biomolecular screening, high through put methods for identifying chemicals that perturb intoxicatology pathways, to see about databases and consume la and aggregate information required to set priorities for chemical testing activities and hopefully to be able to replace some of the invivo approaches we currently have.

On the 15 of February there was an article in "science" which outlined the memorandum.This was titled "transformed environmental health protection" it's in tab 12 of your book let. With regard to that and along in the a similar vain in February, February 5 there was a celebration in Washington, the ten the veanls of the [ Indiscernible ]. At that time we released the five-year plan for the [ Indiscernible ]. And the next day there was a workshop held on acute chemical safety testing. And at this point I think we began the process of integrating some of the thoughts related to intoxicate isty. Coming up with new methods in relation to acute text isty to begin to move in these directions to try to come up with better ways of doing our science.

On April 15 rereleased a draft on BPA. This has led up this meeting. I would like to spend a few minutes talking a little bit about the sere process, what it is we're dealing with today. Before that I would like to mention that tomorrow, for those of you in the audience, we have another number of other important agenda items. We'll be talking about the nominations to the program and the thoughts that the program has towards putting together outlining some research proposals to address the nominations that have been made. Dr. Scott masten will be heading up that activity tomorrow. There's a discussion we will begin concerning creating criteria for evaluating outcomes. We like to be able to articulate the outcomes from our reproductive studies with the same kind of clarity we've achieved in the cancer bioassays. I think in some of the discussions related to today's review on BPA may point out the need to come up with standard criteria for evaluating outcomes.

Dr. Foster is heading up that activity. So today's activity is to review the sere brief on BPA. Just to bring everybody up to speed the center for human risks was created in 1998. We've reviewed about 20 or 25 chemicals for their act to effect human reproduction and development. This activity is not a Rick assessment activity. It is not an activity that is specifically related to any particular risk assessment carried out by a regulatory agency. It's always been the goal of this sere activity to provide an unbiased and complete evaluation of the human and animal literature with regard to every aspect of the literature that might relate to the interpretation of the chemical's affects on human production and development. Taking into consideration the levels and what we understand about human exposures to come up with a statement on behalf of the sciencetific panels that em panel to do this. The statement regarding the concern that we might have that the current exposures to the U.S. population could be potentially resulting in effects on human reproduction and/or development. So I want to emphasize again these are not quantity Tative risk assessments. They're activities that will come up with concern statements. These documents are produced to provide a level playing field, if you will, to provide our best assessments of the state of the science such that regulatory agencies can take that information, use what they wish, don't use what they don't wish, that's fine, we have no qualms about how this information is used, and go forward and come up with regulations with regard to the products that they oversee. That's our goal today, to get through the document on BPA. With that I will conclude my remarks.

Thank you, Dr. boo cere. We turn now to the review on the draft brief on BPA. This is an action item. At the end of the day we'll be voting on whether or not the evidence supports the NTP's conclusions. The material was forwarded to the forward in advance of the meeting. All written public comments were forwarded to the board and were placed on the NTP website. The format for the process of this review on the draft brief is laid out in the agenda. We begin with Dr. Mike Shelby. Doing an overview of the process of the evaluation of BPA from the initial selection through today. Dr. Shelby.

Thank you, Dr. McCarveer for the introduction. And thank you to the board members and the ad hoc reviewers. The members of the staff are few in number and all here today. So it's me, Dr. Paul Foster, Dr. Christine their and Diane. Let me just go ahead with the outline of the presentations this morning. I would like to say a few words about the CERHR process. Then give an overview of the NTP brief. That will be followed by the CDC presentation on the biomonitoring. I'm not sure of the general comments. I looked this morning. There was a small difference between the program and this. There will be an opportunity for discussion by the board of the the overview. That will be followed by the public comment period. This afternoon -- at that point there is no need to get into details of the data that we think support our conclusions as presented in the brief. This afternoon we'll have many presentations on the data supporting our concludes on metabolism and it's relationship to the route of exposure used in the animal studies.That's the opportunity for the reviewers and the board members to enter into detailed discussions about the science underlying the conclusions.

That will be followed by final session of general discussion by the board and a vote of the action item that is before you today. A few words about the process. The evaluation occurs in three phases. The first is the nomination and the selection phase. The nomination process is open to anyone, anywhere. If you think a substance might be presenting a hazard you can call us, write us or go to our website to submit that nomination. We take every one of them into consideration, no matter how bizarre it might seem. The selection is recommended by the CERHR's core committee. And is then reviewed and approved or deferred or declined by members of the National Toxicology Program staff. The expert panel evaluation -- once a compound is selected we begin collecting the literature, we begin putting together an expert panel. These panels are FACA compliance. We check for conflicts and review their backrounds. Once the panel is set it takes six months to eight months -- it's been longer on this one -- for them to go through their evaluation. There are two reports that come out of the sere evaluation process.The second document is the NTP brief. That's the phase we're at now. Where are we today? We've taken, as I mentioned, we've taken expert panel report, we've taken comments and we've searched the literature to update the bibliography in preparing the draft NTP brief. That draft was released for public comments on April 15. It ran to May 23. You received all of the public comments. Here we are today, it's June 11. Following this meeting the NTP will undertake the job of revising it's draft brief in accordance with the recommendations we hear here today. We'll also release the peer review report, as somebody said earlier. What is recorded during this meeting will constitute the peer review report, not the written comments that you submitted earlier. Those will be posted on the website. When we finish the brief it will be released as part of the NTP monograph. That is made up of three pars -- one the final NTP brief, final expert panel report which provides backup, and the public comments that were received on the final expert panel report.

I would like to go rather quickly through a summary of the draft brief. First the rationale, anytime we're considering a substance there's four factors we take into consideration. The production volume of the substance, the extent of human exposure -- the number of people exposed and the levels, we look at the extent of the lit literature and we try to measure the level of public concern. Those four factors go into our decision making. For BPA it's a high production compound, there's wide widespread exposure and high public concern, I think this qualified on all four counts.

The format of the NTP brief is kind of constructed questions. These are the questions.Followed by our current exposured high enough to cause concern. The answers to those questions are shown at the bottom. Might all have been a bit bigger. The answers we come up with are yes, probably, possibly, probably not, no, and un. These categories are not defined. They do not have clear definition, but over the course of ten years and more than 20 evaluations I think there is a rationale consistent use of these terms through all of the briefs. Conclusions on whether human development might be as versely impacted by BPA. There's a range of standard conclusions we use.Over the years all five of these categories are used at one time or another.

What is BPA? I think most in this room probably know. It's a molecule that is used to make plastics that have many consumer good applications from baby bottles, sipe cups, sports water bottles, on and on. Also to line food cans, the epoxy resins are made with a BPA substance. It can leech out. In the past there's been some use in dental see lants or deposits that can contain BPA. Are people exposed? Clearly yes is the answer to this question. From what we knowed to the majority of human exposures is through the diet, either food or drink in contact with BPA. It's detected in the urine. Literature contains reports of it in human blood or breast milk. It's highest in infants and children. These are three summary numbers at the bottom here. Even in breast fed infants it's seen. In adults the 95% [ Speaker/Audio Faint or Unclear ].

Can it affect human development or reproduction? The answer we came up with is possibly. This conclusion can be based on adverse health effects reported in studies of humans or lab animals. The relationship between the dose that [ Indiscernible ] is not considered in this. If a substance is a [ Indiscernible ] in animals then one could conclude that it could affect human reproduction and development if exposures were high or by the appropriate route of exposure.

Only a small number of human studies have been conducted. Like many studies interpretation is limited by sample size. The lack of large variations in exposures or lack of adjustment for confounders. NTP concurred with an expert panel there's an suggestion of an effect on reproductionive hormones, specifically Tess test roan.Overall the human studies provide insufficient information to make a conclusion on potential adverse health affects on development or reproduction. Remember, this is basedded on human studies.

In our figure form, where the green arrow points, insufficient evidence for a conclusion. In lab animals studies for effects, we divided the literature into two groups we consider the high dose and the low dose studies. The break point is 5 milligrams per kilogram per day with 5 milligrams or less constituting the low dose studies. The literature provides clear evidence of adverse effects in development at high doses. Reduced survival and growth and delayed puberty.

You've been through this it includes the brain, altered -- one report on development on the urinary track. Some evidence of adverse effects in reproduction in animalled exposed only during adulthood. This is just one category. And there's evidence that exposure of laboratory row don'ts to BPA can result in lower fertility and effects on the Tess 'tis. Again, this is just what I told you in words and graphic form.

Some evidence of reproductive intoxicate isty and limited evidence of developmental intoxicate isty at low doses.

How did we reach these conclusions? The literature, another way of dividing the literature, it's made up of two categories of reports. One are the guideline studies. They're requested and required by regulatory agencies and are typically used by them to make their decisions regarding regulation. There's a much larger body of literature out there composed of academic studies. How do these compare? First of all, there were few of the multigeneration studies. The end points assessed in the guideline studies are those required by the guidelines and protocols promulgated by such agencies at the EPA. The academic studies address experimental questions. There's a difference in the sample sizes. The guideline studies are generally large ends. Where the academic studies include smaller numbers. Experimental designs differ. The guideline study follow standardized protocols and recordings and reporting is done accord to good laboratory practice. Academic studies the size varies, we found they tend to have more reporting shortcomings. The route of administration is generally the most relevant for human exposure in the guideline studies. And the academic studies many of them use oral route, others used subcutaneous.

So when we were considering the literature and the effects reported we focused on the effects that had been highlighted by the CER expert panel and other recent information of BPA. We asked if the invivo effects were biologically plausible.

So what were the impacts of any limitations in the experimental design? Did it cause us to question the robustness of the effects reported? And have the invivo effects been reproduced by the group who first reports it, or by other laboratories that have undertaken similar investigations? We did not establish a single number for minimal acceptable sample size in any of these study. The small studies were considered in confix of similar studies. There were some of these affects such as on the ma'amry or the prostate. Some studies were very small. One would have doubted whether they were big enough to tell you something meaningful.Inadequate control was doctored -- considered a significant design flaw. We come to the question, are current exposures to BPA high enough for concern? We think there's a possibility of that. This is because of the estimated he can pose ours in infants and children are similar to low dose laboratory animal findings.These are at exposure levels far in excess of those experienced by humans. Of what we knowed to these are thousands of times higher than human exposures. We had negligible concern for pregnant woman.Again, this is base on lab studies that provide clear evidence in animals. Again, BPA levels that far exceed the levels experienced by humans. The fact that multiple studies looked formal formations and saw none.

So NTP conclusions regarding possibility that human development of reproduction might adversely effect by exposure to BPA. We had neglect glijable concern for adults. NTP concurred with the expert panel there's minimal concern for workers that are exposed in occupational studies. We raised one level above negligible concern because of reproductive hormones, especially men, in the workplace. That's our second level on our figure, minimal concern.

NTP concurred with expert panel there was some concern for neural effects. NTP also has some concern that BPA exposure may affect the prostate, ma'amry and age of puberty in females. We raised, we did not raise the overall level of concern beyond that expressed by the expert panel. They had some concern for neurobehavioral effects. Our review of the literature and the public comments and so forth caused us to raise these other end points up to that same level. That level is based on laboratory animals. And because these affects occur in animals at levels similar to levels experienced by humans, infants and children particularly, we could not dismiss the possibility that BPA might alter humor development.

There's our third arrow on our figure, as it appears in the draft NTP brief. The summary of basis for some concern, I'm showing you this to show you the scale, that limited effects is similar to exposures. This is where we landed, at some concern. Reported effects were not expected to be detected in guideline studies. The issue of reproducibility is one of the issues we looked at. Several of the studies that report these affects are conducted in such a way, typically in academic research labs that the standardized guideline studies and the protocols set up in them, the enpoints would not have been looked at. Or one would not expect to see the Februaries reported in these other studies. There were nofs data in three new papers that provided additional report.

Why didn't we go to serious concern? There's questions about the interpretation of the adversity or the relevance of these end points to human health. Many of these end points, it's uncertain whether their adverse effects even in the rodents. It's not clear. And there's a need, a real need for additional replication of those studies, as well as long-term follow-up. To see how these early markers might translate over a longer period of time.

A better ability to link the animal exposures to human exposures. None of these low dose studies ever looked at urine levels or blood levels. That's what, things in favor of some some concern. The things that restricted how high we could go with our level of concern.

So that's the end of the overview. Just are reminder the charge is to determine whether scientific information in our brief is techically correct, clearly stated and supports the NTP's conclusions regarding BPA. I would be happy to answer questions about the CERHR process and this overview of the contents of the draft brief. I would ask that questions regarding specific end points and the data that back them up be put off until the afternoon when we have more detailed data slides to show you.

What is coming up after this? Dr. Rick wang will make a presentation. A public comment period. After lunch we will have the small presentations on age depend metabolism, route of exposure. Thank you for your attention.

Thank you, Dr. Shelby. I think we'll go on to Dr. wang's presentation. He will present a talk on biomonitoring in human populations.

While we're getting set up I need to make people aware that Dr. Robert car to have is online with us. He's an ad hoc reviewer, he's teleconferencing in with us and has a copy of the slides, as well. Dr. wang.

Too many gadgets. Good morning. Want to that Dr. Shelby, Dr. Shane, members of the NTP and visitors. I am standing in for two doctors who could not be here today. I'm going to talk about CDC. I'm going to start off by defining biomonitoring. It's the measurement of the level of the chemical in the body. We work with biomarking data. The quality is important. We break that down into two parts, one is the method used to measure the chemical, the other one is sampling and handling. When it comes to measuring the chemical we characterize the method by describing the detection, the accuracy and the precision. There's a component that assures quality. There's an audit component. We have appropriate reference material within each. When it comes to sampling and handling, within the lab the method is evaluated by including [ Indiscernible ] blanks within each method.

Looking at some of the features of optimal analytical method, they're demonstrated here on the slide. It talks about sensitivity, specificity, accuracy, rugness. High through put, number of specimens that can be processed in a single run. Moving back to specificity, it can be very. There is the enzyme linked to [ Indiscernible ] versus what CDC used, in terms of measuring BPA. The significance of this difference is the specifity is based on antibody recognition. There is some crust reactivity in what you are measuring. What that means is you to measuring something that a BPA byproduct, not BPA itself. Or another chemical that is similar to the antibody BPA. That-- the method used to measure BPA at CDC goes through the following process. The specimen is received. There is a decongregation phase. BPA in the body is congregated to the [ Indiscernible ] or the sulfate. We expose it to an enzyme that breaks down the two to BPA. There's an extraction where backround material is removed to enhance the quantitification of BPA. The separation phase and it's measured by using [ Indiscernible ]. The melt odds -- methods and details are noted below.

Now, where you have to be concerned about contamination, here are the items to consider when you are looking for the chemical. The parent chemical versus the ma tab light. When the levels of the materials are low and when the chemical is ubiquitous. Field blanks are sometimes used. When we go into the field and we are not sure of the specimen containers we will bring back some containers and look at those for contamination. That is used by using saline or water to evaluate how much contamination there is.

Some backround about BPA. It'sizeed in making polly carbon ate plastic. It's used as a controlling reaction of polly vinyl chloride.

Moving on to the activities at CDC with BPA. It's broken down. We just started a study, it's conducted in collaboration with the national center of health. The N hains studies, as well.

The N Haynes III study that is a cohort that was sampled from 88 to 94. Those are archived urine specimens. Only in adults done by sampling. And BPA was measured in these adults. And the detection was 95%. The med odds is noted there. Some concentrations is represented there.

The neck step was to look at a representative sample of the U.S. population. This was done with the N Haynes participatans in 2003 and 2004. Specimens were received and the significance of this, again, it's a sampling design to present data that is representative of the U.S. population.And what we found here [ Interference ] what we found here is that the detection of frequency for BPA was about 93%. The limited detection was .4 Mike grams per liter.We did some comparisons with demographic variables we found that females had higher levels than males. Children had higher levels than adolescents or adults.[ Speaker/Audio Faint or Unclear ] include age, gender, race, and urine concentration.

The significance of the survey, it's representative of the U.S. population. And an extensive, a high prevalence of exposure was found, about 93%. This is another way of looking at the same material. Using a graph form. The demographics are on the X axis. The Y is the mean exposed as the microgram per liter.

Moving on to special studies and investigations. We're here looking at a sample of 30 adults who provided urine. We looked at the break down of the BPA congregates. If you rather back to the method slide, there's the decongregation. Depending on the enzyme and how you sequence it you can estimate the amount of [ Indiscernible ] and the amount of sulfate. These are indirect estimates. You can arrive at the amount of BPA [ Indiscernible ] and sulfate. In these 30 volunteers we looked at the urine specimens. What we found was that the at the dex of frequency for BPA [ Indiscernible ] was 90%. It comprised about 70% of total BPA. That's considering the BBA sulfate and free BPA. The significance of this finding is of total BPA in humans the majority of it is BPA [ Indiscernible ].

Here's serum concentrations from blood samples. We have seesmans from 15 adults. We looked the BPA and other phenols. What was interesting in this study was that one of the 15 specimens we found BPA. All of that BPA was free BPA. The other phenols, the majority was as their congregated form.

Another special study looking at human milk. These are samples of four adults. We looked atburg PA in free and total form and the other phenols. And what was interesting here in looking at BPA in these four specimens submitted to us, we found the free form in all four and it was a fraction of the total form.

So from the N Haynes data and from the special investigations we surmised there was a high prevalence of exposure to BPA in the general U.S. population. It's mostly excreted in the urine.

The next slide is to take a look at comparing the considerations that go -- when you think about trying to measure a chemical versus trying to take that information and to apply it to exposure biomonitoring. We need an analytical standard. We used the isotopic standard. And the use of laboratory blanks to provide for contamination in the laboratory.

As well as other factors such as the bioavailability. Some people would like to extrack late. Sampling considering, stability of the chemical that you are measuring. And that's part of the evaluation of the method as well. Under the category of ruggedness. Number of tissues and inclusion of appropriate field and laboratory blanks.

To sum up, there's a high prevalence of exposure to BPA in the U.S. population. Additional information is needed to understand. Biomarker information is needed. And biomonitoring data from toxicology studies is needed.

Thank you.

Thank you, Dr. wang. We will now have a few minutes for board members to make any general comments about either of the two presentations. Or to request any Claire of courses about this. Keeping in this mind this afternoon we will go into the areas of focus and have more detailed conversations. Is there anyone would like to make a comment? Dr. Hammond?

Dr., wang, thank you very much. I wonder if you could comment on what seems to be a difference in the large N Haynes study. Only 10% of the BPA was in the free form. Whereas in some of the blood bank samples and also in the human milk samples there was a very different percentage.

Can you repeat the last part of the question?

Okay. This slide is a good one. Could you stay with the human milk for a minute? I think she liked your slide you had with the columns.

The human milk slide.

It's a chart.

Right there.

Yes.

In a previous slide you had shown that only 10% of the BPA was in the free form. In the urine samples. The human milk samples it looks 50% to 100% in the free form.

Sure. The amount of the free form and the congregated form, it's difficult to know why. Part of that explanation may be available by understanding that urine is water based. The free form of BPA is more lipid soluble. Those are more water soluble. The body congregates the chemicals.So one question is why the difference? It could be based upon the lipid content, which is greater in milk than in urine.

Are you suggesting that lipid -- the lipid portion, the free form is stored in the lipid tissue? Or -- have you any data on that?

We don't have any data on BPA. We don't know if it's stored in lipids. This is a first look at BPA in milk.

A comment?

Yes, I had a general question about limited detection. I think in a couple of the first slides it looked like you were using the limited detection as a measurement. Because I think that's a really big factor in estimating exposure, where rather than saying less than LOD you put a number in there. You say what, if it's below the limit you put it at the limit.

Right.

Could you talk about a that?

Sure.

There are various ways to handle levels that are below the detected the levels detected. When the reports come out [ Speaker/Audio Faint or Unclear ] when you want to make estimates of the data you need to impiewt a value for those. Otherwise they will not be registered into our data. There are various ways of inpiewting a value. They include using fixed variables. Using detection itself. You can use LOD divided by 2, or by the square root of 2. There are other ways. I need to go back to these studies to find exactly how they were done. At CDC for our format we used the limited detection divided by the square root of 2.

They would be recorded as not present, correct? When you say percent total that considers those that had a true positive value.

Correct.

The percent detected is what was actually measured. Looking at central estimates, for example, let's -- trying to think if that was done with these -- perhaps. We need to go into the papers themselves. This is only 60% here. To arrive at a median value you need to figure out what the other 40% was.

In the interest of time and clarity I think what we might do is return to it this afternoon. We can perhaps get into some more details about individual things, perhaps. If that's acceptable to the board. Others that have questions or comments?

In regard to the 10% where BPA was not nondetected is this a specific demographic, or thought to be a false negative?

Are you referring to [ Indiscernible ] in.

It's also in the document. Thought to be demographic or a false negative.

It was not detected up to the limit of detection. Anything below the limitation was not detected. Values below the limitation we do not know if there was a value there. That was in the 10%. Detection frequency of BPA was about 93% in the N Haynes population. So about 10% it was not detected.

Dr. rai Dell?

I think I can clarify just quickly. If you go back to the chart about, it had the pair bins, it's the table -- yeah, that one. I don't see any sign of his slides that has counted a nondetect as a detect. If you look at proposele pair bin 47% detected the median is reported as less than the detection level. He's not inpiewting or using the limit of detection for that number.

Dr. more Sal is?

Just a quick methodology question. There was an attempt to correlate to possible exposure sources? Was it a survey? Do you drink from bottled water? Anything like that? Or just random samples that came in?

In all of the studies in the N Haynes and the special studies they were not, the purpose was not to relate with food, dietary information, water intake. They were driven for exposure assessment. In the N Haynes to look at the representative sample of the U.S. population.

You mentioned the one individual who had 1 hundred% free. You have to information about that individual.

Very good question. The finding is interesting and it is in explained.

In the N Haynes data was there an attempt to look at the levels in pregnant women, separately?

We have not looked at pregnant women's exposure to BPA. Although in N Haynes there are some pregnant women that participated.

Do you know who were pregnant so you could pull that out?

I imagine you can pull it out, but we have not.

The other comment I had -- I had understood that N Haynes collected a great deal of diettary data. I thought you would be able to do some looking at some relationships. Is that something that you've will any attempt to do?

We've not brought the dietary information together with the exposure information on BPA. That was not the purpose of our involvement with the N Haynes data. Although, it may be done. Just need to understand those dietary questions were not prepared for BPA assessment.

Dr. sharp?

I think my question just got addressed. I was going to raise the issue that comes up in the brief about possible alter rations and ability to gis gis or sulfate BPA in the fetus or in the neo-Nate versus the adult. My question was rather, because fetal exposure is determined by the mother, whether or not there's evidence that ability to inaggravate BPA during pregnancy is altered. I guess you don't have the answer to that.

I think we'll get into that this afternoon. From this data set, you are right, the answer was given.

Dr. Times?

I believe you obvioused that you have a limit of detection different the first and second studies.

That is correct. [ Speaker/Audio Faint or Unclear ] was 0.1 micrograms per liter. In the follow-up study using the 1/3 subset it was 0.4 micrograms per liter. Two different mekt odds were used in these respective studies. In the earlier study it was an HLPLC method.

Other questions from the board?

All right, if not we will move onto human exposure and Dr. Shelby will be doing this presentation.

Thank you, let the record show that the reason that we got off schedule is my fault [ laughter ]

Well, its back here somewhere. Here we go. So what we intended to strike the afternoon with is simply the presentation of this slide which is from our talk this morning. And to have at least that two need a few words in this area, Dr. Hamman and Radell to give their overview. Most exposures is through the Diet, it is in urine, blood, and breast milk and our estimates of daily intakes are given in the bottom three bullets. With no more comic than that, let's hear from the reviewers.

Dr. Hammond you are first.

Thank you and I want to thank the presenters this morning and if researchers who contributed to that work. So I think with this data, as is clearly given here, we do know that there is a widespread exposure. In fact, as some people said the exposure is both to pick peaches and continuous. Given that there is such a short half life. And that was in the main expert panel report but that in the draft report I think it is important to realize that this must be a continuous exposure to have 92% of the population testing positive to a chemical that has a half life that is less than half a day.

So that's the first thing, just realize that there is widespread exposure not just to high levels, and the question to high and low is very difficult when we are talking about this so we have to be careful about that usage as we all know. To look at that. The other thing I noticed in the presentation this morning is going from 1988 to 1994 the earlier data with almost 400 subjects to the more recent data from 2003 to 2004, that the median couple more than doubled. And furthermore the 95 percentile actually tripled. And there is the confidence limits are pretty small in there is really don't overlap at all so it is quite clear that those are real fell use. So the levels of exposure are increasing over that 15 here period, ten to 15 Year period. And again we don't know because of the many issues that have been brought up in the metabolism, we don't know how to do a quantitative risk assessment but at least can be aware that this exposure is happy to in a large portion of the population and is increasing.

Let's see, one of the questions or concerns that I had is that one level there seem to be a discussion that since there is this metabolism to the water soluble metabolites, the free form would be zero and therefore there is not much of a true exposure to the biologically active form. And yet in the data that was presented this morning, 10% of all was found was found in the pre form that is one thing and secondarily, among pregnant women in breast milk is seen to be a much higher percentage in the preform. I think we need to take that seriously. I don't know how to be clear on what that means but it certainly means that the exposure of people at the most affordable time during pregnancy and after may be to higher levels of the preform. So we need to take that into account in but that fact.

Let's see, I was also concerned about, I was not clear as to whether all of the routes of exposure have been explored in the main document -- I should not say the main document, the expert panel report. There was a statement of Bisphenol A issues in his proxy paint and coatings. I saw it there and I did not see it there by sought elsewhere. I was not sure if that was more fully explored. I am not sure what bubbles that happens occupational lead. The highest exposed people that were documented were people who are working with those in those forms. I don't know and I don't know if anybody examined what happens when the paint are used in the home. I think is something that needs to be explored especially since that would be innovation routes of exposure which would be too different senses of what is happening.

It was unfortunate in the very useful study by Wilson with a look at children in daycare centers and homes they did the most extensive level of airborne and different levels and various material levels, a lot of exposure assessment unfortunately that is the one with a did not to be here in Erie levels. -- the one where they did not do the urinary, we don't have that very often will be have the explosion and then the subsequent assays. So I would like to see more on the occupational exposures in the brief. I think that is an important part, even if we don't have three much information on its at least well we do know should be included off an occupational exposures tell us a lot. That may not be true if low exposures are being differently than high exposures.

And I guess, I don't know whether I should comment something that is not in the brief but was in the expert panel of report. Is that appropriate? Just a caveat that I would like to put out there in the expert panel report is that the only occupational standards limit for Bisphenol A was the wheels and that was at 5 milligrams per cubic meter and out of like people to be aware of the fact that that number, that number is actually the value that is used for a particular. I have not looked at the wheel itself but I do not think is based on any further toxicology information. So having brought it up, I want to say, don't put very much weight on that. So thank you.

Thank you , Dr. Hammond. Dr. Raydell, your comments.

Thanks for inviting me to this meeting. We are focused on exposure assessment because I have the most expertise there and I want to say that I support NTPs use of the urine measurements and volumes to estimate Bisphenol A and adults. And I think that is the best to measure intake but it leaves the question of how much free BPA is circulating in blood and tissues especially in the fetus and infants. And risk assessment for Bisphenol A and has been difficult to know because some studies to rely on oral dosing feet and one point of view has been that since Bisphenol A is oral and rapidly metabolized, we only need to consider studies that use oral dosing. And the NTP breed has departed from this position leading the that free BPA may be and not oral study should be considered I think that is a good reason. For reasons, I think the brief could be strengthened a little bit by clarifying that specific issue and at in some information on these points.

One is that some exposures involve the installation of Bisphenol A and that will have elevated low blood levels compared to oral dosing because of metabolism treated related to this I recommend buying the occupational exposure scenario beyond consideration of the inhalation of potters and dust because they may be poorly absorber. In my own research by evaluating an occupational scenario that involved melting sheets of polycarbonite into restaurant menu holders, aquariums and hospital equipment including NICU boxes and baby cribs, shoe displays, and the work is done by hand and a stand over the sheets and milk melts them along seams and bend them and then Airborne Bisphenol A is produced by this. So I measured levels in this case of about 200 nanograms per cubic meter and these are about 100 times higher than what is ambient indoor air concentration in this environment or something like that. And the concentrations that I measured are probably much lower than a particular occupational scenario because our sampling was done when the shop was empty. And one person was doing the work, just as a demonstration essentially. So I think these types of work places are relatively common and that this is an important occupational exposure to consider. I think that NTP could recommend further research on exposure and health effects in this population. And maybe increase the level of concern for occupational exposure. That is reported in that finding of mine, that is reported in the 2001 publication. 2001. Although I do not provide details in there about the fact that that was just one person in an empty shop.

So the second reason that I think that is important to consider other routes of exposure or the non oral animal studies is that the brief and other refuse referred to medical uses of Bisphenol A but nobody provides a very much detail on that. And medical uses are apt to result in non oral routes of exposure which could be a source of high levels of free BPA in tissues. I notice something that I have not seen before is that Bisphenol A has been used in PVC and that is all over hospitals. And I also noted that two of the best quality blood studies where free BPA was in blood was collected from women in the hospital during child birth. So they are routinely hooked up to an I V. So possibly that is an explanation for higher levels of Bisphenol A in serum, free BPA, in those samples. If it turns out that medical uses are significant and associated with increased exposure, I think that would support increasing the level of concern for adults including non occupational the exposed. But there is not enough work done in that area.

Have been put forward as possible explanations, um, I think that researchers in these studies did report efforts to control that. And that is a question that can be evaluated empirically before dismissing those findings. Um, so, again, if NTP wants to make research recommendations, I think it would be specific. Controlling for this contamination, and conversion. The tailor study, which we talked about, and other study that shows that young animals do not as effectively metabolize the oral doses. A final point unrelated to the consideration of oral versus nonoral. In the table 2 NTP presents the ranges of BPA and corresponded estimated intake values based on the [ Indiscernible ] study. It's just assumptions about body weight and urine volume. Recommending that NTP report the maximum concentrated in the NHANES sample. This is important because exposure data are very, very right skewed. And so the 95th percent tile is far lower than the maximum value in that sample. It can be misleading to readers. In the case of the NHANES data the 95th percent tile is an order of magnitude lower than the maximum. Including the maximum value for the sample provide as more realistic range.

We'll now have time for board members that want to comment, clarify anything, ask questions.

Dr. crump.

Kenny crump. Just general comments about the quality of exposure data. The decision we're trying to make here is there risk to humans. In a sense it depends on the intoxicate data -- tox data. If you don't have good information in the either you can't make the judgment. It seems like that we've put for emphasis on the tox side than we have on the human exposure side. I want to make comments about the estimates that are in the report. I think the N Haynes data are useful. And very helpful. Unfortunately, no data in infants. That's where we really need some additional information. I noticed in mother's milk there's one set of data, maybe 30 or so women, there's no indication of how representative they are, or where they came from. Just that they're not exposed occupationally. I think that's a place where we really could use some additional information. And, um, also wanted to comment on the exposure estimates in the report for humans. Like in table 1, particularly for infants, I guess it's difficult for me to put those numbers in perspective and understand what they mean. I mine, I agree with what is said about the N Haynes data and how to look beyond the percent tile and look at the distribution as much as possible. These estimates are based on assumptions about -- in several of those even the low end of the range is based on a maximum value. The upper end of the range is based on a scenario. I don't have a feel for how realistic that is. In the rest of the document the assumptions are not pointed out, just comparing the number to what is seen in the tox data. I think there's a need for better information on exposure, so we can really tell how close we are in these studies to human exposures. If we do a very conservative estimate, it's still way below any level where we have seen a problem. Then we can feel comfortable. I think we've gone beyond that situation. Now we need better information on what the range of human exposure is, especially in infants.

Thank you, Dr. crump. Dr. leader?

I wanted to make a comment concerning the section are people exposed to Bisphenol A that starts on page 3 of the draft report. It might be useful to include in this particular section the fact that although the data are limited, there is evidence that the fetus does get exposed to concentrations of Bisphenol A. Probably the best support for that is the shin felter paper, reference 239 in the draft report. While that paper indicates that the play senta can serve as a sink for Bisphenol A it's worth noting that fetal concentrations were reasonablely similar to maternal concentrations. There's especially a subset of 14 of the 37 samples where the fetal concentrations exceeded the maternal plasma concentrations. I think in the report in terms of the types of populations that are listed, what was missing in this section of the fact that human fetuses do seem to be exposed to Bisphenol A.

Other comments? Dr. Dr. Hammond.

Yes. I would agree with Dr. crump's comments. That the data are skewed and the average exposures will fend to be low -- tend to be low. At the high end it's also very important. I recall when N Haynes came out with their data and the stunning blood drop levels from the 70s to the 90s a comment was made in the paper how much less than 1% of the population was exposed to over 25 micrograms per des liter. That sounds good until you remember that means millions of people. That's the other piece. We're a large country. It doesn't take a lot of percents for it to and lot of people.

Thank you. Other comments by the board? If not we will move on. The next topic is the inure rail behavioral effects.

It's me.Eventually. As we move through these more controversial low dose effects our strategy is first to show you the actual findings that call your attention to. And discuss some of the issues related to replication, data limitations and our weight of evidence for concluding they presented as limited evidence for adverse effects.

Brain and behavior. These are the key studies we cited in the brief. There were three oral studies that reported effects and a number of other studies. The kind of effects included impacts on maternal behavior, exploration, rewferd response, anxiety, cognition and emotional behavior. These studies plus the larger literature suggest a loss or reduction in sexual [ Indiscernible ]. Some of the types of the behavior impacted also suggested there could be an impact on the [ Indiscernible ] system. This is just to give you an example of would we mean by a loss of sexual dimorphism. This is CD1 mice treated during gestation. They used an open field test, it's an measure of exploration, it can be used to look at anxiety responses. This is the response in the control animals. This is the sexual dimorphism. In this test the animals had a home compartment they were familiar with. They were allowed to access this open field. What the researchers did was see how much time the animals spent in that more unfamiliar open field, compared to the familiar home. The sexual dimorphism is the black columns spent pour time in the open field. Following the exposure to BPA that effects gone. This is what we mean by a loss of sexual dimorphism.

Here's another example from the behavioral literature. In this case it's not sexual dimorphism. We're looking at an index of anxiety. This is a study by Ryan. Again this is oral administration to the dam. And they used a light/dark chamber. And mals that are anxious will avoid the light. These are females. The black bar is the control an animals. The BPA animals spent less time in the light, indicating there was an elevation in anxiety. You can see this the same response they saw in their positive group at 5 micrograms per kilogram.

When we looked at the literature it was a challenge. Will are a lot of variations -- there are a lot of variations that people use. There are lots of different strategies and specific tests that investigators use. It was difficult to look at in terms of the reproduce ability's of a specific effect. Again, collectively there seemed to be this loss of sexual dimorphism. It was clear that the effects that were highlighted in these academic studies would have not been detected in the guideline detected studies. Behavior was not assessed. There was a rat and multigeneration study that did include some neural end points. You will see this as a reoccurring theme. We didn't feel for behavior it was so much also insistent literature. We just didn't feel that sufficient attempts had been made to reproduce it.

So the data limitations. The two clearest were that it's hard to understand the adverse consequences of the effects for the row defendants and by -- row defendants and by extension the humans.The new study from the Italian group had all of the same characteristics.

As we talk about why do we think this presents as limited evidence of adverse effects as opposed to some other category, such as insufficient or some indication of evidence for no adverse effect. It was based on a number of well conducted studies that reported effects in the low dose range. And others less than 1 milligram per kilogram. The end points were not included in the guideline studies. So you have these signals and no reason to doubt them, essentially. Why not higher? That rested on these interpretation issues.

So what did the CERHR expert panel conclude? We thought that the behavior affects supported some concern. And then just note this conclusion was strengthed by the new publication from the Italian group. This box shows you some concern falls in the middle of the concern categories that CERHR uses.

I guess now we'll get comment.

Thank you, Dr. Dr. Kristina Thayer.

Dr. Michael balm.

I could concur with the evidence reviewed in the draft. There are concerns that we just saw a minute ago. The report summarized evidence that raises a possibility that perinatal exposure [ Indiscernible ] in two nonreproductive behaviors. One that we just saw. The other is a related measure looking at elevated plus [ Indiscernible ] behavior in which animals are less emotional or likely to spend more time in the open part of the maze. There was also a couple of really excellent studies looking at the morphology of brain region.The other on the locus [ Indiscernible ] which is linked to attention. It is stated that the NTP's conclusion there's some concern for neural and behavioral effects of BPA it seems intellectual consistent to conclude that the literature provides findings that cannot be easily interpreted for biological consistent. In terms of consistency there's some evidence in the open field data and the elevated plus maze data are indeed quite consistent. The work of Rubin and her colleagues showing that perinatal exposure reduces the number of [ Indiscernible ], bringing this value down. The quite a convincing report. That correlates nicely with earlier data from that same group. Showing that perinatal BPA disrupted the ability of mice and rats to show [ Indiscernible ] cycles when they mature. It should be noted though that the immediate translational evidence and the morphology of the mouse remains unclear. In so far as there's no [ Indiscernible ] structure in humans.In the light of the demonstrated neuroand indough crine effects I think additional studies are warranted to sort out this issue. To see if in higher species there's long-term effect of perinatal exposure to BPA. We've heard some of the convincing data of others looking at perinatal effects of BPA until female mice on later loco motor activity. I should point out these were excellent studies, as we heard. All took precautions for group differences. This was a important issue that most of the studies in the brief did not take into consideration and render rather useless. To contrast the two studies that you just heard about now and the Rubin study all controlled for potential litter effects and controlled for adult steroid affects. Thereby enhancing the creditability of the studies. The central hypothesis being tested was that perinatal exposure to BPA organized female surface in females [ Indiscernible ] release or females emotional responses in ways that made them more malelike.Previous research suggests these two sexual [ Indiscernible ] are not feted by adult variations and circulating hormones. In the case of the activity studies we've seen there are convincing data there are organizational effects, early developmental effects on those variables. But there are also interacting effects, it's important to note which studies do and don't control for the adult steroidal environment at the time that the tests are carried out. Another issue that is raised by the studies reviewed in the report, which is only mentioned in passing involves the presumation [ Speaker/Audio Faint or Unclear ] which comes from the fetal Tess 'tis is responsible for the differentiation. [ Speaker/Audio Faint or Unclear ] of the compound at [ Indiscernible ] receptors in female subjects or an antagonist action. Nor sex differentiation as well the behavior we talked about just now, these are convincingly shown in other studies to depend on estrogen signaling in the male during development. The translation of such results is not automatic.There are however data suggests that perinatal receptors [ Speaker/Audio Faint or Unclear ] male typical primate brain. There's one invee grow study cited in the brief suggesting that BPA can act as an antiand Jen in a cell line. Another study suggests that BPA [ Speaker/Audio Faint or Unclear ]. Examples of male typical sexual differentiation in mice. For example, in the mouse brain there are spinal knew clee I and a couple of other sites that are linked to the and Jen receptor in the male during development. And there are examples, the preference of males to seek out females with urinary odors. There's a sex difference that is and Jen receptor dependent. All of these can be studied in mice. A thorough assessment [ Speaker/Audio Faint or Unclear ] any or all of these characteristics in male mice.[ Speaker/Audio Faint or Unclear ] part of the literature that is lacking at this point. [ Indiscernible ] is very, very critical of the conclusion that there's some concern for BPA. First the doctor dismissed the research on many grounds. I think our discussion today raises this as a continuing matter of discussion. I don't think we should automatically rule out every study that is conducted, particularly in the case of pregnant animals. I don't think we can necessarily just rule it out of hand. Um, second, the doctor cited several shortcomings. We've had those acknowledged in the report of the NTP. Very specifically I take issue with this, he criticized the conclusion by Rubin. First of all, it's not only Rubin that claimed this, there are two other studies that are excellent that claim that. He argues that none of the alter rations had an association with BPA. He missed the point. Namely that having demonstrated in treated animals there was a difference, the whole point of the study and that of others is that the limited. There's no significance difference between the males and females that receive BPA. Finally, the doctor argued that the results showed no effect in [ Indiscernible ] of F1 rat offspring. These authors presented no data to document the difference in the vehicle treated animals. I think I'll stop there.

Thank you. Comments by the board? Seeing none we have a choice. We can go to an early break or go to the next topic.

[ Speaker/Audio Faint or Unclear ].

I'm sorry, I can't hear you.

We'll take a break. It was scheduled to be 30 minute's worth. I think we can afford that since we're running ahead. We will come back at 2:30.

Session on afternoon break until 2:30 Eastern Time Zone.

I would like to ask everyone to take their seats. For the record Dr. Rivera is absent for the rest of the afternoon. We're double checking to make sure that Dr. car toff is on the line as we resume the meeting.

The next top imrik is reproduction and puberty. We'll have the slide presentation by Dr. Kristina Thayer.

Okay, puberty. When we looked at the low dose literature in female rodents we looked at mice and rats separately. It mice it seemed this inconsistent literature. There were six studies total. Three were positive and three as negative. In rats there was little indication of an effect. We reviewed eight studies am one positive and the other were negative. We focused most of our attention seeing if there was an explanation for this inconsistent literature in the mouse studies. That's what we will focus on here.

The biggest difference that we saw, the three low dose positive studies are listed here. The difference was the measure of puberty. So first he is tris -- estris is the measurement. The positive studies reported some enpoint that was related to first estris.

The Ryan study, you saw a behavioral part of the study earlier. Exposure does gestation, oral to the dam. What they reported is 4.5 day acceleration. This is again that positive control group. They saw the predicted effect of acceleration in puberty.

Second low dose study was [ Indiscernible ] from 1999. This is CF1 mice. They were treated with a low dose of BPA. This is oral to the mom. And what they reported was a short interval between vau gio nail opening and first estris. This is a phenomenon that you see in certain species of litter bearing animals where you can find differences in post natal phenotype of where they were in utero. They looked at zero M females, which is females surrounded by two females. 0M is no males. And 2 M females, these are females surrounded by two M.s. These are associated with differences in levels of hormones. The 0M females are higher levels of [ Indiscernible ] compared to the 2M.s. What they found, it was clear that any affect they saw on this interval was being driven by the 0 M females. These were the animals that were exposed to higher levels. You can see a bit of a dose response in utero, if I can turn this on. The 1M response intermediate within the 0M and the 2M.

The last low dose positive study was one published in 2002. This is ICR mice. It was 2 and 20 micrograms during gestation. It was a subcue to the dam. They reported an acceleration in age, a one day acceleration. You can see they saw the predicted effect in three doses of DES.

They also reported increased length of estis cycles at boat doses of BPA, that's here. Again, consistent with what they saw in the positive control group.

I want to take this opportunity to discuss one of the points that came up in the public comments in terms of this study also reported an acceleration in age at vau gio nail opening. They did not report a difference between the vau gio nail open willing and the first estris. This addresses the different measures of puberty. It seemed there was this discrepancy in the literature based on the measure of puberty. So -- in the rat these events tend to occur at the same time. For that reason the opening is an accepted surrogate of puberty. In the mouse it's not coupled. If you notice in sprain of mice, in the control animals they're seeing the age around 28 days. They saw the opening at about 27 days in the control animals. So 27 days, right. Very tightly coupled in this strain of mice.

Just bear with me for a second. So in the [ Indiscernible ] study, again, what you see in this orange bar is the interval between the opening and the first estris. You can see they were not as coupled. It took longerrer more than a week after opening to have the first estlis. First estris considered the more appropriate indicater of puberty. That's not to say that vau gio nail opening is not important. It's somewhat different information.

These were ones that did not detect any effect what they used vaginal opening as an indicating. CF1 mice are used here. Oral administration during gestation to the dam.

What they looked at what was the onset and the completion of this event. There was no effect in BPA group, for either measure. But one of the issues with this study, the reason why this study is considered intellectual adequate is because in their positive control group they saw the opposite of the predicted effect. They saw a delay in vaginal opening.

So the second low dose negative study is one by Marky published in 2003. These animals were treated with a very, very low dose of BPA. 25 and [ Indiscernible ] during gestation. In this case the route of administration is this subcutaneous minipump. The reason why the investigators used this it would better model human exposures, more chronic and steady release.

Too many reMoats.

They reported no change on mean age of vaginal opening. A portion showed this four day acceleration for the start of this process. In addition they reported longer estis cycles, as indicated by the percent of animals that spent 8 or more days in estis.

The final low dose negative study is one that the published version has come out recently, 2008. This is a CD1 multigeneration study. It looked at a wide range of BPA. This is oral administration through the diet. And well powered, 28 litters per group.

Hmm.That's interesting. [ Laughter ] All right. The red doses are the BPA group. And you can see at the low doses they reported no effect on vaginal opening. If I can bring up the blue column -- this is the blue column. This is the positive control group which is dietary. They saw the predicted effect. There was question about the sensitivity of this model for looking at the low dose effects of estrogens. Another 2008 publication from the same group where they characterized the dose response for their positive control group in a multigeneration study. They used a range of doses. The interpretation that maybe this study wasn't sensitive for detecting low dose effects they didn't see an effect at any dose. They had three doses below that did not inpact the end point.

To be fair, this is a multigeneration study. They did not see an effect on estis cycle length. But if they had higher doses of [ Indiscernible ] that [ Indiscernible ] the cycle and impacted fertility they would not have had F1 generation to work with. It's a byproduct of the type of study, which can be powerful, but it can also maybe limit you for ability to fully interpret the positive control in this case.

Now as we consider the issue of replication we notice that the three positive study included some measure related to first estris. And I guess the issue for us is given these two events are not tightly coupled in the mouse, it just seemed they could be telling you different pieces of information about puberty. And for that reason, even though boat vaginal opening and first estris are estrogen responses it suggest it's there might be unique drivers.

We also considered whether it was possible there could be species differences that could account for these positive mouse studies and the rat literature which was generally negative. There was some indication that maybe puberty in mice could be determined by external factors. For example, in female mice that are undergoing puberty that process canning accelerated in they're exposed to a mature male. That finding is less robust in the rat. In addition, if it's true that any of these affects in the mice are driven by an interuterine position affect that would be harder to detect in rats. That phenomenon is also less in the rat than in the mouse. For this reason not finding it in rats certainly limits the confidence. I don't think it, there were some indications it might be an explanation for why you might see this. It doesn't neglect gait the positive mouse studies. Each one had its own particular issue.

As we come to our weight of evidence chart you can see we said there was, we thought these findings presented limit evidence of adverse effects. Again, it was based on this consistency in the mouse studies that included a measure of first estris. Again, we didn't ignore, we didn't to discount the studies. It wasn't clear there could be species differences that could contribute to the differences.

Sorry. We didn't go higher though. Because there was little indication of effect in rats. We felt there needed to be more replication, especially for the very, very low dose findings in the 2 microgram per kilogram range. Using a more interpretable sign, rather than this interval.

So what did the CERHR expert panel do? They expressed minimal effects on puberty. Which is number 2 on the 5 point scale, if you will. They elevated based on what they considered to be limited data from the Ryan and [ Indiscernible ] studies.And we elevated to some concern based on consideration of the daily intakes in infants. Even though it's hard necessarily to translate that simply to an acceleration in puberty per se, it was affected reported at 2.4 micrograms per kilogram oral. If you look at the range in infants that's less than the higher end infants am it was that -- it was that connection. It was a little too close to the estimated daily intake in infants. That's the reason we elevated from minute malto some. -- minimal to some.

Oops we're supposed to have a question slide after this. We're done.

Thank you, Dr. Kristina Thayer.

Dr. Tapari.

Thank you. This is the only point in the NTP brief where I disagree with the conclusion. I would stick to the expert panel conclusion. I think that [ Indiscernible ] in his public comment made a good case for that, the paper there's not an advancement of the first estris. It's only this vaginal opening and first estris interval. In the [ Indiscernible ] study there is not a real statistical difference. The real positive result is from the Ryan paper. There was this 4.5 days acceleration in the high dose group. But that's with four or five mouse, very small group, very high possibility of a chance finding. All other evidence would speak against this. So I think it would be, would give too much emphasis to this Ryan paper to say there would be some concern. Especially when it really didn't focus on this effect, but rather on the other behavioral and brain affects. So, a -- my opinion is this should have been minimal concern for adverse effects, or there's insufficient data for conclusion.

Would other board members like to comment? I believe Dr. sharp to make comments later. Would you like to make any now?

I would agree with what was just said. To bring out another point that continues to puzzle me. It's a point that Dr. Kristina Thayer made twice about interuterine position. I have asked how is it a female position between two females in a rodent is exposed to more estrogen, how? They don't makest trow Jen? They don't make and row Jens. How are they exposed to more? I could make a much more convincing case that a female positioned between two males might make more, they might be exposed to some subtrait. I still have my doubts. I think there's a credibility issue there. There's no evidence they are exposed to more estrogen. I've never seen evidence they are.

Well, I mean, those errors are based on a publication in that strain of mice, a 198 9 publication. I don't know if it's looked in at other laboratories, whether you find that robustness in other strains.

So if I can rephrase what he said, you don't really agree with the observation of the different of time between opening and estris is that's a valid end point? And then you would cast off another positive study, leading us with a single positive. Another members that would like to comment on this assessment?

John mir Sal is.

I know it's hard to make a positive go away ever. You get a positive you go ahead and do it 20 more times and you get a negative and that positive sticks in your craw. This is case where I would agree with Mr. [ Indiscernible ]. We don't need for studies on this topic. There was some disagreement, I think shelly tile's study is the gold standard. You look at the number of litters, the way it was done. It's an ideal used study. I would be inclined to agree. It's minimal or less than minimal on puberty. We could spend the next five years, you know, and a lot more money and animals doing it over and over and over again. I think we've done the gold standard study, it's a clear negative. I think we're done and we move on.

Other members of the board that would like to comment on that? Dr. Nancy Kerkvliet.

I wanted to qualify. Was the, um, you showed data with a 2 and 20 subcue injection where they saw an effect. And the tile study that was 2 versus 20 oral, they didn't see an effect. I think in the subcue they only saw it at 20. So that could in fact speak to available dose. Where in 20 oral you don't see the effect. I don't know if you considered that already. Just struck me as you presented it. That could be one of the con founding differences.

Yes.

It could be. I know in Earl gray's comments he reanalyzed based on the values in the graph. The expert panel certainly presented that finding. It's a small effect. But I think that -- I had some concern about minimizing that effect given they saw this impact on the length of the estis cycle.

Uh-huh. Thank you.

This is Dr. Gail McCarver. If there was any dose response it was either flat or negative. That would lend you to think that perhaps that really wasn't a robust finding.

For example, in the tile 2008 study they saw acceleration of opening in their top two doses. We always look for it. As we look through this literature a lot of times we didn't see --

You are right. I would agree with that. You don't always see the dose response curve. Other comments from the board? If not I believe we're ready to move on to the

Are you with us on the ball not?

I am here very good. Onto the mammary gland.

It will be and Dr. Sayer?

Yeah. Where the low dose effects? There were studies of new breast lesions. This is to Randall and Marie, both published in 2007. So, these lesions that were being reported, they were supported by a number of other studies that located the mammary glands produce the kind of the decks been reported in these supported studies included adult maturation or a rate of undifferentiated structure is. It is coming from the same group of collaborators. You heard them on the phone and uses the subcutaneous many pumped. That was one of the issues that as we said we considered that route of administration and a pregnant dam--There was some impact on this undifferentiated structure. So, the relevance of this finding is that the Human Corella's lesions have been described as risk factors for invasive breast cancer in women. Here it is the Durando to the House study they retreated with 25 micrograms per kilogram of BPA. What they report is statistically significant increases in hypoplastic [ indiscernible ] and 180. They also included part of their study, they treated animals with a dose carcinogen at 25 micrograms per kg to see it BPA would alter the potential, that chemical to cause tumors. What they found was, again, this increase in the type of hyperplastic ducts--The second study from this group is using Wistar-Furth. They use a range of speeds above 2.5 to 1,000 with the it subcutaneous pomp. What date reported is statistically significant [ indiscernible ] on post [ indiscernible ] 50 and elevations, but only statistically significant at the 2.5 dose on post [ indiscernible ] 95. They also reported, this is a very small study, 4 to 6 liters per group. The posted carcinoma in the highest two doses, 250 and 1,001 out of four animals at both time points--So, we said that there was some supporting information that identified and Pats on the mammary gland following BPA treatment. This is not one of those. If this is study published in 2001. CD1 mice, using these subcutaneous many pump, they were treated during gestation. What they reported is that an increased number that's just the significance of these findings is the undifferentiated structures are supposed to be more susceptible to carcinogens. So, the new study that has come out since the expert panel evaluation, the rats that were treated with 25 and 250 micrograms per kg, and that this case it is oral administration during the station and post [ indiscernible ] life. They reported a significant number of terminal ducks, geese and differentiated structures in the highest dose Group, 250 micrograms per kg at 20 and 100 days and sought a modified gene expression in both doses.

So, as we consider the Ripper disability of the mammary gland, it became obvious that the effect that would not have been detected in guideline compliance but is. First off, the mammary gland has not been assessed and many of the guidelines Betties that are out there, including the best they published in 2002. Two multi [ indiscernible ] studies, one recently published by [ indiscernible ] and by Emma did collect the mammary gland and did not collect the whole amount. You would not expect them to detect the --It allows the more consistent suctioning. So, when we have talked with our pathologists, it seems reasonable that if you do not do it a whole mount, the ducts that were being [ indiscernible ] could not be detected. NTP has done then a two year bioassay. No effects were detected in female rats or mice. Those more susceptible on different data structures would not be exposed. Nor did it use whole mounts. So, we would consider the data limitations. It is unknown if the Regents would progress to cancer. These studies were under a power statistically to detect differences in the incident of carcinoma, especially the Murray study that had 4 to 6 liters per group. Also, we consider and interpreted issue that the Murray study tested this wide range of BPA, but did not see a clear relationship between the the dose and the percent of hyperplastic ducts. Again, as we mentioned before, the SEC attorneys brought up administration to adult animals was only considered useful for Hazard identification purposes. The expert panel did not have a biological interpretation of the mammary gland studies. The key studies were considered inadequate for one reason or another. If the study was inadequate then the expert panel did not consider it in their deliberations. It is important to note that the basis for the inadequacy was not just because of the subcutaneous route of Administration. If so, for the Durando study the expert panel considered inadequate because they used 100% DSMO. Use is of concentration of DSMO more than 50% are not recommended by the manufacturer. You can get depredation of the pump [ indiscernible ] we considered that. We were not convinced that the use of 100% DSMO could account for the reported defects. There seem to be this consistently a dentist and consistency between the types of regions reported with the [ indiscernible ] Murray study produced an acceptable concentration of DSMO. Critical public comment process based stated that they had no indication of DSMO toxicity, inflammation or edema. We felt that use of one hand % DSMO does raise concerns on accuracy of the administered dose. It is degrading the pomp, that could, clearly, impact, it is released. That, potentially-I will not say that. Another issue related to the expert panel criticisms of this literature was the use of small sample size in the Murray study. It was 4 to 6 liters per proprietor of this was offset for us because the Durando, where you saw a consistent outcome had 11 to 14 liters per group. And a larger sample size study. The expert panel also had concern about whether Murray, the Murray State adequately--The author clarified through the public comment process that only one animal was used in his logical examination. --His --Histological examination. As we do our weight of evidence for the mammary gland, we came to the conclusion of limited evidence for adverse effects. The reason why we felt that it was limited evidence as opposed to insufficient evidence was because of several studies identifying the mammary gland as a target. The interpretation from the authors was the kind of the facts that they were seeing would be consistent with predisposing the tissue to disease later in life. We did not have-it was Apple's and origins, in essence. We have the signals from the academic studies that the mammary gland was having these a packs but the multi generation study did not look at these tissue or did not look at it in a way that would allow us to see whether these effects would be reproduced. So, and that this sense, that a number application, we were hesitant to dismiss the findings. Again, there was a new study that supported the mammary gland as a target tissue using the oral route of Administration. And, we had additional technical information from the author, in particular, controlling for litter defects for Murray. So, why doesn't the draft brief propose a higher level of evidence? A lot of it is the progression of what is the pre-neoplastic lesions. We felt we needed more information on that provoke the small sample size, neither of those studieds reported statistically significant increases in the significance. The use of the subcutaneous many pump, which, again, was considered useful for Hazard identification, it was to the pregnant dam. The use of greater than--it raises questions on the administered dose. Again, the expert panel did not have a conclusion related to the mammary gland because they considered the studies to be inadequate, but did consider it to be a research need.

Thank you. The discussion for this topic is Dr. Robert Cardiff. Are you there?

I am there. I am your also.

I am there and here.

I am a pathologist by trade. I do both human and rodent pathology. I have considerable experience in that memory pathology. I agree with the conclusion and the assessment that was given. I was asked to, specifically, evaluate the threat of the pre [ indiscernible ] in these animals. I find that it is a whole matter of interpretation. There is no biological evidence rendered in any of these studies that these lesions progress to an end a civil carcinoma. That is critical in evaluatings whether the authors are observing true pre cancer or this is an interpretation of a lesion that might or might not become malignant. I find these studies technically flawed and cannot enter to based on the information I have and the images that I saw.

Is at the end of your discussion? I wanted to ask you just to clarify. I think you said that you agreed with the language that was used. You, actually, our in agreement with the view of limited evidence.

Yes.

All right. Do we have board members that would like to make responses or comments?

I have a question about the lack of any mammary tumors in the two year studies the possibility that this phenomenon is related to developmental exposure only. I am trying to think of what would be the biological plausibility for that to happen when these terminal end buds are there during development are there during development and puberty and, maybe, during pregnancy when the Member gland is responding. So, I do not know if you have thought about that at all. To me, the lack of mammary tumors in the two-year study is problematic.

We have thought about it. Actually, we had a workshop a few years ago now to try to look at the utility of the rodent models for detecting formally mediated to Marks and the mammary gland was one. That was a piece of feedback that we got that not having that prenatal exposure in a cancer bioassay was a significant issue. View would be missing the majority of exposure to the most undifferentiated structures. So, they considered it to be key if we wanted to try to improve the [ indiscernible ] of the cancer bioassay for detecting mammary gland carcinogens in.

Do not have to go back to some unknown mechanism? If it is an estrogen receptor type mechanism, then you would not expect that to be limited to prenatal.

Help me out there, done. Was the results from the EE study. The mammary glands were not observed and females in the steady.

No, they were not.

We do not know about prenatal.

I had a question and maybe a comment too. You indicated that there was some discussion and some technical information that you received in that connection with the steadies. I am really curious whether an author with any pathology peer review was conducted on these lesions. This is a difficult area, as I understand it. A lot of the data has to do with an increase percentage of hyperplastic ducts. All have hyperplastic ducts as I read the data that you have presented. I am curious as to whether or not there was some additional opinion gained from pathologist such as Dr. Cardiff and others to look at these leads ands and not just images that were published. I do not know that that is what happened. I am beginning to suspect that that is where we are.

The answer is, no. I was somewhat limited by looking at the publication, which I found the images in the publication somewhat limiting. The supplemental data that was offered was a semi quantitative interpretation of previous data. I do not know what they are looking.

Okay. The comment, if you could go back a slide or two.

More?

Yeah, this is fine. You know what, I think the word used before was biological plausibility. I am struggling with the fact that there might be insufficient evidence for a conclusion on this end point. Hyperplasia can be produced by a variety of things in tissues with an extreme wide range of outcome that often, there is evidence that the cause of the hyperplasia has to do a lot with the biological consequence or the potential for regression or progression in and the Salesians. I am not really convinced that you have provided enough information or found enough information to support the possibility that these are, there is an adverse effect, in fact these animals.

A lot of the biological plausibility it support comes from other studies that have identified the mammary gland as a target and then not having multi generation studies that we felt, and looked at it appropriately. If it had been the case that the multi generational studies have looked at this tissue as a whole mount and not report anything, you would not see it on the list. Again, we felt given the signals, not just these two studies but other studies that have identified this as a target, and as you heard from the public comment, these Leeson's have because people concerned, we felt we needed a good reason not to consider the biological significance. [ indiscernible ] because of all of the issues that we are talking about now about not having information on progression are questions about the pathology.

It really hinges on that lack of any [ indiscernible ] on progression.

I am not going to be able to solve this issue as I wish I could. We had a number of the NTP top collegeses look at the paper and the images on those papers and they agreed with Dr. Cardiff that there was evidence of [ indiscernible ] hyperplasia. They were not certain in terms of the [ indiscernible ] diagnosis as far as the published images, just to confirm what he gave you.

[ indiscernible ] has a comment.

One more thing that bothered me and at the paper by Marie, there seemed to be a lack of any kind of a dose response there at all, especially [ Audio/Speaker not clear] the only dose they saw an effect AG was the lowest dose [ Audio/Speaker not clear].

That is also the small sample study too, the 4 to 6. It is unsurprising.

I guess what I was hearing from you was that you are seeing this more as a hazard identification and the lack of dose response is less important. I understand that it can always be more convincing. As a hazard identification that is less of a critical matter.

Look at the categories. It is limited evidence, insufficient or some. That comfort zone, do I feel comfortable dismissing it? I do not feel comfortable fully interpreting it.

If there are no other comments, we will move onto the next topic.

There is a comment.

Thanks. I have a question and comment. The question is, with the [ indiscernible ] hyperplasia consistent or inconsistent with a larger body of evidence where prenatal exposure to various [ indiscernible ] compounds causes other mammary gland changes in mammary gland structure and function [ indiscernible ] and a whole bunch of holistic compounds that have been looked at, and consistently found to cause changes and not the development of the mammary gland. I think where we are on that now is waiting to see what that ends up meaning in terms of cancer risk. It is, I think, for example, at the meeting that Christina talked about where we talked about models for mammary cancer, a very important and currently not evaluated exposure scenario. So, I kind of support keeping it in here. I do not think-it fits with data on other compounds. I would also say that these are important studies because they represent a careful and creative and thorough examination of how developmental exposure to the [ indiscernible ] compounds might--In ways that are related to breast cancer. Breast cancer is the leading cause of death and not women from their late 30's to about 60 in of the U.S.. As a regulatory toxicologist working for an environmental research organization that was founded by breast cancer [ indiscernible ], I cannot overstate the need for novel approaches to this neglected research area.

Thank you, for your comments. I believe you have a question early on.

How do these endpoint, how are they consistent or inconsistent or not overlapping with what has been reported by Sue Fenton and other.

I have not looked at other compounds for a while. I have been concentrating on BPA. It seemed like the hyperplastic lesions were relevant in terms of the development of the mammary gland cancer and not the relevants. It was consistent with the progression of more severity of the lesion in progress and to a timber. Maybe Dr. Cardiff can talk more about it, there is a publication that women presenting whit hyperplastic lesions, that that is a relative--invasive breast cancer. Even though we have these issues about, did they progress in this study, there seems to be indications that they were relevant to the development of mammary gland tumors in rats and seen to be relevant for breast cancer and map when an. That was the adversity hook, even though we did not see the progression in that the studies. Dr.Cardiff, which like to make any other comments?

Yes. I would like to distinguish between the lesions that and as a typical hyperductal--Regard epithelial pre cancer of any organ as desirable as a typical cell. That is distinguished from a diffuse to hyperplasia. It is not clear to me whether the phenomenon that is being discussed here is a diffuse hyperplasia of the epithelium of the ducts, or there are focal lesions. Not seeing lesions, I would regard this as a-more of a physiological type of hyperplasia a van a neoplastic type of a typical.

Are there any board members that want to comment on that or other things related to the mammary gland? If not, we will move on to the prostate gland. Dr.Thayer is presenting those slides, I believe.

This is the last one.

What were the key low dose findings. 1--That was a publication in 2006 program to other was more morphometric effects in that 2005 brother was a new study subject to the expert panel evaluation that the prostate as a target tissue evaluation of BPA. Development exposure to BPA might expose that tissue to disease later in life. Let's look at the Ho study purpose was an [ indiscernible ] rats that were to do with 10 micrograms per kilogram of BPA. It was subjected to the neonate during--The adult animals were treated with [ indiscernible ] to and dos PIN lesions. For those of you not familiar, rodents are normally resistant to developing prostatic lesions and Tamaras. Researchers in the field use a modified model, whether it be a genetically modified model, where in this case a hormonal manipulation to try to induce lesions and that the animals. The particular model used here is supposed to mimic the ratio of these hormones and that the aging human male. What you are looking at here-we will start with this purpose is the incident of total PIN lesions--It is the son of low grade and high grade PIN lesions. They calculated a PIN score, which is a combination of based on incidents and the grade of the lesion. Four BPA--Animals treated during the neonatal life. They included a positive control group, 17 [ indiscernible ] and the high dose group, 2,500--they also saw a significant elevation of the PIN score probably did not see this in their low dose group. So, the prostate and urethra morphometric changes. This is in CD1 mice purpose is ticking off on its own. This is oral to the dam during gestation. These are control animals. There is an increased number of ducts in the lateral and dorsal [ indiscernible ]--These effects were attributed to a proliferation of basil epithelial cells. It is out of sequence. It worked this morning. You cannot see it but right here, this bottom row should be attended the changes that they saw--The morphometric reconstruction of that. Is the BPA Construction was here it would look like and the DES in that there is a reduced volume compared to the control animals, a construction. So, the new supporting study was one by Ogura. This is in BALB/C. This is oral to the dam. --This is looking at the Andrea prostate or collide related gland. The prostate looked normal. When they did a stain, they saw staining in the DES and BPA animals that they interpreted as squamous differentiation part of the relevance of this to our discussion about the prostate and BPA is that [ indiscernible ] this condition of multi layering of the appeal cells [ indiscernible ]--Considered to be a high dose effect on the prostate. What the authors are saying is that they are seeing an early indicator, the CK10 stating that is consistent with the estrogen. They had components of the study where they treated animals just in adulthood and had an in vitro compound where they reported the same thing. Let's consider reproduce ability. These effects would not like to have been detected in the multi generational studies. No morphometric studies. It is very labor intensive. As we said, rodents tend to be naturally resistant to developing prosthetic lesions. It is not clear that PIN studies would be detected in the multi generational studies. With the new publication, what it does in addition to another study that is showing up that BPA has some effect on the prostate is that it does-might not be detected by H&E study and testing program of the prosthetic samples look normal when you look at the lesion stane. So, the NTP did not attend dissented study did not identify prostate carcinogens. The road is insensitive and the NTP bioassay has never identified a prostate carcinogen. It did not include prenatal exposure, which harkens back to the workshop that we had, not one of the recommendations and that the prostate or group was that the bioassay should include that if we want to try to increase its sensitivity. Limitations of the date. , the morphometric analysis, what are the long-term consequences of the morphometric consequences [ indiscernible ]. Do they persist? It is not clear if the PIN lesions progress to cancer. The lesions falling that hormonal trip treatment often progress to adenocarcinoma. An issue would entertain the data was what appeared to be a hot unexpectedly high potency of BPA relative to the positive control response in morphometric incidents and score. And that that study it was the 10 micrograms per kilogram of BPA that seems to give a response comparable--so, here is our scale. Again, we thought that these effects presented limited evidence of adverse effect. More than insufficient because there were two key studies that identified the prostate as a target. I should mention that the [ indiscernible ] study was considered [ indiscernible ] the PIN study was limited utility, essentially because of the route of Administration. Otherwise, it was a well-regarded. Again, the types of defects that were being reported would not have been detected in that guidelines studies. We have seen thes from these more academic studies that we have no reason not to believe. Then, there was a new study that came out that, again, supported the prostate as a target of BPA. We felt, as we discussed earlier, before lunch, the route of Administration. Looking at the [ indiscernible ] study and the new Taylor publication to give us more information to better allow us to interpret what this of continues injection to a neonate might be subject to oral exposures. Which did not consider it irrelevant for this particular age group. Why not hire? We do not know-We have not seen how the PIN lesions progress as a function of an island and an attending an exposure to BPA. The long term applications of the morphometric findings.

So, the expert panel expressed minimal concern for the facts of the --They consider the prostate to be a research need. We elevated, if you will, to some concern, based on new data, a [ indiscernible ] publication that highlighted the prostate as a target tissue and--The Tim study and the Ho study--overlaps with the range of exposures estimated for infants.

Thank you, very much. We will go now to Dr. Times for the discussion.

Thank you. I would like to thank NTP for inviting me to present my comments. I will preface those by some, perhaps, what might be considered trivial information. I think it is important and relative to this program of study. For those of you that do not know, this was a first synthesized in Russia in 1991. In 1953, it was used to produce polycarbonate plastic in the United States and Germany. With regard to that date, I think is significant that the population that we might consider at most risk are probably those that are aged around 40 years or younger. The plastic was not considered a component of the environment until around that time when we started using plastic for, for example, a baby bottles, which is something that is being questioned. I think Generation X and their offspring are the ones that we should probably focus on. Individuals like myself and older will probably not have the same lifetime exposure, which I think is a key factor in all of this discussion. We have talked about experiments exposing the animal model to a period of opportunity for these compoundses that, in consideration of human exposure, we must consider that this is a lifelong exposure and, perhaps, begins in utero. In 1936 there was an interesting hypothesis that elevated these [ indiscernible ] could predispose males to an enlarged prostate and adulthood. What I think is interesting is 70 years later [ indiscernible ] they have suggested some confirmation of that predisposition with regard to end the current destructors such as [ indiscernible ]. It is also interesting to note that in that 1936 when [ indiscernible ] proposed that elevated enlarged prostate propensity in adulthood, BPA was considered for its [ indiscernible ] in studies that compared it with [ indiscernible ]. DES was chosen over BPA because of its higher potency. We also know that DES was banned in the 1970s. It is also interesting that high doses of [ indiscernible ] where paradoxically used to treat prostate cancer. We are talking high doses. Now, of course, we have newer drugs. I think is important to recognize that there is quite a history to this. In revealing of the NTP brief, I concur with them with regard to the concern in terms of exposure to males, especially when we consider the exposure period. I want to emphasize that and not the beginning, and perhaps at the end of my presentation.

That is when we consider pregnant women and their developing fetuses, the infants and young children we have seen in the report, they seem to be at a higher risk than the adult population. There is a term used and that many of the papers that discussed, not only memory development but also prostate development. That is that there are critical developmental windows of opportunity for these productses or hormones to exert their effects. I think that is also very important, because we are considering the fetuses and neonatal humans are particularly vulnerable because of metabolism issues and developmental issues and because of these windows of opportunity.

With regard to the prostate, I also wanted to note that we are [ indiscernible ] of the list with regard to all of the tissues that have been discussed. Anatomically, the prostate is at the bottom of the anatomical list as well. Perhaps that was delivered. I do not know. There are a considerable number of publications when you look at this [ indiscernible ] and the prostate. Over 50 studies. Most of the experimental studies have, obviously, then done an animal model systems, the mouse and racked rodent, in particular. They have, and I have to admit, some studies that reported no effects, but an overwhelming number of studies that have shown that there is, potentially, and increasing weight of evidence to support the effects of [ indiscernible ], again, during critical formal sensitive windows of opportunity during development that might have the potential for long lasting effects. I think is important to emphasize to the board that's with regard to some of the [ indiscernible ] that exist about corroboration of data, if you look at those studies, in that particular in the prostate and look at the biological effects as a whole rather than individual studies, I believe that you can begin to see that the weight of evidence is much stronger than it has been and is indicating that there is, certainly, a need to express concern about exposure.

Come back to the prostate. When you consider the rodent prostate, and I would like to the thanks Dr. Thayer to see the data, it will give some of the descriptions that I mentioned. I hope you will not feel that I am biased in not discussing a paper with a gentleman has the same last name as me. I will try to not be biased in my summary of that paper as part of this discussion. The road and prostate, unlike the human prostate consists of very distinct Loeb's. That is illustrated in here probably have color-coded those lobes for you. It became very clear in that publication back in 2005, NTP publication number 46 That the region and that the mouse prostate, and this is also shown in the rat that exhibits the most sensitive response to the effects of estrogenic [ indiscernible ] or even estrogen is the dorsal, lateral lobe that is shown in green. That is not the first time that has been reported. [ indiscernible ] 2001 also commented on the observation that in that addition to the dorsolateral prostate the coagulating gland or interior prostate, which is not shown in that this diagram is also a highly sensitive area to [ indiscernible ] effects. What is significant about this and is not in the report, but in a publication by [ indiscernible ] 1994, where this technique was first described and described to illustrate the homologies between different species that we use for prostate studies, including the human fetal prostate, that if you look at the dorsal lateral region, this is the region in the rodent prostate, which is considered homologous to the posteriors some of the human prostate. There is a zone in the human prostate. They are not lobes like you see in the rodent model. What is interesting and that is the posterior zone of the human prostate is the region in humans that is most susceptible to the development of cancer. Relative to this, also, is the fact that many reports mentioned in the NTP brief talked about examining the prostate and using the endpoint of dissecting out the central lobe. If you look at the literature, there is some evidence that this particular lobe in the relevant model, the central lobe is insensitive to the effects of estrogens. One of the reasons that the ventral lobe is chosen because it is very easy to find, dissect and lends itself to prostate weight steadies for that purpose. Accurate dissection of the hot lateral and or dorsal/lateral lobe, which has shown to be sensitive is difficult for an experienced investigator and tedious, even difficult, for an inexperienced investigator and tedious even for an experienced person. This difficulty can be compounded by the smaller size of the mouse prostate. What I am saying is that trying to dissect out the dorsals/lateral region effectively is not very easy. I will point to a discussion on page 25 and also referred to an earlier consensus reports by Grey et al in which they "perhaps the most confounding factor in all of the prostate studies is that [ indiscernible ] wet weight is an extremely poor measure of prosthetic growth which substantially diminish as the strength of data advanced both for and against the effect of BPA prostate growth." The reason I quote that is I think if you look at the studies that have relied on, extensively, on wet weight measurement or weight measurement of specific lobes of the prostate, and specifically the ventral, they are not the best endpoint for looking at some of the effects that we are beginning to see now in some of these newer studies. And Dr. Thayer mentioned that the technique used for this approach is very time-consuming. I agree with that. It is apparent now that there are alternative endpoints that can be used that are faster in terms of the time frame. That was published by Dr. Peterson's Group in medicine [ indiscernible ] Journal of urology, 2004, using scanning electronic my [ indiscernible ]. There has been some computational technology by [ indiscernible ] in 2005 using ductile architecture analysis and that might be a much more reasonable approach to providing this data per pulse also, the use of histo top colleges. We heard about that in the mammary gland. That is becoming more prevalent, the brief reference 43 is an example. This will provide more relying and convincing data [ indiscernible ] and subsequent effects. The compelling evidence, I believe, it needs to look at those studies that use positive estrogenic controls. For example, if you see an effect with a positive estrogenic over and above the normal parameters in the control and see similar effects with your compound of interest, I think one can accept that that is a reasonable evidence for an effect of that compound.

As I mentioned the 2005 study, number 46 in the NTP brief look very specifically at the dorsal/ lateral prostate row, the region that is homologous to the human prostate posterior zone. Another aspect of that study was not just to look at the volume data, a weight measurement, but using [ indiscernible ] analysis, which is much more reliable. It also investigated the proliferation of basil cells. For those of you that no the prostate or even mammary gland, prostate epithelium is not a homogeneous epithelium. It is made up of a mixture of subsets of cells, each with its own specific requirement for growth and development. One of the cells that has had interest for over 30 years are the basal cells. The basil cells more recently have been contained a subset of stem cells. We know they are a very important subject of investigation at the present time. There have been studies to identify a subset of basal at cells [ indiscernible ]--These cells have been identified in the rodent model and considered to have an important role in the formation and growth of the normal gland as well as a potential role in the development of cancer, a reference by Collins in 2007. They also have the same goal, apparently, and not breast cancer.

The interesting facet of that is, rather as I just said to look at the more from a tree and growth, it was found that this subset of cells had an enhanced role for it is response with regard to positive estrogen controls and also [ indiscernible ]. If so, when the animals were treated in utero, the number of basal cells were increased and capacity. There are other studies, again, using positive controls that have shown, for example, we have talked about the increased susceptibility for a precancerous lesions, the high PIN lesions that is relative to prostate carcinogenesis that was in the Ho paper, 2006. There have been [ indiscernible ] showing increased--or genes expression. We know that when we talk about the prostate, we have to consider not just the epithelium but also when they stroma--It is a very relevant to an understanding of how estrogens impact the stromal effects on the epithelium. Related to that, the study related, refer to the 2007 paper showed that you could impact a permanent induction of CK10 expression. That is not normally expressed in the epithelium of the prostate. CK10 is associated with basal cells and their propensity under the estrogenic stimulation to undergo what is called squamous met aplasia. Again, in keeping with what I described early on as sensitivity and that the prostate, estrogenic sensitivity, [ indiscernible ] found the anterior prostate, because by deleting plan followed by the [ indiscernible ] prostate was lobe specifically sensitive to these defects. I should also mention the recent file paper 2008--They also used prostate weight as a parameter despite what I mentioned early on. There was discussion and not the paper about histological typology not been shown, etc., and also discussion about selecting certain tissues for the weight parameters and the conclusions of that paper were based very heavily on the weight analysis and outcomes. There were also some comments about the histo apology but no images representing that data.

I believe there are a significant number of peer reviewed papers that provide evidence of a low dose effect [ indiscernible ] human exposure, particularly for fetuses, infants and Children program the significance of these findings is that the effects of, perhaps, are more pronounced at the cellular and molecular level and might predisposes reproductive organs to disease and adulthood. There is a theory about the origins that I will not discuss here. There is some related evidence that I think is important. One is a study not using BPA but has shown that P10--Is mutated in prostate cancer and P10 mutation or loss is associated with the expansion of the stem cells in mouse prostate and reference my discuss her about stem cells and basal cells in the prostate. This was done by Dr. Wang. If you increase basal cells, you increase the propensity for prostate [ indiscernible ] PIN and, perhaps, cancer. I would also like to refer to another publication that is not in the draft. It was just published this year and environmental health perspectives by [ indiscernible ]. What was interesting about that was that it was, again, another study looking at environmental destructors. The interesting observation was that it appeared that the particular and a grin descriptors was a UV filter and have two effects. There was a dichotomy of response proposed first of all, there was a response in the early outgrowth, the initial growth of the bud in the [ indiscernible ] sign is. That was entries to this destructor. There was an increased branching morphogenesis observed in the Central lobe. If you look at those two phenomenon and the development of processes, you can see that we are talking about, at the molecular level, you can expect to be looking for a facts that might be reflected by, perhaps, the growth rate changes are prostate weight changes. That was indicated in the report. I think is important to look at the molecular level. We need to be very aware that future studies need to be emphasizing that. We have discussed precancerous lesions and not the mammary gland. I want to come back and briefly mention PIN lesions in the prostate. PIN lesions are indicative of precancerous changes in the Human. I believe the evidence is fairly strong to indicate that if you do a prostate biopsy and there is evidence of a high-grade PIN cell there is a particularly high risk for developing prostate cancer. I believe also that in the [ indiscernible ] paper that there was a discussion about the stages of [ indiscernible ] and the high-grade, low-grade proportion. One of the things if you look at PIN lesions in the mouse, they have a very similar to his histo pathology [ indiscernible ] that are all patterns of pathology at one associates with PIN and lesions in the human. There is a correlation between what one finds in the mouse prostate to those that we find in the Human. Another final point is that as males age, the testosterone to estrogen ratio changes and the [ indiscernible ] changes. If so, if one is exposed, to perhaps, a estrogen minute during this developmental opportunity, perhaps certain cells, such as the it basal cells or stem cells within the basal cells population even transient [ indiscernible ], they might be affected by this unnatural fatal exposure and predispose them to what we call estrogen sensitivity later in life. And increasing estrogen novels occur in the male or lifelong exposure to the estrogen's effects impact this tissue, it is possible that that could have a significant effect. I think the three issues that I would like to summarize as a take-home message from my review our: It is important to look at the study as a whole, the overall weight of evidence given that many studies have different endpoints, but some of those endpoints are critical in terms of understanding the physiological significance of exposure to low doses of BPA. I cannot emphasize it enough, but I believe that there is a critical window of opportunity for preservation of this hormonal imbalance that is required. We heard Dr. [ indiscernible ] talk about it later on for development of the reproductive system. With reference to that, there was a paper recently published by [ indiscernible ] that showed that there is, actually, emphasizing that window of opportunity in male Development in terms of the hormonal programming occurring before the more logical evidence of that programming. I also think is important to recognize that we do not, necessarily,-we cannot necessarily decide from a single endpoint such as prostate wait, what is going on at the cellular level. If you look at the cellular level, you might see subtle changes at the molecular level with regard to genes expression or specific cell types being impacted by these moleculeses which might predispose an individual to consequences later in life. I do believe, that we need to follow on with long-term studies to see if these early developmental effects are long lasting. Thank you.

Thank you.

Dr. Sharp, which like to make your comments now?

I wonder if there is anyone who specifically wants to make any comments following up on the prostate.

We will take any board comments on the prostate.

This is Dr. Cardiff, again.

I have comments about D r. Ho's paper. Because something low-grade and something else high-grade.

You can correct me if I'm wrong on that.

That's a separate issue. I agree with you. Rodent models have nice [ Indiscernible ] copy lesions that mimic the human. One can observe intellectual vasive carsinoma in association with the lesions. In some of the particularly mouse models there's nice correlation that we can we assured we're looking at the same biological process. In a like manner -- I guess it's not in a like manner, if we study the lesions there's much better evidence that low-grade lesions in the mouse prostate are associated with progression to intellectual vasive -- invasive disease. In the human prostate the pin is no longer considered a risk of advancing to prostate carsinoma. Only the high-grade pins that are clinically worrisome.

Other comments from the board? Dr. Nancy Kerkvliet?

I would like a clarification. One of the comments that I have heard, that is difficult to internalize with this discussion is that during human pregnancy there's high levels of estrogen whether the fetus is female or male. How does the male fetus control the estrogen affects of the mother if it's so sensitive to estrogen affects? I'm curious. What is known about that? I guess in the same question -- I have noticed a difference in when the animals are treated during gestation. There doesn't seem to be a particular window that is used. Now granted I have noticed that for different end points. I know in immune owe tox you look at certain days of exposure. Can you provide some insight into those issues?

In terms of -- I think where each of the critical health affects --

[ Speaker/Audio Faint or Unclear ].

Thank you. The prostate there was a study and a gestational study. You are right, if you are talking about your inability to latch on to discreet critical period, you are right. You base it in looking at all of these affects presented across the different tissues. I guess I don't have any more insight in that. There's not enough comparable studies to hone in on the most critical windows.

Would other members like to comment on that?

If I could just add one comment. Maybe either Dr. Times or car toff can respond. In the human fetus has epithelial hyperplasia and the cells are shed following delivery. I guess that could be the difference in the rodents. Do you know, is that correct?

I can't comment on that, I don't know.

I believe --

Dr. Times?

There was studies many years ago on levels of estrogen in male fetuses and found a high level of squamous metaplasia. I don't know if anybody has followed up on that. There are some studies that indicate in a males are exposed to different levels of estrogen during development. Dr. Kristina Thayer refer today that. There was a paper lished by our group. We expected irk UP effects in the row dust. We found that the males between two females were exposed to higher levels of estrogen. They had levels of higher prostate, interestingly. There is evidence in the human. Again, if this is incorrect please correct me. I was under the impression that in black American women there's a higher levels of estrogen during pregnancy. It's interesting that black American males have a higher incidence of prostate cancer.

In mice and rats there's a high [ Indiscernible ] protein which will soak up high circulating he is trow dial. I don't know anyone who has looked at this in the context of prostate. I would imagine that both sexes are protected. That doesn't apply to the human.

Other comments about the prostate? I sense people are needing a break. I told Dr. sharp we would go to him. But maybe we'll take a break. We'll come back and start with his comments and move to the general board discussion. Five or ten minutes and then I'll try to get you back pretty quick.

Session on break until approximately 4:15 Eastern Time Zone.

This is the operator, I have no parties online.

I call the meeting back to order. I know people are still moving into their chairs. A little bit of a change. I had several at the break that asked to hear from Dr. Leader before he leaves at 4:30. He will not be here for the full board discussion. We're going to postpone Dr. Sharp yet one more time. Are there particular questions the board wanted to address to Dr. Leader? Or you wanted him to make a summary of his specific view? I think that must mean me want to hear a refresh of your opinion about the draft brief.

Okay. Specific comments regarding the draft brief, the statements included in the brief that relate to the [ Indiscernible ] in animals and humans are accurate. However, they are insufficient, this is not a comment on the draft. The state of the science is really insufficient to make broad sweeping extrap lagses from animals to humans. The statements specifically regarding a reduced capacity to [ Indiscernible ] BPA in either animals or humans is accurate. However, this does not mean that the activity is nil. Especially in neo-Nates. There's likely to be some. If measured on a pap lags basis we would see considerable variability. Especially if we base that on our experience with [ Indiscernible ] P450. One aspect of the metabolism of BPA that was not addressed in the draft, which I think should relates to cul facial. -- sulfacion. It addresses the ice owe forms that are capable of metabolizing BPA, or forming the sulfate congregate. There are several pub lagses -- publications from three groups that address the on tongny -- ontogeny in the fetal liver. The elimination in neo-Nates, human neo-Nates is likely to be slower than it is in infants, older infants and children. That clearance will be [ Indiscernible ] of cul facial and [ Indiscernible ]. Would we know about other compounds that are substraights [ Speaker/Audio Faint or Unclear ] the example I used was aseat minute fin we would find clearance is likely reduced relative to older age groups in the neonatal population. There are aspects of the metabolism that relate to the cul facial that are not addressed. It's an important pathway for some of the substances that are relevant to the toxicologies we've been discussing. And areas for future research would want to look at the interaction with the parent compound and the sulfate congregate. Anything else?

That's excellent. One more question, I think one of the pragmatic questions is whether the study is using [ Indiscernible ] and nonoral routes should be included. I think the question, do you think the first [ Indiscernible ] affect is in fact less likely to be less and therefore those [ Indiscernible ] pump studies are reason to be included for consideration?

When one compares the disappearance of the BPA parent compound in neonatal animals between when the drug is administered subcue versus by the oral route, certainly there is not a statically significant difference in the area under the curve. Implying that the parent compound is the same. From that perspective one could argue that systemic exposure is very similar between the two routes of administration. I believe that is accurately portrayed in the draft. Personally, this is more sort of gut feeling than actually objective in nature. The only reservation I have is related to the distribution to where the drug is going. And in terms of accuracy of the draft report, yes, it's accurate. My reservation is wanting to know a little bit more about where the drug, once it ace dy peers from the compartment where it's sampled, where does it go? If that can be documented, that the distribution and/or began concentrations are the same, I would say yes.

Thank you very much. Hope you have safe travels.

Now we're going to go to Dr. Sharp.

Okay. Thank you. I want to begingy congratulations -- begin by congratulating the brief committee members for their efforts in putting together the reports. I say that because to take such a complex area, such a huge amount of contrasting data and distill something meaningful out of it is an immense achievement. Although we sat around the table and were per received to -- perceived to criticize it it's something we can all get our teeth into. That's a comment that I want to place on public record, as it were. I've got two suggestions to add to the NTP brief. But before I get to that, I want to make some general remarks. It applies to all of the low dose reproductive studies. They're general comments. Their simply scientific common sense. I hope that all of you will say that's obvious. Because of the complexity of this area, I think it's actually worth, again, putting on record. Reminding ourselves that we have to apply, as always, is scientific common sense. Over all I'm in favor of the brief and the stance and the tone that it uses. I'm not in favor of increasing the level of concern. I might be happy to keep it as it it is.So I want to begin which saying what are the three bits of areas that have made me take that stance.

The first is one of the fundmentals of science, that's the importance of reproducibility. If a find something not robustly reproducible, that applies to some if not all of the low dose studies, then there's got to be doubts about its usefulness and validity. And what you can't do, as has been done by some individuals is to dismiss results that do not agree on the basis of various suggested explanations, which are themselves presumptions, that's not science and it's certainly not good science. And more important is to base important decisions on something like that is pure folly. I thought about what word to use, I think it is folly.

The second aspect that has colored by thinking is looking at it from a completely different point of view. That's the importance of using all of the data to arrive at a conclusion. We've heard a built about the route of exposure and whether or not you should include particular studies or exclude them. Although I understand the scientific logic that you might apply to those -- it is again based largely on presumption. It may have a logic to it. But until we have the scientific facts I think it is not good science to dismiss that out of hand and say we shouldn't consider them. We may apply a different level of consideration to them, which is suggested. But I think that what we need is to take the studies and to actually find out whether or not the suggestion that they do lead to higher levels of freebie bee at target organ level is true.

The last thing is further repetitions of the low dose studies. Again, I am not in favor of them. I think it would serve no purpose. They're not going to explain the disparate that we already have in front of us. At least if they're simply repetitions. They've got to bring something new to the table. They've got to include production to adult disease. That is something touched upon. And/or to include measurements of free Bisphenol A. I don't see how they're going to make the old studies go away.

That's some of the thinking behind my stance. What needs to be changed in my opinion? Or added to the NTP brief? I was thinking about how we get around trying to consolidate or arrive at conclusions in this area. I think that it's already been mentioned. Human exposure, or at least comparison of human exposure with the low dose situations is the key. Then we probably don't need to consider for the moment the difficulties in reproducing the low dose studies in animals. If we could show that humans are never exposed to freebie bee in -- free BPA then I think we've solved the problem.

Now, that may be naive thinking. There's some evidence that could be the case. If the majority of BPA that is measured in the human in most situations is not free bee but in is conjugated. I'm not an expert in that. Based on some of the measurements then you could conclude that might be the case in most situations. I think to me is the absolute priority, is to know what the levels of free BPA are in humans, in the situations that we have most concern about, that's in pregnancy and the levels in infants, particularly in the first few moments or birth.We have to compare with it levels of free BPA in the low dose rodent studies where effects are found. And I think the only way to effectively do that where we get everybody on the same train is to actually involve those who consider themselves most expert at doing these studies. Why not involve those in collecting the samples we then make the measurements in using the experts at CDC and taking account and be careful and designing a way any possibility of tax -- contamination. That's something that needs to be emphasized. Also we need to emphasize that is not mentioned in the NTP brief. That's the levels of BPA, not free BPA, in amniotic fluid.The take on those studies is that the levels of total BPA are surprisingly low.

If the majority of that is not free, then I think maybe the issue, the questions that we're addressing will start to go away. Maybe, maybe things don't turn out to be quite that simple.

Okay. The last issue, which I think is a bit of common sense that was there when the low dose studies first emerged, it was one that concerned me the time, I'm surprised it's disappeared from the agenda. It's not mentioned in the brief, I think it's absolutely essential that it's added in. Although it's nothing to do with scientific fact per se or the different studies, the issue of biological ploughsability. -- ploughsability. -- plausibility. The effects that we're interested in the reproductive system, advancement of puberty, the mammary gland oin the prostate are all classic estrogen inducible effects. For certain I know that the prostate lesions you can't induce in estradiol factors am I'm not sure about the mammary gland affects. I would have always thought that was it's affect. I am surprised I can only final one study with BPA with mice that didn't do anything.

When you compare the potency of BPA versus [ Indiscernible ] and [ Indiscernible ] and [ Indiscernible ] cells or in vivo of mice and rats there's broad agreement that BPA comes out 1000 times less potent. Therefore there's an inherent prohibittability about what you should find. That's not what you do find. And that's the bit that I can't understand. Now, the response I know will be it's because you don't have a [ Indiscernible ] dose response. You have a U-shaped curve. Okay. Fine. Well, then estradiol should do the same. If it doesn't, why not? If they're both working through receptor alpha there must be something else, another mechanism. I've not seen anything that says what that mechanism would be. And therefore I think it remains implausible. Maybe there's another mechanism. I guess what people will then turn to are the alternative ways in way BPA might work. There's this quite nice study on pancreatic cells.What those studies suggest that the BPA is working through membrane receptors and it's affecting calcium receptors. That's fine. Estradiol is doing the same. In this instance there's a ten fold difference. BPA ten fold less potent. BPA has Uh shaped response curve, so does estradiol. There's no evidence that the effects on the reproductive system work through that.

Again, it's biologicalically implausible. I think it's asking a bit much to say that something that estradiol induce and BPA induce there's one mechanism for BPA and another for these other compounds.

So, that sort of imploughsability needs to be added into the brief. It's a hurdle that you have to get over if we're to actually make sense of this area and make sense of the decisions. Because when I add that imploughsability to the lack of reproducibility I can't see how you can then start making decisions based on the low dose studies regarding safeguarding human health. I think it's folly times folly.

Can I have a comment?

Dr. Sharp are you complete?

As you know, the issue about nonMonday tonic dose response a large part of BPA. One of the reasons it's not addressed is for the enpoints we focus on we didn't have enough information. For behavior, given it's not assessed at a very broad range of doses we don't know if it's Monday tonic or not. With the mammary gland it wasn't collected. We don't know. We just don't have the dose response span to say something about monotonic or not. That's why it's not in the brief. We weren't dealing with the enpoints that presented a nonmonotonnic dose response. It's an issue for BPA. That was one of the limitations of the data. They were low dose only study. They didn't include the high dose --

I think Dr. John Bucher has a comment. Then Dr. Hammond.

I recognize that perhaps this part of the brief could be beeped up a little -- beefed up a little bit. I think though the whole evaluation of the EPA and the development of the brief has had as a basis the issue that you are bringing up. The ploughsability of these affects happening through estrogen mediated actions given the weak estrogenic activity of BPA. The uncertainties and the level of concern are include influenced from the beginning through this expert panel process. But we do need to articulate those in a way that make it is clearer as to how that has played into the decisions, I believe.

Dr. Hammond?

I agree that the exposure issues are important in trying to interpret the data here. Of course we have imperfect data. What I find striking is on several of the issues that Dr. Sharp brought up we do have some data. And the data we have are somewhat disturbing.We have what it is. The data do indicate higher levels of free BPA in pregnant women. We're seeing high -- not high, levels that are comparable to effects in row dens in breast milk.We have a great need to see the levels in children under 6 in the U.S. That's a high research area. We're talking about very vulnerable people. Where we have the very best data among the U.S. citizens is from the NHANES data. We see a doubling in the BPA levels over the last decade, at the 95% tile more than a tripling. We're seeing an increase in these levels.

I wanted to follow up on that. We do have to keep in mind with the NHANES data it may not be adequately represent certain subpopulations, particularly people with disease with liver disease or gut diseases. Those populations are homentsize -- hospitalized when they're exposed to plastic. We have to put it into the context it's likely to miss a significant portion of the population. The population that I work with in neonatal intensive care is vulnerable. Their exposure would be greater. I wanted to make those comments.

Someone else around the table?

I would like to make another comment. That is, um, that we have been focused, I think, on the estrogenic effects. One thing to consider is these intracellular pathways communicate. You have also within that context to consider the cell context itself. So whereas you may have an active pathway in one tissue type you may have a modification of that pathway in another tissue type. You may have cross interactions. Not to mention the coactive atars that control the profile of genes that are expressed. I think this is another complexity that gets added into the equation of trying to sort this out.

Dr. Tapari?

I would agree with that. To me the impression is that talking about estrogenty of BPA is misleading. We should not look at the weak estrogen affects. Because that has blinded us from the other possible pathways. So even the use of just the estrogen as the positive control, although in some cases it's working fine, it's maybe misleading. All in all I think that the brief is very clear and maybe that's it's strength and weakness. It doesn't really present a complexity of some of the studies that it refers to. And it's not possible to, in a short brief, show the complexity of the studies. It's simple, but then it doesn't come clear to the readers that many of the really big weakens of the -- weaknesses of the study that are used there. Still as I said before I agree with the conclusions for all but that for the puberty conclusion.

Other comments before we start moving to --

One comment. It's worth pointing out. I'm really impressed looking at tables 1 and 2 that the, you know, table 1 you have these broad ranges of exposure and I note the huge difference between the breast fed versus the formula fed. Then if you look at table 2, the estimated intake is in order of magnitude more lower than the estimated. So there's something going on there. I want to call attention, maybe this is consideration is page 4. Children may be higher. We all know, I've done this an NF3. Kids put everything in their mouths. If the breast feeding versus the formula fed bears out by actual exposure levels that would be compelling. We need to get some real exposure data. That will draw us into the next swamp. I'm concerned that people will then start doing epidemiology studies. There's volumes, libraries full of literature that breast fed kids have lower risk of cancer, diabetes, higher IQ, kids with formula have higher risks of disease, on and on and on. I'm worried that somebody will say -- see it's that BPA. Some of these studies go back decades to glass bottles. I think this is a burning need. That's a huge gap in our knowledge. To fill in the missing pieces and see what the story really is about there.

Dr. Hammond?

I concur with all of that with exception of one thing.

Can I make a point? In reference to the breast fed estimates? Just keep in mind that's based on one route of exposure. The other looks at bottles, epoxy, cans that contain powder formula. I'm not sure how big the difference is. It's important to know that's one route of exposure in those kids.

If there's no discussion I think we'll move ahead to taking action. The way we'll do this is to approach it one at a time. I believe the conclusions will be up on the screen for us.

Here's the pier review charge..The first conclusion that we will be voting on is the NTP concurs with the panel there's concern that it causes reproductive effects. It provides some [ Indiscernible ] on reproduction animals exposed as adults [ Speaker/Audio Faint or Unclear ]. I will give you another minute or so to think through that one before I ask for a motion.

Just to clarify, you will be voting on the bolded sections. Not necessarily on these, the explaintory paragraph.

I guess the -- it's just a concern or a thought. When we say causes reproductive effects. Based on the studies that included we've looked overt changes. We know they're not there. We don't know past that. When you get into more subtle effects such as the ability to learn -- it become as very broad statement. My only question, perhaps within the context it should be defined what was looked at. That's just a thought.

Maybe we should -- there are four of these slides. It would be worth while showing you all four before we vote on any one of them. The first one is on negligible concern. The second one is negligible concern with regard to pregnant women. Some of the things you were talking may apply to this one. The next one is minimal concern about occupational settings. And the final one will be the one concerning the some concern for low dose effects that we have spent most the day discussing. Just to show you ahead of time.

They are moving up in terms of the level of concern. The negligible ones are coming first. We thought we would try to get the motions individual used. We go back to the first one. You notice this is on BPA exposure causing reproductive effects in nonoccupationly exposed adults.

I have an overarching question. It seems to me all of these statements resuppose some level of human exposure. It's not stated. It's just assumed. It might be clearer if we make a statement as to what kind of exposures we're talking about. Something that says exactly what context we're taking this statement about.

Yeah. That's probably a good thing to add. With regard to the CERHR process all of the information we've given about what is known about current human exposures. The tables that you just looked at what we're saying are our best estimates of current human exposures. Tables 1 and 2 in the brief.

My point following up on Kenny's would be that maybe the first statement is based on all of the data we're provided there is greater than 90% or whatever the figure was, exposure in the human population to Bisphenol A. Assetting the -- as setting the initial statement. If we follow the paradigm in the report, is there human exposure? What is the aggregate of data that supports the conclusion? We are agreeing there is significant human population. We're agreeing there's human exposure. Should that be the first comment?

Do we need to vote on that?

The conclusions are based on data on current human exposure.

All right.

Dr. Hammond?

Along that line. Again, there's the point that because of the half life of Bisphenol A and the NHANES data tell us that we have ubiquitous exposure and frequent, almost continuous exposure, those are two parts. Secondly, we know that exposure is increasing. Now, the other question is how it relates to the experimental data. I think it's in the same ballpark as the low dose data. So --

I don't think -- I don't think that's a motion. Whether or not there needs to be an insertion here. I think we can handle that.

I see it as a framing --

Dr. Shelby?

It's implicit in all of these statements we're taken into account the exposure information presented earlier in the brief. When the levels differ, they may drive the level of concern that we reach on these. The level of exposure of subpopulations, as well as the life stages in which effects have been observed in laboratory animal studies. Those are two of the factors. It's built in. We can be more explicit about it.

I think we should return to the charge. To determine whether scientific information in the brief is correct, clearly stated and supports the conclusions. We're not asked to redraft, or redo things, particularly in terms of the format of what is presented. Dr. Howard?

[ Captioner Transition ].

Could I see a show of hands of all of thoses who voted in five area of the brief that is significant to support the conclusion.

BPA exposures cause effects in the adults.

If not, we have successfully completed them.

The next conclusion that we will be discussing is that the NTE is that the BFA for pregnant women is reduce birth weight or growth in their offspring. Is there further discussion on this conclusion? [No Response]

If not, could I have a motion?

I'll move that into the motion.

I'll second.

Is there a discussion of this motion?

Seeing no discussion, we will be moving forward to a vote.

All of those in favor that the evidence, that the BPA will be in fetal mortality, all those in favor, indicate by raising your hands.

Could I see a hand of anyone wanting to vote no, that the evidence is insufficient. Dr. Hambling, would you like to share your not thoughts.

It's not that I don't feel there is enough evidence, but I don't feel there is enough evidence to make the conclusion.

There is minimal concern for those at higher levels on the occupational settings.

Discussion about this conclusion?

Dr. Hamblin?

Some of the levels go as high as 100 micro grams per kilo grams per day per the tables. I think there are situations that we haven't examined. I feel uncertain -- when we say minimal concern, that is above members of the juriliable.

It is negligible within the chart. I would ask that there is further research in this document. There is a research needed for the exposures at this point in time.

I guess, I can agree with Dr. Hamblin, we haven't heard a lot about this. There is insufficient data to conclude the concern level, you know, for workers exposed in the occupational settings. This sounds as though we have found something, and I am not sure we have.

Dr. Kirkly, the way I understand is that there is a high/low dose that causes minimal effects. Would that be incorrect?

Perhaps the problem is the minimal concern is the low level of toxicity.

There is two factors. Number one, we know there is a potential for much higher exposures in the occupational settings. We have some evidence of it. The data is pretty limited, but it is pretty convincing that the occupational settings can expose the workers to the higher levels of general occupation. There is a change in the serum hormone levels and this is shown in the occupational studies. So with those two factors in mind, higher exposure levels, bio logical effects, but we feel that we can't say it is a negligible concern.

Dr. Hammond, I think as you identified there is a problem of what the word minimal means, because it is interpreted, meaning the minimalling effect. First of all, I feel the brief itself does not sufficiently discuss the occupational exposures, there is more in the other documents and I would encourage you to put more in that. And then you were saying that the in an occupational study, there is some evidence of reproductive hormonal effects. I this that is a -- think that that is a critical thing. It is only one study, but it is a study in humans. It is surprising that we don't take that above the minimal level. I think that is at a concerned level given that there is evidence.

Dr. Pooray. I would like to confirm that the one study is the lower finding of the FSA levels in the exposed man to the [ inaudible ] Both were in normal range.

Can I add one thing?

Certainly.

This is included for the laboratory animals, but this is focused on the exposures in the adulthood?

When you consider the higher effects in workers, there is a bigger existence in terms of what we have. It was supported by a study that was well-rereviewed by the other panel. I think overall, in general, it is more driven by the laboratory animals and the animals exposed in adulthood. With the hormone study there is an effect there Z but not an adverse effect.

Other comments on this?

Dr. Curvely. I would suggest that you reword that. It says in humans, instead of the adult exposures in animals or humans. We will change the text under the bold, but not the bold text. That is for clarification.

That is a true statement, the way it is worded there. So I don't really need to -- think that it needs to be modified. It's find for people to make suggestions for the modification, but for the non bolded text, we are not going to into discussion on the non bolded text because of the late hour and we have a long ways to go now.

I'm going to ask a for a motion.

Anybody else?

Could have I a motion, please?

Dr. Pena?

I motion that we except this conclusion.

Dr. Novak?

I second.

Thank you.

The motion in front for a vote is that the NTP is that there is minimal concerns for workers in the higher levels of occupational settings. The board believes that the scientific evidence informed of a brief for this conclusion.

A show of hands in favor of yes?

Dr. Kron, would you like to share your vote with us? Maybe I haven't done my homework properly, but I haven't had enough exposure on the information -- personal information to make a judgment based on what I know now.

All right.

Okay.

The next one that we are discussing is that there is concern for the neuroal effects of fetuses and children. Is there a discussion on this first conclusion? [No Response]

If not, I'll entertain a motion.

A motion on what?

I'm sorry --

[ Overlapping/Multiple Speakers ]

We are splitting the two bullets, so we are only going to discuss and vote on the first bullet we are going to restrict the -- I move the first bullet.

Okay.

We have a motion to agree that the scientific evidence is sufficient to some concern.

Second?

Second.

We have Dr. Novak seconding, and someone else, but I don't know who I did was.

Discussion on this motion?

Seeing no discussion, we will vote all of those in favor that we agree that there is some concern for the neuro and behavior effects as indicated by reason. Show by hands.

I believe that is a unanimous vote.

Anyone voting no?

Anyone sub staining?

Thank you very much.

The second procedure is the NTP also has some concern for the BPA exposure in these populations for the ma'am rise glands in a female. I don't disagree with the [ inaudible ] concern, but in the case of the mammory gland, as I said earlier, there is insufficient evidence there. This the a consideration of limited evidence. I would not support it with the Mammory gland.

I would not support the effect on puberty either.

Other discussion on this con institution.

It's just a suggestion that you may want to split those facts. I think what we are going to try to do is when I call for a motion we will see what comes to us for a vote. Is there more discussion on this item?

Keith [ INDISCERNIBLE ] , I am also concerned on the earlier age of -- earlier age of puberty, and the female falsehoods that you change your outcome measures from study to study.

Other discussions?

Motion?

Dr. Pena?

This is another comment and motion together.

Okay.

I haven't been convinced about any of these effects and I would like to say that there is an equivocal evidence for all. We will call this one for a vote and then we may have to go through each end point independently for a vote. Can I have a motion on this?

Dr. Hammond, comment?

I would like to move that NTP have concern for the BPA exposures in these situations based on the populations of the mammary glands and the details knowing that there is sufficient evidence on that. We will make a vote on all of the three end points.

Second?

The initial vote will be on all three end points together as moved by Dr. Ham Monday, assuming that we have a second. I will second for purposes of getting the vote.

Thank you.

Is there a discussion of this?

All right. We will move to a vote.

The motion in front of the board is that we believe that the scientific evidence is sufficient for the BPA exposure in these populations based on the mammory gland and the prostrate gland. Can I show a happeneds of those who vote yes to observe this conclusion?

Can I show a hands of all of those voting no?

And for purposes of completion, can I show of numbers?

All right.I think we are going to have to have a long list of everyone. I think we have [ inaudible ], right?

Maybe we need to do a role call on those voting no, or should we move forward on achieving another motion?

Which is faster?

I think by the regs, we need to go for another motion.

Can I have another motion before the board.

Dr. Kurfley. I think we should change it from some to minimal. So your motion is to go from some to minimal.

Correct.

Okay.

Can I have a second?

I'll second.

I'm sorry, I didn't see that, Dr. Sober?

He is the second.

Discussion on this motion pgh [No Response]

All right. We will go for a vote then. All of those who would agree that there is minimal concern, for the BPA exposure in these populations based on the effects in the prostrate gland and the mammory gland, can you indicate that you voting yes by raising your hand.

Those voting no?

And for purposes of completion as abstaining. It would appear that we are not able to pass a motion on all three points put together.

Ask for another motion?

Who said yes on that one?

Oh, okay. Thank you.

We are going to have to go back and form a motion on -- we can do two end points or one. Okay. Thank you. It would allow us to get to a conclusion, but if we allow it, we can put the two together again.

Can I have a motion?

I move that the board feels that there is sufficient documentation and that there is some concern for BPA and prostrate gland.

Second?

That was Dr. Hammond.

Second?

I'll second.

Is there a discussion on that motion?

If not, we will go for a vote. We are voting on the conclusion that there is sufficient scientific evidence for BPA exposure based on the effects in the prostrate gland. Can I see a show of hands agreeing?

Those voting no?

I'm going to quick check to see if we have anyone abstaining, anyone abtanning pgh [No Response]

So we have Dr. Kurfley and Dr. [ INDISCERNIBLE ] Explaining. The evidence is minimal in my estimation.

I think it is minimal in the prostrate gland because we don't really have information on progression in this scenario.

Okay.

Thank you.

On that motion, can we have another motion?

It's getting tougher.

[ Laughter ]

There is sufficient evidence for some concern, but the BPA exposure and the mammory gland.

Is there a second?

I'll second.

Dr. Novak, second.

Discussion on this motion?

So the vote will be that we agree that the scientific evidence is sufficient and there is some concern for the BPA exposure in these effects in the mammory gland. Can I see a show of hands that agree on that motion?

Now, I need a show of hands of all of those voting no.

And is there anyone abstaining on this vote?

Do I need another show of hands Barbara?

I thought it was a 5 and 7.

Yeah, it was 5.

Those are the show of hands who are voting for.

And all of those voting no.

[ Speaker/Audio Faint & Unclear ]

Okay.

We will go back to doing that.

The vote on this motion is 5 in favor and 7 opposed.

So we couldn't engage in all or no votes, so I could ask for another motion since this motion did not carry.

Dr. Kurfly, I make a motion that it be changed to minimal concern.

Is there a second?

Dr. Robert, I am not sure your Mike is on.

I will second that.

Okay.

The motion on the board is that we agree that the scientific evidence is sufficient and that there is minimal concern for BPA exposure in these populations based on the effects in the mammory glands.

Can I see a show of hands for all though agreeing with that motion?

Can I see a show of hands of all of those disagreeing with the motion?

Is there someone voting to abstain?

The motion will carry, and we will need to discuss with each individual who voted yes or to abstain.

Can I see, one more time, who are those that are voting?

And voting no.

Sorry for the interruption your conference --

Can we see the no one more time so Dr. Shane can get the no votes recorded.

There is one person who is abstaining. The motion carried and as a matter of procedure, we would need to ask each member either no or abstaining.

Dr. Crump.

Well, it depends on what you mean by -- I think it means on how people interrupt some. That's the only reason I can give for that.

Thank you.

Dr. Janzen.

Yes, I abstain, because I don't feel technically qualified.

I think there is insufficient evidence to make the conclusion.

Thank you.

Dr. [ INDISCERNIBLE ] , you voted no.

I don't think there is enough information to make that conclusion.

Dr. [ INDISCERNIBLE ]

Same conclusion, not enough evidence.

So we have finished with that motion, and we need one more motion from the board.

One last end point, puberty and females.

This is Dr. Robins. I would like to move that there is minimal concern for the BPA exposure Affecting the age of -- based on the increase of risk for puberty in females.

Can I see a show of happeneds for all of those voting yes?

Can I see a show of hands for all of those voting no?

All of those abstaining?

Thank you.

I'm waiting for our recorder to get the official numbers to make sure.

Do we need to do it one more time.

The no's again, please.

These are all of those who are voting no.

Okay.

Dr. [ INDISCERNIBLE ] , you voted yes, on that?

The vote on that motion is 8 in favor, 3 voted no, and 1 abstain.

Now we will go to those who voted no, or abtanned the comments.

I agree with Dr. [ INDISCERNIBLE ] 's end points on these studies, but I would tend to go with insufficient evidence rather than medical concern.

Dr. Janzen.

Save reason as last time. I don't feel qualified to make that decision.

Dr. Catley.

[ Speaker/Audio Faint & Unclear ]

Dr. Moraliz. I think there is no -- there is no evidence.

Can I see a show of no's again.

I believe that is our last action item for this afternoon do we have some final comments for this afternoon or some administrative announcements?

While Barbara is coming up with her final numbers, I want to tell you on behalf of the program, that we appreciate the truly extraordinary discussions that have gone on today.

I would like to express the gratitude to our sincere staff of what I can provide of a heroic effort, they all did an outstanding job on that. And finally to our very capable chair thank you for getting us through a difficult day of voting and leading us to the means of democracy.

Those needing a ride to the airport, just call me outside and we will make sure that you get to the airport. We will be meeting at 8:30 in the morning. Unfortunately, there is no breakfast, so you will need to eat breakfast before 8/30.

I want to express my sincere thanks to the board and the ad hoc reviewers who have agreed to travel and the reports and the expert panel reports. We are grateful to you more than what I can say. I would like to thank John Bucher in the toxicology program. We have had a hard time getting the expert panel report out and getting this report out, and we have received full support from the program office, and I don't think we could have done it without this report.

And lastly, Chris [ INDISCERNIBLE ] Who has mastered the massive literature in this substance, and to her I am greatful.

If there is no other business, we will stand adjourned.

(This meeting has adjourned).

[ Relay Event Concluded ]

Day 2

Event ID: 1024967
Event Started: 6/12/2008 8:19:03 AM ET

Could I ask everyone to take their seats.

I would like to call the meeting to order. Good morning, glad to see so much energy in the room after yesterday. We will again begin by introducing the individuals present, starting first with the individuals at the table and then going to around the room. A reminder to -- as you introduce yourself and give your affiliation, please make sure your microphone is turned on, and we'll start again with Dr. Howard.

Pall Howard.

My name is Max Cost I'm professor and Chairman of the environmental medicine and YU medical school.

I'm Ken FORTAY.

Good morning, Russ [ indiscernible ].

John [ indiscernible ] international.

Deep deep robins.

Mike [ indiscernible ].

Nancy Kirkly.

Barbara Shane.

Gail McCarver, Medical College of Wisconsin.

Keith soaper Merck research laboratories.

Tracy Button.

Greg [ indiscernible ].

[ Indiscernible ] NTP.

Stan NTP.

[ Indiscernible ].

Scott [ indiscernible ] NTP.

[ Indiscernible ] integrated laboratory systems.

Ray David, BSF Incorporated.

David Malarkey NTP.

[ Indiscernible ] NIEHS.

Rod [ indiscernible ] NTP.

Tom Goldsworthy ILS.

[ Indiscernible ] pitaPita.

[ Indiscernible ].

Thank you very much, we also have joining us by teleconference, Dr. BeckerHyde, are you there in.

Yes, I am here.

Thank you very much. We want to also particularly thank our ad hoc reviewers. We have some joining us today that were not here yesterday. We would really encourage your ad hoc reviewers to come in on any topic, however, you are not allowed to vote or mace a motion.

The meeting is being individual cast over the internet, a recording is also being made. So I would like to remind you to also turn your microphone on before speaking and identify yourself.

Do you have any announcements?

In your folder, those of you who were not here yesterday, there is an agenda, written comments, and copies of these comments, and a list of oral comments, and a form for you to fill out for your reimbursement. Please be sure you signed in. Please be sure to use the microphone and identify yourself when you make a comment. Please also turn off your micro phones when you have spoken. Apparently yesterday this was a problem. So please remember to turn off your microphones also. The draft reviews on the nominations of preliminary comments by the reviewers will not be included in the minutes. The board and ad hoc members must incorporate any comments they wish to be incorporated in to the minutes. If you have making a public comment and you haven't registered. Please register in the table outside. Now I'm going to read a conflict of interest statement. The Nebraskas of the NTP board serve has individual scientists and not as a representative of any organization. Each member is to exercise judgment prior to any meeting as to whether potential conflict of interest might exist relative to the topics for discussion by the board. Due to your occupational affiliation, professional activities, or financial interests of yourself, spouse, child, or general partner, should there be a potential coon flikt of interest, the member is to decline services reviewer for development topic of concept and not the participation or discussion on any action. To the best of my knowledge there are no conflicts of interest for today. Thank you.

Thank you, Dr. Shane. Dr. Booker has some opening comments.

Thank you, Gail. I would like to welcome everybody who was wasn't here yesterday, and welcome back those especially who were here yesterday, and actually came back today. There were several agenda items that were on the preliminary agenda that have been removed because of time limitations because of yesterday's lengthy discussions on DPA. But the discussions today I hope would engender the same kind of discussions we had yesterday on the BPA draft. We'll be dealing with the next set of NTP nominations to the program, to the testing program, and we'll be going through some of the proposed research projects, and I just want to remind you these are initial thoughts that the staff has put together concerning ways that we might address the research issues, and data needs and data gaps concerning these particular chemicals, and there is net at all set in stone at this point on these -- on these projects, and we are continuing to refine this activity with regard to how we can get the best information from the board and you can provide us with your comments in a -- in a -- the most constructive manner.

The second -- well, there are two other issues that are of particular importance, there will be a concept review for a particular contract, and also the report on the technical report subcommittee, but Paul foster will be introducing an activity that will be beginning with the board in conjunction with the board to come up with criteria for evaluating outcomes and reproductive developmental and immune know toxicity studies, which is an important issue for us, because we would like to begin to codify, if you will, the language that we used to report the findings from NTP reproductive developmental and immunotoks studies. Finally we're finish a w a report on the host susceptibility program, and this is a program we started in the last year. We created a branch -- the host susceptibility branch. It is one of two new branches, the other is a biomolecular screening, and that one was postponed until our next meeting in November. But I could encourage you to give us as -- as -- your thoughts on -- as how we development these new programs. This one dealing with understanding the role of genetics, and genetic susceptibility in responses to environmentally induced diseases.

So with that, I think I will -- oh, and I would like to introduce also, NIGEL Walker.

Thank you, Dr. Booker. We'll turn to the first agenda item, the NTP nominations and concepts. Is not an action item. Will be no votes taken. However, it is very important that the board give feedback, in particular the feedback on the clarity, validity of the rationale, the scope, the appropriateness of the proposed program, and what priorities should be given. We have five concepts and one nomination for review, each will be discussed separately. A reminder again that all comments must be made in public in order for them to be included in the consideration. We begin with Dr. Scott Masten, the Director of The office of chemical nominations and selections, and he's going to be introducing the process and the first topic.

Thank you, Gail. And good morning. For the next couple of hours, we're going to be talking about several new projects, new nominations for the NTP testing program, and I'm just here to give you a bit of an introduction before we jump right in to presentations on each of these individual projects.

I thought I would start with just a little bit of background. Where do these projects come from? How do we get things started in the NTP East testing program? All of our research programs are developed by NTP staff, either internally or in response to external nominations from other parties. In terms of overall, what is the universe we work from, and in considering things for potential studies in our testing program? Generally, fall in to two brood but overlapping categories, for the substance that have high concern of possible health hazard based on the extent of exposure. And those for which, tox logical gay ta gaps exist, and we feel additional studies would nayed extrapolating those effects to human health risks, either by extending the relationship or facilitating cross-species extrapolation.

So with that universe to work from, how do we actually select substances for study? We basically look at a set of four criteria, which should sound fairly familiar. We select substanced based on known or anticipated human exposure, production level, suspicion of toxicity based on structure or existing health affects data, and the public concern.

And we have multiple levels of review, including this review by the board to help us determine merit and priority for study.

So just to orient you where we are, this is a slide of the process for reviewing nominations, and potential projects in the testing program. We have nominations come from many parties, but primarily from other federal agencies, and from NIEHS and NTP staff received in to my office. We then go through a federal inter agency review step. Public comment on the nomination and the proposed projects. NTP staff develops the research concepts at this stage, and we have internal reviews to refine these. They also do out for public comment. We then come to the board as we are today in public meeting to review these nominations and draft a proposed research program. And after this, we'll make changes based on your recommendations and go through our NTP executive committee for the last step before we begin the process of designing studies.

So what is it which ear going to look at today? We have research programs for five substances and one additional nomination that's recommended for a fairly limited set of studies. And NTP staff have prepared draft research concepts for these five substances, and has Dr. Booker mentioned, is a proposed approach to address the outstanding tox logical data for each issue and not meant to be experimental design, sometimes may contain elements of design that are particularly important to consider early in the process. And these concept documents are brief. They outline key issues, data gaps, and hypotheses and/or specific aims that the program is intended to address. Listed here are the six substances we're going to be look at today in order of their presentation. So we have [ indiscernible ] and the industrial chemical which will be presented by Dr. Erwin, followed by the sunscreen element, and compounds relevant to oral exposures from drinking water and dietary supplements. And we have 4710, 113 die mean, which is another industrial chemical, which we are not recommending a very -- very much in the way of study here. I will present this nomination. We have a couple of projects for substances that have been previously evaluated by the program, but where there are still outstanding issues that we feel need to be addressed. melamine and sigh nearic acid, another food contaminant.

So in your notebooks you have the charge that we posed for you, what we're asking for you to do in terms of these nominations and concepts. The charge is quite simple, to determine whether sufficient justification is provided for the use of our testing program resources to carry out these proposed research projects as outlined in the draft research concept documents. So we're asking for your review and comments on these concepts in general, and specifically with respect to the charge questions, which are listed here. So individual reviewers that have been assigned have given these some thought in advance and prepared written comments for us, but we also ask that you address them here today. Please comment on the clarity and validity of the rationale for the proposed research program as outlined in the concept document. Please comment on the merit of the proposed research program relative to the goals of the NTP, the stated goals are listed there. Comment on the scope of the proposed program, and its appropriateness relative to the importance of the issue under study. Are we on the right track? Are there other studies we should be doing? Are there some that we're proposing that may not be as high priority as others. Finally, what priorities should NTP give to the proposed program, given your thoughts on the rationale merit and scope of the program.

How will beproceed for the next couple of hours. After this introduction, we'll jump in to presentation on the individual substances by the project leaders. We'll go through them one at a time. After the project leader's presentation, we'll have public comments for a couple of them. And we do have commenters here. Following that we'll ask for comments from the board, the assigned board and ad hoc reviewers responding to the charge followed by general board discussion. And that's all I have, and be happy to answer any questions about the process in general, or what we're going to do today.

Thank you very much. Our first comment?

Yeah, I have a question about the -- not the nomination process, but the -- now we have project NTP projects that are being addressed, and previously there was referred to as chemical nominations, and then now it's referred to as project. In addition -- in addition to the name changes, what else has happened in terms of how you address chemical nominations that may have changed, since they were previously just identified as chemical nominations?

Very little has actually changed other than, I think, really, the content and scope of what we're bringing forth for public review, both in the public comment, and here before the board, rather than simply looking at what the nomination is. We have developed a proposed way forward to address the nomination. That turns it in to a proposed project, thus the name change. It's really simply what has been developed to date, and what we're asking for review on.

Dr. Booker has a comment.

Mark, I guess the real purpose of this has not changed any. This is the -- I think the third meeting that we've brought actual proposed research projects to the committee to look at, and it's simply the first place and the first time that we have brought initial thoughts about how we might approach something to the -- to the public. In essence this is the public meeting, and in years past, all of our design steps have been sort of inter government design steps. So the primary purpose here is to allow for public access to the initial thoughts of our program. .

Thank you Dr. Booker. We'll now move to the first compound. This will be presented by Dr. Richard Erwin.

So this will be the concept review for 2, 2. This compound was nominated by the national cancer institute for a number of reasons. The current production is in excess of 1 million pounds, but this compound is not included in the HPV program. There is significant potential for occupational exposure. There is virtually in data available on this compound. And as you can see from the structure, there is certainly a potential for the formation, during the member tably. Of this compound. And so for those reasons it was nominationed. It is used as a catalyst in the manufacture of polyurethane foams and hot melt adhesives. During the production, the process is elevated temperature so there is an opportunity for a catalyst to escape. So that's one in which occupational exposure could occur. The other is the fact that there should be exposure to unreacted catalyst. Slap stock foam products, for instance with used in furniture and seat cushions.

Given the scenario there, the most probable routes of exposure, occupationally would be inhalation.

There is really very -- just no information on this compound. The most informative material I found were the material -- the material safety data sheets, and it's DMDEE is listed as a skin, eye, and respiratory irritant. It has a very low vap per pressure. It freezes at nigh must 280 and boils at 320. It is missable with water and has a PH of 10.4.

The key issue addressed in this proposal is to examine the absorption distribution, metabolism and elimination. Obviously, if it is a met tab light it could certainly suggest great efforts should be taken to limit the exposure. First conduct the ADME studies. Undoubtedly, we'll find other met tab lights also. The second specific same to examination the reactivity of this compound. We would look at the bacteria, and evaluate DNA reactivity in a million cells. We know it forms DNA addicts, and it's possible other met tab lights might also form the addicts, and look for DNA reactivity. These studies will give us -- they will address the major issue in the nomination and give us basically information to determine what additional studies we might want to do with this compound. This is a high-production volume chemical, and obviously with absolutely no information available, and obviously if it is a met tablight, all efforts must be made to min mine human exposure of this compound. Thank you.

Thank you, Dr. Erwin. Our first board discussant is Dr. William Jansen.

Thank you. I thought the research program was clear but not completely developed. Some prodetective software programs has showed species and six differentiation of toxicity. Other than the program seemed valid, and I think would address concerns raised by the NCI. I thought it was well aligned with the goals of the NTP, and evaluated a possible hazard that did not fit within the EPA's scope of testing. One question which arose was the question concerning the metabolic route, whether it could be produced by another metabolic root or would have to pass through to be shown as a met tab light. Other than that I thought the program should be assigned a moderate study.

Thank you. Our next discussant is Dr. Michael PINO.

I too think the structure activity relationships showing high productivity for car sen generic activity should be included in the document. Other than that, I thought the program as outlined was clear and valid, and I do think it has merit in regards to the entity's goals of providing information on proten shally hazardous substances. I think the plan to first look at the metabolism is appropriate, and also do the [ indiscernible ] and DNA reactivity studies in the first step before deciding on further studies to conduct. Aye would assign this a moderate high priority.

Thank you. Dr. Erwin, would you or anyone else from NTP like to clarify any comments?

Sure. We generally routinely look at both sexes of rodents, so that would be information that we would definitely obtain. We will do our best to monitor for the parent, and to the best of our ability, we'll try to determine whether that's formed. If that it is the only met tab light we would find that would suggest that, we would have to think hard about it, but I think your comments are completely appropriate, and I thank you.

We have no one registered for public comments, but if there is someone in the room that would like to make a comment, would you please indicate that?

What happens to either case [ indiscernible ] of concern, do you recommend cancer study -- I'm trying to think of how you use this data.

Basically initially -- generally when we get a nomination, usually there's not this kind of specificity, but there was a specific question that was asked, and then we'll have to decide at that point, with the information that we have, what additional studies we would want to do. It's sort of difficult to project at this point, because there's so little known about this compound.

Seems like there's only -- there's two real obvious outcomes right, you either get the compound or you don't. And then what happens, you make the decision to move forward, or wait for a nomination.

We would contact NCI, the nominate for, give then the results, that we do not find that it is a met tab light. We would give this information to NCI, find out if they had any more specific concerns about this compound, and since it is a high-production compound with certainly potential for human exposure, I would guess we might move forward with some other base click characterization, and possibly a two-year study, depending on how we could judge the risk, and what NCI's potential interests are there.

There was no one from the public indicating a comment, but there are many board members are w their hands up.

Just a very quick question. If I read it right, you are not including micro nucleus evaluation. Is there a technical reason behind that?

We usually do that as part of a prechronic study. At least for this initial first pass, we hadn't thought about doing it.

Dr. PINO, did you have another comment?

This not only applies to this chemical, but some of the others. In terms of using the common assay, it looks like it is going to be done invitro. It's a biomarker for a human exposure that I think would be grateful helpful if you also did the comment in vivo.

That's essential we're set up to do the common in vivo, and would be doing that in this particular study.

Other questions or comments by the board? If not, we'll move on to our next compound. The next compound for discussion, the scientist from NTP who will be presenting is Dr. Michael WYDE.

Good morning. Can everybody hear me? Well, all it takes is a step outside in the last week or two year in North Carolina to realize summer is nipping at our heels, kids are out of school, pool is open, yard work to be done. Seems like everybody is outside. So although it's a year-long proposition, it is this time of year that everyone is thinking about sunscreens and protection from the dangers that everybody knows about from UB radiation. So this is probably a good time of year to be looking at this particular compound, which is a common active ingredient in sunscreens. If you were to look at the bottles of sunscreens, you probably won't see it listed as this particular name. It will be listed as its synonym. It is one of the most widely used ultraviolet filters for UVB radiation. It appears in other personal care products. In fact, it is a component in over 2300 personal care products that offer this type of protection.

EHMC serves as a protective barrier on the skin or in the strat up the corn up, and acting as a chemical absorb up. It protects against immunosuppression and the long-term exposure which would be skin cancer. This was nominated by NCI for toxicological evaluation. And there's very limited data available for EHMC in the published literature. What is published demonstrates that there's -- there is perhaps a weak estrogenic effect and has been demonstrated some reproductive effects. We know it's not a skin irritant, itself not a photo sensitizer. It doesn't appear to be immunogeneric, has a high oral 50 in mice. The human data is primarily limited to transdermal studies. This is consistent with the animal studies that show less than 3% absorbed. There have been a couple of studies looking at the effects on thyroid hormones, and these have been inconsistent as well. One study shows there was a recrease in sir rum T4 levels, but the TSH levels were shown at the low dose not the high lows. Another study showed a decrease in T4, T3, and TSH. There is a two-generation reproduction study published in the literature. The authors conclude there is no influence on sexual landmarks of the pups, and the fertility and development toxicity was 450 nano grams per kilogram. They cited the slight increase in F0 and F1 generations were what -- at the 1,000, which was the highest dose they tested, was why they selected the 450 as their noel. I have looked at these studies inside and out, and tend to disagree with the interpretations and corn collusions drawn from this study. In fact, if you look at this study, they show a statistive insignificant effects in both the F2 and F1 generations. And show a reduced number of implantation sites, but this was cock doerdant with reduced litter size. Delayed vaginal opening, which contradicts the lack of sexual landmarks in the pups. Was an increased number of still borne pub pups, and reduced viability index, and reduced pup weight gain. A lot of these effects were consistent between the first and second generations, and some occurs at lower doses in the second generation than in the first generation. Additionally, like I said at these lower doses they have shown to be statistically significant effects that these were observed at what they stated as the noel, which was the 450 milligrams per kilogram. As I mentioned earlier, there has been some indication that EHMC is estrogenic. In some studies it showed to stimulation F7 cells, positive in an in vitro transactivation assay. However, it has not been demonstrated to bind with the estrogen reception. In yut row tropic assay there were two published studies where there has been positive results increased inuterine rate, and pathological effects as well, in the unpin lished study they showed this was negative. There has been shown estrogenic activity as well. And there have been showns effects on cholesterol, HDL, and HDL. Two questions kind of pop to mind. The first is does it indicate potential car sen Guinnessty? Two were shown to be carcinogenic. It raises the question, at least. Second question is does member labially. Result in the formation of twoethal heckal or acid? They have both been demonstrated to be developmental tox can'ts. The research program we have proposed is to look at the studies toe valuate the differential distribution and member taply. Between the two routes of exposure and look at the metabolic profile to see if those two met tab lights are formed. And we would move on with oral or dermal subacute, subchronic, and chronic studies in rats and mice to characterize the Tex sisty. We would look at specific end points, determination of male and female sex hormones to see if we could further clarify these issues. We would determine the products, and produce to perform a robust multi-generational study in the rat incorporate more sensitive end points.

The use is widespread and chronic. I mentioned earlier, everybody thinks about it at this time of year, but sun exposure is a known proposition. Given the known dangers of UV radiation, people apply this throughout their lifetime and throughout the year. This is an mention of sensitivity of the children. There is issue of whether or not the strat up the corn up would be as protective in children as in adults. And children may have a less developed elimination cap as aty. Inyut row exposures may occur, and the study design should, perhaps take this in to account. As I mentioned studies have repeatedly demonstrated endocrine-related effects. Some of these effects have been debated, but believe that these warrant further investigation. And lastly, the day that we would generate from these studies would increase the scientific base on which the regulatory agencies would interpret toxic effect events associated with this compound.

Thank you. Dr. Perkily is our first board discussant.

Thank you for that information. So I found this one a little bit difficult to evaluation. The rationale is certainly there in terms of potential issues, but it's not really linearly developed. It's kind of the circular arguments. And I guess that's because there's not a lot of data available, but it's from oral exposure, there's conflicting results, and the concern is what might happen after dermal exposure.

So I felt that the proposed studies on comparing dermal and oral tox Ico Ken neckic was important for developing the studies in rats and mice that would be proposed. I think -- I think -- it kind of gets to Chris's comment about finding out what is happening before we go in to these multi-General studies with a lot of irnt end points. It would be important to know how much is absorbed, if there is an age effect, and if there's a different distribution following dermal versus oral exposure.

I -- you know, I guess my same questions are, you say you in favor of all of these testing, if you see data that supports that? I guess we do. In a way it would be nice if you could come back to the board with the specific testing after you know distribution, dermal absorption, if there's an issue. I had a -- a question about NCI being the dominator about this, and was wondering, why the proposed studies were so heavily focused on the endocrine end point over cancer end point, for example. So maybe you could -- I realize some of the preliminary data is more endocrine oriented, but --you know, I just kind of the beyond the animal testing and what would we -- how would this day tame pact the use of the chemical, for example, if you have weakest troe generic effects. I hate to see a whole lot of multi-GEN testing until we know more about exposure parameters. Thank you.

Thank you. I think before we give you a chance to respond to that. We'll ask Dr. Bucklehide for his comments.

Good morning, everyone. What I would like to do, is I have a page of comments I prepared. I would like to read those, and hopefully develop some discussion. I think a compelling argument is made for initialling an extensive study of EHMC based on wide-spread use, life-long exposure, and the potential for endocrine disruption. An increase of absorption in children, and decreased metabolic capacity, and the possibility of information on the potential for in yut row exposure. The background material provided is out of date, and fails to consider several additional potentially important issues, including potential effect of various nano particle formulations in sunscreen on absoap shun and potential [ indiscernible ] of EHMC, and also photo degradation. I think this is a particularly important issue when looking at the particular studies in terms of roar oral and dermal exposure. It may be quite important to have also a combined UV exposure taking place at the time of that experiment because of alterations in the form of EHMC.

There are also -- may be potential differences in absorption in susceptible subpopulations that have various skin diseases, including common skin diseases such as exsa ma. I think it may be important to raise that question. The background material consists of two documents. And I did a quick search and found dozens of publications that have appeared since that time that have looked at stability and toxicity of the agency, and I think that information ought to be incorporated in to the board's evaluation. Major focus of the NTP concept brief is look at Texaco Ken etics, comparing the dermal and oral roots. And I think this focus is warranted and acknowledges the difficulties of designing a robust study that covers a large dose range, but I think this is actually really an important issue in terms of metabolism by different roots, and perhaps other roots of exposure might be considered that would potentially better stimulate dermal exposure like subcutaneous roots, as further thinking takes place on this project. The proposal can conduct a multi-generalal study, I think warranted.

The issue of nano particle, photo products, and susceptible subpopulations, I think need to be flushed out more in the concept development. Nano particles may either inhibit absorption or enhance absorption, and I think we're still at a very new stage in that knowledge base, but we ought to see what is throughout in terms of knowledge. The photo summarization could really substantially alter the chemical nature EHMC, and some of the new publications I was looking at suggested this may be rather expense. And it may also then indicate that an alternative exposure strategy is needed that combines a root plus a dermal with UV exposure simultaneously. Finally, the extent to which compromised skin may enhance absorption, I think may be an important consideration.

Now the concept brief wrasz the issue of potential metabolism of EHMC to the known developmental tox can'ts. I think further discussion of this issue is warranted in the development of this idea, including the description of the effect levels of these -- possible met tab lights, and pose a hazard. I raise this question, because my sense is that these potential met tab lights are developmental tox can'ts at rather high levels, and it would be interesting to run through some of the calculations of what is needed to generate a sufficient load of the met lab tights that produce an effect. In summary the ubiquitous exposure of EHMC is a concern. However, an updating of the literature search, and consideration of several issues, particularly root and photo dependent summarization and degradation may critically influence design, and I think further thought and work on developing this proposal may be helpful, and I gave this a moderate priority.

Thank you. I know there are members of the board that may like to make comments, but I think we would like to give the staff a chance to respond back. Dr. WYDE, would you like to respond?

Sure. Is this on? With respect to the comments with the TK ADME studies, I don't think it was laid out as such, but as we move towards the design phase of these studies, I think we're in agreement that we would take a tiered approach to look at some of those effects. Whether or not we move forward with oral order mall studies would be dependent on the TK data that we get. Obviously the two-generation study would have to be done as an oral study not a dermal study for design limitations. But we do plan on moving forward in a tiered approach, not to just in to all of these studies simultaneously. With respect to the outdated background, every time any one of our scientists get these compounds we do an exhaustive search of the new literature as well. Everything in the literature up to the sending out of these drafts has been incorporated in to the concepts. So we have looked at some of these issues with the new formulations, nano capsules and nano formulations, and there is emerging information about these formulations and the effects of penetration. There's some new information on the nano capsules actually increasing the amount of time that the chemical has contacted with the skin, so these -- these things obviously will be looked at as we move in to design phase to see if nano emulsions or nano capsules should be used. Most of the studies up to this point have been simple oil water -- or oil emulsions. So we have considered these issues. The issue with the subcutaneous route was an interesting one, but I think if we move on to two-year studies this would be for exposures for two years. That's about it.

Thank you, doctor. We'll now move to public comments. The first public comment is Dr. Raid Monday David from BASF. Dr. David?

Thank you. I'm hoping my slides made it here. I wanted to talk for a few minutes also -- hoping that --

Let's hold just for a second. And we'll get your slides, if we have them.

Okay.

Once you get started -- procedurally, I need to remind you will have seven minutes, but the clock doesn't start until you do.

I do appreciate that. Thank you. Here we go.

All right. I'm Ray David from BASF corporation, we are a manufacturer of what I'll call OMC, that's what it is called in the market. I'm here actually to make comment that perhaps this particular material is not a very high property for testing by NTP. Next slide, please.

Here we go. The -- I think there was some discussion about the dermal penetration and the need for some long-term studies. According to [ indiscernible ] the dermal penetration through skin -- human skin is less than 1%. So it's fairly minimal. And with respect to the localization of the material, this is a sunscreen. It stays primarily in the strat up the corn up, and in fact the nano encapsulation increases the residence in the strat up the corn up, which is the whole idea of nano encapsulation. So if one looks at nano encapsulation perhaps this is not the best choice. There was discussion about doing a continuous breeding study that perhaps the two-GEN study that is already published may not have sufficient information on endocrine-related effects. Our company has done twos asies. Both of those were negative. And so from our perspective, at least in our hands the material does not appear to be an endocrine disrup for. We did a study of animal effects where animals were studied for 28 days. We didn't find anything that was biologically relevant. These animals were treated for up to four weeks with 900 milligrams per kilo gram. We didn't find any changes in ovary weights or theestrus cycle. We couldn't find any changes in the hormones. T3 and THS concentrations were not changed in this sir rum. T4 was slightly elevated. You see roughly 20% increase, that's statistically different, but without any other change in TSH, we were hard-pressed to figure out what exactly that meant, so we're not sure whether doing a continuous breeding study over a couple of generations is going to really provide any greater in-depth information, and whether or not it is warranted.

And for the cancer studies, I think have been comments made that the original proposal from NCI was a bit dated. Because they proposed high drol sis to [ indiscernible ] acid were concerns. In the meantime, 2 EH has been tested. It is a weak car sen gin. There is no indication of human health concerns. This material OMC has been tested in photo course Guinnessty studies, and in fact it delays the onset, which is what you would want from a UV absorber from a sunscreen. That's seems to contradict an earlier Gallagher study where they indicated in the skin painting that there were 1 or 2 animals that had pap low mas following 40 years of exposure. So just -- it's not clear whether this particular material is as good of candidate, or as high of priority for testing. And this material was also reviewed in the EU, and the only findings that they could come up with, some minor changes in sub chronic studies in clinical pathology, if Is logical professies associated with high dose levels but nothing really that would give an indication that this would be a long-term hazard, that it might produce long-term effects.

So from our perspective perhaps this isn't as high of priority as it might be. Thank you.

Thank you, Dr. David. Our next commenter is Dr. Joseph PELLA, speaking on behalf of Pita.

Thank you, again, for the opportunity to comment on the nomination of EHMC testing program. PETA's comments were prepared by our scientific consultant Dr. Nancy Douglas. [ Indiscernible ] research concept includes objection toco Ken etic studies, acute sub chronic and chronic [ indiscernible ] including inyut row exposure, depending on the results of the TK study, and the toxicity study in rats using an increased number of pups. These studies could consume thousands of animals live.

Echoing Dr. BibmentHyde's comments, the ris dup shun appears to be better studies than indicated in the document or research concept. Our research also yielded a number of relevant studies, some published after the supportive document that were not mentioned. We would like to stress our concern that the board conduct a thorough review of all existing data, or needs to conduct a fair review if it's going to make an informed decision regarding the needs of the studies proposed.

We would also know the NTP proposes dermal and oral studies even though human exposure is expected to be exclusively dermal. The only rationale given to [ indiscernible ] done by oral exposure. Dr. Wived noted his disagreement with the interpretation, but a recent study using oral exposure recorded no adverse effects on a wide-range of reproductive parameters. General toxicity, however, liver, effects, and stomach erosion did interfere with the effects on implantation rate and onset of puberty. Additional oral studies are unlikely to provide useful information for the assessment, but would at least double the number of animals used.

Although the potential toxicity of EHMC is especially well suited to investigation by approaches, these also do not appear to have been considered. EHMC's history and wide-spread use prevent the [ indiscernible ] likely end points for evaluation, such as changes in hormone levels and incident of melanoma and other skin cancers have already been identified. Also several large-scale international studies have already begun to assess the health effect of sunscreens that include EHMC. Researchers in the field who investigated the effects, have emphasized the need for ep determine logical studies.

Additionally proposed animal tests do not differ significantly from previous studies, as [ indiscernible ] address the ambiguities and existing data that prompted this nomination. These studies include the 2005 study by Schneider that was mentioned earlier, as well as recent studies.

Along where ep deem logical approaches, [ indiscernible ] appear to have been considered. Several standard tests have been optimized for assessing topically applied UV filters. These methods include photo toxicity assays, photo muns anity [ indiscernible ] and cell cycle and [ indiscernible ] gene expression assays. Conducting testing on the proposed scale in both rats and mice without consideration for relevant inveto and ep deem logical principals is not good science.

In summary it will no provide additional research data. Additional approaches do not appear to have been considered. We urge the NTP to rethink the extensive animal tests proposed. Thank you.

Thank you. And thank you for your presence today and your interest. I think I'll open it now for board question discussions.

This is a comment and kind of question for Dr. David. I assume there were GOP studies conducted, would BASF be willing to turn the copies of those studies over to the NTP to see if additional tests in fact were necessary?

Yes, please go to the microphone. While he's coming. This is again, Dr. Raymond David.

BASF did conduct the studies actually in its own laboratory which is a GOP facility. And we have -- we have offered the studies to any regulatory agency that would like to have them for risk assessment purposes. The question becomes whether or not we can provide them to the NTP. I'm sure you are aware that under the rules of reach, the -- the availability of documents publicly available may -- is an issue that has not net been resolved with respect to each legislation. So we would certainly provide robust sum roifs the reports, question do that. But the reports themselves, I'm not sure we would be prepared to provide unless they could be maintained confidential.

Thank you for that response. Other comments? Doctor?

Just a few comments on the whole issue of -- well, two things. One is the formulation type issues that -- before you really go in to a long-termed a-me kind of study, you really need to do some invitro assessments of what is going on, because you could essentially be assessing foreign lace versus what the compound is. Most of these encapsulated -- are designed to increase the time and not penetration. The second thing is -- I agree completely with the comments made about the UV, you know, that's a whole area that is is developing. I would be very cautious about the subcoup data, because that is completely abrogating the whole ability to selectively let certain things through. So I think there really needs to be homework done initially before designing these studies.

Dr. Howard?

As you might expect this falls under the regulatory purview of the U.S. Food and Drug Administration. And the FDA has evaluated this nomination, evaluated the background norm nation as well as the data available to the FDA regarding this come bound. I totally agree with the comments shared, especially about formulation, and the FDA really wants to work with NTP to consider this fact, because you can drive compounds in or out based on formulation. So we're definitely willing to help them out. But the bottom line is the FDA does -- well, let me make a comment, these are over the counter drugs. If a product continues EHMC, and claims it has a sunscreen, that's a medical claim so therefore an over the counter drug. It may be contained in some cosmetic products as Michael wide pointed out, but unless the contain the claim that it contains sunscreen it does not fall under the over the counter drug. The FDA concurs to look at the studies, look at distribution and the contract. We con fur on the photo composition, and I would like to make a comment to -- regarding the UV exposure. The previous studies that have been done, a lot of them are to look at the efficacy of the sunscreen ingredient. There are extreme statistical problems of trying to -- while dosing the animal with a very robust amount of ultra vie lot light. There are technical difficulties in being able to see an underlying mechanism. People up to about a year ago have not been exposed to nano particle. So we shouldn't discount the prior exposure, which is really what is manifesting itself these days. The FDA concurs on the data that s it is needed. However the dermal data is much more important. Yes, there will be oral exposure. If you ever watch kids, especially little boys, everything is oral, so there will be some exposure. But the dermal is more problematic. And we do concur with having a robust multi-GEN assay.

Thank you. I actually wanted to make one comment. I do have some concerns about this compound, and I want to make the board aware of thinking through this process about immaturity a little more. You may not think about this, but what we're currently seeing in our culture is young mothers are taking babies to the beech, and everyone is very aware that sun exposure increases cancer. And mothers are being vigilant in applying sunscreen to young children. Look at immature animals, and immaturity in the context of the vehicle, because what we know in studies from humans is that does dramatically increase the risk at an young age. By the same token as the skin ages, the other groups of individuals who have thin skin are the very elderly. Question foresee us coming back in the future to where we were yesterday, saying, yes, but what about the very young? So it's the approaches go forward and people think about this compound, I think that's one of the target age groups we have to give serious consideration to. Dr. Button, and then back to Dr. Howard.

I won't reiterate what other people have said, but I do want to just make a comment that I did have strong concerns about this program as it is present in the relevance of the data that will be achieved at the end based on animal studies and use of resources from the NTP. And I thought Nancy and other individuals as well -- I think that just basically in general, there needs to be a lot of work done before I think we should enter into a large-scale animal testing program. Because there are -- you know, even the questions about epidemiology, are there any studies that indicate that there is a problem with this substance or the met tab light? Are there any data, human data on the PK from this substance. This kind of information related back to information we might get from the animal. The oral versus dermal has been brought up already. So just -- it needs to be very carefully prepared before we launch in to a program.

Thank you Dr. Button. Dr. Howard?

Actually, can I address that comment?

I'm hearing a voice -- I'm like I'm hearing a voice, but I don't see anybody.

I wanted to address some of the issues with human data. There is human data available most of that is transdermal penetration. There are several studies, but those studies are very small sample sizes, and haven't looked very in-depth at distribution of the come pound, mostly just to see if the come spound in the urine and looking at transdermal pen station. We have looked at those studies and considered those as well.

Dr. Howard?

Thank you for making the comment regarding epidemiology, and that has been brought up before. I don't think epidemiology will ever give you sufficient information for one wherein. Sunscreens are efficacious in reducing skin cancer, but vitamin D is becoming more and more of an issue in skin maintenance. So you have a double-edged sword there. Sunscreens do reduce incidents or at least is thought to do that. And there is data to support that. But while you are reducing the skin cancer incidents by use of this material is going to be, I think probably statistically impossible to look at smaller incidents of increase in skin cancer. And that is the problem you have, in ep deem logical studies. You'll never see sunscreen used in the absence of light, which would be your appropriate control. Regarding skin integrity, to the best of my knowledge -- and I appreciate Ray David's comments, and will look at whether or not BASF can release the day to this the public domain -- I do not believe skin intremendousty enters in, unless a drug is used on a particular skin disease. This is not theish -- this is my interpretation of the FDA. I'm not sure it has ever been evaluated sunscreen penetration in diseased skin, because it's not part of the approval process for the intent of use of the drug. So that may be the case, and we do know that from -- from many studies that damaged skin does alter the kinetic profile of drugs entering the skin.

Thank you, Dr. Howard. Dr. Crow?

Ken Crow. I would echo Dr. Button's recommendation to go slow in pursuing this. I do think there -- we look at this kind of from one-sided, and how can animal data be used to answer the question. But I do think there's a lot of opportunity here for getting some skin penetration data in humans, and I do there think there's opportunity for ep deem logical information, and I know that the question has been asked, will we get the answer we need from human data. I know that's questionable. But it's also questionable that we get the answer we really want from a very extensive animal study. So I would just caution about jumping in to study of this magnitude.

Dr. [ Indiscernible ].

I think Mike just referred to the human studies there where they did studies of both standard emulsions, nano emulsions, and nano encapsulations. The ones in the 100 range are the ones that have increased penetration. So there are human studies that have been conducted back in 2005, 2006, that have already shown you can alter the profile. Theish dwlu is they are designed to increase the residence time in the skin, so I'm not sure, another human skin painen study is going to change your understanding that we actually get increased penetration with those. So I'm struggling with delaying or actually moving forward on understanding the PK waiting for another human study. We don't ignore [ indiscernible ] we're only one-sided, but we have considered that.

Thank you, Dr. Walker.

I just have a question. Since these skin -- sunscreens are considered regulated by the FDA, I'm sure the FDA must be getting a lot of animal data and submissions, as these drugs are coming on the market, especially for these new formulations. Is there any cross- -- I don't know, I'm sure there's confidentiality, but it seems like the FDA must have some kind of database of a lot of these issues that we're talking about that may already exist.

Well, I -- Ray David pointed it out, that is proprietary information. We cannot release that information. But let me read what I said, the FDA has nominated [ indiscernible ] does concur and support these studies that have been nominated.

So I think we kind of got that the second time around. Dr. Kirkly?

I don't know if it is a final comment or what? But recommend innocencing over yesterday, and I just see the same thing happening here, especially if the underlying concern is developmental or endocrine related or both, and that if we don't have a good handle on how much gets absorbed, what is in the blood, and how it is distributed before we embark on end point assessment of toxicology.

We have data, it's not -- no, there are -- there are some end points of concern. I can see that. But -- and there is exposure, but I think we have to have that objection toco Ken etic data tirs, and with that then you can design the appropriate toxicology studies.

Thank you. I think you are hearing big concurrence. Other comments around the table? Any comments from the audience? In not we'll move to our next compound. The next compound for discussion is van aid up. The scientists who will be presenting this is Dr. Michelle HOOTH. .

I'll be discussing the vanaidup discussion. The compounds were nominated by NIEHS and EPS for toxicology -- and a multi-generation reproductive objection tosity study. This was based on the potential for exposure to large population of humans as it is used as a dietary supplement, and the occurrence in drinking water. It is listed as a come tap nant list, needing more data to make a regulatory determination. There is lack of sufficient data to assess the human health risk from oral exposure. NTP did conduct a two-year inhalation study of a compound, and we did see lung tumors in male rats, and clear evidence in male and female mice. And also the board is very familiar with our studies on, and the difference [ indiscernible ] compounds based on the data. So this is similar to the compound.

These are the common forms of the tent are vail ent and pen ta va lent. I'll point out here that the sodium sodium -- [ indiscernible ] are more water soluble.

Most of the exposure occurs as occupational exposure through the inhalation rooted. Food is the major source of exposure for the general population. And most foods contain low concentrations. There are higher concentrations found in some feed products. I have listed the concentrations here, and there are also increased concentrations in some prepared foods. Estimated dietary intake for the U.S. population is in the 10s of micro grams per day, and then as I mentioned, there's additional potential exposure through contamination of drinking water. Concentrations up to 100 micro grams per liter have been recorded in tap water although the mean ublly is about 5.

You'll find that it is particular -- particularly on the internet will cure whatever also you. It does not have a defined biochemical base. It does interfere with phosphate-containing enzymes, [ indiscernible ] and there is evidence in -- [ indiscernible ] rats and chickens and get tos that there is a deficiency disease. It is a commentary dietary supplement. Uses doses up to 60 milligrams per day or about 18.6 milligrams per day. Frequently these supplements are also given in conjunction with chrome numb compounds. There is evidence for both forms of anti-diabetic effects. There is also evidence in humans that it increases glucose transport. And increasing metabolism. There are a number of studies in the literature look at anti-tumor activity. There is increased latency, decreased -- number of tumors decrease, size of tumor. I want to give background information. You'll find the chemistry is somewhat complicated. These are the most stable on a decision states. Favor reduction of, but there is some evidence of n though literature of oxidation, and this has been demonstrated in vie woe and in vitro. And in addition this form is able to [ indiscernible ] depending on conditions, [ indiscernible ] or some other polymerization product, and we were wondering about the inner conversion [ indiscernible ] for example to the [ indiscernible ] back and forth. And so you'll see it will become very important we have a good handle on the stability of these compounds before we proceed in any envooef woe study.

It's poorly absorbed by the GI track. And that's thought -- due to the compounds enter cells through active transport and [ indiscernible ] transport system. And once in the cell it is reduced -- and then the tent tra VALENT form is the predominant form. Based on the low absorption why would we be interested in a compound like this? And I'll bring us back to chrome up [ indiscernible ].

The compounds are distributed to multiple tissues. It is excreted relatively rapidly in a couple of days.

In terms of the gee nope toxicity, they generally do not [ indiscernible ] but there's a lot of evidence that both forms produce [ indiscernible ] there's some evidence about producing DNA damage, probably due to the formation of [ indiscernible ] species. The evidence for the [ indiscernible ] aberrations is really mixed. There's reports [ indiscernible ] for the compounds in the literature.

So the overall goal of this proposed research program is to investigate the potential for water-soluble [ indiscernible ] that the compounds are thought to be more toxic, but I'm not sure this hypothesis has been rigrusly tested. And again, a key issue is the selection and chemical characterization of appreciate compounds for study. Water soluble [ indiscernible ] compound is found widely in dietary supplements, and is also interest in being used for anti-diabetic effects, and then we'll need to consider selection for a [ indiscernible ] compound.

Prior to any animal studies, as I mentioned before, we are proposing to conduct invitro best toast evaluate the stability of the compounds. We need to determine if there's on a decision of the [ indiscernible ] in dosing solutions exposed to air, and also under the conditions in our laboratories to take in to account the water disinfection method and [ indiscernible ] potential from that method. And we would also like to identify and characterize the species that may be formed in vivo, and we will consider a variety of methods, but we would like to like at various reducing and oxidizing agents under different PH conditions to try to get some handle, for example, on what might occur as it is traveling through the GI track.

Based on the results of the in vitro studies done, we would hopefully have enough data to ap -- to select appropriate compounds, whether it be [ indiscernible ], and then we propose to conduct subchronic studies? Rats and mice, a [ indiscernible ] and then ultimately, we would consider moving on to chronic studies, and in this case, it would be really helpful if we could speesat it [ indiscernible ] and also [ indiscernible ] to try to tie that with potential [ indiscernible ] lesion.

There's evidence in the literature that suggests that additional end points should be considered in the design of these studies including TK clinical pathology and [ indiscernible ], so we're consider some of those other things when we actually get to the design in vooef woe studies. And some of our designs will incorporate these [ indiscernible ].

A day that need that was identified was also to conduct developmental and reproductive toxicity studies. There are limits of studies of the compounds, but those limited studies do suggest some toxicity decreased fertility and decreased survival rate [ indiscernible ] but most of these studies did not identify nor observe adverse effect level. Several studies have mat ternal or patternal toxicity. The day is insufficient to development [ indiscernible ] populations [ indiscernible ] children [ indiscernible ].

So in terms of the significance and expected outcome of these proposed studies, the available data is inadequate to evaluate the course generic potential, and is also inadequate to reevaluate the toxicity of these compounds. It is listed on the USEPA CCL as a come contaminant [ indiscernible ] population.

Thank you. Our first discussant is Dr. MoreSalas.

I generally agree. I think the rational is appropriate, significant exposure to human [ indiscernible ] water and dietary supplements suggests a need for better understanding. In addition the adverse effects seen in the now probably 20-year inhaled studies as well as questions by gee know toxicity suggest that some further study is warranted. I think it fits within the goalsover the NTP and is addressing [ indiscernible ] compound with significant human exposure.

On the prosed program I have several comments. Let me go through these here. I certainly agree we need upfront studies, very thorough studies on the stability and speesation. Given our past experience with chromium, with questions about whether the hex sa va lent versus other forms, which ones are people exposed to, it suggests that we have got to understand what we're doing on these things, and so we need thorough invitro and invooef woe testing. Really before we dmarj to a buy college call testing program. On the subchronic studies, including [ indiscernible ] and tissue distribution, I think are very important. My one comment is the proposal listed in the documents, said it would be listed by, quote, an appropriate route. I assume oral is the only route we are thinking about. I wasn't sure what they meant by that. The gee know toxicity literature is really interesting. To put it mildly, it is a mess. In my written comments I gave actual citations. But there's one review article that says, compounds are not [ indiscernible ] another review article says that they are mute toe generic and [ indiscernible ] the same lab of the author of the review article said it is not. Another paper said it produces clear increase increases -- [ Audio lost ]

Properly conducted GOP studies across the standard battery to kind of put this issue to rest one way or another. For developmental toxicity, I think the studies are important. I would add that I would also if you weren't planning to do it, look at VANADIUM in milk from lack tating dams is that is possible. Overall, I think the program is important, and given the human exposure risk, although I will say any absence of human effects, I would probably place this at moderate priority.

Thank you. Our next discuss sant Dr. Max costa.

Yeah, I agree with what Michelle said. I think the compounds are very different than the chromium compounds nch when you start with chromium 6 you reduce it to 3, and you can't go anywhere after that. It basically kills the intracellar pro teens in DNA, where has the [ indiscernible ] can cycle back and forth probably. So it's quite different. So I think both of them can be referred to as nutritional supplement, a lot of people call them essential nutrients. I really don't think chromium has a real function in the cell. It helps people who have diabetes because it seems to cross-link the glucose transporters, but VANADIUM, I don't think we really know anything about how it might be working as a new traditional supplement.

Now, with most of these other agents, they have been studied a lot in tissue culture. There's no champion for VANDIUM, nobody who has studies the mechanism. And if you look at what I learned about studying nickel and chromium, is that, you know, you have a lot of effects on signal transduction and a lot of epigenetic effects. The epigenetic effects are huge. I recommend tissue culture studies with these compounds to see whether they do produce gene nope toxic effect, yes, that might be. A lot of the metals are not, except for chromium. But a lot of these things have huge epigenetic effects. So if you can get some researcher to start looking at these effects in tissue culture, I think we'll learn a lot more about VANDIUM. The other problem in studies that you produce, sit very difficult because it is present in cells and media everywhere. It is difficult to tell what you started with and what you end up with. There are stable's sew toeps, and to start with plus 550, and plus 451, and add them you'll be able to use ICP mass speck and be able to tell where they are going, otherwise you'll get confused -- that's a really good way to do these experiments. You are doing them in sir up and biological fluids by I recommend you do them in tissue culture and if you can invitro. You will be able to track the changes much better.

So -- but in general, I think it's a very under studied come pound. The fact that people take it for all kinds of conditions, I think, you know, it needs to be studied much more, and I don't know why it has been ignored. It is used as a tos foe tase inhibitor. So in that sense, there are some things there, but I agree with the previous comment that there hasn't been a good review article, or a good understanding of this. I work on chromium and nickel and other things, but -- so it is very, very under studied. So let's see if I have anything else.

In general, I agree, I think Michelle did an excellent job in reviewing the problem, and the suggested things that she wants to do. I didn't see anything in tissue culture -- because metals are very similar in culture, they don't undergo this complicated metabolism, and basically VANIDATE is going to react and be reduced and oxidized maybe in some situations, so what you are going to see in tissue culture is very similar tar to what you might see in vivo.

Thank you. Dr. HOOTH do you have any comments you would like to make in response?

Sure. Thank you both for your comments. In terms of the appropriate root, I guess I meant the appropriate oral root. So whether that would be in feed or drinking water or depending on which compound we select, particularly if we pick the sulfate that might be more appropriate through feed than drinking water.

We will do some [ indiscernible ] assays on the [ indiscernible ] micro nucleus. I'm not sure our invitros a says will put the debate to rest, but I think the greatest contribution we could make is doing invooef woe toxicity and trying to lie that to lesions that might be seen in a two-year assay, and that's something we didn't have in though chromium study.

Thank you very much for additional methods for consideration, and we will definitely look at that and potential collaborations with our DIR investigators. I did have one question for you about the use of stable isotopes. I was wondering if that -- when you are thinking of those studies, are you thinking about looking at differences in uptake, or actually looking at inner conversion of the compounds?

Dr. Costa.

Sorry. When you give the stable isotope, you know what you are introducing in to the system. The problem is the background from all of the other VANADIUmushgz that is there or whatever. You introduce plus 4 and give it to the system, and you know it changed to plus 5 or you know it went to some other form, so you can always follow it. I think that's a really good way to do these metal studies.

Thank you.

After Dr. Howard, maybe we'll move to public comment, and then I'll open it up for the whole board again. Let's get Mr. MannaPellla's comments. Who is speaking on behalf of PETA.

Thank you, again. So to review, the research concept for these compounds, include [ indiscernible ] studies. Using both the tent ta and [ indiscernible ] chronic [ indiscernible ] using one or both compounds from the subchronic study. [ Indiscernible ] and reproductive and developmental studies also using one or both compounds. Again, these studies will consume thousands of animal's lives.

The weight of evidence clearly suggests that the toxicity is low through exposure. The expert group on the standards agency observed that there have been very few reported cases where exposure has been by roots other than inhalation. Adverse studies consisted of abdominal pain, nausea and weight loss. As we have heard [ indiscernible ] absorbed poorly. The background document cites human data showing absorption to be 1% or less.

Typical oral exposures are well below what might reasonably cause certain. 2001 on [ indiscernible ] this was based on a lowest-observed adverse effect level in rats at 7.7-milligram per kilogram per day and an uncertainty factor of 300. Although the NIEHS cites in more recent publication that the [ indiscernible ] upper limit, the institute of medicine noted [ indiscernible ] consistent with these other studies. The research concept estimates daily dietary intake in the general population to be only 10 through 60 micro grams per day. 9,000 through 54,000 lower than the LOAEL in rats.

The NIEHS based its nomination on exposure through dink water and use as a dietary supplement. The mean intake to be only 8 micro grams per day but even the highest level is still more than 10 fold lower than the UL. Weight-training athletes may use up to 18 milligrams per day to improve performance. This is still well below levels that had no or reversible effect in short-term and subchronic toxicity studies. If there's sufficient evidence or sufficient concern for the toxicity to spend millions of taxpayers dollars and thousands of animals' lives on these studies, it would seem more [ indiscernible ] on a precautionary basis.

The research concept for compounds includes chronic toxicity and [ indiscernible ] studies. The concern over potential car sen Guinnessty appears to be based largelily on a 2002 inhalation study. The incidence of lung neopalace manies, no neo-palacesomes were observed [ indiscernible ] rate of exposure.

The NIEHS notes that administration of [ indiscernible ] with reductions in absolute weight and experimented count, however, the international program on chemical safety argues these results are not convincing due to general toxicity reflected in decreased body weight gain observed in the this study.

Fine ammally, the nice -- short-term and sub chronic studies with both compounds. For example, in the study noted previously, in which reverse [ indiscernible ] 900 to 16,000 higher [ indiscernible ] nearly 7 fold higher than what would be expected from athletic supplement. 6 volunteers were given [ indiscernible ] at 50 to 125 milligrams per day. No toxic reports were given. In another study, also showed no toxic effects.

In summary it is poorly absorbed and exhibits generally low toxicity by oral exposure. Typical exposures will well below levels that might cause concern. There is extensive body of literature on human volunteers. We urge the NTP to find this study of low priority. Thank you.

Thank you for your comments and for your presence with us today. I'm going to open the topic up for general board discussions, comments. Dr. Howard?

Sure. My apologies for interrupting the orders of things there.

That's quite all right.

Couple of comments. I appreciate the comments, and appreciate the outline you put up there. One thing I do want to point out is the Food and Drug Administration evaluated this nomination and was supportive of moving forward. I will not address the concentration of VANDIUM in food or bottled water, but it is included as a dietary supplement. And just to remind the board, U.S. Food and Drug Administration is -- is the regulation of dietary supplements falls under the Shay act, which limits us to be able to ask for any safety data. Dietary supplements can go on the market as long as there's no known toxicity of these materials. What you see, which is -- if you ask 20 relatives, and you'll find this, they consume dietary supplements in exceedingly high levels. The advantage, I think to the work that Dr. HOOTH has outlined, is if we're able to identify action in a potentially small population that will allow studies and other agencies to take a look at perhaps focused zones of toxicity and supersets of the population. That is the distinct advantage of studies like this. In regards to the con sum assumption of the data that was on itted out, a lot was from the 1990s, and dietary supplement trends have changed since the 1990s. So I'm not sure of the relevance to today's consumption.

In addition, the human studies that he cited, most of those studies are very limited in number and scope, and [ indiscernible ] statistic call power to really make conclusions about overarching toxicity. The one thing I want to comment to the doctor's comment is to encourage Dr. HOOTH to look at the epigenetic mechanism. If nothing else to clarify the toxicity would be very helpful to understanding. He mentioned the world drug to inhibit FAS toe tase us. I think that's a laboratory use of that term. It is a chemical used in preparation of cells and tissues. Thank you.

Thank you, Dr. Howard. ? Other questions or comments by the board? Dr. NOVACK.

I have one recommendation. If the study has gone forward, I would recommend in select cases you do the metabolic profile of the lipids and glucose, so you know what the overall effect is.

Other comments? Seeing none, we'll move to the break. I'll ask -- oh, Dr. Booker has a comment.

You not going to be hearing about the screening branch activities, but one of the purposes of this whole effort of the high through-put screening is to begin to identify mechanisms of action before moving in to setting priorities for studies, but also trying to understand if we can design in vivo studies to exploit the kinds of things that have just been brought up. I think this is an excellent example of the kind of information we can generate from invitro studies that will help us take sure we're doing the most efficient and best studies possible as we go forward. I appreciate very much the comments and the whole drift of this conversation.

Thank you. We'll move to the break. I'm going to ask everyone to be back at 10:45.

That was 10:45. Some people heard 10:25. It is is 10:45 to return.

[ Captioner Transition ]

Session on break until 10:45 Eastern Time Zone.

The next compound for discussion is 4710. The discussion will begin with Dr. Scott Masten presenting the compound and the proposed work.

Okay. This is the nominate I referred to this morning, for which we did do a concept. The structure shown here is nominated by the national cancer institute. This compound has a wide variety of industrial uses. Of what we know it's an amean curing agent that being an intermediate in the production of other chemicals, textiles and leather additives. Highest potential for expose is its use in industrial epoxy adhesives. We did not find any consumer epoxy products that contained the compound, these are industrial epoxy. The exposures would to be workers. In terms of human exposure we can only assume that it occurs in the workplace, in places where it is used, manufactured, or used to manufacture other products. There's no specific exposure data available.

In terms of intoxicate toxlogical data it's by the oral and dermal routes. It's a skin irritant in rabbits. It's an eye irritant. This compound is a liquid, across a wide range of temperatures with a PH of 12. It's not surprising that it's a skin irritant. With so little data to go on, there's lots of data gaps and some exercises that one can go through to think about what could be done and what might be available in terms of toxicity. Based on structure alone and predictions from software shows some suspicion of carn know Jenty in a couple of models. No potential prediction of carnls know Jenty in other models. This could be best labeled, calling it some suspicion, but really ee equivalent call.

There's no metabolism information. You can look at the compound and think about the potential me tab lights. You will notice that the compound is diethylene fly koel. Metabolism is likely to occur at one of the Amiens giving you a primary amean alcohol or acid.

There's no workplace regulations for TTD, but it is labeled as core rosive. NCI nommed for testing this. In terms of the recommended assays that do not use animals, focusing on acute tox this information is really available in the literature. And described on MSDS's. We do think there's some value for including this.

So what our study recommendations? Excuse me. We will include this in our HTS initiative for screening studies as John just mentioned before the break. We do not know specifically what assays to but the this in. It's not a focus at this time. But it would be included with a large number of other NTP chemicals. We'll conduct inveto Gino toxty studies.

And that's it.

Thank you, Dr. Scott Masten. Dr. Crump?

I don't have a lot to add to what was just said. This chemical has a moderately high volume. There's potential for fairly high population of workers to be exposed. There's very little tox data available. It seems like a fairly modest proposal. I guess my only question would be is there any idea at this point how this data might be used in going forward? Just suppose an outcome and that would be a question that I would have.

Thank you, Dr. Crump. Dr. Soaper?

I think the summary was clear. I support doing some invitro testing for this, given it's proters it's seems unlikely you will want to do invivo testing. I'm surprised the production volume listed in the document showed a 1000 fold increase in 1998 over 1994 and 500 fold decrease this production from 98 to 2002. I'm wondering if that might be inaccurate. Since the [ Indiscernible ] model did suggest this might be carcinogenic in male rats and female mice I think it's worthy of investigation. I think the limited program here is plenty. Thanks.

Thank you, Dr. Soaper. Dr. Scott Masten would you like to respond in any way to those comments?

In terms of the production volume these are figures that are required to be reported to EPA every four years, it's perhaps possible in a nonreporting year like 99 or 2001 production may have looked closer. We have no other explanation of the differences across these four-year reporting cycles. Dr. Crump's question of where might we go next -- I think the main intent here would be using whatever approaches we can that are nonanimal to derive information that perhaps could even be added to MSDS or used in a classification and labeling scheme for various hazards. A PH of 12, even diluting the material it will be difficult to study. I don't imagine we would go much further.

Thank you, Dr. Scott Masten. We'll move to public comments. Is there anyone in the room that would like to make a comment? Seeing none I'll open this up for general board discussion. Anyone have comments or questions? Dr. Mar Sal is?

I think to expand on what Keith said. I was struck also by the drop in production volume. It's worth determine something this because it's being phased out? If there's an industry phasingout where in five years we won't be using this compound, is it worth doing anything on it? I would look into that. Try to get an answer to that very surprising dropoff.

Dr. Jansen?

It's difficult to comment on the validity of the use of the [ Indiscernible ] data. I would hope to see more of this when we see the update on the [ Indiscernible ] initiative in November. Perhaps using this as a test case.

Thank you. Other comments? Questions? Seeing none we'll move on to the next compound. This will be presented by Dr. Daniel dorj.

All right, now that the hardware issues are resolved. Thank you very much. I'm happy to be here today. This compound was nominated by the [ Indiscernible ] by the Food and Drug Administration for initially testing for carcinogen sis. And what I want to talk about today is go through the background information generated by the agency on the levels of furan in food and how those data were used to generate an exposure assessment for the U.S. population. And go into a brief discussion of the metabolism of furan and how that relates directly to its carn know Jenic properties and expand that theme into the regulatory issues that these reactions raise. Go further into the study elements that we're proposing to address the particular regulatory issues and then finally, summarize and show how the results of these studies will move this issue forward.

First of all, furan is produced in a wide variety of common foods through the process of cooking. Particularly in canned and food jarred, canned and jarred foods. A wide variety of bake and toasted cereal products have it as well, coffee is also a big exposure element for furan. I should point out though that the levels of furan in food are dick dated by the -- dictated by [ Indiscernible ] about the same boiling point of diEthel ether. Actually radiation was the first, the first pathway shown to Jen rate furan in food. I'll be it at lower levels that it turned out occurred from heating. There's pathways involving food constituents that lead to furan formation. Ascore bait thermal used to furan. And similarly proximate oxidized [ Indiscernible ] also leads to furan formation.

These data have been published for the last few years. There's fair literature out there in terms of ranges of furan concentrations in foods as purchased and as eaten. One of the initial areas of focus was this peculiar, you know, the use of jarred retorted foods for infants. And the wide variety of these infant foods contain measurable levels of furan. As we'll see formula is also a contributor for kids.

Once these kinds of food concentration data are available sciencetivities use these data in conjunction with food frequency data. They can do a Monday at the Carlo simulation. This is useful. You can see these are more adult foods, in addition to the children's foods. Quite a range of exposures. Again, using these food concentration data then the estimated daily intake, these are mean values we're looking at here. In this case from adult foods, you can see looking at individual compounds in isolation from each other, you can look at the range of daily exposured anticipated. The other advantage of this simulation it allows for investigation of substitution affects and their effect or lack of effect when various foods are removed or somehow the exposure levels are modified in a particular food type. And it brings up a point, if one looks at this list one might assume if coffee is eliminated from the diet that the furan exposure issue would be largely dissipated. In fact, when the substitutions effects are taken into indicate in this model process it actually removal of furan from coffee would have a measurable effect, a significant effect, but not dramatic. Based on the variety of foods or drinks that could be substituted and the ubiquity of furan exposure in the diet.

So, what in terms of average daily intake across the whole diet, these are for adult foods. In the population it's over two years of age. The mean intake is .25-milligram per kilogram per day. For kids on infant foods more likely to consume these foods the exposure is higher. This includes the fact that kids eat higher amounts of food per body weight.

If one looks at the mean concentrations of furan in infant formulas one can get a estimate of the average daily exposure to kids consuming infant formula as their sole source of nutrition. This is higher than any of the others that we've looked at so far.

What does this means in terms of biochemistry?Here's a diagram for you. As the scheme shows it's react be with a number of biological nuke low files. Reaction with glue toe thigh own leads to excretion in the urine of this conjugate product. And I'm showing reaction with an amino group on hemoglobin. This is theoretical at this point. These others are identified and characterized pretty well.

I bring this, I show this slide pointing out the similarities with akrill mid, we're now near the completion of a large set of studies of akrill mid that has many similarities to furan. They're both formed during cooking of common foods and they're widely distributed in the food supply, as a result. Studies done in the 80s and 90s when traditional salmonella and [ Indiscernible ] testing was negative. Further investigations the [ Indiscernible ] in the case of furan are direct acting mute Jens. Both compounds are course know Jenic in rodent bioassays. In addition to evidence for gene owe toxic methods, there is also evidence in boat cases for nonGino toxic impacts on the carnls know Jenic process. Furan was investigated by the NTP and reported out in the 90s as having clear evidence of carcinogenty in mice based on a two-year gay vage study. In the mouse the increases of adenoma and B9 [ Indiscernible ]. Similarly in the rat, clear evidence was reported for carcinogenty [ Speaker/Audio Faint or Unclear ] based on lower doses to the rat and mouse, again by gavage.Significant increases of [ Indiscernible ] Luke keepas in the rat.

Somewhat similar to that in the mouse. For the bile duct tumors there's nearly 100% incidence of tumor incidences. Again, because mechanism is important in the way that carcinogens are receipted I wanted to talk about the evidence.

As I pointed out there are these DNA add deducts that are identified. And the fact that it's a direct acting mute Jen. There's some evidence that liver tumors from the mice in the bioassay related studies were analyzed for H ras mutations they found in furan dosed mice they found evidence for these CA and A to G transitions. A dosing paradigm that has shown to be useful in identifying [ Indiscernible ] that is administration of high doses early in life for very limited number of injections of a compound then inducing significant increases in liver carcinogen sis.

In addition though, there's strong evidence for regenerative hyperplace and the role this plays in the carcinogenic process cannot be ignored. Because in both species of rodents there was high incidence of liver toxicity evident in the tumor bioassays at doses that accused tumors as well.

So what has the data stand, where does that leave the regulatory issues? I think first and foremost based on this virtually quantititive incidence of tumor formation in the rat we need more information about the dose response curve. This would be the bile duct tumors in the fish and rats. Can the dose response curves for bile duct tumors can they be distinguished from the appearance of sighto toxicity in the liver as well?Corollary to that, is there evidence that furan is directly mute Jenic? This would be more of a subchronic occurring in time before tumors would occur. If so, can we determine which DNA add deduct may be involved?And use that to help inform us about this particularly vexing issue.

So I think -- first and foremost we're talking about extending the dose response range for carcinogenty of furan. Because of the similar responses in the rat, being more sensitive than the mouse we're proposing to use only male fish or rats.

In concert we're talking about looking at the dose response for indications of he pat toe toxicity to scorchment the data that will emerge from the two-year study. Similar kinds of doses we envision from the range from .1, going up higher than we might need to go for the, for the two-year studies. A corollary of this he pat toe toxicity issue, is there evidence that this is reversible? If we dose to a point where we get strong indication, significant increases in indices if we then stop treatment how long does it take for the symptoms to go away? Or are they retained?

It would be nice to understand a relationship for DNA add deduct formation as a way to distinguish some of these Gino toxic dose response curves.

In addition, we want to look closely at the mute Jenic process. That would involve these blue transJenic mice. This is more of a hazard ID mechanistic study. Mutations can be sequenced then to allow us to gain information about DNA add deducts that may or may not be causative.

There are genes that are routinely interrogated as well that have other properties in detecting mute Jens that might be useful.

We want to tie these affects with intoxicate cokinetic measurements and really to build into these studies exposure biomarkers that we can develop and validate in controlled exposure paradigms using rodent studies from single and repeated dosing with the idea then that we can, these are the kinds of biomarkers that would be available from human biomonitoring studies that have yet to be conducted, but would be more empowered with this kind of information. The idea then is to use physiologically based model that integrates the information that is already available on furan with these controlled exposures pushing the dose range as far down as we can.

But more importantly including the biomarkers of exposure that will reduce the uncertainty even further using these models.

So, what do we hope to be able to accomplish with the studies? First and foremost we want to know the dose response for this most sensitive cancer end point. Because of the importance in mechanism on the way these compounds are regulated we want to know if there's a [ Speaker/Audio Faint or Unclear ]. We want to be able to go further with the studies than has been possible in the past by establishing and validated biomarkers of exposure as a means to link rodent [ Indiscernible ] with human exposure using these biomarkers. To reduce the uncertainty for the interspecies extrapolations that are required.

Thank you, Dr. Dorj. Dr. Russell cattily.

Thank you. I guess this is a very ambitious proposal to my way of thinking. It has a lot of disaspects to it. And represents a significant investment of effort. I take the approach is to maybe not conduct a new risk assessment for furan but to provide the parts that would be needed to put together a cancer risk assessment for furan. This kind of a unique proposal for this area, it's carnls know Jenty is clearly established. The question is -- how will you improve risk assessment. Having done so I wonder what you would do. I wonder how our meeting would function if we stopped drinking coffee, for instance. It's the dietary exposure we will focus on. I guess, I'm really sort of -- would like to hear how the dots are connected. What are we going to be able to do with this information? Going into the proposal itself, there were several questions that were addressed. I think the first one, the one that was key was to provide a new dose response of furan in rats. Emphasizing the lower daily doses. This is one of the things I would be interested in knowing about. How the doses would be established. I guess in terms of sequence I think it would be more interesting to address the dose response for the other indicators of potential mechanism. That is the role of toxicity, regenerative cell proliferation and DNA damage. And having established dose responses for these, then one would be in a position to generate hypotheses about the relative contributions of these features. There's clearly evidence established that did occur under conditions of the bioassay. We're less clear in terms of DNA damage and our ability to drive a dose response for that end point. Rather than conduct a bioassay and then try to analyze the mechanism. Another way would to be establish some hypothesis using these indicators of response and then derive a bioassay that can take advantage of thresholds --

Your conference contains less than three participants at this time --

Okay. I think another aspect of the mechanism that is brought out is the ability of furan to induce invivo mute genesis. I guess the -- the ability of the big blue rat to detect the kinds of DNA damage proposed is something I'm not familiar with. But would need to have a strong rationale to know this was an appropriate and valid test system to use. Um, just, I don't mean to skip around too much. Just talking a little bit about establishing the dose response relationship and DNA damages. I know we're not really, the goal is not to design the experiment. There's discussion of CI67. I would propose that some more long-term labeling would be in a more appropriate way to approach the low end of the dose response curve. One of the interesting things to me about this compound and what we know about it's activity in the rat, it induces [ Indiscernible ] tumors and bile duct tumors. I think one of the things that should be considered in these studies is think being the cell origin of these tumor types and define approaches to cell specific analysis for these end points. Such as injury and cell proliferation. And so if the focus is on [ Indiscernible ] carcinoma, as was stated in the presentation, then it would be, it would probably be a good idea to evaluate the mechanism in the bile duct epithelium of the liver. I think that, moving on then, establishment of biomarkers is very interesting. It's a little bit daunting to me. And whether or not there's any ability to work in a range where you can modify any background levels of biomarkers of exposure in humans based on dietary manipulation.

Interestingly, the other biomarker to be considered which is not addressed in the proposal is, um, would be important but if in fact the regenerative cell proliferation are key drivers of the mechanism for this tumor end point one would to be be consider how to establish a biomarker to address that particular aspect of liver injury and response. The one thing that I didn't see in the presentation, but was listed in the concept was this [ Indiscernible ] of furan. I don't know whether that's still part of the proposal. For me this represents a significant effort is more than merely a [ Indiscernible ] on to a standard carcinogenty study. The rationale for why we would anticipate differences in sensitivity in the developmental period would be useful.

I think that thinking about the proposal in total it does kind of fit the NTP's goal of strengthing the scientific basis. I do think some relevant parallels in the human population and one of the things in parts of the world where humans are chronic billary injury, there's increased risk of [ Indiscernible ] carcinoma. And these are, there is a relevance question from that stand point and some scientific, some interest to be had by understanding this dose response for furan.

Um, I think, again, the public health significance of furan is really going to be difficult to judge. And, um, putting more context around what we think the data is going to buy. It is going to cost a lot to get there. In terms of public health implications and any potential mitigation strategies would be interesting. I think the balance of these kinds of observations that I have made give any a moderate priority within the long range plans for the NTP.It's very interesting in terms of unusual kind of lesion, the understanding of the toxicology end points and how they can be related to chemical exposure.

Thank you, Dr. Cattily. Dr. Gregory ket rise.

Thanks. I have a number of comments here. I will start with the nailgy to [ Indiscernible ]. They're both occurring in foods. But chemically these are very different compounds. It's metabolized to a relatively stable ee pox identify. Furan is a stable compound. The reactive intermediate doesn't appear to leave the liver. The early studies show a tremendous amount of binding in the liver, very little in other tissues. It leads -- it leads into some of the biomarker work. I think that's an important aspect to try to make sense out of the data that exists. I'm not sure that pursuing a hemoglobin as deduct is going to get anywhere.

Generally, I think the idea of extending the bioassay down is a very good idea, certainly. I would like to call your attention to the fact that Dr. Robert [ Indiscernible ] and his colleagues at NIEHS and NTP have done this work, not for [ Indiscernible ] carcinomas. They did a study in female mice. The groups were from 50 to 100 animals. TheAnd generally what, they used the female mice because they have low background incidence of tumors compared to the males. There were adenomas and carcinomas at 4 and 8-milligrams per kilogram. They measured other markers as well. They didn't see the tumors at the lower doses. This information is now in a manuscript that is accepted for publication. I would urge you to incorporate this in your information. You give a lot of plaintiff sis to the -- emphasis to the chemical studies that have shown [ Indiscernible ] formation. They're unstable. The boo teen [ Indiscernible ] is unstable such that you can't purify it and characterize it. One of the potential products is hydrogen per oxide. I'm really very concerned that there's an undue weight placed on that evidence. Versus a large amount of literature that is uncited in your proposal. The major public health concern, I would agree, it's through the diet. I'm wondering why you wouldn't propose a feeding study. It's possible that preparing feed, rodent feed with furan wouldn't be stable. But that would really give you some indication of the -- the bioavailability of the furan measured in foods. You know, I mean, it's been known for 30 years or more in foods. But I haven't seen any data that shows that furan is actually bioavailable. If someone ate food they would then have furan in their system. I mean, again, there's a difference between naturally occurring degradation products. Those questions need to be addressed at the beginning. You need a biomarker to make that assessment. I think -- I have a great deal of curve about how furan -- concern about how furan is measured in foods. Of course, it's present in coffee. That's known for a long time. In Jim's cold cup of coffee here how much furan is left? They're not put in a context of actual human exposure. I would think that's a very welltively straightforward thing to do.

The mute genesis study proposed, Russ mentioned about that. I have concerned there too. This sort of system you wouldn't detect a deletion. If you were going through a citeo toxic mechanism those are the events that you would expect to see. You probably wouldn't detect it in a big blue type of a bioassay.

Um, I have the same question as Russ did. In your concept document you had mentioned about the developmental carcinogenty study, it wasn't in your presentation. I thought that's a valid question to investigate. I think it's premature at this time. We don't really understand how, um, neonatal rats would handle furan. Again, that needs to be looked at before any sort of this kind of assay would be undertaken. I know from my work in furan we did one experiment, not just one experiment, a series of them where we used [ Indiscernible ] to completely disstroy [ Indiscernible ]. Those animals when we dosed them with furan, they were intoxicated. The furan itself is reported to have this kind of far cohelp tick kind of effect.-- narcoleptic kind of effect.

Thank you. Would you like to respond, Dr. Dorj?

I will start with Dr. Cattily, since he went first. Um -- yeah, ambitious, I think so. We're well served by our experiences with [ Indiscernible ]. Sort of blazed the way and showed what could be done. Really the utility of such a data set in reducing the uncertainty for the risk assessment. Particularly, the issues involved with the regulation of cooking carcinogens in food. Because they're so much lower than in the doses that accuse tumor incidence. So the number one question that you asked, how will this effect risk assessment? That's, of course, the $60 million question. Even if one accepted all the uncertainty reductions that we're trying to accomplish with modeling and biomarkers and whatever, it's still an open question if it's even possible to regulate these levels. This is something that didn't come up in discussions, but I will bring it up now, that is with akrill mid the findings in food really Fostered a huge effort worldwide to reduce the levels of akrill mid in various commercial food products. It's had mixed success. With furan we're not there yet. But because of the volatility issues and this really is a great way, I think, for technological hook for manufacturers to get ahold of. I'm a little more optimistic about their ability to do an more effective job with reducing furan levels in food, perhaps. None of this addresses the issue of food that is cooked in the home, which is a huge source of exposure that is very difficult to get at.

Um, Dr. Cattily also asked about how the doses would be established. That's an excellent question. Not one I addressed here, this is an issue that is handled at our toxicology meetings that we have annually with the NTP scientists involved. Those scientists at NCTR are conducting the investigations and the regulatory side is from the affected product centers at FDA who all sit at the table and are involved in all aspects of study design, all of the critical elements. This is really a group effort to arrive at these critical study parameters.

The next question, the validity of big blue. Greg touched on this as well. These have been used, again, quite a bit across the world to look at Gino toxic mechanisms. I wouldn't say it's a technique that's been embraced by the regulatory community per se. But these are primarily mechanistic studies that give us information about the ability of metabolism in a whole animal to impact the mew toe Jenic process. The transgenes are in all of the target tissues. That goes directly to our next point, to focus on the cells of origin. We thought about that, certainly. It's not clear an tomorrowically how would do the. This may be the best way to look at those cells specifically. But we are, we are still considering that, absolutely. That's a key, a key point we agree with.

In terms of biomarkers, looking at incorporating more biomarkers, I don't know. The study that Dr. [ Indiscernible ] mentioned in the mouse looked at clinical chemistry markers for short-term indices. I'm not sure whether for human studies where we're looking at very low levels whether the variability would allow us to tease things out. That's certainly that we can consider.

Again, Dr. Cattily and Dr. [ Indiscernible ] raised the issue of the developmental aspect. I think this issue arose because in the interim between the reporting out of the furan results in the 90s and now the default exposure paradigm by the NTP has gone from adult only to 2 years of life to now incorporate a transplay sental. So the whole life span. In that context, the additional studies were proposed.

Thank you, Dr. Dorj. We now have opportunity for public comment. Is there anyone in the like that would like to make a very brief comment? Seeing none I will open this for board discussion. Dr. Novak?

I have a question. Has the incidence of discarsinoma increased in the population over the last decade?

In the U.S.? I'm not really sure. You know there are a lot of other underlying factors effecting liver cancer in the U.S.

Removing the hepatitis component, some of the break down might be in the CERHR database.

I haven't seen anything convincing.

One of the aspects that is interesting to me is that in some cases people with hepC do convert fully fully. Wondering, you brought up a question that I found interesting, that is if you look at this treatment in the context that you had mentioned what would happen if you stopped treating the animals at a certain point. You might have chronic nonalcoholic liver disease, if you stopped treating the animals at that point in time, would it reverse? Or would it continue forward? I'm thinking about this in terms of the classic initiation promotion for [ Indiscernible ] carcinoma. I think you have an opportunity here to address something that is somewhat buried in this. If you have these events occurring and then you have a subsequently pro motional event then do you get the [ Indiscernible ]? In the terms of the issue of risk, buried in what you had presented there's some intriguing questions. Second, I would recommend that you look at methylation patterns and hybridization. I think in terms of deletions, translocations on chromosomes you can pick that information up from the isolated DNA. And lastly, in terms of the physiology, I can't comment on the resolution of this, but if you are going to look at the bile duct-related areas, perhaps in using technologies that involve the whole animal imaging you might be able to do something in that area.

Some of these are just thoughts. The latter a thought about reporter contracts. You raise interesting questions that have some relevance that might be pertinent to what happens in terms of promotional events. Even including the development of metabolic diseases, which change the pattern. In that context I think your question about the cessation of treatment and perhaps following what happens there -- is the repair happening subsequently to that. Or does this sit there and later you have a promotional event that lead to a subsequently carcinoma?

A follow-up on Ray's question. In the [ Indiscernible ] study that I mentioned they did a stop dosing group. That group did not progress to having cancers. The other thing is there has been initiation promotion studies done that are published previously. It's not an initiator in that paradigm.

This is Dr. Gail McCarver. I would take a different view. I see them as more critical. The reason I say that is largely related to exposure data. Human infants are back in the large E. exposure group. I wanted to take a comment about [ Indiscernible ]. Regulation of 2E1 is different in the rodent species and humans. In humans we have clear data that shows it's expressed in the second trimester. I don't think we can postulate we wouldn't see risk. I think there's some other comments? Did you have one?

I seem to recall in the furan rat study there was a [ Indiscernible ] exposure group. There were tumors in that group. Versus the [ Indiscernible ] follow-up study that was a male study. In this case there's a difference.

Dr. Howard?

I want to bring up a issue. What will we do with this data once we get it? You must understand the mission of the FDA is not only to regulate products, but also one of the key missions is to provide the public with appropriate science data to make health risk decisions. Dr. Dorj has mentioned the one that has already occurred. Even if we don't take regulatory action, knowledge and information to the public of how to change their diet is within the mission of the Food and Drug Administration.

Thank you. Dr. Morsalis.

I have several comments on the big blue study. Just because that's an area of expertise for me. My group developed the DNA recoveries kit and we receive royalties when those are sold. We would get a whopping $200 probably. I feel obligated to sigh that at the outset. Very little on big blue rat. I understand why you picked the rat. Because of the [ Indiscernible ] course know mas. But there's a N of zero for [ Indiscernible ] course know Jens that are -- carcinogens. You might just consider that against the possibility of doing it it in mouse, where you did have [ Indiscernible ] carcinomas. The flip side, it may be that furan is causing tumors in rats by a [ Indiscernible ] mechanism and in mice by a cell proliferation. So you might consider. I'm reluctant to recommend both. You might consider the choice of species. To address a comment Greg made, it's often said that big blue is not good at picking up deletions. Small deletions it picks up readily. Large delusions it shouldn't, it would fall outside the range of the, um, of the transgene. Having said that, in practice it does pick up agents. You can have a large deletion where you take out ten copies of the transgene, but you still end up with a deletion ee venlts there. I would recommended aking to the studies, if you do them, do a cell proliferation measuremental in the liver. That measurement should include separate inloose dation of [ Indiscernible ], [ Indiscernible ] and possibly even cooper cells. If you see mutations it would be important to know if it's only dose it is to induce proliferation. From a human health stand point if you know that it's only mute Jenic as doses that cause proliferation monitoring [ Indiscernible ], and [ Indiscernible ] gives you some sense of whether there's greater or lesser risk. That's easy that is easy to do with PCNA.

I would include saving of mutants and sequencing. You want to know if it's due to [ Indiscernible ]. Those are my comments.

Dr. Dr. Nancy Kerkvliet?

Yeah. I'm not convinced about the public health significance of this study. I don't think the public is going to care whether or not a lower dose is shown to be carcinogenic, it already has activity. If people were going to change the way they eat they probably would do it now if we were educating them in that regard. Um -- it seems to me there's human studies that could be done that might give us a better sense of risk, anyway. I think coffee just stands out there as four times higherly level intake than any other commodity. And coffee drinking has increased in the past 10 or 15 years, since Starbucks came on board. It would seem to me there's opportunities for epidemiology or human clinical studies to give us a sense of a risk given that it's a he patio carcinogenty, is there a higher risk in humors that have a higher coffee consumption.

There's several -- the challenge with human studies is you have a lot of confounders. We have a huge amount of fatty liver. Trying to sort out all of that -- I mean the human literature on this is difficult to sort out. I mean, I do agree with you. Human data would be helpful. But it would be tough to sort this.

When you come to the bottom line in public health significance -- I mean, from a research perspective and understanding more about carcinogen sis, fine. But --

If you think about the things that contribute to liver cancer and you think about drinking, fatty liver, hepatitis C -- I think there's a real change to try to sort this out.

Dr. Howard?

Can I response to Nancy's comment? With all due respect, I disagree. Right now we do not a noel. Those were in a much less sensitive strain. Right now we have an undefined no L. I Harkin back to the days of saccharin. When you have a dose response curve that is high people ignore it. When it drops to human relevant doses people wake up. They're more alerted. I think human behavior is that as the studies move into a dose range which is more relevant to what I do every day people do pay for attention. Just knowing human behavior, I think it's true. Better definition of the no L will help the public and inform the scientists to say this is approaching realistic doses.

Thank you.

I have a different perspective on this, I guess. We're talking about trying to -- A, we're not taking about hazard identification here. It's a different kettle of fish. This is a pretty well studied chemical, you know. I don't know if you've ever really looked at how regulatory agencies use these kind of information and setting levels of human exposure. If you haven't looked at that, I suggest that you do that. You might be surprised at how crude the methods are and how much of the data can't be used. I don't think it's because regulatory agencies are not smart enough to do it, I think it's difficult to translate this information into actual action levels for humans. I think the dose response in animals basically has limited utility in humans. I think it has some utility, but I think it's limited. I think the best we can get out of that is a crude measure of potency. That's about as far as we can go..Use of animals, I'm not sure that's a legitimate use of resources. The gavage route is already questionable. Just to find a lower dose, I really question if that is a useful use of resources. I really think the best use of the animal data is in a hazard identification. Perhaps resources would be better used in all of these myriad of chemicals to get more information on those, rather than on trying to add one more dose, or two more dose it is to a well studied chemical.

We're already into our lunch hour. I would like to move on to the next chemical. If you have something that really pertinent to share, I'm sure they would be interested. The next compound is melamine and [ Indiscernible ]. It's presented by Dr. [ Indiscernible ].

I'm going to start by making a small presentation on the background.So melamine is a [ Indiscernible ] structure. It's a high production volume chemical that is used in the manufacture of countertops,. glues glues and in the manufacture of number of houseware items such as cups, plates and mugs.

It's also a high production volume chemical. It's using in the manufacture of [ Indiscernible ] and antimicrobial agents and as a stabilized in swimming pool water.

In the spring of 07 there was a [ Indiscernible ] and there for a large number of cats and dogs which was followed by the massive recall of pet food from the market. This triggered the largest FDA response in history. It was found that the reason for the toxicity was that pet food that was manufactured with glutin and rice protein that had scrap melamine. It's the residue from the final stage of the purification ever melamine industrially. TheThe idea behind this is the value of wheat glutin is determined by its protein component. If you are adding compounds that are rich in nitrogen the level of wheat glutin is higher.

This figure represents a typical histology of a cat affected. These acute toxicity was in the laboratory. All of them presented the same sort of symptoms. And the same kidney histology. Suggesting a common mechanism of toxicity. What was known? There's a wealth of studies out there. All of them demonstrate that melamine and [ Indiscernible ] present low [ Indiscernible ] on the range of 3 grams per kilogram in rodents. For the [ Indiscernible ] acid the low toxicity is even more unapparent. They are dwarfed by the results of some [ Indiscernible ] where animals were treated with four oral doses of 14-milligrams per kilogram. The only symptoms were that the animals were showing some discomfort. So per se the distal compounds are essentially very low, present low toxicity. So what seems to be so special about the melamine and [ Indiscernible ] acid exposure?

For reasons that are not clear they precipitate in the kidneys.This gives us a good clue as to what might be happening. This toxicity seems to be triggered by the low sollability of this crystal that is formed between the two compounds.

Okay. The whole situation changed when all of a sudden it became apparent that other the [ Indiscernible ] tissue that contaminated glutin has been [ Indiscernible ] such as poultry, swine and [ Indiscernible ]. This constituted a spillage into the human food chain. Based on the data was available at the time the [ Indiscernible ] released its assessment. It was based on the presumption that melamine was present at the level of 50 parts per billion in all of the food that was consumed. The outcome at the time was that consumption of pork, chicken and fish from animals that had been fed tainted feed with melamine was that it very unlike to pose a human health risk. However, given what we know about the sin tick [ Speaker/Audio Faint or Unclear ]. If we now consider the sources overall that exist for melamine and [ Indiscernible ] acid in humans. If we focus first on the food and food contamination we have the example of the recent contamination on pet food. There's previous evidence that what happened here is not entirely new. There's evidence in pets in Asia in 2004 there was an earlier outbreak. Perhaps more interestingly, literature that suggests that in the period between 1979 and 87 in Italy there was [ Speaker/Audio Faint or Unclear ] we're talking about 70% being positive with levels of 1.9 by wealth, which is a huge contamination. At least for the past 29 years melamine is incorporated in feed.

Of particular concern is the fact that the bags that contained the contaminated wheat glutin were poor labeled as to whether they were distinned Separation. This is of particular concern because a number of facilities process human food. If we can see the scenario of the veg tear diet which is very rich in glutin, the overall exposure can be very, very actually. Possibly higher than what some of the pets were exposed to.

And they can leave amounts of melamine in specific foods. Per one hundred square centimeters. Probably twice the areas. So it gives you an idea of so much can be invested by this. Not a surprising finding, but apparently is an FDA component which is a [ Indiscernible: Speaker/Audio faint and unclear] by law it can contain actual 30% of as it. Acid is a disinfectant. Although the concentration that it recommended and the regulations vary from state to state and county to county. The concentration is 100 parts per million. In these managed pools it may peach higher levels especially on privately owned pools. Evaluated that was the average amount of water ingested by children in the swimming pool and it can go up to 154 in that particular study. Which ingestion of sigh nearic as id which is a reasonable amount.

The key question is that after the recommended to better understand the [ Indiscernible ] [Speaker unclear due to accent.] in different species the determination of markers might be predictive of renal failure [ Indiscernible: Speaker/Audio faint and unclear] possibility of human exposure. Finally regional study that might the long term exposure. There is a clear need for the FDA can misconception.

So the work that we're proposing to do is based on the external review panel. Also on a number of recommendations that were issued by an FDA interagency group. We were proposing to conduct this multiphase study [ Indiscernible: Speaker/Audio faint and unclear] out come of the previous one. So the first stage will be the development of methodology to [ Indiscernible: Speaker/Audio faint and unclear] melamine in the blood of animals, which will also -- we also need to determine which kind of appropriate for those studies because we need to conduct that at the level where at the same time we have a sensitivity to follow up the levels that is not toxic for the animal. Also we would like to estimate which of those we should be using for the studies. Melamine and sigh nearic acid as a preform which is the form which is very insoluble. In a time stable manner so that the concentration. We would like to conduct [ Indiscernible: Speaker/Audio faint and unclear. ] for combined treatment of buy nearic as id for. [ Indiscernible ] [Speaker unclear due to accent.] side of the study we are proposing. Occur at the same time and the idea of suggesting early mile markers of melamine use [ Indiscernible ] This is important because the idea is in our hands that would allow us to evaluate whatever might happen in humans. We're including a number of mile markers that are currently be evaluated in NCTR. Mile markers that has been proposed. We also propose to do a metabolic protein [ Indiscernible ] [Speaker unclear due to accent.] we is a very high import regular protocol. The next slide because the key issue that seems to be driving the melamine [ Indiscernible ] [Speaker unclear due to accent.] study in an animal model that mick hims the human physiology at the absorption and excretion level. We think that that can be provided by these high interests. Finally, we would like to keep open the possibility and also on the grounds of what the external review panel recommended the possibility of longer term studies, we'd like to keep open for the time being the possibility of conducts after this study the chronic study the longer term exposure might be [ Indiscernible: Speaker/Audio faint and unclear]

Thank you.

Thank you. [ Indiscernible: Speaker/Audio faint and unclear]

To address the questions to review this. Represents the rational for looking at the potential toxicity. Real concern for potential human exposure but the combination presents a novel toxicologic mechanism that has not been studied. In the state by the FDA risk assessment and is later needed for them to perform that. The research addresses the [ Indiscernible: Speaker/Audio faint and unclear] information exposure to these to the biomarkers toxic exposure relative to -- in terms of comments on the specific experimentsal design the acid exposure, they will address exposure simultaneously as well as staggered exposure and see how the crystal formation occurred. These are crucial since it's not known what the relationship is between exposure and the renal afts. After these studies are analyzed you should get 90 day toxicology studies to better try to define what it is. Some other toxicants so this will also be basically a lot more information. You also have to realize it addresses one other point later this is a different mechanism of toxicity that can be chronic. Cause irritation. The dog and cat scenarios were really acute and a lot of bodies hanging around and haven't figured out why certain dogs and cats were susceptible.En tirely different species, this is wet food, not dry food. No clue why those animals actually had this massive level of toxicity. With the potential of human exposure in this line we need to find out. Another aspect of this research is to determine more comparable body mass similar to humans, this is really important for potential for this toxic mechanism because it's really related to the ratios of a chemical, the PH in the urine volumes. That's hard to speculate that in small animals. Finally in addition a Serb vees of studies that might improve invitro studies looking at this crystal formation as a function of individual melamine con Venations rates of input, PH solution. We nettics of the process probe the mechanisms of that crystal exposure. We have no clue why these things are actually causing toxicity since it's not obstructive. Precision cut Tish hue slices and the ability to control those provisions sequence of the exposures and what's really recorded before you camp duct a large number of studies in that line. That also more potential markers because it would link those two species.

Next discussion is Dr. Button. I would agree with the comments. I only have a few things to add. I think it is a very important study to understood take because of the nature of the exposure and toxicity as mentioned. I would only add -- we don't have all the details for the studies, we you would want to consider putting a recovery phase on one of these studies just to find -- maybe you're 90 day study. I don't -- just to get an idea of how the recovery looked in this type of injury, the renal injury. You mentioned that you wanted to compare the knoll that you end biomarker in the rat with what you find out with the mini pig. It could be very difficult. Could be very different with those two species, which would be fine. Your biomarkers may be different too. You have to think about how you're going to the that interpretation between species.

Thank you Dr. Button. You have a response you'd like to make?

Yes. First I agree there are a number of studies that need to be better gauge it. Started doing that. We've started [ Lost audio. ] Relation between how we see [ Indiscernible ] [Speaker unclear due to accent.] bounced to proteins in the plasma and how we detect the stabilizing. I fully agree. There's a lot recover later on. So there is a potential for the clearing of the variety there. Remain in tact. On the issue of the biomarker is perfectly good [ Indiscernible ] [Speaker unclear due to accent.] the idea of the biomarker is that we thought that it would be very interesting to follow, not only the final event but to look at how to keep that from doing that. The time course of the events and traditional biomarkers of renal functions which is creating and cocreating [ Indiscernible: [ Indiscernible ] [Speaker unclear due to accent.] probably too late. One of the issues is that while participation of biomarkers they do not necessarily exist for the core responding proteins. That's an issue we're still considering.

Thank you. Next one to public comments. We have no one preregistered to make comments. Anyone that would like to make a very brief comment.

Saying none we'll open it up for board discussion.

Dr. Green. I was looking at your-- when you do the combinations are you envisioning it as a mix sure a lot of -- little bit of this?

I then I -- spreading very fast. Now one concern is that the case seems to have been a contamination by the [ Loud noise on the line. ] If the contamination has been done melamine [ Indiscernible ] [Speaker unclear due to accent.] no one would have noticed it. We need to be sure about this. It is a limited study on the levels and exposure to the melamine. It's very limited. Other comments or questions by the board?

If not we're ready to adjourn for lunch. We're going to have to curtail our lunch break slightly. We'll come back at 1:15. .

[ Brake taken take -- break taken until 1:15 p.m. ET. ]

Please stand by for real-time captioned text.

Can I ask everybody to come back to the table? I guess we will go with it. We have enough to get moving. We will be resuming with the presentation of the concept NTP and NIEHS investigative support contract. This is an action item for the board. At the end we will vote to approve the concept. We begin with a presentation by Ms. JoAnn Lewis. She will briefly outline what can and cannot be discussed while doing the review of a concept. Ms.Lewis. I don't think we have our back on.

Where do you turn it up?

I think we have it now. Try it again.

I am Joanne Lewis. I would like to give you just a few guidelines. The board members are asked to review the present concept for the NTP and NIEHS investigative research reports for overall value and scientific relevance as well as for fulfilling of the program pool of protecting public health. That specific area it should include scientific, technical, or program significant proposed activities, availability of technology and other resources necessary to achieve the required goals, extent to which they are identified practical, scientific, or clinical uses for the anticipated results. Adequacy of methodology to be used to perform at the activity. One thing I would like to point out is that discussion should be limited to a review of the general purpose, is built, cool, and optional approach is to pursue the overall program objectives. Note that this meeting will be closed to the public should discussions turn to the development or selection of its sales of the project work request for proposals such as specific technical approaches, protocol, statement of work, the data format, or program specifications. If we have to close this meeting it is for the purpose to protect free exchange of the advisory group's members opinions and to avoid premature release of the details of proposed contract project or request for proposal. Are there any questions?

Thank you, Ms. Lewis. NIEHS will now present the concept.

Thank you.Good news today is if you saw and that is peppered the average life that has gone up to 70 years old. Did you hear that. We are making progress. I just wanted to point that out. I am the project officer for this contract. Colette's Malone is the contract officer. I will provide a general overview of the contract. This is review of a general project purposes. We are asking you to approve the concept based upon the overall value and scientific relevance for propelling the program goal of protecting public health. I will discuss three areas. The history of the contract, the purpose of the contract and that I would give highlights and examples of projects that have been done under the projects. This contract has evolved over time. It is currently entitled The molecular oncology and toxicology support contract. It has been in place for the last five years. It's previous history is a consolidation of three other contracts. The genotyping contract. Also in addition recently have been added is the genetic alteration and cancer data base. This is a comprehensive database of the genetic mutations of red and human cancer that are related to environmental agents. The purpose of the contract is to provide scientific support, are rarely by conducting in the vote, in vitro, and retrospective investigative research projects for NTP and NIEHS investigators. Some examples of the types of support would be conducting mechanistic studies. For example, the toxicology studies or prejudices studies, breeding or housing of a specific pathogen free animals and characterizing animal models such as genetically altered models. It would also provide a molecular biology support such as quantitative biology. It is also supported that by a market development and abdications -- and I will give you some examples of that. Reproductive and developmental pathology which is up coming in the fall. Lastly to maintain the genetic alterations and cancer data base. How many projects are supported by this cuemack well, in the last four years there have been 40 different investigators. They have been injured Merrill and extramarital collaboration's. There have been 140 different projects. I will give you examples of those right now. There is an effort for the toxicogenomics of the liver and heart. These have look that -- they have been a major effort. Some have been done by NTP. There is genotipic anchoring. Genetically modified models were considered for the NTP such as that TJ6 and the P19. There have been studies, screening for the non responder which has reverted back to where the gene is not expressed. There have been a number of efforts among the 20 or so genetically modified models that have been studied in the last four years. Some of the Dubai Air markers are [ indiscernible ], a disease. There have been AHR neurotoxicity. There are recent studies looking at liver slices exposed to fluoridated chemicals. There are two more recent initiatives that deal with the host susceptibility initiatives. Lastly, I have a slide that depicts some of the notes were the findings from these studies. We have gene expression which varies. This is for the NCT or at least eight were studied. The time of day matters when sampling occurs. The liver lobe is actually very between gene expression depending upon which slope is a sample. The hair follicles and sell gives rise to. Another investigator has found the receptors required for the recants there. Found influences of the mag one gene and cox two. There is another example of that gene expression pattern. That is an overview of the contract history. We are proposing to renew that.

Thank you, Dr. Mallarky. Before we have comments we will go to public comments. There were no individuals making a request to make a comment. Is there anyone present who would like to make a very brief comment? Seeing none, we turn to Dr. Novak for his comments.

Thank you. Basically I think the context document appears to summarize the major concepts, programs, and goals. Quite reasonable, very clearly laid out. The provision of support and resources for the activities of the NTP scientists appears reasonable. I think a very positive aspects of this is the in try agency agreement between NIEHS and NAGRI of EPA to facilitate high throughput technologies. I think that will help with high throughput approaches. The only thing I would add is it would seem to be that this overall activity offers an approach to facilitate translation of research in terms of biomarkers and cell-based assays. I would encourage additional high throughput technologies to be incorporated. Discovery and edification of novel biomarkers since the cell-based approaches will be taken. Other types of technologies. I would also suggest in terms of the imaging that additional approaches be looked at in terms of imaging. There are a number of the -- which offers events is. So there are different types of imaging including the animal whole body imaging with the reporter construct. I think overall my comments are a very good and clear document. It is a generic as it did need be. The biggest thing would be if this could be used to facilitate the translation of research of NIEHS and NTP activities.

Thank you, Dr. Novak. Are there other members of the board that have comments?

I wonder if somebody could give us the full range of extra barrel support that is available to the NTP? Are there other similar vehicles?

This is not really extra real support. This fits under the research and development contract capability. This is just one additional way we have of carrying out things that are more experimental in nature. They could be more akin to the kind of epidemic investigations that you are all familiar with that are not really the kinds of things that are easy to put into our large contract laboratories that carry out our cancer studies and general toxicology studies.

I want to ask for a clarification. Is this a single contract that would be awarded to a single vendor? They would be expected to potentially cover activities ranging all the way from traditional medicine through the things you have listed in your slide and in your sheet here?

Is that something I can answer?

Is this going to be difficult to find a vendor? They also have the specialty that you will need.

You are right.

I am assuming. I've wanted to check. Is this done through the master agreements with smaller contracts, is the hell it is medicine that your stickers propose to use this facility -- I'm wondering also much about the specifics but health this research is used.

Principal investigators will come to me and ask about the availability of the contracts and availability and will help bring ideas and proposals to us and we have a small community that this together as a peer review really of the proposal before it is started. There are checks and balances for every project that gets done. For.

Dr. Howard, did you have a comment? Any other comments or questions by the board? Dr. Bradfield?

How are you going to equate to --

Could you speak into the microphone.

How do you equate the cost benefits of this? It is hard for me to imagine -- how are the calculations made that you need an outsourced resource for something that a lot of scientists might think it's a personal experiment that they need to play with and observe the data in real time?

I probably said quantitative. More people can do it in their lab. There might be more novel techniques that they don't do or they might not have a lab. For example, Gary Borman who has gene array data. He was to confirm that data. He would use this mechanism to confirm the data.

There is the cost here, I think, that doesn't is calculated. That is the innovation that might come as opposed to outsourcing. Sometimes when you have to think about how to make it work better you do it more efficiently and cheaper. When I think about how we are a large institution and we don't ulcerous. We do a lot of the same kind of its parents and we don't have contractors for any of these things. It is a very different.

Well, I guess this -- primarily NTP is a bond laboratory activity within but the institute. We have pretty much the laboratories that we have, laboratories of support pathology for the institute, clinical pathology, Special topics and pathology, things of that nature. But there are lots of are rigidities that we have to observe something in a contract laboratory study that is going on that we want to investigate in a little more detail, in a more hands-on way. This really is an outlet for us to do smaller studies that could be done, perhaps, more quickly and could help us focus a question that we are trying to answer in a larger study, for example. And also, Dave went through a lot of that these that have come out of other kinds of things, questions that have come out of our larger contracts studies that have been addressed during the past five years. So these are not things that aren't necessarily -- they kind of fit between doing them in your own laboratory as intramural scientist and doing them under a contract in a larger contract leverage right. That is where these projects fall.

Comments or questions? Dr. Novak?

I just have one other question. Since a number of these studies are being done under contract and they involve treatments, I know you have a repository of tissues that come from these, but do you save the DNA as well? Do you have spotted DNA samples on paper that could give rise to subsequent studies?

For each study we determine whether to archive tissue or not. NTP studies get archived in but the NTP archives of for NIEHS investigators that are not part of the NTP, they may go back to that person's lab. Most of the materials get archived. Does that answer the question?

I was specifically thinking about the DNA. If you archive DNA?

If no canceled samples are staked taken in the study. We make a decision on a case-by-case basis.

Comments or questions? Seeing none, I will ask for a motion on this item.

I motion for approval.

Dr. Novak motions for approval.

I second.

Second by Dr. Marcellus. If not, can I see a show of hands voting to approve. I think we have it. Show of hands for those voting no. We will come back to you in a moment. Anyone choosing to abstain. Would you share your thoughts?

I don't believe you are going to be able to find a single vendor that can provide this range of services.

Thank you very much. We move on to the Technical Report Review Subcommittee Report from February 2008. A reminder, this is an action item. There is a reminder under tab six. There was a report that was e-mail and I believe it is also an your binder at your desk. Dr.Kirkly, the chair will make a presentation. The subcommittee's recommendation on the draft technical reports from February 2008.

Okay. So the subcommittee reviewed reports on eight different chemicals. I am going to run through the conclusions that we came to war agreed to on those chemicals. In this handout the minutes of our discussion is outlined. If you have additional questions you can look at the minutes. Let me get organized here. Okay. Well, can I move this out if the vote that's. I have a hard time. Okay. Great. Thank you. Okay. The first chemical was a water disinfection byproducts. It was a two-year drinking water study. The subcommittee approved the following conclusions with a 7-1 vote that there was clear evidence of it carcinogenicity in rats based upon [ indiscernible ] or carcinomas. There was some evidence in female rats. Clear evidence in male mice and female mice based upon the papillomas. Our action items are for each chemical --

For the whole report.

We also reviewed the technical report on acetic acid which is also a water disinfection byproducts. In this report it was a 2-year drinking water study. The subcommittee unanimously approved the conclusion with an 8-0 vote that there was there evidence in the male and female rats and mice for malignant mesothelioma is and Evan Thomas of the large intestine. Neoplasms and paddle customers in the male mice and neoplasms in the female mice. We also looked at an interesting report on via photo indscernible, a study of Aloe Vera in different preparations. This was done in SKH1 perilous mice exposed to simulated the solar light. These products are used in cosmetics as well as therapeutic preparations. Based upon a 46 week topical application of the creams containing these different preparations the subcommittee unanimously approved the reports and conclusions. There was no effect in the mail mines and a weak enhancing effect and female mice for the different products shown here, though whole leaf or decolorized extract. The asteric indicates that there was an increased multiplicity. In this case the incidence was nearly 100 percent. We reviewed the reports of monohydrate which is found and dietary supplements. Eighty-two here feeding study. There was a 7-0-1 abstention vote to approve the conclusions. There was equivocal evidence for carcinogenicity in male rats, the precrucial gland. There were tumors.There was no evidence for tumors in the remaining animals. For one that to Dibrom all which is used in cosmetics as well as other household products 82-year dermal exposure study.The report was approved on an 8-0 vote showing no evidence of a carcinogenicity. We looked at a struggle which is a natural product, plants derived. It's used as an additive, fragrance, and flavoring agent. There was a three month study we reviewed. We approved the conclusions within 8-0 vote that there was significant activity in the male rats. Evidenced by carcinomas and cellular Adamas into mice. There were no tumors in the other animals after this three month exposure. The conclusion of no carcinogenicity is based on the qualification that this is not a full assessment of an activity of this chemical. Given that the exposure was only three months. [ indiscernible ] is a natural product used as a fragrance and flavor in agent. A two-year study.The subcommittee unanimously approved the conclusions with an 8-0 vote. There was equivocal evidence in male rats for cars that tenacity based upon memory gland. No evidence in female rats. Clear evidence in the male rats with the data cellular and no or carcinoma. Equivocal evidence and female mice with a history of six are. Finally five hydroxy methyl to which occurs naturally in many foods and is used in the synthetic reactions. There was a two-year study with unanimous approval of the conclusions for no evidence of carcinogenicity in the male or female rats or male mice. Some evidence and female mice based upon a cellular adenomas. That was the extent of our deliberations.

Think you.

Are there members of the board who would like to make any clarifications or ask any questions? Dr. Crile?

In the write up I think we have given new meaning to the word unanimously. Seven yes, one no. We need to correct that.

Thank you. Other questions or comments? Seeing none, we have no one registered publicly to make a comment. If there is someone who would like to now would be the time. Seeing none, I would like to request a motion on this item.

I moved to accept the report.

Dr. Marsalis, a motion to approve. Do I have a second?

[ indiscernible ] onn the second. But I have a show of hands cuemack.

Are you voting on the bus and has written or as presented because there is a slight mistake on one of the slides.

The written report is what we are voting to approve.

All those who vote to approve the written report. I believe it is unanimous, but let's just make sure. Anyone voting no.Anyone voting to abstain. Thank you very much. We move now to the discussion of criteria for evaluating a outcomes and reproductive developmental and immune a toxicology studies. That will be presented by Dr. Paul Foster. We have a technical problem with some slides. We will hold for a minute.

Is that a specific tab? the good news while we are waiting is we are back on schedule. while we are waiting, this is not a vote of them. Input is highly desired. Of what to hold them. I doubt it is attempting to escape, but this is a very important item that there is to be feedback on. Could I call the meeting back to order. Dr.Foster will proceed without slides. Thank you. Could I have order.

This will be something completely different. What I was hoping to do today -- I have is really elegant slides. They are not with us. I want to give you a bit of a stage setting. So as you have all seen -- in fact you have just gone through, the NTP over a fairly large period of time has had these evidence statements. So use of the clear evidence, some evidence, equivocal evidence, no evidence, inadequate studies. Basically you have to that really show positive and one that is equivocal, when no effect. One, something must have gone wrong with that study. So the idea, these things are included in all of that carcinogenesis the report as one-page inclusion. Many of you actually looked at the reports and seen that. It's easily those five levels of evidence with a bit of a preamble followed by about a dozen different both points that explain how those level of evidence are actually arrived at. Now, I think you are also aware that just recently we have also started to introduce other fairly large studies that are being brought to the board for review. Particularly just recently we had multi generations studies and the Ethinyl Estradiol studies. The thing is that we don't have the same kind of levels of evidence statements for these kinds of events. What has happened is the NTP over a number of years, you can make fairly comparisons for the same test article across studies. You saw it was actually by sex and species. You can also compare using the same criteria across other studies with different chemicals. So what we would like to do is see if we can develop similar levels of evidence criteria for reproductive studies, for developmental studies and for immunotoxins do studies. So that is what we are planning on doing. Obviously if we can use the same equivocal type of approach I think that would be beneficial, not just for the program because I think we are using similar kinds of. I think it might be more clear for the board because most of you as you have already just gone through are familiar. I think it might actually be helpful for the public as well. How are we helping to generate this and get there? What has happened is the discipline leaders, we have sat down and discussed how we can do this. We have gone through these exercises to see how we might be able to make this work. I think we feel fairly confident. The way forward as far as we are concerned, we are now hoping during the summer to actually form to small work groups and also include both practitioners and users of these non cancer data. We are looking for people to do the kind of studies and the regular bodies that might use that data and how they might use that in a risk assessment. So these two groups are actually currently being constituted. They will be chaired by board members and I think the immunotoxin is going to be chaired by Dr. Curtly. The reproductive and developmental work groups will run sequentially. They will be chaired by Ed Carney who is now with us but he is a board member. Other board members would be most welcome to attend. What we hope to do at these meetings is actually run through some datasets. These are the sort of sets that we get from these studies. Then we want to see what the utility of the criteria is actually going to be helping you get clear evidence from this kind of study versus equivocal. And then I think having worked through and seeing whether or not our proposals actually do make sense and have utility, the idea is then to bring their recommendations that come from these workers back to the board and hopefully that will be November of this year. So I think that was basically all I wanted to say. I apologize that you don't have the slides to look at, but I think it's something that you have obviously got there.The distinction between some evidence and the equivocal evidence is very easy to do. For those of you who have been on the subcommittee can see that we may have to finance some of these things to make it work for these other areas. Thank you.

The queue.Are there any individuals in the room who would like to make any comments before we go to board discussion? Seeing none, I will open it up to comments and questions by the board.

Well, I thought that was very useful and important to standardize.

We are almost done. We will be certain that you each receive a discernible. I'm pleased to be able to provide you with a refresher.

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