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### FIFRA SCIENTIFIC ADVISORY PANEL (SAP)

OPEN MEETING

REEVALUATION OF SCIENTIFIC ISSUES ASSOCIATED WITH CHLORPYRIFOS

HEALTH EFFECT

DOCKET NUMBER: EPA-HQ-OPP-2012-0040

FIFRA SAP WEB SITE http://www.epa.gov/scipoly/sap/ OPP Docket Telephone: (703) 305-5805

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY CONFERENCE CENTER LOBBY LEVEL ONE POTOMAC YARD (SOUTH BUILDING) 2777 SOUTH CRYSTAL DRIVE ARLINGTON, VIRGINIA 22202 APRIL 10TH



### – 12TH 

### , 2012

### Page 2 1 DR. FRED JENKINS: Good morning again 

### 2 everyone. I want to welcome everyone to this FIFRA Scientific 

### 3 Advisory Panel meeting. The topic of this meeting is 

### 4 Chlorpyrifos health effects. My name is Fred Jenkins, and I am 

### 5 the designated federal official for this meeting. 

### 6 Before we get started, I just wanted to take a 

### 7 couple of minutes to go over a few administrative items. As the 

### 8 DFO, I serve as the liaison between the panel and the agency. I 

### 9 am responsible for insuring that provisions of the Federal 

### 10 Advisory Committee are met. 

### 11 I want to extend my thanks to this entire 

### 12 Panel for agreeing to serve in this meeting. I want to extend 

### 13 my thanks to the public for attending. 

### 14 The FIFRA SAP is a Federal Advisory Committee 

### 15 that provided independent scientific peer review and advice to 

### 16 the Agency on pesticide issues. It is important to note that 

### 17 the Panel only provides advice and recommendations to EPA, and 

### 18 all regulatory decision making and implementation authority 

### 19 remains with the Agency. We have worked with appropriate agency 

### 20 officials to ensure that all appropriate ethics regulations are 

### 21 satisfied for this meeting. 

### 22 Panel Members have been provided the

### Page 3 1 provisions of the Federal Conflict of Interest Laws, and each 

### 2 participant has filed a financial disclosure report. I, along 

### 3 with our Deputy Ethics Officer and in consultation with the 

### 4 Office of General Counsel, have reviewed these reports to ensure 

### 5 that all ethics requirements are met. 

### 6 This meeting provides an opportunity for the 

### 7 public to comment. We will have several people who will be 

### 8 speaking during the public comment period. If you have not made 

### 9 prior arrangements and you wish to make a public comment today, 

### 10 please let me know or someone else in our SAP Staff Office. 

### 11 Everyone in our Staff Office is seated right here to my right. 

### 12 Let any of us know, and we will make sure that we accommodate 

### 13 time for you to speak. 

### 14 Without having made prior arrangements, we ask 

### 15 that you please limit your comments to 5 minutes. There is a 

### 16 Public Docket for his meeting. The Docket number is listed on 

### 17 the Agenda. All background materials and other related 

### 18 documents are available in the Docket. I will work to ensure 

### 19 that the EPA slide presentations will be available very soon, 

### 20 hopefully today on the Docket as well. 

### 21 At this point, I want to introduce and extend 

### 22 my thanks to Dr. Kenneth Portier, who is the Chair of the FIFRA

### Page 4 1 SAP and also the Chair of this meeting. Thank you, everyone. 

### 2 DR. KENNETH PORTIER: Thank you and good 

### 3 morning. I want to extend my appreciation to the Panel for all 

### 4 of you being here and taking part in this meeting. At this 

### 5 point, I would like to introduce the Panel. 

### 6 I am Ken Portier. I am a Biostatistician and 

### 7 Managing Director of the Statistics and Evaluation Center at the 

### 8 American Cancer Society in Atlanta, and we will start with Dr. 

### 9 Pope. 

### 10 DR. CAREY POPE: I am Carey Pope. I am 

### 11 Professor of Toxicology from Oklahoma State University and the 

### 12 Center for Veterinary Health Sciences. 

### 13 DR. STEPHEN KLAINE: I am Steve Klaine, 

### 14 Director of the Institute of Environmental Toxicology at Clemson 

### 15 University, and I am a member of the permanent Panel. 

### 16 DR. MARTHA SANDY: I am Martha Sandy. I am a 

### 17 Toxicologist with the Office of Environmental Health Hazard 

### 18 Assessment, part of California EPA and I am member of the 

### 19 permanent Panel. 

### 20 DR. HEATHER YOUNG: I am Heather Young, 

### 21 Associate Professor of Epidemiology of George Washington 

### 22 University School Public Health and Health Services.

### Page 5 1 DR. CHARLES VORHEES: Hi, I am Charles 

### 2 Vorhees. I am Professor of Pediatrics at the University of 

### 3 Cincinnati. I am a Neuroscientist by training, and I am in the 

### 4 division of Pediatric Neurology at Children's Hospital. 

### 5 DR. JOHN VENA: Good morning, I am John Vena. 

### 6 I am UGA Foundation Professor and Public Health at the 

### 7 University of Georgia College of Public Health, and I am an 

### 8 Environmental Epidemiologist. I am Head of the Department of 

### 9 Epidemiology and Biostatistics. I am Member of the Chartered 

### 10 Science Advisory Board of EPA. 

### 11 DR. ALVIN TERRY: Alvin Terry, Professor of 

### 12 Pharmacology and Toxicology at Georgia Health Sciences 

### 13 University. 

### 14 DR. BARRY RYAN: Good morning, my name is 

### 15 Barry Ryan. I am a Professor in the Department of Environmental 

### 16 Health at Rollins School of Public Health of Emory University in 

### 17 Atlanta. 

### 18 DR. WILLIAM POPENDORF: Morning, I am Will 

### 19 Popendorf, Emeritus Professor of Industrial Hygiene, Utah State 

### 20 University. 

### 21 DR. BETTE MEEK: I am Bette Meek, Associate 

### 22 Director in Chemical Risk Assessment at McLaughlin Center,

### Page 6 1 University of Ottawa with a background in Regulatory Risk 

### 2 Assessments. 

### 3 DR. CHENSHENG LU: Good morning, Alex Lu, I am 

### 4 Associate Professor for Harvard School of Public Health. 

### 5 DR. STELLA KOUTROS: Hi, I am Stella Koutros. 

### 6 I am an Epidemiologist in the Occupational Environmental 

### 7 Epidemiology Branch in the Division of Cancer Epidemiology and 

### 8 Genetics at the National Cancer Institute. 

### 9 DR. GAYLIA JEAN HARRY: I am Jean Harry, Head 

### 10 of the Neurotoxicology Group at the National Institute of 

### 11 Environmental Health Sciences. 

### 12 DR. ELLEN GOLD: I am Ellen Gold. I am 

### 13 Professor and Chair of the Department of Public Health Sciences 

### 14 at the University of California-Davis. 

### 15 DR. ABBY COLLIER: I am Abby Collier, 

### 16 Associate Professor of Pharmacology at the University of Hawaii 

### 17 School of Medicine. 

### 18 DR. RUSSELL CARR: Russell Carr, Associate 

### 19 Professor of Toxicology at the College of Veterinary Medicine, 

### 20 Mississippi State University. 

### 21 DR. BRIAN BUCKLEY: Brian Buckley, Executive 

### 22 Director of Laboratories at the Environmental and Occupational

### Page 7 1 Health Sciences Institute, Analytical Chemist and Graduate 

### 2 Faculty Member of the School Public Health Environmental 

### 3 Sciences and Joint Graduate Program of Toxicology for Rutgers 

### 4 University. 

### 5 DR. MICHAEL ASCHNER: I am Michael Aschner. I 

### 6 am Professor of Pediatrics and Pharmacology at Vanderbilt 

### 7 University Medical Center. 

### 8 DR. KENNETH PORTIER: Thank you very much. As 

### 9 you can see, we have a good Panel of experienced experts. I 

### 10 think most of them, except for 2, have been on a previous SAP, 

### 11 so they know what this is all about. 

### 12 We have a pretty full agenda for the next 

### 13 couple of days. By my count, we have 16 issue questions that 

### 14 EPA wishes the panel to discuss. We are going to move forward 

### 15 with the presentations by EPA. It will start with an 

### 16 introduction by Dr. Bradbury. 

### 17 DR. STEVEN BRADBURY: Thank you, Dr. Portier. 

### 18 Welcome to all the members of the Panel. As I mentioned at many 

### 19 SAP Meetings, I first want to start off by thanking you all for 

### 20 the effort you will be putting in, already have put in, in 

### 21 preparing for the meeting this week and the efforts you will be 

### 22 undertaking during the course of the week and of course as you

### Page 8 1 prepare your report. 

### 2 The SAP, Science Advisory Panel, is a really 

### 3 instrumental component to our overall program. The Science 

### 4 Advisory Panel, if you will, is Chartered through our statute. 

### 5 The Federal Insecticide, Fungicide, and Rodenticide Act sets up 

### 6 the Scientific Advisory Panel as a Panel of independent 

### 7 scientific experts that can give the agency advice on 

### 8 challenging scientific issues that underlie our decision making. 

### 9 10 Clearly, as many of you know from previous 

### 11 experiences on the SAP that the science is the foundation to the 

### 12 decisions that we make. Science, transparency and rule of law 

### 13 are the 3 themes that our administrator feels are very important 

### 14 in the day-to-day work of our agency. The Science Advisory 

### 15 Panel is an important component to our overall efforts to ensure 

### 16 that we are bringing forward the best available science and the 

### 17 best insights we can to the decisions that we have to make. 

### 18 Sometimes, the Science Advisory Panels are 

### 19 focusing on broad methodological issues in certain areas of 

### 20 science, from ecological issues to human health, and the merging 

### 21 of the two. Sometimes, we need your advice on a specific 

### 22 chemical as we are taking a look at chlorpyrifos over the next

### Page 9 1 week. 

### 2 I think as you will see in our charge 

### 3 questions and in the documents that we have provided, there are 

### 4 some broad cross-cutting themes that come forward in the 

### 5 specific examples of chlorpyrifos. So, we are looking forward 

### 6 to getting your advice about some of the issues specific to 

### 7 chlorpyrifos, and expecting we will see some other principals or 

### 8 concepts or ideas that will come through your review that can be 

### 9 applicable more broadly. 

### 10 So, the challenges that we will be talking 

### 11 about over the course of the week, I think reflect some of the 

### 12 concepts that we have been working with you in different SAPs 

### 13 over the last several years. 

### 14 In February 2010, we had an SAP that was what 

### 15 we called our framework document that we prepared that was 

### 16 taking a look at the NRC Report of 2007 in terms of toxicology 

### 17 testing in the 21st Century, and beginning to shape some ideas 

### 18 with you in terms of how do we take a look at the concept of 

### 19 adverse outcome pathways or toxicity pathways as they are called 

### 20 in the NRC Report. 

### 21 How do we start looking at experimental 

### 22 toxicology information and begin to integrate it with

### Page 10 1 epidemiological information to ensure that we are using the best 

### 2 available information and start to think about how do you 

### 3 integrate that information. How do you develop a hypothesis or 

### 4 hypotheses around toxicity pathways and integrate that 

### 5 information from experimental toxicology information to 

### 6 epidemiological information. 

### 7 That framework and the concepts in the 

### 8 framework we tried to carry forth in the chlorpyrifos document 

### 9 that you have been working on. We have also used some of those 

### 10 concepts and some series of atrazine SAP reviews that we have 

### 11 had over the last year or so, again trying to understand 

### 12 epidemiological information, how to best use that in the context 

### 13 of experimental information. How do you generate hypotheses 

### 14 thinking about adverse outcome pathways as a way of putting 

### 15 together our risk assessments. 

### 16 In the NRC Report of 2007, we also brought 

### 17 those concepts to the SAP, I think it was last May or at least 

### 18 spring or summer of 2011. A specific SAP around 21st Century 

### 19 Toxicology, if you will, and adverse outcome pathways and how to 

### 20 start to think about the evolution of that technology, and how 

### 21 to start using that kind of information, and if not information, 

### 22 that thought process in a way we undertake risk assessments.

### Page 11 1 You will see some of those themes, I think, I hope, in the paper 

### 2 that you have been reading. In some, it is reflected in many of 

### 3 the charge questions that you will be working on with us. 

### 4 I think one of the challenges in the concept 

### 5 of the toxicity pathway looking both at experimental information 

### 6 and epidemiological information is trying to understand 

### 7 perturbations as the NRC 2007 Report talks about. As you look 

### 8 at a toxicity pathway, the ability to measure perturbations in a 

### 9 pathway and with the new technology, it is becoming increasingly 

### 10 easier, if you will, to measure perturbations in systems. 

### 11 I think the challenge, and some of the 

### 12 challenge in the science that we are bringing forth to you, is 

### 13 how to interpret those perturbations in terms of whether or not 

### 14 there is enough perturbation that you have knocked the system 

### 15 off its normal pathways and put it on a trajectory toward a 

### 16 toxicity pathway or an adverse outcome. 

### 17 You will see in some of the charge questions 

### 18 that we are trying to get at that concept. Within that concept, 

### 19 issues of dosimetry come up. Dosimetry, you will see, is a 

### 20 major theme both in terms of understanding how much of a dose 

### 21 does it take to cause a perturbation in terms of magnitude, 

### 22 frequency, duration of that exposure. How do you link those

### Page 12 1 different steps in a toxicity pathway together to move from a 

### 2 hypothesis to starting to formulate causal relationships? In 

### 3 some of our charge questions, I think you will see we are trying 

### 4 to get some advice or some help on that. 

### 5 Some of the advances in the concepts around 

### 6 adverse outcome pathways and toxicology testing in the 21st 

### 7 Century, in some ways it is new, the technology is new, but in 

### 8 some way the concepts is kind of old in terms of mode of 

### 9 action. How do you start to put together hypotheses in a risk 

### 10 assessment as well as in the research laboratory to start to put 

### 11 together information to tell a story? In the world of risk 

### 12 assessment, telling a story would make sense. It understandably 

### 13 has always been a significant challenge as many as you know in 

### 14 your careers. 

### 15 One of the documents that we rely on in the 

### 16 pesticide program, but in the agency as a whole, is the agency's 

### 17 risk characterization handbook, which talks about the importance 

### 18 of a risk assessment and a risk characterization component of a 

### 19 risk assessment being transparent, clear, consistent and 

### 20 reasonable, TCCR. If a risk characterization is putting the 

### 21 information well, it should be transparent, it should be clear. 

### 22 Information in there should be consistent not only within the

### Page 13 1 risk assessment, but consistent with other risk assessments that 

### 2 may be tackling similar issues, and it is reasonable. 

### 3 Let me just touch a little bit upon some of 

### 4 the concepts in the Risk Characterization Handbook. I think 

### 5 those themes will be helpful as we all reflect on that as we go 

### 6 through the charge questions, and maybe ask clarifying questions 

### 7 in our presentations. 

### 8 So in the context of transparency, and that is 

### 9 really the foundation to ensure that you have a clear and 

### 10 consistent reasonable risk assessment, some of the issues or 

### 11 some of the concepts in the Agency's Risk Characterization 

### 12 Handbook that it stresses are that in risk characterization, 

### 13 assumption should be clearly articulated. Knowing what the 

### 14 assumptions are should not be implicit, they should be explicit. 

### 15 The impacts of those assumptions should be clearly articulated 

### 16 in the risk characterization. 

### 17 What is the influence of different assumptions 

### 18 in the conclusions that are coming together in the risk 

### 19 characterization? The use of extrapolation was to be clearly 

### 20 articulated in a risk characterization. I think issues of 

### 21 exposure in particular for this specific case study before us is 

### 22 an important aspect of the extrapolations or the assumptions

### Page 14 1 that it will have to bring forward into this risk assessment, 

### 2 both from the experimental toxicology data as well as the 

### 3 epidemiological information, and how are we going to extrapolate 

### 4 from the empirical exposure measurements that we have, either in 

### 5 an in vitro system or through measurements from subjects in the 

### 6 epidemiological study and extrapolate that to kind of exposure 

### 7 scenarios we expect this chemical to have in the environment. 

### 8 Again, there is not a right answer. It is 

### 9 knowing the different approaches that can be employed, what the 

### 10 assumptions are in those different approaches and how that needs 

### 11 to be interpreted in terms of the uncertainty as we go forward. 

### 12 13 The use of models and measurements clearly 

### 14 articulating how the different choices of models or empirical 

### 15 information can influence the characterization of the risk. 

### 16 Making sure that there have been plausible 

### 17 alternatives that has been exercised. Usually, there is more 

### 18 than one way to try to tackle a problem. It is not so much to 

### 19 find the perfect solution, but to make sure that we are looking 

### 20 at reasonable approaches, reasonable plausible ways of 

### 21 interpreting the data and articulating that clearly. 

### 22 Obviously, there will be some gaps in the

### Page 15 1 information and understanding what the implications of those 

### 2 gaps may be in our overall decision making. Not all gaps are 

### 3 created equal, and understanding how different gaps can 

### 4 influence our overall conclusion would be very helpful and part 

### 5 of the concept of transparency. 

### 6 Clarity, of course, is very important. I 

### 7 think the word sort of speaks for itself, but our conclusions 

### 8 and our thoughts should not be obscured. It should be very 

### 9 clear, very obvious, what our thinking is in our documents and 

### 10 any advice that we can get from you and ensuring as we go 

### 11 forward that there is not obscure conclusions or obscure 

### 12 thinking going on in the document that it is clear. 

### 13 Consistency; certainly you would want to be 

### 14 consistent in following Agency Guidelines or basic approaches 

### 15 that we use. But I think it will be very helpful in this peer 

### 16 review in terms of consistency is helping us think about this 

### 17 specific risk assessment and the context of risk assessments 

### 18 that may be similar in terms of the kinds of information or the 

### 19 kinds of challenges that are before us in terms of 

### 20 epidemiological knowledge bases or experimental knowledge bases. 

### 21 As we look at this body of information, how does that body of 

### 22 information compare to other kinds of compounds or maybe similar

### Page 16 1 kinds of challenges that have been addressed and how were those 

### 2 tackled, and is there some connectivity between this specific 

### 3 issue and some issues that we maybe have faced in the past in 

### 4 the Agency or other parts of the Government or may face in the 

### 5 future for that matter. 

### 6 Reasonably, I will just touch on a few 

### 7 concepts there, but certainly we want to ensure that there is a 

### 8 clear logic to how we are putting together our concepts. Here I 

### 9 think the ideas of the adverse outcome pathway, the toxicity 

### 10 pathway that the NRC report of 2007 articulates, give us a 

### 11 foundation or a game plan or an approach to ensure that we are 

### 12 putting together our thoughts in a logical and consistent 

### 13 manner. 

### 14 If this is happening at one level of 

### 15 biological organization, what are the concepts in terms of 

### 16 dosimetry or biological systems that give us confidence that the 

### 17 next step in biological organization could be in play. What is 

### 18 that linkage that is going on and what is the information that 

### 19 connects those linkages? How does the experimental information 

### 20 and the epidemiological information give us insights into 

### 21 putting together various adverse outcome pathways and 

### 22 understanding what they mean, what the uncertainties are, what

### Page 17 1 some of the assumptions are as we try to understand the 

### 2 strengths or limitations of different hypothesis-based adverse 

### 3 outcome pathways in our risk assessment. 

### 4 I think another aspect of reasonableness in 

### 5 our deliberations and the feedback we can get from you is in the 

### 6 context of generalizability. As we take a look at the 

### 7 epidemiological information or take a look at the experimental 

### 8 information and we are putting that together and making 

### 9 inferences from that information, all that knowledge is coming 

### 10 from and experimental system. They are basically models for 

### 11 everybody in the country. Empirical data is a model 

### 12 essentially, just a physical model. Sometimes there are 

### 13 mathematical models. 

### 14 Understanding the generalizability of the 

### 15 various models of information or mathematical models or studies 

### 16 that are models, physical models trying to mimic reality, giving 

### 17 us a sense of how generalizable the data is before us will be 

### 18 very important too. An important part of the reasonable concept 

### 19 in the Agency's Risk Characterization Handbook. 

### 20 As we go forward through the charge questions, 

### 21 you are going to see that we are asking you for advice on many 

### 22 principals around transparency, clarity, consistency,

### Page 18 1 reasonableness, using the adverse outcome pathway, the NRC 

### 2 Report of 2007 as sort of a framework to be getting our thoughts 

### 3 together. We will be asking you to give us advice on different 

### 4 hypotheses, if you will, in this risk assessment, and the 

### 5 strengths and limitations of those different risk hypotheses as 

### 6 we put them together as we move forward with your advice. 

### 7 That will be very helpful because as with this 

### 8 chemical, as with most chemicals, there usually is not one right 

### 9 answer that pops up. There are usually lots of different ideas 

### 10 and different concepts that need to come together, not all 

### 11 created equal necessarily, but understanding the strength, the 

### 12 limitations, the uncertainties associated with this information 

### 13 as it comes together is really helpful for the Agency in terms 

### 14 of the risk managers making their decisions. 

### 15 We make decisions everyday in the face of 

### 16 uncertainty. I have been in the Agency for 30 some years. I do 

### 17 not think we have ever made a decision with absolute certainty, 

### 18 or ever made a decision with 100% certainty. So, we are dealing 

### 19 with uncertainty all the time. What is helpful is to get 

### 20 insight as to the nature of the uncertainty. Big uncertainty, 

### 21 little uncertainty, uncertainty that has this impact, this 

### 22 uncertainty has that impact, so that we can put it together and

### Page 19 1 understand the nature of the uncertainty and how that 

### 2 uncertainty could influence our decision making in terms of our 

### 3 risk management activities. 

### 4 So, transparency, clarity, consistency, 

### 5 reasonableness is what we hope we can offer and try to offer in 

### 6 our document, and hope to get that kind of feedback from you as 

### 7 we go forward over the next week. 

### 8 So with that, if it is okay with the Chair, I 

### 9 would like to introduce Karen Whitby, who is the Acting Division 

### 10 Director for the Health Effects Division in our Pesticide 

### 11 Program to give a few opening comments. We will proceed from 

### 12 there if it is okay Dr. Portier. 

### 13 MS. KAREN WHITBY: Thank you Steve. As Steve 

### 14 said, my name is Karen Whitby and I am serving as the Acting 

### 15 Director of the Health Effects Division in the Office of 

### 16 Pesticide Programs. I welcome the Panel and reiterate Steve's 

### 17 appreciation for their time and efforts. Your feedback is an 

### 18 important component of improving the science foundation of our 

### 19 regulatory decisions. 

### 20 We understand the large amount of material 

### 21 that you have been asked to consider and appreciate your 

### 22 commitment to high quality science. I acknowledge the entire

### Page 20 1 OPP Chlorpyrifos Team, but particularly the efforts of Anna 

### 2 Lowit, Aaron Niman, Carol Christensen, Chester Rodriguez, Joel 

### 3 Wolf, Jeff Dawson, Tom Myers, Wade Ritten, and many others that 

### 4 have also contributed in significant ways. 

### 5 I recognize Rebecca Zubo from the Office of 

### 6 Children's Health Protection for her contributions as well. I 

### 7 extend my sincere gratitude to the ORD Team, Ginger Moser, Bill 

### 8 Mundy, Stephanie Padilla and Danelle Lobdell. Both Ginger and 

### 9 Bill will be speaking today. I also appreciate the written 

### 10 comments from Marsha Morgan and Cecelia Tan. 

### 11 Our colleagues at ORD are vital to this 

### 12 effort, and we truly appreciate their support, time and talents. 

### 13 The Agency's Risk Characterization Handbook describes concepts 

### 14 of transparency, clarity, consistency and reasonableness as key 

### 15 to scientifically supportable risk assessment. 

### 16 Our commitment to transparency, clarity and 

### 17 consistency is reflected by OPP's development of a draft 

### 18 framework for integrating epidemiology with other lines of 

### 19 scientific evidence. This framework describes the steps for 

### 20 analysis and evaluation of data from multiple areas, such as 

### 21 adverse outcome pathways and modes of action, in vivo outcomes 

### 22 from experimental toxicology studies and epidemiology studies.

### Page 21 1 The framework further describes the use of the 

### 2 Agency's mode of action framework and modified Bradford-Hill 

### 3 Criteria to bring all of this information together in a 

### 4 systematic way into a weight of the evidence analysis. 

### 5 For chlorpyrifos, we are at the stage where we 

### 6 have completed detailed analysis of specific scientific areas, 

### 7 but have not integrated across lines of evidence. Before we can 

### 8 perform the integration, we are looking for your feedback on our 

### 9 current analysis. It is important to ensure that the scientific 

### 10 analysis of each area is strong and supportable before we begin 

### 11 the difficult challenge of integrating across lines of evidence. 

### 12 With that in mind, we are not asking the panel 

### 13 to perform the weight of evidence for us. Rather, we are asking 

### 14 that you provide review of our interpretation of individual 

### 15 lines of evidence along with the relative strengths and 

### 16 uncertainties. 

### 17 It would also be helpful to hear your advice 

### 18 on alternative hypotheses or additional scientific 

### 19 considerations we have not included in the white paper. The 

### 20 concepts of reasonableness and ranges of risk and uncertainty 

### 21 are described in the agency's Risk Characterization Handbook. 

### 22 Similarly, the NRC's Science and Decisions Report recommends the

### Page 22 1 agency consider alternate hypotheses and alternate approaches in 

### 2 the risk assessment process. 

### 3 Consistent with this, we request that in your 

### 4 deliberations you consider a variety of options and importantly, 

### 5 the relative strength and uncertainty associated with them. 

### 6 This kind of feedback will assist the agency in evaluating the 

### 7 ranges of risk and uncertainty. 

### 8 With this, I conclude my introductory remarks. 

### 9 We look forward to your thoughtful deliberations over the next 

### 10 few days. Our next speaker is Anna Lowit. 

### 11 DR. KENNETH PORTIER: Before we go to Dr. 

### 12 Lowit, are there any questions from the Panel for Dr. Bradbury 

### 13 or Dr. Whitby? 

### 14 One of the things that came to mind as you 

### 15 were talking is does the handbook address the issue of how you 

### 16 handle alternate but reasonable AOPs for the same process? I 

### 17 mean, that is part of what this white paper is all about, right, 

### 18 kind of looking through all the adverse outcome pathways that 

### 19 chlorpyrifos may presume. So, is the handbook to that stage yet 

### 20 that talks about, well I have 5 competing and reasonable and 

### 21 consistent and clear pathways, what am I going to do with that? 

### 22

### Page 23 1 DR. STEVEN BRADBURY: Well since the Risk 

### 2 Characterization Handbook was written probably 10 years ago, 

### 3 roughly, the NRC Report was not there yet. So, some of this 

### 4 vocabulary, toxicity pathways or adverse outcome pathways, did 

### 5 not exist. My thoughts on the document, though, are that it is 

### 6 compatible or it is consistent with, or anticipatory of the kind 

### 7 of issues we have now when we talk about adverse outcome 

### 8 pathways. The Risk Characterization Handbook talks about taking 

### 9 a look at plausible reasonable alternatives to the information 

### 10 that you may have in front of you in a risk assessment. 

### 11 NRC 2007 did not create the realization that 

### 12 sometimes you can look at a body of information and formulate 

### 13 different mode of action hypotheses, or think about the fact 

### 14 that the chemical could have multiple initiating events, and if 

### 15 you can use the words back then in terms of how it may start a 

### 16 mode of action. The Bradford-Hill Criteria had been around for 

### 17 quite a while, right Dr. Meek? 

### 18 So, the Risk Characterization Handbook, I 

### 19 think is broader than that. I think it encompasses some of the 

### 20 challenges that we have seen chlorpyrifos or other risk 

### 21 assessments coming up. I think what the NRC report does is 

### 22 perhaps provide us some vocabulary. I realize we are still kind

### Page 24 1 of debating what an adverse outcome pathway is, but I think 

### 2 there is some clarity around that. 

### 3 I think the NRC report of 2009 helps provide 

### 4 some framework and a way to integrate different kinds of 

### 5 information, but consistent with the concept the Risk 

### 6 Characterization Handbook is laying out; which is take a look at 

### 7 alternative ways of looking at the information. 

### 8 What are the strengths and limitations of that 

### 9 information? How close do you think you are to causal 

### 10 relationships, quantitative causal relationships, where are you 

### 11 more at the other extreme; got some good information to form a 

### 12 hypothesis, but you may not have the information that you have 

### 13 to really test that hypothesis. But you can see where to go in 

### 14 terms of the kind of information that may be needed to take the 

### 15 hypothesis and start to put more oomph behind sort of the 

### 16 linkages in the different levels of biological organization. 

### 17 So the Characterization Handbook does not 

### 18 capture vocabulary 2007 and 2008. In my opinion, it captures a 

### 19 way of thinking that is very compatible with the new kind of 

### 20 information we are starting to get. 

### 21 DR. KENNETH PORTIER: Okay, thank you. Dr. 

### 22 Lowit, please introduce yourself as well.

### Page 25 1 DR. ANNA LOWIT: My name is Anna Lowit. I am 

### 2 a Senior Scientist in the Immediate Office of the Health Effects 

### 3 Division in the Office of Pesticide Programs. One of my roles 

### 4 as a Senior Scientist is the Technical Lead for the chlorpyrifos 

### 5 team. On behalf of the entire team, which spans 3 offices, the 

### 6 Pesticide Program, Multiple Division, the Office of Research and 

### 7 Development and with help from the Children's Health Protection 

### 8 Office, we would like to again thank each and every one of you 

### 9 for being here, for all of the work that you have done to get to 

### 10 this point. There is a lot of work after we all walk out as you 

### 11 know. It takes a lot of time and talent to put these meetings 

### 12 together. Without you, this would not happen and we genuinely 

### 13 appreciate everything and your contribution. 

### 14 So, you have heard our themes for the day, 

### 15 transparency, clarity, reasonableness, consistency, adverse 

### 16 outcome pathways. You are going to see those themes, integrated 

### 17 across multiple lines of evidence. You are going to hear those 

### 18 themes over and over and over again today and over the next 

### 19 couple of days. These are good starting principles and good 

### 20 organizing principles. We are going to keep coming back to them 

### 21 because they are probably the best place to start. This is a 

### 22 very complicated case, and to begin with some solid,

### Page 26 1 transparent, clear principles, it is a good place. 

### 2 So if we just begin, to restate, there are a 

### 3 couple of NRC reports that really provide the foundation for a 

### 4 lot of the thinking that went into the white paper that each and 

### 5 every one of you have. Particularly under the Toxicity Testing 

### 6 in the 21st Century. We think about adverse outcome pathways as 

### 7 a beginning point to organize information, to think about key 

### 8 events and how they link together, but also how to bring 

### 9 information across multiple lines of evidence. 

### 10 So, you bring in in vitro studies, 

### 11 biomonitoring studies, epidemiology studies, to bring it all in 

### 12 a way that begins to make sense together by integrating across 

### 13 all these multiple lines of evidence. You are also going to 

### 14 hear us talking about thinking about disruption of homeostasis 

### 15 leading to adverse outcomes. 

### 16 As Dr. Bradbury mentioned, science is getting 

### 17 better and better at measuring things smaller and smaller and 

### 18 earlier and earlier in the process. The challenge is to take 

### 19 those things and to make sense of them to think about how they 

### 20 link together and what is required to disrupt homeostasis and 

### 21 eventually lead to an adverse outcome. 

### 22 From the Science and Decision Point document,

### Page 27 1 it is important as an Agency to think about doing improved 

### 2 technical analysis, including not only mode of action, but 

### 3 pharmacokinetics thinking about biomonitoring, how to use that 

### 4 kind of information. 

### 5 Science and Decisions recommends that we do a 

### 6 better job of evaluating alternative interpretations and 

### 7 alternative approaches. You certainly heard of those themes 

### 8 from Dr. Bradbury and from Karen Whitby. 

### 9 I think the last theme that you may not have 

### 10 heard about yet this morning is this idea that risk assessment 

### 11 needs to be aligned with the needs of risk managers, and the 

### 12 idea that problem formulation is the best place to start. As I 

### 13 will go through in a few minutes, we have actually been thinking 

### 14 about problem formulation for chlorpyrifos for several years 

### 15 now. We are doing this entire analysis and this assessment in a 

### 16 very step-wise systematic approach. 

### 17 So, we will just start at the beginning and 

### 18 give you a sense of the regulatory history of chlorpyrifos 

### 19 because there is quite a bit there. 

### 20 It was first registered in 1965 as an OP. 

### 21 There was a long history of use. In June of 2000, Dow, the 

### 22 technical registrant, entered into an agreement with the Agency

### Page 28 1 to eliminate and phase out nearly all of the residential uses. 

### 2 At that same time, there was some agricultural mitigation on 

### 3 some key crops and some mitigation on workers. Chlorpyrifos was 

### 4 the Registration Eligibility Decision in 2006, which would have 

### 5 come at the same time as the OPQ Mode of Assessment. 

### 6 About a year later, a petition came in from 

### 7 the National Resources Defense Counsel and the Pesticide Action 

### 8 Network of North America to revoke all the tolerance and cancel 

### 9 the registrations. 

### 10 In 2008, we came before this panel with an 

### 11 initial new literature review focused on many of the same topics 

### 12 that we will talk about today. I think of that 2008 SAP as our 

### 13 first take at problem formulation of looking at the new science 

### 14 available since 2000 on infants, children and pregnant women in 

### 15 the laboratory, but also from epidemiology studies. 

### 16 In that review, some of you were there. We 

### 17 did an extensive literature review of all of the available 

### 18 cholinesterase data at the time. We did an extensive review of 

### 19 metabolic ontogeny of the potential for young children to be 

### 20 more sensitive based on pharmacokinetics. We did a review of 

### 21 paraoxonase as a potential mediator of sensitivity. We also did 

### 22 a review of the epidemiology at the time, and the available data

### Page 29 1 on experimental toxicology in animals for long-term effects. 

### 2 Many of those same themes appear in this current issue paper. 

### 3 In 2009, we also did an SAP on looking at 

### 4 approaches for semi-volatile pesticides. Why that is relevant 

### 5 is because it is part of the petition from NRDC. 

### 6 In 2010 as you have heard already, we brought 

### 7 a draft framework for incorporating human epidemiology and 

### 8 incident data into human health risk assessment. I will go into 

### 9 that a little bit more in a few minutes, but it really begins 

### 10 the conversation about using the concepts from the NRC 2007 and 

### 11 2009 to integrate lines of evidence. 

### 12 So to bring the regulatory context into 

### 13 present day, currently the pesticide office is undergoing the 

### 14 registration review process. For chlorpyrifos, this opened in 

### 15 March of 2009, which in English means that we put out a plan of 

### 16 how we were going to do the assessment along with the schedule. 

### 17 What that means is over the course of several years, we will be 

### 18 doing review and analysis and different stages of risk 

### 19 assessment in hopes of having all of that completed in 2015. 

### 20 As part of that process, we put out a risk 

### 21 assessment in July of last year. The Docket number is there in 

### 22 case you do not have it already. If you have seen that

### Page 30 1 assessment, the focus of that assessment is entirely on the 

### 2 cholinesterase inhibiting potential of chlorpyrifos. Based on 

### 3 the recommendations from the SAP in 2008 and based on our own 

### 4 independent review of the data, cholinesterase data continues to 

### 5 be the most sensitive dose response data available for deriving 

### 6 quantitative points of departure. That is the focus of that 

### 7 July assessment. That assessment also states very clearly that 

### 8 we are continuing our review and our analysis of the 

### 9 epidemiology data by monitoring data and experimental toxicology 

### 10 studies with not only the data that we looked at in 2008, but 

### 11 things have come out since that time. 

### 12 So a little bit more detail about 2008. 

### 13 Actually I covered that. So for brevity, I am just going to 

### 14 keep going. So, in 2008, some of the key recommendations that 

### 15 bring us to today were what I just said, was that the 

### 16 cholinesterase data remains the most appropriate data for 

### 17 deriving points of departure. That is risk assessment jargon. 

### 18 In English what that means is that the cholinesterase data 

### 19 provides the most sensitive data for bringing the starting point 

### 20 for extrapolation for human health risk. 

### 21 We have lots of data from many sources. We 

### 22 have root specific data, so we have oral data, we have dermal,

### Page 31 1 we have inhalation and why that is important is because the 

### 2 exposure to chlorpyrifos can be to all of those routes. Route 

### 3 specific is going to be the best way to go. We have life stage 

### 4 specific data. So, we have things from pregnant rats. We have 

### 5 newborn rats. We have rat data from PND11, which is close to 

### 6 what you would think of as a human newborn all the way up to 

### 7 adult rats of many different durations. 

### 8 There is a large database that you will hear 

### 9 from Ginger Moser today on in vivo rodent studies and the 

### 10 long-term effects from early life exposure. We did an extensive 

### 11 review of that in 2008, and many of the same themes you will 

### 12 hear today. There is limited dose response data, which makes 

### 13 that data challenging for deriving points of departure. 

### 14 Across the board generally, you see that only 

### 15 doses of about 1 mg/kg or greater demonstrate early effects on 

### 16 behavior. You will see in a few minutes that the points of 

### 17 departure we have from cholinesterase are lower than that. 

### 18 In 2008, the recommendations from the SAP were 

### 19 that the epidemiology studies supported the idea that 

### 20 chlorpyrifos likely plays a role in the findings, particularly 

### 21 out of the Columbia Cohort, but that there are challenges of 

### 22 using the data from Columbia for deriving points of departure.

### Page 32 1 For example, they only measured the biomarkers at one point in 

### 2 time, which makes it difficult to match that one point in time 

### 3 to windows of susceptibility. 

### 4 In another issue that we have a charge 

### 5 question about is the idea that you cannot exclude the 

### 6 possibility that you have combinations of effects of 

### 7 chlorpyrifos with other cholinesterase inhibiting pesticides, 

### 8 particularly diazinon propoxur. 

### 9 A couple of years ago, we brought to this 

### 10 Panel a draft framework from incorporating epidemiology into our 

### 11 assessments. Some of you served on that Panel. We appreciate 

### 12 you coming back. But if you have not seen that document or were 

### 13 not part of that peer review, just to hit the highlights, that 

### 14 framework focuses largely on the concepts from the NRC in 2007 

### 15 and 2009, and relies heavily on the Agency's mode of action 

### 16 framework with the modified Bradford-Hill Criteria. 

### 17 So, there is really nothing in that framework 

### 18 that is new or different. It is really based on standard 

### 19 practice in epidemiology, toxicology and risk assessment. The 

### 20 idea is to bring everything together in one place to think about 

### 21 transparency, clarity and also this idea of consistency that we 

### 22 are using the same organizing principles in all of our

### Page 33 1 assessments. 

### 2 What we like about the framework and the 

### 3 Bradford-Hill Criteria and the idea of the AOP concept is it 

### 4 provides not only a foundation for consistency and transparency, 

### 5 but also flexibility because you can bring in lots of different 

### 6 information. It is a nice way to weigh information in a very 

### 7 transparent way. 

### 8 So for those of you not familiar with the 

### 9 Bradford-Hill Criteria, I will just go through it quickly just 

### 10 to make sure that we are all on the same page. This is the 

### 11 modified version used in the Agency's Mode of Action Framework. 

### 12 You begin with a postulated mode of action, or 

### 13 I think what we will call today adverse outcome pathways. You 

### 14 think about a series of key events in that path to an outcome. 

### 15 So, we will talk about initiating events and the events that 

### 16 would be disrupted, perturbations that would disrupt homeostasis 

### 17 leading to adverse outcome pathways, new jargon for the same 

### 18 ideas. 

### 19 You think about the experimental support for 

### 20 that, concordance of dose response for key events and temporal 

### 21 relationships for key events. You might hear us talk about 

### 22 causality and the idea that we are linking events from A to B to

### Page 34 1 C. This is the idea that we are talking about that A happens 

### 2 before B before C before D, and that there is a reasonable 

### 3 logical dose response relationship between them. Remember, dose 

### 4 response is important for our purposes. So, we are always 

### 5 coming back to dose response. 

### 6 As we put things together, think about 

### 7 biological plausibility, how the ideas come together and make 

### 8 sense, and the strengths and the specificity and the consistency 

### 9 of that. Certainly uncertainties is one of the big words we 

### 10 will talk about a lot today. 

### 11 So the next figure, the adverse outcome 

### 12 pathway: this is a slide that we have been showing quite a bit 

### 13 out of the framework. It is adapted from the NRC report 

### 14 overlaid with some circles to give you a sense of where 

### 15 different kinds of information come together. It is a nice 

### 16 picture of how complicated it can get. If you step back from 

### 17 it, almost all that information exists for chlorpyrifos. The 

### 18 integration across multiple lines is certainly not an easy task. 

### 19 Okay, this is too much animation for me, so I am just going to 

### 20 go to the end. 

### 21 So, a figure straight out of the NRC from 

### 22 2007, this is where we like to take that same adverse outcome

### Page 35 1 pathway and put it in a different idea that you have the normal 

### 2 function, and then you have events that would occur that would 

### 3 take you away from that normal function. Certainly one of the 

### 4 big challenges here is to think about how much and when 

### 5 perturbation from homeostasis does it require to bring you down 

### 6 into adverse outcomes. It is when, it is how much, it is what 

### 7 life stage. Bill will show this again in a few minutes, so I 

### 8 will not go too much into that. 

### 9 So, bring it to grounding. So in the July 

### 10 assessment, one of the questions that we had before the meeting, 

### 11 so I slipped this slide in, was about how we would derive points 

### 12 of departure. Dose response is important. The quality of the 

### 13 dose response is important, the route is important. The life 

### 14 stage is important. 

### 15 Cholinesterase data continued to be the most 

### 16 robust source of all of that information. There are many 

### 17 studies with multiple doses that go from very low dose to very 

### 18 high dose. We have a strong sense of the dose response for that 

### 19 for multiple routes and multiple life stages. We can use that 

### 20 life stage and route specific information as a very strong 

### 21 confident starting point for extrapolating human risk. 

### 22 In 2008, we performed what we thought was a

### Page 36 1 pretty comprehensive, I think we call it just about every 

### 2 dataset out there, not only had it been developed by individuals 

### 3 in academia but also from Dow and other companies. We have 

### 4 supplemented that since then with newest data, not only from the 

### 5 literature, but some state of the art studies developed by Dow. 

### 6 We have used a benchmark dose approach, which 

### 7 means we are doing empirical modeling of that data using a 

### 8 decreasing exponential model, which has been reviewed by this 

### 9 panel 3 or 4, if not more times depending on how you count. It 

### 10 is an incredibly transparent, robust approach that we have used 

### 11 for many cholinesterase inhibiting compounds by this point. 

### 12 So, the points of departure in our assessment 

### 13 and the numbers are not that important, but they do provide a 

### 14 point of comparison as we think about other datasets that you 

### 15 will hear over the next few days. There is a fairly brand new, 

### 16 what we call a comparative cholinesterase study for 

### 17 chlorpyrifos. 

### 18 What that means it that it is a specially 

### 19 designed study to directly compare the relative sensitivity of 

### 20 adults and juvenile rats, and the juvenile rats are aged PND11 

### 21 to most closely match that of human birth. There is a small 

### 22 amount of sensitivity that shows up in that study, which

### Page 37 1 provides the point of departure in the juvenile rats. That 

### 2 makes sense because juvenile animals tend to be more sensitive 

### 3 because of their immature metabolic system. 

### 4 With respect to repeated chronic exposure from 

### 5 oral exposure, the datasets out of pregnant rats provides the 

### 6 most sensitive data, also using a benchmark dose for approach. 

### 7 So a lot of what we are going to talk about 

### 8 today comes around 2 central ideas and 2 central science 

### 9 questions. The first is more qualitative. We will think about 

### 10 it in that way that qualitatively, what are the lines of 

### 11 evidence and the relative strength and uncertainties of those 

### 12 lines of evidence that suggest the possibility that chlorpyrifos 

### 13 exposure may or may not result in long-term neurodevelopmental 

### 14 effects from early life exposure. 

### 15 The second question is more quantitative, and 

### 16 we like to think about it that way, that the lines of evidence 

### 17 and the strengths and the uncertainties associated with that 

### 18 evidence that the adverse effects from the first question could 

### 19 be attributed to doses lower than those, which elicit 10% 

### 20 cholinesterase inhibition and the 10% cholinesterase inhibition 

### 21 is our response level we use in regulatory decision making. 

### 22 Compared to 2008, some of the things we will

### Page 38 1 talk about are the same. Some of them are quite different. 

### 2 Either way, we have gone into a lot of depth on some topics. 

### 3 Certainly, cholinesterase inhibition is a key area. We have 

### 4 done, with help from our colleagues at ORD, a great deal of 

### 5 digging into the mechanistic data, looking at plausible 

### 6 hypotheses and modes of action adverse outcome pathways. 

### 7 We have done a deeper analysis of adverse 

### 8 outcomes in rodents, thinking about neurodevelopmental effects 

### 9 on particularly behavior and cognition. We have done a much 

### 10 deeper and more thorough analysis of the epidemiology studies 

### 11 from the 3 major children's cohorts, from not only Columbia, but 

### 12 CHAMACOS and Mt. Sinai. That also includes some of the newer 

### 13 studies. 

### 14 We have done, compared to 2008, a much more 

### 15 detailed evaluation of available biomonitoring data, 

### 16 particularly urinary data from multiple populations across the 

### 17 U.S. We are thinking about the available physiologically-base 

### 18 pharmacokinetic models that exist and alternative approaches 

### 19 that are maybe less sophisticated that could help us interpret 

### 20 biomonitoring data so that we can begin to make connections 

### 21 across datasets. 

### 22 So this slide I will bring back later. I will

### Page 39 1 not talk about it too much, but it is a nice, 

### 2 pull-it-all-together, it is a plot out of the NRC that brings 

### 3 all of the major components together to think about how to do 

### 4 risk characterization. It is largely in line with the AOP 

### 5 concept as you begin with the idea of compounds and metabolites, 

### 6 whether those are active metabolites or not. Then you have this 

### 7 whole idea of modes of action of adverse outcome pathways coming 

### 8 together in a dose response analysis. 

### 9 What I like about this figure is it brings 

### 10 together this idea that you are calibrating in vitro and human 

### 11 dosimetry together in one place. I think that is really one of 

### 12 the biggest challenges we have the chlorpyrifos is to really 

### 13 bring in line and to make sense of not only in vitro data, but 

### 14 epidemiology data and animal toxicology data all together. 

### 15 Calibration is sort of the key areas. We have epidemiology 

### 16 studies, we certainly have lots of urinary biomarker data. 

### 17 So this one does not show too well on the 

### 18 screen, but it is directly out of the issue paper. We put 

### 19 together this organizing framework for the chlorpyrifos just 

### 20 almost for ourselves to keep everything straight, so that we 

### 21 know who we are looking at, what the populations are. It is 

### 22 important to think about how they are exposed, because certainly

### Page 40 1 infants are exposed in a very different way than is the fetus 

### 2 and is mom. 

### 3 We have multiple AOPs that we are tracking. 

### 4 We have cholinesterase inhibition that we know quite a bit about 

### 5 and that we have a lot of experience with. Then, we have 

### 6 multiple hypotheses for the neurodevelopmental outcomes. 

### 7 It is important to think about critical 

### 8 duration from a risk assessment point of view. Are they single 

### 9 day events, are these chronic events or is it more complicated 

### 10 than that. We have windows of susceptibility that may have 

### 11 different durations. Certainly what the adverse outcome related 

### 12 to those are, is it cholinergic toxicity or is it some sort of 

### 13 neurodevelopmental outcome. 

### 14 With that, I think the last slide is just the 

### 15 outline of today. So, we are done with the introduction. I 

### 16 will be passing the microphone in a few minutes over to Bill 

### 17 Mundy. He is going to give the presentation. Stephanie Padilla 

### 18 is also at the table. She was a major contributor to that 

### 19 section. Ginger Moser was also a contributor to that piece of 

### 20 the document. 

### 21 After the break, I think Ginger Moser will be 

### 22 giving the presentation on the Effects in in vivo Studies in the

### Page 41 1 Developing Brain, followed by Carol Christensen who is going to 

### 2 talk extensively about the epidemiology cohort. Lieutenant 

### 3 Aaron Niman along with Chester Rodriguez developed the chapter 

### 4 on biomonitoring and interpretive approaches. You will hear 

### 5 from Lieutenant Niman on that. I will finish it up at the end 

### 6 to bring all of the themes back together and talk about the 

### 7 charge questions and where we are headed next. 

### 8 DR. KENNETH PORTIER: Okay, at this point, we 

### 9 open it up to any clarifying questions from the Panel. I just 

### 10 remind you if you have questions, state your name and use the 

### 11 microphone. Anyone? Dr. Harry. 

### 12 DR. JEAN HARRY: So, just a concept as you are 

### 13 going through and you define periods of exposures and then you 

### 14 also define, looking at the complicated graph at the end, you 

### 15 also define susceptible windows of exposure. You are also now 

### 16 talking about disruption of homeostasis. So, you have a lot of 

### 17 concepts within those 3 statements. 

### 18 Just before we get into it, I would like to be 

### 19 clear about how are you thinking about animal studies that do a 

### 20 low-level exposure across a long time period, which may actually 

### 21 catch your windows of susceptibility, but may not represent 

### 22 disruption of homeostasis during that susceptibility? Is that

### Page 42 1 making any sense? 

### 2 DR. ANNA LOWIT: I was following you until the 

### 3 last phrase. I will speak more at a high level and I do not 

### 4 want to get into discussion, but I think certainly you have hit 

### 5 on one of the challenges of this whole enterprise that you have 

### 6 lots of studies. I think Ginger's presentation particularly 

### 7 will highlight that you have lots of studies with lots of 

### 8 different dosing regimens, lots of different labs doing lots of 

### 9 different, very interesting things. They are not always in line 

### 10 with each other. They have different hypotheses about why they 

### 11 are doing different things. 

### 12 The challenge is really to bring all of that 

### 13 together and looking at it from multiple points of view, almost 

### 14 a 3-dimensional, multidimensional look of what are the strengths 

### 15 of those dosing regimens, where are the uncertainties, where can 

### 16 you bring in information from other sources to focus what that 

### 17 window of susceptibility may have been, where is the uncertainty 

### 18 and strength in doing that, and bringing this multidimensional 

### 19 thing together will help us understand where those uncertainties 

### 20 and strengths lie, and help us define in our risk assessment, 

### 21 what are the critical durations if you think about it as ranges. 

### 22 I think I will just stop with that.

### Page 43 1 DR. KENNETH PORTIER: Any additional 

### 2 questions? Okay, I think we will move on. Dr. Mundy. I am 

### 3 sorry, I will put my glasses on here and get this right. That 

### 4 is what I get for reading all the way over. 

### 5 DR. WILLIAM MUNDY: That is okay, I can barely 

### 6 see the screen. My name is Bill Mundy. I am a 

### 7 Neurotoxicologist in the Office of Research and Development. I 

### 8 have laboratories. I work in our laboratories down in research, 

### 9 Triangle Park, North Carolina. I am going to spend the next 20 

### 10 minutes or so summarizing some of the data that suggests there 

### 11 are multiple biologically plausible pathways by which 

### 12 chlorpyrifos and its metabolites could result in developmental 

### 13 neurotoxicity. 

### 14 My talk is going to focus on those pathways 

### 15 that are not associated with the inhibition of 

### 16 acetylcholinesterase. 

### 17 So here is an outline of my talk. I am going 

### 18 to start out giving you a little bit more detailed overview of 

### 19 the adverse outcome pathway concept. I will give a definition, 

### 20 talk about how it can be used to place data that is derived at 

### 21 different levels of biological organization in the context. I 

### 22 will give an example of an AOP that has been developed for a

### Page 44 1 chemical that causes neurotoxicity. I will talk a little bit 

### 2 about the criteria you would use to evaluate how well data in 

### 3 the literature would support an adverse outcome pathway. 

### 4 I am then going to go on and give you an 

### 5 overview of the potential pathways or the data that exists that 

### 6 suggests there are potential pathways for chlorpyrifos to result 

### 7 in adverse neurodevelopmental outcomes. I will give a specific 

### 8 example for the pathway of neurite outgrowth. I will talk about 

### 9 where the data currently exists where chlorpyrifos and these 

### 10 metabolites have effects at different levels of biological 

### 11 organization, and then talk just a little bit about how these 

### 12 pathways relate to the presence or absence of inhibition of 

### 13 acetylcholinesterase. 

### 14 So here is our working definition of an 

### 15 adverse outcome pathway. So, an adverse outcome pathway or an 

### 16 AOP, is a conceptual framework that portrays existing knowledge 

### 17 concerning the linkage between a direct molecular initiating 

### 18 event and an adverse outcome at a level of biological 

### 19 organization relevant to risk assessment. 

### 20 So as we have already mentioned, this AOP 

### 21 concept incorporates concepts that we normally think about such 

### 22 as mechanism of action, which we think about as being a detailed

### Page 45 1 understanding of the molecular basis of the toxic effect in the 

### 2 concept of mode of action, which we think about as the likely 

### 3 key or critical events that lead to the ultimate toxic outcome. 

### 4 5 So this next slide has a diagram of a generic 

### 6 adverse outcome pathway. As you can see, it explicitly lays out 

### 7 the steps between the molecular initiating event and an adverse 

### 8 outcome of concern to a risk assessment. Note that this adverse 

### 9 outcome can be at the level of the individual, so for example, 

### 10 development of cancer; or at the level of a population, so there 

### 11 is loss of a species and an ecosystem. 

### 12 So what this does is explicitly lays out the 

### 13 key events that occur at increasing levels in biological 

### 14 organization. You have the first interaction of the chemical 

### 15 with the cell with molecules in the cell as the molecular 

### 16 initiating event. This interaction may be something like the 

### 17 receptor ligand interaction or bindings to macromolecules in the 

### 18 cell, DNA binding, protein oxidation for example. 

### 19 This effectiveness at the molecular level 

### 20 would then lead to effects at the cellular level. For example, 

### 21 gene activation, increased levels of protein expression, altered 

### 22 signaling, you would have changes in cell structure or function.

### Page 46 1 These changes at the cellular level would then lead to changes 

### 2 at the tissue or organ level, such as altered tissue 

### 3 development, altered tissue function. These changes at the 

### 4 level of the tissue organ would ultimately lead to the effect in 

### 5 the individual or the population, which we would consider 

### 6 adverse. 

### 7 So by thinking of toxicity in terms of adverse 

### 8 outcome pathway, you get a number of things. First, it sort of 

### 9 forces you to explicitly propose a set of biologically plausible 

### 10 linkages between your molecular initiating event and your 

### 11 adverse outcome. 

### 12 As an experimental toxicologist, I think Steve 

### 13 mentioned this, it is like forcing you to actually lay out your 

### 14 working hypothesis at all levels of biological organization. 

### 15 When you do that, it allows you to place data that is collected 

### 16 at different levels of biological organization into a context 

### 17 with which you can evaluate the relationship between these 

### 18 different levels of organization. 

### 19 Finally, as we all know, most chemicals be 

### 20 they a pharmaceutical chemical, an industrial chemical, an 

### 21 environmental contaminant, have more than one site of action or 

### 22 mechanism of action. By having an explicitly laid out adverse

### Page 47 1 outcome pathway, it helps you to focus on those chemical 

### 2 mechanisms that are related to this specific adverse outcome 

### 3 that you are interested in or you regulate. 

### 4 I would also like to talk about the adverse 

### 5 outcome pathway in terms of the toxicity pathway concept that we 

### 6 have already heard mentioned. So, most of you know the toxicity 

### 7 pathway concept was laid out in the NRC report, Toxicity Testing 

### 8 in the 21st Century. The toxicity pathway is a normal cellular 

### 9 response pathway as outlined there, which is then perturbed by 

### 10 the introduction of a chemical stressor, which we would call a 

### 11 molecular initiating event. 

### 12 Now, this introduction of the chemical would 

### 13 perturb the cellular pathway away from normal. So you have a 

### 14 perturbed function or structure of the cell. Now depending upon 

### 15 the degree of perturbation, so depending upon factors like dose 

### 16 or time of exposure, the cell may have adaptive responses that 

### 17 return the cell back to its normal cellular response pathway, if 

### 18 that degree of perturbation is greater. So thinking about 

### 19 things like an increase in dose or an increase in time of 

### 20 exposure, you overcome those adaptive responses. 

### 21 The cell now continues down a maladaptive 

### 22 response to cell injury, cell dysfunction and ultimately leading

### Page 48 1 to the adverse outcome. 

### 2 So, the toxicity pathway, molecular initiating 

### 3 event the perturbed cellular response can be seen as the first 2 

### 4 steps in an adverse outcome pathway. 

### 5 So, I would like to briefly talk about this 

### 6 example of an adverse outcome pathway with a neurotoxicity of 

### 7 domoic acid. Now, this was a case study that was put together 

### 8 to understand how adverse outcome pathways could be used as part 

### 9 of a Pellston Workshop. This case study has actually been 

### 10 published by Watanabe et al, which is referenced in your Draft 

### 11 Issue Paper. What they have done is listed explicit molecular 

### 12 initiating event, key events at increasing levels of biological 

### 13 organization and related them to an adverse outcome. 

### 14 So, domoic acid is an algal toxin. It has a 

### 15 structure of excitatory amino acid. Both in humans, wildlife 

### 16 and experimental animals, it has been shown to produce memory 

### 17 loss, seizures and ultimately death. So, based on this 

### 18 structure of domoic acid, they propose the following pathway. 

### 19 Domoic acid acts as an excitatory amino acid, 

### 20 and the molecular initiating event would be binding to and 

### 21 activating glutamate receptors in the brain, specifically the 

### 22 kainate receptor. The 3D structure of kainate structure is

### Page 49 1 shown below. Activation of the kainate receptor increases eye 

### 2 influx, causes neuronal depolarization, and ultimately at the 

### 3 level of the cell results in disruption of normal intracellular 

### 4 calcium levels. 

### 5 At the cellular level, you can see that 

### 6 increasing levels of domoic acid cause an increase in the amount 

### 7 or level of intracellular calcium. What you probably cannot see 

### 8 in that lower graph is increase in intracellular calcium as 

### 9 associated with increasing cell death. 

### 10 Now because these kainate receptors are 

### 11 expressed primarily in the hippocampus, the organ level response 

### 12 is an in hippocampal cell death. Below there, you can see some 

### 13 photomicrographs of the pyramidal layer of the hippocampus. On 

### 14 the left side, it is from a control animal, and on the right 

### 15 side is from an animal treated with domoic acid. I think even 

### 16 in these small pictures, you can see there is a large amount of 

### 17 cell loss in the treated animal. 

### 18 Now because hippocampal circuitry is important 

### 19 for learning and memory, disruption of hippocampal circuitry by 

### 20 the loss of these cells in the pyramidal layer leads to memory 

### 21 loss. The data there shows impaired performance on a memory 

### 22 task by a rat treated with domoic acid.

### Page 50 1 So, what this case study shows is that you can 

### 2 explicitly lay out an adverse outcome pathway, stating plausible 

### 3 biological connections at increasing levels of biological 

### 4 complexity and support that with data from the literature. 

### 5 I would like to continue to use this example 

### 6 to talk about some of the criteria you would use to evaluate how 

### 7 well data supports an adverse outcome pathway. If you think 

### 8 about plausibility, there needs to be an excepted theoretical 

### 9 basis for the biological connections you are proposing. In the 

### 10 case of domoic acid, there is a huge toxicology and 

### 11 neurobiological literature on excitatory toxicity and the 

### 12 relationship between excitotoxicity and behavioral changes. 

### 13 There should be a temporal relationship. 

### 14 So, effects that occur at a lower level of 

### 15 biological organizations should occur prior to effects that 

### 16 occur at the next. There are a number of examples of this for 

### 17 domoic acid, but one is we do not see behavioral changes in the 

### 18 animal before you see significant cell loss in the hippocampus. 

### 19 20 Of course with any study of toxicology, dose 

### 21 response is important. In terms of the adverse outcome pathway, 

### 22 doses that cause a significant effect at a lower level of

### Page 51 1 biological organization should be less than or about the same as 

### 2 doses that would cause a change at the next level. In the case 

### 3 of domoic acid, if you look at the concentrations that activate 

### 4 the kainate receptor, they occur at concentrations that are 

### 5 lower than or about the same as the concentrations that increase 

### 6 intracellular calcium. 

### 7 The other important issue to think about in 

### 8 dose responses is the adaptive response. At what concentration 

### 9 do you see an effect at one level of biological organization 

### 10 that overcomes any adaptive response at that level lead to an 

### 11 effect at the next level? 

### 12 I know that it is hard to see, but if you look 

### 13 at that calcium dysregulation graph, you can see at the lower 

### 14 level of domoic acid, calcium goes up rather significantly. 

### 15 Over the time course, which is shown there, which is about 20 or 

### 16 30 minutes, it starts to come back down to baseline. So, the 

### 17 cell can buffer at increases in intracellular calcium. Indeed 

### 18 at that level of domoic acid, you do not see very much cell 

### 19 death. However, at the next level of domoic acid, you see a 

### 20 large increase in intracellular calcium, and it does not return 

### 21 to baseline. In fact, you have overwhelmed the calcium 

### 22 buffering capabilities of the cell, and now get cell death and

### Page 52 1 subsequent loss of cells in the hippocampus. So, dose response 

### 2 is critical. 

### 3 Finally, you want to think about 

### 4 experimentally verifying the relationship between the effects at 

### 5 each level of biological organization. So, altering the effect 

### 6 at one level should alter the effect at the next. There are 

### 7 lots of examples in the literature for domoic acid. If you use 

### 8 an antagonist at the kainate receptor in the presence of domoic 

### 9 acid, you block the increase in intracellular calcium. If you 

### 10 buffer intracellular or chelate intracellular calcium in the 

### 11 cell, you block the cell death, experimentally verifying these 

### 12 links between different levels of organization. 

### 13 So I would like to move on and talk about some 

### 14 of the potential biological pathways that could lead to 

### 15 neurodevelopmental toxicity through chlorpyrifos or its 

### 16 metabolites. So, this is just an overview showing that for 

### 17 chlorpyrifos metabolites, data exists at a number of levels of 

### 18 biological organization. What we have done is taken this data 

### 19 and sort of arbitrarily named some domains based on the 

### 20 molecular or mechanism under which this data falls. 

### 21 Each one of these domains, I do not have time 

### 22 to go into it but it is in the draft report, has a biologically

### Page 53 1 plausible connection between disrupting the domain and the 

### 2 pathway and resulting in an adverse neurodevelopmental outcome. 

### 3 These domains including disrupting the morphogenic properties of 

### 4 the acetylcholinesterase protein, directly interacting with 

### 5 cholinergic receptors, perturbing the endocannabinoid system, 

### 6 increasing the amount of reactive oxygen species, perturbing the 

### 7 serotonergic system and binding to tubulin or 

### 8 microtubule-associated proteins, or MAPs. 

### 9 So, I think you can see there is at least some 

### 10 data at some level of biological organization for each one of 

### 11 these proposed domains or pathways. I think one thing that is 

### 12 obvious fairly quickly is that there is not a complete set of 

### 13 data at every level of biological organization for anyone of 

### 14 these pathways. For example for the reactive oxygen species 

### 15 pathway or domain, there is no proposed molecular initiating 

### 16 event, although there is data both in vitro and in vivo showing 

### 17 that there is increase in reactive oxygen species at the 

### 18 cellular level, and also data at the level of the CNS showing an 

### 19 in vivo stress response genes to reactive oxygen species. 

### 20 The other point I would like to make here is 

### 21 my opinion is that one reason that there is not a complete set 

### 22 of data for any one of these is that in reality, these domains

### Page 54 1 have not been explicitly proposed as adverse outcome pathways. 

### 2 Without that framework, the appropriate data has not been 

### 3 generated to test that pathway. 

### 4 So, what we have done in this slide is 

### 5 actually propose a potential adverse outcome pathway based on 

### 6 the morphogenic properties of acetylcholinesterase. We have 

### 7 proposed a molecular initiating event, key events at the 

### 8 cellular level and organ level, and an adverse outcome of 

### 9 concern to risk assessment. This pathway is based on the 

### 10 neurobiological literature showing that the acetylcholinesterase 

### 11 protein can act as a morphogen and control cell growth in the 

### 12 developing nervous system. 

### 13 In this pathway, the molecular initiating 

### 14 event is binding to and altering the morphogenic properties of 

### 15 the acetylcholinesterase protein. Alteration of the 

### 16 acetylcholinesterase morphological part of the protein would 

### 17 then alter neurite outgrowth, so the outgrowth of axons and 

### 18 dendrites at the cellular level. This effect on neurite growth 

### 19 at the cellular level would perturb the normal connectivity or 

### 20 normal development of the connections in the developing nervous 

### 21 system. This impaired neural connectivity would then cause 

### 22 impairment in cognition in the whole organism.

### Page 55 1 So, there is data for both chlorpyrifos, 

### 2 chlorpyrifos oxon and trichloropyridinol both in vitro and in 

### 3 vivo at several levels of biological organization. As you know, 

### 4 both chlorpyrifos and chlorpyrifos oxon can bind to the 

### 5 esteratic site of acetylcholinesterase. That has been proposed 

### 6 to result in a conformational change that alters the morphogenic 

### 7 properties of the protein. In addition, chlorpyrifos oxon 

### 8 combines with the peripheral anionic site of the protein, also 

### 9 proposed to alter its morphogenic properties. At the level of 

### 10 the cellular response, there is data in vitro showing that 

### 11 chlorpyrifos, chlorpyrifos oxon and trichloropyridinol can 

### 12 decrease neurite outgrowth in vitro, in some cases at levels 

### 13 that do not inhibit acetylcholinesterase, but also at levels 

### 14 that do inhibit acetylcholinesterase. In vivo, there is data 

### 15 showing the chlorpyrifos oxon can decrease axon outgrowth. 

### 16 However, this data is only shown in the presence of inhibition 

### 17 of acetylcholinesterase. 

### 18 So, this was our attempt to place some of the 

### 19 data at different levels of biological organization in the 

### 20 literature into a biologically plausible adverse outcome 

### 21 pathway. This slide gives a little bit more detail on some of 

### 22 the data that exists at different levels of biological

### Page 56 1 organization. So, if you look at the morphogenic properties of 

### 2 acetylcholinesterase, as I just said, the molecular initiating 

### 3 event would be binding to acetylcholinesterase and altering that 

### 4 morphogenic site. 

### 5 There is data showing that that leads to 

### 6 decreased or altered neurite outgrowth at the cellular level in 

### 7 at least one piece of data showing that that leads to change in 

### 8 axon length at the level of the central nervous system. 

### 9 For cholinergic receptors, a molecular 

### 10 initiating event would be binding to and activating the M2 

### 11 subtype of the muscarinic receptor. At the cellular level, this 

### 12 leads to a decrease in production of cyclic AMP. 

### 13 For perturbation of the endocannabinoid 

### 14 system, we have data suggesting an initiating event in binding 

### 15 to and inhibiting the CB1 receptor and also inhibition of a 

### 16 downstream enzyme, a fatty acid hydrolase. 

### 17 For reactive oxygen species, there is no 

### 18 proposed molecular initiating event, but there is data showing 

### 19 increased reactive oxygen species formation at the cellular 

### 20 level both in vitro and in vivo. At the organ level, there is 

### 21 data showing that this increase in reactive oxygen species leads 

### 22 to an increase in expression of oxidative stress response genes.

### Page 57 1 For the serotonergic system, again there is no 

### 2 explicit molecular initiating event, but there is data at the 

### 3 cellular level showing that there are changes to serotonin and 

### 4 serotonin signaling. These changes in serotonin signaling are 

### 5 also observed in the central nervous system and different brain 

### 6 regions at the organ level. This has been shown to result in 

### 7 changes in serotonergically mediated behavior, both in the basal 

### 8 response and after drug challenges. 

### 9 Finally for tubulin and microtubule-associated 

### 10 proteins, the molecular initiating event would be binding to 

### 11 these 2 proteins. This leads to a change at the cellular level 

### 12 of impairing axonal transport. 

### 13 So, I would like to sort of finish up here by 

### 14 showing some data that suggests that these pathways may be 

### 15 initiated at levels or doses that do not necessarily inhibit 

### 16 acetylcholinesterase. I have given four examples here, where 

### 17 acetylcholinesterase activity was assessed in the same system 

### 18 comparably. These examples all have concentration or dose 

### 19 response relationships. There is a significant response in the 

### 20 absence of significant inhibition of acetylcholinesterase. 

### 21 So, the first example is in vitro example 

### 22 using primary neuronal cultures, again showing a decrease in

### Page 58 1 neurite outgrowth and the absence of significant inhibition of 

### 2 acetylcholinesterase. 

### 3 The second example looks at neonatal exposure 

### 4 to the rat, chlorpyrifos showing an increase in oxidative stress 

### 5 response genes at levels that did not inhibit 

### 6 acetylcholinesterase in the brain. 

### 7 The third example again is in vitro looking at 

### 8 primary neuronal cultures. It was shown that there can be 

### 9 inhibition of axonal transport in these cultures in the absence 

### 10 of acetylcholinesterase inhibition. 

### 11 The last example again is perinatal exposure 

### 12 to the rat, showing changes in serotonergic tone in the adult 

### 13 CNS in the absence of cholinesterase inhibition. In this 

### 14 particular case, acetylcholinesterase activity was measured in a 

### 15 separate experiment using identical exposure protocol. 

### 16 So, just an overall summary of the data for 

### 17 multiple plausible events induced by chlorpyrifos and its 

### 18 metabolite: So in terms of plausibility, there is data 

### 19 suggesting multiple biologically plausible initiating events 

### 20 and/or downstream events. However, as I mentioned, few of these 

### 21 have been explicitly outlined as adverse outcome pathways and 

### 22 few of them have been studied as such.

### Page 59 1 In terms of temporal relationship, almost all 

### 2 of these studies, the data show there is a temporal relationship 

### 3 between exposure and effects at increasing levels of biological 

### 4 organization. In terms of dose response, there is limited data 

### 5 showing dose response relationships across increasing levels of 

### 6 biological organization. However, as I just showed in the last 

### 7 slide, there is evidence for effects, which are either similarly 

### 8 sensitive or more sensitive to chlorpyrifos or its metabolites 

### 9 in the inhibition of acetylcholinesterase. 

### 10 Finally, in terms of experimental 

### 11 verification, there is limited data showing experimentally a 

### 12 verification between an effect at one level of biological 

### 13 organization and the next. I think that is the last slide. 

### 14 DR. KENNETH PORTIER: At this point, we open 

### 15 up the questions from the panel. I think Dr. Aschner wanted to 

### 16 ask one way early in your presentation, so he is probably going 

### 17 to ask you to flip back to a previous slide. 

### 18 DR. MICHAEL ASCHNER: Michael Aschner, hi 

### 19 Bill. Thanks for the presentation. I have a question. Maybe 

### 20 we can go back to the linear path. It is like the second slide. 

### 21 It is more of a framework for the panel, but are we supposed to 

### 22 think in those terms, is this sort of the way that you would

### Page 60 1 like us to think about chlorpyrifos or any other chemical? 

### 2 Because the way that I envision things, and we 

### 3 can argue about chlorpyrifos is that there are many chemicals 

### 4 that do not work this way where you cannot go to this linear 

### 5 pathway. I can envision chemicals which affect the third box 

### 6 from the left right away, skipping the first two. When we are 

### 7 done here, are we supposed to say one, two, three, four, five, 

### 8 six happen in a sequence? I do not think we can use this as a 

### 9 framework. Even if it works for chlorpyrifos, and I am not sure 

### 10 it will. It does not work with many, many other chemicals, so 

### 11 it may put the agency into some - I mean you want consistency 

### 12 between different compounds. With this kind of framework, it is 

### 13 not going to work. 

### 14 DR. WILLIAM MUNDY: I cannot answer what we 

### 15 want the Panel to do. Maybe Anna can describe that. I will say 

### 16 that this is obviously a very simplified linear flow. Adverse 

### 17 outcome pathways may have multiple initiating events leading to 

### 18 a common downstream event, or conversely there may be an initial 

### 19 initiating event that leads to multiple adverse effects. 

### 20 So, as we know, biology is not linear, it is 

### 21 three-dimensional or four-dimensional if you include time. But 

### 22 the concept is really linking an effect at one level to the next

### Page 61 1 level. I would challenge you to show me a compound that does 

### 2 not interact with a molecular level yet causes an effect. 

### 3 DR. MICHAEL ASCHNER: Sugar. 

### 4 DR. WILLIAM MUNDY: Sugar is a nutrient. 

### 5 There is a huge metabolic pathway for sugar. 

### 6 DR. MICHAEL ASCHNER: Osmotic shock with 

### 7 sodium chloride. 

### 8 DR. WILLIAM MUNDY: Sodium chloride will start 

### 9 affecting calcium fluxes. 

### 10 DR. MICHAEL ASCHNER: Sodium chloride will 

### 11 skip DNA binding, protein oxidation, receptor ligand 

### 12 interactions, gene activation, protein production, alter 

### 13 signaling. It is going to go straight into the third box if 

### 14 there is any. 

### 15 DR. WILLIAM MUNDY: Those are examples. There 

### 16 are obviously innumerable initiating events. That is one of the 

### 17 problems if we start talking about adverse outcome pathways is, 

### 18 what is the initiating event. We have not identified all of 

### 19 those yet, but I think this is a more general discussion that 

### 20 may not answer your question. I do not know if Steve wants to 

### 21 talk about how we want the panel to think about adverse outcome 

### 22 pathways.

### Page 62 1 DR. STEVEN BRADBURY: You should think as your 

### 2 mind takes you into challenges. I am not trying to put you in a 

### 3 box, but I think it is fair to say that not only EPA but NIH and 

### 4 FDA are trying to use this concept as we think about risk 

### 5 assessments and work in our research labs to help put 

### 6 information together. 

### 7 As Bill said, biological systems are 

### 8 inherently nonlinear. It is hard to write and talk in nonlinear 

### 9 ways, some do better than others. I think the NRC Panel is just 

### 10 trying to help us think about putting some thoughts together, 

### 11 some of the events that link to change in an inherently 

### 12 nonlinear system. 

### 13 With regard to an initiating event, I am 

### 14 trying to think of a way a chemical does not interact with 

### 15 something to cause a change at a tissue level. It covalently 

### 16 binds to something. It non-covalently binds to something. It 

### 17 starts redox cycling or it does not, but I think the idea of the 

### 18 NRC report is that a chemical interacts with something at that 

### 19 level. What that interaction would be, those are just some 

### 20 examples. These are not going to inclusive of all of the 

### 21 examples, by way a xenobiotic may, or nutrient may, interact 

### 22 with the system.

### Page 63 1 I think what we are curious about is if a 

### 2 chemical could cause something at a higher level of biological 

### 3 organization. I think the thought of the NRC Panel was that 

### 4 something must have happened at a lower level of biological 

### 5 organization. If we are having changes at a population level 

### 6 and reproductive failure in birds due to cholinesterase 

### 7 inhibition, which you might be able to see, something probably 

### 8 happened that leads to a change in fecundity in the females. 

### 9 To what degree can you start to piece together 

### 10 that, realizing there is going to be multiple pathways 

### 11 interacting with each other and it is going to be a nonlinear 

### 12 relationship, but a way to try to organize our thoughts. If you 

### 13 all come up with a different way of organizing the thinking 

### 14 around this data, that would be helpful. 

### 15 In the context of our charge questions, we are 

### 16 trying to get some advice building on previous SAPs and how to 

### 17 use this concept to organize our thoughts. If it cannot be 

### 18 done, it cannot be done. I would be curious to hear why, but 

### 19 then what would be the alternative way to try to link 

### 20 information at different levels of biological organization 

### 21 together to try to put a story together. We understand the 

### 22 strengths and limitations of this clearly.

### Page 64 1 DR. CHARLES VORHEES: I have a lot less 

### 2 complicated question. So, I am just interested you talked 

### 3 about these various effects and these hypothesized mechanism 

### 4 studies, and you talked about them as some of them occurring at 

### 5 doses below which cholinesterase inhibition occurs. Could you 

### 6 give us a little feel for what those doses are and how far 

### 7 removed they are from cholinesterase inhibition levels? 

### 8 DR. WILLIAM MUNDY: Yes, I did not give 

### 9 details. A lot of them are in the draft document. Some of the 

### 10 in vitro cases, there may be a 100 fold less than inhibiting 

### 11 acetylcholinesterase. In the in vivo situations, Stephanie? 

### 12 Not as much. So, the examples I gave without giving the details 

### 13 of the levels were showing in the same system that there was at 

### 14 least not significant change in acetylcholinesterase with a 

### 15 statistically significant change in the outcome. 

### 16 That relationship does depend on the system, 

### 17 whether be it in vitro or in vivo. Frankly, there is really not 

### 18 that much data surprisingly where researchers have done a 

### 19 careful dose response relationship between a molecular event, 

### 20 cholinesterase inhibition, in the next level of event. That is 

### 21 where I think getting toxicologists to use this adverse outcome 

### 22 pathway as a concept, as a framework. It allows you to think

### Page 65 1 about the experiment you need to do to answer that question. It 

### 2 can range from less than 10 fold to over 100 fold in some of the 

### 3 in vitro studies. 

### 4 DR. WILLIAM POPENDORF: My reading of it, I 

### 5 guess I did not quite grasp that linkage and it is done on a 

### 6 molar basis, right? How is that done in terms of then going 

### 7 from a dose that is typically not measured at a molar level 

### 8 within a cell or to a cell to the in vitro studies that you are 

### 9 talking about? 

### 10 DR. WILLIAM MUNDY: Sure, that is a really 

### 11 good question. In some cases, that is part of the difficulty in 

### 12 developing those experiments, especially going from an effect 

### 13 that goes from an in vitro prep, no matter what level of 

### 14 biologic organization is at, from an in vitro to an in vivo. 

### 15 So, some of the examples you would use as looking at an in vivo 

### 16 dose, estimating a molar concentration in the blood or brain. 

### 17 What we did not talk about at all here is the extrapolation 

### 18 issues and how you extrapolate quantitatively between levels of 

### 19 biological organization. 

### 20 So, within in vitro experiments or without in 

### 21 vivo experiments, you can make the direct comparison. But you 

### 22 are right, going from an in vitro at a molar basis, in vivo to a

### Page 66 1 dose basis, what you would at the first level do is try to 

### 2 convert that dose to a blood or a target tissue concentration in 

### 3 a molar basis. Of course, with better pharmacokinetics, you may 

### 4 be able to get that quantitative relationship down to a finer 

### 5 degree. That is a very excellent point, though. 

### 6 DR. WILLIAM POPENDORF: That is basically what 

### 7 you did to derive, when you say 100 fold, you have done that on 

### 8 those examples? 

### 9 DR. WILLIAM MUNDY: So, the 100 fold was 

### 10 actually measuring neurite outgrowth, for example, and 

### 11 acetylcholinesterase in the same system at the same time. So, 

### 12 it was purely a molar basis. 

### 13 DR. RUSSELL CARR: In an in vitro system, it 

### 14 is real easy to make that jump between the molecular target and 

### 15 the cholinesterase inhibition. However, in an in vivo system, 

### 16 unless you really have a well-established dose response as to 

### 17 over time, you cannot make a claim that there is no 

### 18 cholinesterase inhibition when you just take one time sample. 

### 19 That is an issue with a lot of the studies that they just depend 

### 20 on one time sample, and say that there is nothing there when we 

### 21 know in developing animals, their cholinesterase activity 

### 22 recovers so fast because they are growing, a lot of de novo

### Page 67 1 synthesis. So, if you miss that window where you may have had 

### 2 40% or 50% inhibition, it may have recovered by the time you 

### 3 measured it if you did not select a correct time. 

### 4 DR. WILLIAM MUNDY: I agree. 

### 5 DR. KENNETH PORTIER: Any additional 

### 6 questions? As I was looking at this, I was trying to think 

### 7 where do you include things like promoters, chemicals that 

### 8 actually act as promoters rather than direct toxicants? I do 

### 9 not know if I see it in this one or maybe in the next slide as a 

### 10 modifier of homeostasis, right? 

### 11 DR. WILLIAM MUNDY: Yes, I think the whole 

### 12 idea of the toxicity pathway concept is not that there has to be 

### 13 a toxic effect, but indeed that you are just perturbing a normal 

### 14 pathway. So in that case, any pathway could be a toxicity 

### 15 pathway if you are perturbing it from going to its normal 

### 16 function. 

### 17 I think that would include the concept of a 

### 18 promoter. The idea would be though, you need to show that 

### 19 perturbation at that particular level of biological organization 

### 20 overcomes any adaptive response and leads to an adverse effect 

### 21 at the next level. So does it respond to a chemical that is 

### 22 actually an adaptive response of increasing proliferation to

### Page 68 1 replace damaged cells actually overcompensate and lead to cell 

### 2 proliferation and tumor at the next level? So, you could have 

### 3 normal pathways that are perturbed outside of normal to a degree 

### 4 at least, to an effect at the next level. I think that is 

### 5 pretty inclusive in my opinion. 

### 6 DR. KENNETH PORTIER: Any other questions? 

### 7 Otherwise, we are going to go ahead and take a 15 minute break 

### 8 at this point. I am going by this clock over here, definitely 

### 9 not that one over there. This one says 10:37, so we will return 

### 10 in 15 minutes. 

### 11 (WHEREUPON, a recess was taken) 

### 12 DR. KENNETH PORTIER: So during the break, I 

### 13 am sure there were a lot of new questions that came up, but we 

### 14 will have a couple of more opportunities to ask those questions. 

### 15 At this point, I am going to turn back to EPA for the next 

### 16 presentation, Dr. Moser. 

### 17 DR. GINGER MOSER: Okay, good morning. I am 

### 18 Ginger Moser. I am a Neurotoxicologist with ORD down in the 

### 19 North Carolina Research Triangle Labs. What I am going to talk 

### 20 about is to go over the animal studies, looking at chlorpyrifos 

### 21 effects on the developing brain. 

### 22 By way of introduction, I want to start out

### Page 69 1 with the discussions that we had in 2008 with the SAP back then. 

### 2 They reviewed the animal studies and concluded that independent 

### 3 of the time of exposure, whether it be gestation or postnatal, 

### 4 dose of 1 mg/kg and greater demonstrated significant effects on 

### 5 behavior. They did express 2 areas of concern, being the 

### 6 inconsistent behavioral effects and the lack of dose response of 

### 7 data on cholinesterase inhibition. At that time, they 

### 8 recommended that we review the critical events at the time of 

### 9 the exposure and targeted end points. What we had done back 

### 10 then was only look at the effects of 1 mg/kg. 

### 11 So, what we have done in this current review 

### 12 is to look at the behavioral changes in terms of the domains of 

### 13 neurological function, what type of neurobehavioral effects are 

### 14 being altered. We wanted again to try to look at critical 

### 15 exposure periods and of course, the primary thing to look at is 

### 16 brain cholinesterase inhibition during the critical periods. 

### 17 So, in the document you saw a targeted review 

### 18 of the papers that have come out since 2008. We wanted to look 

### 19 at those papers carefully in terms of what new information they 

### 20 gave and how well they integrated with the existing database. 

### 21 What I am going to try to cover today is that full database and 

### 22 not just focus on those more current papers.

### Page 70 1 So, the existing literature for chlorpyrifos 

### 2 is really kind of a moving target. There was actually another 

### 3 paper that came out just within 2 weeks ago, bringing the total 

### 4 papers up to 26. They come from 11 different laboratories. So, 

### 5 not all of these studies are being conducted at 1 or 2 places. 

### 6 There were 9 papers that have come out since 

### 7 2008 adding 2 new laboratories. I should note one of the papers 

### 8 that came out since 2008 is in Chinese, so it was kind of 

### 9 difficult to evaluate that one, even though I do have an 

### 10 informal translation of that paper. I am not going to include 

### 11 that data. 

### 12 So, in the document, we focused our review on 

### 13 the studies where they were dosing the animals at any time up to 

### 14 weaning. We have only looked at the papers where the animals 

### 15 were assessed after weaning, because we wanted to look at more 

### 16 long term impacts. We did not want to have the confound of 

### 17 concurrent cholinesterase inhibition. We only looked at the 

### 18 papers where they had lower doses because we wanted to avoid a 

### 19 lot of cholinesterase inhibition and the toxicity that is 

### 20 involved with that. We also focused on the rodent studies. 

### 21 That left us with 20 papers from 9 different 

### 22 laboratories. Of those 20 papers, there were 25 actual studies

### Page 71 1 because several of the papers looked at different exposure 

### 2 periods within the same paper. So, there is a lot of 

### 3 variability in these 25 studies. They include differences in 

### 4 the exposure paradigms. In fact, there are 10 gestational 

### 5 studies that have 7 different dosing periods, 13 postnatal 

### 6 studies with 5 different dosing periods, and then they have 2 

### 7 perinatal studies, each of which have different dosing periods. 

### 8 So, it is next to impossible to really compare across the 

### 9 studies that have the same dosing period. 

### 10 There are 4 different routes of 

### 11 administration, 4 different vehicles that have been used. One 

### 12 of the vehicles that is widely used is DMSO. That has been a 

### 13 concern. It was a concern of the 2008 SAP because it does 

### 14 change the pharmacokinetics of the chemical somewhat. The dose 

### 15 selections, about half of the studies actually only used 1 dose. 

### 16 A few of the other papers have looked at either 2, 3 or 5 

### 17 doses. As just as far as the species go, about half of the 

### 18 studies have been done in rats and about half in mice now. 

### 19 So, as I am going through this, I want to just 

### 20 kind of keep in mind the guidelines that the agency has issued 

### 21 for neurotoxicity risk assessment. Concerning developmental 

### 22 neurotoxic studies, the conclusions and the guidelines for

### Page 72 1 interpretation were the developmental effects in animals do 

### 2 indicate the potential for altered neurobehavioral development 

### 3 in humans, and that the specific types of developmental effects 

### 4 that are seen in the animal studies may or may not be the same 

### 5 as those seen in the humans. You can kind of keep that in mind 

### 6 as we are going through the animal studies and as we go through 

### 7 the human studies this afternoon. 

### 8 So, what I wanted to do is go through the 

### 9 studies, summarize the studies in terms of the different 

### 10 functional domains that are being measured, give an overview of 

### 11 the outcomes and some representative data in a couple of places, 

### 12 and then try to give an indication of the strengths and the 

### 13 limitations of some of those studies. 

### 14 So, for cognition, there were quite a few 

### 15 studies that have looked at measures of cognition. The spacial 

### 16 learning and memory has been looked at using a radial arm maze, 

### 17 using a morris water maze and then a foraging task in a radial 

### 18 arm maze. Eight out of the 9 studies where they have used these 

### 19 tests have reported altered function. Most of those studies 

### 20 show deficit in cognition or impaired cognition, but a few have 

### 21 actually shown improvement. I will show an example of that in a 

### 22 minute.

### Page 73 1 These 9 studies include gestational and early 

### 2 postnatal exposures. The effects have been seen at 1 mg/kg per 

### 3 day and above. Maybe at 0.3 mg/kg per day, but that was one 

### 4 study that has some other issues with it. In fact, the 2008 SAP 

### 5 had a lot of concerns with that study and felt like it really 

### 6 should not be considered. The lowest no effect level that has 

### 7 been reported, and this is in a newer paper, is 0.2 mg/kg per 

### 8 day. In that study, they did use the water maze. 

### 9 There have been five studies that looked at 

### 10 alternation learning in a T maze, all of which showed no effect. 

### 11 There were two studies that looked at classical conditioning 

### 12 using a passive avoidance, and all of those showed no effect. 

### 13 These tests that have been used are all 

### 14 validated and accepted and widely used in the literature with 

### 15 the only exception being the foraging task, which is a novel 

### 16 task. In that paper, it was presented as an alternative to the 

### 17 radial arm maze. The morris water maze has of course been used 

### 18 for two or three decades. There have been some replications 

### 19 using this test within one laboratory, two different studies 

### 20 that I will show in a minute. 

### 21 The radial arm maze has been used across 

### 22 several laboratories, but unfortunately they have used different

### Page 74 1 procedures and different equipment. The gender differences that 

### 2 have been reported differ in terms of the affect and also in the 

### 3 control values. 

### 4 With cognitive tests, it is important to have 

### 5 measurements of the activity level or any kind of motor 

### 6 disturbances because this can confound the performance. So, six 

### 7 of the studies actually did look at some measure of activity. 

### 8 Out of those 6 studies, 5 did not show changes in the activity 

### 9 levels. 

### 10 There was dose response seen in a little over 

### 11 half of the studies where they used two or more doses. Of 

### 12 course, again, a lot of the studies only used one dose. 

### 13 Sometimes the effect size was small, sometimes not. Sometimes 

### 14 the differences were transient and sometimes they were 

### 15 persistent. 

### 16 This is an example of the morris water maze. 

### 17 These are two papers that came from the same laboratory. They 

### 18 had multiple studies within these papers looking at mice that 

### 19 had been exposed only during gestation from GD9 through 18. 

### 20 What is being measured here is the latency for 

### 21 the animal to find a hidden platform in this large tank of water 

### 22 that is a little bit dark, hopefully you can see that as a

### Page 75 1 morris water maze. So, over time, the animals learned this 

### 2 pretty easily. You can see a learning curve where the latency 

### 3 decreases in the controls. 

### 4 In this study, they looked at four different 

### 5 doses. They reported effects at 1 and 3 mg/kg per day, but not 

### 6 at the higher doses, the 5 and the 10. The graphic quality here 

### 7 is just really difficult for me to see. It is very difficult to 

### 8 pick out the different symbols, but right there, the red arrow 

### 9 points to the 3 mg/kg dose group. You can see that it is higher 

### 10 than the controls, which I think is that right there. They did 

### 11 report no changes in swim speed, which is an important measure 

### 12 in this test. 

### 13 Now the purpose of these papers was to look at 

### 14 potential treatments or attenuation of the chlorpyrifos effects 

### 15 by using either nicotine or stem cell transplantation. So, 

### 16 ignoring all that data, we only wanted to focus on the 

### 17 chlorpyrifos alone group. In three more groups of animals, they 

### 18 looked at 3 mg/kg of chlorpyrifos and the learning curves are 

### 19 indicated by the red arrows. In all cases in all three of these 

### 20 studies, there was slower learning that was taking place in the 

### 21 treated animals compared to control. Again, in all studies, 

### 22 there were no changes in swim speed.

### Page 76 1 These were some studies using the radial arm 

### 2 maze. In this case, they came from the same laboratory. They 

### 3 are using rats and they are using the radial arm maze shown 

### 4 there where some of the arms are baited, so the animals runs 

### 5 down the arms to get the food. Some of the arms are not baited. 

### 6 A reference memory error is when the rat goes into an arm that 

### 7 never has food in it. 

### 8 Again with training, the control animals 

### 9 learned this. Their number or errors go down. Both slides were 

### 10 seeing PND 1 through 4 exposure at 1 mg/kg only. They had no 

### 11 dose response here. What they reported in both of these studies 

### 12 were increased errors in the males, but decrease, which means 

### 13 improvement, in the females. 

### 14 This is the data for the males here. The 

### 15 controls are learning the task and the treated animals are 

### 16 learning it, but they learn it slower. The females of the 

### 17 treated animals tend to learn it more quickly. The authors 

### 18 state that in both cases, there was a significant overall effect 

### 19 of treatment, but not a significant treatment by time 

### 20 interaction, so they concluded that even this change was 

### 21 significant across training, even though it looks like here at 

### 22 the end of training, these data points are closer together.

### Page 77 1 In this other study, you see the same pattern 

### 2 with the females where the treated animals are improved in terms 

### 3 of their learning, and the males show a higher number of errors, 

### 4 but only at the beginning of training. In this case, they said 

### 5 it was significantly different only at the first trial. The 

### 6 overall story here with the difference in the sexes was same in 

### 7 both of these studies, but the actual values looked a little bit 

### 8 different. 

### 9 The next domain is the anxiety, emotion effect 

### 10 type of domain. Anxiety is measured with elevated plus mazes 

### 11 and a light/dark box. In seven out of the eight studies, there 

### 12 were reported altered behaviors, again either with gestational 

### 13 or postnatal exposures, and all the effects were seen at 1 mg/kg 

### 14 per day and above. 

### 15 There were a couple of studies that looked at 

### 16 novelty and chocolate preference, which is preference for a 

### 17 novel substance, the two studies that looked at novelty 

### 18 exploration showed no effect, but there was a change in 

### 19 chocolate preference, but this was only in one study. There has 

### 20 only been one study that looked at despair using a forced swim 

### 21 test, and there was no effect. 

### 22 Now again, these tests are validated, they are

### Page 78 1 well accepted and used in the literature, but the specific end 

### 2 points within the tests have not been consistently measured or 

### 3 altered across the studies. Even within the same laboratory and 

### 4 across studies, there have been different procedures, different 

### 5 end points that they look at, which may contribute to some of 

### 6 the differences. There are also differences in the direction of 

### 7 change. 

### 8 In the mouse studies, there were six mouse 

### 9 studies, three showed increased anxiety and three showed 

### 10 decreased anxiety. There were only two rat studies, one of 

### 11 which showed decreased anxiety. As with the cognitive test, 

### 12 activity measurements can confound the measurement in these 

### 13 studies, and six of the studies did look at activity levels and 

### 14 five of them reported no differences. There was only dose 

### 15 response in one out of the four studies seen where they used two 

### 16 or more doses. Again, sometimes the effect sizes were small, 

### 17 sometimes they were not. 

### 18 This study shows a couple of replications 

### 19 looking at anxiety using the elevated plus maze or the 

### 20 light/dark box. Both of these tests capitalize on the rodent's 

### 21 preference for the dark and/or the enclosed size of the 

### 22 chambers.

### Page 79 1 In this first study, they looked at anxiety in 

### 2 mice that had been exposed during gestation and lactationally. 

### 3 They only looked at females. They reported increased anxiety. 

### 4 This is the measurement with the light/dark box. The effect was 

### 5 only seen at 1 mg/kg. It is a pretty clear difference between 

### 6 the 1 mg and the low and the high dose. In the elevated plus 

### 7 maze, they also saw a change in the time of the open arms, which 

### 8 is indicative of increased anxiety. This was again only in the 

### 9 1 mg dose. 

### 10 Now, these were litter mates. They were not 

### 11 the same animals that were tested. They were litter mates, but 

### 12 it showed replication within the same study of the same type of 

### 13 effect using two different tests. 

### 14 Now, this other study looked at mice using 

### 15 just the elevated plus maze. These were mice that were exposed 

### 16 during the last postnatal period. Here we have a nice dose 

### 17 response and the percent of time spent in the open arms, which 

### 18 indicates decreased anxiety only at the high dose, even though 

### 19 the 1 mg dose tended to be kind of falling in between the 

### 20 controls and the high dose. So, there were changes in both of 

### 21 these studies, but the direction of change was different. 

### 22 The next domain that has actually had quite a

### Page 80 1 few studies now is looking at social and maternal behaviors. 

### 2 The most studies have looked at the same sex social 

### 3 interactions, so these are male/male and female/female 

### 4 interactions. Six out of 10 studies have reported altered 

### 5 behaviors, again as across either gestational or postnatal 

### 6 exposures. 

### 7 It has been pretty consistent that the social 

### 8 interactions are increased, but with increased agonistic or 

### 9 aggressive responses, which is only seen in the males. Five 

### 10 studies have looked at maternal behaviors, although there are 

### 11 some differences in how they actually did these maternal 

### 12 behavior studies. They did show changes in four out of the five 

### 13 studies. 

### 14 There are several of the studies that have 

### 15 consistently reported decreased reactions to an intruder, where 

### 16 an intruder male is placed in with the female, but then there 

### 17 are increased or decreased behaviors towards the pups. It 

### 18 should be noted that all of these studies have come from the 

### 19 same laboratory and have all been conducted in mice, but the end 

### 20 points have not been standardized across those studies within 

### 21 the same laboratory. In some cases, there have just been one or 

### 22 just a few significant changes out of a fair number of behaviors

### Page 81 1 that are measured. 

### 2 It should also be noted that test of social 

### 3 behavior has not been widely used in developmental neurotoxicity 

### 4 studies, although they have been recommended to be studied more. 

### 5 They are used a lot in other area of research, but not as much 

### 6 in developmental neurotoxic. 

### 7 The motor activity domain is another one where 

### 8 there have been quite a few studies that have looked at this. 

### 9 Fourteen studies have looked at spontaneous or exploratory 

### 10 behavior. This includes generalized locomotion and rearing. 

### 11 Basically, the tests have been conducted in figure-8 chambers or 

### 12 open fields. Eight out of the 14 studies have reported changes 

### 13 in the activity levels with either gestational or postnatal 

### 14 exposures. 

### 15 Now, the rat studies have been pretty mixed 

### 16 with one study showing increased, two showing decreased and two 

### 17 showing no effect on activity. Those have all been with 

### 18 postnatal exposures. There has been no effect reported at all 

### 19 with rats with gestational or perinatal exposures. It has been 

### 20 more consistent in that increased activity has been seen in all 

### 21 three of the studies where they looked at this in mice. That is 

### 22 gestational and postnatally.

### Page 82 1 Now, habituation is the change in activity 

### 2 over time. This is different from the total overall activity 

### 3 levels. There have only been six studies where they have 

### 4 actually analyzed habituation. Out of those six, three have 

### 5 reported alterations in this pattern. There have been different 

### 6 statistical approaches across the laboratories, so it is more 

### 7 difficult to make any kind of comparisons on this end point. 

### 8 Overall, the motor activity is accepted, widely used in 

### 9 toxicology, in pharmacology and psychology, so this is widely 

### 10 used behavior. 

### 11 And then to just touch on the neuromotor 

### 12 domain, the last one, this is very limited. There have only 

### 13 been three studies where they have even looked at this. There 

### 14 have been two studies that show no change in the auditory 

### 15 startle response, and one study that reported a change in other 

### 16 measures of neuromuscular performance. Again, with so few 

### 17 studies, there is not much that could be said there. 

### 18 Now, an important thing is to look at the 

### 19 cholinesterase inhibition in either the pup or the fetus during 

### 20 an exposure to try to relate this to the studies where they see 

### 21 behavioral changes. What I have shown here are the studies 

### 22 where they looked at cholinesterase inhibition at 1 mg/kg given

### Page 83 1 either once or repeatedly. 

### 2 As you notice, this dose is the one that 

### 3 produced effects in almost all the domains. When 1 mg/kg is 

### 4 given gestationally, there have only been two studies that 

### 5 looked at the fetal brain cholinesterase inhibition. In both 

### 6 studies, it showed no inhibition either 4 hours after the dose 

### 7 to the dam on GD20, or 24 hours after the dose to the dam. But 

### 8 there is no information on the fetal cholinesterase inhibition 

### 9 at any shorter times after dosing or whether there has been any 

### 10 inhibition on any other days. GD20 was the only day that has 

### 11 been looked at. 

### 12 When you look at the early postnatal studies 

### 13 where the pup is directly exposed between PND 1 to 4, you do see 

### 14 inhibition in the pup brain, whether it be given 1, 2 or 4 hours 

### 15 after dosing. If you give it on PND 1 just a single dose, you 

### 16 do see inhibition at 2 and 4 hours, but when it is given from 

### 17 PND 1 to 4 and then look at them on PND 4, you see inhibition at 

### 18 1 hour, but not 4 hours. This shows the faster recovery, which 

### 19 it is known that the very young pups recovery very quickly. 

### 20 As you can see, both of these studies in rats 

### 21 and mice show inhibition at 1 mg/kg. There have been no studies 

### 22 that have looked at potential inhibition at any lower doses at

### Page 84 1 this time exposure period. When you look at the later exposure 

### 2 period, PND 11 through 14, one study showed inhibition that was 

### 3 in rats, one study showed no inhibition in mice. 

### 4 So, there are a lot of potential sources of 

### 5 variability in these outcomes that you can see have been 

### 6 somewhat inconsistent, although there are some consistencies. 

### 7 These include the differences in experimental design that have 

### 8 already given some information about procedural equipment 

### 9 differences, lack of a dose response, differences in species and 

### 10 strains, route of exposure, differences in the ages, the periods 

### 11 of exposure and the differences when they are tested as adults. 

### 12 13 There are differences in control values in 

### 14 some cases and differences in the treatment effects, and that 

### 15 they are not always exactly reproduced across studies. There 

### 16 are differences in whether there might be brain cholinesterase 

### 17 inhibition in the pup. It looks like there probably is not. At 

### 18 least the gestational studies show that there is not fetal 

### 19 inhibition, but postnatally clearly there is. There are 

### 20 differences in the interpretations that have to do with 

### 21 statistical analyses. 

### 22 In some of the studies, the method of analyses

### Page 85 1 and also the acceptance criteria are not consistently applied. 

### 2 As I have mentioned, there are a lot of cases where the effect 

### 3 size is fairly small, which could represent either subtle 

### 4 effects or they could be false positives. There is also the 

### 5 potential for false negatives, either by having conservative 

### 6 acceptance criteria, which was especially the case in one paper, 

### 7 or by having underpowered study and not having a great enough 

### 8 sample size to really be able to pick up an effect. Then of 

### 9 course, there is a publication bias against studies of negative 

### 10 data, which can also influence interpretations. 

### 11 So to summarize, it is clear that there are 

### 12 multiple studies and laboratories now that have reported changes 

### 13 in various aspects of neurobehavioral function in the adult 

### 14 rodents following developmental exposure. These effects are 

### 15 seen long after the chemical exposure for the most part. If 

### 16 there is any cholinesterase inhibition, it has recovered by the 

### 17 time the rodents are tested. 

### 18 These behavioral alterations show some 

### 19 consistency if you look at the broad domains of neurological 

### 20 function, the most consistent effects being in cognition, 

### 21 especially with spacial learning and memory with being changes 

### 22 in anxiety, even though the direction of that change is

### Page 86 1 different, and in social behavior. As I say, the differences in 

### 2 direction and the magnitude of change and sometimes differences 

### 3 in the gender specificity, there are differences in the 

### 4 procedures, etc., that really impact the comparability and make 

### 5 it very difficult to compare directly across studies. 

### 6 There does not seem to be any clear evidence 

### 7 of a critical period of exposure. These effects are seen pretty 

### 8 much whether the exposure is during gestation or during 

### 9 postnatal periods. There is not a large difference in species 

### 10 between the rats and the mice. Basically, the new publications 

### 11 support the previous analyses in that the behavioral effects 

### 12 were again seen at doses of 1 mg/kg per day and above, and that 

### 13 again there is still not sufficient dose response data for 

### 14 effects relative to cholinesterase inhibition. 

### 15 There is just not enough data to be able to 

### 16 definitively conclude the relative sensitivity between these 

### 17 developmental outcomes and the cholinesterase inhibition because 

### 18 there have just not been enough studies that have looked at 

### 19 dosed below 1 mg/kg and actually measured cholinesterase 

### 20 inhibition at those time points. 

### 21 So what we really need are more robust dose 

### 22 response and time course data to really be able to be sure that

### Page 87 1 you are not just missing a critical time of cholinesterase 

### 2 inhibition in the pups. There needs to be more systematic 

### 3 replications of the exposure periods. With that, I can try to 

### 4 answer some questions. 

### 5 DR. KENNETH PORTIER: So we open it up to any 

### 6 questions from the Panel? Dr. Harry? 

### 7 DR. JEAN HARRY: Ginger on point of 

### 8 clarification with all the work you went through going through 

### 9 all of these papers, I have a few questions. I am just going to 

### 10 put them out to save time. One was you talked about the morris 

### 11 water maze and its use in neurosciences as an established model. 

### 12 Most of the studies you appeared to look at were only looking 

### 13 at the acquisition and we are not following the extended 

### 14 protocols for the morris water maze. 

### 15 DR. GINGER MOSER: In that they did not do 

### 16 probe trials, if that is what you mean. 

### 17 DR. JEAN HARRY: Or reversal or any other 

### 18 types 

### 19 DR. GINGER MOSER: No. 

### 20 DR. JEAN HARRY: They just did the initial 

### 21 acquisition? 

### 22 DR. GINGER MOSER: These studies that were

### Page 88 1 done that I showed only looked at the acquisition, learning with 

### 2 several trials a day over a week and did not do probe trials. 

### 3 The Chinese paper actually does do a probe trial, but again, it 

### 4 is a very informal translation, so it is difficult to make 

### 5 positive statements of that. 

### 6 DR. JEAN HARRY: So continuing with that, I 

### 7 guess there are just a couple more. One is the differences in 

### 8 the age that the animals are tested. That can vary especially 

### 9 when you are doing the anxiety, when you are doing the locomotor 

### 10 activity, there are some ages that the data is close to 

### 11 irrelevant because you get counts of five depending on the 

### 12 apparatus that you are using. I was wondering how that crossed. 

### 13 14 I was also wondering when you started to talk 

### 15 about one needing the robust data, and this is the first time I 

### 16 have heard things come out about the studies in mice. So, now 

### 17 you are considering mice versus the rat studies. Is there 

### 18 consistent data to tell you from these papers the housing 

### 19 conditions postnatally of the mice, because they are often 

### 20 handled differently than rats where females are group-housed, 

### 21 males in an appropriate setting are singly housed due to 

### 22 aggression, but that is going to significantly impact these

### Page 89 1 behavioral aspects. 

### 2 Is there any consistency that you are seeing 

### 3 in the literature about them maintaining that, or is it the 

### 4 standard situation where everything is too expensive, so we are 

### 5 going to group house the males and hope they do not fight? 

### 6 DR. GINGER MOSER: So actually I think that is 

### 7 two questions. One is about the motor activity. We only looked 

### 8 at motor activity tests that were conducted in post weaning 

### 9 animals. So, we were not looking at the pre-weaning where there 

### 10 are the lower motor activity counts. I think the very earliest 

### 11 that motor activity was assessed was about 4 to 6 weeks of age 

### 12 and sometimes older. To look across the age of testing, it just 

### 13 is all over the place. So again, I did not even attempt to pull 

### 14 that into the analyses because it is just too varied. Although 

### 15 within one lab, they tended to test them at the same time. 

### 16 As far as the housing conditions, there is 

### 17 just simply not the information in there to say. One would 

### 18 assume or one would hope that within the same laboratory, they 

### 19 would house them the same way across studies. It is not always 

### 20 the case though, but the information is just not there. 

### 21 Definitely, it can affect, especially the social behaviors of 

### 22 the mice and looking at the conspecific behaviors of the same

### Page 90 1 sex. There is just not the information there to be able to make 

### 2 those evaluations one way or the other. 

### 3 DR. KENNETH PORTIER: Any additional Dr. 

### 4 Popendorf. 

### 5 DR. WILLIAM POPENDORF: I have a question kind 

### 6 of on the other side on the cholinesterase side. I am not sure 

### 7 how familiar you are with it, but you know that is kind of one 

### 8 of those tests that has a lot of nuances that makes measurements 

### 9 and small changes very tricky, shall we say. I wondered has 

### 10 anyone looked at the methods that were used on those particular 

### 11 studies of cholinesterase and sort of evaluated their 

### 12 reliability and the ability of those studies to detect small 

### 13 changes. 

### 14 DR. GINGER MOSER: Well again, there is not a 

### 15 lot of information given on these assays because for the most 

### 16 part, these studies are behavioral people that are doing the 

### 17 studies that do not give a lot of information. I have looked at 

### 18 them. They just cite the Ellman method. If you are lucky, it 

### 19 says what the substrate concentration was. For the most part, 

### 20 the substrate concentration, the acetylcholine concentration is 

### 21 sufficient in the range of 0.8 to 1mL. Otherwise, there is not 

### 22 much detail given. They do not really have a great track record

### Page 91 1 in doing these assays. 

### 2 In some cases, it is just almost a side 

### 3 comment, saying we did this as pilot experiments. That is what 

### 4 one laboratory tended to do a lot, the one that did a lot of the 

### 5 mice and no control values given or anything like that. It is 

### 6 very hard to do a critical review of the way they did the assay 

### 7 because there is just not the data there. 

### 8 The good thing is that with chlorpyrifos, of 

### 9 course as an OP, so the inhibition is relatively stable as 

### 10 opposed to say a carbamate. Hopefully, some minor differences 

### 11 and deletions whatever would impact the assay that much. 

### 12 DR. KENNETH PORTIER: Anyone else? Oh, Dr. 

### 13 Vorhees. 

### 14 DR. CHARLES VORHEES: So, I am going to ask 

### 15 you a question that I hope you take right. So, the agency 

### 16 understood these deficiencies in the design of the developmental 

### 17 neurobehavioral studies for a long time trying to look at the 

### 18 literature and determine the relationship to cholinesterase 

### 19 inhibition. So within the agency, you understand these issues 

### 20 better than anyone. So, why isn't the agency undertaken to do a 

### 21 more definitive test internally to address these gaps in the 

### 22 literature?

### Page 92 1 DR. GINGER MOSER: Well that is a fun one to 

### 2 answer. In the past, we have conducted some studies internally, 

### 3 especially for some of the acute cholinesterase inhibition of 

### 4 various ages. But as you probably know, Hurl's focus on the 

### 5 different research efforts has changed over the years. Just 

### 6 like, I think the funding agencies are not as interested in 

### 7 funding this kind of work anymore, Hurl is looking at other 

### 8 aspects of research. With limited resources, which we have very 

### 9 limited resources, we just cannot do everything. That has been 

### 10 how it has ended up being. Clearly, there has been no really 

### 11 definitive studies that have been done here. 

### 12 DR. JEAN HARRY: Not that hard of a 

### 13 question for you. So, on the next one as you are looking at the 

### 14 academic literature versus somewhat of a control guideline 

### 15 driven study, could you clarify and point out your finding of 

### 16 power in the academic? I mean if we are being asked to sort of 

### 17 evaluate how you are looking at all of the data, so that is why 

### 18 I am asking for the point of clarification. 

### 19 You have certain types of controls that can 

### 20 run in a definitive or at least one more step in a definitive 

### 21 type study, but yet in many times, they are limited in the 

### 22 extensiveness that their behavioral analysis can go through.

### Page 93 1 So, they stop at an acquisition versus probe test or that type 

### 2 of thing. Your academic studies, if they are done on a 

### 3 mechanistic base or they really want to go after something, they 

### 4 could go deeper into the behavior and they could go further in 

### 5 assessing them, which is something that is not often capable of 

### 6 being done when you have an N of 10 and males and females and 

### 7 four to six dose groups, you really cannot handle all of that. 

### 8 Are you seeing that the studies that are 

### 9 coming from that academia environment are providing you data 

### 10 that are letting you take things further or do they seem to be 

### 11 stopping at a screening type level? 

### 12 DR. GINGER MOSER: It kind of depends. There 

### 13 are studies that I did not cover, but then they go on with the 

### 14 same animals, do challenges with specific pharmacological probes 

### 15 and that sort of thing. With the goal of trying to address 

### 16 certain hypotheses about changes in this neurotransmitter system 

### 17 versus this one, as far as this went, we were just trying to 

### 18 focus on what the neurobehavioral outcomes were themselves. But 

### 19 there have not been a lot of those studies overall out of the 25 

### 20 studies. A lot of them are more just this is what we get. 

### 21 In some cases, for instance with the foraging 

### 22 one, it was almost more of this is a new test that we are

### Page 94 1 proposing, and here we are doing it with chlorpyrifos. With the 

### 2 morris water maze data that I showed you, they were more focused 

### 3 on the looking at stem cell transplantation and the effect of 

### 4 that and being able to attenuate the effects of chlorpyrifos. 

### 5 So, the purposes are somewhat different across the studies. 

### 6 In some cases, they will mention, make 

### 7 statements about sample sizes that, you know, in one of 10 we 

### 8 have found in our experience to be sufficient to detect effects 

### 9 of blah, blah, blah. That has not happened very often either. 

### 10 So, it is a different kind of mindset than say a guideline. 

### 11 There is the one study that was conducted 

### 12 purely by the test guideline, had a lot of information about the 

### 13 power of the studies and the statistical analyses and correction 

### 14 for multiple testing, etc. So, it varies basically across the 

### 15 studies. Academic labs, when they are reporting a lot of this 

### 16 stuff, just typically do not give the kind of details that we 

### 17 would like to have for making those really critical assessments 

### 18 of the data. Just like the housing information, we do not know. 

### 19 20 In some cases, there may only be eight animals 

### 21 per dose group. I would say that for a lot of behaviors, eight 

### 22 animals may not be enough. That is why I was saying some of the

### Page 95 1 negative data may be more an issue of power rather than being 

### 2 negative data. If they do not show the data in graphs or give 

### 3 your data in tabular form, you cannot really assess that. A lot 

### 4 of times, they do not. They will only show the significant 

### 5 effects and say other things were not significant. I will leave 

### 6 it at that. It does make things, like what you are trying to 

### 7 assess much harder to do when you are looking at cross studies. 

### 8 DR. CHARLES VORHEES: I would like you to just 

### 9 comment on what appears to me to be a disconnect between the 

### 10 issues of cholinesterase inhibition, which is as I understand 

### 11 cholinesterase inhibition and there are people here with a lot 

### 12 more expertise than I have, but it appears that the regulatory 

### 13 action is based on an acute short-term effect and what the 

### 14 neurodevelopmental studies do are they are looking really for 

### 15 whether or not there is some effect that is a permanent, long 

### 16 term, maybe even irreversible effect. 

### 17 I am having trouble with the question what is 

### 18 the connection between -- because it does not seem to me, while 

### 19 I can understand cholinesterase inhibition as a marker for 

### 20 setting some safety standard, it does not seem to relate at all 

### 21 to the long-term irreversible effect, which is apparently there 

### 22 because I think the EPI studies, if I am understanding them

### Page 96 1 properly, show some long-term effects and the animal 

### 2 developmental studies show long-term effects. So, can you help 

### 3 me pull that together. 

### 4 DR. ANNA LOVIT: I think that is more of a 

### 5 risk assessment question, so I will take a stab. There are 

### 6 multiple parts to this. I am going to go on for a minute or 2. 

### 7 The first piece is that we are interested in all durations of 

### 8 exposure. In people, whether it is through the food or through 

### 9 work or activities in the field are exposed, can be exposed to 

### 10 chlorpyrifos from a single-day event or from repeated days of 

### 11 from repeated years of exposure. 

### 12 So, we are interested in all durations, 

### 13 certainly not just the acute effects. Cholinesterase inhibition 

### 14 is a key event in a pathway of toxicity, if we go back to our 

### 15 AOP concept, leading to cholinergic toxicity. If you think of 

### 16 cholinesterase in a vision as the initiating event to 

### 17 cholinergic toxicity, by protecting for that key event, that 

### 18 initiating event, in other words using a point of departure for 

### 19 which there is very little inhibition of cholinesterase, we 

### 20 prevent cholinergic toxicity. That is the idea of using a 10% 

### 21 inhibition in cholinesterase to prevent for cholinergic 

### 22 toxicity. That is whether it is an acute event or a very

### Page 97 1 long-term very low level exposure like you may experience, let's 

### 2 say in a worker kind of activities. 

### 3 The bulk of what we have talked about so far 

### 4 today and the bulk of what it is in the white paper and what you 

### 5 heard from both Dr. Moser and Dr. Mundy would be a different set 

### 6 of adverse outcomes. So, this would be a different set of 

### 7 adverse outcomes related to neurodevelopmental effects unlikely 

### 8 to have much to do with inhibition of cholinesterase. The 

### 9 protein acetylcholinesterase may have a big role. I think that 

### 10 is one of plausible hypotheses on the table, but the inhibition 

### 11 leading to cholinergic toxicity would be a different pathway, a 

### 12 different adverse outcome. 

### 13 If you go back to my last slide before the 

### 14 outline with the issue paper of our conceptual framework for 

### 15 this whole analysis, it is keeping all of the moving parts 

### 16 separate, thinking about the dose response for cholinesterase 

### 17 inhibition leading the cholinergic toxicity, and how that 

### 18 relates in a quantitative dose response way to those initiating 

### 19 events or other key events or adverse outcomes that are related 

### 20 to neurodevelopmental. That is the fundamental question that we 

### 21 are incrementally getting to. 

### 22 What we are asking of all of you is to help us

### Page 98 1 ensure that our review of the pieces that form that ultimate 

### 2 question are sound, our reviews are sound, the science that is 

### 3 in those reviews is sound with thinking about alternative points 

### 4 of view and how the strengths and the weaknesses of all those 

### 5 alternatives come together as we work to those conclusions. 

### 6 DR. KENNETH PORTIER: Dr. Vena? 

### 7 DR. JOHN VENA: One question, well two 

### 8 questions. One is you mentioned in your summary slide the 

### 9 behavioral alterations and, of course, the consistent effects 

### 10 you mentioned, cognition, anxiety and social behavior. In your 

### 11 opinion, where is the strongest evidence in which of those 

### 12 domains? So the second question is what time period of exposure 

### 13 in the animal evidence appears to be most important, the 

### 14 gestational, the perinatal or the postnatal? 

### 15 DR. GINGER MOSER: I think the second question 

### 16 is the easiest to answer. Across all of these studies, there is 

### 17 no critical window of exposure that has emerged. You can get 

### 18 cognitive effects when they are exposed gestationally. You can 

### 19 get it when they are exposed postnatally. Nothing has fallen 

### 20 out that shows any critical window of exposure. 

### 21 As far as the first part of it, I think there 

### 22 are several ways to answer that. If you just look at the most

### Page 99 1 consistent findings as being where you actually get significant 

### 2 effects that when the data are shown, you kind of agree with the 

### 3 facts and the tests were done correctly and that there are tests 

### 4 that are well accepted and used in neuroscience, I would 

### 5 probably have to say either that the cognition and then the 

### 6 anxiety, but again you have the differences in the direction of 

### 7 change on those end points. 

### 8 For instance, there have been some hypotheses 

### 9 as to why that might be. For the radial arm maze where you see 

### 10 the improved performance in the females and worsened performance 

### 11 in the males, the authors said that that was evidence of 

### 12 endocrine changes or endocrine effects, even though there was no 

### 13 data that has ever been presented to support that hypothesis in 

### 14 any way. So, we just kind of have to take it as that, just a 

### 15 hypothesis. 

### 16 There has never really been any hypothesis to 

### 17 explain the differences in the anxiety level increased versus 

### 18 decreases, but anxiety is one of these tests that you really 

### 19 have to be careful with what you are doing to try to get the 

### 20 exact same effects over and over. Some of the differences could 

### 21 be subtle differences. 

### 22 For example, whether the animal is put into

### Page 100 1 the dark part of the box to begin with, or put into the light 

### 2 side of the box to begin with. That can influence the actual 

### 3 outcome. When I went through all these papers, there were 

### 4 differences, even though it is in the same lab. Sometimes they 

### 5 would start in the light side and sometimes they would start in 

### 6 the dark side. 

### 7 So, you cannot explain it away in terms of 

### 8 that. It was not completely clear, but those are the kinds of 

### 9 factors that probably do weigh in on those outcomes. Some of 

### 10 the other changes, like I said the motor activity, it is really 

### 11 all over the place. The increases, decreases, no effect. When 

### 12 you see that much increases, decreases, no effect, you kind of 

### 13 start to wonder is there something specific going on that we 

### 14 have not captured. I am not sure if that answered your question 

### 15 or not, but yeah. 

### 16 DR. CHARLES VORHEES: So, one of the things I 

### 17 would just like to point out I think kind of fits with what you 

### 18 are saying, and that is that a lot of these tests that are being 

### 19 used to evaluate chlorpyrifos or other toxins or possible toxins 

### 20 have been taking out of the neuroscience literature, and their 

### 21 intended purposes when they were developed were very different 

### 22 than using them in a toxicological screen.

### Page 101 1 Tests of effect are a perfect example. They 

### 2 are being taken in a way out of context and used as if they can 

### 3 be used as toxicological outcome measures. There is really no 

### 4 proof that I know of that they can be transplanted in that way. 

### 5 I would say the same is true of social tests. They have a 

### 6 particular application in neuroscience as models of human 

### 7 disorders where you are giving explicit neurotoxins or you are 

### 8 giving drugs or you are giving genetic changes. They work on 

### 9 those contexts. 

### 10 Whether or not they translate very well into 

### 11 this setting is very hard to say. When you look at those social 

### 12 interaction tests that you mentioned, it is very difficult to 

### 13 know how to interpret that after exposure to chlorpyrifos. Does 

### 14 that mean anything the same as it means in an autism model? I 

### 15 am not so sure. It is very difficult to know what it means when 

### 16 transplanted without validation stuff. 

### 17 DR. KENNETH PORTIER: Dr. Pope? 

### 18 DR. CAREY POPE: Ginger, on your next to last 

### 19 slide and in your response to Dr. Vena, you talk of most 

### 20 consistent effects. Dr. Bradbury and others have brought up 

### 21 this word consistency. I am just wondering in the context of 

### 22 all the end points that are studied, does that mean that there

### Page 102 1 are changes or it is consistent that there are changes that are 

### 2 the same between studies? 

### 3 DR. GINGER MOSER: At the broader level, I 

### 4 would say consistent in terms of changes. Narrowing it down a 

### 5 little bit, consistent across studies in some cases for example 

### 6 where I showed you with the morris water maze and they did 4 

### 7 different studies and got pretty much the same effects. But as 

### 8 anybody knows if you do the same study over and over, you are 

### 9 not going to get the exact same effect, at least not in any of 

### 10 the studies I have ever seen you get the exact same effect. So, 

### 11 I would not expect them to replicate exactly unless everything 

### 12 was done exactly the same and even then, you just have 

### 13 differences in animals. When you get into behavioral type 

### 14 changes, a lot of things can affect it. Even the set of animals 

### 15 that get in from the vendor can have an effect. 

### 16 So overall, the consistency I mean is more 

### 17 that there are effects and that for the most part, there is 

### 18 consistency when they are replicated, like within the same lab 

### 19 or if they are looking at the same end points. That is what I 

### 20 was thinking of when I was talking about consistency. 

### 21 DR. CAREY POPE: I would not, of course, 

### 22 expect to see the exact same results from a behavior or a

### Page 103 1 biochemical study, but different directional effects. To me, I 

### 2 have to wonder about the word consistency if they are going in 

### 3 different directions. 

### 4 DR. GINGER MOSER: That is a little bit more 

### 5 where you have to give it a little bit more consideration. Are 

### 6 the changes that take place in the different directions, you 

### 7 know -- the change in activity for anxiety for example is that 

### 8 just because these are random effects that happen to be 

### 9 significant, which some people could interpret it that way, or 

### 10 is it because if you look closely enough, you will find the 

### 11 reason? 

### 12 I did look at this, things like which side 

### 13 they started testing the animals in. There are all these other 

### 14 things that are not reported. They do not report the light 

### 15 level in the room. They do not report things like how the 

### 16 animals are placed or how it is defined whether they are 

### 17 entering into one side versus the other. Some of these very 

### 18 specific details are not in the papers, but they can impact the 

### 19 outcome. 

### 20 So, I do not want to say that those findings 

### 21 are inconsistent, but it would just be nice to have more 

### 22 information to be able to evaluate the differences, I guess.

### Page 104 1 DR. KENNETH PORTIER: Dr. Harry? 

### 2 DR. JEAN HARRY: So Ginger, based upon that, I 

### 3 just want to get your thinking on something. In the guideline 

### 4 recommendations, it says in your choice of a learning and memory 

### 5 task is to choose it based upon if you have information. Based 

### 6 upon information of the compound and what you think would be, 

### 7 basically use your intelligence and do not just pull cubical A 

### 8 off and put it for every compound. So, that crosses over to 

### 9 what was just mentioned as a number of these tests have been 

### 10 pulled off. 

### 11 While they are using neuroscience, and very 

### 12 few of them actually have a neural substrate basis for the 

### 13 behavior, but there are a number that do like the morris water 

### 14 maze has condition place preference, a number of those, but they 

### 15 have been taken over and used. I guess we do have a lot of data 

### 16 in the morris water maze, but morris water maze looks at 

### 17 something in learning and memory that is very different than 

### 18 what a radial arm maze looks at and how the learning and memory 

### 19 are conducted. 

### 20 What I was interested in was the very last 

### 21 thing in your summary, which was that you need a robust dose 

### 22 response and time course data. I think that that might come

### Page 105 1 back to some of the questions that have been asked. I would 

### 2 sort of like to know for clarification what you might have 

### 3 pulled out of there. 

### 4 Is there data in the literature that if you 

### 5 were going to go and do that, if anybody was going to go do that 

### 6 study to let you know, is there an end point that raises itself 

### 7 as something that might give you a robust end point that you 

### 8 could hope from that change you could get a dose response? Or 

### 9 are we still looking for that functional outcome test 

### 10 measurement that would give us that robust data? 

### 11 DR. GINGER MOSER: I think we are still 

### 12 looking to some extent because we do not know, for example, what 

### 13 the neural substrate might be for these behavioral changes. We 

### 14 do not know if it is just generalized or what. So, that goes 

### 15 back to the AOP thoughts about what could actually be causing 

### 16 these effects. We could be talking about just differences in 

### 17 neuronal connectivity. Why would that happen? That is what we 

### 18 do not know. 

### 19 Because we do not know that part of it, it is 

### 20 a lot harder to say, well since we know that there is a change 

### 21 in this, then this test measure is a good evaluator of that. We 

### 22 do not know the reason, so it is harder to pull up to use

### Page 106 1 justifications like that to decide what kind of test we are 

### 2 going to do. 

### 3 I think that most of these tests actually are 

### 4 used because that is what the laboratory is good at doing. They 

### 5 have seen other effects with other chemicals on these tests, so 

### 6 they want to see whether chlorpyrifos affects these tests as 

### 7 well. Some of the anxiety and especially some of the social 

### 8 behaviors have been based actually, the more recent ones, have 

### 9 been based on some of the EPI studies, maybe not with 

### 10 chlorpyrifos, but with other EPI studies that are beginning to 

### 11 suggest that chemical exposures during development at some point 

### 12 may be causing some changes in social behavior of the kids or 

### 13 anxiety levels of the kids. 

### 14 So the later studies have been using those 

### 15 tests because of that. A lot of these more recent studies have 

### 16 been looking at the social behaviors and some of the anxiety. 

### 17 You kind of have to look at the timeline in what is being looked 

### 18 at. I am not sure if that was everything you were asking or 

### 19 not. I just did want to clarify what I am talking about. 

### 20 The dose response, we really need to be able 

### 21 to understand brain cholinesterase inhibition after exposure. 

### 22 It may be a very short time after exposure, and the animals have

### Page 107 1 recovered by an hour. If that happens day after day, that could 

### 2 actually produce some long-term changes. We do not have the 

### 3 data to be able to make that assessment. 

### 4 First of all, you need to look at the 

### 5 cholinesterase data. You need to end up with doses that you 

### 6 know do not inhibit cholinesterase and bracket that, and then 

### 7 look at the neurobehavioral outcomes of those doses. We just do 

### 8 not have that full information that we could just follow the 

### 9 whole way through. Even combining all the studies together just 

### 10 does not give us that. 

### 11 DR. KENNETH PORTIER: Dr. Lowit? 

### 12 DR. ANNA LOWIT: Yes, I appreciate that 

### 13 exchange. That was a nice exchange. I just want to, I think as 

### 14 we progress through the afternoon and into the charge questions, 

### 15 there are a lot of very neat questions here. 

### 16 There are many, many experiments that you can 

### 17 contemplate in your mind to run, and decades-long work you could 

### 18 do in the laboratory. I just would like to remind all of you to 

### 19 think of the time scale that the agency makes decision in light 

### 20 of uncertainty and pulls in information. This is what we do 

### 21 every day. 

### 22 The time is going to come around 2013 or 2014

### Page 108 1 or whatever the date was, a couple of years from now, that we 

### 2 will need to make another regulatory safety findings on 

### 3 chlorpyrifos. As you think about your deliberations, if you can 

### 4 think about it in multiple levels that they were looking for the 

### 5 strengths and weaknesses of existing information, but were also 

### 6 looking to think about given the strengths and the limitations, 

### 7 how would you think about filling holes. Despite that, we need 

### 8 to know how those strengths and limitations today can be weighed 

### 9 against each other so that we can go back and do a weight of the 

### 10 evidence and think across multiple lines of evidence. 

### 11 I think these exchanges of what could be done 

### 12 and how it could be done are very important for the totality of 

### 13 the science around chlorpyrifos, but I also just want to 

### 14 remember that there are some very grounded questions that given 

### 15 today's science, where are we, and how best to use today's 

### 16 science. 

### 17 DR. KENNETH PORTIER: This is Ken Portier. 

### 18 One last question. How many of these 26 papers were new from 

### 19 2008 to present? You did not mention that. 

### 20 DR. GINGER MOSER: There are nine since 2008 

### 21 and two new labs. 

### 22 DR. KENNETH PORTIER: Did any of those nine

### Page 109 1 replicate previous studies or are they all new? You see, that 

### 2 is one of the issues that I have been kind of having with the 

### 3 neurobehavioral. They do not really replicate. They keep 

### 4 pushing an edge. They do not go back and help us establish or 

### 5 validate. 

### 6 DR. GINGER MOSER: The newer studies do not as 

### 7 much. Some of the earlier studies, for example from Duke, tend 

### 8 to replicate each other. They would use the same testing 

### 9 procedures, but then they would add their pharmacological 

### 10 challenge with the serotonin agent or with the cholinergic agent 

### 11 or whatever, but the first part of the testing would be the same 

### 12 and they did replicate those effects. 

### 13 For things like the radial arm maze with the 

### 14 different gender differences and the direction of the cognitive 

### 15 effects, that was replicated three times within the Duke lab. 

### 16 More recently, one of the more recent papers did replicate the 

### 17 same finding at a different laboratory. So yeah, in some cases 

### 18 they did, but in other cases, the newer studies would report one 

### 19 set of data and then the next study would say okay given that, 

### 20 we are going to now look at this. They did not replicate that. 

### 21 They just went on to the other thing. 

### 22 Basically, the answer is sometimes they do and

### Page 110 1 sometimes they do not. The Duke lab was good about it. I talk 

### 2 about the Duke lab and the Italian lab, because they are the two 

### 3 that have the most papers. The Italian lab really has not tried 

### 4 to replicate their own data as many times as the Duke lab did. 

### 5 The Italian lab tended to do different things. They are 

### 6 actually the more recent papers. 

### 7 DR. KENNETH PORTIER: Dr. Meek? 

### 8 DR. BETTE MEEK: Ginger another question. I 

### 9 tend to think of weight of evidence in relation to data sets 

### 10 across chemicals. So, have you looked at the results of similar 

### 11 studies for other chemicals? 

### 12 DR. GINGER MOSER: Well the simple answer is 

### 13 no. There are studies looking at developmental outcomes of 

### 14 other OPs for example, but they are far fewer. As far as 

### 15 pesticides go, chlorpyrifos has the bulk of the literature. So, 

### 16 out of those few studies for other OPs, most of them do not have 

### 17 the same end points. So, it makes it even harder to kind of 

### 18 make any kind of comparisons. The only exception that I can 

### 19 think of and again, I have not done a literature search, so I do 

### 20 not know, but I do know that the Duke lab has looked at diazinon 

### 21 and they find some similar outcomes, not sure whether the Duke 

### 22 lab has done others.

### Page 111 1 One or two of the other studies have also 

### 2 looked at parathion or methyl parathion, one of the more recent 

### 3 studies that I only talked about the chlorpyrifos data, they 

### 4 also looked at methyl parathion I think it was. There were some 

### 5 differences and some similarities in the effects of the two 

### 6 chemicals. 

### 7 As far as doing an overall literature 

### 8 evaluation, no, we have not done that. I can say there is just 

### 9 not nearly the amount of data and it would be very hard to make 

### 10 comparisons of the chemicals. 

### 11 DR. KENNETH PORTIER: It is noon, and I think 

### 12 what we are going to do is break for lunch and send you out with 

### 13 the rest of the office workers to forage. We will be back at 1 

### 14 o'clock and begin our discussion on the epidemiology data, thank 

### 15 you. 

### 16 17 18 19 20 (WHEREUPON a break was taken for lunch)DR. 

### 21 KENNETH PORTIER: So we are ready to move on with our discussion 

### 22 of epidemiology. And I guess Dr. Christensen, are you ready?

### Page 112 1 Go for it. 

### 2 3 DR. CAROL CHRISTENSEN: Good afternoon. My 

### 4 name is Carol Christensen. I am an epidemiologist with the 

### 5 Pesticide Program Office and at this time we will present our 

### 6 review of children's health epidemiology cohort studies. 

### 7 I will note that the presentation at this time 

### 8 will track closely with section 4 of the draft white paper as 

### 9 well as Appendixes 4-6 of that draft white paper. And I believe 

### 10 we have left ample time at the conclusion of the presentation 

### 11 for any clarifying questions on either the oral presentation 

### 12 today or the written material. 

### 13 So as it has been mentioned this morning, in 

### 14 September of 2008, EPA presented its targeted review of these 

### 15 three children health cohort studies, the database available at 

### 16 that time. The FIFRA SAP at that time concluded that while 

### 17 chlorpyrifos likely played a role in the adverse 

### 18 neurodevelopmental outcomes, it cannot conclude that 

### 19 chlorpyrifos was the sole contributor due in part to the fact 

### 20 that participants were exposed to several other chemicals and 

### 21 pesticides, including other OPs. 

### 22 The panel further noted that the epidemiology

### Page 113 1 study should not be considered as a basis for the 

### 2 characterization of the point of departure due in part to the 

### 3 lack of a biologically plausible mode of action, which is of 

### 4 course our topic of discussion this week as well, in addition to 

### 5 exposure uncertainties that were present in the database at that 

### 6 time. 

### 7 The panel also recommended some supplementary 

### 8 analyses it presented in Appendix 4 of the material, but was 

### 9 clear to note that these analyses would help clarify the results 

### 10 and interpretation of the observational studies for use and risk 

### 11 assessment, but not likely change the overall inference from 

### 12 that database at that time. 

### 13 Though today we update and expand our targeted 

### 14 review of these three children health cohort studies, we have 

### 15 included new etiologic papers. About one year ago this month, 

### 16 researchers from Egypt, the three respective children's health 

### 17 cohort studies, simultaneously published their results of 

### 18 prenatal exposure in relation to Intelligence Quotient in 

### 19 school-age children. 

### 20 In addition, there are new methodological 

### 21 papers, and evaluation of socioeconomic status is a potential 

### 22 confounder using hierarchical regression techniques as well as

### Page 114 1 some exposure characterization and validation work, which go to 

### 2 further clarifying and in some ways reducing uncertainties 

### 3 around exposure measurement methodology particularly in the 

### 4 Columbia University cohort. The supplemental analyses to which 

### 5 I just referred have been completed by the principal 

### 6 investigators with the Columbia cohort. Those have been 

### 7 published in full as Appendix 4 of the draft material. 

### 8 In addition, today's presentation and the 

### 9 written material you have been provided is informed by our 2010 

### 10 draft framework for the analysis and incorporation of 

### 11 epidemiology research and to the risk assessment process. So 

### 12 overall, at this time we are asking for the panel's guidance 

### 13 regarding the qualitative and quantitative use of these data in 

### 14 our risk assessment process. 

### 15 So the three cohorts are briefly denoted here. 

### 16 17 The Columbia Children's Environmental Health 

### 18 Study cohort recruited participants between 1998 and 2002. The 

### 19 study is located in New York City. Authors restricted 

### 20 enrollment to women who self-identified as Dominican or 

### 21 African-American decent. There are about, give or take, 

### 22 three-hundred mother-infant pairs enrolled within this cohort.

### Page 115 1 Notably, the Columbia cohort researchers were 

### 2 the only ones to measure chlorpyrifos parent compound directly 

### 3 as a measure of exposure in their analytical search. As I have 

### 4 just briefly alluded to, researchers with this cohort also 

### 5 performed a validation study, which we will get into in some 

### 6 detail. 

### 7 The Mt. Sinai Children Growth and Development 

### 8 cohort, also located in New York City, enrolled participants in 

### 9 a similar timeframe, between 1998 and 2001. Similarly a 

### 10 multi-ethnic cohort comprised of African-American, Hispanic and 

### 11 about 20 percent of the cohort self-identified as Caucasian. 

### 12 In contrast to the Columbia cohort, these 

### 13 researches measured nonspecific biomarkers of chlorpyrifos 

### 14 exposure; TPCy, as you will hear about a little bit further from 

### 15 my colleague Lieutenant Niman, is a nonspecific biomarker of 

### 16 chlorpyrifos. Chlorpyrifos, chlorpyrifos methyl as well 

### 17 triclopyr, so three different pesticides could possibly result 

### 18 in a urinary concentration of TPCy as well as environmental 

### 19 exposure to the degredate itself. 

### 20 Dialkyl phosphates are nonspecific measures of 

### 21 OPs. There are several different OPs that could result in DAP 

### 22 concentration in urine. But I will note that for each of the

### Page 116 1 investigations that measured DAPs, they further broke out that 

### 2 sub-class into both diethyl and dimethyl phosphate, and it is 

### 3 the diethyl phosphate that is the potential result of 

### 4 chlorpyrifos exposure. 

### 5 The University of California at Berkley 

### 6 designed the CHAMACOS cohort, Children and Mothers of workers in 

### 7 Salinas Valley, recruited participants between 1999 and 2000, 

### 8 with some additional data collection through 2002. 

### 9 So this cohort in contrast to the two located 

### 10 in New York City is comprised of Mexican-American, agricultural 

### 11 farm worker populations. So these participants either report 

### 12 that they themselves have been employed in agricultural work or 

### 13 they reside with an individual who is employed in agricultural 

### 14 work. 

### 15 Similar to the Mt. Sinai cohort in their 

### 16 analytic investigations they have measured TPCy and DAPs as a 

### 17 biomarker of chlorpyrifos and/or organophosphate exposure. And 

### 18 both the CHAMACOS and the Mt. Sinai cohort measured PON1 in 

### 19 relation to the neurodevelopmental outcomes as well as an 

### 20 interaction with the pesticide exposure. 

### 21 So these three perspective birth cohorts were 

### 22 designed to examine environmental exposures and adverse health

### Page 117 1 outcomes among children. But for our purposes today, of course, 

### 2 we are focusing on those evaluations looking at chlorpyrifos 

### 3 and/or organophosphate exposure in relation to birth outcomes 

### 4 and neurodevelopment. Each cohort enrolled women about midway 

### 5 through pregnancy and followed the children of those pregnancies 

### 6 over time, making multiple measures of health outcomes. So 

### 7 there is clearly a longitudinal component. These are 

### 8 longitudinal birth cohort studies. 

### 9 And we note that the Children's Environmental 

### 10 Health and Disease Prevention research centers through which 

### 11 these studies are performed are funded in part by EPA and NIEHS. 

### 12 So looking across these cohorts, of course, 

### 13 eligibility criteria are specific within each cohort. But 

### 14 looking across these cohorts I have noted some general 

### 15 characteristics of eligibility. 

### 16 Women were recruited when they were seeking 

### 17 prenatal care prior to the midpoint in pregnancy. The CHAMACOS 

### 18 cohort, I believe, enrolled women up through 26 weeks of 

### 19 pregnancy. The New York City cohort there was a residency 

### 20 requirement and participants had indicated their intent to 

### 21 deliver at participating study hospitals for the purpose of 

### 22 medical record linkage and other information exchange.

### Page 118 1 To isolate the effect of chlorpyrifos or 

### 2 organophosphate exposure on these neurodevelopmental outcomes, 

### 3 the researchers restricted enrollment to those who did not 

### 4 report having other comorbidities or health risk factors that 

### 5 could also adversely affect neurodevelopment. So participants 

### 6 were not included if they reported history of diabetes, 

### 7 hypertension, known HIV or other birth defects. Similarly it is 

### 8 a no smoking population, very low alcohol use as well as no 

### 9 reported illegal drug use, which was confirmed by biomarker. 

### 10 11 So overall, these three cohorts represent 

### 12 multi-ethnic studied populations. On average, across the three 

### 13 cohorts, the average age at first birth is somewhat young, about 

### 14 25 years of age; and again, given the restriction criteria, low 

### 15 prevalence of risky health behaviors and comorbidities that 

### 16 could also adversely affect neurodevelopment. 

### 17 So the next several slides go over some common 

### 18 characteristics of study design, method and analyses. Of 

### 19 course, exposure assessment is a key component to understanding 

### 20 both the validity of the epidemiology studies as well as 

### 21 possible use in risk assessment. Across these three cohorts we 

### 22 have differing exposure profiles, different pathways, and

### Page 119 1 different routes. The intercity populations may have been 

### 2 exposed to chlorpyrifos through residential use of the pesticide 

### 3 in the home environment prior to the period of the voluntary 

### 4 cancellation of pesticide products for in-home use. As we noted 

### 5 in the written material, each of these cohorts sort of span the 

### 6 time period in which the products were removed form the 

### 7 residential marketplace. 

### 8 Within the CHAMACOS cohort, of course, 

### 9 participants could have been exposed in occupational type of 

### 10 setting, so inhalation or dermal exposure is possible. 

### 11 Unintentional oral exposure; take-home exposure is another 

### 12 potential route. 

### 13 So across the cohorts of multiple measures, 

### 14 biomarkers of exposure as well as environmental measures of 

### 15 exposure were assessed. Again, it's noted that the Columbia 

### 16 cohort is the only one to have measure chlorpyrifos directly. 

### 17 Both Mt. Sinai and CHAMACOS measure TCPy and 

### 18 DAPs within a validation study that we'll get into. TCPy in 

### 19 meconium was measured. Meconium is considered to be an 

### 20 integrative biomarker of exposure to the fetus weeks 13 through 

### 21 delivery, so it's somewhat of a longer term biomarker of fetal 

### 22 exposure.

### Page 120 1 Uniquely, within the CHAMACOS cohort, 

### 2 researchers measured both acetyl- and butyrylcholinesterase as a 

### 3 third marker of organophosphate exposure, and each of the 

### 4 cohorts administered a self-report questionnaire regarding 

### 5 pesticide use overall in occupational characteristics. 

### 6 So as we move to consider the quality of 

### 7 exposure assessment and uncertainties in exposure assessment 

### 8 which are key to the deliberations this week, it's useful I 

### 9 think, as suggested by David Savitz, to consider kind of what's 

### 10 an ideal measure as compared to an actual measure. 

### 11 So considering the research question of 

### 12 interest, that prenatal chlorpyrifos or organophosphate exposure 

### 13 in relation to adverse neurodevelopmental outcomes in childhood, 

### 14 an ideal measure may be an estimate of external exposure during 

### 15 a known critical window of susceptibility. And as we heard this 

### 16 morning from Dr. Moser, there's some lack of clarity as to what 

### 17 exactly that critical window of susceptibility may be. 

### 18 Repeat samples would also be ideal; a better 

### 19 characterization of the periodicity or variability of exposure; 

### 20 the variation in exposure within an individual over time, which 

### 21 may influence exposure response relation. And also to be 

### 22 accurately and precisely reflective of the true rank of the

### Page 121 1 categorization of actual exposure within the study population, 

### 2 and ideally this would also include the timing of sample 

### 3 collection with the application of the pesticide or with the 

### 4 ingestion event. 

### 5 So you know, with any epidemiology study -- 

### 6 not just these children's health cohorts -- an ideal measure is 

### 7 often unattainable so actual measures include a one-time or, in 

### 8 the case of CHAMACOS, an average of two urine samples taken over 

### 9 the latter period of pregnancy. 

### 10 For the most part, measures were taken in the 

### 11 third trimester, both the etiologic measures as well as the 

### 12 validation measures with the exception of meconium, and specific 

### 13 and non-specific biomarkers of chlorpyrifos were currently used. 

### 14 So sort of using that as a rubric to think 

### 15 about sources of uncertainty or measurement error, that's why I 

### 16 delineated here within these three cohort study sources of 

### 17 measurement error: so the difference between external exposure 

### 18 and internal dose, the use of the single measure, and the lack 

### 19 of clarity around some of the temporal and spatial patterns of 

### 20 exposure; the lack of ability to measure during a critical 

### 21 window, although it's likely because the third trimester is a 

### 22 period of rapid brain growth and development of the fetus that

### Page 122 1 the exposures during the third trimester possibly play a role in 

### 2 neurodevelopmental outcomes. Missing information is common 

### 3 across epidemiology studies. Authors used several methods to 

### 4 impute when available. And of course, laboratory errors are a 

### 5 source of overall measurement error. 

### 6 But with the exception of the measurement of 

### 7 urinary TCPy in relation to fetal growth and development in the 

### 8 Mt. Sinai study, each of these biomarkers were measured at CDC 

### 9 laboratories with extensive QA/QC measures published. 

### 10 So since the time of the last Panel review, 

### 11 researchers with the Columbia cohort have published about some 

### 12 validation work, the Whyatt studies from 2007 and 2009. 

### 13 But in forming that work was some basic data 

### 14 collection performed at enrollment, specifically questionnaire 

### 15 data from that cohort indicating that 85% of the participants 

### 16 report use of a pesticide at least once during pregnancy and a 

### 17 significant proportion reporting pesticide use at least monthly 

### 18 during the period of the pregnancy. 

### 19 So there is some evidence from self-report 

### 20 questionnaire data that prior to the time period of the 

### 21 volunteer cancellation within the Columbia cohort that there is 

### 22 consistent and relatively use of pesticide.

### Page 123 1 Information external to this cohort, the study 

### 2 authors reported that the New York City Housing Authority -- and 

### 3 I think I failed to note when I was discussing cohort 

### 4 characteristics, a majority of the participants in the Columbia 

### 5 cohort reside in rental housing units managed by the New York 

### 6 City Housing Authority, so public housing dwellings. 

### 7 So the New York City Housing Authority 

### 8 reported that use of chlorpyrifos in the residential setting. 

### 9 Again, this is the period prior to the cancellation of these 

### 10 pesticide products in the home environment were actually greater 

### 11 than any other county in the state of New York, which would 

### 12 include the agricultural areas. So again, there's information 

### 13 that exposure and prevalence was high. 

### 14 So to further address some of the exposure 

### 15 uncertainties present in the methodologies, and again, went 

### 16 ahead and performed an exposure validation study. It collected 

### 17 several different environmental as well as biological measures 

### 18 of exposure. In Whyatt et al., 2007, both the personal air 

### 19 monitoring -- so sort of a backpack apparatus, which was worn by 

### 20 participants for a 48-hour period -- as well as stationary 

### 21 two-week integrated air monitoring units were in the home. I 

### 22 think they were located adjacent to the bed in the home

### Page 124 1 environment. 

### 2 So these air concentration measures were 

### 3 taken, and from those data, we understand that the 

### 4 intra-individual variability was much lower than the 

### 5 inter-individual variability. So it indicates that at least 

### 6 with air measurements, there is some stability in exposure 

### 7 within an individual over time. 

### 8 However, we must note that this validation 

### 9 study was performed between 2001 and 2004, which was right at 

### 10 the period of the voluntary cancellation, so exposures were 

### 11 rapidly declining. And as we noted in the paper, the extent to 

### 12 which these validation results sort of reflect that pre-exposure 

### 13 period is still in the area of uncertainty. 

### 14 With regard to biomarkers or biological 

### 15 matrices in which exposures were measured within this validation 

### 16 study, authors measured repeat maternal urine samples. Meconium 

### 17 is fecal matter that collects in the intestines of the 

### 18 developing fetus beginning around week 13 and 14 and expelled 

### 19 right around the time of delivery. 

### 20 So TCPy in meconium was also measured, as well 

### 21 as neonatal urine. So the purpose of the validation study, of 

### 22 course, was to both evaluate other kind of biomarkers, which

### Page 125 1 could be, you know, valid measures of exposure as well as 

### 2 reporting of the correlations of different biomarkers which 

### 3 reflect, importantly, different windows of exposure. 

### 4 So this is just a qualitative kind of 

### 5 schematic of the gestational period indicating when the 

### 6 biomarkers were collected. Again, meconium considered to be 

### 7 reflective of an exposure period, generally speaking, the last 

### 8 two trimesters of pregnancy. The personal backpack air monitors 

### 9 were worn during week 32 for a 48-hour period, and the repeat 

### 10 urine samples and the integrated air monitoring stations were 

### 11 implemented week 32 through delivery, so the last eight weeks of 

### 12 pregnancy. 

### 13 And importantly, in that paper, authors 

### 14 reported a moderate but significant correlation, and this is the 

### 15 table repeated. So importantly, from this table six of the 

### 16 Whyatt publication, we see that there is a moderate -- not high, 

### 17 a moderate but statistically significant correlation between the 

### 18 one-time measure of chlorpyrifos in umbilical cord blood and 

### 19 TCPy levels in meconium, which of course reflect that longer 

### 20 period of exposure; so lending some evidence that that one-time 

### 21 measure of exposure within the Columbia study may accurately 

### 22 reflect the ranking or the categorization of participants with

### Page 126 1 respect to prenatal chlorpyrifos exposure at least within 

### 2 two-to-three-fold as suggested by study authors. 

### 3 So this is new information available to the 

### 4 agency and to the Panel since the time of our last 

### 5 deliberations. The exposure measures within these studies are 

### 6 generally very good and, you know, greater than you would see in 

### 7 other types of environmental epidemiology studies. 

### 8 With the aid of the validation work that I 

### 9 just detailed, we have the ability to characterize uncertainty 

### 10 to a large extent. However, there are uncertainties that still 

### 11 remain. Of course, within the analytic studies, we will have a 

### 12 one- or two-time measure of exposure. Again, the validation 

### 13 study which I just detailed offers some suggestion that that 

### 14 one-time measure is a relatively good way to rank participants 

### 15 with respect to prenatal chlorpyrifos exposure. 

### 16 And we still lack clarity as to the 

### 17 periodicity or the variability of exposure within an individual 

### 18 over time. But the repeat urine samples in women during the 

### 19 last eight weeks of pregnancy clearly show that there is a high 

### 20 degree of individual variability using TCPy and the urine. 

### 21 And as we noted, the prevalence of pesticide 

### 22 exposure is generally thought to be high among these cohorts,

### Page 127 1 particularly the time prior to the cancellation. But as we hear 

### 2 in greater detail in the subsequent presentation, the median 

### 3 concentration of TCPy in the urine is certainly within the range 

### 4 of the general population across each of these cohort studies, 

### 5 so this may indicate a difference between actual and measured 

### 6 exposure. 

### 7 So moving on to confounding bias and other 

### 8 important characteristics of epidemiology studies to consider 

### 9 when evaluating both the accuracy in the epidemiology inference 

### 10 made as well as use in risk assessment. Across these studies, 

### 11 authors used several methods to control for confounding, 

### 12 including some very clear restriction or enrollment criteria; so 

### 13 controlling through variability within the comparison groups 

### 14 through design. 

### 15 Extensive information or data collection was 

### 16 performed, including information concerning race, education, 

### 17 income, housing, quality, those vary individual-level variables 

### 18 were considered for inclusion in statistical modeling. And with 

### 19 respect to socioeconomic status, which is generally considered 

### 20 to be a challenging type of variable to measure in any 

### 21 epidemiology study, not just in these birth cohort studies. 

### 22 Within the Columbia cohort, again, researchers performed

### Page 128 1 methodological work on the role of SES. 

### 2 So methods used to identify confounding 

### 3 variables; we generally found them to be kind of traditional and 

### 4 established methods based upon both biological and statistical 

### 5 evidence. 

### 6 There were some instances in which formal 

### 7 forward and backward step-wise selection procedures were used, 

### 8 but generally speaking, it was kind of testing model stability 

### 9 in whether risk estimates changed appreciably with and without 

### 10 the inclusion of a confounding variable. And overall, we found 

### 11 that model selection was based on Parsimony, given the sample 

### 12 size and the question on the table. 

### 13 So general confounding factors; of course, 

### 14 demographic, health-related, other environmental exposures to 

### 15 which these participants may have been exposed is also key. 

### 16 Across the studies, authors measured PAH; measures of 

### 17 environmental tobacco smoke or secondary smoke; organochlorines, 

### 18 particularly within the CHAMACOS cohort within which a majority 

### 19 of participants reported that a non-U.S. country as their 

### 20 country of origin, particularly Mexico. And information about 

### 21 the postnatal environment was also collected. 

### 22 But over the next few slides, we'll go over

### Page 129 1 some of the specific types of environmental chemicals that have 

### 2 been evaluated for a potential confounding bias as well as SES. 

### 3 So this is just a very basic slide on kind of 

### 4 when is a confounder a confounder? Of course, not every 

### 5 variable could be a confounding variable. Confounders must be 

### 6 causally related to the outcome, must be statistically 

### 7 associated with the exposure. And not only statistically 

### 8 associated, in work outside of these three cohorts, we know that 

### 9 associations have to be moderately high to have some potential 

### 10 confounding effect. So of course, blood lead and methylmercury 

### 11 are two known neurotoxicants. 

### 12 But we know from these studies that the 

### 13 correlation between these factors and the mean exposure prenatal 

### 14 chlorpyrifos and/or organophosphate exposure is low. Each of 

### 15 the cohorts evaluated prenatal lead as a potential confounder, 

### 16 and none of them found it to be a confounder. So we do have 

### 17 that information to add to our consideration of these data. 

### 18 Concerning other organophosphate pesticides, 

### 19 the table presented in Appendix 4 was produced. It's an 

### 20 unpublished table, but it was produced as a result of suggested 

### 21 analyses by the SAP in 2008. 

### 22 So from this table, the question had arisen as

### Page 130 1 to the effect of both diazinon and propoxur as two other 

### 2 organophosphate pesticides as potential confounding variables in 

### 3 the relation with neurodevelopment. 

### 4 So in these unpublished analyses, again, 

### 5 presented in Appendix 4, we see that with the addition of 

### 6 diazinon and propoxur, the magnitude and the direction of the 

### 7 association is comparable with and without these variables and 

### 8 suggesting that, at least with respect to mental development 

### 9 index on the Bayley Scale, these variables are not strong 

### 10 confounders. 

### 11 So with respect to socioeconomic status, 

### 12 Lovasi et al., in 2010, produced results of the multi-level 

### 13 analysis considering individual as well as group-level type of 

### 14 characteristics in the modeling of, again, this very kind of 

### 15 broad, multi-level characteristic which we refer to as 

### 16 socioeconomic status. 

### 17 Outside of these cohorts and across 

### 18 epidemiology in general, there's lots of literature about the 

### 19 challenge of appropriately modeling factors around SES. So it 

### 20 was illustrative for the researchers with the Columbia 

### 21 University cohort to produce these data. 

### 22 So within their assessment, Lovasi et al., in

### Page 131 1 2010, Table Number 2 -- I apologize for the very small font on 

### 2 this replicated table, but I'm only trying to show that when you 

### 3 consider both these kind of group level variables, it's kind of 

### 4 the idea that there could be aspects, in this case, of 

### 5 socioeconomic status which are very difficult to measure -- 

### 6 possibly even immeasurable -- but that can be best reflected by 

### 7 a decision to be part of a certain kind of group or just by 

### 8 virtue of the fact that you are part of a certain group. 

### 9 So in considering both group-level variables 

### 10 and individual-level variables, we see in this, again, very 

### 11 small font that the estimates for chlorpyrifos across those 

### 12 different models, the magnitude and the direction is very 

### 13 similar, indicating that socioeconomic status using these 

### 14 methods is well-accounted for as a potential confounder. 

### 15 So just a few general notes on statistical 

### 16 analyses before we get into study results; overall, looking 

### 17 across these several different studies published within the 

### 18 three prospective birth cohorts, we found statistical modeling 

### 19 decisions to be appropriate to the research question, 

### 20 characteristics of the data and so on. 

### 21 Sample size, we believe, is adequate to assess 

### 22 the main effects proposed by study authors but possibly

### Page 132 1 underpowered for the evaluation of interaction or effect 

### 2 modification. And in many instances, sensitivity analyses were 

### 3 performed to evaluate different modeling options, different 

### 4 transformations of the data, different statistical models with 

### 5 and without confounders, et cetera. 

### 6 So over the next several slides, we'll go over 

### 7 the combined results of the three cohorts with respect to fetal 

### 8 growth and infant and childhood neurodevelopment. 

### 9 The fetal growth data, again, were presented 

### 10 to the panel in 2008; presented now in our written material in 

### 11 some greater detail than at that time, again, with the benefit 

### 12 of our draft framework for evaluating incorporating epidemiology 

### 13 into risk assessment. 

### 14 To evaluate fetal growth characteristics, 

### 15 authors again hypothesized this link a priori. Each of the 

### 16 study authors performed medical record linkage to identify the 

### 17 outcome, birth weight, birth length, et cetera. 

### 18 So across these studies, we see a mixed 

### 19 picture and certainly a set of inconsistent results with 

### 20 expected fetal growth and other birth characteristics within the 

### 21 Columbia cohort. 

### 22 Again, Columbia cohort measured chlorpyrifos'

### Page 133 1 parent compound directly. Those authors reported an inverse 

### 2 association with both birth length and birth weight; so the 

### 3 greater the chlorpyrifos exposure, the less the measure of birth 

### 4 length and birth weight. 

### 5 But looking across to the Mt. Sinai cohort 

### 6 which measured TCPy in maternal urine as a biomarker of 

### 7 exposure, those authors reported no effect. And surprisingly, 

### 8 within the CHAMACOS cohort, authors reported a non-significant 

### 9 and slight, but yet seemingly positive, association. 

### 10 So across the studies, three different 

### 11 results. Some have suggested this could be due to differences 

### 12 in the measure of exposure. 

### 13 With regard to head circumference and 

### 14 gestational age, not a compelling set of results and generally 

### 15 no findings; but some suggestion of an inverse relation with 

### 16 head circumference within the Mt. Sinai cohort and gestational 

### 17 age within the CHAMACOS cohort but only in the presence of a 

### 18 PON1 genotype or phenotype. The Columbia folks did not measure 

### 19 head circumference or gestational age. So overall, a mixed 

### 20 picture across these cohorts using, again, different biomarkers 

### 21 of exposure. 

### 22 To evaluate neonatal neurodevelopment, authors

### Page 134 1 with two of the three cohorts used the Brazelton Neonatal 

### 2 Behavioral Assessment tool, the goal of which was really to 

### 3 assess the newborn and provide information to parents and 

### 4 caregivers as to the best way to, you know, care for that 

### 5 infant. 

### 6 There are 28 behavioral and 18 primitive 

### 7 reflex domains included within the Brazelton index. They 

### 8 included things like, for example, range of state, which is, you 

### 9 know, we all know that some infants are a little more irritable 

### 10 or excitable than other infants, and the extent to which those 

### 11 kinds of responses could be related to primitive or innate and 

### 12 neurological functioning as evaluated within this tool. The 

### 13 tool was assessed by a trained neonatologist, administered in a 

### 14 hospital setting within several days of delivery. 

### 15 So the Mt. Sinai cohort and the CHAMACOS 

### 16 cohort both measured DAPs; again, that non-specific biomarker of 

### 17 OP exposure. We see some evidence of consistent results. Again 

### 18 using a similar measure of exposure with respect to number of 

### 19 abnormal reflexes, the two cohorts reported positive 

### 20 associations, i.e., the greater the concentration of DAPs in 

### 21 maternal urine, the greater the odds of an increased number of 

### 22 abnormal reflexes; and I believe it's a two or more of the 18

### Page 135 1 abnormal reflexes. 

### 2 Similarly, there's a consistent but no finding 

### 3 across the two cohorts with respect to the other behavioral 

### 4 domains assessment of Brazelton index. Overall, the Brazelton 

### 5 tool is used extensively in both clinical and research settings 

### 6 and is found to be a good measure of this outcome. 

### 7 The characterization of the relation with DAPs 

### 8 as opposed to chlorpyrifos is, of course, a limitation. With 

### 9 regard to infant neurodevelopment, each of the three cohorts 

### 10 made this measure using the Bayley Scales. 

### 11 Bayley Scales make two measures of mental 

### 12 development index and the psychomotor development index. The 

### 13 Bayley Scales sort of get at infant kind of curiosity or how the 

### 14 infant interacts with the world to how the infant reacts to the 

### 15 world measured on these two scales. 

### 16 Across the cohorts, this tool was utilized 

### 17 between 6 and 36 months. It's thought to have high reliability 

### 18 and validity. The interrater reliability coefficients are 

### 19 around 0.85, so that's pretty good. But it's considered to be a 

### 20 screening tool to assess infants that might be at need for early 

### 21 intervention. 

### 22 So in combination with the Bayley Scale,

### Page 136 1 authors also utilized the Child Behavior Checklist designed to 

### 2 assess social competence and behavioral problems. It's based 

### 3 upon a 99-item questionnaire, administered to the mom by a 

### 4 trained psychologist. 

### 5 The HOME tool, the Home Observation 

### 6 Measurement of the Environment, was also used across the three 

### 7 cohorts. The nature of the stimulating environment is thought 

### 8 to be a key confounder in this relation, so it's measured across 

### 9 the three cohorts. 

### 10 So here, similarly see a somewhat mixed 

### 11 picture; some areas of consistency, but still a mixed picture 

### 12 within the Columbia cohort, which again measure chlorpyrifos in 

### 13 cord blood. We see some evidence of increasing risk over time 

### 14 or at the 36-month time point inverse associations with both the 

### 15 mental and the psychomotor development scale identified. So the 

### 16 greater the chlorpyrifos exposure, the lower the score; and a 

### 17 lower score, in this case, is indicative of an adverse effect. 

### 18 We see similarly within the CHAMACOS cohort a 

### 19 non-significant inverse association measured at six months 

### 20 becoming statistically significant at 24 months. But within the 

### 21 Mt. Sinai cohort, that association is attenuated over time, so 

### 22 that is an area of inconsistency.

### Page 137 1 Overall, the effects were seen with MDI, or 

### 2 the Mental Development Index, more than the psychomotor 

### 3 development index. And importantly, the measure of TCPy was 

### 4 universally not associated with either MDI or PDI within any of 

### 5 the timeframes in which these are measured. 

### 6 Attention problems again were measured by two 

### 7 of the three cohorts with a combination of maternal report and 

### 8 direct observation. Participants were scaled using DSVM ADHD or 

### 9 ADHD-like symptoms and assessed between three and five years of 

### 10 age. 

### 11 Within the Columbia cohort, positive 

### 12 associations were identified at 36 months for both pervasive 

### 13 developmental disorder, which is distinct from ADHD but similar; 

### 14 and the CHAMACOS cohort reported, again, positive effects at 24 

### 15 months and then at five years. 

### 16 We know that the sensitivity of identifying 

### 17 attention or hyperactivity-related issues at 36 months across 

### 18 the literature has noted it to be limited; but having said that, 

### 19 there is some evidence of consistent positive associations. So 

### 20 in this case, positive would again mean greater exposure is 

### 21 greater risk of these types of attentional issues. 

### 22 And lastly, intelligence measures. As I noted

### Page 138 1 about a year ago, each of the three cohort authors 

### 2 simultaneously published their evaluation of prenatal exposure 

### 3 and intelligence measured in school-age children, each of which 

### 4 used the Wechsler Scale for measuring intelligence, which has 

### 5 four components and an overall full scale IQ measure. 

### 6 This tool has been standardized in U.S. 

### 7 populations and has norms in both English and Spanish speaking 

### 8 subpopulations. We note that the developers of the Wechsler 

### 9 Scale have identified cultural bias as a possible limitation to 

### 10 their tool. 

### 11 But as we indicated in the written material, 

### 12 we believe that the somewhat homogeneous composition of the 

### 13 studied populations with respect to race and ethnicity would 

### 14 somehow ameliorate the potential effect of this bias somewhat. 

### 15 So overall, across the three cohorts, again 

### 16 measuring chlorpyrifos in the non-specific measure, we see some 

### 17 evidence of consistent results. Each cohort reported inverse 

### 18 associations, i.e., the greater the measure of prenatal 

### 19 exposure, the lower the measure of intelligence. 

### 20 Notably, each cohort identified effects with 

### 21 working memory as a subcomponent of the Wechsler tool. These 

### 22 studies took place again within school-age children, average age

### Page 139 1 of seven years. So over that period of time in this 

### 2 longitudinal birth cohort study, there were some issues with 

### 3 dropout. And in some instances the number of missing tests is 

### 4 large, but the authors were able to show that on measured 

### 5 variables. Those included and those excluded from that study 

### 6 were comparable. 

### 7 So having reviewed some study methods and 

### 8 analysis issues as well as summarizing these results, we'll go 

### 9 on to our evaluation and synthesis formed by our Draft 

### 10 Framework. 

### 11 So overall, there are several strengths 

### 12 looking across the studies: measures of outcome again used, or 

### 13 tools used in both the clinical and in a research setting and 

### 14 validated in several different subpopulations and with different 

### 15 primary languages spoken in the home; exposure measures of an 

### 16 extensive, which include the validation work performed by 

### 17 researchers with the Columbia cohort. 

### 18 In many cases, important confounding variables 

### 19 were measured and modeled when appropriate. Again, it appeared 

### 20 to be an emphasis on parsimony and statistical model selection. 

### 21 And the comparability of study design, i.e., the prospective 

### 22 cohort design across the cohorts as well as other similarities

### Page 140 1 such as the similar use of outcome assessment tools aid 

### 2 comparability between the groups. Study design reduces many 

### 3 potential sources of bias. 

### 4 Limitations have to do with both some issues 

### 5 around exposure measure, especially when we consider these data 

### 6 for use in risk assessment, as well as other factors around 

### 7 confounding. There could be unknown factors, unmeasured 

### 8 factors, which could correlate with chlorpyrifos exposure and be 

### 9 potentially associated with neurodevelopmental outcomes. 

### 10 However, we note those have not been 

### 11 hypothesized yet in the literature; and among those that have a 

### 12 known or potential confounding bias -- those that have been 

### 13 measured -- there's lack of evidence to explain the positive 

### 14 associations that have been observed. 

### 15 Additionally, residual confounding in the form 

### 16 of SES is a potential; however, the additional work performed by 

### 17 researchers within Columbia, the hierarchical regression paper 

### 18 suggests that this variable, given the restriction criteria, the 

### 19 similarity of comparison groups through design as well as the 

### 20 ability to model on both an individual and group level reduce 

### 21 the potential. And there's limited discussion of the postnatal 

### 22 environment across these cohorts as limitations.

### Page 141 1 So some issues on study design; looking again 

### 2 across the three cohorts, each of these three studies was based 

### 3 on a priori hypotheses, other information in the published 

### 4 literature. So we believe that the potential for multiple 

### 5 comparison or artifactual observations are somewhat limited due 

### 6 to these well-founded a priori hypotheses. 

### 7 Statistical modeling, we found again to be 

### 8 appropriate, although we did note that they were discussed in 

### 9 varying degrees of detail across the publications. Imputation 

### 10 of missing data, we found also to be appropriate and useful to 

### 11 enhance statistical power and methods of imputation differed 

### 12 across the different study groups but were sufficiently 

### 13 explained. 

### 14 The selection criteria, as I noted at the 

### 15 beginning of the presentation, were extensive. It enhances 

### 16 internal validity, again, the comparability of the groups on 

### 17 factors relating to race, ethnicity, and income. However, it 

### 18 could reduce the generalizability of these data as these are 

### 19 relatively narrowly focused study populations. 

### 20 The high prevalence of exposure; I think each 

### 21 of these populations were identified because both the 

### 22 residential and occupational exposure is typically higher than

### Page 142 1 in the general population. 

### 2 Enhances study power or the ability to 

### 3 identify an effect if an effect exists; however, we do note that 

### 4 there's likely limitation in study power with respect to 

### 5 evaluating interactions. 

### 6 Statistical analysis and grouping; we found 

### 7 overall, several methods were used, motivated by sample size and 

### 8 study hypothesis. Generally, the grouping and the 

### 9 categorization, we found to be straightforward. The use of 

### 10 sensitivity analyses to evaluate, for example, different 

### 11 transformations of data. Inclusions of different variables in 

### 12 the model, we also found to be appropriate and well-discussed. 

### 13 Regarding exposure measurement, as noted 

### 14 earlier, the use of the different biomarkers of chlorpyrifos 

### 15 exposure somewhat hinder the direct comparability of these 

### 16 results. Again, others have suggested that heterogeneity in 

### 17 risk estimates could be due to differences in biomarker 

### 18 measurement. 

### 19 The use of one-time or, in the case of 

### 20 CHAMACOS, the average of the two exposure markers during the 

### 21 third trimester of exposure again do not inform the temporal and 

### 22 spatial patterns of exposure, which could have occurred during a

### Page 143 1 critical window of exposure. 

### 2 And the generalizability, as Dr. Bradbury 

### 3 mentioned earlier this morning, is of key interest to us. We 

### 4 know that while the populations are somewhat narrowly defined -- 

### 5 and we'll hear a little bit more about this in a moment -- the 

### 6 urinary concentration of TCPy is within the range of the general 

### 7 U.S. population. 

### 8 With regard to outcome measures, again, 

### 9 standard tools utilized similarly across the cohorts; tools that 

### 10 emanate from both the clinical and in a research setting. 

### 11 Quality assurance and control, we found to be adequate looking 

### 12 across these studies. 

### 13 Limitations in contrast to the fetal growth 

### 14 and development outcomes; assessment of neurodevelopment is 

### 15 somewhat more subjective. 

### 16 But overall, we feel that the potential for 

### 17 non-differential error is likely greater than for differential 

### 18 measurement error in the assessment of these outcomes. 

### 19 Just to summarize, for confounding bias, 

### 20 multiple methods of control were utilized. Multiple measures of 

### 21 potentially positive confounding factors were made including 

### 22 other environmental exposures -- lead and mercury as well as

### Page 144 1 SES. Overall, we thought there was a lack of examination of 

### 2 interaction or heterogeneity by other exposures with the 

### 3 prenatal chlorpyrifos or organophosphate measurement. 

### 4 Other sources of bias which may impact 

### 5 epidemiological inference: selection bias. As I noted, these 

### 6 are birth cohort studies perspective in nature. At seven years, 

### 7 the retention rate for participants was moderately high in the 

### 8 60 to 80% range. When available, comparison of those included 

### 9 and excluded from various evaluations were found to be 

### 10 comparable on many important factors but the extent to which 

### 11 they're comparable and unmeasured factors, of course, is 

### 12 unknown, is an uncertainty. 

### 13 Again, the potential for non-differential 

### 14 bias, we believe, is greater than for differential bias; given 

### 15 both a study design, the fact that these exposures were measured 

### 16 at birth prior to either the identification or the measurement 

### 17 of these outcomes. And with respect to outcome ascertainment, 

### 18 for the most part, researchers or psychometricians or study 

### 19 staff that implemented these neurodevelopment assessment tools 

### 20 was blinded to exposure status. 

### 21 In most, but not all cases, this was mentioned 

### 22 in the publications. And also, each of these cohorts measured

### Page 145 1 various environmental exposures, not just the chlorpyrifos or 

### 2 the organophosphate exposure, so that would also reduce the 

### 3 potential for differential measurement error in the assessment 

### 4 of the outcome. 

### 5 So moving toward our conclusions; 

### 6 synthesizing. Kind of again going back to this Bradford Hill 

### 7 type of considerations: considering the strength of the 

### 8 observations identified. There were some strikingly large odds 

### 9 ratios noted across these studies but not all. We believe that 

### 10 in instances in which moderate or no association was observed it 

### 11 could be due to non-differential measurement error or other 

### 12 factors. 

### 13 There is some evidence of exposure-response in 

### 14 the studies, which had more than two categories or who measured 

### 15 exposure on a variable. 

### 16 As we noted in the risk section, there is some 

### 17 consistency across the multiple cohorts that looked at similar 

### 18 neurodevelopmental outcomes, particularly with respect to the 

### 19 number of abnormal reflexes, with respect to the mental 

### 20 development index component of the Bayley Scale, and with 

### 21 respect to IQ measurement and particularly the measurement of 

### 22 working memory.

### Page 146 1 Again, these prospective studies are shielded 

### 2 from many sources of potential bias that you encounter in an 

### 3 epidemiology study. The measurement of exposure in-utero 

### 4 assures that exposures preceded these effects being measured in 

### 5 the neonatal time period or the infant time period or in 

### 6 school-age children. 

### 7 Biological plausibility; this, of course, is a 

### 8 key interest in other areas of our draft paper. While generally 

### 9 plausible, still lacks specific detail surrounding biologically 

### 10 plausible mode of action. This is discussed extensively 

### 11 elsewhere. 

### 12 And with respect to the sort of criteria or 

### 13 the consideration of cessation of exposure, in the Whyatt 

### 14 evaluations in both 2004 and 2005, authors note that prior to 

### 15 the voluntary cancellation of chlorpyrifos from in home 

### 16 environment, there was that inverse association that we noted 

### 17 with the characteristics with birth weight and birth length. 

### 18 However, subsequent to that voluntary 

### 19 cancellation, that association was no longer identified. That 

### 20 could be perceived as sort of in support of a cessation 

### 21 consideration or criteria, for lack of a better word, but we 

### 22 note in our written material that there's -- and authors note as

### Page 147 1 well in the supplemental analyses provided in Appendix 4 -- that 

### 2 there's probably limited statistical power to make that 

### 3 evaluation. The studies were not really designed for that 

### 4 purpose. 

### 5 So in summation, we believe that the current 

### 6 database strengthens the conclusion of the 2008 SAP and our 

### 7 conclusion at that time that chlorpyrifos likely plays a role in 

### 8 neurodevelopmental outcomes observed. 

### 9 Given the study conduct, design, and methods, 

### 10 as we've detailed today and in our written material, we believe 

### 11 that it is more likely that risk estimates have been under 

### 12 rather than over-estimated and that this information, of course, 

### 13 will continue to be evaluated and integrated with other lines of 

### 14 information over time. 

### 15 So that's a lot of information in about an 

### 16 hour. I'll stop my rapid-fire delivery and ask if there are any 

### 17 questions. 

### 18 DR. KENNETH PORTIER: And we'll all take a 

### 19 deep breath here, integrate that, and then I'll open it up for 

### 20 questions. Does anybody want to begin? Yes, Dr. Buckley and 

### 21 then Dr. Vena. 

### 22 DR. BRIAN BUCKLEY: Do you have any idea how

### Page 148 1 much of the data was imputed in these studies, or more or less 

### 2 from study to study what percent of the data, if you will? 

### 3 DR. CAROL CHRISTENSEN: So I guess the short 

### 4 answer would be no, I can't give you a number kind of off the 

### 5 top of my head. In some instances, it was significant. If I 

### 6 recall correctly, within the Rauh 2011 publication looking at 

### 7 prenatal chlorpyrifos exposure and IQ, there was about 40% of 

### 8 those exposure data that were below the limit of detection. 

### 9 DR. STELLA KOUTROS: I'm sorry. I don't 

### 10 remember it that way, so you might want to just double-check 

### 11 that. I was under the impression that the imputation was for 

### 12 the confounding variables and that was minimal, not for the 

### 13 exposure. 

### 14 DR. CAROL CHRISTENSEN: I'd be happy to double 

### 15 check that. 

### 16 DR. STELLA KOUTROS: Yeah, maybe there was 

### 17 also for some of the exposure, but I think that, from what I 

### 18 recall, the imputation of the confounders was mostly what the 

### 19 imputation was referring to. 

### 20 DR. CAROL CHRISTENSEN: Okay. I can clarify 

### 21 and get back -- 

### 22 DR. BRIAN BUCKLEY: Can I follow up then and

### Page 149 1 ask how they dealt with non-detects? 

### 2 DR. CAROL CHRISTENSEN: Across the studies, 

### 3 they dealt with non-detects and using different methods from a 

### 4 standard kind of LOD divided by the square root of two to an 

### 5 imputation, you know, kind of considering the distribution of 

### 6 the data above the limit of detection. So it varied. 

### 7 DR. JOHN VENA: Just a few points of 

### 8 clarification, in your presentation in, I guess, slide 26; you 

### 9 said that head circumference was not studied in the Columbia. 

### 10 Is that correct? But on Table 10, you say it's null, head 

### 11 circumference is null. 

### 12 DR. CAROL CHRISTENSEN: Thank you for bringing 

### 13 that up to allow me to clarify: there were some formatting 

### 14 errors within this table. In fact, to my recollection, it was 

### 15 not measured. That was an error that there was a null in that 

### 16 cell. 

### 17 DR. JOHN VENA: Right. Because you say in the 

### 18 text that Whyatt, 2004 did not report an association with head 

### 19 circumference, so I wasn't sure if that was that they didn't 

### 20 find it or they didn't study it. 

### 21 DR. CAROL CHRISTENSEN: I believe it's they 

### 22 didn't study it, and that again was an error in Table 10. So

### Page 150 1 thanks for the chance to clarify. 

### 2 DR. JOHN VENA: Okay. And also, you mentioned 

### 3 in these tables and in your presentation that the Mt. Sinai 

### 4 study was TCPy, but -- 

### 5 DR. CAROL CHRISTENSEN: Only for fetal growth 

### 6 and development. And I think for the remainder of the -- sorry, 

### 7 I'll let you continue. 

### 8 DR. JOHN VENA: Yeah, I know. But -- okay. 

### 9 So TCPy was just up through gestational age. Okay. But then in 

### 10 the next table, you say DAPs on -- let's see -- slide 28. You 

### 11 say chlorpyrifos was for -- okay, that's the Columbia. But the 

### 12 Mt. Sinai then was the -- was DAPs that looked at abnormal 

### 13 reflexes and neurodevelopment. They didn't -- 

### 14 DR. CAROL CHRISTENSEN: That's correct. 

### 15 DR. JOHN VENA: They didn't look at TCPy. I 

### 16 was curious why they didn't do that. Why they -- 

### 17 DR. CAROL CHRISTENSEN: I can't answer for the 

### 18 study authors. I do know that only for the evaluation of fetal 

### 19 growth and development did they use TCPy, and in that 

### 20 measurement of TCPy, they did not use the CDC laboratories; I 

### 21 think they used their own internal laboratory for that 

### 22 measurement.

### Page 151 1 I could -- you know, I could conjecture as to 

### 2 why they went another way, but -- 

### 3 DR. JOHN VENA: Okay. I'm just trying to get 

### 4 all this stuff straight. 

### 5 DR. CAROL CHRISTENSEN: Yeah, it's a lot of 

### 6 details. 

### 7 DR. JOHN VENA: And then the University of 

### 8 California Berkeley cohort in the table -- in your chart 28, you 

### 9 say it's DAPs; but in the Table 10, you say TCPy. 

### 10 DR. CAROL CHRISTENSEN: Yeah. Again, thank 

### 11 you for the opportunity to clarify. There are some formatting 

### 12 errors on that Table 10. That should be DAPs. 

### 13 DR. JOHN VENA: That should be DAPs. 

### 14 DR. CAROL CHRISTENSEN: Yeah. 

### 15 DR. JOHN VENA: Can we get a corrected table? 

### 16 DR. CAROL CHRISTENSEN: Sure. 

### 17 DR. JOHN VENA: Because it's just -- 

### 18 DR. CAROL CHRISTENSEN: Confusing. 

### 19 DR. JOHN VENA: Just trying to keep it 

### 20 straight, that's all. 

### 21 DR. CAROL CHRISTENSEN: Sure. 

### 22 DR. JOHN VENA: Confusing, okay. Because

### Page 152 1 they're different measures, they're different, they mean 

### 2 different things, and so it's important to understand which 

### 3 measure they're using for which outcome and how you can compare 

### 4 across studies and all of that stuff. 

### 5 DR. CAROL CHRISTENSEN: Yeah. Absolutely. 

### 6 DR. JOHN VENA: Okay. And the other question 

### 7 I had was about ADHD. 

### 8 DR. CAROL CHRISTENSEN: Yeah. 

### 9 DR. JOHN VENA: In the table, you don't say 

### 10 that Columbia looked at it; but then in your slide, you said 

### 11 they did at 36 months. The only thing on the table with ADHD 

### 12 was listed under Berkeley study. 

### 13 DR. CAROL CHRISTENSEN: They did. Within the 

### 14 Rauh 2006 publication, they measured ADHD or ADHD-like symptoms 

### 15 as measured at 36 months. 

### 16 DR. JOHN VENA: Okay. I'll have to re-read 

### 17 the summaries of those studies. Thanks. 

### 18 DR. CAROL CHRISTENSEN: Yeah. 

### 19 DR. KENNETH PORTIER: I think we sent you an 

### 20 email asking for that Table 10 update maybe for the Panel by 

### 21 tomorrow morning. 

### 22 DR. CAROL CHRISTENSEN: Absolutely. Yeah.

### Page 153 1 DR. KENNETH PORTIER: So okay. Up next is Dr. 

### 2 Collier. 

### 3 DR. ABBY COLLIER: Just a point of 

### 4 clarification, is Agency in slides 13 and 14 saying that 

### 5 meconium is a suitable reservoir to measure exposure over 

### 6 pregnancy as opposed to doing earlier studies? Is that sort of 

### 7 what you're implying? 

### 8 DR. CAROL CHRISTENSEN: I'm sorry. I missed 

### 9 the other clause: as opposed to -- 

### 10 DR. ABBY COLLIER: Are you saying that as 

### 11 opposed to, say, taking blood samples earlier in pregnancy that 

### 12 you can use meconium at term and it sort of counts as a 

### 13 reservoir for the chlorpyrifos? So are you using it as a marker 

### 14 tissue for exposure over pregnancy -- the meconium? 

### 15 DR. CAROL CHRISTENSEN: I'm relaying that the 

### 16 study authors in that validation work reported moderate yet 

### 17 significant correlation between meconium and the cord blood 

### 18 measure at delivery. And in fact, other studies outside of 

### 19 these cohorts are supporting that meconium might be a valid 

### 20 biomarker of exposure. 

### 21 DR. ABBY COLLIER: Thank you. 

### 22 DR. KENNETH PORTIER: Dr. Popendorf, I think,

### Page 154 1 is next. 

### 2 DR. WILLIAM POPENDORF: Yes, thank you. I've 

### 3 got a few questions, but let me just follow up on that one. 

### 4 These other studies are in human populations as well or are 

### 5 there animal studies on meconium? 

### 6 DR. CAROL CHRISTENSEN: Oh, on meconium. 

### 7 Yeah, I cannot speak to the animal studies; I was referring to 

### 8 other biomarker validation work that I've seen. I've not 

### 9 extensively evaluated those data for this purpose, but part of 

### 10 my general knowledge, I've seen kind of a growing consensus that 

### 11 meconium is looking like a decent biomarker of exposure in 

### 12 general. 

### 13 DR. WILLIAM POPENDORF: Okay. One of my 

### 14 questions had to do with a miscellaneous population in 

### 15 characterizing it. It's agricultural, which I guess it is; but 

### 16 it also said there was only like maybe 10 percent, as I recall, 

### 17 of the pesticides used in that area were chlorpyrifos. No 

### 18 indication what the other ones were -- other ones that might 

### 19 have similar biomarkers in particular, if they had DAP in their 

### 20 tests? 

### 21 DR. CAROL CHRISTENSEN: If I recall correctly, 

### 22 yes, other OP --

### Page 155 1 DR. ANNA LOWIT: The investigators have 

### 2 provided us with that list, and if you'd like to see that list, 

### 3 we can find it. It would take a little bit of time. But if you 

### 4 think the other two that form the TCP would be chlorpyrophos 

### 5 methyl, which is predominantly used on wheat, correct? 

### 6 DR. ANNA LOWIT: Historic Grains. And we're 

### 7 talking about Southern California, so it's unlikely that 

### 8 chlorpyrophos methyl is used. And the other one would be 

### 9 triclopyr, and that one, we don't know; we'd have to look up. 

### 10 The CHAMACOS group has given us a list of the 

### 11 other OPs and their use because it's California; you can get the 

### 12 use from California during the period of the recruitment. But 

### 13 it would take a little digging, but if you want it, we could 

### 14 have it by tomorrow. 

### 15 DR. WILLIAM POPENDORF: I guess I would like 

### 16 to see that because they use both TCPy and DAP, and I guess I'd 

### 17 have to look to see what -- or let's say, eventually looked at 

### 18 and just to get a sense of, you know, what was the agricultural 

### 19 component or you implied that it was and -- I'm not so sure that 

### 20 it is, but that would be good. 

### 21 So you got the recruitment 

### 22 Oh, slide 19, I guess. Because I wondered in

### Page 156 1 the text as well and you kind of went through this, in terms of 

### 2 assessing confounding biases, I wasn't clear what exactly you 

### 3 were looking at there in terms of what was correlating with what 

### 4 to qualify or not qualify as a confounding bias. Maybe you 

### 5 could just clarify it in that, Carol, are you saying that for 

### 6 instance, the chlorpyrifos exposure in something else is 

### 7 correlated and that would determine whether it's a confounder? 

### 8 DR. CAROL CHRISTENSEN: So right. So my point 

### 9 in this slide was to note, particularly for those who don't have 

### 10 a background in epidemiology, that, you know, often we hear, 

### 11 "Oh, such-and-such could be a confounder." 

### 12 But there are actually very specific criteria 

### 13 which must be met in order for confounding bias to occur; one of 

### 14 which is that that confounding variable -- and I'm using lead 

### 15 and mercury as an example on this slide -- must be causally 

### 16 related to the outcome. So we know that lead and methylmercury 

### 17 are known neurotoxicants, so that criteria are satisfied. 

### 18 It's also key or vital that the confounder in 

### 19 this, again lead and mercury, must be statistically associated 

### 20 with the main exposure, in this case chlorpyrifos. And I was 

### 21 emphasizing within this little box at the bottom left that not 

### 22 only must it be correlated, but methodological work outside of

### Page 157 1 these cohort studies suggest that that correlation must be 

### 2 moderate, not just a correlation, but a somewhat moderate or 

### 3 significant correlation to have a potential confounding bias. 

### 4 And so in the case of lead and methylmercury, 

### 5 as reported by study authors, those correlations are either very 

### 6 low; below 10 percent, for example. Within the Columbia cohort, 

### 7 the correlation is actually -0.08, so it's very, very low 

### 8 correlation between the confounder and the exposure. 

### 9 And when authors included lead in the model, 

### 10 there was no change in the effect estimates. So each of the 

### 11 three cohorts measured prenatal lead; each of the three cohorts 

### 12 evaluated prenatal lead as a potential confounding variable 

### 13 across these studies, and none of them included blood lead as a 

### 14 confounding variable. 

### 15 DR. WILLIAM POPENDORF: So if I followed that, 

### 16 right, you not only look for correlations between the two 

### 17 exposures but between, for instance, lead and the outcome. 

### 18 DR. CAROL CHRISTENSEN: Correct. 

### 19 DR. WILLIAM POPENDORF: Because I'm wondering 

### 20 in the case where chlorpyrifos is accounting for maybe 10 

### 21 percent of the effect, you could see a non-correlation in two 

### 22 exposure variables but still have a significant effect of, let's

### Page 158 1 say, lead independent of -- 

### 2 DR. CAROL CHRISTENSEN: Correct. 

### 3 DR. WILLIAM POPENDORF: Yeah. 

### 4 DR. CAROL CHRISTENSEN: That's absolutely 

### 5 correct. 

### 6 DR. WILLIAM POPENDORF: But you did look at 

### 7 both to disqualify it as a confounder? 

### 8 DR. CAROL CHRISTENSEN: That's correct. 

### 9 DR. WILLIAM POPENDORF: That wasn't clear. 

### 10 Thank you. 

### 11 DR. CAROL CHRISTENSEN: Okay. 

### 12 DR. KENNETH PORTIER: Next. Next, I have Dr. 

### 13 Carr; then Dr. Ryan. 

### 14 DR. RUSSELL CARR: Hello. On slide 34, using 

### 15 the Wechsler, Rauh 2011 said that in the Columbia cohort that 

### 16 lower IQs and lower working memory associated with chlorpyrifos 

### 17 exposure, and they did, in their model, they eliminated 

### 18 polycyclic aromatic hydrocarbons and other compounds. 

### 19 In another publication by that same group, 

### 20 they found that PAHs cause attention deficit syndrome in the 

### 21 same cohort of children, but yet they put in there that 

### 22 chlorpyrifos played no role in that.

### Page 159 1 Physiologically, you can't separate attention 

### 2 of a child from IQ. If he has a poor attention, his IQ's going 

### 3 to be lower; much like the same if he has a poor attention he's 

### 4 not going to do working memory very well. And I'm trying to 

### 5 wrap my head around how you can say one chemical affects this 

### 6 process in the brain, and another one affects this, when those 

### 7 two processes are linked really strongly. 

### 8 DR. CAROL CHRISTENSEN: Okay. So I'll start 

### 9 with, right, both within the Columbia cohort, there's been 

### 10 evaluations of both chlorpyrifos and PAH. And within the PAH 

### 11 paper on attention, it was determined that chlorpyrifos and PAH 

### 12 are independent predictors of that outcome. They both predict 

### 13 that outcome. 

### 14 So you could have a multi -- you know, there's 

### 15

-- 

### 16 DR. RUSSELL CARR: So they both create 

### 17 attention deficit syndrome -- I mean, the problem, the attention 

### 18 problems? 

### 19 DR. CAROL CHRISTENSEN: There's evidence of an 

### 20 association with that outcome with both chlorpyrifos and PAH. 

### 21 DR. RUSSELL CARR: Independently of one 

### 22 another.

### Page 160 1 DR. CAROL CHRISTENSEN: Independently of one 

### 2 another, and they've tested for confounding within both. 

### 3 DR. KENNETH PORTIER: Let me just follow up: 

### 4 does that also mean -- when you say independent, it means if you 

### 5 put them both in multiple regressions, they're both significant? 

### 6 Or do you mean you put one in, associate it, you put another 

### 7 one in? What did they mean by independently of each other? I'm 

### 8 just trying to -- 

### 9 DR. CAROL CHRISTENSEN: They're both 

### 10 independent predictors of that outcome, so chlorpyrifos in the 

### 11 presence of PAH within the statistical model would be predictive 

### 12 of that outcome. PAH in the presence of chlorpyrifos, you know, 

### 13 when you add both of them together, it depends on what else is 

### 14 in the model. 

### 15 I mean, I would suspect that, yes, when 

### 16 they're both in there, you can see -- right. I just know that 

### 17 they're separately and independently predictive of that outcome. 

### 18 Now your second part of your question with 

### 19 respect to the Wechsler tool, I'm not a child psychologist. I 

### 20 don't administer these exams, but I do know from my reading 

### 21 about the Wechsler tool is that you can assess intelligence in a 

### 22 child who has attention issues.

### Page 161 1 DR. RUSSELL CARR: But if you know going in 

### 2 that child has ADHD and has very strong indication, but is that 

### 3 mentioned in these methods that they go in and say, "Okay. This 

### 4 child is showing symptoms of attention deficit disorder," 

### 5 because a lot of times when they administer the Wechsler and 

### 6 they understand that, they realize that his IQ's probably going 

### 7 to be about 10 points higher. 

### 8 I mean is that in the methodology or this 

### 9 paper that they actually considered that these children had 

### 10 attention deficit disorder before they administered an IQ exam? 

### 11 DR. CAROL CHRISTENSEN: I do not recall in 

### 12 that a mention of that within the methods section that they 

### 13 separately administer these tests differently among kids who 

### 14 have known or reported ADHD or are medicated for ADHD. I would 

### 15 have to go back and double-check that. I don't recall it off 

### 16 the top of my head. 

### 17 DR. RUSSELL CARR: Okay. 

### 18 DR. KENNETH PORTIER: Next is Dr. Ryan. 

### 19 DR. BARRY RYAN: Yes, I'd just like to explore 

### 20 a little bit this exposure validation study, and I guess it's 

### 21 the slides beginning 11, 12, 13, 14, and those areas. And I'm 

### 22 particularly interested in slide number -- I guess it is 12

### Page 162 1 where we talk about maternal urine in the last trimester and 

### 2 then the figure that goes after that is a kind of a depiction of 

### 3 the time course of the validation study here. 

### 4 DR. CAROL CHRISTENSEN: Okay. 

### 5 DR. BARRY RYAN: I just want to clarify that 

### 6 the data that are in the table after that -- I'm sorry to keep 

### 7 on having you jump through the slides here, but the data in the 

### 8 table after that where it says, "First prenatal, second 

### 9 prenatal, third prenatal," and so on, that represents only from 

### 10 week 32 on? 

### 11 DR. CAROL CHRISTENSEN: That is correct. 

### 12 DR. BARRY RYAN: Okay. And so the fourth 

### 13 prenatal visit, the reason the end is dropped is probably 

### 14 because several women went in and delivered their children in 

### 15 there. So the temporal variability on that really is only over 

### 16 a relatively short period of time. 

### 17 DR. CAROL CHRISTENSEN: Over an eight-week -- 

### 18 DR. BARRY RYAN: An eight-week period. 

### 19 DR. CAROL CHRISTENSEN: Up to a maximum of an 

### 20 eight-week timeframe. I think the average was 6.25 weeks. 

### 21 DR. BARRY RYAN: I'm sorry. I missed the 

### 22 average of -- I missed the number.

### Page 163 1 DR. CAROL CHRISTENSEN: Maximum of an 

### 2 eight-week timeframe. I think the average across this 

### 3 validation study population was an evaluation period of about 

### 4 6.25 weeks. 

### 5 DR. BARRY RYAN: Okay, but so something on the 

### 6 order of six weeks? 

### 7 DR. CAROL CHRISTENSEN: Yes, up to eight. 

### 8 DR. BARRY RYAN: And the correlation there, 

### 9 obviously it's statistically significant and you lose some of 

### 10 the significance at the forefront because, again, it's 

### 11 relatively small. But those numbers are still pretty small, and 

### 12 there's a lot of stuff that's not accounted for by knowing that 

### 13 this is the relationship between TCPy and maternal urine and 

### 14 whatever it is we're looking at -- meconium. Is that right? 

### 15 TCPy levels in meconium and chlorpyrifos in 

### 16 maternal and umbilical cord blood, right? 

### 17 DR. CAROL CHRISTENSEN: Right. These are 

### 18 merely correlation coefficients; these are not adjusted 

### 19 estimates. And yes, we acknowledge that these are moderate 

### 20 correlations. They're not high correlations. 

### 21 DR. BARRY RYAN: And again, the meconium, you 

### 22 think, integrates from week 14, 13 -- I can't remember.

### Page 164 1 DR. CAROL CHRISTENSEN: I've heard different 

### 2 and read different things -- 13 or 14, yeah. 

### 3 DR. BARRY RYAN: Somewhere in that range, 

### 4 though. So we're looking at something that was really collected 

### 5 at the very end of pregnancy correlated with something that's 

### 6 been integrated over the entire pregnancy -- well, not the 

### 7 entire, but two-thirds of the pregnancy. 

### 8 DR. CAROL CHRISTENSEN: Right. And that is 

### 9 the gist of this slide, yes. 

### 10 DR. BARRY RYAN: Okay. That's all. I just 

### 11 wanted clarification on that. Thank you. 

### 12 DR. KENNETH PORTIER: Dr. Vena. 

### 13 DR. JOHN VENA: It's not my area, but I don't 

### 14 think ADHD and IQ are along the same domain. It seems to me 

### 15 that -- I'm not sure what the basis for your comment is -- that 

### 16 somebody who has ADHD has a lower IQ. I mean, what's the 

### 17 evidence for that? 

### 18 DR. RUSSELL CARR: I'm not saying they have a 

### 19 lower IQ; I'm saying their scores on a test could possibly be 

### 20 lower. 

### 21 DR. JOHN VENA: Again, I don't know, but I'm 

### 22 not sure if that's the case. I'm not.

### Page 165 1 DR. RUSSELL CARR: I mean, that was my 

### 2 understanding. 

### 3 DR. KENNETH PORTIER: Dr. Young. 

### 4 DR. HEATHER YOUNG: If you check that -- the 

### 5 paper that you're talking about, they do acknowledge that child 

### 6 behavior issues can affect the score on the working memory 

### 7 index. And so they did a supplementary analysis that looked at 

### 8 that and took it into account. So it's in the Rauh paper that 

### 9 you can see they did acknowledge that, and they did something to 

### 10 look at that. 

### 11 DR. KENNETH PORTIER: And this is why we have 

### 12 a big Panel. Dr. Vena again. 

### 13 DR. JOHN VENA: Thanks for that clarification. 

### 14 And I did go back and look at the summary in Appendix 6 of 

### 15 Whyatt 2004, and it does say on page 4 in this first paragraph: 

### 16 "Head circumference was not significantly associated with 

### 17 maternal personal air or cord blood chlorpyrifos levels." So in 

### 18 fact, they did look at head circumference. And so the table's 

### 19 right; it is null -- Table 10. 

### 20 DR. CAROL CHRISTENSEN: Thanks for that 

### 21 clarification. I'll make sure that that's accurate when I 

### 22 distribute that table tomorrow.

### Page 166 1 DR. JOHN VENA: Right. 

### 2 DR. KENNETH PORTIER: Dr. Harry. 

### 3 DR. GAYLIA JEAN HARRY: So I have a question 

### 4 for clarification, just as we're trying to see across these 

### 5 studies is what you're asking us to look at. So I've 

### 6 administered the Wechsler, but I really don't know the Bayley 

### 7 Scores that you're looking at. But there are different things 

### 8 that would come in at the 36 months that you would not be able 

### 9 to detect at 24 months because of the developmental aspect of 

### 10 it. 

### 11 And I was wondering if you could provide the 

### 12 Panel, in general, some information on what you might expect to 

### 13 see changing between 24 and 36 because you've got -- you've got 

### 14 a couple studies suggesting you've got an inverse relationship 

### 15 at 24 months, but then you've got the Columbia study that says 

### 16 you don't see any inverse association 'til 36 months. 

### 17 Could you help us out with what some of those 

### 18 pivotal changes might be between the 24 and the 36 months of 

### 19 changes you would be detecting, things you are able to measure, 

### 20 at 36 months that you cannot measure at 24 that change over? 

### 21 DR. CAROL CHRISTENSEN: Right. Again, I think 

### 22 my best answer to that question -- and then I would have to go

### Page 167 1 back into looking at materials published by those who developed 

### 2 the Bayley Scale -- but my best answer to that question would 

### 3 be, you know, certainly as children develop, motor coordination 

### 4 is always increasing over time. 

### 5 My understanding of the Bayley is it's, you 

### 6 know, sort of looking at the same time of the child's kind of 

### 7 interest and attention and interest in exploring the world and 

### 8 interacting with that world as a way to develop mental capacity 

### 9 and cognition, combined with the ability to explore and 

### 10 experiment with the world, i.e., the psychomotor issues. 

### 11 So as, you know, young children age, those two 

### 12 things come closer together; and uncommonly those differences, 

### 13 if they do occur, are more notable. So I think my simple answer 

### 14 would be that over time, if deficits are occurring, it's going 

### 15 to be a little bit easier to identify those deficits. 

### 16 But more specific than that, I would have to 

### 17 go back to the references concerning the Bayley Scales. 

### 18 DR. KENNETH PORTIER: Dr. Aschner. 

### 19 DR. MICHAEL ASCHNER: Quick question: in 

### 20 looking at the nutritional data of the different cohorts, is 

### 21 there anything there about fish consumption between -- any 

### 22 differences between the three? Some generalized comments about

### Page 168 1 that? 

### 2 DR. CAROL CHRISTENSEN: About fish 

### 3 consumption. Overall dietary information was not reported 

### 4 within these published evaluations, and we're going with what is 

### 5 available in the published peer review literature. Through 

### 6 personal communication with the principal investigators, we had 

### 7 asked that question around methylmercury exposure and fish 

### 8 consumption; and overall qualitatively, my understanding is that 

### 9 it's low. 

### 10 In fact, the correlation with methylmercury 

### 11 and chlorpyrifos is also low. I believe, at least with respect 

### 12 to the Columbia cohort, for which I have some informal 

### 13 information, fish consumption is not high. 

### 14 DR. MICHAEL ASCHNER: I was just wondering if 

### 15 in the Berkeley area, it was higher; I realize in New York, it's 

### 16 probably pretty low. 

### 17 DR. CAROL CHRISTENSEN: Pretty low. I have no 

### 18 information to share about that. 

### 19 DR. KENNETH PORTIER: Dr. Popendorf. 

### 20 DR. WILLIAM POPENDORF: Yeah, I've been 

### 21 looking for the information, but I just had one question. I 

### 22 might as well just ask you than trying to find it in the text.

### Page 169 1 But slide 28, the Brazelton outcomes -- the two positives; 

### 2 refresh me: was it just total numbers of measures that were 

### 3 positively associated, or was there particular measures within 

### 4 that? 

### 5 DR. CAROL CHRISTENSEN: It was total numbers. 

### 6 So that positive association is referring to increasing urinary 

### 7 concentration of DAPs in moms, measured in the third trimester, 

### 8 were positively correlated with the odds of having two or more 

### 9 abnormal reflexes measured. 

### 10 But I think it's three or more in CHAMACOS and 

### 11 two or more in Mt. Sinai. One is two and one is three, but it 

### 12 is two or more abnormal reflexes out of the 18 measured. 

### 13 DR. KENNETH PORTIER: Dr. Pope. 

### 14 DR. CAREY POPE: Yeah, there was some mention 

### 15 about TCPy levels earlier and where they're coming from methyl 

### 16 parathion or wheat and triclopyr. 

### 17 DR. ANNA LOWIT: Chlorpyrophos methyl. 

### 18 DR. CAREY POPE: Methyl chlorphyrophos, right. 

### 19 And triclopyr, there was a question about. It's, as far as I 

### 20 know, used on broadleaf weeds, and it's about the -- according 

### 21 to this group's work -- it's about the seventh as far as amount 

### 22 of pesticide use for industry and commercial purposes. And

### Page 170 1 roughly speaking, it's anywhere from a quarter to a half of the 

### 2 amount of pesticide used compared to chlorpyrifos. 

### 3 So yeah, that is a substantial, you know, 

### 4 pesticide use. It may not be used as broadly across multiple 

### 5 purposes or multiple sites compared to chlorpyrifos as far as 

### 6 amount. It's quite substantial. 

### 7 DR. ANNA LOWIT: Well, certainly right now, we 

### 8 can't confirm the numbers that you just gave, but you are 

### 9 accurate that triclopyr is in residential products and can be 

### 10 bought by individuals at your local store as a herbicide. 

### 11 DR. CAREY POPE: I have a ten-gallon container 

### 12 at home. I use it personally. 

### 13 DR. ANNA LOWIT: We're in the process of 

### 14 getting the Ag use right now. We've sent some emails out, so we 

### 15 won't confirm the numbers, but certainly it is a residential 

### 16 product. 

### 17 DR. CAREY POPE: Yeah. 

### 18 DR. KENNETH PORTIER: Dr. Young. 

### 19 DR. HEATHER YOUNG: Carol, can I just confirm 

### 20 slide 20? None of that's published, right -- the stuff where 

### 21 they look at the confounding with the other pesticides? 

### 22 DR. CAROL CHRISTENSEN: That's correct.

### Page 171 1 DR. HEATHER YOUNG: Oh, okay. 

### 2 DR. CAROL CHRISTENSEN: It's replicated in 

### 3 full in your Appendix 4, but it is unpublished. 

### 4 DR. HEATHER YOUNG: Okay. But it's not 

### 5 published. Okay. 

### 6 DR. CAROL CHRISTENSEN: Correct. 

### 7 DR. HEATHER YOUNG: Thank you. 

### 8 DR. KENNETH PORTIER: Dr. Lu. 

### 9 DR. CHENSHENG LU: Just a quick question: so 

### 10 in addition to DAP and TCPy, what other OP -- what other 

### 11 pesticide data you have received from all the three studies? 

### 12 Not just pesticide data; like, metabolite data. In addition to 

### 13 DAP, like, do you have MDA -- the metabolite for Malathion? 

### 14 DR. CAROL CHRISTENSEN: Oh, outside. I 

### 15 believe Malathion was measured in the Mt. Sinai cohort. 

### 16 DR. CHENSHENG LU: But not across all three 

### 17 studies? 

### 18 DR. CAROL CHRISTENSEN: Not across -- for 

### 19 Malathion specifically, not across all three studies, no. 

### 20 In addition to diazinon and propoxur, I think 

### 21 there were other OPs measured by Columbia. Diazinon and 

### 22 propoxur and chlorpyrifos were the most frequently detected

### Page 172 1 within the cohorts, so those were the ones that they considered 

### 2 for their model adjustment; but there were other measures made, 

### 3 and I can get you that list. 

### 4 DR. KENNETH PORTIER: Okay. I think we've 

### 5 exhausted that. Why don't we move on then to discussion of 

### 6 biomonitoring? Mr. Niman? 

### 7 MR. AARON NIMAN: Good afternoon. My name's 

### 8 Aaron Niman. I'm an industrial hygienist with the Office of 

### 9 Pesticide Programs, Health Effects Division. My presentation 

### 10 today focuses on Section 5 of the issue paper, which provided a 

### 11 review of chlorpyrifos biomarkers of exposure; and then 

### 12 presented a TCPy biomonitoring study comparison; then discuss 

### 13 evaluation of the relationship between urinary TCPy levels and 

### 14 acetylcholinesterase and human populations. 

### 15 And then finally, it discussed risk-based 

### 16 biomonitoring interpretation options currently being evaluated 

### 17 by the Agency to further incorporate biomonitoring data into the 

### 18 risk assessment process. 

### 19 So my presentation today is basically going to 

### 20 follow the outline of the Section 5 of the issue paper. 

### 21 Just to begin with, chlorpyrifos biomarkers of 

### 22 exposure. There's fairly extensive literature on chlorpyrifos

### Page 173 1 biomonitoring, some of which was discussed in the previous 

### 2 presentation, but the most common biomarkers of exposure are the 

### 3 urinary metabolites, TCPy, and the non-specific dialkylphosphate 

### 4 metabolites DEP and DETP. 

### 5 In addition to those, chlorpyrifos has been 

### 6 directly measured in biologic media, including blood and other 

### 7 biologic media such as meconium. 

### 8 I won't go into a lot of detail, since a lot 

### 9 of this was just discussed in the last presentation. But 

### 10 certainly in terms of scientific considerations about evaluating 

### 11 and interpreting biomonitoring results with specificity in 

### 12 issues related to longitude and variability are particularly 

### 13 important. 

### 14 And as it's been mentioned, both DEP and DETP 

### 15 are considered non-specific biomarkers because they are 

### 16 metabolites of multiple OP pesticides. And similarly, TCPy is 

### 17 generally considered more specific than the dialkylphosphates, 

### 18 but it is a metabolite of a couple different parent compounds as 

### 19 well. So there are specificity considerations. 

### 20 In addition to just the metabolic profile of 

### 21 the compounds, additional considerations, both these -- all of 

### 22 these biomarkers are also environmental degradates, so they're

### Page 174 1 present in environmental media, whether it's dust or food 

### 2 samples. 

### 3 So when evaluating, in this case exposure to 

### 4 chlorpyrifos, if you're measuring TCPy, although TCPy is because 

### 5 of chlorpyrifos exposure, you'll tend to overestimate exposures 

### 6 if you don't account for the direct exposure to TCPy. 

### 7 In terms of longitudinal variability, most of 

### 8 the literature suggests that there's fairly high day-to-day 

### 9 variation within a person and their levels of both the DAPs and 

### 10 TCPy. This is likely due to the fact that these compounds have 

### 11 fairly short biologic half-life, and the nature of exposure 

### 12 particularly outside of occupation, the populations tends to be 

### 13 fairly intermittent. So for that reason, it's not surprising 

### 14 that you'd see fairly high variability. 

### 15 It's been suggested, because of the 

### 16 variability that's been observed, it's difficult to quantify 

### 17 pesticide exposure in the typical risk assessment metric, 

### 18 exposure or intake per day over an extended duration of time. 

### 19 However, it's also been suggested that, 

### 20 particularly for the purposes of epidemiology where the goal's 

### 21 either to assign broad exposure categories or simply rank 

### 22 exposure, that the spot-urine measurements can be suitable for

### Page 175 1 those purposes. 

### 2 And then some of the validation work discussed 

### 3 in regard to the Columbia cohort adds some credibility to that; 

### 4 particularly spot-urine samples can be used for the purposes of 

### 5 exposure assessment in epidemiology. 

### 6 Moving onto blood biomarkers, a benefit, or a 

### 7 strength, of direct measurement of chlorpyrifos in blood is a 

### 8 direct measure of the internal dose of chlorpyrifos. However, 

### 9 in general, blood measurement seems to be much less common in 

### 10 the literature. Part of this probably has to do with it require 

### 11 more sensitive analytical methods. 

### 12 In addition, it also places a greater burden 

### 13 on study participants, so there might just be fewer 

### 14 opportunities to collect blood to measure chlorpyrifos. 

### 15 An additional interpretation consideration is 

### 16 that given the rapid half-life of chlorpyrifos, particularly in 

### 17 blood, it represents a narrower period of exposure even relative 

### 18 to urinary biomarkers. 

### 19 I'm now going to transition to the TCPy 

### 20 biomonitoring study comparison presented in the paper, and the 

### 21 main goal of this was to compare summary results reported in the 

### 22 literature focusing on TCPy urinary concentrations, both in the

### Page 176 1 general U.S. population and targeted study populations, which 

### 2 includes the three children's health cohorts. 

### 3 And this comparison was intended to be fairly 

### 4 broad in nature and just essentially provide a frame of 

### 5 reference for the three children's health cohorts. And it's 

### 6 notable there are some key differences, and all the studies 

### 7 considered that we didn't want to take the comparison too far. 

### 8 Unique differences related to the time and 

### 9 relative to the residential phase-out in addition to unique 

### 10 study populations, whether it is differences in age, location, 

### 11 setting, which might influence the dominant route of exposure, 

### 12 for example. 

### 13 A number of these studies have specific 

### 14 research objectives, so the goal is to provide sort of a broad 

### 15 base comparison, not do an "apples to apples" comparison. 

### 16 In terms of studies that were selected, of 

### 17 course we considered NHANES to get general population estimates. 

### 18 We also included observational studies conducted by EPA's 

### 19 Office of Research and Development. 

### 20 In addition to those also included a subset of 

### 21 studies that have been performed by Dow. These are 

### 22 observational studies of individuals applying pesticides both in

### Page 177 1 occupational and residential use scenarios. And the subset are 

### 2 intended to provide both the high and the low for occupational 

### 3 and residential use scenarios because there have been much more 

### 4 studies that have been submitted to the Agency. 

### 5 In addition to that included studies from the 

### 6 peer-reviewed literature, many of which that have previously 

### 7 been reviewed and evaluated by the Agency in the 2008 SAP. And 

### 8 there's a fairly comprehensive review by Eaton et al., 2008. 

### 9 This is just a summary of the studies. I 

### 10 won't go into any detail; it's more for your reference if you 

### 11 have any questions at the end of the presentation. But I'll 

### 12 just emphasize the studies, in terms of age, had different study 

### 13 populations, and included different collection periods. 

### 14 This first figure was presented in Section 5 

### 15 of the issue paper, and it's a summary of TCPy urinary levels in 

### 16 child study populations. 

### 17 All the way to the left are the reference 

### 18 ranges based off of summary statistics reported by CDCs in their 

### 19 exposure report. And these ranges reflect the 5th and 95th 

### 20 percentile -- between the 5th and 95th percentiles of urinary 

### 21 TCPy levels in 6- to 11-year-olds. 

### 22 And again, we made general conclusions in the

### Page 178 1 issue paper just looking across various studies, the ranges seem 

### 2 somewhat similar, although some studies did note higher median 

### 3 levels, for example, in a number of the ORD studies under Egeghy 

### 4 et al., which included all the ORD observational studies. 

### 5 Moving onto the study comparison of adult 

### 6 populations. Again, all the way on the left includes the study 

### 7 results from NHANEs, and again, this time it's adults ages 20 to 

### 8 59. And all the way to the right, we've highlighted the results 

### 9 from the three children's health cohorts. I will narrow in on 

### 10 the children's health cohorts in the next slide, but I just 

### 11 wanted to make the point where the Dow studies fit in. And 

### 12 again, these were studies where they monitored individuals 

### 13 applying pesticides in both occupational and residential use 

### 14 scenarios. 

### 15 And particularly, the high end were observed 

### 16 to be quite a bit higher than the levels observed in the general 

### 17 U.S. population. 

### 18 Narrowing in on the three children's health 

### 19 cohorts in comparison to NHANES, again, in comparison of the 

### 20 entire distribution, the distributions seemed somewhat similar. 

### 21 There were comparison of median levels; they were reported to be 

### 22 slightly higher both in the CHAMACOS and Mt. Sinai cohorts, and

### Page 179 1 slightly lower in the Columbia cohort. 

### 2 And these findings have been noted by the 

### 3 investigators in some of their publications, and they're noted 

### 4 in the discussion section of Section 5. 

### 5 We also noted that in regard to the Columbia 

### 6 paper, in contrast to the other cohorts, some of that urinary 

### 7 TCPy data was collected during the residential phase-out, which 

### 8 might provide some sort of explanation to why median TCPy levels 

### 9 were lower than NHANES'. 

### 10 I'll now move on to the evaluation of the 

### 11 relationship between urinary TCPy levels and 

### 12 acetylcholinesterase inhibition in human populations. Just a 

### 13 quick overview on monitoring of acetylcholinesterase. 

### 14 The main biomarkers are red blood cell 

### 15 acetylcholinesterase and plasma butyrylcholinesterase. Red 

### 16 blood cell acetylcholinesterase is considered an early marker of 

### 17 potential chlorpyrifos toxicity, and plasma 

### 18 butyrylcholinesterase has been shown to be inhibited at lower 

### 19 levels of exposure than red blood cell acetylcholinesterase. 

### 20 And it's considered a more sensitive biomarker 

### 21 for purposes of evaluating potential physiological change or 

### 22 exposure to chlorpyrifos and other OP pesticides, but its

### Page 180 1 toxicological relevance is still unclear. 

### 2 In terms of previous Agency findings, at the 

### 3 2008 SAP, the Agency did evaluate the literature on the 

### 4 association between TCPy and acetylcholinesterase activity in 

### 5 human populations largely based on a number of 

### 6 registrant-submitted studies as well as other studies in the 

### 7 literature. 

### 8 And the main conclusions at that SAP is that 

### 9 there were some particular individuals within studies where 

### 10 inhibition was noted, but it was difficult to draw definitive 

### 11 conclusions about the overall relationship between urinary TCPy 

### 12 and acetylcholinesterase inhibition. And this is largely due to 

### 13 the large variability in response that was observed in those 

### 14 studies. 

### 15 Since the 2008 SAP, there've been a couple 

### 16 more recent publications that have done a fairly nice job of 

### 17 evaluating the association between urinary TCPy and 

### 18 acetylcholinesterase inhibition. 

### 19 The first of these, Garabrant et al., 2009, 

### 20 was a study that focused on manufacturing facility workers that 

### 21 are involved in the production of chlorpyrifos and a comparison 

### 22 of their TCPy and acetylcholinesterase activity relative to a

### Page 181 1 reference group of other unexposed chemical manufacturing 

### 2 workers. 

### 3 The second study, Farahat et al., was a 

### 4 longitudinal study involving cotton field workers in Egypt who 

### 5 were involved in chlorpyrifos application. 

### 6 Just a note about these studies: there was -- 

### 7 when you look at the results in the publications, it's pretty 

### 8 clear that these are occupational level exposures. In 

### 9 comparison with the creatinine-adjusted results reported by CDC, 

### 10 general population urinary concentrations range from about 1.5 

### 11 to roughly 10 micrograms TCPy per gram creatinine. 

### 12 In contrast, if you look at the exposed 

### 13 populations in both of these studies, they range anywhere from 

### 14 an order of magnitude to three orders of magnitude higher than 

### 15 the NHANES urinary concentrations. 

### 16 This figure wasn't presented in the paper. We 

### 17 focused on the main findings, but we thought it would be useful. 

### 18 These figures were not included in the actual 

### 19 issue paper, but we thought it would be useful to present some 

### 20 of the data, and this just shows the results of the Garabrant 

### 21 study evaluating the association between TCPy in both red blood 

### 22 cell and plasma acetylcholinesterase activity.

### Page 182 1 As you can see, the figure on the left, they 

### 2 reported no statistical significant association between urinary 

### 3 TCPy and red blood cell acetylcholinesterase. And the figure on 

### 4 the right, they noted an inflection point at which they observed 

### 5 a statistically significant dose response, and that was based on 

### 6 the more sensitive biomarker, plasma butyrylcholinesterase. 

### 7 This second figure is from the Farahat et al., 

### 8 2011 study. And interestingly, they did observe a statistically 

### 9 significant association between urinary TCPy and red blood cell 

### 10 acetylcholinesterase. 

### 11 It's probably notable that the levels of 

### 12 exposure or the urinary levels observed by Farahat et al. are 

### 13 even higher than the levels observed in Garabrant's. That might 

### 14 be part of the reason they were able to observe that 

### 15 statistically significant dose response relationship. 

### 16 So the main findings that are summarized in 

### 17 the issue paper is that Garabrant did not observe a 

### 18 statistically significant association between TCPy and red blood 

### 19 cell acetylcholinesterase, but they did observe a significant 

### 20 association between TCPy and plasma butyrylcholinesterase above 

### 21 a cutpoint of 110 micrograms TCPy per gram creatinine. 

### 22 In contrast, the Farahat et al. study did note

### Page 183 1 a statistically significant association above an inflection 

### 2 point or a cutpoint of around 3,100 micrograms TCPy per gram 

### 3 creatinine. 

### 4 It also noted consistency between both the 

### 5 studies with regard to the association between urinary TCPy and 

### 6 butyrylcholinesterase. In particular, both observed the 

### 7 inflection point or cutpoint at around 110, 114 micrograms TCPy 

### 8 per gram creatinine. 

### 9 Moving on to the interpretation options being 

### 10 evaluated by the Agency. In the issue paper, we outlined 

### 11 several different qualitative, semi-quantitative, and 

### 12 quantitative interpretation options that vary in their level of 

### 13 sophistication and how they would be incorporated into risk 

### 14 assessment. 

### 15 Regardless of the interpretation approach, 

### 16 there are some key challenges, many of which have been noted 

### 17 before related to the specificity and issues related to 

### 18 longitudinal variability. 

### 19 And additional consideration or challenges is 

### 20 the toxicological relevance of the biomarker. And the TCPy, for 

### 21 example, it is formed as part of the detoxification of 

### 22 chlorpyrifos and it can occur in the absence of the

### Page 184 1 chlorpyrifos-oxon, which is the toxic form of chlorpyrifos. 

### 2 And also particularly environmental levels, 

### 3 the relationship between urinary TCPy and acetylcholinesterase 

### 4 is currently unclear. So these are additional considerations 

### 5 when trying to make sense of biomonitoring data. 

### 6 In terms of the interpretation approaches, the 

### 7 most general approach outlined in the issue paper are the 

### 8 qualitative approaches, which we just characterized as a 

### 9 non-comparative and comparative approach. In both of these 

### 10 approaches, the goal would be to evaluate biomonitoring data 

### 11 without coming up with a quantitative estimate of chlorpyrifos 

### 12 exposure. 

### 13 Some of the analysis I presented in the first 

### 14 half of this presentation is probably an example of a 

### 15 non-comparative approach where the goal is to provide general 

### 16 comparisons and trends in exposure across studies, but there's 

### 17 no direct link to chlorpyrifos, particular routes, or health 

### 18 outcome. 

### 19 The second approach would be a comparative 

### 20 approach where it would be biomonitoring data would be compared 

### 21 to controlled human studies, and the study that is probably most 

### 22 suitable for doing this type of comparative approach is the

### Page 185 1 Nolan et al. study in which they administered a single dose of 

### 2 chlorpyrifos to human adult volunteers. 

### 3 However, there are some uncertainties and only 

### 4 fairly general comparisons could be made using this approach. 

### 5 The next approaches outlined in the paper are 

### 6 semi-quantitative approaches, the first of which is a screening 

### 7 approach that makes the use of biomonitoring equivalence. And 

### 8 the idea or the goal of this approach would be to estimate the 

### 9 biomarker level that's likely associated with the regulatory 

### 10 exposure guidelines, such as a reference dose. 

### 11 And the general methodology that would be used 

### 12 would be to incorporate relevant pharmacokinetic information 

### 13 with forward dosimetry methods to convert a reference dose or 

### 14 other regulatory guideline into a metric that can be directly 

### 15 compared with biomonitoring data. 

### 16 At this point, there's a fair amount of 

### 17 uncertainty using this approach, so we've proposed it mostly as 

### 18 a screening approach to characterize or understand results in 

### 19 biomonitoring studies. 

### 20 The next semi-quantitative approach is a 

### 21 reverse dosimetry approach, and this would be used to estimate 

### 22 -- actually estimate chlorpyrifos exposure in terms of intake

### Page 186 1 per day so that it can be compared to a regulatory screening 

### 2 value. 

### 3 The Mage et al., 2004 is commonly cited in the 

### 4 literature, and it's example of a reverse dosimetry method that 

### 5 incorporates creatinine-adjusted urinary levels to estimate 

### 6 daily exposure. 

### 7 It also has considerations that would have to 

### 8 be evaluated relative to -- it lacks route-specific information, 

### 9 so assumptions would have to be made as well as considerations 

### 10 related to biomarker specificity. 

### 11 The final approach outlined in the paper is a 

### 12 fully quantitative approach where risk would be evaluated using 

### 13 exposure linked physiologically based pharmacokinetic model. In 

### 14 terms of PBPK models, the preferred quantitative approach would 

### 15 be to use a fully calibrated and evaluated PBPK model. 

### 16 And this schematic here just shows the 

### 17 Timchalk et al., 2002 model, which was most recently presented 

### 18 at a 2011 SAP. 

### 19 There are several groups currently working on 

### 20 the chlorpyrifos PBPK modeling, all of which is based off of the 

### 21 Timchalk et al., 2002 model, which has been refined since it was 

### 22 originally published back in 2002.

### Page 187 1 And as I mentioned, it has recently been 

### 2 evaluated by the SAP. Some Panel members here, I believe, were 

### 3 part of that Panel. 

### 4 And some of the key limitations that were 

### 5 noted during that SAP is that the model parameters that go into 

### 6 the PBPK model are based on a typical adult human, so as a 

### 7 result it does not incorporate life-stage changes related to 

### 8 either pregnancy or childhood development. 

### 9 And the model also only simulates oral 

### 10 exposure to chlorpyrifos with an emphasis on dietary exposure. 

### 11 As a result, it does not simulate either dermal or inhalation 

### 12 exposure, which may be relevant in some circumstances. 

### 13 So just in summary, on the various 

### 14 interpretation options, in the paper we've outlined several 

### 15 approaches to analyze biomonitoring data associated with 

### 16 chlorpyrifos exposure. 

### 17 Each approach has its limitations that need to 

### 18 be carefully considered for any type of interpretation. And at 

### 19 this SAP, we're soliciting recommendations regarding the 

### 20 strengths and limitations of approaches, as well as alternative 

### 21 approaches not yet considered by the Agency. 

### 22 With that, I'll take any questions.

### Page 188 1 DR. KENETTH PORTIER: Okay. Any questions? 

### 2 Dr. Buckley. 

### 3 DR. BRIAN BUCKLEY: Brian Buckley. I have a 

### 4 few questions. First is that for most of the studies that we've 

### 5 looked at all sort of ended around 2004 with a couple exceptions 

### 6 related to far more populations and such. 

### 7 The concentrations for non-occupationally 

### 8 exposed or indirectly occupationally exposed were in the 

### 9 ballpark of that 1 to 10, you know, ppb or so. Any idea what 

### 10 the general populous might look like today or yesterday or last 

### 11 week? 

### 12 MR. AARON NIMAN: We've actually -- we've been 

### 13 waiting for (Maurice) and (Haynes). 

### 14 DR. BRIAN BUCKLEY: Maurice's got it. 

### 15 MR. AARON NIMAN: Yeah. And there's been a 

### 16 delay in getting that published. I know we're hoping -- I think 

### 17 actually later, towards the end of this year -- to get more 

### 18 recent urinary TCPy data for the general pop, so we would like 

### 19 to do that. 

### 20 DR. BRIAN BUCKLEY: It hasn't been the same 

### 21 since Dana left, huh? 

### 22 MR. AARON NIMAN: Yeah.

### Page 189 1 DR. BRIAN BUCKLEY: Next question: How 

### 2 important do you think it is to correct for creatinine with 

### 3 these measurements, and Barr and Angerer paper suggesting that 

### 4 that may not be the best way to go. How do you sort of rectify 

### 5 that? 

### 6 MR. AARON NIMAN: I guess ideally, it's nice 

### 7 to present things both ways, both creatinine and 

### 8 volume-adjusted. I know because of differences in excretion of 

### 9 creatinine between like, demographic groups, if you're trying to 

### 10 do a comparison between kids and adults, some of those 

### 11 differences could be because of differences in the amount of 

### 12 creatinine that they excrete in urine. And same if you're 

### 13 comparing Caucasian and African American populations. 

### 14 So I think the ideal: present both ways, just 

### 15 understand that some of the differences could be because of 

### 16 creatinine. 

### 17 DR. BRIAN BUCKLEY: So do you think that it 

### 18 may be better to, within a population, sort of limit or to 

### 19 present creatinine corrected within a subgroup or a 

### 20 subpopulation as being more effective and across populations 

### 21 that may not have the same sort of strength? Is that a fair 

### 22 assessment?

### Page 190 1 MR. AARON NIMAN: Yeah, I think that's 

### 2 reasonable. 

### 3 DR. BRIAN BUCKLEY: Okay. The other question 

### 4 that I have is, as we try to link exposure to dose to effect, 

### 5 all of the exposure in all of the models that you've taken into 

### 6 account all occur at the biomarker level with not so much link 

### 7 to the potential exposure based on the air particulate and the 

### 8 dust and the soil and all those other guys that we have a lot of 

### 9 data on. 

### 10 Is there a reason you don't want to reach out 

### 11 to that next level and try and -- you know, especially in terms 

### 12 of risk characterization -- go the media upon which people are 

### 13 exposed and incorporate that in your model? 

### 14 MR. AARON NIMAN: Yeah, I think certainly, 

### 15 there's a lot of multimedia studies that are -- certainly, 

### 16 there's a lot of data out there, whether it's dietary exposure 

### 17 or levels of chlorpyrifos residue, in dietary samples. A lot of 

### 18 the ORD work -- they've taken multimedia samples and they've 

### 19 tried to predict urinary levels with those. 

### 20 Certainly that data out there, and I think 

### 21 there's definitely opportunities to look at the multimedia 

### 22 concentrations and try to go from exposure to internal dose.

### Page 191 1 Ideally, I think you'd look at both and they 

### 2 would tell a consistent story; but if not, understand where the 

### 3 differences might lie. 

### 4 DR. BRIAN BUCKLEY: I would think that if 

### 5 you're trying to assess the alternate pathways of exposure other 

### 6 than just dietary ingestion, inhalation, dermal absorption, 

### 7 things like that, those other media concentrations would play a 

### 8 much bigger role in assessing where the potential pathway is. 

### 9 MR. AARON NIMAN: This might be better for the 

### 10 discussion tomorrow, but the way you can link the information at 

### 11 least qualitatively is you can, for example, use a reverse 

### 12 dosimetry method and then to try to characterize that, look at 

### 13 the multimedia concentrations and say, "Even though we can't 

### 14 make a direct connection between a particular route, when we 

### 15 look at the different routes of exposure, we would expect this 

### 16 one to dominate." 

### 17 DR. KENNETH PORTIER: Dr. Lowit. 

### 18 DR. ANNA LOWIT: Yeah. So I think you have 

### 19 hit on one of the big areas of uncertainty that we'd really like 

### 20 to get some feedback on. Thinking about whether it's reverse 

### 21 dosimetry or dose reconstruction, that's largely what you're 

### 22 getting at, dose reconstruction.

### Page 192 1 There are a variety of ways you can do that. 

### 2 So in our July 2011 risk assessment, as in also what would have 

### 3 been done for 2000 or 2003, the Agency does extensive exposure 

### 4 assessment in food and water and estimates of worker populations 

### 5 for different activities. 

### 6 So those assessments already exist within the 

### 7 public docket. What we have not done is to link to the media, 

### 8 which you're talking about, and then to do either dose 

### 9 reconstruction and get to urinary biomarker or vice versa, go 

### 10 the other way. 

### 11 One of the big challenges that we'd like to 

### 12 hear some feedback; around the uncertainties is this idea of 

### 13 route-specific metabolism and uptake, that you get different 

### 14 tissue dosimetry across different routes, keeping in mind that 

### 15 chlorpyrifos generally has to be activated to the oxon. 

### 16 And so you have to think about bypassing liver 

### 17 metabolism, site-specific metabolism to the oxon, all those 

### 18 things. It gets very complicated quickly. And so while we talk 

### 19 about it, thinking about the strengths and the uncertainties 

### 20 associated with all these existing procedures. 

### 21 This is an important question for us because 

### 22 it's an area where we have to go. And so as you think about the

### Page 193 1 range of possibilities, as Lieutenant Niman described, of what I 

### 2 describe as hand waving being the -- largely what we're doing 

### 3 right now up to various levels of sophistication including some 

### 4 of the proposals that Dow has put together that they presented 

### 5 to the SAP in 2011 -- heavily sophisticated, fully 

### 6 compartmentalized PBPK modeling to exposure assessment, all the 

### 7 bells and whistles. 

### 8 Those are largely research efforts and they 

### 9 have great promise, but as we talked about earlier, we're in a 

### 10 position to make regulatory decisions on a real-time basis in 

### 11 the next couple of years. 

### 12 So as you think about these issues, think 

### 13 about where the science is headed and where we can encourage 

### 14 people to go in that direction of what we can do now and where 

### 15 the uncertainties would be and what those considerations might 

### 16 be. 

### 17 DR. KENNETH PORTIER: Dr. Collier. 

### 18 DR. ABBY COLLIER: I have a question similar 

### 19 to Dr. Buckley about integrating these approaches. We heard a 

### 20 lot in the previous section about pregnancy, development, 

### 21 neonatal; and in this section, we've heard a lot about adult 

### 22 pharmacokinetics.

### Page 194 1 And while it's a lovely model that you've got, 

### 2 it's not a pediatric PK model and they are very, very different. 

### 3 And I was just wondering if you could comment moving forward on 

### 4 how you plan on addressing that because kids aren't small 

### 5 adults. 

### 6 MR. CHESTER RODRIGUEZ: Chester Rodriguez, 

### 7 EPA. As you know, we're not proposing to use the PBPK model 

### 8 that's been developed for the typical adult human. You know, we 

### 9 just brought it up as a potential approach. But yeah, the model 

### 10 has not been developed to include different life stages at this 

### 11 point. 

### 12 DR. ANNA LOWIT: So thank you, Chester. So 

### 13 in line with my comments a minute ago, the ideal preferred 

### 14 situation would be that we would have available to us today a 

### 15 fully compartmentalized PBPK model for a pregnant woman, even 

### 16 that would age of the child. And that would include food. We 

### 17 could do food; we could do water; we could do air; and we can do 

### 18 dermal. 

### 19 And that's a little bit of a pipe dream. It's 

### 20 certainly in the next two or three years. So I think one of the 

### 21 things I would really encourage you to do is to think about all 

### 22 of the approaches that are available and what the limitations of

### Page 195 1 those would be for extrapolating adults to human, a non-pregnant 

### 2 adult to a pregnant female. 

### 3 Where are those uncertainties and where are 

### 4 they qualitative and where are they quantitative; and what those 

### 5 uncertainties are, where are the strengths in those and how we 

### 6 can use those strengths and limitations to get at some of the 

### 7 answers to these really difficult questions? 

### 8 DR. ABBY COLLIER: Well, I would like to 

### 9 follow up on that and say that, yeah, pregnancy is kind of a 

### 10 pipe dream for everyone at the moment, but there are nice 

### 11 pediatric PK models out there at the moment. Simcyp Paediatric 

### 12 is lovely. I mean, they're not cheap, but they're lovely. 

### 13 And so we need to sort of go a little bit 

### 14 beyond our comfort zones to say, "If it exists, can we use it?" 

### 15 Thanks. 

### 16 DR. KENNETH PORTIER: I think you want you to 

### 17 hold that concept for our discussion, too, and bring it back up 

### 18 again. Dr. Buckley. 

### 19 DR. BRIAN BUCKLEY: Yeah, to follow up again, 

### 20 it would seem to me that dose reconstruction is a lot easier to 

### 21 accomplish at this stage of the game than a more complicated 

### 22 PBPK model. And if you're going to use a validation potentially

### Page 196 1 for your PBPK model, dose reconstruction might not be a bad way 

### 2 to go in the sense that you're going to close the loop at that 

### 3 point in time and characterize the whole issue. 

### 4 I mean, in terms of dose reconstruction, BPA 

### 5 and others already have models as to how much dirt kids eat and 

### 6 how much we breathe and all that other good stuff. And you have 

### 7 good studies out there that have measured the air and the water 

### 8 and all that other good stuff. So it would just seem to me that 

### 9 to not include dose reconstruction as a tool at this point in 

### 10 time leaves a powerful tool out of the toolbox. 

### 11 DR. KENNETH PORTIER: Clearly, the Panel's 

### 12 ready to go on this questions. Dr. Popendorf. 

### 13 DR. WILLIAM POPENDORF: Yes, just a couple of 

### 14 things that I guess I missed going through on page 5, those 

### 15 other data, the Dow data. My question's really on the Dow data. 

### 16 Was all that Dow data then either during application or shortly 

### 17 thereafter? 

### 18 MR. AARON NIMAN: So there were observational 

### 19 studies where at the start of the study, there was no known 

### 20 exposure to chlorpyrifos or they may have had background 

### 21 environmental levels of exposure. And during that period, they 

### 22 collected, for example, baseline acetylcholinesterase activity

### Page 197 1 measurements. 

### 2 And then there was a period, whether it was an 

### 3 occupational or residential pesticide, they performed some sort 

### 4 of activity where they applied a pesticide and then their 

### 5 urinary measurements were collected at time points after that. 

### 6 DR. WILLIAM POPENDORF: Okay. So I guess, you 

### 7 know, those were applicators then basically or possibly mixed or 

### 8 loaders, but occupational. 

### 9 MR. AARON NIMAN: Yeah. 

### 10 DR. WILLIAM POPENDORF: They are. Okay. I 

### 11 wanted to make sure. And my other question's on the Garabrant 

### 12 and Farahat results, the PBPK modeling. What model was that 

### 13 that generated those? 

### 14 MR. CHESTER RODRIGUEZ: Okay. So they used 

### 15 the same model that is the same schematic. Yeah. So the way 

### 16 they approached this is that they ran the model for different 

### 17 doses of chlorpyrifos to steady state to find out or to assess 

### 18 the relationship between acetylcholinesterase activity and the 

### 19 biomarker, you know, TCPy. 

### 20 So it's more of a prediction of the dose 

### 21 response behavior, or can they match that to the data they 

### 22 collected in the study.

### Page 198 1 DR. WILLIAM POPENDORF: Steady state. When 

### 2 you say that, I'm thinking that like, that usually would take 

### 3 several days if it's urgent, so is that a defect, I mean, within 

### 4 the model context? 

### 5 MR. CHESTER RODRIGUEZ: Right. So, you know, 

### 6 that's what's nice about models. You can simulate just a bunch 

### 7 of scenarios. But basically, you know, are they running the 

### 8 model based on constant exposure and at a steady state? Because 

### 9 if you don't do that, then are you going to have this episodic 

### 10 behavior. So that's why they had to do it that way. 

### 11 DR. KENNETH PORTIER: Did I see another 

### 12 question? Oh, Dr. Lu. 

### 13 DR. CHENSHENG LU: Oh, just a question about 

### 14 these two studies they introduced 2009, 2011. What is their 

### 15 analytical methods in terms of comparing to the NHANES method? 

### 16 It seems like, as I can recall, that they have a very high limit 

### 17 detection. Is that true? 

### 18 MR. AARON NIMAN: We can look into the 

### 19 analytical method. I don't know offhand. 

### 20 DR. KENNETH PORTIER: Dr. Vena. 

### 21 DR. JOHN VENA: Could I just have a 

### 22 clarification that these studies use DAP, which uses a

### Page 199 1 combination of a multiple metabolites DMP, DEP. You know, your 

### 2 tables, you had the DEP and DETP, which is part of the DEP, so I 

### 3 guess I'm trying to get at is, I'm not sure, but I have to 

### 4 reread these, but how they looked at all of these DAP, total 

### 5 DAP, and then they used DMP and DEP and some of the models. 

### 6 And so I guess is they found some associations 

### 7 with some of these metabolites and some with others. So really, 

### 8 what is considered the best? You know, if you're using this 

### 9 kind of estimate, what's the best estimate to use for 

### 10 chlorpyrifos? Is it the total DAP? Is it the DMP? Is it the 

### 11 DEP or, you know, what? 

### 12 Just maybe kind of explain that for me what 

### 13 your take is on all that. 

### 14 MR. AARON NIMAN: Now you're talking about the 

### 15 epi studies previously presented or the study summary 

### 16 comparisons here? 

### 17 DR. JOHN VENA: Sorry, the epi studies that 

### 18 are part of this use these different measures, and so they're 

### 19 summarized in the literature in terms of these combinations of 

### 20 these biomarkers that they use. 

### 21 MR. AARON NIMAN: I'm sorry. I guess I'm 

### 22 still a little confused. They're just the relative strengths of

### Page 200 1 the different biomarkers. Can you repeat the question? 

### 2 DR. JOHN VENA: If you're going to use any of 

### 3 these measures, what's the best measure to use to look at 

### 4 chlorpyrifos? You know, is it total DAP, which is -- here they 

### 5 use -- this defines the sum of my molar of six DAP metabolites. 

### 6 DMP metabolite was a sum of molar concentrations of three. 

### 7 Dimethylphosphate only and dimethylphosphate metabolite level is 

### 8 a sum of molar concentrations of three dimethylphosphate 

### 9 metabolites. 

### 10 And so they use all of these, and it looks 

### 11 like they used all of these in their models and looked at all of 

### 12 them: DAP, DMP, DEP. 

### 13 MR. AARON NIMAN: I guess an ideal situation, 

### 14 direct measurement of the parent compound would be preferred 

### 15 because there's less uncertainty because it's this actual 

### 16 measurement of the parent compound. Relative to that, I would 

### 17 say that TCPy is probably preferable because it has fewer parent 

### 18 compounds that are metabolites. 

### 19 And then DEP and DETP, but there'll be 

### 20 specific biomarkers. 

### 21 DR. JOHN VENA: It's helpful. So in terms of 

### 22 hierarchy, in terms of thinking about these, in terms of getting

### Page 201 1 at what kind of exposure misclassification there is, et cetera, 

### 2 to think about these different measures that they use as 

### 3 estimates of exposure. 

### 4 DR. KENNETH PORTIER: Dr. Pope. 

### 5 DR. CAREY POPE: Yeah. Dr. Vena, so as far as 

### 6 the DMP versus DEP, if you're thinking about chlorpyrifos, it is 

### 7 ethyl-containing chemical. So dimethylphosphate wouldn't be a 

### 8 particularly good one, if you're interested in chlorpyrifos 

### 9 exposures. Diethyl would be much better. 

### 10 DR. KENNETH PORTIER: I think at this point, 

### 11 we'll move on to Dr. Lowit and a summarization of everything, 

### 12 after which we'll take a break. 

### 13 DR. ANNA LOWIT: Go and do a little musical 

### 14 chairs, so okay. Carol Christensen is going to come back up to 

### 15 the table to join me in case there are any other clarification 

### 16 questions. 

### 17 So I'm going to not jibber-jabber too long but 

### 18 come back to our major things from this morning just to bring us 

### 19 full circle. We've heard a lot of exciting, very technical, 

### 20 very detailed presentations over the late morning and early 

### 21 afternoon. 

### 22 Just bring us back to first principles and to

### Page 202 1 talk about what's in our Charge questions and the kinds of 

### 2 feedback that will be most helpful from all of you to help us 

### 3 move on in the next steps of our analysis. 

### 4 And I'll take a minute briefly and talk about 

### 5 what we mean by "weight of the evidence" from a risk assessment 

### 6 point of view, how to bring information together, and what does 

### 7 it mean to be transparent and clear. 

### 8 So if we start back at organizing principles 

### 9 and the ideas that we started the morning with, it goes back to 

### 10 the Risk Characterization Handbook, the NRC reports from the 

### 11 Toxicity Testing in the 21st Century, and Science and Decisions. 

### 12 13 They collectively provide the conceptual 

### 14 foundation for the ideas that we've been talking about: being 

### 15 transparent; having everything out on the table for everyone to 

### 16 see so that people understand how information was brought 

### 17 together and conclusions were made; how you take information 

### 18 across multiple lines of evidence, whether it's in vitro 

### 19 studies, in vivo studies, epidemiology, other biomonitoring. 

### 20 Thinking about adverse outcome pathways and 

### 21 modes of action and key events leading to adverse outcomes and 

### 22 how to make causal linkages across those key events.

### Page 203 1 Thinking about, as science and technology get 

### 2 more and more sophisticated, we can measure more and more 

### 3 sensitive, smaller things. But those don't necessarily mean 

### 4 adverse outcome; they can just mean change. And so how to 

### 5 interpret disruptions, perturbations from homeostasis and when 

### 6 we're on a path to an adverse outcome. 

### 7 These are all important concepts as we think 

### 8 about putting all this chlorpyrifos information together in a 

### 9 coherent story that makes sense. 

### 10 So just to remind you, we've been on a very 

### 11 step-wise, methodical systematic approach starting in 2008 with 

### 12 an initial -- what was really a problem formulation -- no, we 

### 13 didn't call it that at the time -- which was a preliminary 

### 14 review of chlorpyrifos and many of the issues that we're talking 

### 15 about here. 

### 16 In 2010, we put together a draft framework for 

### 17 incorporating epidemiology in our risk assessments. We're 

### 18 gaining more and more experience with that framework. We've 

### 19 done a lot of work with atrazine, and so here we're thinking 

### 20 about using this for chlorpyrifos as we move forward. 

### 21 So in 2011, in July of last year, we put out a 

### 22 risk a preliminary risk assessment that focused on

### Page 204 1 cholinesterase inhibiting potential of the compound based on the 

### 2 most sensitive dose response data available for driving points 

### 3 of departure. 

### 4 That assessment explicitly states that there's 

### 5 a plan to conduct a full weight of evidence evaluation, and that 

### 6 evaluation is where we're headed right now. 

### 7 So the analysis that we've done for this SAP, 

### 8 for this white paper, largely builds on the 2008 and the risk 

### 9 assessment and the public comments we received from that with a 

### 10 lot of new data and far more in-depth analysis on some critical 

### 11 areas such as epidemiology, biomonitoring, and adverse outcome 

### 12 pathways. 

### 13 And what we're going to be looking for from 

### 14 all of you on our charge questions is really a consideration of 

### 15 the strengths and uncertainties associated with all these lines 

### 16 of evidence. And we'd like for you to think about this in both 

### 17 qualitative terms and quantitative terms. 

### 18 So go back to a slide I used a few minutes 

### 19 ago, a few hours ago, a slide right out of the NRC from 2007 

### 20 that really puts together all the pieces in a risk 

### 21 characterization. But what I've done on the next slide is 

### 22 overlay this same figure with the chlorpyrifos situation.

### Page 205 1 So as you move from the left side of the 

### 2 figure, the parent compound, of course, is chlorpyrifos, but we 

### 3 have to always keep in our mind that the oxon metabolite is the 

### 4 active metabolite for cholinesterase inhibition. 

### 5 And there's still some lack of clarity, 

### 6 whether it would be the oxon or the parent that would be 

### 7 associated with neurodevelopmental outcomes. And of course, we 

### 8 spent a lot of time talking about TCPy today and the challenges 

### 9 interpreting all of that data. 

### 10 Inside the big blue circle is this idea of 

### 11 Mode of Action and adverse outcome pathways; that we think about 

### 12 perturbations and key events and causal linkages, and taking 

### 13 information from in vitro studies and in vivo studies and 

### 14 putting them together in a pathway. 

### 15 So we're tracking two different health 

### 16 outcomes: one is acetylcholinesterase inhibition leading to 

### 17 cholinergic toxicity, and the other one being the biological 

### 18 plausibility and the hypotheses around neurodevelopmental 

### 19 outcomes. 

### 20 So what I really wanted to highlight here is 

### 21 more the right side of the figure where we have information from 

### 22 the children's cohorts. The Columbia cohort provides the most

### Page 206 1 robust information because it's specific to chlorpyrifos. 

### 2 We also have TCPy measures from a variety of 

### 3 populations. Some of them, you can tease out exposure to 

### 4 chlorpyrifos; some others, it's much more difficult to do. And 

### 5 we also have, as Dr. Buckley pointed out, we have a great deal 

### 6 of information on exposure from different media. We also have 

### 7 exposure assessments performed by our own assessors from the 

### 8 Registration Eligibility Decision, and from the 2007 risk 

### 9 assessment. 

### 10 All those things come together, and the real 

### 11 question is the calibration of the in vitro, the modes of 

### 12 action, and across the human dosimetry. All of these things 

### 13 lead to these questions, these quantitative and qualitative 

### 14 questions about linking and about dosimetry. 

### 15 So weight of the evidence; what do we mean by 

### 16 that? So if you don't have experience with a lot of panels or 

### 17 dealing with the Agency, we'll just take a minute to explain to 

### 18 you what we mean by that and how we would go about it. 

### 19 So in the Draft Framework for incorporating 

### 20 epi, it's really founded on several things: the Bradford Hill 

### 21 criteria, the Agency's Mode of Action framework, which is also 

### 22 built on a strong international basis from many years of review

### Page 207 1 and contribution. We have the NRC reports from 2007 and 2009. 

### 2 But what we want to do in weight of the 

### 3 evidence analysis is to characterize the extent to which data 

### 4 support a hypothesis, and particularly thinking about 

### 5 dose-response assessment. That involves a number of steps, some 

### 6 of which we're talking about here. 

### 7 We're assembling data, which we've done quite 

### 8 a bit of over the last few years. We've evaluated that data for 

### 9 quality and relevance, and we have done that and now we're 

### 10 asking you to give us feedback on how well we've done and what 

### 11 more we need to do. 

### 12 And then the next step would be followed by 

### 13 integration across different lines of evidence, and certainly 

### 14 we're moving in that direction. 

### 15 Transparency. We've heard a lot about 

### 16 transparency starting this morning. Transparency is important, 

### 17 if not vital, to this process. Because we're talking about a 

### 18 very complicated situation across many lines of evidence, it's 

### 19 very important to be clear and transparent about what 

### 20 information is used, how it's used, and how it's evaluated and 

### 21 how things are brought together; how we've weighed information 

### 22 in certain directions; how we've thought about the strengths and

### Page 208 1 the limitations; and how we've thought about how those 

### 2 limitations and those uncertainties affect the outcome. 

### 3 And this is one of the reasons we talk about 

### 4 ranges and options, because if we think about ranges and options 

### 5 in a weight of the evidence analysis, we can get a good picture 

### 6 of the totality of the decisions and where we are strong and 

### 7 where we are weak. 

### 8 So we've been through a lot of presentations 

### 9 today, everything from adverse outcome pathways to effects on 

### 10 the developing brain and epidemiology and biomonitoring, and I 

### 11 certainly won't take time to go through all of that. 

### 12 But there are two key scientific questions 

### 13 we're really focusing on with this SAP that I'd like you to keep 

### 14 in the back of your mind. The first one is largely a 

### 15 qualitative one around: what are the strengths and the 

### 16 limitations of the different signs of evidence that suggest the 

### 17 potential for chlorpyrifos result in long-term 

### 18 neurodevelopmental effects. 

### 19 And the second one is more of a quantitative 

### 20 question: Given the first one, to what extent do these adverse 

### 21 effects may or may not be attributed to doses lower than those 

### 22 elicit 10 percent inhibition of acetylcholinesterase, which is

### Page 209 1 typically our benchmark for regulatory decision-making. 

### 2 So if we just pull the most salient pieces of 

### 3 information across the presentations you've heard, let's start 

### 4 with the qualitative evidence around long-term effects from 

### 5 early-life exposure. 

### 6 So very broadly speaking, there are things 

### 7 from three lines of evidence: the mechanistic studies that we 

### 8 heard about from Dr. Mundy; the in vivo studies that Ginger told 

### 9 us about; and epidemiology that we heard about after lunch. 

### 10 So in Charge question 2.1 will be our 

### 11 qualitative consideration of the mechanistic studies and the 

### 12 adverse outcome pathways. 

### 13 It is our preliminary conclusion that an 

### 14 adverse outcome pathway has not been firmly established for 

### 15 neurodevelopmental outcomes, but we do acknowledge that there's 

### 16 a growing body of literature that does demonstrate that 

### 17 chlorpyrifos or its oxon are biologically active on processes 

### 18 that affect the developing brain. 

### 19 With respect to the in vivo experimental 

### 20 studies, we have a qualitative question we're going to ask for 

### 21 feedback on, which is 3.1. 

### 22 And certainly, we heard from Dr. Moser this

### Page 210 1 morning that there is difficult interpretation because you have 

### 2 some studies going up and some studies going down. 

### 3 But from a broad, higher-level consideration, 

### 4 multiple studies and multiple labs report changes in 

### 5 neurobehavioral function in adults following developmental 

### 6 exposure, and those are generally long after the chemical 

### 7 exposure has ended and any inhibition that may have existed has 

### 8 long gone. 

### 9 Consistency is a challenge when looking at 

### 10 these studies, but there are a few domains for which there is 

### 11 more consistency than the others, and I think we certainly heard 

### 12 about cognition and anxiety some earlier today. 

### 13 So from the epidemiology studies, if we look 

### 14 at it from a qualitative point of view, I think question 4.1 is 

### 15 about the quality of our analysis. Question 4.2 is about 

### 16 thinking about the role that chlorpyrifos may or may not have 

### 17 played in the neurodevelopmental outcomes, particularly those 

### 18 reported by Columbia. 

### 19 And as we heard from Dr. Christensen, there's 

### 20 consistency in some outcomes and not others, but particularly 

### 21 notable are the abnormal reflexes across a couple of the 

### 22 cohorts, the ADHD-like behavior across some of the cohorts, and

### Page 211 1 the MDI and the more recent IQ paper across all three cohorts. 

### 2 So from a qualitative point of view, our 

### 3 preliminary conclusion is take all this information together, 

### 4 and I've summarized rings and rings of information in a matter 

### 5 of 120 seconds, I think; that they do together support a 

### 6 preliminary conclusion. 

### 7 The exposure to chlorpyrifos may result in 

### 8 adverse neurodevelopmental outcomes with an important caveat 

### 9 that the conditions for which those occur are still unclear and 

### 10 uncertain. 

### 11 And that lack of clarity and that uncertainty 

### 12 leads us to question number 2, around the more quantitative 

### 13 issues. And so this is a fairly grounded risk assessment point 

### 14 of view kind of question. 

### 15 Our typical practices develop points of 

### 16 departure based on 10 percent inhibition of acetylcholinesterase 

### 17 from dose-response studies, and then that would be our starting 

### 18 point for extrapolation. So for example, if you had a rat 

### 19 study, you'd then extrapolate to humans and then to sensitive 

### 20 humans. 

### 21 So we have the same three lines of evidence: 

### 22 the mechanistic and the adverse outcome pathway studies; the in

### Page 212 1 vivo experimental tox studies; and the epidemiology. 

### 2 So in charge question 2.2, we'll ask you to 

### 3 give us some feedback about what is known or not known about the 

### 4 relative sensitivity from the AOP studies around these end 

### 5 points and the cholinesterase inhibition. 

### 6 And we certainly have noted in our 

### 7 presentation from Dr. Mundy, and it's noted on this slide, this 

### 8 in our minds remains an area of uncertainty. 

### 9 In charge question 3.2, we'll ask for some 

### 10 similar feedback from the in vivo experimental toxicology 

### 11 studies. As you heard from Dr. Moser, a dose of one milligram 

### 12 per kilogram per day or even higher is a very common dose. In 

### 13 many of these studies, it's a common comparison point, as you 

### 14 saw Dr. Moser use across domains. It's a common place to think 

### 15 about what there is from these studies compared to the domains? 

### 16 And it is notable that our points of departure 

### 17 are based on the animal studies are lower or the same, 

### 18 certainly. They're certainly all lower than the one milligram 

### 19 per kilogram. 

### 20 In a more recent study, by an author's name 

### 21 I'm not going to try to pronounce, does show one of the lowest 

### 22 NOELs in these studies of 0.2. And it is notable that our

### Page 213 1 acute, single-dose endpoint is about the same as that, the 0.2, 

### 2 and that our chronic end point is about an order of magnitude 

### 3 lower. 

### 4 So as we move on to think about the 

### 5 epidemiology studies, we do ask you to think about in -- let me 

### 6 take a step back. 

### 7 In 2008, the SAP was fairly clear about the 

### 8 uncertainties in the Columbia study and that those made it 

### 9 challenging to direct points of departure from the Columbia 

### 10 epidemiology study. And we largely remain in concurrence with 

### 11 that, and we see a proposal to continue to use the animal study. 

### 12 But all that said, it's important to look at 

### 13 the Columbia study in particular and think about what the levels 

### 14 reported in that study. We're going to try to make sense of 

### 15 them. So the upper tertile reported in the Rauh in the 2006 

### 16 study, which would be the first of the neurodevelopmental 

### 17 outcome papers. 

### 18 The upper tertile is 6.17 picogram per gram 

### 19 higher and what you see in this table is that with the 

### 20 cancellation of chlorpyrifos, there is a fairly rapid decline of 

### 21 -- if you look in the top three rows of this table -- there's a 

### 22 very rapid decline of the mean chlorpyrifos and cord blood

### Page 214 1 across that time. Once the voluntary cancellation occurred, the 

### 2 in-home use, either from the city or from the actual homeowners 

### 3 or from the residents in the rental properties, declined 

### 4 rapidly; so that 6.17 is not a magic number, but certainly a 

### 5 point to think about for purposes of comparison. 

### 6 So the question remains: the degree to which 

### 7 levels and the picogram per gram in blood are they likely to 

### 8 elicit acetylcholinesterase inhibition? 

### 9 And our preliminary thought on that is most 

### 10 likely not, but there's limited evidence to get you to that 

### 11 point, and that's one of the reasons we're looking for some good 

### 12 feedback on not only reverse dosimetry but dose reconstruction 

### 13 to help put some meat around some of these evaluations. 

### 14 So one of the best places of -- one of the 

### 15 only places of information where you get chlorpyrifos and 

### 16 cholinesterase inhibition is a deliberate dosing study in adult 

### 17 males done back in the eighties. And just to make sure that you 

### 18 know that this study was reviewed by the Human Studies Review 

### 19 Board and found to be both ethically and scientifically 

### 20 conducted. And so because of that, we use it in our 

### 21 evaluations. 

### 22 That study has two components: one is an oral

### Page 215 1 dose, and one is a dermal dose. And it's notable that neither 

### 2 dose nor the men in the study, none of the men exhibited red 

### 3 blood cell cholinesterase inhibition. But you did see in the 

### 4 oral dose a good amount of plasma. 

### 5 But as Lieutenant Niman indicated, plasma 

### 6 butyrylcholinesterase, the degree in which this is a 

### 7 toxicologically relevant endpoint is still unclear. 

### 8 But the peak blood levels from that study in 

### 9 the oral study are worth comparing to the Columbia. But before 

### 10 I show you the comparison, I want to just make sure it's on the 

### 11 table that this is a very tenuous comparison because we're 

### 12 actually comparing apples and oranges. We have males in a 

### 13 clinic versus pregnant females in their real life, the males 

### 14 getting a single dose whereas the women are probably exposed 

### 15 daily in their homes. 

### 16 You have a very controlled, clinical setting 

### 17 where the people could be monitored, and there's a time course 

### 18 -- they took their blood every few hours and looked at their 

### 19 time course -- versus a real-world exposure where you're getting 

### 20 multiple pathways. People are living their life. 

### 21 And in the Nolan study, you have an oral dose, 

### 22 and they can control for the other routes; but in the real

### Page 216 1 world, that's not the way it happens. So you have to be careful 

### 2 with the comparison, but it's still important. 

### 3 So something happened since yesterday. That 

### 4 red arrow got moved between computers. The red arrow should be 

### 5 somewhere between the 0.1 and the 1, not between the 1 and the 

### 6 10. But either way, the point is still the same. 

### 7 If you can look on the x-axis, this is a plot 

### 8 on that Dow -- I let them know I was going to use this plot. 

### 9 This is an adaptation of Figure 40 from their paper from the 

### 10 2011 -- I guess that should be 2011 -- the PBPK paper that was 

### 11 reviewed by this panel. What's important is that the units on 

### 12 the x-axis are picogram per gram so that we can match units from 

### 13 single oral dosing to what's in the Columbia. 

### 14 So the Nolan error should be between the 0.1 

### 15 and the 1, and that tracks over to something in the order of 

### 16 approximately 10,000 picogram per gram. And keep in mind, with 

### 17 the Columbia cohort, we're talking about things in the order of 

### 18 10 or less, largely below the limit of detection. 

### 19 For most of the women, a 6 or higher in the 

### 20 upper-tertile. So the degree to which the men in the Nolan 

### 21 study did not exhibit any red blood cell cholinesterase in the 

### 22 order of 10,000 picogram per gram; yet it seems to us that the

### Page 217 1 likelihood at 6 is also quite low. 

### 2 But there are some uncertainties with that 

### 3 because the 6 picogram per gram in the upper-tertile, in and of 

### 4 itself, needs to be interpreted with some care because we're 

### 5 unaware of the time of application within the apartments, so we 

### 6 certainly have not matched blood levels in the cord blood or the 

### 7 women to the time of application. So we do not know in any way 

### 8 when those applications were made. 

### 9 We also don't know the critical windows of 

### 10 susceptibility -- that applications occurred during those 

### 11 critical windows or the degree to which chlorpyrifos exposure 

### 12 occurred in those windows. Given that there's still a lack of 

### 13 clarity around the adverse outcome pathway, it's challenging to 

### 14 think about critical windows. 

### 15 We also don't know the contribution of other 

### 16 cholinesterase-inhibiting pesticides to the idea of 

### 17 cholinesterase inhibition. We know that diazinon and propoxur 

### 18 were detected at fairly high rates in the same women in this 

### 19 cohort. 

### 20 And if you also go back to one of the early 

### 21 Whyatt papers, it's 2003 through 2004 -- I'm not sure which one 

### 22 -- there's a list of other cholinesterase-inhibiting pesticides

### Page 218 1 that were detected in the blood of the women. For example, 

### 2 something in the order of a quarter to a third of them had 

### 3 measurable levels of 3-Hydroxycarbufuran, and some of you know 

### 4 that carbufuran is extremely potent cholinesterase inhibitor. 

### 5 So this is an area of uncertainty with respect 

### 6 to thinking about whether or not exposure to multiple chemicals 

### 7 could elicit 10% inhibition. 

### 8 And we're certainly looking for your feedback 

### 9 on all of these issues. They're multi-factorial issues across 

### 10 multiple lines of information. This is a key area for us to 

### 11 think about: interpreting the Columbia data; interpreting the 

### 12 other chemicals; interpreting across the in vitro to the in 

### 13 vivo, and not only the in vivo animal, but interpreting all the 

### 14 way up to the human. 

### 15 So charge questions 5.3 and 5.4 begin to get 

### 16 at approaches for thinking about reverse dosimetry and also dose 

### 17 reconstruction. And there was an exchange with Dr. Buckley 

### 18 where I think I really laid out the sorts of things we're 

### 19 looking for in this question. 

### 20 There are a number of research groups pursuing 

### 21 these same questions. There is Dr. Lu and his group is doing 

### 22 some of this work. Dale Hattis, who's a collaborator with the

### Page 219 1 Columbia group is also pursuing some of this work. Dow is 

### 2 pursuing some of it and it was to some degree presented at the 

### 3 SAP a year or so ago. 

### 4 There are less sophisticated ways of doing 

### 5 this kind of thing. And it's important that we get a sense of 

### 6 the strengths and the limitations of all of those not only in 

### 7 the immediate term, but in the long term of where the science is 

### 8 going so we have a sense of what we can do now and where the 

### 9 science may be heading or where we can encourage the science to 

### 10 go. 

### 11 This is also an area where we might want to 

### 12 think about ranges because each of these approaches may provide 

### 13 a different answer and how to understand those different 

### 14 answers, given their own limitations and strengths. 

### 15 So charge question 6.0 is about really 

### 16 thinking about it at a high level. Thinking about pulling out 

### 17 of the details, out of the weeds, at the 1,000- to 10,000-foot 

### 18 level of thinking about all of the multi-dimensional plausible 

### 19 responses across dose, across species, across route. 

### 20 To think about the overall uncertainty and the 

### 21 variability and the strengths and the limitations across the 

### 22 totality, this is consistent with the advice from the NRC. It's

### Page 220 1 also consistent with the Agency's Risk Characterization 

### 2 Handbook. 

### 3 I think that may be the last one. So just to 

### 4 end, obviously we're committed to transparency. We're bringing 

### 5 you the issue paper, and we're asking you some very difficult 

### 6 questions and hoping to get some excellent feedback. 

### 7 We'll be taking all the feedback that we get 

### 8 and moving to the next steps of bringing all these lines of 

### 9 information together in a weight of the evidence to do a 

### 10 Bradford Hill criteria analysis to look at ranges of risk and 

### 11 different levels of uncertainty. 

### 12 And I think that's my last slide. 

### 13 DR. KENNETH PORTIER: Any clarifying questions 

### 14 from the panel? I guess that's why we scheduled through Friday, 

### 15 right? There's a lot of questions. 

### 16 Not seeing any questions. We're going to go 

### 17 ahead and take a break just for the Panel and the audience. We 

### 18 have scheduled for this afternoon two groups of public 

### 19 commenters. 

### 20 Before I do that, Dr. Lowit, are your staff 

### 21 going to be here tomorrow morning if there are additional 

### 22 questions that come up to the Panel that, you know, if need be

### Page 221 1 we can bring some of you up after the public comments section 

### 2 tomorrow for some final clarifying questions? 

### 3 DR. ANNA LOWIT: Yeah, our entire team will be 

### 4 here tomorrow. 

### 5 DR. KENNETH PORTIER: Okay. Good. Dr. 

### 6 Popendorf? 

### 7 DR. WILLIAM POPENDORF: I guess I would like a 

### 8 little clarification on that one slide, 21. The data in the 

### 9 right column, both what's in the brackets and how did those 

### 10 values by year -- what is that? What are you saying here, by 

### 11 year or groups of years, in some cases -- the rows? Are those 

### 12 different publications? It just wasn't clear what that data 

### 13 represented. 

### 14 DR. CAROL CHRISTENSEN: Sure. So slide number 

### 15 21 was showing within -- yes, within the Whyatt 2003 and 2004 

### 16 publications -- I think more in 2003, they delineate average or 

### 17 mean chlorpyrifos concentration in cord blood. 

### 18 DR. WILLIAM POPENDORF: Cord blood. 

### 19 DR. CAROL CHRISTENSEN: By year. So within 

### 20 those births that took place in 1999, in which there were 87, 

### 21 the mean concentration of chlorpyrifos in cord blood is noted on 

### 22 the right-hand side, 5.0 picogram per gram, and that's a

### Page 222 1 standard deviation. 

### 2 DR. WILLIAM POPENDORF: Standard deviation? 

### 3 DR. CAROL CHRISTENSEN: I mean, sorry. I'm 

### 4 95% confidence-bound. Sorry. 

### 5 So similarly for your 2000 and 2001, the 1998 

### 6 to 2002 is the overall average, so this is the cohort sample 

### 7 size used for the analytical evaluation, so it's 1999 through 

### 8 2002 summed together, so the end there is 314 with a mean 

### 9 chlorpyrifos concentration in cord blood of 4.0 picogram per 

### 10 gram. 

### 11 DR. WILLIAM POPENDORF: 1999 through 2002? 

### 12 DR. CAROL CHRISTENSEN: Right. And then 

### 13 moving to the Whyatt 2009 validation paper, the summation of 

### 14 years between 2001 to 2004, as I mentioned, this work was done 

### 15 right around the time of the voluntary cancellations. 

### 16 And this was a validation study inclusive of a 

### 17 proportion of the total cohorts, but it wasn't everybody in the 

### 18 cohort. It was a subset of the cohort for which these 

### 19 additional environmental and biological exposure measures were 

### 20 made. 

### 21 So within that cohort, the average was below 

### 22 the limit of detection at that point in time, looking across

### Page 223 1 those three years. And I reported the 95th percentile as 2.5 

### 2 picogram per gram of chlorpyrifos in cord blood. 

### 3 DR. WILLIAM POPENDORF: Our printed versions 

### 4 aren't as clear as that, I can tell. I was trying to help. 

### 5 Thank you. 

### 6 DR. KENNETH PORTIER: Okay. We'll go ahead 

### 7 and take a 15-minute break because it's a fairly large group. 

### 8 We'll meet again at 10 to 4:00. That's the good news. The bad 

### 9 news is we're going to be here until at least 6:00, so prepare 

### 10 for another about two-and-a-half hour presentation. 

### 11 (WHEREUPON, a recess was taken.) 

### 12 DR. KENNETH PORTIER: At this point, we've 

### 13 finished with the formal EPA presentations and we're moving into 

### 14 the public commenters. And as a public meeting, I'm reminding 

### 15 everyone that any material presented before the Panel will be 

### 16 part of the public docket. 

### 17 There was a copy of a research paper in draft 

### 18 form that was distributed. We've pulled those back right now 

### 19 because we need to double-check on copyright issues and whether 

### 20 we can put that in the public docket or how we'll manage that. 

### 21 But we'll work on that. Hopefully, you'll get the paper. Dr. 

### 22 Pope's already read it, so there's nothing I can I can do about

### Page 224 1 that. 

### 2 We've talked to Dow, and they've agreed to 

### 3 kind of cut their presentation, half this afternoon and half 

### 4 tomorrow morning. So we're hoping to break somewhere around the 

### 5 5:30, 5:45 time period. 

### 6 Our first public presenter is Dr. 

### 7 Rhomberg, please identify yourself and move forward. 

### 8 DR. LORENZ RHOMBERG: Thank you. Yes, I am 

### 9 Lorenz Rhomberg. I'm a principal at Gradient, which is an 

### 10 environmental consulting firm in Cambridge, Massachusetts. 

### 11 My opportunity to be here is sponsored by Dow 

### 12 AgroSciences, but I'm actually going to be talking about some 

### 13 interests of mine that have gone on for a long time on the 

### 14 fairly more general question about weight of evidence and 

### 15 questions of incorporating human and animal data together. 

### 16 I really appreciate the Panel for giving me 

### 17 this time, and I hope you will indulge me for awhile while I 

### 18 talk about something that isn't really about chlorpyrifos as 

### 19 such, but rather about the larger questions that we heard about 

### 20 in this morning's presentation from EPA about the implications 

### 21 for the chlorpyrifos case for how you do some of these larger 

### 22 questions of incorporating epidemiology and doing weight of

### Page 225 1 evidence, merging multiple lines of evidence from animal and 

### 2 humans and so on and so forth. 

### 3 So I'm going to be just addressing that wider 

### 4 question in the hope that putting the framework on the table 

### 5 will help further discussion. 

### 6 Well, we have epi, and we have tox here. And 

### 7 of course, the advantage of epi is that it's relevant, 

### 8 real-world stuff; but on the other hand, it's observational. 

### 9 The things are uncontrolled, and it's difficult to measure 

### 10 exposures and to isolate individual potential causes. Because 

### 11 it's observational, we're stuck with the complexity of the real 

### 12 world. 

### 13 On the other hand, in toxicology and Mode of 

### 14 Action studies, we can control things and we can look at one 

### 15 causal element at a time with a systematic approach. But it's 

### 16 indirect, and we have to somehow infer the role for that in the 

### 17 larger inference that we want to make about humans. 

### 18 So there's really role for both of these. 

### 19 It's not that one should trump the other. We really want to 

### 20 find a way to merge these and both bring them to bear, and 

### 21 that's what my comments are going to be about. 

### 22 There is a paper -- and this one is open

### Page 226 1 access so it's in the docket, but if you come across it however, 

### 2 you're free to read it and pass it around -- called 

### 3 Hypothesis-Based Weight of Evidence Evaluation of the 

### 4 Neurodevelopmental Effects of Chlorpyrifos by me and some of my 

### 5 Gradient co-authors from Critical Reviews in Toxicology. 

### 6 We submitted it with our comments. It should 

### 7 be in the docket, and it's available for you to look at. 

### 8 This paper does several things. It discusses, 

### 9 first of all, this, what we're calling, hypothesis-based weight 

### 10 of evidence approach as a method for combining human, animal, 

### 11 and Mode of Action data as a methodology in itself. And then it 

### 12 uses chlorpyrifos as an example for some of that. 

### 13 It also goes on to make some comments about 

### 14 the EPA framework for merging human and animal data and 

### 15 comparing that with our method. 

### 16 And then it goes on, as I say, to actually 

### 17 apply this to the case of chlorpyrifos. That third part, I'm 

### 18 not going to be talking about today, but Dr. Julie Goodman will 

### 19 be talking about it later on from this paper. 

### 20 So what is this hypothesis-based weight of 

### 21 evidence? Well, this is the name that we've given to an 

### 22 approach that we've taken to really try to grapple with some of

### Page 227 1 the questions that you have put on the table here and have tried 

### 2 to grapple with. 

### 3 How, in the end, do we really weigh evidence? 

### 4 How do we bring together these different lines of animal and 

### 5 human evidence and put them together? How do we work through 

### 6 the implications of inconsistencies among studies, of further 

### 7 assumptions that need to be made, of ambiguities in the studies 

### 8 and so on, in order to do a weight of evidence? 

### 9 We talk about weight of evidence all the time, 

### 10 and in the end the question about how to make the leap between 

### 11 some data that you have on the table and how do you make the 

### 12 judgments about it has always been sort of problematic. 

### 13 The theme of consistency -- so transparency 

### 14 has been struck several times here, and I think that one way to 

### 15 explain what we're trying to do with this hypothesis-based 

### 16 weight of evidence is to lay out the inferential basis for why 

### 17 you think you're getting your conclusions from the data so that 

### 18 they can be discussed as scientific matters and that we can 

### 19 somehow unpack that kind of leap of judgment so that we can 

### 20 understand it. It's very much in the aid of transparency. I 

### 21 just wanted to mention that. 

### 22 And in addition to this paper of chlorpyrifos,

### Page 228 1 the first one listed up here, we also have some other papers 

### 2 that have been published recently. 

### 3 We also have some other papers: one on 

### 4 methanol carcinogenicity; one on dioxin thyroid hormone 

### 5 perturbation, all done by the same kind of method and also 

### 6 setting out further elements of the methodology; formaldehyde as 

### 7 a leukemogen has some commonality with chlorpyrifos in that it's 

### 8 a case that should sound familiar. 

### 9 We have epidemiology studies that are mixed. 

### 10 Some are positive; some are not. The ones that are positive 

### 11 have to be analyzed several different ways with different dose 

### 12 measures to find the positive effects. 

### 13 And then we have real questions from the 

### 14 animal data about whether those effects are plausible in humans, 

### 15 and that's the thing to be sorted out. There's some 

### 16 commonality. As I said, the question's on the table. And then 

### 17 we have naphthalene carcinogenicity, the first one in the series 

### 18 that really laid out a lot of our methodology. 

### 19 And I was glad to see that this was cited as a 

### 20 good model of how to weight of evidence in EPA's proposed 

### 21 Endocrine Disruptor Screening Program Weight of Evidence 

### 22 Guidance. They cited it as a favorable example of a good way to

### Page 229 1 approach this question. In their own weight of evidence 

### 2 processes in there actually showed a lot of the same kind of 

### 3 thinking. 

### 4 So what we have now is this draft framework 

### 5 for incorporating epidemiologic evidence from EPA, and I'm going 

### 6 to make a few quick comments on it. 

### 7 First of all, it really focuses on the human 

### 8 data and their usefulness. In a way, it's sort of how to bring 

### 9 the human data in rather than talking about the toxicology data 

### 10 that much in themselves. 

### 11 It reviews strengths and weaknesses and 

### 12 interpretation issues of many of the common study designs. In a 

### 13 way, it's sort of a primer of the ways you should think about 

### 14 these things. 

### 15 It really encourages a systematic review of 

### 16 the human data. That's something that's really to be 

### 17 encouraged, and we would hardly endorse. 

### 18 It encourages this "multiple lines" of 

### 19 evidence thinking to include animal and Mode of Action evidence 

### 20 using the extended Bradford Hill criteria, and the human 

### 21 relevance framework is a way to do that. 

### 22 Now with all that said, in the end, it doesn't

### Page 230 1 really though say that much about exactly how you should 

### 2 accomplish this integration. And in fact, that very question is 

### 3 the question that's sort of on the table here for chlorpyrifos. 

### 4 And that's what I wanted to address, simply 

### 5 about: how do we actually go about this integration question? 

### 6 And we'll say however that the, what we're calling now, the 

### 7 draft white paper, I guess, actually does much better than this 

### 8 than the Guidance that it's supposed to be following. 

### 9 The white paper that you've seen actually 

### 10 points to the questions in a very productive way, I think, and I 

### 11 was very happy to see that and I think it's a very good start on 

### 12 this question. I'm trying to offer some help for how to go a 

### 13 little bit farther with it. 

### 14 So what are these Bradford Hill postulates 

### 15 that we are now extending? Here are the familiar Bradford Hill 

### 16 postulates. He called them postulates, not criteria. I won't 

### 17 go over them; they're familiar to all epidemiologists. 

### 18 But the point I want to make is that these are 

### 19 guides for thinking through observational data where we don't 

### 20 really have the benefit of isolating causes very well. And so 

### 21 these are patterns that you should see in data when there is a 

### 22 causality present, and some of the ones that are really

### Page 231 1 important here are the idea of consistency and specificity of 

### 2 effects that we talked about before and so on. 

### 3 The question now is: if we were going to take 

### 4 these and extend them, how would we do that? And that's what 

### 5 this EPA guidance does; it makes the extended Bradford Hill 

### 6 criteria, and now the question is -- we add a Mode of Action and 

### 7 the key event steps and the human relevance of the animal data 

### 8 via common Mode of Action can be evaluated in order to bring 

### 9 those in. 

### 10 The question now really comes: where among 

### 11 Bradford Hill's areas -- his postulates or his criteria -- does 

### 12 the animal data usually really come into the question? Well, in 

### 13 some ways, in lots of places, but two in particular. 

### 14 I'll, first of all, say that sometimes people 

### 15 say, "Oh, experiment is one of the criteria," right? What he 

### 16 was really talking about there was an intervention in the human 

### 17 data. It was taking the handle off the Broad Street pump and 

### 18 stopping the cholera epidemic. 

### 19 So that's really not experiment in the sense 

### 20 of animal experiments. Where animal experimental work really 

### 21 comes in is in biological plausibility because we are now 

### 22 invoking biological causes for the patterns that we see in

### Page 232 1 epidemiology because epidemiology can mostly see patterns of 

### 2 associations. The underlying modes and mechanisms of action of 

### 3 that can be backed up with this kind of mechanistic work that we 

### 4 can do with animals. 

### 5 And also in some sense, consistency in that we 

### 6 are saying that these animal data are relevant because they are 

### 7 observing something about those biological properties that we 

### 8 can observe directly in the animals that ought to be common to 

### 9 the humans. And so in some sense, there's a consistency between 

### 10 the effects and animals and humans, and that's the main places 

### 11 where the animal data would come in. 

### 12 I will say that we really should remember that 

### 13 these postulates are not a checklist; we don't say, "We've got 

### 14 some of this, we've got some of this, and therefore, there we 

### 15 go." I did once get told by somebody at a regulatory agency 

### 16 that will remain unnamed, "Oh, we don't really need plausibility 

### 17 because we have enough of the other criteria already." 

### 18 Yeah, that's not the right attitude, I don't 

### 19 think, because there aren't measures of evidence in themselves. 

### 20 They're rather, in Bradford Hill's own words, "guides to 

### 21 thinking through the data." What does he mean by that, thinking 

### 22 through the data?

### Page 233 1 Here, if you read down past the criteria, in 

### 2 that 1965 paper is a really important quotation. He says what 

### 3 the fundamental question is is this: "Is there any other way to 

### 4 explain the set of facts before us, is there any other answer 

### 5 equally or more likely than cause and effect?" 

### 6 A set of facts now is all the epi studies; the 

### 7 positive effects and the negative effects, the Mode of Action 

### 8 and animal studies and all the other potential explanations for 

### 9 what we have. 

### 10 So what he's saying is we have this array out 

### 11 outcomes that we have in the studies among the human studies for 

### 12 different endpoints and different dose measures. We've got the 

### 13 animal studies and so on. Somehow those have to have 

### 14 explanations. One of those is the common causal thread that we 

### 15 are trying to assess with these criteria and these evaluations. 

### 16 But the other possibility is that they have 

### 17 other reasons other than that causality. Instead of thinking of 

### 18 weight of evidence as a bathroom scale -- how much do we put on 

### 19 it and how heavy does it come down -- he's saying, "We should 

### 20 look at weight of evidence as a two-pan balance." 

### 21 So on the one hand, you have sort of that 

### 22 story that you would make with a causal explanation, and then

### Page 234 1 the other story says, "How else would you explain the same set 

### 2 of facts, which are in fact in front of us and needs some kind 

### 3 of explanation if we denied that causal element of the chemical 

### 4 at hand. 

### 5 It's weighing those alternative ways of 

### 6 explaining those facts that gives you the weight of evidence. 

### 7 That's what he meant by thinking through, and that's how I think 

### 8 he intended his criteria to be used. 

### 9 That's really the basis that I try to work out 

### 10 in hypothesis-based weight of evidence, so I see this proposal 

### 11 on my part being, one, very consistent with Bradford Hill 

### 12 criteria -- extended Bradford Hill criteria, Mode of Action 

### 13 human relevance framework, and the EPA's guidelines as far as 

### 14 they go. And I'm trying to suggest ways to maybe bring them a 

### 15 little bit farther. 

### 16 So the question is: how much does evidence 

### 17 weigh? We have to weigh this evidence. How much does evidence 

### 18 weigh? What process do we have for judging how compelling it is 

### 19 and how to trade off among apparent contradictions in the data 

### 20 -- effects that weren't consistent from one study to another, 

### 21 things that seem to happen here but not there? 

### 22 So my contention is that evidence has no

### Page 235 1 meaning except in relation to specific hypotheses; otherwise, 

### 2 it's just data. The difference between data and evidence is 

### 3 that you're bringing those data to bear on a question. 

### 4 So what we should do is we should organize the 

### 5 weight of evidence around evaluating specific hypotheses against 

### 6 the data. So what we want to do is we want to articulate: 

### 7 what's the proposed basis for inferring that some phenomenon 

### 8 that we've seen in an animal study or in a human study also 

### 9 applies to our target population? 

### 10 What is it that we think that those things 

### 11 have in common so that one constitutes evidence for the other? 

### 12 What is it? We sort of say, "Oh, yeah, we use animal evidence 

### 13 as evidence because we do it all the time. That's what we do 

### 14 and that's convention." 

### 15 But there's a scientific reason behind it and 

### 16 it is worthwhile going back to that scientific reason, realizing 

### 17 that what it is is it's not just an extrapolation from the one 

### 18 study to the humans or to the human target populations. It's 

### 19 really a generalization. There's something in common that they 

### 20 have that underlies the response here and the response that 

### 21 you're worried about in humans that suggests one provides 

### 22 evidence for another. That's why it's evidence.

### Page 236 1 So if it's a generalization, then the question 

### 2 arises: where else should it apply? Not just in this study and 

### 3 in our target population, but where else in our data should we 

### 4 see it and do we really see it? 

### 5 That's why we have to look at all the data, 

### 6 the positive, the negatives, and reconcile that with that 

### 7 proposal about what's being in common. 

### 8 If there are inconsistencies, how should they 

### 9 be explained? There are always inconsistencies, especially in 

### 10 epidemiologic data. We know that's why we don't just rely on 

### 11 one study. But there's got to be some kind of reason, known or 

### 12 unknown, for those inconsistencies. And so we have to have 

### 13 plausible reasons for why things that don't agree shouldn't be 

### 14 counted as refutations of our idea, but it rather can be 

### 15 accommodated in. 

### 16 What's being relegated to error, chance, 

### 17 happenstance? And if this generalization isn't true, this basis 

### 18 for using these data as evidence, how else would we explain the 

### 19 result if this is not causing such-and-so in humans. We've got 

### 20 this animal study, and it's got a positive, what does that mean? 

### 21 Is it an animal-specific effect? How are we going to explain 

### 22 that?

### Page 237 1 So we're here about different but related 

### 2 endpoints because that really comes in here with the idea of 

### 3 domains of effect in the neurotoxicity with what kinds of 

### 4 effects in the epi studies should be considered to be supporting 

### 5 one another, even if they're different endpoints. 

### 6 How do we decide when different endpoints 

### 7 support one another? In this framework, it's important to 

### 8 articulate the commonality of what the different endpoints are 

### 9 taken to represent as the very manifestations of the same 

### 10 underlying thing. And then you have to sort of further specify 

### 11 what accounts for the variation and how that comes out in this 

### 12 study versus that study. "It's because males are different from 

### 13 females; it's because of the shadows in this end of the maze," 

### 14 or whatever like that. 

### 15 What accounts for the failures of some 

### 16 manifestations to appear in some cases? Is it specificity? Is 

### 17 it the conduct of the study, the way the endpoint was measured 

### 18 or whatever? 

### 19 And what other consequences of this 

### 20 hypothesized common process ought to be seen, and do we, in 

### 21 fact, see them? That's a way of putting our reasoning on the 

### 22 table and testing it against all of the data and not just

### Page 238 1 saying, "Is this something that's consistent with our idea?" 

### 2 So if you define endpoints too broadly, you 

### 3 may be gaining some positive effects by saying in this broader 

### 4 definition of what constitutes an endpoint, we now have more 

### 5 things that are considered positive. But you also got more 

### 6 negatives of all the places that those things didn't happen, or 

### 7 you've got more cases of where you have to explain why it ended 

### 8 up differently this way, then that way. 

### 9 A lot of these explanations could be 

### 10 constructed, but if you're -- and assuming them without data, 

### 11 you're sort of adding to the burden of your hypothesis with 

### 12 things not in evidence, to use the legal term. 

### 13 So what we really might want to do in the end 

### 14 is create competing accounts of the data, and I'm using accounts 

### 15 sort of as a technical term here -- an articulated set of 

### 16 proposed explanations for all of the observations. 

### 17 We've got Bradford Hills' set of facts out on 

### 18 the table. All of the results that we have, we have to account 

### 19 for them somehow. One possibility is that a lot of them or all 

### 20 of them have to do with some common underlying causal effect of 

### 21 the chemical. That's the one on the left, and that would say, 

### 22 "These findings indicate some human risk."

### Page 239 1 And they have to lay out the reasonings why, 

### 2 how we resolved the contradictions in those studies, and how 

### 3 reasonable are the things we've had to assume to do those 

### 4 resolutions. 

### 5 On the other hand, on the other pan of the 

### 6 balance, we'd say, "If these results don't indicate some kind of 

### 7 effect in humans," then we have to say, "what are the reasons 

### 8 not?" It's also an assertion, and it also has to be as an 

### 9 assertion tested against the data. It's the countervailing 

### 10 assertion because of the opposite assertion. 

### 11 The reasons why not -- how the findings that 

### 12 we have are otherwise explained. If it's not caused by 

### 13 chlorpyrifos, why is there this effect that looks like something 

### 14 that was associated with the chlorpyrifos in appearance? And 

### 15 are those assumptions reasonable? 

### 16 And it's balancing those two that we have to 

### 17 deal with. So we've got these two epi -- we've got these epi 

### 18 studies of chlorpyrifos. And these are sort of in a way, in a 

### 19 nutshell, the alternative accounts for them. 

### 20 On the one hand, on the left there, you say, 

### 21 "Well, there are some specific endpoints here, and we're going 

### 22 to say those associations that we see really are true positives

### Page 240 1 and they're indicative of an effect of chlorpyrifos." And then 

### 2 the things that don't agree, the ones that are in the opposite 

### 3 direction, or the nulls or something like that have to have some 

### 4 reasons for why they didn't happen as well. 

### 5 If this is a real generalization, it should 

### 6 happen in all the cases and not just on Tuesdays but not Fridays 

### 7 or in this study but not that study. There has to be some 

### 8 reasons for why it didn't appear universally. And we put our 

### 9 reasoning for that or our tentative explanations on the table 

### 10 and evaluate it. 

### 11 On the other hand, we could say, "Well, maybe 

### 12 those specific findings are the null ones are the true ones and 

### 13 there really is no effect, and it's the positives in those 

### 14 studies that are really the aberrations. 

### 15 And we say, "What is the reasoning by which we 

### 16 would see those as aberrations? Confounding factors, residual 

### 17 confounding hasn't been eliminated, other kinds of questions and 

### 18 measures and so on and so forth." And we have to adjudicate 

### 19 between those. 

### 20 That's what you're doing when you're being an 

### 21 epidemiologist and just looking at the epi data. What happens 

### 22 when you introduce the animal data in-between here?

### Page 241 1 Now what I'm suggesting is that Mode of Action 

### 2 and plausibility of the effects is what the animal data have to 

### 3 tell you about how you shift the balance there. So it's not 

### 4 simply that you're taking -- are there familiar endpoints among 

### 5 the human data and the animal data that somehow seem to be 

### 6 reminiscent of one another. 

### 7 It's not just that, "Oh, the animal data 

### 8 provides some sort of weight. We put that weight in the hat 

### 9 along with the human conclusion." We're not merging conclusions 

### 10 here; we're actually merging at the level of underlying 

### 11 explanations in terms of Mode of Action, Steps in Mode of 

### 12 Action, dose response for Mode of Action as we understand it, 

### 13 and indeed, these adverse outcome pathways that is the 

### 14 organizing principal in the EPA guidelines for doing this that 

### 15 so much was said about. 

### 16 So the questions here really are: do these 

### 17 animal data corroborate the specific endpoints? Is any kind of 

### 18 specificity or lack of specificity explained by that? We 

### 19 hypothesize common mammalian Mode of Action to actually say this 

### 20 underlines the animal effect and the human effect. 

### 21 And when we do it from a dose response point 

### 22 of view, does that make sense? We can identify Mode of Action,

### Page 242 1 and then we can ask is this plausibly operating at 

### 2 subcholinesterase inhibition levels. This is plausibly 

### 3 accounting for the effects that we see in the humans to help us 

### 4 tip the balance there between those two alternative ways of 

### 5 looking at the human data. 

### 6 We're not looking at hard proof here; we're 

### 7 looking at trying to see how far we're leaning towards one way 

### 8 or the other. That's what we're doing with weight of evidence. 

### 9 We're not trying to prove or disprove; we're trying to say, 

### 10 "Where in the poles between these alternative interpretations 

### 11 should we say the bulk of the evidence lies?" 

### 12 I guess my own view is with the size of those 

### 13 arrows, it's fairly clear: I think that the human data are not 

### 14 particularly compelling in themselves, and that the real 

### 15 question about how are you going to get effects in those humans 

### 16 given the high doses that animals need to do the kinds of Mode 

### 17 of Action elements that are necessary would sort of tip you 

### 18 towards that idea of saying that, really, the human data aren't 

### 19 showing us something. 

### 20 But that's my view, and we'll have a lot of 

### 21 discussion of that as we come along. I will say, just a couple 

### 22 of points here, that there are two ways of sort of looking some

### Page 243 1 of these things I think need to be distinguished. One is 

### 2 chlorpyrifos inhibition as a Mode of Action itself -- in other 

### 3 words, cholinergic effects. And that would be an important 

### 4 thing to work through from this point of view in those 

### 5 possibilities. 

### 6 We also have the possibility that chlorpyrifos 

### 7 is causing things that are not strictly cholinergic effects 

### 8 themselves, but nonetheless don't happen at significant levels 

### 9 far below the levels at which acetylcholinesterase inhibition 

### 10 occurs. 

### 11 It's a separable question, and it could be 

### 12 that the evidence on whether effects can be seen in the absence 

### 13 of cholinesterase inhibition can say whether there are such 

### 14 things as non-cholinergic effects. But if there are, that 

### 15 doesn't say that they happen at all other doses. That has a 

### 16 dose response level, too. 

### 17 We heard in the adverse outcome pathway 

### 18 discussion this morning about how the doses that are necessary 

### 19 to do the first steps are smaller than the doses that are 

### 20 necessary to do the subsequent steps at the higher levels of 

### 21 organization and so on and so forth. 

### 22 And so the real question is: given the doses

### Page 244 1 that are necessary and the animals are given the doses that we 

### 2 have available to humans, is that a plausible kind of thing to 

### 3 say that those kinds of things are happening? Dose response is 

### 4 key. 

### 5 So my final slide here is this: this is the 

### 6 seven steps that we call our hypothesis-based approach. We 

### 7 would like to suggest this as good practice that could be 

### 8 followed. I know the writing is tiny. I just wanted to use the 

### 9 table from our paper, so I epitomized it on the right-hand side 

### 10 there. 

### 11 First step: systematic review and evaluate 

### 12 study quality. That's very important. EPA has done that. 

### 13 Systematic review, of course, has to have standardized criteria 

### 14 for evaluation, so you don't just find the good points of the 

### 15 studies that you like and note the bad points of the studies 

### 16 that you don't like. You have to define those criteria ahead of 

### 17 time, and that's important. 

### 18 Then you look for consistency, specificity, 

### 19 and so on within the epi and also within the tox. Consistency 

### 20 among studies, because after all, if these effects are real, 

### 21 they ought to happen regularly; and if they don't, it's not that 

### 22 explanations for why that isn't can't be had, but you have to

### Page 245 1 put them on the table. It's part of your reasoning. The degree 

### 2 that you can make ad hoc assumptions in order to work out, one 

### 3 of these things are not refuting assumptions, adds to the burden 

### 4 of what you're trying to explain without data and that, in some 

### 5 sense, weakens the weight of evidence. 

### 6 And then we articulate the logic for why these 

### 7 data constitute evidence. Why is it that we think that those 

### 8 phenomena are telling us something about the target population? 

### 9 And so then we can evaluate those generalizations across animals 

### 10 and humans and say, "How do they actually match up with respect 

### 11 to the data we have?" 

### 12 So we evaluate the hypotheses is step four. 

### 13 In step five, we really look for this commonality of causes 

### 14 across epi and tox as an underlying sort of Mode of Action 

### 15 adverse outcome pathway level. And then we formulate these 

### 16 competing accounts, the two pans of the balance. 

### 17 If this really is a causative effect, here's 

### 18 how we explain the things that it would explain; and here's how 

### 19 the way we explain the discrepancies. If there isn't that 

### 20 causative effect, here's how we explain all the things that look 

### 21 like they were pointing in that direction that are, in some 

### 22 sense, false.

### Page 246 1 And by weighing those two things, we can come 

### 2 to conclusions and also identify data that could help us tip us 

### 3 one way or the other. 

### 4 I think it's important to realize here that 

### 5 quantitative evaluation is really -- even when you're doing this 

### 6 in a hazard identification mode, you're really looking for 

### 7 hazard; you're looking for the qualitative question of whether 

### 8 this can do something. 

### 9 The quantitative aspects of dose response of 

### 10 the Mode of Action really are important part in deciding whether 

### 11 you actually have the evidence for that kind of qualitative 

### 12 process happening at the doses that we have. 

### 13 A separate question: then using those data to 

### 14 set a human safety level, but the quantitative stuff actually 

### 15 does come into the dose response in this. 

### 16 And so with that, I will finish and hope that 

### 17 you find these comments useful for your further deliberation. 

### 18 Thank you. 

### 19 DR. KENNETH PORTIER: Any questions from the 

### 20 Panel? I'm not seeing any. Thank you very much. 

### 21 DR. LORENZ RHOMBERG: Thank you. 

### 22 DR. KENNETH PORTIER: I can't read the writing

### Page 247 1 either here or here, so you're saying this is in your 

### 2 publication, though? Dr. Rhomberg? You said this table on the 

### 3 left is in your publication referenced at the beginning? 

### 4 DR. LORENZ RHOMBERG: Right. 

### 5 DR. KENNETH PORTIER: Okay. And your 

### 6 publication is probably one of the things on the docket that was 

### 7 submitted. 

### 8 DR. LORENZ RHOMBERG: Submitted with public 

### 9 comments. There's a link to it, and it's an open access paper, 

### 10 so anyone with the link is free to go download the paper and 

### 11 read it. Thank you. 

### 12 DR. KENNETH PORTIER: Okay. Thank you. Next, 

### 13 we're going to move on to the Dow Public Comments, and I guess 

### 14 Dr. Juberg, you're going to be kind of coordinating this? 

### 15 DR. DALAND JUBERG: Yes, I will be. I'll be 

### 16 doing much as Dr. Lowit was, serving as the beginning and end 

### 17 for the Dow presentations, and I agreed with Dr. Portier and Mr. 

### 18 Jenkins. We'll cut the Dow AgroSciences presentation in half. 

### 19 We'll focus on a couple epidemiology presentations today and 

### 20 then conclude tomorrow with a couple that relate back to animal 

### 21 and exposure. 

### 22 So let me first begin. I'm going to offer a

### Page 248 1 few opening remarks. I'm Daland Juberg with Dow AgroSciences. 

### 2 By title, I'm the North American leader of the Human Health 

### 3 Group within the R&D organization. By training, I'm a 

### 4 toxicologist and environmental health scientist. I've been the 

### 5 principal toxicologist for chlorpyrifos since 2006 with the 

### 6 company. 

### 7 As a team, let me just explain; we have 

### 8 toxicologists, fate and metabolism, ecotoxicologists, so forth. 

### 9 We brought some of those with us today, specifically to hone in 

### 10 on a few of the charge questions that you've been tasked with 

### 11 looking at. 

### 12 And before I go too much further, let me, one, 

### 13 thank Dr. Portier and the Panel for giving us this time. I know 

### 14 this is a long day. We're very appreciative. I'd like to thank 

### 15 the Environmental Protection Agency, the Office of Pesticide 

### 16 Programs, and Dr. Bradbury. And particularly, I'd like to thank 

### 17 the whole HED team, we know, as they do, that this is a 

### 18 voluminous literature to work through. 

### 19 These are very vexing, challenging questions, 

### 20 pushing the science on risk assessment these days, so we're 

### 21 appreciative of the attention to deep science, and that's what 

### 22 we're here to do briefly is to help you all with presentations

### Page 249 1 and with submitted comments that have been given to you in the 

### 2 docket and otherwise for assistance with some of these very 

### 3 challenging scientific questions. 

### 4 So purpose today -- broadly, and it gets back 

### 5 to some of what Dr. Bradbury was indicating because we're ardent 

### 6 advocates of deep science -- to bring an awareness of recent 

### 7 investigations and study data for consideration in risk 

### 8 assessment. And these will involve some studies that we've 

### 9 done, some independent reviews, and some even what I call 

### 10 pushing the science on the risk side; using scientific 

### 11 principles including causality, scientific methodology, 

### 12 integration of hazard and exposure, and weight of evidence; in 

### 13 addition, to provide perspective on chlorpyrifos exposure, 

### 14 epidemiology, neurodevelopment, and utility of in vitro studies. 

### 15 Over the years, as the primary registrant of 

### 16 this molecule, we've done many, many studies, but what we're 

### 17 going to do is try to target a few today with some additional 

### 18 perspectives that at some of the Charge questions that are for 

### 19 you all. 

### 20 We've been on this journey as well, and you 

### 21 know, we're well-aware of some of the challenging literature 

### 22 that's been developed; the academic studies; the epidemiology

### Page 250 1 studies that exist over the last four to five years. 

### 2 We've been fortunate to participate in a 

### 3 number of these panels and thank the SAP and the EPA for 

### 4 allowing us to participate. So what we're going to do just 

### 5 briefly is, you know, I want to illustrate that we take science 

### 6 in different directions. 

### 7 Sometimes, it's the conduct of a new study 

### 8 where appropriate; oftentimes, it's pushing science in terms of 

### 9 risk approaches; oftentimes, we have the need to recruit and 

### 10 have independent reviews and individuals look at data aside from 

### 11 us. That's a very important part of it. So I'm just, through 

### 12 this slide, highlighting a few of those. 

### 13 A couple of years ago, we conducted a 

### 14 comparative cholinesterase study. This is, as Dr. Lu had 

### 15 indicated, a very common and consistent study that the agency 

### 16 has used for assessing points of departure and ultimately risk. 

### 17 18 This study, in this case, has provided some 

### 19 data in EPA's recent risk assessment and, you know, all cases, I 

### 20 would say with all these journeys, we continue to publish this 

### 21 literature. These are two that are in publication right now. 

### 22 I'm the fellow that did agree to pull this one

### Page 251 1 back. I did have authority to give it to you, but it looks a 

### 2 little uncorrected proof. I said, "Fine, we'll give this to you 

### 3 another way." 

### 4 So these two publications relate to that 

### 5 particular study. One was entitled Cholinesterase Inhibition 

### 6 and Toxicokinetics in Immature and Adult Rats After Acute or 

### 7 Repeated Exposures to CPF or CPFoxon. This was just accepted 

### 8 this week, and that's why we don't have that. 

### 9 And the second one was a modeling approach 

### 10 after that entitled Acetylcholinesterase Inhibition Dose 

### 11 Response Modeling for Chlorpyrifos and Chlorpyrifos-oxon. So to 

### 12 the extent those data help you and the publications help you and 

### 13 the publications help you in your deliberations, we can get 

### 14 those to you. 

### 15 A second push here, has been the subject of 

### 16 some thought today, was the recent SAP last year, February, the 

### 17 PBPK linked modeling. This was an initiative that we undertook 

### 18 a number of years ago where we basically said, "We're going to 

### 19 combine exposure data and modeling with effects data and 

### 20 modeling." 

### 21 And this was the subject of an SAP, which we 

### 22 appreciate. We appreciate the Agency's attention and

### Page 252 1 willingness to devote time to that. I'm encouraged and we 

### 2 continue to push those kinds of data. 

### 3 I will note that within the Society of 

### 4 Toxicology -- some of which you are familiar with --that work 

### 5 this year garnered highlighted by the best paper awarded by the 

### 6 mechanism section was also highlighted by the risk assessment, 

### 7 specially sectioned. So it's gotten some notoriety. We 

### 8 continue to think that, as was alluded to by the HED and a 

### 9 scientist this morning, that there's a need at least to continue 

### 10 to explore those approaches. 

### 11 I would draw your attention to some outside 

### 12 efforts that we've had done for us. These are independent 

### 13 publications on neurodevelopment, exposures, and weight of 

### 14 evidence for epidemiology. These have all been published. I 

### 15 think they've been given to you, the Eaton, et al., Li, et al., 

### 16 Pruiett, et al. papers. 

### 17 Traditionally, Dow longstanding, we're one of 

### 18 the few industrial labs that still has a tox lab, and we've are 

### 19 some of the first to have been integrating continually now 

### 20 kinetic data into all of our tox testing. 

### 21 And so what this allows us to do is, point 

### 22 number four, improved animal kinetic data in conjunction with

### Page 253 1 cholinesterase effects. This allows a direct comparison of 

### 2 exposure and effects and strengthens those models of PBPK that 

### 3 we have. 

### 4 And then finally, my colleague Dr. Carol Burns 

### 5 will talk further about this, just recently this past year, she 

### 6 conducted and led another study of manufacturing exposures with 

### 7 resultant of inhibition of plasma or RBC cholinesterase 

### 8 observations. 

### 9 And this again, the point here is that the 

### 10 more data we collect, the more consistent the science becomes. 

### 11 And again, this becomes very consistent with what some of the 

### 12 models are predicting. 

### 13 This is just one slide, and then I'll move on 

### 14 to who our presenters are today. This is just an example of 

### 15 that recent CCA Study, or Comparative Cholinesterase, that the 

### 16 Agency has used in part for deriving new points of departure. 

### 17 And there was a comment this morning about 

### 18 attention and need to protect both acute and repeated exposures. 

### 19 I would say that this study has been used for some of that. I 

### 20 would draw your attention to that when you have a point of 

### 21 departure, there's been much talk around the one milligram per 

### 22 kilogram per day, but clearly, there's need to go more

### Page 254 1 conservative when you're doing risk assessment for regulatory 

### 2 decision-making. Those levels tend to be 0.36 and, I think, 

### 3 0.03 milligrams per kilogram per day. 

### 4 But then importantly, it's important for us to 

### 5 realize that there are safety factors or additional factors put 

### 6 beyond that that allow us to then protect Human Health. So the 

### 7 levels do drop down a bit; hence, that's what the acute PAD and 

### 8 chronic PAD are. Ultimately, those are the ones that are 

### 9 proposed. 

### 10 So what I'd like to do now is basically 

### 11 introduce two of our presenters for today and one for tomorrow. 

### 12 13 Dr. Carol Burns will speak about epidemiology 

### 14 regarding children's health. She is with The Dow Chemical 

### 15 Company in Midland, Michigan. Dow AgroSciences physically is in 

### 16 Indianapolis, Indiana, so we're separated. That's where we are. 

### 17 She will address charge questions -- I won't read them to you 

### 18 -- but she's going to cover a few of them, as you'll see. 

### 19 She will be followed by Dr. Julie Goodman of 

### 20 Gradient. She will talk further about the specific paper that 

### 21 Dr. Rhomberg mentioned entitled Hypothesis-Based Weight of 

### 22 Evidence Evaluation of Chlorpyrifos and Neurodevelopmental

### Page 255 1 Effects. 

### 2 Tomorrow, we'll begin with Dr. Michael 

### 3 Bartels, who will shed light on use of a validated PBPK/PD model 

### 4 for chlorpyrifos to correlate in vitro substrate concentrations 

### 5 with in vivo systemic exposures. 

### 6 Dr. Paul Price is here. He will be here. 

### 7 He's not prepared to make comments, but if there are comments 

### 8 that come up about the modeling, please feel free to ask him. 

### 9 And I would encourage you to engage these presenters. We're 

### 10 here to help you all and to shed light on data perspectives that 

### 11 we can as we continue on this journey. 

### 12 So with that, I'll turn it over to Dr. Burns, 

### 13 unless there are questions for me. 

### 14 DR. KENNETH PORTIER: Any questions from the 

### 15 Panel? Okay. Good. Thank you. 

### 16 DR. CAROL BURNS: Thank you for letting me 

### 17 talk today. It's late in the afternoon; I have lots of 

### 18 pictures, so hopefully we'll stay awake and we'll go through 

### 19 these points. Oh, thank you. Ah, thank you. 

### 20 I'm an epidemiologist at The Dow Chemical 

### 21 Company. I've been at Dow 17 years now. The mission of our 

### 22 department is product support and responsible care, so we do

### Page 256 1 studies of our employees and studies of people who use our 

### 2 products, and present at panels like this. 

### 3 So today, I'll cover a few of the Charge 

### 4 questions. For epidemiology for me, exposure is integrated 

### 5 within the hazard assessment as well, so they're sort of 

### 6 intermingled. Talking about the role of chlorpyrifos, I don't 

### 7 believe is confirmed in the health outcomes. 

### 8 And so you see the Charge question is in 

### 9 parentheses afterwards, so you can keep track if you're assigned 

### 10 to one of those questions. 

### 11 The presumed chlorpyrifos exposures based on 

### 12 urinary TCPy are dominated with co-exposure to dietary and 

### 13 preformed environmental TCPy. 

### 14 Chlorpyrifos blood exposure in the Columbia 

### 15 study is pretty low, and it is below the current revised Limit 

### 16 of Quantitation by the 2010 CDC method. 

### 17 And blood chlorpyrifos levels in the Columbia 

### 18 study are well below what would be expected for plasma and red 

### 19 blood cell cholinesterase inhibition. 

### 20 So I'll talk about each of those points in 

### 21 detail. 

### 22 So first of all, let's talk about the role of

### Page 257 1 chlorpyrifos in the epi studies. Now Dr. Christensen talked a 

### 2 lot about confounding and bias and misclassification, and I 

### 3 thought she did a good job, so I'm not going to cover that. 

### 4 But I will talk about, today, looking for 

### 5 replication across multiple studies. And I think it's important 

### 6 to me that the Draft Framework said that it would place higher 

### 7 confidence in results that were replicated or reproduced from 

### 8 multiple studies. 

### 9 And because of its use of chlorpyrifos in 

### 10 blood, Columbia has the most robust exposure metrics. So I'm 

### 11 going to start with the Columbia data and give an example of 

### 12 looking for replication across that using birth weight and birth 

### 13 length. 

### 14 As Dr. Juberg commented, there are some formal 

### 15 reviews that have been written and, you know, many, many pages, 

### 16 but I would recommend that you look through those, looking at 

### 17 the discussions on confounding and bias and so forth. 

### 18 To start out though, I think it's important to 

### 19 talk about exposure, and there were some questions earlier about 

### 20 what is the best biomarker of exposure for chlorpyrifos. And I 

### 21 have these sort of in hierarchical order of what might be the 

### 22 most specific, and that would be chlorpyrifos in blood.

### Page 258 1 And then going down, we have the TCPy in 

### 2 urine, which has some limitations, primarily because it's also 

### 3 present in food and the environment. 

### 4 Next is the diethylphosphates, and I think 

### 5 it's important to know that 10 of the registered OPs metabolize 

### 6 to the DEPs, whereas the dimethylphosphates are not a biomarker 

### 7 for chlorpyrifos. 

### 8 And lastly, I think this is important to 

### 9 remember that the DAPs, as a group, are not specific and they 

### 10 could represent one or many of the 27 registered 

### 11 organophosphates. 

### 12 Dr. Christensen and I think had similar ways 

### 13 of presenting the data. So this is a piece of Table 10 from 

### 14 page 59. Again, just looking at birth length and birth weight 

### 15 because both of those outcomes were statistically significant in 

### 16 the Columbia study. 

### 17 As you look across, you see that Mt. Sinai 

### 18 study was null for birth weight and birth length, and the UC 

### 19 Berkeley study was also null or not significant for those 

### 20 endpoints. 

### 21 Some improvements or considerations for this 

### 22 type of summary is -- the differentiation between a

### Page 259 1 non-significant and null is not entirely clear to me. And as I 

### 2 pointed out before, the DEPs are much more specific and 

### 3 appropriate to evaluate chlorpyrifos than the DAPs. 

### 4 And I think it's important to realize that 

### 5 other analyses were done in these studies and to somehow 

### 6 characterize the number of comparisons that are made with, for 

### 7 example, cholinesterase and PON1, and the -- that there have 

### 8 been two additional studies looking at birth weight besides 

### 9 these three cohorts. 

### 10 So this is how a revised table might look. 

### 11 And so you see there in this column, we have our Columbia data 

### 12 that we've seen before. But for Mt. Sinai, remember that in 

### 13 addition to TCPy, they had analysis for DEP, PON1, and plasma 

### 14 cholinesterase. So they did eight analyses using some or many 

### 15 of these, and ten for birth weight, all of which were not 

### 16 statistically significant. 

### 17 Berkeley had several analyses as well, 

### 18 numbering up to nine analyses. None was statistically 

### 19 significant. 

### 20 And then we have two new studies: one in New 

### 21 Jersey where they did look at chlorpyrifos in blood and using 

### 22 analysis of maternal serum and cord serum, found no statistical

### Page 260 1 association. 

### 2 And lastly, the Ag Health Study, looking at 

### 3 women who reported ever using chlorpyrifos; found no association 

### 4 for birth weight. They did not test for birth length. 

### 5 So in conclusion, just using these two 

### 6 outcomes, these results have not been replicated in four 

### 7 studies. 

### 8 And getting back to the specificity of 

### 9 exposure; comparing the DAPs to TCPy in urine and chlorpyrifos 

### 10 in blood. Here's an example of how you might come to different 

### 11 conclusions based on what specific biomarker you're using. 

### 12 I'm sorry. These three slides I added just 

### 13 after the break, so these won't be in your printed copies. So I 

### 14 apologize for the confusion. 

### 15 So here, we see the Rauh 2006 data for the 

### 16 PDD, pervasive developmental disorder. Indeed, the association 

### 17 is -- the PDD increases with increasing chlorpyrifos; and the 

### 18 DAPs have a similar increase with increasing DAPs. 

### 19 However, it's important to remember that TCPy 

### 20 in urine was not statistically significant, even though the 

### 21 direction was not reported. 

### 22 The DMP, which is not a marker of

### Page 261 1 chlorpyrifos, was increased with increasing DMPs. But the DEP, 

### 2 which is more specific to chlorpyrifos than the general DAP, was 

### 3 in the opposite direction. 

### 4 So in conclusion, you get a different 

### 5 conclusion if you're looking at TCPy in urine and DEP than just 

### 6 cord blood and DAPs. And similar is true with the recent papers 

### 7 on IQ. Again, chlorpyrifos in that blood was statistically 

### 8 significant. This is from CHAMACOS, I think. This is the 

### 9 California data. 

### 10 They did not report any results for their TCPy 

### 11 in urine. And the DAP was significant; DMP, which is not a 

### 12 marker of chlorpyrifos, was significant; and the DEP was not 

### 13 statistically significant. 

### 14 So keeping this in mind, I created a table 

### 15 with all the statistically significant hypotheses generated by 

### 16 Columbia, thinking that Columbia uses blood. It's probably the 

### 17 most robust. So how well do the other four studies support 

### 18 these conclusions? 

### 19 And only one study found in it the p value was 

### 20 equal to 0.05. None of the other studies that evaluated these 

### 21 endpoints found a statistically significant association 

### 22 confirming Columbia's.

### Page 262 1 Now let's switch gears and talk about exposure 

### 2 for a little bit and comparing TCPy in urine to chlorpyrifos in 

### 3 blood. And there's been some talk already about biomonitoring 

### 4 alone does not provide duration, source, or timing of exposure. 

### 5 And we know that presence alone does not indicate an adverse 

### 6 effect. 

### 7 And it's important to remember that these epi 

### 8 studies didn't collect behavior on or around the time when they 

### 9 collected the urines. And so it's really difficult to speculate 

### 10 prior exposure levels without additional data about how, when, 

### 11 or why any of these women were exposed. 

### 12 But we do know that the observed range is 

### 13 consistent across general population studies. So let's look at 

### 14 how this might fall out. And this is adapted from Figure 5 that 

### 15 Lieutenant Niman put together, but I'm more pictorially 

### 16 oriented, so I did it just a little bit different. 

### 17 So here's our NHANES data, and these data are 

### 18 years before and after the change in urban use patterns. And 

### 19 it's interesting to me that we don't see a drop in the median of 

### 20 the general population for urinary TCPy. 

### 21 Now these next studies here, these next four, 

### 22 are the Columbia study, the Mt. Sinai, and the UC Berkeley

### Page 263 1 study, for which we have urinary TCPy data. 

### 2 And this New Jersey study, this is Barr et 

### 3 al., which has also looked at birth weight and found no 

### 4 association. So you see, even though some of the means are a 

### 5 little bit higher or lower from one city to another, for the 

### 6 most part, most of the participants are within the shaded area, 

### 7 which is the NHANES range. 

### 8 And the last study was the Ag Health Study, 

### 9 and we don't have biomonitoring data on all those participants 

### 10 of that analysis, but we might consider that those women might 

### 11 be similar to agricultural spouses, which is represented by the 

### 12 Alexander's spouses study here. 

### 13 So you see they're slightly higher than NHANES 

### 14 with a few outliers of women that were applying chlorpyrifos. 

### 15 Conversely, the Ag Health Study women, since 

### 16 they reported using chlorpyrifos, might be considered an 

### 17 applicator. The Thomas study is actually information -- urinary 

### 18 biomonitoring from Ag Health Study participants -- a sample of 

### 19 them. I think it was about 30. And the Alexander study is 

### 20 applicators as well. 

### 21 So it's possible that the Ag Health Study 

### 22 women in the birth weight paper may have been comparable to

### Page 264 1 applicators or spouses. And so this is how those data might 

### 2 look. 

### 3 The problem with urinary TCPy at the levels 

### 4 consistent with the U.S. population is that it doesn't 

### 5 adequately quantify exposure. 

### 6 And on this one, I disagree that TCPy is 

### 7 valuable in epidemiology studies below this point. Can you 

### 8 really differentiate, say, three from eight at this level to say 

### 9 someone is higher or lower exposed? And the reason for that is 

### 10 that most TCPy in population studies is ingestion of the 

### 11 metabolite. 

### 12 And Dr. Lu's study, looking at kids who ate an 

### 13 organic diet, really demonstrated that well; that the organic 

### 14 diet kids had very, very low urinary TCPy compared to more 

### 15 traditional diet. 

### 16 Recently, the study by Morgan et al. confirmed 

### 17 that urinary TCPy does not reliably quantify exposure to 

### 18 chlorpyrifos. 

### 19 And then most recently, we have two studies 

### 20 that collected urine and blood at the same time, and that study 

### 21 was the Whyatt 2009 validation study and concluded that TCPy and 

### 22 chlorpyrifos were not correlated.

### Page 265 1 And then the recent study that we did on our 

### 2 Dow employees; we had 16 unexposed employees. Again, we 

### 3 collected blood and urine on the same day, and 80% of those with 

### 4 detectable TCPy did not have any detectable chlorpyrifos in 

### 5 their blood. 

### 6 This is just from the Morgan paper to 

### 7 demonstrate that when they collected data on TCPy and 

### 8 chlorpyrifos in food, air, soil, and surfaces, you can see that 

### 9 10 times the levels -- the absorbed dose was due to the TCP. 

### 10 However, if we want to look at higher levels 

### 11 of TCPy in urine, the biomonitoring studies of the applicators 

### 12 inform very well on behaviors, and this is coming from the 

### 13 Alexander and Thomas studies on applicators. 

### 14 They found activities like wearing gloves, how 

### 15 much you apply, the type of tractor, if you have a breakdown, 

### 16 all that type of activity is predictive of the urinary levels. 

### 17 And interestingly, the study of Egyptian 

### 18 applicators who had very high exposures confirmed that the 

### 19 behaviors and exposures that they had are inconsistent with the 

### 20 practices in the U.S. I grew up in Nebraska, and I don't know a 

### 21 single farmer who applies barefoot. 

### 22 And then the manufacturing employees; these

### Page 266 1 workers are protected under OSHA, and that includes a monthly 

### 2 monitoring of cholinesterase. 

### 3 And I think we're all on the same page here. 

### 4 We've seen this slide before. So this is the Garabrant study. 

### 5 So these are workers -- these are data that were collected in 

### 6 '99 and 2000, and these exposures were related to job 

### 7 activities. 

### 8 And I think it's remarkable that the predicted 

### 9 dose response for cholinesterase in Midland, Michigan workers, 

### 10 men and women working in a manufacturing plant, identified an 

### 11 inflection point for cholinesterase at 110 micrograms per gram 

### 12 creatinine. And the Egyptian applicators study concluded the 

### 13 same. I think that's pretty interesting. 

### 14 So here, let's look at the same data that we 

### 15 saw before. We have our NHANES people over here; our three 

### 16 cohorts: the New Jersey cohort, and then some applicator 

### 17 studies. And I've added over here the Garabrant data, the 

### 18 Egyptian Farahat applicator data. And then these are the 

### 19 results from the recent Burns study in which we collected data 

### 20 from manufacturers in May. 

### 21 And we see here the shaded area is consistent 

### 22 with NHANES; the blue data is the inflection point for plasma

### Page 267 1 cholinesterase; and the green line is the inflection point from 

### 2 the Farahat study for acetylcholinesterase inhibition. 

### 3 And what we see is that the studies that 

### 4 collected cholinesterase, we can see that we would not expect to 

### 5 have plasma cholinesterase in these population studies down 

### 6 here. And indeed, both Mt. Sinai and CHAMACOS collected 

### 7 cholinesterase data. 

### 8 The recent study of our current workers, even 

### 9 though this line goes above the predicted for plasma 

### 10 cholinesterase, none of our employees had depressed 

### 11 cholinesterase at 20 percent. 

### 12 So now, we've been talking about urine, let's 

### 13 look at blood levels. And there are two additional studies that 

### 14 have blood levels if I wish to compare the Columbia data. 

### 15 First, let's look at the Columbia data. There was a lot of 

### 16 discussion about the blood levels over time, and these results 

### 17 -- these ranges are children born in '99, children born in 2000 

### 18 and so forth. 

### 19 So you can see that, indeed, exposure levels 

### 20 appear to decline by year. This, slide 20, is the current Limit 

### 21 of Quantitation for the 2010 CDC method. And we know from the 

### 22 validation study that TCPy levels, at least in these last three

### Page 268 1 years, are consistent with the U.S. population levels if not 

### 2 lower and that no cholinesterase depression is plausible for 

### 3 these later years. 

### 4 Now on a log scale, I've circled those four 

### 5 years, so you can see where they fit. And then the New Jersey 

### 6 study, we have maternal serum and cord serum. We can see, 

### 7 again, those levels are within U.S. -- the Columbia data and 

### 8 below the current Limit of Quantitation. 

### 9 And then the study by Berman took place in 

### 10 Israel, and they used the newer methods, so their lower level is 

### 11 half of the Limit of Quantitation. 

### 12 So where does that fit with our estimation for 

### 13 cholinesterase? Here are those studies again, and this is the 

### 14 level predicted for 10% plasma cholinesterase. This is the 

### 15 range predicted for acetylcholinesterase. And this is where the 

### 16 animal birth weight studies would fall. 

### 17 So you can see this is 100 times higher than 

### 18 these levels over here. 

### 19 So I'm summary, there are statistically 

### 20 significant effects reported by Columbia, but they aren't 

### 21 replicated in the other cohort studies. Urinary TCPy at the 

### 22 population level is a poor exposure metric for epi studies,

### Page 269 1 other than saying you're above or below. 

### 2 Chlorpyrifos exposure in the Columbia study 

### 3 are low and below the 2010 CDC revised Limit of Quantitation. 

### 4 Blood levels in the Columbia study are well below expected 

### 5 plasma cholinesterase and red blood cell acetylcholinesterase 

### 6 inhibition. 

### 7 I can answer questions, or we can have Julie 

### 8 talk and do a Q&A after. 

### 9 DR. KENNETH PORTIER: And we'll open it up for 

### 10 questions right now. Anyone? Dr. Popendorf. 

### 11 DR. WILLIAM POPENDORF: Yes, I just had a 

### 12 couple there, but that last slide -- the one before that, you 

### 13 were talking about ChE and the AChE. Those two bars, those 

### 14 represent a 10 percent range, is that -- 

### 15 DR. CAROL BURNS: 10 percent range. 

### 16 DR. WILLIAM POPENDORF: For both of them, 

### 17 okay. The other question on your recent work on the 

### 18 applicators, do they involve -- 

### 19 DR. CAROL BURNS: Manufacturers. 

### 20 DR. WILLIAM POPENDORF: Oh, manufacturers. 

### 21 Was most of their exposure dermal? 

### 22 DR. CAROL BURNS: I don't know.

### Page 270 1 DR. WILLIAM POPENDORF: You haven't -- or 

### 2 could you -- 

### 3 DR. CAROL BURNS: We didn't -- 

### 4 DR. WILLIAM POPENDORF: I don't know if you -- 

### 5 DR. CAROL BURNS: Well, just briefly, there's 

### 6 about 50 people in the plant, so we had volunteers. So I had 

### 7 eight individuals from the saran plant and I think 30 from the 

### 8 chlorpyrifos plant. And they came in on Monday and provided 

### 9 urine, blood, and saliva, and so presumably, they had no 

### 10 exposure over the weekend. And then the next day, on Tuesday, 

### 11 came in, provided another blood, urine, and saliva. 

### 12 And so on day two, that was the day that I 

### 13 showed. 

### 14 DR. WILLIAM POPENDORF: Sounds good. 

### 15 DR. CAROL BURNS: So I didn't collect if it 

### 16 was dermal or oral. That was all speculation. 

### 17 DR. WILLIAM POPENDORF: Okay. 

### 18 DR. BRIAN BUCKLEY: If I could follow up. 

### 19 What was the detection limit for the methods for your worker 

### 20 study? 

### 21 DR. CAROL BURNS: Mike wrote those down for 

### 22 you. So the TCPy in urine, that limit of detection was two

### Page 271 1 parts per billion. And we did that analysis in-house, and just 

### 2 for clarification, the Garabrant study, that was done at Dow as 

### 3 well and that Limit of Quantitation was one to two compared to 

### 4 NHANES, which was 0.4, and then the blood was 20. 

### 5 And Mike, did you send that out or did you do 

### 6 that? 

### 7 DR. MICHAEL BARTELS: Mike Bartels, Dow 

### 8 Chemical. The TCP methods across the various studies were quite 

### 9 comparable, one to two parts per billion. The chlorpyrifos 

### 10 method used for the new Burns 2012 study was comparable to the 

### 11 newer CDC-published method. In fact, that was the method used 

### 12 for the analysis that was done in-house, and that was 20 parts 

### 13 per trillion in blood. 

### 14 DR. KENNETH PORTIER: Dr. Vorhees. 

### 15 DR. CHARLES VORHEES: So I'm trying to 

### 16 understand sort of the bigger picture that you're driving at. 

### 17 So we heard a presentation just a few minutes ago that says, 

### 18 "Well, if you're going to weigh hypotheses, what is your 

### 19 alternate hypothesis to explain that human epi neurobehavioral 

### 20 data?" 

### 21 DR. CAROL BURNS: What I see is that we have a 

### 22 study that it looks like the kids born in '99, 2000 may be

### Page 272 1 different than the kids born in 2000, 2001. And is it due to 

### 2 their levels of chlorpyrifos, or is it something else that those 

### 3 levels of chlorpyrifos are related to? I mean, why does someone 

### 4 apply chlorpyrifos in their home and someone else doesn't? 

### 5 I think those are issues of confounding and 

### 6 bias in this classification, so that's why I look for 

### 7 replication. Are we seeing the other studies done in different 

### 8 states, different methods, different investigators? Are they 

### 9 coming to the same conclusion on the same endpoints? I don't 

### 10 have a reason for why those aren't the same, but it's not. 

### 11 What we're not seeing is every other story 

### 12 that's consistent isn't consistent with those stories. 

### 13 DR. CHARLES VORHEES: So am I hearing you 

### 14 right? Are you saying that there may be a relationship in the 

### 15 early data where the levels are higher but not later? 

### 16 DR. CAROL BURNS: No, I'm saying that the 

### 17 relationship isn't due to chlorpyrifos. 

### 18 DR. CHARLES VORHEES: Just some unknown? 

### 19 DR. CAROL BURNS: Mm-hmm. 

### 20 DR. CHARLES VORHEES: And you don't have a 

### 21 hypothesis about what that unknown is? 

### 22 DR. CAROL BURNS: Mm-hm.

### Page 273 1 DR. KENNETH PORTIER: Dr. Lu? 

### 2 DR. CHENSHENG LU: Could you tell us under 

### 3 what circumstances that CDC need to revise their old LOQ for the 

### 4 blood level of chlorpyrifos in 2010? 

### 5 DR. CAROL BURNS: I don't know under the 

### 6 circumstances about their method, no. 

### 7 DR. CHENSHENG LU: Oh, because it sounds very 

### 8 unusual, and I'm not aware of that. 

### 9 DR. CAROL BURNS: Maybe Dr. Bartels has, as an 

### 10 analytical chemist. 

### 11 DR. MICHAEL BARTELS: This is a newer method. 

### 12 It's not specifically superseding the prior method, but it's the 

### 13 newest method that's been published by the same laboratory. It 

### 14 incorporates analysis of more classes of pesticides for a 

### 15 broader survey of exposure to chemicals. The detection limit is 

### 16 20-fold higher with half the sample size, so it's not 

### 17 necessarily superseding, but it is the latest method out of that 

### 18 laboratory. 

### 19 DR. CHENSHENG LU: So my understanding is that 

### 20 they add a new chemical to the method that eventually drive the 

### 21 LOQ higher. 

### 22 DR. MICHAEL BARTELS: They've probably listed

### Page 274 1 a newer method for the same analysis of chlorpyrifos in blood, 

### 2 and detection limit is 20-fold higher than the prior method. 

### 3 DR. KENNETH PORTIER: Dr. Harry. 

### 4 DR. GAYLIA JEAN HARRY: So I think I have the 

### 5 same baffled look that Dr. Vorhees has because one of the things 

### 6 that had struck me about that Columbia study when it was being 

### 7 initially looked at was somewhat of a power of within that 

### 8 cohort where there was exposure, and then you took the compound 

### 9 off of the market. 

### 10 So it almost gave you that great experimental 

### 11 control that you never would have gotten otherwise, and where 

### 12 I'm having a little trouble is if you don't have an alternative 

### 13 -- I mean, right now it looks like I have exposure. I found in, 

### 14 I mean, your slide number 5, I think, one of your slides were 

### 15 showing that you had a difference in birth length and birth 

### 16 weight that was inverse, but then that was no longer present 

### 17 after 2000. 

### 18 So that one interpretation could be that you 

### 19 lost the effect and that one of the known things that you knew 

### 20 happened was the loss of exposure to the compound that seemed to 

### 21 correlate with the loss of an effect. 

### 22 So unless there is an alternative, given that

### Page 275 1 that is a defined cohort within a population, you know, within a 

### 2 set population and not different ones, that's actually pretty 

### 3 strong evidence that there may be something happening with the 

### 4 chlorpyrifos exposure. 

### 5 DR. CAROL BURNS: Yeah. Here's the data, and 

### 6 here they did analysis these two years by birth weight and this 

### 7 was statistically significant with birth weight. These years 

### 8 were not. Now you wouldn't expect this to be statistically 

### 9 significant because you have no heterogeneity in exposure. 

### 10 The question that I have, and the 2008 SAP 

### 11 asked in Appendix 4 I think it is -- one of the appendices -- is 

### 12 the question is: do these kids have higher birth weight than 

### 13 these kids? That's the question. 

### 14 It's not is this statistically associated with 

### 15 birth weight; it's as a group has these kids with lower birth 

### 16 weight, is the effect now gone? And as I interpreted it in the 

### 17 answer in the appendix was they said, "Well, we weren't designed 

### 18 to do it, and we don't have enough statistical power." 

### 19 Now in another paper, in the paper looking at 

### 20 the MDI/PDI, again they used statistical testing to say, "Over 

### 21 these years, looking at statistical significance." I had a 

### 22 slide on this in 2008, but I don't have it this time.

### Page 276 1 If you look at the PDI scores of the children 

### 2 born in '99, 2000, and 2001, the scores do not improve. The 

### 3 scores of the children born in 2001, if you look at the Rauh 

### 4 pediatrics paper 2007, the scores of the children in 2001 are 

### 5 not better than the scores of the kids in 1999. 

### 6 So even though the authors say that, you know, 

### 7 the study was not designed to analyze in that way when they have 

### 8 presented it. They aren't showing a rebound of any effects in 

### 9 the kids when they do analysis by levels. They don't do 

### 10 analysis by years to see if there's a rebound, looking at the 

### 11 natural experiment that they have; that there's no more exposure 

### 12 in these later years. 

### 13 But all of the problems that might exist in a 

### 14 New York City housing development would still exist. 

### 15 That's my alternative hypothesis. But, you 

### 16 know, I don't want to criticize the Columbia study. It's a 

### 17 strong study. They did good analysis. It's a complicated 

### 18 scenario. I can't even begin to imagine. But what I do know is 

### 19 these levels of chlorpyrifos are very low and, you know, they're 

### 20 comparing low versus very low versus extremely low. 

### 21 DR. BRIAN BUCKLEY: If I could follow up on 

### 22 Dr. Lu's question. Do you have any reason to doubt those

### Page 277 1 original CDC values even though they've changed their method 

### 2 last year or two years ago? 

### 3 DR. CAROL BURNS: The Limit of Quantitation 

### 4 below 15 is, can they really tell a difference between 3 and 8? 

### 5 I don't know. 

### 6 DR. BRIAN BUCKLEY: But they had published 

### 7 those methods previous as well, right? 

### 8 DR. CAROL BURNS: They had. 

### 9 DR. BRIAN BUCKLEY: And those methods had been 

### 10 used quite a bit by CDC, right? 

### 11 DR. CAROL BURNS: Only for this study and the 

### 12 Barr study. I haven't seen them used elsewhere. 

### 13 DR. BRIAN BUCKLEY: Which Barr study, there 

### 14 were a couple? 

### 15 DR. CAROL BURNS: The New Jersey study. 

### 16 DR. BRIAN BUCKLEY: There were a couple New 

### 17 Jersey Barr studies. 

### 18 DR. CAROL BURNS: Yeah, but it's the same 

### 19 data. 

### 20 DR. BRIAN BUCKLEY: It is. 

### 21 DR. CAROL BURNS: Barr and Yan. Yeah. 

### 22 DR. BRIAN BUCKLEY: But you don't have any

### Page 278 1 reason to doubt the values for this? 

### 2 DR. CAROL BURNS: I don't have any reason that 

### 3 why -- I don't know. Hi, Mike. 

### 4 DR. KENNETH PORTIER: Dr. Bartels. 

### 5 DR. MICHAEL BARTELS: Mike Bartels from Dow 

### 6 Chemical. I didn't give a critique on that method. It wasn't 

### 7 part of our discussions planned for today, but since the topic 

### 8 was brought up, I do have some concerns about the methodology. 

### 9 After speaking with the laboratory and 

### 10 critically reviewing the method as published and additional data 

### 11 that I received, my opinion is that the method was not validated 

### 12 below 15 parts per trillion. In analytical methodology, if you 

### 13 want to measure something down to X level, you fortify the 

### 14 matrix down to X level, and you show you can measure it 

### 15 appropriately. 

### 16 In the published method, the blood was 

### 17 fortified down to 15 parts per trillion and not below. It was 

### 18 good solvent recovery or solvent standards that showed linearity 

### 19 and sensitivity and solvents, but in the presence of blood 

### 20 matrix, the method was only valid down to 15 parts per trillion. 

### 21 There were different quality controls run on 

### 22 multiple days showing about 20 percent RSD, which is good, but

### Page 279 1 the reality is 20 percent RCM 15 can give you an error of five 

### 2 or six parts per billion at that low level. There were no 

### 3 measurements done below that. 

### 4 As far as I know, there were no replicated 

### 5 analyses of any of the individual samples, especially the high 

### 6 exposure samples. There were no field fortifications on the 

### 7 samples to show that there was not any contamination at the 

### 8 place of collection or between collection and transport to the 

### 9 analytical lab, which was New York City to Atlanta. 

### 10 There were also no storage stability samples 

### 11 with the samples to verify stability, so that summary of my 

### 12 critique is in the 2008 docket. I can go over that again later 

### 13 tomorrow when I come back up, if you wish. 

### 14 DR. KENNETH PORTIER: You can go read it in 

### 15 the docket. 

### 16 DR. CAROL BURNS: You can find it. 

### 17 DR. KENNETH PORTIER: Yeah, it's in the 

### 18 docket. Dr. Vena. 

### 19 DR. JOHN VENA: The figures up here, you said, 

### 20 were maternal blood because -- 

### 21 DR. MICHAEL BARTELS: Those are cord blood 

### 22 data.

### Page 280 1 DR. CAROL BURNS: Yeah, that's the cord blood 

### 2 from -- 

### 3 DR. JOHN VENA: It's the cord blood, because 

### 4 that's what they -- 

### 5 DR. CAROL BURNS: Yeah, and these data came 

### 6 from Eaton's publication, which he got the ranges from. 

### 7 DR. JOHN VENA: Right. So what we're talking 

### 8 about here is not maternal blood then. These are the cord blood 

### 9 samples because that's what they use in their paper to correlate 

### 10 with the birth weight and the other outcomes, right? Am I 

### 11 correct? 

### 12 DR. CAROL BURNS: Right, except for a few when 

### 13 they didn't have cord or maternal, and they imputed -- I don't 

### 14 know - 17 percent or so. 

### 15 DR. MICHAEL BARTELS: There was about 20 

### 16 percent of the cord blood samples that were not taken or 

### 17 measured, so those levels were imputed from the overall 

### 18 relationship of cord to maternal blood ratios. And there's an 

### 19 equation for that in one or two of the Columbia papers. 

### 20 DR. JOHN VENA: I guess part of my head was 

### 21 comparing to all these other datasets. You said these are cord 

### 22 blood samples that we're using, which is a different measure

### Page 281 1 than the blood samples that you're measuring in adults. I'm not 

### 2 sure you can really compare them. It's a different metric. 

### 3 It's a whole different scenario. 

### 4 DR. CAROL BURNS: Another thing that Larry 

### 5 Needham had written about was controlling for blood lipids, and 

### 6 that was one thing that we collected in our recent manufacturing 

### 7 study to see if, indeed, lipid levels were changing our 

### 8 interpretation of exposure. I think there's still some 

### 9 interpretation and some work to be done about that role and how 

### 10 well cord blood versus maternal blood tells you the story. 

### 11 I think we see here there's a difference in 

### 12 the cord blood in the New Jersey study versus the maternal. 

### 13 It's a different range. 

### 14 Does your head hurt now? 

### 15 DR. WILLIAM POPENDORF: In the New Jersey 

### 16 study, for instance, it's merely my question: is there any other 

### 17 study that looked at cord blood than these three epi studies? 

### 18 That's all. 

### 19 DR. CAROL BURNS: Not that I'm aware of. 

### 20 DR. KENNETH PORTIER: For the record, that was 

### 21 Dr. Popendorf. 

### 22 Okay. I think we'll go ahead and move on,

### Page 282 1 given the lateness of the hour. Dr. Goodman is next. Dr. Julie 

### 2 Goodman. 

### 3 See, even our pointers are giving up, right? 

### 4 I said, even our pointers are giving up at this point. 

### 5 DR. JULIE GOODMAN: Should I get started? 

### 6 Well, thank you very much for the opportunity to speak today. 

### 7 I'm Julie Goodman, a principal at Gradient, which is an 

### 8 environmental consulting firm in Cambridge. 

### 9 I have a master's in epidemiology, a Ph.D. and 

### 10 board certification in toxicology, and I'm also on adjunct 

### 11 faculty at the Harvard School of Public Health, where I teach a 

### 12 graduate class on research synthesis and data analysis. 

### 13 And today, I'm going to be talking about 

### 14 hypothesis-based weight of evidence evaluation of chlorpyrifos 

### 15 and neurodevelopmental effects. This is a study we conducted 

### 16 independently with funding from Dow. 

### 17 I'm primarily going to be focused on Question 

### 18 4, which is about how you integrate the epidemiology data into a 

### 19 risk assessment. 

### 20 And I'm going to start by describing our 

### 21 approach, and I know you still can't read this slide, but you 

### 22 saw it before. But the idea was I would go through each step.

### Page 283 1 I can't go through the specifics; they're in this 82-page paper 

### 2 we did. I hope you all -- it's on the docket -- have time to 

### 3 read it because the specifics are really what make a weight of 

### 4 evidence analysis. 

### 5 But I just want to show you that the framework 

### 6 and the thought process so you can see how we arrived at our 

### 7 conclusions. And then I will show how we can then apply this to 

### 8 answer questions about how to integrate epidemiology data into 

### 9 the chlorpyrifos risk assessment. 

### 10 Step one is to systematically review 

### 11 individual studies relevant to the causal question at hand and 

### 12 separately for each line of evidence; so separately for 

### 13 epidemiology, toxicology, and mechanistic studies. 

### 14 So for example, for the epidemiology studies, 

### 15 we looked at the cohorts that evaluated neurodevelopmental 

### 16 effects in children -- the Columbia, Mt. Sinai, Berkeley, and 

### 17 the New Jersey cohorts -- and then we did the same for the 

### 18 animal and mechanistic studies. 

### 19 Step two. As opposed to many reviews, which 

### 20 look study by study, step two is actually looking endpoint by 

### 21 endpoint. So for every study that looked at newborn head 

### 22 circumference, we evaluated all of these studies and all of the

### Page 284 1 ways that these studies looked at newborn head circumference; 

### 2 meaning if they looked at it using different exposure metrics or 

### 3 different statistical analyses, we tried to consider everything. 

### 4 We did the same for infant neurobehavior, 

### 5 cognitive and motor development, child behavioral outcomes. 

### 6 And then we essentially looked at all the 

### 7 factors that could influence how one interprets the epidemiology 

### 8 data. For chlorpyrifos, exposure assessment plays a huge role. 

### 9 In terms of issues with the specificity of the exposure metric 

### 10 to precise or accurate the exposure metric was; issues with 

### 11 exposure misclassification. 

### 12 Also, similar issues with the outcome 

### 13 assessment: how precise and accurate it was, when it was 

### 14 assessed relative to when exposure was measured. Also, the 

### 15 clinical significance, this was brought up earlier today by EPA. 

### 16 When we're using that framework that talks testing in the 21st 

### 17 century, the concern is really adverse effects, so we want to 

### 18 understand: are we just looking at homeostatic processes or are 

### 19 we looking at actual adverse effects? 

### 20 In terms of epi, we also look at the 

### 21 confounding and bias, whether we see exposure response. And 

### 22 then again, statistical analyses; all of these studies have

### Page 285 1 many, many statistical analyses. And so there's not only a 

### 2 concern for the multiple comparisons issue, but also are you 

### 3 seeing similar results when you do analyses in different ways, 

### 4 and if not what does that tell you about causation? 

### 5 We then do a similar analysis for the animal 

### 6 studies, again looking endpoint by endpoint. We looked at 

### 7 social and maternal behavior, emotion and anxiety, motor 

### 8 function and cognitive function. 

### 9 Considering similar types of issues, many of 

### 10 which Dr. Moser brought up earlier today, such as was DMSO used 

### 11 as a vehicle? Were the controls appropriate? 

### 12 Also looking at factors like consistency of 

### 13 outcomes across studies, dose-response, and again, this 

### 14 biological significance of response. We'll be looking at 

### 15 homeostasis, and we'll be looking at actual adverse responses. 

### 16 And then similarly for the mechanistic data, 

### 17 looking at neuronal differentiation, oxidative stress, 

### 18 cAMP-related cell signaling, serotonergic dysfunction. And 

### 19 looking at factors that affect not only the interpretation of 

### 20 these results, but the applicability of these results to humans. 

### 21 Once this is done, we've sort of gotten the 

### 22 lay of the land of what's out there regarding these data. We

### Page 286 1 identify the hypotheses, and I think this is really where 

### 2 hypothesis-based weight of evidence varies from a lot of other 

### 3 weight of evidence frameworks in that we're not just testing the 

### 4 hypothesis. 

### 5 Does chlorpyrifos induce adverse 

### 6 neurodevelopmental effects at doses blow those that protect 

### 7 against acetylcholinesterase inhibition? 

### 8 We're also evaluating an alternative 

### 9 hypothesis that chlorpyrifos induces neurodevelopmental effects 

### 10 only at doses above which inhibit acetylcholinesterase. And the 

### 11 reason why this is important: I think a lot of people feel that 

### 12 that second hypothesis is kind of implied; that if your data 

### 13 support the first, they're not going to support the second. 

### 14 But really, the idea is, is you have to 

### 15 evaluate the data with respect to all possible hypotheses and 

### 16 see -- as I'll go through in this talk -- is it more likely they 

### 17 support this hypothesis of causation, or is it more likely that 

### 18 they support this hypothesis of some alternative cause or 

### 19 alternative explanation? 

### 20 And in some cases, you have enough information 

### 21 that you can really judge that one is really most likely to be 

### 22 the truth, and that's the one we should hang our hat on.

### Page 287 1 The first way we evaluate these hypotheses is 

### 2 within the silos within each line of evidence. So we first 

### 3 looked at the epidemiology data, and after considering all the 

### 4 factors I discussed, we concluded that factors other than 

### 5 chlorpyrifos likely cause the reported outcomes or the observed 

### 6 associations are statistical anomalies. 

### 7 With regard to the animal toxicology data, we 

### 8 concluded that most observed effects occurred at doses that did 

### 9 not induce systemic toxicity but were high enough to inhibit 

### 10 acetylcholinesterase. 

### 11 And that regarding the mechanistic studies, 

### 12 that mechanisms in vitro below exposures that cause 

### 13 acetylcholinesterase inhibition may be attributable to study 

### 14 limitations -- and I believe Dr. Bartels is going to be talking 

### 15 about that tomorrow -- but also that no mechanism has been shown 

### 16 in vivo in the absence of acetylcholinesterase inhibition. 

### 17 So that brings us to step five, which is 

### 18 really bringing it altogether, looking at the lines of evidence 

### 19 holistically. And so I tried to, you know, summarize pages and 

### 20 pages in one table. I hope I've done it justice, but 

### 21 essentially on the left, these are the human data. Here's the 

### 22 animal data. And essentially, based on Eaton's paper, in the

### Page 288 1 two -- the Columbia and the Berkeley cohorts -- he estimated 

### 2 exposure of about seven to eight nanograms per kilogram per day 

### 3 and rain levels at 0.33 to 3.3 nM. 

### 4 But then when you go to the animal studies, 

### 5 you're seeing plasma cholinesterase inhibition at 100 micrograms 

### 6 per kilograms per day, and then the LOAEL for 

### 7 acetylcholinesterase inhibition in rat pups at 1 milligram per 

### 8 kilogram per day. 

### 9 So we have a margin of exposure of 10 to 

### 10 100,000, based on these metrics. And then if you go, you know, 

### 11 looking at brain concentrations in rat pups exposed to the LOAEL 

### 12 for acetylcholinesterase inhibition, it estimated brain 

### 13 concentration of 0.5 to 4.6 micromolar. 

### 14 Looking at the minimum dose in all but three 

### 15 of the in vitro studies, we have a dose of one micromolar. And 

### 16 here, we see a margin of exposure of 1,000. 

### 17 So the take-home here is that we have these 

### 18 exposures and the epidemiology studies that are at least 

### 19 1,000-fold lower than exposures that appear to be causing 

### 20 effects in animal studies. 

### 21 How do we account for this? So step six is 

### 22 about evaluating the alternative accounts. So we see that

### Page 289 1 there's two possible ways to account for the data: the first is 

### 2 that the epidemiology evidence is sufficiently compelling that 

### 3 even though it is inconsistent with evidence from animals 

### 4 exposed to much higher doses, there must be some proposed 

### 5 mechanism that must be right regarding low-dose 

### 6 neurodevelopmental effects. That's one way to account for the 

### 7 data that I just showed you in that table. 

### 8 Another way is to say that these doubts about 

### 9 these mechanisms at doses below those that inhibit 

### 10 acetylcholinesterase have merit and that apparent associations 

### 11 from epidemiology studies don't indicate causation, and these 

### 12 associations must be attributable to something else, for 

### 13 example, bias or confounding or exposure measurement error. 

### 14 And I just want to bring up here, a question 

### 15 was asked of Dr. Burns, you know, what's the alternative? If 

### 16 you're saying it's not chlorpyrifos, what could it be? 

### 17 Obviously if we could, I mean, answer that, we wouldn't be here 

### 18 today, right? I mean, yeah, I guess the point I want to bring 

### 19 home is that you're not looking at this epidemiology data in a 

### 20 vacuum. You have to consider the animal and the mechanistic 

### 21 data, and how does that inform your results? 

### 22 So it's not just that, "Well, there's

### Page 290 1 inconsistencies in the epi, and we need to figure out how to 

### 2 explain it." It's we need to figure out how to explain it in 

### 3 light of the animal and the mechanistic data. And essentially, 

### 4 in order for that first account to be true, you have to come up 

### 5 with many, many more ad hoc assumptions about what's occurring 

### 6 than if you accept the second account in that it just seems that 

### 7 there's far fewer ad hoc assumptions you have to make for the 

### 8 data to support that account. 

### 9 And so because of that, that led us to the 

### 10 conclusion that that is the most likely way to account for the 

### 11 data in front of us and essentially led us to our conclusion 

### 12 that a causal association between chlorpyrifos and 

### 13 neurodevelopmental effects in the absence of 

### 14 acetylcholinesterase inhibition is not plausible for humans and 

### 15 that the few statistically significant associations observed in 

### 16 the epi studies are likely attributed to some alternative 

### 17 explanations. 

### 18 And in terms of next steps, the idea is to 

### 19 then apply this to a chlorpyrifos risk assessment. So now that 

### 20 I've briefly gone over our framework and evaluation, I want to 

### 21 talk about how we can apply this to looking at the end risk 

### 22 assessment and specifically at the Charge questions.

### Page 291 1 So Charge question 4.1 asks about the 

### 2 sufficiency, clarity, and quality of the review. Section 4.0 is 

### 3 laid out in such a way that it's very consistent with many 

### 4 weight of evidence frameworks in that it discusses the cohorts 

### 5 first, and then the endpoints; so endpoint-by-endpoint analysis, 

### 6 like I talked about before and then also the strengths and 

### 7 limitations. 

### 8 And this is a very good approach, but I think 

### 9 this discussion would really benefit from a more complete 

### 10 discussion of several things, including the fact that there were 

### 11 multiple comparisons in studies. 

### 12 This discussion often missed that they were 

### 13 evaluations using different exposure metrics, some with more or 

### 14 less specificity in that they weren't always consistent or that 

### 15 statistical methods weren't always results from different 

### 16 statistical methods. And just to bring to your attention, one, 

### 17 in the Rauh study, chlorpyrifos is looked at as a continuous 

### 18 variable in terms of looking at associations with MDI and PDI, 

### 19 and there was no association found. 

### 20 And then it was looked at in quartiles, and 

### 21 there was an association between the lowest quartile and the 

### 22 highest, but there was no dose response in that the middle

### Page 292 1 quartiles were, I believe, higher than the lowest and the 

### 2 highest. 

### 3 And a lack of dose response is evidence 

### 4 against causation, you could say. Then the data were divided in 

### 5 sort of the highest quartile versus the other three combined, 

### 6 and that's when you see statistical significance. 

### 7 So it is possible that that's the truth, so to 

### 8 speak, that there really is an association, and you really only 

### 9 see it that way. But the only way to know that is to take a 

### 10 step back and evaluate all these statistical analyses and 

### 11 determine if that's so, and that hasn't been done. 

### 12 Another very positive thing had to do with -- 

### 13 the draft issue paper discusses factors that could have led to 

### 14 an underestimation or an overestimation of effects, but there 

### 15 was really an emphasis on those that could have underestimated 

### 16 effects, and I think it would benefit from a more balanced 

### 17 discussion. 

### 18 For example, a common misconception is that 

### 19 non-differential misclassification will always bias towards the 

### 20 null. This is the case if you're comparing two groups. But if 

### 21 you have more than two groups, it could bias results in any 

### 22 direction, and so we really don't know how that's going to

### Page 293 1 affect results. 

### 2 And another issue is that even, I mean, as Dr. 

### 3 Burns said, the study design is, I mean, it's excellent in terms 

### 4 of epidemiology studies. But if there are issues, if you don't 

### 5 actually know what exposures are, for example, or if you have 

### 6 lots of exposures around the limit of detection that could shift 

### 7 people in one group or another. 

### 8 Even though your study design is laid out, 

### 9 that might be enough to push you into the direction of saying, 

### 10 "We don't really know what these results mean in terms of 

### 11 causation." 

### 12 And then probably another thing that I think 

### 13 would benefit -- the draft document does a very good job at sort 

### 14 of saying, "How do the epidemiology inform our interpretation of 

### 15 the toxicokinetic studies?" But it doesn't go the other way. 

### 16 There's no discussion of how the results of the toxicokinetic 

### 17 studies inform how we interpret the epi studies, and I think the 

### 18 document would really benefit from that discussion. 

### 19 And then finally, as I said, in Section 4, 

### 20 there is an endpoint-by-endpoint discussion, but I think a more 

### 21 detailed evaluation of this both in the tables and the text 

### 22 would be helpful. Right now in the appendices, there's a very

### Page 294 1 detailed table, study by study. 

### 2 But I just want to take a minute to talk about 

### 3 how doing this will help this evaluation. So I've copied here 

### 4 Table 10 from the draft issue paper and was very encouraged to 

### 5 see this. This is very in line with our weight of evidence in 

### 6 that you're looking weight endpoint by endpoint. Each row is a 

### 7 different endpoint, each column or the major columns are the 

### 8 studies, and then the minor columns -- if you want to call it 

### 9 that -- are different exposure metrics. 

### 10 And so this really helps you get an idea of: 

### 11 are you seeing consistency across studies? But this table would 

### 12 be much more compelling if all of the exposure metrics were 

### 13 listed, or at least the more compelling ones. So for example, 

### 14 in the Mt. Sinai and the Berkeley cohorts, the DAPs is listed, 

### 15 but not DEP and DEP is more specific to chlorpyrifos. 

### 16 Another issue is that there's no definition of 

### 17 when a result is put as null and when it's put as either inverse 

### 18 or positive but not significant. I didn't look too much into 

### 19 it, but I did find one case where the confidence interval for a 

### 20 no was actually tighter than the confidence interval for a 

### 21 positive non-significant. If you're going to do it this way, 

### 22 you really need to be consistent.

### Page 295 1 One issue with doing it this way, of course, 

### 2 though is you have no idea of the strength of the association. 

### 3 Because, of course, if you really want to see consistency, you 

### 4 could have nulls findings across the board, but if they're all 

### 5 in the same direction, that might indicate there's something 

### 6 going on, and you can't get that information from this kind of 

### 7 table. 

### 8 And another issue is, I talked about before 

### 9 when multiple statistical analyses were conducted in the same 

### 10 study, that's not really reflected in this table. 

### 11 So I just discussed these points, so I'll go 

### 12 onto the next slide. 

### 13 We're going to stick with Table 10, which I 

### 14 feel like my big issue is just that -- again, that the null 

### 15 doesn't really tell you anything about strength of association, 

### 16 but this might be a way that you could see a grand overview. 

### 17 I just took that box. These are just the MDI 

### 18 and PDI results. But the idea here is I put in columns for the 

### 19 DEPs, and what happens is, is for example, if you look at MDI at 

### 20 24 months in Table 10, all you see is this inverse and positive 

### 21 association with the DAPs. 

### 22 But then when you add the DAPs, you see that

### Page 296 1 you have null results. So with the more specific biomarker, 

### 2 you're not seeing any association. So I think spreading it out 

### 3 like that is really helpful. And also stretching it out in 

### 4 terms of MDI and PDI were kind of crammed together, and it was, 

### 5 I found, a little hard to interpret as opposed to having kind of 

### 6 as little as possible in one row so you can really -- you're not 

### 7 going to mix up different endpoints. 

### 8 But as I said, having the null and not showing 

### 9 how many statistics per paper doesn't really get a weight of 

### 10 evidence, so in here, I've just taken a piece of Table 5 from 

### 11 our analysis. So this is just showing the MDI scores, but what 

### 12 we've done is, you know, we have for all the cohorts that looked 

### 13 at MDI scores, we have this study. We have all the different 

### 14 ways that MDI scores were looked at so, you know, for example, 

### 15 in the Berkeley study, it was looked at by maternal urinary TCPy 

### 16 with, you know, less than the median detected or greater. 

### 17 It was looked at by maternal urinary DEPs and 

### 18 then concurrent child urinary DEPs, and then, of course, by 

### 19 different ages. And then you can look down the column where it 

### 20 says the estimate to get an idea of the strength of association 

### 21 and then the confidence interval and the p-value to see what's 

### 22 going on. And just to make it easier for this talk, I've boxed

### Page 297 1 in red the two statistically significantly associations. 

### 2 So it's pretty clear here that, yes, there was 

### 3 a statistically significant association, but it's among a sea of 

### 4 null associations. 

### 5 And you can see this is a huge table, and this 

### 6 is only part of a table and there's lots of endpoints, so it's a 

### 7 very tedious process, but I think it's really the best way to 

### 8 understand for each endpoint what do all the data say? 

### 9 And you need to take it a step further. I 

### 10 just grabbed a few bullets. This isn't really a complete 

### 11 evaluation, but factors you have to look at. Well, in terms of 

### 12 the MDI and the PDI evaluation in these statistically 

### 13 significant associations, the mean score is in the high exposure 

### 14 group. We're actually within the normal range. They weren't 

### 15 adverse. There was also a very modest difference between low 

### 16 and high, so even though it was statistically significant, it 

### 17 wasn't necessarily biologically relevant. There weren't any 

### 18 multiple comparison adjustments in the epi studies, no evidence 

### 19 for exposure response. 

### 20 Some factors were considered, we felt that 

### 21 confounding by certain exposures and SES weren't completely 

### 22 adequately controlled.

### Page 298 1 And then also, again, you're not looking at 

### 2 these data in a vacuum. I realize that these measure different 

### 3 factors than the WISC-IV scores, but there's still all -- I 

### 4 mean, if the idea is, is there's some sort of similar Mode of 

### 5 Action that's getting at this, you want to at least understand 

### 6 is it consistent with other endpoints? So would you expect if 

### 7 there's effects on MDI and PDI, do you think there should be 

### 8 affects on WISC-IV? I mean, maybe you do, maybe you don't, but 

### 9 you -- that's something you need to think about and come to a 

### 10 conclusion about that. 

### 11 And then of course, finally, an association is 

### 12 not consistent or coherent with a toxicology and mechanistic 

### 13 data. So you have to consider that. 

### 14 All right. So moving onto Charge question 

### 15 4.2, and my response is much shorter, I promise. 

### 16 This is a question about the preliminary 

### 17 qualitative conclusion that chlorpyrifos likely played a role in 

### 18 the neurodevelopmental outcomes in the epidemiology studies. 

### 19 And I would say that EPA's conclusion would be more compelling 

### 20 if there was a comparison to determine whether the causal 

### 21 hypothesis or some other explanation is or are better supported 

### 22 by the data, if there was a more complete assessment of the

### Page 299 1 impact of studying limitations, a more detailed assessment of 

### 2 discordant results both within and across studies among the same 

### 3 and related endpoints, like I just showed for MDI, and then a 

### 4 discussion of how results of toxicology and mechanistic studies 

### 5 affect the interpretation of epidemiology results. 

### 6 And it's my opinion, and my colleagues, when 

### 7 we did our hypothesis-based weight of evidence analysis, by 

### 8 going through that exercise, we felt that the evidence indicated 

### 9 that effects and exposures below those that cause 

### 10 acetylcholinesterase inhibition are just not plausible. 

### 11 So I would say we disagree with this 

### 12 conclusion off EPA for Question 4.2. 

### 13 And finally, regarding Question 4.3., the 

### 14 Agency proposed that an acetylcholinesterase inhibition data 

### 15 from lavatory animals is the most appropriate data to use for 

### 16 the dose-response modeling and the depravation of points of 

### 17 departure. 

### 18 And we agree with this conclusion, and I did 

### 19 just want to bring up that in the preamble, there was an 

### 20 implication that because some effects are observed in the 

### 21 studies, there must be some mechanism by which they occur. And 

### 22 it also mentioned that there are limitations in the exposure

### Page 300 1 assessments in the epi studies that affect their use and risk 

### 2 assessment, and I would argue that for the same reason why you 

### 3 shouldn't be using these data in a risk assessment, this also 

### 4 affects how you interpret the epidemiology data themselves. 

### 5 You have to decide if these data are robust 

### 6 enough to use, and if they are, you could use them for both. 

### 7 But if they're not, they shouldn't be used for either. And 

### 8 again, there is evidence from the animal and mechanistic studies 

### 9 that calls into question the plausibility of the effects of the 

### 10 low exposures. 

### 11 So again, this supports evidence that 

### 12 acetylcholinesterase inhibition is the most appropriate. And I 

### 13 know I said finally, but I forgot about 4.3 being this is really 

### 14 finally -- and essentially, this is a question asking for 

### 15 approaches to incorporate epi data into the Grow pretty fast 

### 16 risk assessment. And I think epi data should be incorporated in 

### 17 the same way as any other kind of data. You evaluate it for 

### 18 quality, for robustness, what does it all mean. And 

### 19 essentially, we think this should be done using some kind of 

### 20 weight of evidence analysis where you compare whether the data 

### 21 more strongly support a hypothesis of causation or some other 

### 22 alternative explanation for apparent associations.

### Page 301 1 And as I've said several times, it's our 

### 2 conclusion that a hypothesis-based weight of evidence analysis 

### 3 indicates that a causal association between chlorpyrifos 

### 4 exposure and neurodevelopmental effects in the absence of an 

### 5 acetylcholinesterase inhibition is not plausible for humans. 

### 6 This can inform the hazard characterization in 

### 7 that we've evaluated this data, and we've determined that it 

### 8 doesn't indicate there'll be hazards below those that cause 

### 9 acetylcholinesterase inhibition and essentially informs the 

### 10 dose-response as well because we're confirming the use of that 

### 11 for the dose-response analysis and point of departure. 

### 12 And then finally, as we discussed, you cannot 

### 13 determine precise exposures from these studies, but it does give 

### 14 us sort of a sense of a range of human exposures and sort of a 

### 15 comparison of human exposures versus those in the animal and the 

### 16 in vitro studies. 

### 17 So in that sense, it can give us an idea of 

### 18 margins of exposure, which can then, you know, lend support to 

### 19 whether we're using the right endpoint of acetylcholinesterase 

### 20 inhibition. 

### 21 So that is our 82 pages in 25 minutes, and I'm 

### 22 happy to take any questions. Thanks.

### Page 302 1 DR. KENNETH PORTIER: Dr. Vorhees. 

### 2 DR. CHARLES VORHEES: So maybe I missed it 

### 3 because you went through this one part pretty fast, but correct 

### 4 me if I'm mistaken, it seemed like you swept all the little 

### 5 animal studies aside kind of quickly and focused on the human 

### 6 data. Did I understand you right that you just don't regard 

### 7 them as reliable in providing useful information? 

### 8 DR. JULIE GOODMAN: No, I didn't -- 

### 9 DR. CHARLES VORHEES: What is your take on it 

### 10 other than sort of they're irrelevant? 

### 11 DR. JULIE GOODMAN: No, there's no data are 

### 12 irrelevant. I think that's kind of a key is that we evaluate 

### 13 everything. It's just whether or not they support or don't 

### 14 support the hypothesis. 

### 15 And I think yeah, I didn't spend time talking 

### 16 on it today because it seemed like a lot of the focus of this 

### 17 draft issue paper and the Charge questions were highly 

### 18 incorporated for genealogy, so I wanted to spend my time talking 

### 19 about that. 

### 20 But we do talk a lot about the animal data, 

### 21 and Dr. Lee's going to be talking about it a lot tomorrow. I'm 

### 22 wondering if it's better to wait until she talks because she'll

### Page 303 1 be giving a more in-depth talk about those data. But we 

### 2 certainly didn't just sweep them under the rug. We did as a -- 

### 3 DR. CHARLES VORHEES: So you have a view on 

### 4 that. 

### 5 DR. JULIE GOODMAN: Yes, yes. 

### 6 DR. CHARLES VORHEES: And that is? 

### 7 DR. JULIE GOODMAN: Oh, my view is that 

### 8 basically that the overall evidence does not indicate that neuro 

### 9 -- how do I phrase this? It's like neurodevelopmental effects 

### 10 occur below those doses that causes acetylcholinesterase 

### 11 inhibition. 

### 12 DR. CHARLES VORHEES: But you don't dispute 

### 13 that there are effects? There are neurobehavioral effects at 

### 14 some level of exposure. You're just arguing that you don't see 

### 15 an effect below the level at which cholinesterase inhibition 

### 16 occurs. That's all you're trying to say. 

### 17 DR. JULIE GOODMAN: Yes. 

### 18 DR. CHARLES VORHEES: Okay. So you accept the 

### 19 findings in the studies at above the level at which 

### 20 cholinesterase inhibition occurs as real, true effects. 

### 21 DR. JULIE GOODMAN: Yeah, I don't want to 

### 22 speak to specific studies right now. I'm not really prepared to

### Page 304 1 talk about that, but I think that it's -- yeah, I'm not 

### 2 dismissing those studies at all. I mean, really, what I was 

### 3 focused on was whether we see effects below those that cause 

### 4 acetylcholinesterase inhibition. 

### 5 DR. KENNETH PORTIER: Dr. Harry. 

### 6 DR. GAYLIA JEAN HARRY: Yeah, it was a 

### 7 whirlwind presentation, so if you may have cut across something 

### 8 and we thought that you, you know, sort of trimmed it aside, 

### 9 we'll take that into account. 

### 10 But when you were going back, and I guess 

### 11 there's a caution that I'll raise to you in presenting this as 

### 12 you did, okay? I need to set it within that framework. 

### 13 When you got to the table that you were 

### 14 putting in and putting all of the different effects -- Table 5 

### 15 -- you made a comment that you had these two endpoints, and they 

### 16 frame of no effects is the way that it was sort of worded, okay? 

### 17 18 And I just want to put caution in there 

### 19 because the different things you're looking at, they're not 12 

### 20 months and 24 months and 18 months on a test is not the same 

### 21 thing as what that 36-month test is going to be because there's 

### 22 a developmental dynamics that's happening, and you may not see

### Page 305 1 the effect until that aspect of the development of the organism 

### 2 has gotten to that component so it will manifest as a deficit. 

### 3 DR. JULIE GOODMAN: That's a very good point, 

### 4 right. 

### 5 DR. GAYLIA JEAN HARRY: Just keep that in mind 

### 6 with your presentation of the data because it's not a lot of 

### 7 endpoints at one age that would represent lots of different 

### 8 things. It represents a developmental process. 

### 9 The other one, and I guess I'm a little 

### 10 concerned about this and I'm not real sure you have an answer, 

### 11 but it seemed to come across in one of the other presentations 

### 12 from the public is that I think it was in 2008 maybe where we 

### 13 proposed the caution that be cholinesterase inhibition could be 

### 14 used as a mode of action to look to see if it could be used for 

### 15 the regulatory aspect. 

### 16 But we cautioned the Agency that that may not 

### 17 be the only affect that these types of compounds may have on 

### 18 development. That really hasn't been presented by the Agency 

### 19 right now, and yet the presentations that have come from Dow 

### 20 have potentially opened up a very big can of worms of now coming 

### 21 back to say, "Is there something else we should look at on 

### 22 development that does not come back to the cholinesterase

### Page 306 1 inhibition that we have looked at about trying to regulate this 

### 2 compound?" 

### 3 So it's sort of implied. No, actually, it's 

### 4 very clearly stated that you were saying that you didn't think 

### 5 that there would be an effect that would be under a level that 

### 6 you had cholinesterase inhibition. And I think there's some 

### 7 animal data out there that suggests that you can get adverse 

### 8 effects, and I don't know how well that's been reviewed. 

### 9 So I'm now at a quandary of being asked to 

### 10 look at data to say, "How do you pull all this together if 

### 11 you're looking at a mode of action?" And now there are 

### 12 arguments that that may be the only mode of action or no, now 

### 13 there are other modes of action we should take into 

### 14 consideration. 

### 15 So I wasn't even going to bring it up in any 

### 16 of the things during the week, but the two public presentations 

### 17 have now raised that as a possible concern that you may open a 

### 18 can of worms you don't want to open in that there may be other 

### 19 mechanisms that we need to take into consideration when we look 

### 20 at the developmental aspects of things. 

### 21 And I don't know whether you guys want to 

### 22 address it or you want to sort of reword a few things in there.

### Page 307 1 DR. JULIE GOODMAN: I mean, one thing I 

### 2 actually chose the wording of the hypothesis to not say that 

### 3 that was actually the mode of action was through 

### 4 acetylcholinesterase. So in essence, the hypothesis is just -- 

### 5 it's almost like that could be used as a marker. 

### 6 So even if it's a totally different mechanism, 

### 7 we can use that to say, "If exposures are below us, those at -- 

### 8 that inhibit acetylcholinesterase -- we're below levels of 

### 9 concern." That's what I was getting at. 

### 10 Daland, do you want to answer that? 

### 11 DR. DALAND JUBERG: No, I don't want to 

### 12 answer. I just wanted to say that's the reason we're at a 

### 13 challenging point here because what you'll hear tomorrow, I 

### 14 think, will put into perspective some of the in vitro dose 

### 15 levels as with Dr. Abby Li, some of the attention on the other 

### 16 side of the equation, the animal studies and so forth. 

### 17 So if it isn't addressed tomorrow, please, I 

### 18 mean, it's in our minds now, and let's -- yeah, let's raise this 

### 19 further and talk about it. 

### 20 DR. KENNETH PORTIER: Dr. Vorhees. 

### 21 DR. CHARLES VORHEES: I'd like the chemists 

### 22 and the toxicologists to help inform an ignorant neuroscientist

### Page 308 1 about something that I'm not understanding. So when you're 

### 2 measuring these metabolites, how is it that you're getting 

### 3 measurements below the limit of the detection? Can you just 

### 4 explain to me? How do you have valid data? In most essays I 

### 5 know, if it's below the limit of detection, you don't use those 

### 6 numbers even if your analytical instrument generates a number. 

### 7 So I'm finding this very difficult to try to 

### 8 comprehend. 

### 9 DR. MICHAEL BARTELS: I agree with you. 

### 10 That's my simple answer. In fully comprehensive methodology, 

### 11 that's used for residue analyses according to very concise EPA 

### 12 guideline. You might have a limit of detection, a range, and 

### 13 then a Limit of Quantitation, where you can actually assign a 

### 14 number to the sample. 

### 15 The method, as it's written -- and I would 

### 16 encourage you to look at the Barr 2002 paper. It's -- I'm not 

### 17 sure if it's open access, but you can probably get access or we 

### 18 can present some details of it again tomorrow. 

### 19 They did an extrapolation of their lowest 

### 20 fortification level at 15 parts per trillion and showed that 

### 21 they had good linearity of the solvent standards down to the 

### 22 instrument detection limit where they could see it in solvents

### Page 309 1 -- down to one part per trillion or a little below. 

### 2 It wasn't validation data presented within the 

### 3 method paper to show they can look and measure it in blood 

### 4 accurately. 

### 5 DR. CHARLES VORHEES: So even if you 

### 6 extrapolate down below your limit of detection because you find 

### 7 that it's linear, but what's the data down in that range then 

### 8 mean? 

### 9 DR. MICHAEL BARTELS: If you're talking about 

### 10 a different molecule in a different matrix, say, you know, 

### 11 benzene and dirt or something. If you're below your limit of 

### 12 quantitation, but you can see it and you're above what you've 

### 13 defined as the limit of detection -- if you defined it in your 

### 14 method, that means you can see it and you can say it's there but 

### 15 you can't put a number to it. You can't say what the 

### 16 concentration is in this sample. 

### 17 DR. CHARLES VORHEES: So as I understood it, 

### 18 the CDC limit of detection was 20. 

### 19 DR. MICHAEL BARTELS: The one used for the 

### 20 Columbia study samples was one part per trillion. The method 

### 21 used by the CDC lab for the more recent Berman study was 20 

### 22 parts per trillion, which is the 20/10 paper, I think. It's the

### Page 310 1 Israel -- 

### 2 DR. JOHN VENA: He's talking about the 

### 3 Columbia data. 

### 4 DR. MICHAEL BARTELS: Correct. The earlier 

### 5 work. 

### 6 DR. JOHN VENA: It's stated, published, limit 

### 7 of detection is one. 

### 8 DR. MICHAEL BARTELS: Right. My opinion is it 

### 9 was validated to 15. 

### 10 DR. KENNETH PORTIER: Dr. Ryan, we're also 

### 11 running up against my deadline here, and I'm seeing the panel 

### 12 sitting back here, which means we're losing engagement at this 

### 13 point. 

### 14 Before I forget, Dr. Ryan, I wanted to ask Dr. 

### 15 Juberg, as team leader, whether Dr. Burns and Dr. Goodman will 

### 16 be available in the morning to continue discussions as the panel 

### 17 kind of thinks through more of these things? 

### 18 DR. DALAND JUBERG: They absolutely will, yes. 

### 19 DR. KENNETH PORTIER: Dr. Ryan. 

### 20 DR. BARRY RYAN: I think it was you that 

### 21 pointed out that the new method, the 2010 data that we've been 

### 22 talking about, the 2010 limited detection we've been talking

### Page 311 1 about. Will it include the number of other compounds? 

### 2 DR. MICHAEL BARTELS: Yes, some other classes. 

### 3 I don't have all of them in my head. Yes, but that's how the 

### 4 authors their new method: it's more multifunctional. 

### 5 DR. BARRY RYAN: It would not be the least bit 

### 6 surprising to be that the limit of detection would go up for a 

### 7 particular compound if you are monitoring 20 different things. 

### 8 You have to give up something to get something else, 

### 9 essentially, on that. And it wouldn't surprise me if there were 

### 10 a factory of ten different between the limit of detection for a 

### 11 single analysis, and one that looked at 20 different compounds. 

### 12 Would you agree with that? 

### 13 DR. MICHAEL BARTELS: Yes, however the method 

### 14 used in the earlier study was also a multi-compound assay. They 

### 15 had 20 or more analytes in the earlier 2002 method. 

### 16 DR. BARRY RYAN: Were they the same compounds? 

### 17 DR. MICHAEL BARTELS: No, in different 

### 18 classes. 

### 19 DR. BARRY RYAN: Were they in the same matrix? 

### 20 DR. MICHAEL BARTELS: Yes. Well, yes. When 

### 21 we talk about blood, actually, all these studies were done with 

### 22 serum or plasma.

### Page 312 1 DR. BARRY RYAN: Okay. 

### 2 DR. KENNETH PORTIER: Dr. Koutros, we haven't 

### 3 heard from you in a while. 

### 4 DR. STELLA KOUTROS: Yes, I wanted to say I 

### 5 know this comment really isn't in line with what we've been 

### 6 talking about in the last 15 or 20 minutes. But given that we 

### 7 just spoke about all of the integration of the epidemiology 

### 8 results, I wanted to make a comment on that. 

### 9 I appreciate the inclusion of adding the 

### 10 various biomarkers to the tables that were presented. I think 

### 11 that's actually a really useful thing. But I also wanted to say 

### 12 that there are still some limitations, I think, in the tables 

### 13 that were presented and it's hard to really look at the epi 

### 14 results in a table that just says, "Null, null, null, inverse, 

### 15 inverse." 

### 16 So I think what we probably have to talk about 

### 17 with respect to the epi results is why are interpretations 

### 18 different, not what all the results show. So for example, you 

### 19 gave a, you know, example about these statistical analyses and 

### 20 why you thought there was an issue with that. I didn't really 

### 21 understand that at all. 

### 22 So I think we have to really be on sort of the

### Page 313 1 tables. I know we have to synthesize data, but it's really sort 

### 2 of the specifics of our interpretation, I think, that are more 

### 3 important. 

### 4 DR. JULIE GOODMAN: And I would agree with 

### 5 that. My concern is that, the idea is that, you know, what I've 

### 6 been hearing not necessarily today, but just in general is that 

### 7 we have these three cohorts and we consistently see results. 

### 8 We found in our analysis that the results 

### 9 really consistent, and the only way to really judge whether they 

### 10 are -- I mean, you might disagree, but the only way to judge 

### 11 whether they are consistent or not is to lay them all out in 

### 12 that way, and they're not really laid out in a way that you can 

### 13 make that judgment. 

### 14 And so that's sort of why I'm proposing to 

### 15 look at it that way. And conveniently, they have all been laid 

### 16 out for you in our paper so, you know, you're welcome to look at 

### 17 that. 

### 18 And maybe it isn't the best way or you could 

### 19 come up with another way to do it, but that's just my concern. 

### 20 I want to make sure that it's all on the table so you can really 

### 21 evaluate whether there's consistency or not. 

### 22 DR. KENNETH PORTIER: Dr. Lu.

### Page 314 1 DR. CHENSHENG LU: I guess if there's 

### 2 opportunity for tomorrow morning, I would not keep the Panel 

### 3 here after six. So I would rather defer my question to tomorrow 

### 4 morning. 

### 5 DR. KENNETH PORTIER: And I appreciate that. 

### 6 I think what we will do is break at this point. We start again 

### 7 tomorrow morning at -- is it 9:00? 

### 8 SPEAKER: Yeah. 

### 9 DR. KENNETH PORTIER: I've got to double-check 

### 10 my agenda here. So tomorrow morning at 9:00, we will reconvene, 

### 11 and we'll see you then. 

### 12 (WHEREUPON, the MEETING recessed for the day 

### 13 at 6:00 p.m.) 

### 14 15 16 17 18 19 20 21 22

### Page 315 1 DR. KENNETH PORTIER: Welcome to the second 

### 2 day of this FIFRA Scientific Advisory Panel Meeting on 

### 3 Scientific issues associated with Chlorpyrifos Health Effects. 

### 4 I'm Ken Portier, the Chair of the SAP and 

### 5 Chairman of this session, and I welcome you to the continued 

### 6 discussion. We're going to continue this morning with a public 

### 7 presentation by Dow. But before we do this we're going to 

### 8 reintroduce the panel, as we normally do on our second day. 

### 9 We'll go around and introduce everyone. 

### 10 As I said, I'm Ken Portier. I'm a 

### 11 biostatistician and managing director of the Statistics and 

### 12 Evaluation Center at the American Cancer Society. 

### 13 DR. CAREY POPE: Good morning. My name is 

### 14 Carey Pope. I'm a professor of toxicology at Oklahoma State 

### 15 University. 

### 16 DR. STEPHEN KLAINE: Good morning. I'm Steve 

### 17 Klaine. I'm a professor at Clemson University and I direct the 

### 18 Institute of Environmental Toxicology. 

### 19 DR. MARTHA SANDY: I'm Martha Sandy. I'm a 

### 20 toxicologist with the Office of Environmental Health Hazard 

### 21 Assessment Cal/EPA. 

### 22 DR. HEATHER YOUNG: Heather Young,

### Page 316 1 epidemiologist, George Washington University School of Public 

### 2 Health and Health Services. 

### 3 DR. CHARLES VORHEES: Charles Vorhees, 

### 4 professor of pediatric in pediatric neurology at the University 

### 5 of Cincinnati and Children's Hospital. 

### 6 DR. JOHN VENA: John Vena, professor of 

### 7 epidemiology at the University of Georgia, College of Public 

### 8 Health. 

### 9 DR. ALVIN TERRY: Alvin Terry, a professor of 

### 10 pharmacology and toxicology at Georgia Health Sciences 

### 11 University. 

### 12 DR. BARRY RYAN: Barry Ryan, professor in 

### 13 environmental health at Rollins School of Public Health at Emory 

### 14 University. 

### 15 DR. WILLIAM POPENDORF: Will Popendorf, 

### 16 Emeritus professor in Industrial Hygiene at Utah State 

### 17 University. 

### 18 DR. BETTE MEEK: And Bette Meek, associate 

### 19 director in chemical risk assessment at McLaughlin Center, 

### 20 University of Ottawa. 

### 21 DR. CHENSHENG LU: Good morning. Alex Lu. 

### 22 I'm an associate professor from Harvard School of Public Health.

### Page 317 1 DR. JEAN HARRY: Jean Harry, neurotoxicologist 

### 2 at NIHS. 

### 3 DR. ELLEN GOLD: Ellen Gold. I'm professor 

### 4 and Chair of the Department of Public Health Sciences at the 

### 5 School of Medicine at UC Davis. 

### 6 DR. ABBY COLLIER: Abby Collier, associate 

### 7 professor of pharmacology at the University of Hawaii, School of 

### 8 Medicine. 

### 9 DR. RUSSELL CARR: Russell Carr, associate 

### 10 professor of toxicology, MSU State University College of 

### 11 Veterinary Medicine. 

### 12 DR. BRIAN BUCKLEY: Brian Buckley, executive 

### 13 director of laboratories, the Environmental and Occupational 

### 14 Health Sciences Institute, Rutgers University and a member of 

### 15 the graduate faculty of Environmental Science, School of Public 

### 16 Health and Toxicology. 

### 17 DR. MICHAEL ASCHNER: Michael Aschner, I'm 

### 18 professor of pediatrics and pharmacology at Vanderbilt 

### 19 University Medical Center. 

### 20 DR. KENNETH PORTIER: Thank you all. Before 

### 21 we get started, I'd ask Dr. Jenkins here if he's got any opening 

### 22 business remarks.

### Page 318 1 DR. FRED JENKINS: Good morning, everyone. 

### 2 I'm Fred Jenkins, designated Federal Official for this meeting. 

### 3 This morning is the last opportunity for public comments. Our 

### 4 public comments will be closing after this morning. 

### 5 If you are here and scheduled to give a public 

### 6 comment, particularly after Dow's presentations, please see me 

### 7 so we can have your presentation uploaded to the computer - me 

### 8 or someone else on the SAP staff. Thank you. 

### 9 DR. KENNETH PORTIER: Thank you very much. 

### 10 I'll remind everyone, this is a public meeting and it's being 

### 11 recorded and I ask the panel and all the speakers to identify 

### 12 themselves and to use the mic. At this point, I'll turn to Dr. 

### 13 Juberg for any opening remarks in this continuing public 

### 14 presentation from Dow. Dr. Juberg. 

### 15 DR. DALAND JUBERG: Thank you, Dr. Portier and 

### 16 members of the panel. We appreciate the opportunity to be here 

### 17 again before you and thank you for your time. We have one more 

### 18 Dow presentation. I'll have some concluding remarks, but there 

### 19 will be another presentation in between those. I did have just 

### 20 a couple of clarifying points from yesterday. 

### 21 Any questions on pre and post exposure, 

### 22 relative to the voluntary withdrawal and how those may have

### Page 319 1 shifted or affected scores of various magnitude and types. Dr. 

### 2 Carol Burns has a couple of slides. We're not requesting time 

### 3 for those, but if that's clarification for you all, please make 

### 4 that request. 

### 5 Similarly, Dr. Paul Price, who's not up here, 

### 6 we haven't requested time. He's got some, you know, expansion 

### 7 of overall exposure between Columbia, all the way up to other 

### 8 metrics. If Dr. Bartles doesn't address those today, I would 

### 9 encourage you -- we have those available at your disposal if 

### 10 you're wanting those. 

### 11 And then finally, I would just encourage, 

### 12 we've submitted comments over the course of many years and we 

### 13 have some of the Sentinel publications or the Eaton Lee and 

### 14 Pruitt papers. I know it's been a very challenging four to six 

### 15 to eight weeks to get all this under your belt. If there's 

### 16 nothing else, I would encourage to read some of those, along 

### 17 with our comments or some questions yesterday raised that I 

### 18 think some of the points we have, from our perspectives, have 

### 19 given insight or input on. So I would encourage you to look at 

### 20 those materials. 

### 21 Finally, all our speakers remain available 

### 22 today. Again, for any clarifying points that you may have.

### Page 320 1 With that, I would like to turn it, at this point, over to Dr. 

### 2 Michael Bartles. 

### 3 DR. MICHAEL BARTLES: Good morning. Thank you 

### 4 for giving me the opportunity to speak today. My name is Dr. 

### 5 Michael Bartles. A little background on my technical expertise: 

### 6 I'm a scientist at Dow Chemical Toxicology Laboratory. I've 

### 7 worked in the area of metabolism and pharmacokinetics and 

### 8 biomonitoring method development for a number of years. 

### 9 I've published on biomonitoring methods for 

### 10 the TCBY metabolite of chlorpyrifos, chlorpyrifos and the oxon 

### 11 metabolite in blood and other tissues. I've collaborated with 

### 12 the EPA on cross-validation of biomonitoring methods and I've 

### 13 also worked with the CDC on biomonitoring methods for other 

### 14 molecules. 

### 15 What I'm going to speak about today is the use 

### 16 of the physiological base kinetic model that was presented in 

### 17 last year's SAP to help estimate in vitro exposures from some of 

### 18 the in vitro substrate concentrations used in the many 

### 19 publications that have been discussed and are on the topic of 

### 20 chlorpyrifos non-cholinergic effects. 

### 21 My talk is responsive to Charge Questions 1 

### 22 and 2.2. Chlorpyrifos is well known to inhibit the activity of

### Page 321 1 numerous esterases in mammals. An inhibition of cholinesterase 

### 2 is the most sensitive biomarker of chlorpyrifos exposure and 

### 3 biological effects. 

### 4 The goal of the evaluation I'm discussing 

### 5 today is to show that the estimates in vivo exposures derived 

### 6 from in vitro assays of non-cholinergic effects are generally at 

### 7 or above levels known to cause cholinesterase inhibition. 

### 8 To start off, I'll go over a little chemistry. 

### 9 Chlorpyrifos shown at the top of the slide is known to be 

### 10 highly metabolized, especially by the oral route through an 

### 11 activated intermediate to give primarily the trichlorpyridinol 

### 12 metabolite and the corresponding diethyl phosphates. This 

### 13 metabolite is a variety of conjugates. It is the primary 

### 14 urinary biomarker used in most exposure study estimates. 

### 15 Chlorpyrifos itself and the oxon metabolite 

### 16 are only minor metabolites in blood. What's circulating is 

### 17 generally greater than 99 percent trichlorpyridinol. The trace 

### 18 levels of oxon metabolite that are formed are generally rapidly 

### 19 hydrolyzed. And this metabolite is also responsible for 

### 20 phosphorylation of using residue of cholinesterase, resulting in 

### 21 cholinesterase inhibition. 

### 22 The high metabolism of chlorpyrifos has been

### Page 322 1 shown to be consistent across a number of animal studies and 

### 2 also across a serious of doses it's been shown that above about 

### 3 a milligram per kilogram, there's a more substantial saturation 

### 4 of this metabolism. 

### 5 What we have in the Y-axis of this graph is 

### 6 the ratio of the TCPy to chlorpyrifos in blood. And as I said 

### 7 before, certainly at the lower doses, the chlorpyrifos -- the 

### 8 TCP of the chlorpyrifos ratio is generally 100 or higher. Above 

### 9 a milligram, it tends to drop, most in young animals, adult 

### 10 animals. Most of these are old studies. There are some data, 

### 11 also, from an inhalation study we recently conducted. 

### 12 Back to the oxon, as I mentioned before, the 

### 13 low levels of oxon that are formed are known to phosphorylate, 

### 14 both albuterol and acetylcholinesterases. This metabolite has 

### 15 also been shown in a variety of numerous recent publications to 

### 16 chemically react with a number of different amino acid sites on 

### 17 a variety of different proteins. And this is probably not a 

### 18 complete list, but these are some of the representative recent 

### 19 indentified targets of various proteins at various sites. So 

### 20 overall, what this tells us is that the oxon metabolite, if is 

### 21 present, can react with a variety of proteins. 

### 22 Now, numerous biological effects have been

### Page 323 1 reported for both chlorpyrifos and the oxon, following in vitro 

### 2 incubations with cells, homogenates, purified proteins. There 

### 3 are several exampling points are accidental outgrowth, 

### 4 cytotoxicity, cholinesterase inhibition, even genomic response 

### 5 changes. 

### 6 Most in vitro studies have been conducted with 

### 7 the oxon only or have shown that the oxon is substantially more 

### 8 active than chlorpyrifos. This summary here is consistent with 

### 9 the fact that the chlorpyrifos oxon is quite reactive with 

### 10 protein and may elicit its effects through that mechanism. 

### 11 To properly assess how these in vitro effects 

### 12 relate to human health relevance, it's important to try and 

### 13 correlate what these in vitro or substrate exposures are to the 

### 14 various preparations, with in vivo exposure levels. 

### 15 To this estimation, we used a validated, 

### 16 physiological-based kinetic model with pharmacodynamic end 

### 17 points that was well-discussed and reviewed by the 2011 SAP. 

### 18 This model accounts for saturable processes 

### 19 like absorption, metabolism. It accommodates life stages from a 

### 20 few weeks old through adulthood. Also, it can be used in a 

### 21 Monte Carlo fashion, incorporate variations in physiology and 

### 22 metabolism for assessment of exposure across populations. The

### Page 324 1 cartoon of this model design, which was presented by the EPA 

### 2 yesterday, as shown here, fairly classic. The original adult 

### 3 model has multiple compartments for both chlorpyrifos and the 

### 4 oxon for tissue distribution; metabolism of the deformed 

### 5 trichlorpyridinol that occurs from both chemicals and is 

### 6 excreted out of the -- in the model as urinary elimination in a 

### 7 one compartment fashion. The model also includes parameters for 

### 8 estimation of inhibition and regeneration of esterases. 

### 9 Beyond the first 2002 version of this model, 

### 10 additional modifications have been made. In summary, what was 

### 11 presented last year was a life stage version of this model in 

### 12 which the physiology across all tissue compartments was scaled 

### 13 with age and body weight. The fat compartment is also varied, 

### 14 based on population, distribution, which indirectly affected the 

### 15 slowly perfused compartment volume. Blood to volume also were 

### 16 scaled. 

### 17 Metabolism rates in brain, liver, and blood 

### 18 were also varied, based on tissue size in brain and liver and 

### 19 logged normally distributed across the range that's been 

### 20 identified and compared to the literature values. 

### 21 In addition, PAN1 hydrolysis activity in the 

### 22 blood was scaled with both age and blood volume and varied,

### Page 325 1 based on log distributions. More details on these are in last 

### 2 year's report, which is available in the docket and a paper by 

### 3 Smith 2011. 

### 4 The output of this model is what we're using 

### 5 for this evaluation I'm discussing today. What we have here is 

### 6 a graph which shows in the top two bands the estimates of 

### 7 chlorpyrifos blood levels, following a single oral dose of 

### 8 chlorpyrifos in micromolar concentrations against dose. These 

### 9 are population estimates with simulated groups of 5,000 

### 10 individuals, nephron physiology and metabolism. 

### 11 The blue data represent predicted blood levels 

### 12 from 30-year-old adults. The corresponding green band here 

### 13 represents the chlorpyrifos levels in a three-year-old 

### 14 population. These top two bands are for chlorpyrifos. The 

### 15 bottom two bands are predicted levels of chlorpyrifos oxon 

### 16 metabolite in blood; again, in blue for adults and in young 

### 17 children in green. 

### 18 You can see here an increase in the scattering 

### 19 and a slight super linearity in the kinetics, about a 

### 20 half-milligram or higher, per kilogram dose. This is consistent 

### 21 with the saturation of metabolism that I pointed earlier from 

### 22 several of our animal studies.

### Page 326 1 As points of comparison, in addition to the 

### 2 micromolar concentrations, we present several of these dose 

### 3 level concentrations in terms of nanograms per gram for 

### 4 comparison to existing biomonitoring cohort data. 3.5 nanograms 

### 5 per gram is the equivalent to .01 micromolar and the only order 

### 6 of magnitude lower is the 3.5 picogram per gram concentrations. 

### 7 8 As presented by the EPA yesterday, the Nolan 

### 9 biomonitoring set had blood levels in this range, consistent 

### 10 with a half-milligram per dose administered to those human 

### 11 volunteers. The Burns 2012 data has blood levels a little off 

### 12 the chart here, but in this range, following along the axis, and 

### 13 the one human cohort study that measured blood levels. In the 

### 14 Columbia experiments, it had blood levels off the graph here, 

### 15 about two or three orders of magnitude below the lowest level 

### 16 presented on this graph. 

### 17 Now, utilizing this graph to interpret in 

### 18 vitro data requires that we get some estimate of chlorpyrifos or 

### 19 cholinesterase inhibition. There have been a lot of discussions 

### 20 and presentations on what the accrued and repeat cholinesterase 

### 21 inhibition points of departure are. The model output, which is 

### 22 a little conservative here, shows 10 percent inhibition for RBC

### Page 327 1 cholinesterase at about .1 milligrams per kilogram, and brain at 

### 2 about .5. 

### 3 So for the remaining use of this graph, I have 

### 4 a gold bar indicating cholinesterase inhibition range and 

### 5 starting at .1 milligram and going higher. The inhibition 

### 6 curves are based on the right Y-axis, which is cholinesterase 

### 7 inhibition from 100 to zero percent of control. 

### 8 Okay. So if we take a look at a selection of 

### 9 recent in vitro biological effects data where people looked at, 

### 10 in the top three lines, cholinesterase inhibition -- excuse me 

### 11 -- and the in vitro assays, or the bottom lines are various in 

### 12 vitro, generally a cellular end points, often dealing with 

### 13 neuronal cells. 

### 14 You can see that I've presented these data in 

### 15 terms of test material and no effect concentration for the in 

### 16 vitro end point for both chlorpyrifos, in the left two columns, 

### 17 and the oxon on the right. 

### 18 I also categorized the test material exposures 

### 19 based on the presence or absence of serum in the culture media. 

### 20 Initially, what you're going to observe from these data are that 

### 21 most of assays have been conducted with either the oxon or have 

### 22 shown that the oxon is substantially more active than the parent

### Page 328 1 chlorpyrifos. Generally, several orders of magnitude lower 

### 2 effect levels. 

### 3 Also, in the case of this data set and most of 

### 4 the publications, there are generally an absence of serum, 

### 5 certainly in the neuronal culture, incubations. And we 

### 6 generally see lower effect levels in the absence of serums, 

### 7 often in the low animal concentrations versus micromolar effect 

### 8 levels in the presence of serum. 

### 9 Now, if we take one example of cholinesterase 

### 10 inhibition in the first publication and these eight references 

### 11 are the first eight references in my reference slide at the end 

### 12 of my presentation. 

### 13 If we take the first example of cholinesterase 

### 14 inhibition in the presence of serum at one to five micromolar 

### 15 for a no effect concentration, go back to our predicted graph of 

### 16 blood levels and assume that immediate concentrations are 

### 17 synonymous with blood concentrations, in terms of exposure to 

### 18 the tissues their selves, you can see that one to five 

### 19 micromolar on the Y-axis in a simple read-across at the top of 

### 20 prediction of oxon levels in the population, which would sort of 

### 21 be the 95th percentile sensitive subpopulations. 

### 22 That one micromolar oxon concentration in

### Page 329 1 vitro correlates to a 10 milligram per kilogram does in vivo. 

### 2 And the five, correspondently, it's off this graph, but well 

### 3 above 10 milligram per kilogram. This is certainly above any 

### 4 cholinesterase points of departure that have been measured in 

### 5 animal studies or the few human studies where they've shown 

### 6 cholinesterase inhibition. And again, these bands are 

### 7 chlorpyrifos and then the bottom one is the oxon, which is being 

### 8 used for this read-across. 

### 9 Doing this kind of read-across can give us an 

### 10 estimate of what in vivo exposures are relative to in vitro 

### 11 concentrations, but there are some confounders that have to be 

### 12 taken into consideration when utilizing this kind of approach. 

### 13 As I mentioned earlier, the protein is often 

### 14 absent from some of the culture media. Since chlorpyrifos is 

### 15 highly protein-bound, greater than 99 percent, these no effect 

### 16 levels can represent 100 percent above availability, so to 

### 17 speak, relative to the one percent that's available out of 

### 18 blood. 

### 19 So for the purposes of the read-across that 

### 20 I'm going and presenting after this, there's a 100-fold 

### 21 correction for serum-free culture medium experiments. For 

### 22 example, 10 nanomolar serum-free would be equivalent to 1,000

### Page 330 1 nanomolar in blood. 

### 2 Second point that DMSO is often used as a 

### 3 vehicle for in vitro media incubations. This is a very useful 

### 4 solvent. It works well and it is used quite widely in a lot of 

### 5 in vitro study types. The problem with it is it's not an inert 

### 6 solvent. It does have pharmacological activity. The 

### 7 concentrations used that can range from .1 to .5 percent of 

### 8 total media volume are comparable to in vivo dose levels of 

### 9 1,000 to 5,000 milligrams per kilogram, assuming a volume 

### 10 distribution of 1. These concentrations are not outside the 

### 11 range of acute tox effects for this solvent in rodents, which 

### 12 have been reported in a review in the past to range from 4,000 

### 13 to 20,000 milligrams per kilogram. 

### 14 Finally, some of the end points, while very 

### 15 sensitive may not be specific. Specifically, one assay that's 

### 16 on the bottom of the table I'm using, utilizing an ELISA-based 

### 17 assay to look at increases in phosphorylation of the CREB 

### 18 protein. This phosphorylased version of the protein, which is 

### 19 measured by an ELISA assay, could potentially have been 

### 20 confounded by the fact the chlorpyrifos sites on itself has been 

### 21 just shown to chemically react with a wide variety of protein 

### 22 and therefore, the diethylphosphorylated protein, which has been

### Page 331 1 reported in vivo and in vitro, could've cross-reacted with a 

### 2 native phosphorylation for this protein and given some 

### 3 artifactual results. 

### 4 So with these confounders in mind, if we go 

### 5 back to the table that we had, using read-across approach that I 

### 6 did for the first line, for the other examples on the table, we 

### 7 see that most of this data correspond back to in vivo exposures 

### 8 of 10 milligrams per kilogram or something in the milligram per 

### 9 kilogram range. 

### 10 There are a few examples that are lower than 

### 11 that, that when we classify or qualify these data with the fact 

### 12 that some of them use DMSO as vehicles. We can see that some of 

### 13 the lower effect levels were when DMSO is used as a solvent in 

### 14 the medium and this may have compromised the effect levels. We 

### 15 don't know that yet because we don't have corresponding data 

### 16 with other solvents in that test system. We do know that DMSO 

### 17 can synergistically enhance cholinesterase effects in vivo, and 

### 18 it's been shown to have effects on membrane permeability for 

### 19 chemicals. 

### 20 In addition, I mentioned that phosphorylation 

### 21 of the CREB protein, which the authors report a fairly low 

### 22 effect level could potentially been compromised by

### Page 332 1 cross-reactivity in the end point of the enzyme-based assay. 

### 2 Regardless of the qualifiers, what we tend to 

### 3 see then that most estimates of in vivo exposures from these in 

### 4 vitro media substrate concentrations are at or above the levels 

### 5 required for cholinesterase inhibition for in vitro and in vivo. 

### 6 So beyond this extrapolation, if we take one 

### 7 example from axonal growth in Reference 4 here, look at effect 

### 8 levels that are in the lower milligram per kilogram range, we 

### 9 can see that some of these effects are, although reported at 

### 10 lower levels, in vitro, actually have higher effect levels, in 

### 11 vivo, in some type of in vivo blood system. The example I chose 

### 12 there, Yang, et al. (2008) reported a decrease in axonal growth 

### 13 and in vitro substrate concentrations in picomolar 

### 14 concentration, 1 to 10 picomolar of the oxon. 

### 15 As a point of reference, these authors found 

### 16 the cholinesterase inhibition was 10-fold higher than the axonal 

### 17 effect at 10 to 100 nanomolar. When this group evaluated these 

### 18 type of effects in vivo in the zebra fish, which is a nice model 

### 19 of in vivo animal with little metabolic capability, they showed 

### 20 that the oxon-based cholinesterase inhibition was substantially 

### 21 higher in vivo than in vitro; it was 10 to 30 nanomolar versus 

### 22 .01 to .1 in vitro. The neuronal effects were also

### Page 333 1 substantially higher at 10 to 1,000 nanomolar in vivo in the 

### 2 zebra fish model versus 10 to 30 nanomolar for the 

### 3 cholinesterase inhibition. 

### 4 So in summary, there are numerous in vitro 

### 5 studies that report non-cholinergic effects from chlorpyrifos 

### 6 and the oxon. The effect levels are generally and substantially 

### 7 lower with the oxon metabolite, consistent with the chemical 

### 8 reactivity of this material with numerous proteins. 

### 9 There's another good review of this topic 

### 10 Flasco, et al. last year. Estimates of in vivo exposures from a 

### 11 variety of in vitro data can be determined with a validated life 

### 12 stage-based, physiological-based kinetic model with 

### 13 pharmacodynamic end points. Utilizing this approach to estimate 

### 14 in vivo exposures from in vitro substrate concentration show 

### 15 that nearly all the in vitro experimental conditions were 

### 16 conducted at levels that were at or above levels that caused 

### 17 cholinesterase inhibition in vivo. 

### 18 Comparisons of some studies have shown that 

### 19 there are few non-cholinergic effects seen in vivo or at higher 

### 20 exposure levels than those reported in vitro. And as a result 

### 21 of this evaluation, we agree with the agency that the 

### 22 cholinesterase inhibition seen in animals and human is still the

### Page 334 1 best biomarker of cholinergic and non-cholinergic effects to be 

### 2 used for risk assessment purposes. And as I mentioned, on the 

### 3 last slide I have References 1 through 8, which are out of the 

### 4 table and additional references beyond that. 

### 5 Questions? 

### 6 DR. KENNETH PORTIER: We would open it up to 

### 7 any questions from the panel. Dr. Collier. 

### 8 DR. ABBY COLLIER: Hi, Abby Collier. May I 

### 9 have two points of clarification, please? 

### 10 The first one is on your second slide where 

### 11 you showed the metabolic pathways. Can you comment on which 

### 12 conjugation enzymes are more important? 

### 13 Is it sulfonation or glucuronidation? Do you 

### 14 know? 

### 15 DR. MICHAEL BARTLES: Both are farmed. I want 

### 16 to say the glucuronide is a little more prevalent, but since 

### 17 it's known that there are individual differences between those 

### 18 when different laboratories have done biomonitoring of the TCP 

### 19 metabolite, they've used enzymes that are mixtures of both 

### 20 glucuronidase and sulfatase, or in our case, we've done acid 

### 21 hydrolysis and have shown complete cleavage of both conjugates 

### 22 under the conditions used.

### Page 335 1 DR. ABBY COLLIER: And my question relates to 

### 2 your variability in your model. And you said that you varied 

### 3 PAN1 with age, blood volume, and volume of distributions, 

### 4 basically, so you can vary the PAN1. Can you also do that for 

### 5 your P450 divisions and have you looked at that? 

### 6 Because as you probably well know, the P450s 

### 7 are not always present at birth either, and they vary up to a 

### 8 couple of years of age. So for the young kids that might be 

### 9 important. 

### 10 DR. MICHAEL BARTLES: I'd refer you 

### 11 specifically to the Smith paper, which is one of my references 

### 12 in the SAP report, which is in the docket from last year. Both 

### 13 PAN1 and the CYPs were varied with age and with physiology and 

### 14 there's a very good description of that. We also did a 

### 15 comparison of our experimental results with literature data for 

### 16 CYP variations for this type of metabolism for organophosphates. 

### 17 18 DR. ALVIN TERRY: So I think one point of 

### 19 clarification in the culture studies where DMSO was utilized, 

### 20 it's also in the control samples. So making the argument that 

### 21 there's a big DMSO effect wouldn't be confirmed in the study 

### 22 where the controls didn't show any effect.

### Page 336 1 DR. MICHAEL BARTLES: I agree that the 

### 2 controls were generally negative in the end points measured; 

### 3 however, there's a big body of literature on the effects of DMSO 

### 4 in vivo and in vitro used in culture media or as a vehicle in 

### 5 vivo for a variety of administration routes. 

### 6 There have been several reported studies where 

### 7 people have shown synergistic enhancement of a cholinesterase 

### 8 inhibition with DMSO used as a vehicle. There are also two sort 

### 9 of sets of experiments either within a paper or within two 

### 10 papers for in vitro systems where the authors had discussed DMSO 

### 11 altering the effects of the system. One is an ROS paper by 

### 12 Jeter, out of our laboratory and then there was another 

### 13 discussion by Prendergast, where they compared their data to an 

### 14 earlier reference that had lower no effect levels and had DMSO 

### 15 in their culture systems. 

### 16 So there is a precedent for both in vitro and 

### 17 in vivo with this test material. I agree that the controls 

### 18 within the experimental designs have been negative. Some of the 

### 19 effects seen in vivo, though, occur slightly after some of the 

### 20 in vivo sacrifice times. We have a whole separate response 

### 21 we've given to the EPA in the past, and I would be happy to talk 

### 22 about it further offline.

### Page 337 1 DR. PORTIER: Dr. Harry. 

### 2 DR. JEAN HARRY: Jean Harry. So the approach 

### 3 is usually taken if you do use DMSO and you find an effecting 

### 4 culture, is to determine whether your effect is DMSO dependent 

### 5 because if you do open the cell membrane, you allow greater 

### 6 permeability in there. 

### 7 In the studies that you were outlining and 

### 8 that you've looked at, were here efforts made to see if those 

### 9 effects were indeed DMSO dependent? You use a different solvent 

### 10 if you did or did or did not use it in serum. I mean, neuronal 

### 11 cells don't see serum. So that creates another whole different 

### 12 problem in these things. Did you look to see whether these some 

### 13 of these specs were truly DMSO dependent or just sort of assume 

### 14 that it might've been a DMSO confounder? 

### 15 DR. MICHAEL BARTLES: Right now we're 

### 16 mostly assuming it. There haven't been a lot of control 

### 17 experiments where did with and without. Most of the studies use 

### 18 that as a test material and the controls were negative. If it 

### 19 enhances membrane permeability for test material, though, if the 

### 20 test material is not present in the control, it's not a full 

### 21 evaluation of the changes to the cell. 

### 22 DR. KENNETH PORTIER: Dr. Buckley.

### Page 338 1 DR. BRIAN BUCKLEY: How does the model account 

### 2 for interspecies difference of the glucuronidation and sulfation 

### 3 as rat models or rats themselves, tend to sulfate more than 

### 4 humans? 

### 5 DR. MICHAEL BARTLES: Let me go back to the 

### 6 cartoon here. As published in 2002, this is an interspecies 

### 7 PBPK model. As I mentioned earlier, formation of the 

### 8 trichlorpyridinol occurs from both the chlorpyrifos by direct 

### 9 dearylation and by hydrolysis of the oxon. 

### 10 The TCP, once formed, as a free phenol is 

### 11 assumed to be virtually all conjugated and excreted as one or 

### 12 the other. There are no specific rates for conjugation. 

### 13 There's just an elimination once formed. And then the methods 

### 14 used to measure TCPy, again, like I've stated, either for 

### 15 enzyme-based hydrolysis or chemical hydrolysis has been 

### 16 validated to show that there are complete hydrolysis of either 

### 17 conjugate. 

### 18 DR. BRIAN BUCKLEY: But if the conjugation 

### 19 rate was rapid with respect in one species, say, rat versus 

### 20 human, then the oxon concentration would naturally be less in 

### 21 the rat than the human, correct? 

### 22 DR. MICHAEL BARTLES: The oxon concentration?

### Page 339 1 DR. BRIAN BUCKLEY: Sure. If you follow a 

### 2 pathway and you're grabbing that TCPy concentration as rapidly 

### 3 as it forms, then the oxon is going to change the TCPy more 

### 4 rapidly, correct? 

### 5 I mean, that's chemically collaborative, 

### 6 right? You start pulling from one end, you're going to pull the 

### 7 formation from the other, correct? 

### 8 DR. MICHAEL BARTLES: Well, it depends on 

### 9 which ends the step rate is limiting, oxon hydrolysis or TCP 

### 10 conjugation. 

### 11 DR. BRIAN BUCKLEY: Right. And what I'm 

### 12 saying is if TCP conjugation is not a rate limiting step, then 

### 13 the oxon will form TCPy potentially more rapidly, correct? It's 

### 14 a concentration that TCPy will continue to decrease as its 

### 15 conjugated. 

### 16 DR. MICHAEL BARTLES: Which department are you 

### 17 talking about, blood or urine? 

### 18 DR. BRIAN BUCKLEY: Blood at this point in 

### 19 time, yeah. 

### 20 DR. MICHAEL BARTLES: Well, yeah. The blood 

### 21 concentrations will drop as the material gets more highly 

### 22 conjugated. It'll eliminate in a different fashion.

### Page 340 1 DR. BRIAN BUCKLEY: So if there's a different 

### 2 kinetic pathway between the TCPy conjugation in a rat and a 

### 3 human, then it would be a more protective effect because the 

### 4 oxon concentrations at any given time would potentially be less 

### 5 for a given dose, correct? 

### 6 DR. MICHAEL BARTLES: Right. But when we've 

### 7 measured oxon hydrolysis rates, we've done that in the absence 

### 8 of conjugation. We've looked either in liver or blood 

### 9 preparations. So those enzymatic rates aren't relevant for 

### 10 looking interspecies differences in hydrolysis. And we have 

### 11 seen those, and those are incorporated into the model. 

### 12 DR. CAREY POPE: Mike, the point about the P 

### 13 CREB phosphorylation, is it possible like an adduct? I mean, 

### 14 that also sounds, potentially, kind of important if it is 

### 15 adducting CREB as opposed to modifying its phosphorylation. 

### 16 DR. MICHAEL BARTLES: Oh. The fact that there 

### 17 could be chemical modification to proteins. Yes, that's been 

### 18 well-discussed in the literature. The importance is at what 

### 19 concentration that does that occur because as I described in the 

### 20 slide back here, the oxon metabolite, if present, will react 

### 21 with different proteins. We've shown that metabolism of the 

### 22 chlorpyrifos itself, to either the TCP or oxon is

### Page 341 1 concentration-dependent and saturates it higher animal level 

### 2 toxicity study dose levels. You have much higher rates of 

### 3 metabolism, 2 TCPy and hydrolysis rates of oxon to TCPy is the 

### 4 in vivo dose levels get lower. 

### 5 The use of a physiological-based kinetic model 

### 6 will let us predict tissue dosimetry of the chlorpyrifos and on 

### 7 the oxon. So I think the important useful take-home from this 

### 8 estimation evaluation is that if the oxon is eliciting 

### 9 cholinergic and non-cholinergic effects through presence of 

### 10 oxon, then the cholinesterase inhibition in the tissues is a 

### 11 good biomarker for oxon activity against other end points in 

### 12 that tissue. 

### 13 DR. ABBY COLLIER: Abby Collier. Just to 

### 14 follow-up on Dr. Buckley's comment, point of clarification, 

### 15 you're not scaling the conjugative metabolism at with age then. 

### 16 Yes or no? 

### 17 DR. MICHAEL BARTLES: The conjugation rates of 

### 18 TCPy, no, I do not think we are. 

### 19 DR. ABBY COLLIER: You're not scaling 

### 20 clearance with age. Okay. Thank you. 

### 21 DR. KENNETH PORTIER: Last chance. No? Thank 

### 22 you very much then, Dr. Bartles. The next public commenter is

### Page 342 1 Dr. Li from Exponent. 

### 2 Dr. Li, I think we have copies of your slides 

### 3 and then two other articles; is that right? 

### 4 DR. ABBY LI: Yes, there was a paper that -- 

### 5 DR. KENNETH PORTIER: Press the mic, please. 

### 6 DR. ABBY LI: Oh. 

### 7 DR. KENNETH PORTIER: Thank you. 

### 8 DR. ABBY LI: Yes. There's a paper that was 

### 9 recently published that we got permission from the publisher to 

### 10 distribute here. I think they're waiting for my slides to come 

### 11 up. 

### 12 The other thing is that I distributed updated 

### 13 comments. My colleague, Dr. Carole Kimmel, is a co-author on 

### 14 our comments. She has been able to have the time to have her 

### 15 input and these are the updated comments. 

### 16 Okay. I might need some training here. Thank 

### 17 you very much for allowing me to participate in this SAP. I'm 

### 18 going to focus on Charge Questions 1 through 3, with an emphasis 

### 19 on the in vivo neurodevelopmental studies and risk assessment. 

### 20 I'm been asked by Dow AgroScience to make independent comments, 

### 21 and these oral comments have been developed by Dr. Carole Kimmel 

### 22 and me. We are both from Exponent Health Sciences.

### Page 343 1 Dr. Carole Kimmel is an expert on 

### 2 developmental and reprotoxicology and risk assessment. She was 

### 3 previously a senior scientist at EPA, working in this area and 

### 4 she was a pioneer in participating in the conduct of 

### 5 developmental neural studies that formed the basis for the EPA 

### 6 Guidelines. 

### 7 I've had many years of experience conducting 

### 8 and devaluating adult in developmental neurotoxicity studies and 

### 9 have a lot of experience with pesticide risk assessment and I 

### 10 was an author on the NCR's Tox 21 Report. 

### 11 So today, what I'd like to do is first 

### 12 summarize what we believe are the key risk assessment issues; 

### 13 show you some data on cholinesterase inhibition important to 

### 14 question of relative sensitivity with non-cholinergic modes of 

### 15 action. 

### 16 To respond to the Charge Questions 1 through 

### 17 3, with examples of issues to consider. And what I hope to do 

### 18 is to provide a different perspective than that which was 

### 19 already presented in the EPA Science Advisory Panel Issue paper. 

### 20 And I think Dr. Ginger Moser did an excellent job reviewing the 

### 21 data. I'd like to not show the same data that she has shown. I 

### 22 just want to make it clear that we agree with much of what's in

### Page 344 1 there and what we're trying to do is pick out those things that 

### 2 we might help you to see the data from a different angle. And 

### 3 finally, to end my talk with some concluding remarks. 

### 4 There are relatively few studies with dose 

### 5 response data on both cholinesterase inhibition and neural 

### 6 behavioral effects and neurodevelopmental effects with 

### 7 non-cholinergic end points. But you can take a look at the 

### 8 entire data set and there's pretty good evidence that there's 

### 9 greater sensitivity of RBC or brain cholinesterase inhibition in 

### 10 the dams or pups, compared to that for neural behavioral and 

### 11 neurodevelopmental effects. 

### 12 When we evaluate the data, as I will describe 

### 13 later, we come to the conclusion that the lower L, N-O-A-E-L -- 

### 14 that means an adverse effect level for neurobehavioral effects 

### 15 is around one milligram per kilogram per day. And the BMDL10 

### 16 for cholinesterase inhibition is .03. So our overall conclusion 

### 17 is that cholinesterase inhibition is the most sensitive end 

### 18 point and protective of other effects. 

### 19 So now I'm going to show you some of the data. 

### 20 I purposely picked some of the data from the labs that are 

### 21 spending the most time evaluating non-cholinergic modes of 

### 22 action and hypothesize that these might be independent of

### Page 345 1 cholinesterase inhibition. These, you have to go back into the 

### 2 early literature where some of these cholinesterase inhibition 

### 3 studies were conducted because they weren't conducted 

### 4 concurrently in the later studies. 

### 5 So here you can see at PND1, you get 80 

### 6 percent brain cholinesterase inhibition, two hours after dosing, 

### 7 with one milligram per kilogram per day, SC. That's 

### 8 subcutaneous DMSO. By four hours, this drops by half to 40 

### 9 percent. So the detection of cholinesterase inhibition depends 

### 10 on the time of sacrifice after dosing. 

### 11 You can see here that 24 hours after dosing at 

### 12 one milligram per kilogram per day from PND, 1 through 4, you 

### 13 get 20 percent cholinesterase inhibition. This means that we're 

### 14 getting significant brain cholinesterase inhibition, despite the 

### 15 24-hour time point. And you can imagine what might happen at 

### 16 earlier time points. 

### 17 There's very little data on cholinesterase 

### 18 inhibition after gestational exposure in the fetus, but there's 

### 19 one study that showed that at two milligrams per kilogram per 

### 20 day, and this is 24 hours after the dose, you get 20 percent 

### 21 brain cholinesterase inhibition. 

### 22 So you have to ask the question, if you looked

### Page 346 1 at it earlier, would it be a good bet that you might see 

### 2 something at one, under the conditions that they're dosing? 

### 3 So when you take a look at the entire data 

### 4 set, though, this is just a few of the studies that are reported 

### 5 in EPA'S Table 4. And this highlights that the most sensitive 

### 6 cholinesterase inhibition, BMDL is .03. This data looks at 

### 7 pups, fetus -- it's just a lot of data there that they can pick 

### 8 out this .03 as being more sensitive than all the other ends 

### 9 points. 

### 10 So now let me move right into the charge 

### 11 questions. Please comment on the Agency's preliminary 

### 12 conclusion that cholinesterase data remain the most robust 

### 13 source of data for deriving points of departure for 

### 14 chlorpyrifos. 

### 15 We agree with this conclusion. For 

### 16 cholinesterase inhibition, you have the advantage of many 

### 17 studies, as I've described earlier, multiple dose levels and 

### 18 really good dose response data that's amenable to quantitative 

### 19 modeling, and then you have many oral studies at different ages, 

### 20 which is the most relevant for the general population that gets 

### 21 its exposure primarily for dietary exposures. 

### 22 In the neurodevelopmental studies, especially

### Page 347 1 the non-cholinergic data, most of the studies have one or two 

### 2 dose levels. The effects are often just at one dose level or 

### 3 not dose-related. So not amenable to quantitative modeling, and 

### 4 you're pretty much left with having to say you have an effect 

### 5 level at one milligram per kilogram per day and derive points of 

### 6 departure from that. 

### 7 A point that I think is really important is 

### 8 that the majority of the mechanistic studies are subcutaneous 

### 9 DMSO. I think that -- well, we -- Carole and I -- believe that 

### 10 the route of administration is very relevant for deriving points 

### 11 of departure. 

### 12 Now, don't get me wrong; I understand that for 

### 13 mechanistic studies and academic research, there are many 

### 14 legitimate reasons for different routes of administration, but 

### 15 when you're deriving the POD and looking at these studies and 

### 16 seeing whether you're going to use these studies for risk 

### 17 assessment, route of exposure is extremely important. 

### 18 For example, one of the reasons for using SC 

### 19 has been stated that it avoids the potential confounds of 

### 20 different rates of gastrointestinal absorption and first past 

### 21 effects on bioavailability. However, first past effects on 

### 22 bioavailability in GI absorption are, indeed, very relevant for

### Page 348 1 deriving safe levels of exposure to humans. 

### 2 So we know that SC versus oral route does 

### 3 impact toxicology and pharmacokinetics. In a side-by-side 

### 4 comparison by Carr and Nale, they found that there's greater 

### 5 brain cholinesterase inhibition with SC route of exposure and 

### 6 that you get decreased body weights in pups with SC DMSO, but 

### 7 you don't see that with the oral. 

### 8 Smith, et al., more recently, has data and 

### 9 using that with pharmacokinetic analysis, found that SC prolongs 

### 10 brain cholinesterase inhibition versus oral, due to slower 

### 11 release from injection site depot and localized brain 

### 12 metabolism. 

### 13 Their issue is not only with the route of 

### 14 exposure, but the DMSO, which is a potential confounder for 

### 15 determination of cellular and pharmacologic effects. This is 

### 16 going to be very important as we move towards Tox 21 with end 

### 17 points that are more subtle and precursor events. 

### 18 Two EPA scientists found in the 1980s that 

### 19 DMSO in developmental exposures produced endocrine and 

### 20 neurochemical changes and they cautioned the readers in hope 

### 21 that their examples would discourage its continued use in 

### 22 toxicological studies.

### Page 349 1 So we have hints -- and these are not 

### 2 side-by-side experiments, but these are a few of the behavioral 

### 3 studies or results that actually was repeated in more than one 

### 4 study. In this particular case, it's improved performance on 

### 5 radial arm maze in the females. 

### 6 So in this example, you can see that you get 

### 7 an effect at one milligram per kilogram per day. It was the 

### 8 only one dose level tested. When you give it orally, there's no 

### 9 effect at one milligram per kilogram per day. In fact, that was 

### 10 a much stronger study because it had three dose levels and a 

### 11 number of other design features that made this a stronger study. 

### 12 13 So when you are asking the question for risk 

### 14 assessment, the one on the right is the most relevant one for 

### 15 use for risk assessment and there was not an effect at one 

### 16 milligram per kilogram per day using oral route of exposure. 

### 17 Another general comparison that's notable and 

### 18 of interest is increased male aggressive response that was 

### 19 measured by the same lab in two different studies. In the first 

### 20 earlier study, they used DMSO and they found effects that one in 

### 21 three milligram per kilogram, but then they saw the light and 

### 22 they changed to peanut oil in all subsequent studies and they

### Page 350 1 found no effect at one milligram per kilogram, and really very 

### 2 subtle marginal effects at three milligram per kilogram per day. 

### 3 So the next question is please comment on the 

### 4 Agency's preliminary conclusion that although there are multiple 

### 5 biological possible hypotheses, the mechanistic experimental tox 

### 6 data do not yet support a coherent set of key events. 

### 7 Dr. Mundy did an excellent job describing 

### 8 this. We agree with their conclusions. There's a dearth of 

### 9 studies designed to test the hypothesis regarding causal 

### 10 relationships between perturbations and functional changes. 

### 11 I'd like to point your attention to the 

### 12 Exponent comments that Carole and I put together that gives an 

### 13 example for serotonergic end points that describe some of the 

### 14 additional issues with these non-cholinergic modes of action. 

### 15 The next question is please comment on the 

### 16 degree with which these studies suggest that end points relevant 

### 17 to evaluating neurodevelopmental outcomes may or may not be more 

### 18 sensitive. 

### 19 As I said, there are few studies that did this 

### 20 concurrently, but there's enough data to come to the conclusion 

### 21 that these neurodevelopmental effects are reported in one to six 

### 22 milligram per kilogram. And we know that these doses causes

### Page 351 1 acetylcholinesterase inhibition at those dose levels and that 

### 2 these neurodevelopmental effects are occurring at doses that are 

### 3 higher than the lowest BMDL10. 

### 4 Question 2.2 continued, it's a very long 

### 5 question. I only have time to focus on the issue of what is the 

### 6 kind of magnitude and duration or perturbations that you need to 

### 7 start worrying about that might lead to adverse effects later. 

### 8 I'd like to address that a little bit, but before doing that I'd 

### 9 like to point out that whether perturbations are key events 

### 10 leading to adverse effects on the developing nervous system 

### 11 simply can't be answered with the current data. 

### 12 Part of the problem we have is that we are 

### 13 hampered by the lack of replication of studies using exactly the 

### 14 same experimental conditions. The example that I gave you 

### 15 showed that even in the hands of the same laboratory, they're 

### 16 not able to repeat the same results exactly, and that raises a 

### 17 lot of questions about the different modes of action. 

### 18 Now I would like to address the question of 

### 19 magnitude. There is no magic number that you can apply across 

### 20 the board. The biological significance of percent change -- and 

### 21 I talk about this because the majority of the non-cholinergic 

### 22 data that's published out there expresses the data, graphically,

### Page 352 1 in percent change. That depends on the reliability and 

### 2 variability of the control values for the specific brain area 

### 3 and age of animal. 

### 4 So in this particular case, in adults, they 

### 5 saw a 50 percent decrease in dopamine hippocampus levels after 

### 6 developmental exposure. That's huge. And that's something to 

### 7 be concerned about. But the first thing that we need to do is 

### 8 take a look at the control dopamine levels. 

### 9 In this particular case, compared to the other 

### 10 regions, it's really very low. It's 1.2 to 1.3 nanogram per 

### 11 region. That is unreliably low. The same authors in other 

### 12 studies report that they don't evaluate that because it was 

### 13 unreliably low. Thus, the 50 percent decrease is not 

### 14 biologically meaningful and yet this paper is out and published 

### 15 and there are many other papers that have cited this as evidence 

### 16 of an alternative mode of action effecting dopamine levels. 

### 17 So the other thing to take a look at -- and 

### 18 these are just examples -- I think we need to apply to every end 

### 19 point is to consider when the time point was taken, and when 

### 20 they are taken at earlier time points to recognize that 

### 21 concurrent control values are important, but they may be 

### 22 changing rapidly at young ages and that impacts how you

### Page 353 1 interpret what a percent change means. 

### 2 So whether effects are adverse should consider 

### 3 historical control values. I encourage the EPA to seek and 

### 4 request those data so that they can better evaluate whether 

### 5 these findings are truly adverse. 

### 6 Question 3.1: Please comment on the degree to 

### 7 which these studies -- and it says behavioral -- support the 

### 8 qualitative conclusion that chlorpyrifos exposure may result in 

### 9 long-term adverse effects. 

### 10 There is evidence of long-term effects on the 

### 11 developing nervous system and they have been reported and we 

### 12 believe that they happen around the 3 to 5 milligrams per 

### 13 kilogram per dose level. 

### 14 The findings of these multiple studies are not 

### 15 consistent with each other and we agree with the EPA that the 

### 16 behavioral data do not provide evidence for a specific profile 

### 17 of effects. Based on the criteria I will describe next, we 

### 18 believe that the threshold is somewhere around one milligram per 

### 19 kilogram per day with more convincing effects up at three. 

### 20 I do this evaluation of studies because this 

### 21 addresses the question: "Please comment on the scientific 

### 22 quality and robustness of the animal neurodevelopmental

### Page 354 1 studies." 

### 2 Now there are more than 60 mammalian in vivo 

### 3 neurodevelopmental papers, and they all have varying results for 

### 4 particular outcomes that could be related to a number of 

### 5 important variables. You need to keep that in mind when I'm 

### 6 giving you these examples in trying to provide a different 

### 7 perspective. 

### 8 None of these studies are done side-by-side, 

### 9 so there's always some change in the experiment, as Dr. Moser 

### 10 pointed out, that makes it hard to really make complete 

### 11 confident comparisons. 

### 12 What one approach would be to take all of 

### 13 these data and say I can't make heads or tails of this. I'm 

### 14 just going to identify the lowest dose level at which any 

### 15 alteration is found in any parameter and that's actually what we 

### 16 did in the paper, Lee, et al., where we tried to provide the 

### 17 tables -- I tried to put it in way that I was hoping that if the 

### 18 authors, themselves saw the table, they would think that it 

### 19 accurately reflected what they reported in their paper. But the 

### 20 second approach is to evaluate the utility of those studies for 

### 21 risk assessment purposes and to assess whether the pattern of 

### 22 findings is consistent with the adverse effect. And that's what

### Page 355 1 we tried to do in the text of that paper. 

### 2 This requires critical evaluation of the 

### 3 methods and results for purposes of setting safe levels of 

### 4 exposure, not just how well do they contribute to the 

### 5 mechanistic research, which all of these papers really do a 

### 6 great job doing. Now we're asking a different question for risk 

### 7 assessment purpose. 

### 8 This also requires us to evaluate the patterns 

### 9 of outcome with respect to study design, methods and procedures, 

### 10 consistency of alterations within cross studies, absence and 

### 11 presence of findings, and dose response patterns. 

### 12 So for the neurobehavioral studies, here's an 

### 13 example of some of the stronger studies or how we regarded a 

### 14 study to be stronger. We considered a study to be stronger if 

### 15 it had an oral route of exposure. We did not ignore the 

### 16 subcutaneous studies, but if they had similar effects then the 

### 17 oral study, if it was a strong study on the basis of the other 

### 18 parameters, would break the tie. 

### 19 A number of dose levels, two to three is like, 

### 20 minimal in my regard. I mean, you need to have at least two to 

### 21 actually get a sense of a dose response. The sample size for 

### 22 behavior, we considered a stronger study to be 8 to 10. There

### Page 356 1 were several that were up in the 20s. The experimental unit for 

### 2 developmental studies needs to be in the liver, especially for 

### 3 gestational and early post-natal exposures. 

### 4 We looked at the behavioral methods, including 

### 5 the control for environmental influences and we carefully 

### 6 evaluated how they derived the statistical analysis and 

### 7 sometimes the data was evaluated more than one way. Part of the 

### 8 evaluation requires an assessment when they transformed the data 

### 9 to ask the question how well do they actually reflect the 

### 10 original data? 

### 11 Let me give you one example of why this is 

### 12 important to look at the data. Here is an example of motor 

### 13 activity over a 60-minute period and each of the -- is there -- 

### 14 okay. So the X-axis is every five-minute time bend. You can 

### 15 see a nice habituation curve for control one and five milligram 

### 16 per kilogram. I've looked at a lot of this kind of data. This 

### 17 is really good data and I don't see an effect at one and five 

### 18 milligram per kilogram. 

### 19 In fact, when they did the repeated measures 

### 20 analysis of variance they did not get a dose effect. There was 

### 21 no statistically significant effect in the over mean activity, 

### 22 but they did get a dose times time interaction. And in many of

### Page 357 1 the other papers they would report the post-tox group 

### 2 comparisons on each bend and there was nothing there. So I 

### 3 would simply say that no statistical significance was reported. 

### 4 However, when the data was analyzed using a 

### 5 linear trend, which is basically described as the slope of the 

### 6 decrease in activity over consecutive five-minute blocks, they 

### 7 get, in effect, at one and five milligrams per kilogram and I 

### 8 believe that this effect, based on linear trend, is not an 

### 9 adverse finding. 

### 10 So that may be why we come to a different 

### 11 conclusion than what the EPA's report does because we looked at 

### 12 this data and made some judgments as to whether this finding was 

### 13 actually adverse. 

### 14 The other thing that we think is important, 

### 15 especially for the studies where there's only one dose level or 

### 16 no consistent dose response relationship, it's important to take 

### 17 a look at the available historical and positive control data to 

### 18 assess the reliability of the methods and variability of the 

### 19 control behavior. 

### 20 So here's an example that I'd like to present 

### 21 that puts a different perspective on data. Unfortunately, the 

### 22 pointer doesn't work, but what you can see here is this is

### Page 358 1 radial arm maze. On the Y-axis is the errors, and the X-axis 

### 2 are trials. There are different trial blocks. 

### 3 Yes. Okay. So here are the males. Here are 

### 4 the females. You can see here -- and I'm going to focus on the 

### 5 first trial block because it's fairly representative of the rest 

### 6 of the data. If you look at the first trial block, you've got 

### 7 about eight across the board for a control low and high dose 

### 8 level. There's no effect in the males. 

### 9 For the females, for control, you have around 

### 10 eight and then you have at one milligram per kilogram it goes up 

### 11 to 13 and then hovering around 10. 

### 12 So this would be considered an adverse effect 

### 13 where at one milligram per kilogram you have an increase in 

### 14 errors at the low dose but not the high dose. I was interested 

### 15 in this because there were a number of other studies that did 

### 16 not show an inverted U-shaped curve dose response curve. Not 

### 17 only that, because I evaluated all the other studies from that 

### 18 same laboratory, they actually made a big point in all the other 

### 19 studies where they tried to show that chlorpyrifos disrupts the 

### 20 sectoral differentiation of the brain. 

### 21 They make the point that ordinarily, in their 

### 22 lab, there's a male difference compared to females. That

### Page 359 1 females do worse and that in fact, the other hypothesis that 

### 2 wasn't considered is that maybe what's causing this is that the 

### 3 females are unusually low in this particular control group. In 

### 4 fact, if you take a look at the first time bends, here's the 

### 5 Study B that I just showed you with the controls: males and 

### 6 females are comparable. And Study B for one milligram per 

### 7 kilogram, you have this normal sex difference that they got in 

### 8 two other historical controls. 

### 9 So in fact, if you look at this one milligram 

### 10 per kilogram, this is an effect at 13 that is right about, 

### 11 smack-dab where the other studies are. So this raises a 

### 12 question of whether this non-monotonic change in learning in 

### 13 memory is a real adverse effect. 

### 14 So the next question is please comment on the 

### 15 scientific quality and robustness of the animal 

### 16 neurodevelopmental studies. 

### 17 We agree that the total database is robust, 

### 18 but some, but not all studies and findings are robust. So if 

### 19 all the findings are treated equally, then the scientific 

### 20 quality and robustness of the risk assessment is compromised. 

### 21 Here's an example: In this study -- this is 

### 22 developmental reflexes -- in these two studies happen to be the

### Page 360 1 studies that epidemiologists love to cite as demonstrating 

### 2 biological plausibility for abnormal reflexes that they think 

### 3 there's an association in their cohorts. 

### 4 These two studies are probably the weakest 

### 5 studies in terms of providing that biological plausibility 

### 6 because in the first case, it's conducted up at 25 milligrams 

### 7 per kilogram, which is a really big dose. And in the other 

### 8 case, there's only one dose level in this experimental design is 

### 9 especially weak in that you don't even have information on the 

### 10 number of sample size there are. And there were two pups per 

### 11 set from an unstated number of litters. 

### 12 Whereas you have other studies that are much 

### 13 stronger that evaluated this data across three dose levels, used 

### 14 oral doses that tell you exactly what the number of litters they 

### 15 have in the sample size and they have no effects. 

### 16 So the conclusion, looking at that data, is 

### 17 that there's no effect on developmental reflexes rather than 

### 18 picking out one study that is the weakest study and claiming 

### 19 that that show biological plausibility. You go on and see the 

### 20 other data, and for the mouse, there's, again, a pattern of lack 

### 21 of effect in better studies that have actual dose response data, 

### 22 and we conclude that there's no effect up to about six to ten

### Page 361 1 milligrams per kilogram. 

### 2 Here's another example of the importance of 

### 3 comparing behavioral methods, and this is just to show that 

### 4 motor activity is not all the same. You can have a home cage 

### 5 one hour activity and figure eight maze is one of the better 

### 6 motor activity tests. Then you have this open field, 

### 7 five-minute number of line crossing, and in this particular 

### 8 study, they don't describe the criteria for what makes them 

### 9 decide that that line was crossed, as compared to other really 

### 10 well, you know, good behavioral studies that give you more 

### 11 confidence. They will say something like, well, we considered 

### 12 it when the two paws crossed or something. It just gives you a 

### 13 greater sense that they had control over what they were looking 

### 14 at. So if you get an effect here but you don't get an effect 

### 15 here, then these should have greater weight. 

### 16 Here's a third example: Evaluation of pattern 

### 17 and magnitude of effect. Here's a study in which you have 

### 18 errors in the first eight visits on a radial arm maze and you 

### 19 have the average errors at Week 1, Week 2, Week 3, Week 4. 

### 20 First, you need to note that there's a very small range of 

### 21 errors. Here's the axis from two to four. I want you to 

### 22 concentrate on and focus on control versus the low dose because

### Page 362 1 I am saying that I think that at one, we don't have an adverse 

### 2 effect. 

### 3 So here's controls, and it's the closed 

### 4 circles, and the one milligram per kilogram tracks just right on 

### 5 top of it until the fourth week there's this strange uptick. So 

### 6 the question is, is that an adverse effect? We conclude that 

### 7 that's not an adverse effect because we're talking about 2.7 

### 8 versus three errors. 

### 9 In fact, this group actually expresses the 

### 10 data in a different way. And when they did this, the data 

### 11 actually was really very nice. For the purposes of comparing 

### 12 with another OP, they were able to show really nice dose 

### 13 response data. What they did here is they took a 16-day average 

### 14 and what they found, statistically, this is the control low, 

### 15 mid, and high doses, is that statistically, they only got 

### 16 effects at the highest dose. And the text says they've got 

### 17 effects at the mid and high dose. 

### 18 So taken together, we believe that the no 

### 19 effect level, for the purposes of risk assessment would be one 

### 20 milligram per kilogram in this particular case. I just wanted 

### 21 to show you that this is the data that shows what I showed you 

### 22 just previously. You have these errors in the males. You have

### Page 363 1 females with improvement. You get nice dose response curves, no 

### 2 inverted U-shaped curves here. 

### 3 I showed you this slide earlier and this shows 

### 4 that with SC DMSO, you get effects at one. At oral, you get no 

### 5 effects at one milligram per kilogram and this one breaks the 

### 6 tie for us, given the design of the studies, and that's how we 

### 7 come to a different conclusion that perhaps, EPA came to. 

### 8 So the final slide is: "Please comment on the 

### 9 degree to which studies that measure cholinesterase inhibition 

### 10 provide more sensitive end points the end points measured in the 

### 11 experimental neurodevelopmental studies. 

### 12 Well, I hope that all the data I showed you 

### 13 for the cholinergic end points convinced you, but here is the 

### 14 bottom line for risk assessment. You've got the BMDL10 at .03. 

### 15 Regardless of your point of view of whether one is a no observed 

### 16 adverse effect level, there are clearly effects that are 

### 17 reported at one, up until six for a neurodevelopmental. 

### 18 This comes from a paper that is in press that 

### 19 Carole and I published together, focused on birth outcomes and 

### 20 developmental effects. You can see here at five milligrams per 

### 21 kilogram, that's the low L for maternal toxicity. You're 

### 22 getting quite obvious signs of autonomic effects of

### Page 364 1 cholinesterase inhibition. 

### 2 So here you've got one through 12. You've got 

### 3 the BMDL10 and we agree with the Agency that that is protective 

### 4 of the effects on developmental effects in the animals. When 

### 5 you ask the question of biological plausibility, you have to 

### 6 reconcile the problem that these effects are being seen at doses 

### 7 that are orders of magnitude higher than what might be estimated 

### 8 for human exposure. And these are all in milligrams per 

### 9 kilogram because that's how I think of the world. 

### 10 This is my last slide, and my concluding 

### 11 remarks are based on our evaluation of both the SC and oral 

### 12 studies. We believe that the low L, NOAEL for neurobehavioral 

### 13 outcomes is 1) that the specificity of direction of finding the 

### 14 dose response pattern and the attention to methodologic issues 

### 15 should play a prominent role in evaluating the weight of 

### 16 evidence. And regardless of the point of view on 

### 17 neurobehavioral outcomes, cholinesterase inhibition is indeed 

### 18 the most sensitive objective and reproducible end point on which 

### 19 to base hazard and risk assessment. Thank you very much. 

### 20 DR. KENNETH PORTIER: Thank you. That was 

### 21 very clear. I even understood it. 

### 22 DR. ABBY LI: Oh, good.

### Page 365 1 DR. KENNETH PORTIER: Let's see if the panel 

### 2 did. Any questions? Let's start with Dr. Aschner. 

### 3 DR. MICHAEL ASCHNER: Michael Aschner. Thanks 

### 4 very much, Abby. I have a couple of questions or comments. The 

### 5 first one is can you comment a little bit more about what you 

### 6 define as maternal toxicity in the study that just came out? I 

### 7 think it was in your last slide. 

### 8 DR. ABBY LI: Oh, okay. Yeah, they saw 

### 9 tremors. You know, that sort of thing for the maternal 

### 10 toxicity. This is the Morrison, et al. (2000) paper. 

### 11 MR. MICHAEL ASCHNER: My second question is, 

### 12 again, I'm coming back to your last slides. The three criteria 

### 13 that you have, in terms of toxicity related to dose are, you 

### 14 know, pretty much putting a bullet into somebody's head, 

### 15 maternal weight -- I mean, fetal weight. 

### 16 DR. ABBY LI: Oh. Yeah, I'm sorry about that. 

### 17 This is just what I could conveniently get out of another paper 

### 18 that was focused on those end points. So that's just what 

### 19 happened to be in that particular paper. 

### 20 I'm trying to make the point here, based on 

### 21 the tox, that you have lots of neurodevelopmental effects at 

### 22 this dose. That's where the doses are that the papers are

### Page 366 1 reporting it. I was just trying to put a picture up that 

### 2 allowed you to compare this with the others on this log basis. 

### 3 MR. MICHAEL ASCHNER: My other question would 

### 4 be then, do you feel that there is any information between the 

### 5 .03 and the 1 that might be useful? Or do you think that -- 

### 6 DR. ABBY LI: There's none. Dr. Moser did a 

### 7 really good job explaining that. 

### 8 DR. MICHAEL ASCHNER: Okay. 

### 9 DR. ABBY LI: I think that's the reason why -- 

### 10 is it the Billauer study? 

### 11 Yeah. This is one study that I think looked 

### 12 at anxiety, if remember correctly. It's not one of the 

### 13 strongest studies, but it's the only one that you have an effect 

### 14 at one milligram per kilogram and an NOAEL at .02. But I want 

### 15 to point out that you have a Morrison paper that is actually 

### 16 very nice, in terms of learning and memory. They use a spatial 

### 17 delayed alternation test, really nice beautiful data. They got 

### 18 no effects at all. And that study is not used because they 

### 19 didn't get an effect at one, but maybe it should be, in terms of 

### 20 weight of evidence. 

### 21 DR. KENNETH PORTIER: Anyone else? Dr. Harry. 

### 22 DR. JEAN HARRY: Jean Harry. Nice

### Page 367 1 presentation. Thanks for pulling that together. I have a 

### 2 couple of questions for clarification of how you guys are 

### 3 looking at this. 

### 4 When you were going through the first note on 

### 5 slide -- just as a point for you -- on slide, I can't even tell 

### 6 the number. The one about the DMSO vehicle study. 

### 7 DR. ABBY LI: Yeah. 

### 8 DR. JEAN HARRY: You don't need to go back to 

### 9 it. Your investigators there were not at EPA, they were at 

### 10 NIHS. 

### 11 DR. ABBY LI: Oh. Thank you. I'm sorry. 

### 12 I thought Plaque was one of them. I thought he was an EPA 

### 13 scientist. 

### 14 DR. JEAN HARRY: That's when he was at NIHS. 

### 15 DR. ABBY LI: Oh. Okay. 

### 16 DR. JEAN HARRY: You were asking about 

### 17 historical data and historical controls. 

### 18 DR. ABBY LI: Which slide are we talking 

### 19 about? 

### 20 DR. JEAN HARRY: Just as a general concept. 

### 21 That you were talking about the need for, when you look at a 

### 22 percent change or you look at that type of aspect, you need to

### Page 368 1 look at the historical controls, which, I agree, you need to 

### 2 know what your control values are like, but how are you viewing 

### 3 that recommendation you're making for historical controls? 

### 4 Because sometimes that becomes a very stagnant 

### 5 data set and not a living, moving target which it really has to 

### 6 be. 

### 7 DR. ABBY LI: Well, I mean, I think that 

### 8 this -- so I think what you're saying is that you can get this 

### 9 huge historical control data. It may not be relevant for the 

### 10 particular experiment. Is that what you're trying to say? 

### 11 DR. JEAN HARRY: Well, it might be something 

### 12 that you got two years earlier, but it now doesn't apply with 

### 13 exactly the person that's running the assay now, exactly the 

### 14 enzymes that are being done now. That type of thing. 

### 15 So how are you looking at -- what are you 

### 16 considering a historical control base at which to compare to? 

### 17 DR. ABBY LI: Well, what I'm encouraging 

### 18 the Agency to do when they're dealing with non-cholinergic modes 

### 19 of action, especially these subtle kind of perturbations and 

### 20 effects, to ask for the control values and ask them to give you 

### 21 the data where it was conducted under identical conditions. I 

### 22 think that's really important.

### Page 369 1 DR. JEAN HARRY: Like, within a two-year 

### 2 period of time or something like that. 

### 3 DR. ABBY LI: Oh, okay. Yeah, that would 

### 4 be fine. Right. But that sense really makes a difference. And 

### 5 I'm sure you, as an investigator, understand that, especially 

### 6 for some of these end points that are being evaluated. 

### 7 DR. JEAN HARRY: So if you come back to that 

### 8 example, if you go to Example Number 3. 

### 9 DR. ABBY LI: Can you tell me the slide 

### 10 number, please? 

### 11 DR. JEAN HARRY: If I can see it. It's 

### 12 40-some. I'm going to guess 46. There we go. 

### 13 So where was a point where you were sort of 

### 14 talking about that and you were talking about the magnitude of 

### 15 the effect and that fact that it is, I don't know, a 

### 16 half-an-error difference, which is true. But if you come back 

### 17 to this and you look at this slide and you ask about your 

### 18 control data, do you have an issue with this Figure that 

### 19 potentially your control animals did not show learning in this 

### 20 procedure? 

### 21 DR. ABBY LI: Yes. 

### 22 DR. JEAN HARRY: Okay.

### Page 370 1 DR. ABBY LI: But it is what it is. The point 

### 2 is that the Agency has all this data out there. They have to 

### 3 make a call. I don't think you should dismiss any study. I'm 

### 4 just thinking that you should take a very close look at the 

### 5 data. Like I was saying, that's why I was looking at the left 

### 6 panel here because it was really nice data. 

### 7 DR. JEAN HARRY: So in this basis, you would 

### 8 raise an issue that in looking at your control data that if your 

### 9 controls do not show learning and memory, then therefore it's 

### 10 very difficult to determine -- 

### 11 DR. ABBY LI: Well, it changes my level of 

### 12 concern for the outcome and it starts becoming judgment, whether 

### 13 you're going to call it an adverse effect. What would you call 

### 14 it, Jean? 

### 15 DR. JEAN HARRY: I would call it an invalid 

### 16 study. 

### 17 DR. ABBY LI: Okay. But I don't think that's 

### 18 completely fair. I don't think it's completely fair because, 

### 19 you know, I think you'd just want to make the best use of that 

### 20 data. I think this was interesting and there was just a 

### 21 consistent pattern that I thought was -- they did many with 

### 22 another OP and they did the comparisons. It was just very nice

### Page 371 1 data. 

### 2 DR. JEAN HARRY: There would be lots of other 

### 3 things I would ask about this data before I would accept it in 

### 4

-- 

### 5 DR. ABBY LI: Well, then you're tougher than I 

### 6 am. Okay. My point is that you've got to have that toughness 

### 7 when you're looking at the literature or else you're going to 

### 8 end up with saying I don't see any pattern because you're 

### 9 accepting everything as equal and you have all the noise. So 

### 10 you should get rid of the noise and focus on whether you have 

### 11 patterns on the good studies. 

### 12 DR. JEAN HARRY: Now, I have one other point 

### 13 of clarification from you, which is just more your opinion of 

### 14 how you're looking at this. 

### 15 So you've gone through this and you gave a few 

### 16 studies. In the study that you considered the best stud to make 

### 17 the decisions on -- again, you want a number. 

### 18 DR. ABBY LI: Yeah. So this was just trying 

### 19 to show you that, you know, there was this nice pattern here. I 

### 20 mean, I agree that it's kind of an equivocal effect given all 

### 21 the other things going on in the study, but that also shapes how 

### 22 you view how big of an effect there is on learning and memory.

### Page 372 1 DR. JEAN HARRY: What I was going to ask you 

### 2 about that is that's one study with nan of 20. What you've 

### 3 raised in some of your concerns is how consistent are you 

### 4 getting your studies and whether you could replicate them. 

### 5 Now, I realize a nan of 20 puts it within sort 

### 6 of the guideline recommendations of animals, but how would you 

### 7 view it if the same lab had run a cohort of an nan of 10 and had 

### 8 run it as a replication study, so two cohorts of 10? 

### 9 DR. ABBY LI: Mm-hmm. 

### 10 DR. JEAN HARRY: Let's say the first one they 

### 11 found no effect; the second one they did. I mean, we all know 

### 12 that happens, especially when you look at it that way, but yet 

### 13 when you're talking about your historical controls, you could 

### 14 potentially give a replicate study designed in such as way that 

### 15 you have two replicates that's fully handled, just a time point 

### 16 out, greater weight than one study where you sorted through 20 

### 17 animals in of all these doses to try to get that much type of 

### 18 work done. How do you view that? 

### 19 DR. ABBY LI: Oh. So you have a replicate 

### 20 design. You see one in one replicate. You don't see one in the 

### 21 other. 

### 22 DR. JEAN HARRY: Just in general, would you

### Page 373 1 view a replicate study as stronger data? 

### 2 DR. ABBY LI: Well, in a replicate study, I 

### 3 would consider that you designed it upfront as a replicate 

### 4 design. So I feel that you should do the statistics like you 

### 5 intended a priori. 

### 6 DR. JEAN HARRY: Yes. 

### 7 DR. ABBY LI: And evaluate the study and see 

### 8 what you get first and not try to pick and choose the data 

### 9 afterwards. 

### 10 DR. JEAN HARRY: No. That's not what I'm 

### 11 asking. I'm asking would you view that if you set your design 

### 12 up, not as running 20 all at one time -- 

### 13 DR. ABBY LI: And just with sets of 10. 

### 14 DR. JEAN HARRY: -- but that you set it up as 

### 15 a replicate study of 10. So you've designed it that way and you 

### 16 analyzed it that way, is there one you would have more 

### 17 confidence in than the other? 

### 18 DR. ABBY LI: Whether a replicate design is 

### 19 better than not a replicate design? 

### 20 DR. JEAN HARRY: Mm-hmm. 

### 21 DR. ABBY LI: Okay. So here's my experience. 

### 22 The more you -- it's a balance. In fact, I struggled with this

### Page 374 1 when I was first trying to decide how to do the 

### 2 neurodevelopmental guidelines, right. I ended of thinking 

### 3 replicate design is nice because you can maybe control the time 

### 4 of testing and all that kind of thing, but you end up spreading 

### 5 the study out across many days, which has the other type of 

### 6 error that comes up with. 

### 7 So I think that a replicate design can appear 

### 8 to be better, but is not necessarily. It really depends. I 

### 9 don't think there's a straight answer on that. 

### 10 DR. KENNETH PORTIER: Dr. Terry. 

### 11 DR. ALVIN TERRY: Yes. I'd like you to go 

### 12 back to the slide just before this one. And maybe I'll sort of 

### 13 defend this graph a little bit from both of your criticisms. 

### 14 First of all, if I'm understanding this 

### 15 correctly, this is probably 11 Graph from the radial arm maze. 

### 16 DR. ABBY LI: I can't hear you. I'm sorry. 

### 17 DR. ALVIN TERRY: Okay. I just want to make 

### 18 sure this graph isn't misinterpreted. From my understanding, 

### 19 this is working memory errors averaged by week. So a controlled 

### 20 set of animals is going to reach an asymptotic level of working 

### 21 memory errors within a week. So you're not going to see an 

### 22 acquisition curve like you would a water maze or something of

### Page 375 1 this nature. 

### 2 DR. ABBY LI: I think there's like, if I 

### 3 remember correctly, four trials. So it's still on the low side 

### 4 for errors. 

### 5 DR. ALVIN TERRY: I don't remember how many 

### 6 arms this particular maze is. Is this an eight-arm, 12-arm, 

### 7 16-arm? 

### 8 DR. ABBY LI: I have to look that up. I think 

### 9 it's a 12-arm. 

### 10 DR. ALVIN TERRY: So if you're thinking about 

### 11 an asymptotic level performance in controls, you know, three 

### 12 errors would probably be very reasonable. So you're looking at, 

### 13 over the course of several weeks, the very first week controls 

### 14 can reach asymptotic levels. So they're not going to have very 

### 15 many errors. 

### 16 So I think it's a misinterpretation to say 

### 17 there's not any evidence of acquisition there and that there's 

### 18 not a difference between the control and the chlorpyrifos 

### 19 treated. 

### 20 DR. ABBY LI: Well, I mean, I do think that it 

### 21 is valid to say that you've really got a very narrow range of 

### 22 errors.

### Page 376 1 DR. ALVIN TERRY: And that's just the manner 

### 2 of this task. 

### 3 DR. ABBY LI: I mean, I showed you the other 

### 4 study on the other radial arm maze that they were up at eight to 

### 5 13, right? This one. 

### 6 DR. ALVIN TERRY: Yes. And you're looking at 

### 7 Sessions 1 through 3. It depends on whether you add the 

### 8 sessions. 

### 9 DR. ABBY LI: So one through three is 

### 10 equivalent to Week 1. 

### 11 DR. ALVIN TERRY: One through three? 

### 12 DR. ABBY LI: Well, I think it's wonderful 

### 13 that I got the EPA SAP behaviorists talking. So I'm going to 

### 14 let Vorhees talk and I'll be quiet. 

### 15 DR. CHARLES VORHEES: Charles Vorhees. This 

### 16 is a 16-arm. So you can't compare them very easily. 

### 17 DR. ABBY LI: Okay. 

### 18 DR. CHARLES VORHEES: Did you look at the -- 

### 19 and this is addressed to Dr. Carr -- did you look at the 

### 20 learning within sessions on your data that Dr. Li is showing 

### 21 there? That's your data, right? 

### 22 DR. CARR: Yes, it's my data. And I will be

### Page 377 1 honest. My graduate student did this, and when he brought it to 

### 2 me I was concerned. But there was a small amount of learning, 

### 3 not as much as I would've expected, but it does appear, you 

### 4 know, the way he presented it -- it doesn't appear that there 

### 5 is, but there was. 

### 6 DR. CHARLES VORHEES: So within Week 1, was 

### 7 there a learning curve? 

### 8 DR. CARR: A slight learning curve, yes. it 

### 9 wasn't as strong as I would've expected, but it was present. 

### 10 DR. CHARLES VORHEES: Okay. Do you have any 

### 11 idea of why that was? 

### 12 DR. CARR: I cannot tell you that. 

### 13 DR. ABBY LI: I have a speculation. 

### 14 DR. CHARLES VORHEES: Sometimes it's just 

### 15 nature of the beast when you do these and -- and to touch back 

### 16 on how you do them, sometimes the manpower dictates that you 

### 17 spread it across the top. So you can't set up 20 animals and 

### 18 run them in a 12-arm radial maze together. It's really 

### 19 difficult to do that. 

### 20 DR. ABBY LI: You know, there are so many 

### 21 different factors, right? What I tried to look at in my tables, 

### 22 I tried to look at this but I have no evidence. I tried to say

### Page 378 1 well, could it be the way they were depriving food, right? 

### 2 So in this particular study, it's started out 

### 3 with a 90 percent deprivation. There was a good reason for 

### 4 doing that because they didn't want to interfere too much with 

### 5 causing problems on top of trying to look at the effect of 

### 6 chemical. There could be -- we don't know, but that's the data. 

### 7 Well, I would be interested. Would you agree 

### 8 that in that particular case maybe the NOAEL is one? 

### 9 DR. CHARLES VORHEES: In that particular case, 

### 10 yes. 

### 11 DR. ABBY LI: Okay. I didn't do too badly. 

### 12 Thank you. So this is the kind of thing. It shows up on the 

### 13 EPA table as an effect, but in my paper, it shows up as an 

### 14 effect in the lab in the table, but in my analysis, I say that 

### 15 that's an NOAEL of one. And that's how I can come to a 

### 16 different conclusion than someone else by looking at the data, 

### 17 critically. 

### 18 DR. RUSSELL CARR: This is Dr. Carr. I would 

### 19 also like to say that improvement in Week 4, I would never ever 

### 20 say that chlorpyrifos improved performance in a radial arm maze. 

### 21 So therefore, I would say, Dr. Li, that's possibly not a true 

### 22 effect.

### Page 379 1 DR. KENNETH PORTIER: This is Ken Portier. 

### 2 Dr. Li, you obviously looked very closely at all these studies 

### 3 and the analyses. I was just wondering if any of them used 

### 4 anything like a Bayesian, an empirical Bayesian model approach 

### 5 to analysis because a lot of what you're talking about here is 

### 6 kind of incorporating expectation into this analysis. 

### 7 So the expectation, you wouldn't see 

### 8 improvement in the fourth week, and yet you did see it. So a 

### 9 Bayesian or an empirical Bayesian analysis would have shrunk 

### 10 that estimator close to the -- and it would've shown up as not 

### 11 significant. So there are new statistical analysis approaches 

### 12 that help you incorporate that thinking. And we've seen that 

### 13 before other panels, it's just I haven't hear the "Bayes" word 

### 14 in a day in a half. I had to bring it up, clearly. I just 

### 15 wondered. 

### 16 DR. ABBY LI: No. That has not been applied. 

### 17 At the most, you know, I was hoping to see maybe some kind of 

### 18 principal component analysis in some of the social behavior 

### 19 stuff rather than a T-test for each of the individual behaviors, 

### 20 right? 

### 21 DR. KENNETH PORTIER: So looking for some kind 

### 22 of latent underlying structure that would lead to these --

### Page 380 1 DR. ABBY LI: You know, like some of the 

### 2 social behaviors that Dr. Moser presented, you know, you get a 

### 3 lot of effects at one milligram per kilogram, but if you look at 

### 4 the data, you're looking at eight to ten, even more at different 

### 5 kinds of parameters. And you look at duration and frequency of 

### 6 each one, you're going to get a hit. 

### 7 So that's why we're saying if you look 

### 8 carefully at the statistics, you look carefully at the pattern, 

### 9 I'm not that impressed in some of the social behavior. 

### 10 DR. KENNETH PORTIER: Any additional 

### 11 questions? Seeing none. Thank you very much, Dr. Li. 

### 12 DR. ABBY LI: You're welcome. Thank you. 

### 13 DR. KENNETH PORTIER: At this point, Dr. 

### 14 Juberg is going to have closing remarks. 

### 15 DR. DALAND JUBERG: Yes. I will be very 

### 16 brief. Hopefully we haven't overextended our welcome. I know 

### 17 you all have precious time to do a lot of work. I just wanted 

### 18 to go back -- I think I have a couple of slides. To reiterate 

### 19 Dr. Bradbury's recommendations that we go after transparency, 

### 20 clarity, consistency and reasonableness, I think these are not 

### 21 only tenets of process, but also as guiding principles in 

### 22 conjunction with the evaluation of all the animal and human data

### Page 381 1 that you have seen, that you'll continue to see. So I just want 

### 2 to break this into four points, really. I'm just going to read 

### 3 these to you. 

### 4 Based on what you've heard, it's our 

### 5 conclusions that new toxicological data and advancements in 

### 6 PB/PK/PD modeling has increased the reliability and confidence 

### 7 in the current risk assessment for chlorpyrifos. 

### 8 Secondly, laboratory data reporting adverse 

### 9 outcomes from non-cholinergic perturbations are not anchored 

### 10 with a biologically plausible mode of action relevant to humans 

### 11 at exposures below those causing cholinesterase inhibition. 

### 12 And finally, third, recent independent reviews 

### 13 which integrate human animal data have concluded that protection 

### 14 against cholinesterase inhibition is protected against 

### 15 neurobehavioral and neurodevelopmental effects. And finally, 

### 16 critical epidemiological analysis have considered hazard, 

### 17 exposure and relevant biomarkers and does not support a causal 

### 18 role for chlorpyrifos in reported adverse outcomes in humans. 

### 19 So with that, I'm going to adjourned and our 

### 20 panelists will remain if you have any further questions for 

### 21 them. Dr. Portier, thank you very much and Dr. Jenkins as well 

### 22 and to the panel.

### Page 382 1 DR. KENNETH PORTIER: Don't leave. Don't 

### 2 leave. There might be some questions here. Dr. Lu. 

### 3 DR. CHENSHENG LU: So I meant to ask this 

### 4 question yesterday, but I figured there was going to be some 

### 5 information coming up this morning. The question is directly to 

### 6 your conclusion. 

### 7 The first conclusion here that the Dow team, 

### 8 you know, has raised this concern over and over again in terms 

### 9 of seeing some new behavioral effect but no cholinesterase 

### 10 inhibition is not a plausible conclusion in terms of at certain 

### 11 levels this causes harm. 

### 12 I have two concerns. One is that we're 

### 13 talking about two different outcomes; one is acute house 

### 14 outcome, which is acetylcholinesterase inhibitions and then the 

### 15 other one is a chronic house outcome, which is 

### 16 non-cholinesterase or neural behavior development. So I don't 

### 17 know how you can conclude that this two things has to have some 

### 18 kind of relationship in order to make a conclusive evidence that 

### 19 level is a concern. 

### 20 Many chemicals, if not all of them, behave 

### 21 very differently in terms of acute versus chronic. For example, 

### 22 if kids ingest a bolas of lead, obviously these kids are going

### Page 383 1 to have heavy metal poising symptoms right away, but not 

### 2 necessarily mean that this kid will instantaneously become low 

### 3 IQ here. But whereas, if the kid is exposed to very low level 

### 4 of lead over a period of time, obviously it's going to impair 

### 5 his or her IQ. 

### 6 So I don't see -- there has to be a link 

### 7 between these two measures. You know, pasteurized solvent, you 

### 8 mentioned, chemical does have these kinds of two different 

### 9 behaviors. So I kind of disagree that these two things has to 

### 10 be linked in a way, you know, identifying the association 

### 11 whatsoever. I just don't -- I disagree, but maybe you have 

### 12 different insight on this or the panel has different insight. 

### 13 DR. DALAND JUBERG: No. Just to say that, you 

### 14 know, for regulatory risk assessment, we are doing studies on 

### 15 both acute and chronic durations of exposure. Cholinesterase 

### 16 inhibition in both situations appears to be the most sensitive 

### 17 marker. And through a weight of evidence evaluation, much of 

### 18 what you heard from a lot of scientists, we're not seeing that 

### 19 these effects are occurring for either duration below those 

### 20 doses that inhibit cholinesterase inhibition. So that seems to 

### 21 still be a critical sensitive marker that seems to be protective 

### 22 against other neurobehavioral outcomes, regardless of duration.

### Page 384 1 DR. CHENSHENG LU: But at the moment when we 

### 2 measure cholinesterase inhibition, that reflect acute response 

### 3 to the exposure. Cholinesterase has been used in an 

### 4 occupational setting many, many years ago. The only reason that 

### 5 we're looking at cholinesterase inhibition in farmers is because 

### 6 we want to document the exposure either for today or for the 

### 7 workweek. 

### 8 If the measurement was not correct, according 

### 9 to the protocol, then that number would be rejected, according 

### 10 to either California or Washington State protocol because that 

### 11 number does not reflect acute response to the exposure. 

### 12 So again, that's my point that when we look at 

### 13 acetylcholinesterase, we look at it as an acute response, not 

### 14 necessarily chronic low-level exposures. Disagree that there 

### 15 has to be a link unless there is data. And that's why I 

### 16 remember one of the slides that Dr. Li showed that there are 

### 17 very few studies show the link between acetylcholinesterase and 

### 18 neural behavior. To me, I think that's obvious because we're 

### 19 talking about two different outcomes. How could you link these 

### 20 two different outcomes together in a scientific way? 

### 21 DR. DALAND JUBERG: I guess the only other 

### 22 think I would add is that is in many reasons why the chronic

### Page 385 1 referenced dose and point of departure is lower than the acute 

### 2 by a couple of orders of magnitude. And then on top of that, 

### 3 for what we're trying to do here, and regulatory risk assessment 

### 4 protection of public health, that's why in addition to those, 

### 5 you've got additional factors below that that we're 

### 6 incorporating to maybe address any remaining uncertainty. 

### 7 Yeah, we can talk about frank effect levels 

### 8 and then no effect levels but then moving beyond that, that's 

### 9 where, you know, to account for some of those remaining 

### 10 uncertainties. There's always going to be uncertainty in 

### 11 science. We bring in other additional factors. I may not have 

### 12 adequately addressed it. 

### 13 DR. KENNETH PORTIER: Dr. Goodman, you want to 

### 14 join in on this? 

### 15 DR. JULIE GOODMAN: I just wanted to add that 

### 16 the issue is that you have these associations in epidemiology 

### 17 studies that are occurring at exposures or is a magnitude lower 

### 18 than acetylcholinesterase inhibition. So you may have a point 

### 19 that what's happening, these neural behavioral effects might not 

### 20 be through that pathway, but the point is we need to understand, 

### 21 do we think that those associations are indicative of causation 

### 22 or due to some alternative explanation?

### Page 386 1 And the fact that when you do this weight of 

### 2 evidence analysis and look at all the data together that you're 

### 3 not seeing any of these effects at exposures below that when you 

### 4 have that biomarker of acetylcholinesterase inhibition indicates 

### 5 that those effects -- the reported associations in epidemiology 

### 6 studies are not likely indicative of causation. 

### 7 DR. KENNETH PORTIER: One last comment, Alex, 

### 8 and then we're dying for a break here. 

### 9 DR. CHENSHENG LU: Okay. So I guess my 

### 10 comments are actually simpler than what was just described. I'm 

### 11 talking about two boxes; one is acute toxicity and one is 

### 12 chronic. In this case, prolapsus. I say for many other 

### 13 chemicals as well. There's no breach cross over these two boxes 

### 14 because if you look at outcome, they're very different. So how 

### 15 can you just argue that there has to be some sort of association 

### 16 between acetylcholinesterase inhibition versus smaller head size 

### 17 or shorter baby body length? 

### 18 I don't see the connection unless there's a 

### 19 defined issue that one is constant to the other. But at this 

### 20 moment, I don't think that's the case. I used lead as example. 

### 21 I think there are many, many chemicals that actually behave very 

### 22 differently, not what you said in the Caucasian, because that's

### Page 387 1 not what I'm saying. I'm just in a very simple box model. 

### 2 DR. KENNETH PORTIER: Yeah, that's good. You 

### 3 know, I'm sure you'll be able to bring this up again so the 

### 4 panel discusses it. At this point we're going to take a 

### 5 15-minute break. 

### 6 And the remaining public commenters, please 

### 7 make sure that your material is loaded if you're going to use 

### 8 slides at this point. And if there any additional public 

### 9 commenters who have not registered, this is the last call. 

### 10 Please meet with Fred Jenkins up front here. We'll meet back at 

### 11 11:00 by this clock. 

### 12 (WHEREUPON a brief recess was taken) 

### 13 DR. KENNETH PORTIER: Okay. Let's reconvene. 

### 14 At this point, we're going to continue with the public comment 

### 15 section. Our next public commenter is Jennifer Sass with the 

### 16 NRDC. And by previous arrangement, she's going to be addressing 

### 17 the panel via the telephone. 

### 18 We agree that this is not a good precedent 

### 19 that we want to set for the panel for having people address the 

### 20 panel via technology. We like to see them face-to-face, but in 

### 21 this case it was unavoidable and it was done prearranged. So 

### 22 we're not setting a new precedence here; we're just making one

### Page 388 1 exception. So Dr. Sass. 

### 2 DR. JENNIFER SASS: Hello. Thank you very 

### 3 much. Can the panel hear me clearly? 

### 4 DR. KENNETH PORTIER: Yes. We can hear you 

### 5 very clear. 

### 6 DR. JENNIFER SASS: Okay. I have prepared 

### 7 comments and was hoping to be there to circulate them to you. 

### 8 Thank you very much, EPA, for accommodating this. I wasn't able 

### 9 to be with you today, unfortunately. Although I know you've all 

### 10 seen me enough, but I'm only tiresome in person. 

### 11 I will be reading through my comments, which 

### 12 I've circulated electronically. Thank you very much to the SAP 

### 13 for giving your service to this important assessment of 

### 14 chlorpyrifos. A decade ago, EPA took the important step towards 

### 15 protecting human health by canceling inborn uses of 

### 16 chlorpyrifos, and as a result, children today are not being 

### 17 exposed to these high and unsafe levels from many of the 

### 18 household uses of chlorpyrifos. 

### 19 Unfortunately, though, chlorpyrifos is still 

### 20 widely used in agriculture at about 10 million pounds annually, 

### 21 and this puts rural populations, including farm workers and 

### 22 their families and bystanders that live or work or go to school

### Page 389 1 near fields at risk, as well as continues to have chlorpyrifos 

### 2 residue on food, putting consumers at risk, generally. 

### 3 My organization, NRDC, petitioned the EPA in 

### 4 2007 to cancel the remaining uses of chlorpyrifos. As part of 

### 5 the settlement with EPA, EPA was scheduled to release an updated 

### 6 assessment of its health risk by June 2011. That deadline has 

### 7 now passed. So we're asking the EPA to use its authority and 

### 8 its obligation to protect human health, especially mothers, 

### 9 infants, and children from chlorpyrifos by canceling remaining 

### 10 uses. 

### 11 My responses to the questions are here. For 

### 12 Question 1, that was a comment on whether cholinesterase was the 

### 13 most robust source of data for deriving a part of departure. 

### 14 I'll refer to the SAP's expertise, except to 

### 15 say that cholinesterase inhibition may or may not be the most 

### 16 robust source of data. I don't know the answer, but I do know 

### 17 that it's not the only source of data regarding mechanism of 

### 18 toxicity or end point of concern. 

### 19 The SAP can recommend that EPA adjust for 

### 20 potential risks of non-cholinergic toxic effects, through either 

### 21 additional safety factors or by quantitatively adding the risks 

### 22 together for multiple toxic pathways. This was an approach that

### Page 390 1 is similar to the one used by the EPA integrated risk 

### 2 information, or IRIS program, to calculate an acceptable level 

### 3 of exposure, the trichloroethylene, TCE. In that most recent or 

### 4 final assessment, they considered multiple end points of concern 

### 5 together. 

### 6 Question 2 points out that there are multiple 

### 7 biologically plausible hypotheses, but mechanistic data is 

### 8 inadequate to support alternate modes of action or adverse 

### 9 outcome pathways. 

### 10 NRDC would like to suggest that EPA has not 

### 11 actually shown that it can protect all end points of concern, 

### 12 using its current end point selection and methodology. It is a 

### 13 matter of weight of evidence versus weight of speculation. 

### 14 EPA is speculating with inadequate evidence 

### 15 that by setting its point of departure based on a 10 percent 

### 16 inhibition of cholinesterase, it is protective of all adverse 

### 17 end points; however -- and I quote NIEHS scientists -- "Health 

### 18 protective assumptions are the default, must always be the 

### 19 approach, unless informed otherwise by multiple 

### 20 utility-consistent, adequately powered studies covering the full 

### 21 range of human exposures." 

### 22 Dr. Lorenzo Tomatis, former director of the

### Page 391 1 International Agency for Research on Cancer said, and I quote, 

### 2 "The issue is not singularly the adequacy of mechanistic or 

### 3 epidemiologic evidence but certainty for protecting public 

### 4 health." 

### 5 The NAS 2009 report by the National Academies, 

### 6 titled Science and Decisions, Advancing Risk Assessments, 

### 7 otherwise known as the Silver Book, recommended that when 

### 8 information is missing or unreliable that the agencies use 

### 9 scientifically-based default assumptions that protect health 

### 10 rather than waiting for more data. And then this way agencies 

### 11 could speed up chemical assessments and decision-making 

### 12 processes while still being protective of health. 

### 13 The NAS Committee concluded in their report, 

### 14 and I quote, "Established defaults need to be maintained for the 

### 15 steps and the risk assessment that require inferences." NAS 

### 16 recommended that EPA and other agencies update their defaults 

### 17 and assumptions, including where they are unstated or implicit 

### 18 assumptions, replace these with explicit ones. 

### 19 For example, for this question EPA does not 

### 20 have data on other mechanisms of action and is therefore, 

### 21 essentially quantitatively ignoring that potential contribution 

### 22 to risk. SAP could recommend that EPA acquire additional

### Page 392 1 uncertainty factors where it has inadequate data to describe 

### 2 alternate mechanisms of toxicity or adverse outcome pathways. 

### 3 Question 3 is regarding the neurodevelopmental 

### 4 data from laboratory animals. NRDC believes that the rodent 

### 5 data do support the conclusion that prenatal or early postnatal 

### 6 chlorpyrifos exposure may result in long-term adverse effects. 

### 7 And sadly, this is also supported by the epidemiologic studies 

### 8 that you will review in children who are exposed prenatally. 

### 9 The SAP could recommend that EPA revoke all 

### 10 tolerances and cancel remaining uses of chlorpyrifos in light of 

### 11 these unsafe continued uses. EPA has the authority and, in 

### 12 fact, the obligation to protect human health and the environment 

### 13 from continued exposures to this unnecessary and unsafe 

### 14 pesticide. 

### 15 Question 4 is regarding epidemiology. EPA has 

### 16 identified new epidemiologic studies published in the last year 

### 17 that demonstrate lasting impairments in children exposed, 

### 18 prenatally to organophosphates, including chlorpyrifos. 

### 19 Particularly the Chimariko study, which is 

### 20 rural in agriculture populations, provides real world evidence 

### 21 that EPA's current restrictions or label mitigations are not 

### 22 working. EPA rarely actually has data to test whether its label

### Page 393 1 restrictions are providing effective mitigation and they're 

### 2 effectively protecting people in the environment. But here with 

### 3 this study, we actually have evidence in real world that the 

### 4 mitigations are not protected enough and that children are being 

### 5 exposed and suffering lasting consequences. 

### 6 SAP could recommend that EPA consider these 

### 7 data as evidence that continued use of chlorpyrifos presents an 

### 8 unacceptable risk to expose populations, particularly where 

### 9 prenatal exposures occur. 

### 10 Question 5 is regarding biomonitoring and 

### 11 exposure data. I'm going to move a little off the actual 

### 12 question, but to bring up some important exposure and 

### 13 biomonitoring data. Residential bystanders' post-application 

### 14 inhalation exposures are too high. EPA's own analyses of some 

### 15 of the volatilization for exposures for residential bystanders 

### 16 indicates an end quarter of the acute ambient air concentrations 

### 17 resulted in risk estimates that exceeded EPA's level of concern. 

### 18 19 Over half of the acute application site air 

### 20 concentration resulted in risk estimates of concern. And some 

### 21 of the spray drift risk estimates calculated by EPA were also 

### 22 exceeding levels of concern, particularly for acute adults and

### Page 394 1 children inhalation exposures from ground mosquito treatment. 

### 2 These data point strongly to the need to 

### 3 assess both drift and volatilization as a significant pathway of 

### 4 exposure for people. In some cases this pathway alone exceeds 

### 5 level of concern, according to EPA's own analyses, and 

### 6 therefore, presents an unacceptable risk. 

### 7 SAP could recommend that EPA consider these 

### 8 data as evidence that continued use of chlorpyrifos presents an 

### 9 unacceptable risk. The drinking water assessments that EPA 

### 10 conducted in 2011, presented in a preliminary health risk 

### 11 assessment proved that drinking water alone exceeded many of 

### 12 EPA's risk estimates. I presented a Table from EPA's own 

### 13 assessment -- I haven't altered it in any way -- in my comments 

### 14 on page 5. I've highlighted all of the areas where the 

### 15 exposures exceed EPA'S acceptable limit. 

### 16 If EPA had actually used the 10 times stpA 

### 17 factor to protect children instead of no stpA factor, all of 

### 18 these actually would've been 10 times higher and all scenarios 

### 19 for all populations at all application rates would have exceeded 

### 20 the Apad. So SAP could recommend that EPA consider the data as 

### 21 evidence that continued use of chlorpyrifos is unacceptably high 

### 22 from drinking water alone.

### Page 395 1 There's also evidence that occupational 

### 2 exposures are unsafe. EPA's own assessment reports that many of 

### 3 the exposure scenarios, 350 exposure scenarios for workers 

### 4 exceeded acceptable limits. Some, even when the full level of 

### 5 personal protective equipment was used. And importantly, it is 

### 6 important to remember that occupational exposures are not just 

### 7 to adult workers, it is also farm workers that are under age and 

### 8 pregnant women who work in fields as well. 

### 9 In conclusion, I'd like to suggest that SAP 

### 10 could recommend that EPA finalize its policy to protect workers 

### 11 and children of workers in agriculture fields to provide a 

### 12 measure of protection for these young farm workers and their 

### 13 families. This policy was announced in a Federal Register in 

### 14 2009 by EPA, but has been held up and has not been finalized 

### 15 yet. 

### 16 I'm happy to answer any questions. Thank you. 

### 17 DR. KENNETH PORTIER: Thank you. Do we have 

### 18 any questions from the panel for Dr. Sass? 

### 19 Dr. Sass's written comments were in the 

### 20 docket; is that correct? 

### 21 DR. FRED JENKINS: Yes. 

### 22 DR. KENNETH PORTIER: Yes. We'll distribute

### Page 396 1 hard copies for you so that you can look at that. Thank you 

### 2 very much, Dr. Sass. It doesn't seem to be any questions here. 

### 3 DR. JENNIFER SASS: Thank you. 

### 4 DR. KENNETH PORTIER: So the next public 

### 5 commenter before the panel is Dr. Dale Hattis from Clark 

### 6 University. Dale. 

### 7 DR. DALE HATTIS: Yes. I must preface my 

### 8 remarks by saying that these are my personal views and are not 

### 9 representative of Clark University, my EPA funders, or even my 

### 10 collaborators on the project. 

### 11 As you may know from the EPA background 

### 12 materials, and my colleague has been working for a number of 

### 13 years, funded by an EPA STAR Grant on chlorpyrifos dosimetry in 

### 14 people. 

### 15 The aim of this is to bridge a gap in the 

### 16 epidemiological literature between the biomarkers used in the 

### 17 epidemiological studies, in particular, blood chlorpyrifos and 

### 18 the chronic oral and inhalation doses that EPA will need to 

### 19 consider if it wants to use the epidemiology rather than the 

### 20 animal experiments as a basis for the determination of 

### 21 tolerances in RfDs and RfCs. 

### 22 Slide 2. Next slide. Oh, I do it. Okay.

### Page 397 1 Let's see. This discussion has two parts; first, and the more 

### 2 extensive part, will be talking about this dosimetry issue, 

### 3 where I can sort of abbreviate by shorthand of saying the 

### 4 dosimetry ratio. That is the ratio of chronic dose, either by 

### 5 inhalation or ingestion to the blood level. So all of the PBPK 

### 6 modeling and et cetera, and another analysis are designed to 

### 7 give some insight into that ratio. We're way below in these 

### 8 experiments, in these observations, levels where saturation is a 

### 9 problem. 

### 10 So it's reasonable to take this, more or less, 

### 11 as a linear function, the amount of blood chlorpyrifos 

### 12 reflecting at least some measure of the chronic doses. And 

### 13 these doses, at least to the extent of the air levels, are 

### 14 relatively consistent within houses, within apartments for the 

### 15 Columbia study. 

### 16 The dosimetry discussion involves developing a 

### 17 prior, and this is at least a Bayesian inspired analysis, if not 

### 18 a true Bayesian analysis, from a bounding of the possible range 

### 19 of this dosimetry ratio, external dose to internal dose, based 

### 20 upon the data that are internal to the Columbia study that was 

### 21 shared with me. 

### 22 The second part is a PBPK-based uncertainty

### Page 398 1 distribution, varying a couple of key parameters: the metabolism 

### 2 rate and the tissue blood partition coefficients. And then I'll 

### 3 do something like a Bayesian combination of these, although you 

### 4 should have the caveat that I'll give you the formula, but it's 

### 5 not exactly Bayes theorem. 

### 6 After that, I'll talk about how one might 

### 7 interpret the Columbia study results for reduced short-term 

### 8 memory and IQ in terms of RfD and RfC type standards. So there 

### 9 are risk management considerations in defining what a benchmark 

### 10 dose -- that benchmark response is in this context, and these 

### 11 are beyond where a techy like me usually ventures, but in order 

### 12 to show these implications, I have to make assumptions about 

### 13 what our reasonable range of choices might be and then we'll 

### 14 conclude with implications of some alternative benchmark 

### 15 response definitions for lower confidence limits on associated 

### 16 inhalation and oral intake studies using the central estimates 

### 17 for the dosimetry ratio and the lower confidence limits on the 

### 18 doses, or upper confidence limits on the potency indicated by 

### 19 the Columbia epidemiologic study of the neurological indices in 

### 20 relation to the blood levels measured in the mothers. 

### 21 I'm first going to talk about the bounding 

### 22 calculation from the Columbia data themselves. I defined a

### Page 399 1 lower limit as the observed ratio of measured air intake for the 

### 2 individual women projected to the birth date of the babies 

### 3 because there are secular trends in all these biomarkers. So 

### 4 basically there was some lag time between the measurement of the 

### 5 air levels and the actual birth of the babies. 

### 6 So I at least took into account the decline 

### 7 expected in that period for the average of the whole population. 

### 8 Basically, that gives rise to a dosimetry ratio of about half a 

### 9 nanogram per kilogram a day, per picogram per gram of 

### 10 chlorpyrifos in the blood. For an upper limit I also had 

### 11 measurements in the same women of the excretion rate of TCP, 

### 12 normalized creatinine, which I could then interpret in terms of 

### 13 a daily excretion rate. And this gives a much larger -- so 

### 14 basically, assuming that some of the TCP might've come from 

### 15 other sources, this represents an upper limit on the possible 

### 16 dose that chlorpyrifos that people could have -- that the 

### 17 mothers could have gotten. 

### 18 We know the lower limit is, you know, of the 

### 19 order of half a nanogram per kilogram per day. The upper limit 

### 20 calculated in this way is something like 55, 54 nanogram per 

### 21 kilogram per day, per picogram per day. So that sets some 

### 22 reasonable limits. I decided that I wouldn't consider those as

### Page 400 1 absolute limits, that there's some chance that the real value 

### 2 could be outside that, so I assigned subjective one percent to 

### 3 99 percent confidence limits to these bounds and that results in 

### 4 a geometric mean, a log normal distribution with a geometric 

### 5 mean of about 5.5, a very large geometric segregation of 2.43. 

### 6 And that's what that distribution looks like in sort of 

### 7 anti-logs, you know, unlogged space. If I plotted the log, it 

### 8 would be symmetrical. 

### 9 The PBPK analysis of the dosimetry ratio 

### 10 starts with the Timchalk model results. The Timchalk model was 

### 11 published, originally, in 2002. He presented results in SAP 

### 12 hearings in 2008 that implied a ratio of about 40 nanogram per 

### 13 kilogram per day for ingestion exposure and 26-fold less for 

### 14 inhalation exposure, giving a ratio or about 1.5 in the terms 

### 15 that I had prior being .5 to 50. 

### 16 The Timchalk metabolism rate estimates, 

### 17 however, were derived -- the large difference between, in the 

### 18 Timchalk model, expectations for oral versus inhalation exposure 

### 19 come from a huge first pass effect. That is, essentially, stuff 

### 20 that's ingested has to be passed through the liver before it 

### 21 reaches the rest of the systemic circulation. And in the case 

### 22 of the original rat-derived metabolism rates, that ratio is, you

### Page 401 1 know, something like 99 percent of the material. So that 

### 2 creates a big difference from the inhalation, which gets the 

### 3 systemic circulation more directly and only a quarter of the 

### 4 blood volume get though the liver with each per minutes. 

### 5 So essentially, that creates this huge 

### 6 difference between the oral and the inhalation route of 

### 7 exposure, in terms of its interpretation, in terms of blood 

### 8 level. 

### 9 Our uncertainty analysis of the adapted model 

### 10 takes into account uncertainties in both metabolisms. I had 

### 11 updated metabolism rate information in people. So this is 

### 12 people who died, but they had various ages that -- you know, we 

### 13 had a total of 30 people worth of recent information published 

### 14 by Smith, I believe. I took from that the five adult women as 

### 15 the basis for our thing. But there's uncertainty because there 

### 16 is variation from person-to-person. There's uncertainty in that 

### 17 average, calculated from only five people. So I took into 

### 18 account the statistical confidence limits expected from that 

### 19 information. 

### 20 Also, the people who died and gave rise to 

### 21 these liver microsome measurements weren't known to be pregnant. 

### 22 So there's at least potential for there to be a systematic

### Page 402 1 difference between pregnant people and non-pregnant people in 

### 2 their liver metabolism rate. So I found a substantial 

### 3 compilation of -- well, it was seven different drugs where the 

### 4 clearance values have been measured, in vivo, both for the 

### 5 pregnant people and the non-pregnant people. And that 

### 6 difference was usually approximately two-fold, with confidence 

### 7 limits ranging from, more or less, equal to about four-fold 

### 8 larger. So I incorporated that uncertainty as well, into the 

### 9 overall analysis of how uncertain I should be about these 

### 10 recalibrated PBPK measurements. 

### 11 It's important to note that in calibrating the 

### 12 model at this stage, I have not used the results from the 

### 13 Kisicki and Nolan, et al. direct administration studies because 

### 14 of EPA concerns for the informed consent procedures. EPA 

### 15 considers that it is barred from using the Kisicki data, and 

### 16 therefore, to make it potentially useful to EPA, I haven't done 

### 17 that. But I will do that later before, just to add another 

### 18 point of comparison that can give perspective on the likely 

### 19 uncertainties. 

### 20 So here's what the results come out to be. 

### 21 The best estimate projections are in the upper left. For 

### 22 ingestion, I've basically got a central estimate of about 188

### Page 403 1 ratio of nanogram per kilogram day, per picogram per gram of 

### 2 chlorpyrifos in blood. Inhalation is projected to be about six 

### 3 or seven times more efficient in producing blood level, compared 

### 4 to the ingestion where the central estimate is only 28. And you 

### 5 can see that one standard deviation, high or low, or one 

### 6 centered, high or low, in both the metabolism parameter and the 

### 7 tissue blood partition coefficients as derived from -- has 

### 8 modest, you know, effects on the overall results. 

### 9 So basically, I used these results with the 

### 10 uncertainties in these two dimensions to construct an overall 

### 11 stratified random sample of the overall distribution. So this 

### 12 is the distribution that I get from that process of permuting 

### 13 both of those parameters. 

### 14 Now, there are other uncertainties. I 

### 15 probably should be more uncertain than I have represented here 

### 16 about the metabolism rate because there could be differences 

### 17 between the functioning of the enzymes in human liver and those 

### 18 that are inferred from the in vitro microsome measurements 

### 19 combined with the amount of microsomal protein per gram of 

### 20 litter and things and that sort. So there's probably more 

### 21 uncertainty than I have mentioned in these PBPK model results, 

### 22 but that's what I've got so far.

### Page 404 1 So what you see here is something that instead 

### 2 of the prior, which had a central estimate of about 5.5, this is 

### 3 a central estimate of approximately 27 or a bit more, and it 

### 4 spreads out between 20 and 40 in ways that are interested. So 

### 5 the formula for combining the two distributions is a posterior 

### 6 probability that the inhalation dose to blood level is 

### 7 essentially the product -- the probability that's in any 

### 8 interval of the dosimetry factor -- measured in log space 

### 9 usually -- is a product of product of the probability that the 

### 10 value is in that interval of the prior. The probability that 

### 11 it's in that interval times the calibrated model, divided by the 

### 12 sum of all of such products. So essentially, this is 

### 13 integration over all of the reasonable values of the thing. 

### 14 So what I get when I do this combination is 

### 15 this very much resembles the model projection because the model 

### 16 projection was considerably narrower in its distribution. So 

### 17 that heavily influences this result with a central estimate of 

### 18 about 26. And I think I've got the statistic. 

### 19 So the updated -- with the geometric mean of 

### 20 26 and 2.5 percent to 95 percent confidence levels, something 

### 21 like 20.5 to 33.5 nanogram per kilogram/day inhaled, per 

### 22 picogram per gram in maternal blood. Using the central estimate

### Page 405 1 for the ingestion to inhalation ratio, you get something like 

### 2 175 nanogram per kilogram per day, per picogram in maternal 

### 3 blood. 

### 4 So all of that stuff goes to how we use, how 

### 5 we can convert the dosimetry findings, which are in terms of 

### 6 either maternal or child blood, core blood in the Columbia 

### 7 epidemiology study to doses that EPA could potentially use in 

### 8 its determination of ADIs and RfCs and RfDs. Essentially, the 

### 9 ultimate result -- okay. 

### 10 Now, we'll turn to the Columbia 

### 11 neurodevelopmental findings. Essentially, what they developed 

### 12 was a series of progression relationships controlling for other 

### 13 confounders of the relationship to either the working memory 

### 14 index or full scale IQ. 

### 15 The working memory index was the kind of 

### 16 parameter that gave the most clearly positive results, 

### 17 essentially, with basically, they related the national log 

### 18 algorithm of the working memory index with a particular 

### 19 coefficient to the blood chlorpyrifos levels with a P-value of 

### 20 less than .01. Full scale IQ was also positive, but at a much 

### 21 more marginal P-value of .05 or so. 

### 22 So basically, now that I have these

### Page 406 1 relationships I can then go on to then translate those into 

### 2 external ingestion or inhalation exposure levels. Most of the 

### 3 exposure in the Columbia cohort, might well have been 

### 4 inhalation. 

### 5 So possible risk management choice; we need to 

### 6 talk a little bit about possible risk management choices for 

### 7 defining a benchmark dose. One possibility is that you would 

### 8 have a 10 percent excess risk of being below the first 

### 9 percentile of the index. Both IQ and the working memory index 

### 10 are constructed similarly to have a population mean of 100 in a 

### 11 standard deviation of 15, so that the first percentile 

### 12 corresponds to a reading of about 65. 

### 13 So the question is okay, if you want to have a 

### 14 10 percent excess risk as your benchmark, raising the incidence 

### 15 of scores as low as that from one percent to 1.1 percent, how 

### 16 much do you need to shift the population mean in order to get 

### 17 that result? The Columbia findings are in terms of, 

### 18 essentially, population means or population geometric means. 

### 19 Essentially, to do that requires a shift of 

### 20 overall distribution of about .54 index points. If you want to 

### 21 take another possible definition of the benchmark response, that 

### 22 is, beyond the fifth percentile -- that's the 75.3 or so, on the

### Page 407 1 index -- and you want to again, use this as the benchmark dose, 

### 2 a 10 percent excess risk from five percent to 5.5 percent would 

### 3 require a shift in the mean of about .7 index points. I'm going 

### 4 to present some results based upon this second criteria. 

### 5 Now, there's another possible way in which you 

### 6 could value individual shifts in IQ for risk management 

### 7 considerations and that is to say, okay, well, we know that IQ, 

### 8 and probably related neurological functions, are important for 

### 9 long-term worker productivity and therefore, lifetime income. 

### 10 So Gross, in conjunction with Joel Schwartz and others at 

### 11 Harvard did a study, or published in a study in about 2002 that 

### 12 suggested that each index point reduction, in the context of 

### 13 lead, was estimated to be associated with a loss of about two 

### 14 percent in lifetime income for 2-year-olds, or about $14,500 in 

### 15 2002. 

### 16 So let's say that we wanted to consider that 

### 17 you wouldn't want to suffer more than $100 per exposed person 

### 18 damaged for a lifetime income. If you want to do that, then of 

### 19 course, you need to limit the population shift to less than 

### 20 about 100th of an IQ point, which is a pretty stringent type of 

### 21 standard. 

### 22 So anyhow, that's another basis that you might

### Page 408 1 consider for risk management. Still, there are people who would 

### 2 want to be more stringent than that because $100 of lifetime 

### 3 income might not be. Although it wouldn't be detectable, it 

### 4 might not trivial be either when considered as a population 

### 5 average and there might be variation among people as well. 

### 6 So what does that all mean for the overall 

### 7 numbers and how do they compare with the RfDs/RfCs derived from 

### 8 the animal studies? 

### 9 I have made a study of the animal studies, but 

### 10 my recollection is that you come out with a population aggregate 

### 11 dose of about 300 nanograms per kilogram/day for the ultimate 

### 12 ingestion. Now, this is an inhalation intake. As you see, the 

### 13 inhalation dose that's associated with .7-point change in the 

### 14 index, if you consider that as your benchmark, that comes out to 

### 15 be about 18 nanogram per kilogram/day. If you then apply a 

### 16 traditional uncertainty factor, you get down to 1.8 nanogram per 

### 17 kilogram/day. And if you want to apply the FQPA factor in 

### 18 addition, it gets down to .18. If you want to just accept your 

### 19 benchmark of 100th of an IQ-point standard, that gets you to 

### 20 about .26 nanogram per kilogram/day by inhalation. 

### 21 Now, this is not for IQ, this is working 

### 22 memory. There's a similar, but only a little less stringent

### Page 409 1 effect for the IQ. So this is now the same working memory end 

### 2 point and the ingestion in an ingestion index. This comes down 

### 3 to, you know, with all the calculations, either something 

### 4 between 1 and 12 nanogram per kilogram/day for the .7 IQ point, 

### 5 7-point shift and 1.8 for the ingestion. 

### 6 So these are now similar calculations for the 

### 7 full-scale IQ measurements. Suffice it to say that these 

### 8 numbers -- the points of departure are comparable to the EPA's 

### 9 ultimate population aggregate dose target, but if you then go on 

### 10 to the 300, I think it would be on that scale. But then if you 

### 11 go on to apply the uncertainty factors to that, you get much 

### 12 lower. Or if you adopt the .01-point change in the index 

### 13 standard, then you get too much lower values, all of which may 

### 14 suggest that if you believe the Columbia results and the other 

### 15 epidemiological findings that are somewhat parallel to that, 

### 16 that there's some indication that the usual procedure to base 

### 17 your standard on the 10 percent benchmark inhibition in the 

### 18 animal studies is not picking up the effects of dose levels that 

### 19 are needed -- that may impair neurodevelopmental of higher 

### 20 neurological functions in people. And I would be happy to 

### 21 expand on any of these suggestions if the panel has questions. 

### 22 DR. KENNETH PORTIER: Thank you, Dale. Any

### Page 410 1 questions? Dr. Collier. 

### 2 DR. ABBY COLLIER: Abby Collier. Hi, Dale. 

### 3 DR. DALE HATTIS: Hi. 

### 4 DR. ABBY COLLIER: I ask this question mostly 

### 5 out of interest, but I think it is relevant for the panel. When 

### 6 you built your pregnancy model, did you include metabolic 

### 7 contribution from the placenta? 

### 8 The reason I ask is because from the Bisphenol 

### 9 A literature, we have a lot of people starting to say that 

### 10 clearance across the placenta may be predicative. 

### 11 DR. DALE HATTIS: I didn't. I didn't put that 

### 12 in. Basically, there's a convention PBPK modeling to put all 

### 13 the metabolism in the liver. It's reasonable to possibly do 

### 14 that, but I didn't have any separate measurements. What I did 

### 15 have was these ratios of whole body clearance for pregnant women 

### 16 versus non-pregnant women. So that should implicitly include 

### 17 that kind of conjugates, but the model itself didn't have that. 

### 18 Were you to put a fair amount of metabolism outside the liver, 

### 19 it would decrease the difference between an ingestion and 

### 20 inhalation pathway, but it might not change the inhalation much. 

### 21 It would change mainly the ingestion numbers, I think. 

### 22 DR. KENNETH PORTIER: Dr. Lu.

### Page 411 1 DR. CHENSHENG LU: Just for clarification, 

### 2 when you mentioned external dose, you're really referring to 

### 3 inhalation dose? 

### 4 DR. DALE HATTIS: Well, inhalation exposure or 

### 5 absorption through the gut. So I haven't got an absorption 

### 6 factor in there. So I'm basically saying that the -- basically, 

### 7 what I do in the model is take the stuff that I call 

### 8 ingestion-absorbed dose and send it directly into the artery 

### 9 feeding the liver. So that it all has to go to the liver before 

### 10 getting anywhere else. 

### 11 DR. CHENSHENG LU: All right. So I think this 

### 12 external dose, the terminology seems very confusing if you also 

### 13 take into account the absorption through the injection, then 

### 14 obviously that's not external anymore. 

### 15 DR. DALE HATTIS: Injection? 

### 16 DR. CHENSHENG LU: Yeah, the oral injection. 

### 17 The absorption taking place in the gut. 

### 18 DR. DALE HATTIS: I think, and I stand to be 

### 19 corrected on this, that chlorpyrifos is relatively well 

### 20 absorbed. That there's not a whole lot of loss through the 

### 21 feces, but if that's wrong, then that would differ -- that would 

### 22 cause you to adjust upward, slightly, the ingestion dose.

### Page 412 1 DR. CHENSHENG LU: So the other question is 

### 2 that your model built on the moment at age 7 when the IQ test 

### 3 was taken place -- 

### 4 DR. DALE HATTIS: Well, the dose response 

### 5 relationship is based on that. 

### 6 DR. CHENSHENG LU: Right. So would this model 

### 7 be generalized to other age groups? Say, for example, I mean, I 

### 8 look at your model and it seems like there's no time lag time in 

### 9 the models. So what happens is if the same kid that was tested 

### 10 at age 7, have a certain number of IQ knowing the 

### 11 neurodevelopmental level. 

### 12 Would your model be robust enough when the 

### 13 kids become 11 years old? 

### 14 DR. DALE HATTIS: The blood measurements were 

### 15 all made at the time of birth, but we're measuring the 

### 16 implications for neurodevelopment at age 7, which is when you 

### 17 can measure and other things more robustly; although, they 

### 18 measured other things earlier in the same populations, the 

### 19 Bailey Scales and things like that. 

### 20 DR. CHENSHENG LU: But my point is the basis on 

### 21 what you provide here that if the same kids -- we measure the 

### 22 same kids' IQ at age 9, the outcome would be the same as age 7.

### Page 413 1 DR. DALE HATTIS: It might be. The 

### 2 measurements don't yet exist, but I think that by the time 

### 3 you've got a difference at age 7, you know, it's reasonable to 

### 4 presume that that's a predicator of the lifetime 

### 5 neurodevelopmental scores. We won't know that for some decades, 

### 6 I think. 

### 7 DR. KENNETH PORTIER: Any additional 

### 8 questions? Dr. Pope. 

### 9 DR. CAREY POPE: Early on in your presentation 

### 10 you said something about the metabolism of chlorpyrifos appeared 

### 11 to be somewhat lower in humans liver samples -- 

### 12 DR. DALE HATTIS: Than rats. 

### 13 DR. CAREY POPE: -- than lab rats. With the 

### 14 rat, it's kind of easy to control what the animal is consuming 

### 15 and to see states and stuff like that. What kind of control on 

### 16 the human tissues do you have as far as tobacco or alcohol 

### 17 consumption or disease or cause of death? 

### 18 DR. DALE HATTIS: Done. The experimenters 

### 19 harvested the liver, essentially, early after death, but didn't 

### 20 further characterize -- they characterized the -- and this is 

### 21 actually stuff that went into some Dow modeling as well, later 

### 22 -- but it did -- they characterized the age and the gender of

### Page 414 1 the people but not prior exposures. 

### 2 Basically, it's catch if catch can, you know, 

### 3 for those kinds of studies. I think there may well have been a 

### 4 listing of cause of death in the paper and I don't remember. 

### 5 Many of the subjects for these kinds of studies, they try to 

### 6 favor head injury victims and things like that, but it's 

### 7 whatever they died of. 

### 8 DR. CAREY POPE: What about the variability if 

### 9 you were comparing -- and this is not my area -- but the 

### 10 variability of kind of metabolic rates and some of the processes 

### 11 you're looking at in human samples versus the rodent tissues? 

### 12 DR. DALE HATTIS: I've got observations that 

### 13 can be analyzed that way and I haven't done it. My guess is 

### 14 that humans are more variable as a general matter because 

### 15 they're not genetically uniform and they're not uniform in their 

### 16 exposures that can induce liver enzymes. 

### 17 DR. KENNETH PORTIER: Dr. Popendorf. 

### 18 DR. WILLIAM POPENDORF: Just one comment and 

### 19 then a question. As far as the oral absorption, it's 70 

### 20 percent, based on the Nolan data. It's a small difference. 

### 21 DR. DALE HATTIS: Okay. 

### 22 DR. WILLIAM POPENDORF: I'm just trying to

### Page 415 1 figure out here, just to get a clear idea as to how these 

### 2 numbers were derived in the last, you know 13, 14. 

### 3 What's the relationship between, like for 

### 4 instance, the inhalation dosage you got here and the airborne 

### 5 concentrations that were measured in Columbia data? 

### 6 DR. DALE HATTIS: The air concentrations in 

### 7 the Columbia study -- let me go and look that up. 

### 8 DR. KENNETH PORTIER: Dale, use your mic a 

### 9 little better too, so people in the back can hear. 

### 10 DR. DALE HATTIS: Oh, sorry. I've got to look 

### 11 it up in order to answer your question fairly. 

### 12 DR. WILLIAM POPENDORF: Well, I'm thinking 

### 13 conceptually, not quantitatively. You referred early on to the 

### 14 fact that the Columbia's study, when they were looking at air 

### 15 concentrations, they were decreasing over time. I presume you 

### 16 meant over the years. 

### 17 DR. DALE HATTIS: Yeah. Right. For example, 

### 18 for 110 samples that were collected in 1999 were the women 

### 19 before they gave birth. The average air levels were 6.91 -- oh, 

### 20 wait a minute. That's the average blood levels. The blood 

### 21 level was about 6.91 for 1999. Let me go look at the air 

### 22 levels.

### Page 416 1 The average air levels in 1999 were 3.4. 

### 2 Well, that's the air intake that I calculated by applying a 

### 3 breathing rate from average pregnant people. For 1999, that 

### 4 left about an average of 3.4 nanogram per kilogram/day. For 

### 5 2000, I got 2.2; for 2001, I got 2.63; and then for 2002 and 

### 6 2003, I got 1 and 1.2. so there's a trend there. And in 1998, 

### 7 based on only four samples, I got 10. 

### 8 So there is a secular trend toward reduction 

### 9 over the years, partly as a result, most likely of EPA's phased 

### 10 reduction and the slow outgassing phase of the residential uses 

### 11 and probably the relatively slow outgassing of the chlorpyrifos 

### 12 absorbed on surfaces. 

### 13 DR. WILLIAM POPENDORF: So I guess I'm -- 

### 14 DR. DALE HATTIS: So now we're talking about 

### 15 -- in terms of nanogram per kilogram/day, we're talking about 

### 16 two or three as the range of observed levels in the early years. 

### 17 Now, that's ingestion. So let's go back a slide. 

### 18 DR. WILLIAM POPENDORF: Yeah. 

### 19 DR. DALE HATTIS: This is the inhalation doses 

### 20 for the IQ effect. The estimated inhalation dose to produce the 

### 21 .7 change is 31. The inhalation dose to do the .01-point change 

### 22 in the index was .4. So the .4 is close to 8-fold less than the

### Page 417 1 levels that went into the study. The 31 is of the order of 

### 2 10-fold more than the average air level. 

### 3 DR. WILLIAM POPENDORF: And that's within, I 

### 4 guess, the range of the measurements, a lot of variability to 

### 5 incur that. 

### 6 DR. DALE HATTIS: Yeah. Oh, yeah. There's 

### 7 quite a lot of variability. I'm just basically using the 

### 8 averages in a particular year as the way of washing out some of 

### 9 that. 

### 10 DR. KENNETH PORTIER: Dr. Popendorf, can I 

### 11 recommend that may you go to lunch with Dale and kind of work 

### 12 through it. We'll leave it open. We'll come back after lunch. 

### 13 It's 12:05. We're going to go ahead and take our one-hour lunch 

### 14 break. Yes, Dr. Vena? 

### 15 DR. JOHN VENA: I just have one question. It 

### 16 looks like you're trying to say that you looked at air 

### 17 distribution and you developed and you looked at the modeling 

### 18 for the maternal blood. Are these all maternal blood or is this 

### 19 core blood? 

### 20 DR. DALE HATTIS: Yeah. There's a strong 

### 21 correlation between the maternal -- it's actually quite, and not 

### 22 very much difference, like seven or eight percent difference, on

### Page 418 1 average, for the maternal blood and a child blood, which is a 

### 2 huge surprise because maternal blood has much more fat in it 

### 3 than the core blood, So that the concentrations that are 

### 4 observed are comparable. 

### 5 So I should make the additional correction for 

### 6 what the average ratio is of child to maternal and I didn't do 

### 7 that yet in these calculation. I expected to, but I ran out of 

### 8 time. Nevertheless, it's one of the most puzzling aspects of 

### 9 this modeling that there is not a bigger difference because 

### 10 there is a several fold difference in the amount of fat in core 

### 11 blood plasma versus maternal plasma. 

### 12 DR. JOHN VENA: So these final slides are 

### 13 maternal blood? 

### 14 DR. DALE HATTIS: In terms of maternal blood, 

### 15 but applied with less than perfect accuracy to the core blood 

### 16 measurements. So an additional correction should be made to 

### 17 make that they're on the same basis, but the differences won't 

### 18 be very large. 

### 19 DR. KENNETH PORTIER: I'm going to give 

### 20 the panel lunch to think about this. Dale, are you going to be 

### 21 here after lunch? 

### 22 DR. DALE HATTIS: I'll come back.

### Page 419 1 DR. KENNETH PORTIER: So we'll leave the open 

### 2 comment period open until right after lunch. We'll entertain a 

### 3 couple more questions if you think of them, as the panel thinks 

### 4 of clarifying questions from any of the public commenters and 

### 5 then right after that we're close the public comment period and 

### 6 EPA will come back to the table to read the questions but we'll 

### 7 open up for any clarifying questions that panel may have 

### 8 developed over night that they want to ask EPA. At that point 

### 9 we'll close the general questions and move onto our panel 

### 10 discussions. So we're going to try to get back here at 1:00, by 

### 11 this clock. It gives us 55 minutes. We'll probably let it 

### 12 slide five minutes, but let's try to be back by 1:00. Thank 

### 13 you. 

### 14 (Whereupon, a luncheon recess was taken.) 

### 15 * * * * * 

### 16 17 DR. KENNETH PORTIER: I know the panel 

### 18 was very productive over lunch; that is why I did not want to 

### 19 rush them back because they were working on it and now the 

### 20 memory stick floating around; they are getting organized. 

### 21 Continuing with the public comment section, I 

### 22 wanted to ask Dr. Popendorf if he had gotten his question

### Page 420 1 clarified and if he had something he wanted to potentially share 

### 2 with the panel from his discussions with Dr. Hattis. 

### 3 DR. WILLIAM POPENDORF: Thank you, yes, we did 

### 4 get my questions answered and I think I will have some comments 

### 5 based on that when we talk about PBPK modelling. 

### 6 DR. KENNETH PORTIER: Are there any additional 

### 7 questions from the panel for Dr. Hattis? No. Dale I hope you 

### 8 had a good lunch. Thank you. Are there any additional 

### 9 clarifying questions for the other public commenters? This is 

### 10 your last chance here, although it is never the last chance; we 

### 11 end up bringing them back anyway. In theory this is the last 

### 12 chance. Dr. Harry. 

### 13 DR. JEAN HARRY: So there was a mention that 

### 14 there was a slide or data available on the differences in the 

### 15 Columbia Cohort and the before and the after, that was mentioned 

### 16 that you had. Yeah. 

### 17 DR. KENNETH PORTIER: If you can provide that 

### 18 to Fred here he can have that table printed out. The staff over 

### 19 here at the table can take care of it and then we will get that 

### 20 distributed. You did not have a question about it; you just 

### 21 wanted that to look at, right? Dr. Harry? 

### 22 DR. JEAN HARRY: Well, I do not know if I have

### Page 421 1 a question about it until I look at it, sorry. But, no I mean 

### 2 we had asked that question yesterday and they were saying they 

### 3 would provide that data today and it was mentioned so it would 

### 4 be nice to have it. 

### 5 DR. KENNETH PORTIER: Yes, Dr. Popendorf. Two 

### 6 questions. 

### 7 DR. WILLIAM POPENDORF: Two questions, yes. I 

### 8 don't know if Dr. Sass is still available, but one of my 

### 9 questions was related to Table 5. 

### 10 DR. KENNETH PORTIER: Yes, we would have to 

### 11 call her. 

### 12 DR. WILLIAM POPENDORF: Okay, the other 

### 13 question, I'm not quite sure it is probably directed generally 

### 14 towards EPA or anyone else that could. I'm sort of looking to 

### 15 see if there were any estimates of ingestion of chlorpyrifos 

### 16 through foods? Market basket type data done by survey type work 

### 17 would not necessarily; I mean certainly it is related to these 

### 18 cohorts that we are looking at but I did not actually see that 

### 19 type of data in materials presented. 

### 20 DR. KENNETH PORTIER: Well let me just ask 

### 21 first a question from the public commenters. If anybody wanted 

### 22 to comment on that question, you know, DOW if they have got any

### Page 422 1 data or any experts, because I really want to close off the 

### 2 public comment section. 

### 3 I do not think there are any more questions. 

### 4 I think at this point we are going to close the public comment 

### 5 section and open up back to EPA for comments. I know they had a 

### 6 couple of things they promised the panel yesterday that they 

### 7 wanted to mention to us and then they can ask your question, so 

### 8 we will turn it over to Dr. Lowit. 

### 9 DR. ANNA LOWIT: This is Anna Lowit. We do 

### 10 have a couple of things we had committed to chasing down over 

### 11 night that we have followed up on and we are loading the slides 

### 12 now, but in the meantime I think we can answer Dr. Popendorf's 

### 13 question fairly quickly. 

### 14 DR. JEFF DAWSON: For the record, Jeff Dawson; 

### 15 I'm an exposer scientist in the Health Effects division and Dr. 

### 16 Popendorf in the paper there is an appendix with different dose 

### 17 estimates that we incorporated in there for -- it is at the very 

### 18 end, related to exposer scenarios and I think there is one in 

### 19 there for dietary estimates of dose, so if you want to look at 

### 20 that. It is attachment 1 or Appendix 1; it is a table. 

### 21 DR. KENNETH PORTIER: Dr. Young. 

### 22 DR. HEATHER YOUNG: I just wanted to follow

### Page 423 1 up. There is an epi paper too by Lu et al. that talk about 

### 2 dietary exposer from OP sources. I do not think it was included 

### 3 in this but it is referenced in one of the other papers. 

### 4 DR. KENNETH PORTIER: Any additional questions 

### 5 for EPA, that came up? Dr. Pope. 

### 6 DR. CAREY POPE: This is for Dr. Christensen. 

### 7 Yesterday, I think Dr. Vena had brought up the idea of 

### 8 questioning the dialkylphosphate and what DMP and DEP and DETP 

### 9 represented or what the importance of those was. 

### 10 In your presentation you gave some of the 

### 11 later behavioral changes from the epi studies showing the APS; 

### 12 and I think one of the other presenters also brought this up and 

### 13 suggested there was not kind of some correlation between DEPS 

### 14 and some of the behavioral endpoints. 

### 15 Can you kind of clarify that for me? 

### 16 Specifically addressing the diethyl phosphate correlation with 

### 17 some of the epi findings? 

### 18 DR. CAROL CHRISTENSEN: Sure, Carol 

### 19 Christensen, EPA. I think on the first issue we have some 

### 20 information to present as to the potential parent compounds for 

### 21 the different DAP in DAP subclass groups, and Jeff Dawson will 

### 22 be presenting that.

### Page 424 1 Concerning the epi studies, as I noted in my 

### 2 presentation yesterday, although I sort of tabularly depicted 

### 3 the results in terms of the DAP each of the respective 

### 4 investigations that used this nonspecific measure of OP exposure 

### 5 as their analytic tool in the epi studies broke out DEP and DMP. 

### 6 Chlorpyrifos exposure would not go to DMP as was discussed 

### 7 yesterday. Chlorpyrifos plus other OPs may go to diethyl 

### 8 phosphate. 

### 9 So regarding your latter point as to 

### 10 clarifying what results were attributable to DEP versus DAP 

### 11 versus DMP, that information should be pretty clearly laid out 

### 12 in Appendix 5 of our materials. It is not laid out in Table #10 

### 13 as we know. 

### 14 But there were instances in which the DAP 

### 15 association appeared to be driven by DMP as noted yesterday. 

### 16 But there were other situations in which the DEP association you 

### 17 could theorize that that was driving the DAP. So it varied and 

### 18 I cannot recall off of the top of my head kind of which went 

### 19 where but it should be in Appendix 5. 

### 20 DR. CAREY POPE: Particularly for your 

### 21 presentation on that slide 34 do you have any feeling about 

### 22 whether DMP is driving those correlations?

### Page 425 1 DR. KENNETH PORTIER: A slide on Intelligence 

### 2 Measures. 

### 3 DR. CAROL CHRISTENSEN: Yes I do, in fact I 

### 4 was just looking at that as I was updating Table 10. If I'm 

### 5 recalling correctly, for the CHAMACOS cohort in which I have DAP 

### 6 listed. The DEP, the beta coefficient representing the inverse 

### 7 association between DEP and these various measures of 

### 8 intelligence were at greater magnitude, i.e., a greater inverse 

### 9 association with the DEP then with the DMP in that instance. It 

### 10 is notated in the paper clearly, but that is my recollection 

### 11 having looked at that recently. You are talking about the 

### 12 intelligence measures, yes. 

### 13 DR. KENNETH PORTIER: Okay, Dr. Dawson. or Dr. 

### 14 Lowit, you want to introduce this? 

### 15 DR. ANNA LOWIT: Yes, I will just give you a 

### 16 sense of what we have done. We have four small things to follow 

### 17 up on from either yesterday afternoon or from this morning. 

### 18 Jeff Dawson will cover the first two. The 

### 19 first one is just to make sure there is clarity around the limit 

### 20 of detection, limit of quantitation for the Columbia study. The 

### 21 next one is the issue of the DAPs and which OPs contribute to 

### 22 DMPs and DAPs.

### Page 426 1 And then I will turn it over to Bill Mundy, 

### 2 who has one clarification on Averse Outcome Pathways and then I 

### 3 will finish with one small issue around the Johnson paper that 

### 4 was discussed earlier. 

### 5 DR. JEFF DAWSON: Thank you. Again, Jeff 

### 6 Dawson, from the Health Effects division. Yesterday there was 

### 7 some discussion about the analytical methodology related to cord 

### 8 blood analysis and we did some checking between the end of 

### 9 yesterday and now to put some clarity around it as Dr. Lowit 

### 10 indicated. So this was a published method Barr et al., 2002 and 

### 11 we could potentially make that paper available for you to look 

### 12 at in more detail if you desire. 

### 13 In Table 4 of Barr, she reported an LOD of 1 

### 14 pg/g with a very high R2. Then we did a quick overview of this 

### 15 paper and had some conversations with the chemist in our 

### 16 analytical lab as well and they felt pretty comfortable with the 

### 17 methodology; they believe it is a sophisticated and sensitive 

### 18 method. And it was really designed to get at low levels and we 

### 19 estimate that the limit of quantification would be around 3 

### 20 pg/g. 

### 21 We also had some communications with Dr. 

### 22 Whyatt at Columbia, and they felt confident in the method as

### Page 427 1 well. 

### 2 And the table there on the bottom is just a 

### 3 representation of the years that the data was collected and the 

### 4 ranges of the measure in cord blood. So you can see if you look 

### 5 at 3 pg/g is the limit of quantification, or compare them to 

### 6 that or the limit of detection of 1 pg/g. Any questions? 

### 7 DR. KENNETH PORTIER: Dr. Buckley? 

### 8 DR. BRIAN BUCKLEY: In the meantime I spoke to 

### 9 Barr without the et al., but I found out the difference between 

### 10 the two methodologies; and basically the second was the more 

### 11 recent, the 2010 which is also a Barr paper, was at a difference 

### 12 suite of pesticides; and the compromised conditions that they 

### 13 needed for that secondary suite of pesticides is one of the 

### 14 contributing factors. 

### 15 They also had a slight difference in 

### 16 methodology in the sense there is smaller injection volume and 

### 17 smaller blood volume, but they did not feel the need to get any 

### 18 lower because they had enough sensitivity, which is why they 

### 19 were able to get away with smaller blood volume, et cetera. But 

### 20 the principle difference between the two methodologies between 

### 21 '02 and 2010 was the difference in the pesticide suite that was 

### 22 analysed in '02 versus 2010.

### Page 428 1 DR. KENNETH PORTIER: Any additional 

### 2 questions? Thank you. 

### 3 DR. JEFF DAWSON: The next slide talks about 

### 4 the origin of the different alkyl phosphates, so we just copied 

### 5 this slide directly from the NHANES, a forth report, the link is 

### 6 there on the bottom. 

### 7 There are six basic categories of metabolites. 

### 8 They are all considered a dialkylphosphate, so when we talk 

### 9 about DAP it really represents all six of those compounds. 

### 10 Then the DEPs are the ones outlined with the 

### 11 red box around them and as you go down the different columns you 

### 12 can see what pesticides contributed or you would have a 

### 13 metabolite of that pesticide ending up as a DEP. So just to add 

### 14 some clarity and we can make copies of this so you can have it 

### 15 for your records. 

### 16 You can see chlorpyrifos and diazinon are on 

### 17 the list that contributes to DEPs; they are pretty broadly used 

### 18 in agriculture. Several of the others are more limited in their 

### 19 use so you would not expect probably as wide as of exposure kind 

### 20 of contribution in the general population for example to those 

### 21 different pesticides. 

### 22 DR. KENNETH PORTIER: Any questions on this?

### Page 429 1 And we would like a copy of that to pass it around. Dr. 

### 2 Popendorf. 

### 3 DR. WILLIAM POPENDORF: Just kind of going a 

### 4 little beyond that but I also, that would relate perhaps to, did 

### 5 you come up with the list of the pesticides used in Monterey 

### 6 County, because that will relate to this, thank you. 

### 7 DR. JEFF DAWSON: Next slide, so this was a 

### 8 slide that was provided to us from Brenda Eskenazi, one of the 

### 9 investigators on CHAMACOS; so they went through and created this 

### 10 list as part of their data collection. And you can see in their 

### 11 cohort, the ones who contribute to DEPs, predominately used are 

### 12 diazinon, chlorpyrifos and disulfoton. 

### 13 DR. KENNETH PORTIER: Any questions on this 

### 14 one? And additional questions? Yes. 

### 15 DR. STELLA KOUTROS: I forget, did they report 

### 16 on the correlations with these, on chlorpyrifos? 

### 17 DR. CAROL CHRISTENSEN: So the CHAMACOS 

### 18 cohort, they measured DAPs and they measured the diethyl and the 

### 19 dimethyl separately. So you are referring to the correlation 

### 20 between diazinon and chlorpyrifos, and disulfoton? They would 

### 21 not have had that information. 

### 22 DR. STELLA KOUTROS: Was there a different

### Page 430 1 study that had some other measures of certain pesticides? I do 

### 2 not recall which one it was. 

### 3 DR. CAROL CHRISTENSEN: The Columbia study 

### 4 measured out the parent compounds. 

### 5 DR. KENNETH PORTIER: Any additional questions? 

### 6 DR. JEFF DAWSON: There was also some 

### 7 discussion yesterday about sources of TCPy and as we heard 

### 8 yesterday chlorpyrifos, chlorpyrifos methyl, which are both 

### 9 organophosphate insecticide, and triclopyr which is a selective 

### 10 herbicide. 

### 11 Just a little perspective on how they are 

### 12 used. Chlorpyrifos is a broad use insecticide, a lot of crops 

### 13 and it is also still registered for a number of nine crop uses, 

### 14 for example, in ornamentals and industrial sites. 

### 15 Chlorpyrifos methyl is much more limited in 

### 16 use. It is used predominately as an insecticide for grain 

### 17 storage. So if you were going to be exposed to that it would be 

### 18 through the diet pretty much is the prevalent source. 

### 19 And then triclopyr, the only agricultural 

### 20 commodity you can find is upon rice as an herbicide. It is also 

### 21 available on home-use products and it is used for controlling 

### 22 range land in certain forestry areas where they have done

### Page 431 1 cutting to keep it manageable to go in and replant. 

### 2 Last night we look through the data for the 

### 3 California pesticide use reporting to see how much was used in 

### 4 the CHAMACOS area. We used Monterey County which is in Salinas 

### 5 Valley, as an indicator and I'm not sure if that covers the 

### 6 entire Salinas Valley or not. 

### 7 But triclopyr, you can see over the years 1998 

### 8 2002, around 3000 - 4000 pounds were used and that is dwarfed 

### 9 by the amount of chlorpyrifos that is used in that area during 

### 10 that timeframe and it is 50 100 and some thousand pounds per 

### 11 year. We think that spike is from some certain pest outbreak or 

### 12 something over that year. I also looked last night at the 2007 

### 13 2009 data for chlorpyrifos and it is kind of in the same range. 

### 14 15 Just to give you an idea so you can end up 

### 16 with the relative contributors potentially to TCP, and I will 

### 17 pass them along. 

### 18 DR. WILLIAM MUNDY: This is just to clarify 

### 19 some of the terminology I used yesterday. Terms of mode of 

### 20 action or adverse outcome pathways, that could be alternatives 

### 21 to cholinesterase inhibition. In the tables I have listed them 

### 22 as domains, but this is just to be clear that those domains

### Page 432 1 could be considered as potential alternative modes of action. 

### 2 So we had six of them listed; they are now on here just called 

### 3 pathways, so just to clarify the terminology. 

### 4 DR. KENNETH PORTIER: Any questions on this? 

### 5 Dr. Harry. 

### 6 DR. JEAN HARRY: This saves me bringing it up 

### 7 later. What I wanted to know is exactly what are you defining 

### 8 as morphogenic? 

### 9 DR. WILLIAM MUNDY: So acetylcholinesterases 

### 10 (AChE) during early periods of development can control cell 

### 11 differentiation and cell growth, neuronal growth. So a 

### 12 morphogenic role would be altering the morphology of the cell. 

### 13 DR. JEAN HARRY: It might have just been how I 

### 14 was reading it in the document; it sort of went through 

### 15 self-proliferation being a component of that. 

### 16 DR. WILLIAM MUNDY: That is a potential 

### 17 component. The adverse outcome pathway that we proposed, as an 

### 18 example, focused on neurogenic -- the neurite outgrowth that 

### 19 could be controlled by cholinesterases. 

### 20 DR. JEAN HARRY: The reason I was asking is 

### 21 just probably more for clarification as you get down the road 

### 22 when you start using the term exactly what does it mean because,

### Page 433 1 as you know, if cells are proliferating, they are not going to 

### 2 differentiate; if they are differentiating they are not going to 

### 3 be proliferating. But yet if you are taking both of those, in a 

### 4 way you might just want to set a very define definition, or at 

### 5 least an explanation for within the Agency, how you are going to 

### 6 be using that term because it can start to take a life of its 

### 7 own. 

### 8 And if you cluster the things together, you 

### 9 might get data that you would be interpreting as being 

### 10 contradictory but it might be complimentary with lots of people 

### 11 that are not in the field that would know the area of how they 

### 12 might be interpreting it. So it was just a point of 

### 13 clarification you might want to think about doing. 

### 14 DR. WILLIAM MUNDY: Sure, thanks. I should 

### 15 have defined morphogen. 

### 16 DR. MICHAEL ASCHNER: It is just a comment and 

### 17 I do not know your view on this Bill, but I would actually, Russ 

### 18 (phonetic) to me would not be necessarily -- it is more of a 

### 19 response to alterations in any of the other rather than an 

### 20 initiating event. 

### 21 DR. WILLIAM MUNDY: That is why in the 

### 22 literature there is no initiating event proposed but it has been

### Page 434 1 suggested that the reactive oxygen species levels that are shown 

### 2 to be increased after response to chlorpyrifos or the oxon could 

### 3 be responsible for further downstream effects on 

### 4 neurodevelopmental processes. 

### 5 So, again, that is why I did not call them 

### 6 pathways initially but domains under which the data were 

### 7 falling. 

### 8 DR. KENNETH PORTIER: Any additional questions? 

### 9 Dr. Vena. 

### 10 DR. JOHN VENA: These events as well as the 

### 11 domains, are these related to exposure to chlorpyrifos a parent 

### 12 compound or all the additional metabolites that occurs, the ones 

### 13 that we just went through on the table, and TCPy? 

### 14 DR. WILLIAM MUNDY: The three metabolites that 

### 15 have been associated with one or more of these events are 

### 16 chlorpyrifos the oxon and the TCP, in more limited cases, not to 

### 17 my knowledge the DAPs. 

### 18 DR. ANNA LOWIT: And one little issue just to 

### 19 make sure there is clarity and accuracy in the report. We heard 

### 20 a fairly lengthy detailed presentation from Dr. Li and I think 

### 21 largely she concurred with the preliminary conclusions of the 

### 22 Agency.

### Page 435 1 But there was a good bit of discussion about a 

### 2 paper out of Russell Carr's lab, a Johnson et al., paper. And 

### 3 we just want to ensure that the discussion on that paper is 

### 4 accurate as it is in the paper and that the appropriate 

### 5 statistics are considered in the report because we are unsure 

### 6 that the conversation accurately reflected the statistics that 

### 7 were done on the report. If we can just ensure that if this 

### 8 Johnson paper gets a lot of play in the report, that it is 

### 9 accurate. 

### 10 I think what is more important is that with 

### 11 the analysis done by the Agency and the analysis done by Dr. 

### 12 Lee, as none of those studies were being proposed for points of 

### 13 departure. Any one individual point of data, any one study, is 

### 14 not necessarily any more or less important than any other given 

### 15 the nature of that database. So we would like to ensure that 

### 16 one study for which got a lot of discussion is not weighted 

### 17 heavily against an entire database of 20 some odd other studies. 

### 18 DR. KENNETH PORTIER: Dr. Carr. 

### 19 DR. RUSSELL CARR: Based on what I said this 

### 20 morning, I was a little confused. I got my sexes mixed up just 

### 21 trying to recall the paper from memory. Our lowest effect level 

### 22 was a 1 mg/kg and it was in male rats. In female rats was where

### Page 436 1 we saw a little bit of the opposite effect but not significant. 

### 2 But the statistics that were in the paper do match the data as 

### 3 Anna said. 

### 4 DR. KENNETH PORTIER: And that completes EPA 

### 5 presentation, one last call for clarifying questions before I 

### 6 close the presentation part of the meeting. 

### 7 DR. ANNA LOWIT: Just to make sure Dr. Portier 

### 8 that we circulated the revised version of Table 10 just to make 

### 9 sure everyone got it. 

### 10 DR. KENNETH PORTIER: That was handed out over 

### 11 lunch. At this point I'm going to go ahead and close the public 

### 12 presentations part of the meeting and we are going to move 

### 13 forward with the panel discussion of the issues put before the 

### 14 panel by EPA. 

### 15 So, we release the EPA staffers and Dr. Lowit, 

### 16 are you going to be reading the questions this afternoon? 

### 17 DR. ANNA LOWIT: Everyone is running away. I 

### 18 will read the first one and then I will start delegating all the 

### 19 others. Of course they are all very long. 

### 20 Question 1.0. It is well established that 

### 21 AChE inhibition is the primary mode of action/adverse outcome 

### 22 pathway for OPs, like chlorpyrifos. Because AChE inhibition is

### Page 437 1 the initiating event for this mode of action/adverse outcome 

### 2 pathway (AOP), using AChE inhibition as a regulatory endpoint is 

### 3 protective of downstream cholinergic effects. Moreover, 

### 4 historically, given the sensitivity of AChE inhibition data for 

### 5 OPs, these data have been considered to be protective of other 

### 6 potential toxicities and/or modes of action for OPs. 

### 7 In 2008, the Agency performed a comprehensive 

### 8 review of the available AChE data from multiple life stages. 

### 9 This review has been supplemented with the newest studies. 

### 10 Consistent with the recommendations from the 2008 SAP, the 

### 11 Agency believes that AChE data remain the most robust dose 

### 12 response data for deriving points of departure in in vivo 

### 13 experimental toxicology studies with laboratory animals. 

### 14 Please comment on the Agency's preliminary 

### 15 conclusion that AChE data remain the most robust source of data 

### 16 for deriving points of departure for chlorpyrifos. 

### 17 Please include a discussion of the strengths 

### 18 and uncertainties of this preliminary conclusion. 

### 19 DR. KENNETH PORTIER: And we have asked Dr. 

### 20 Carr to lead off the discussion this afternoon. Dr. Carr. 

### 21 DR. RUSSELL CARR: I agree with the Agency's 

### 22 conclusion that ChE data remains the most robust source of data

### Page 438 1 for deriving points of departure for chlorpyrifos. This is 

### 2 based on observation that all negative effects reported on in 

### 3 vivo developmental exposure to chlorpyrifos have been 

### 4 accompanied by acetylcholinesterase inhibition. 

### 5 And those studies that measured ACh activity 

### 6 at an appropriate time point following the administration of 

### 7 chlorpyrifos did not use a confounding potentially toxic vehicle 

### 8 that is DMSO or utilize an exposer paradigm that would allow it 

### 9 to be useful to determine the point of departure. 

### 10 While this being said, there are candidates 

### 11 that could replace acetylcholinesterase as a more sensitive 

### 12 indicator but at this juncture those have not been fully 

### 13 validated and their alteration has not been determined to result 

### 14 in a measureable neurotoxic response. 

### 15 DR. KENNETH PORTIER: Thank you. Next, Dr. 

### 16 Collier. 

### 17 DR. ABBY COLLIER: I agree with Dr. Carr and I 

### 18 have only one thing to add, which is that I think uncertainties 

### 19 relating to life stage levels of blood cholinesterase in human 

### 20 exists and that we have to be sure that we are comparing apples 

### 21 with apples if we are going to use cholinesterase as an 

### 22 endpoint.

### Page 439 1 DR. KENNETH PORTIER: Thank you. Dr. Pope. 

### 2 DR. CAREY POPE: I agree, I think the question 

### 3 asked for strengths or uncertainties. let me expand a little 

### 4 bit. I think there are a huge number of strengths in using 

### 5 cholinesterase dose response data for deriving points of 

### 6 departure and so far I have not seen anything else that fits 

### 7 this. So obviously, to me, it is the most robust set of data 

### 8 for doing so. If you put that together, since 1940's the 

### 9 mechanism of toxicity has been acetylcholinesterase inhibition 

### 10 demonstrated in multitudes of studies over the years. 

### 11 SAP panels have discussed this and kind of 

### 12 keep concurring, so I think it is undeniable and most extensive 

### 13 database available for evaluating neurotoxicity in developmental 

### 14 neurotoxicity and applicable for determining points of 

### 15 departure. I stop there. 

### 16 DR. KENNETH PORTIER: Dr. Popendorf. 

### 17 DR. WILLIAM POPENDORF: I also agree with the 

### 18 previous speakers by and large and I think the only thing that I 

### 19 would add would be in terms of other candidates. I think if you 

### 20 consider the metabolites we have discussed, there are a lot of 

### 21 problems with most of them and I think the only other viable 

### 22 potential candidate would be the actual chlorpyrifos itself in

### Page 440 1 blood for instance. That is not a good substitute, which is why 

### 2 I agree with the basic premise that acetylcholinesterase is the 

### 3 best available. 

### 4 DR. KENNETH PORTIER: At this point we will 

### 5 open it up to anyone else on the panel who wants to comment on 

### 6 this question. Or anyone who wants to add. Dr. Carr. 

### 7 DR. RUSSELL CARR: I just want to go ahead and 

### 8 add this for the record. 

### 9 There has been discussion about using DMSO as 

### 10 a solvent, which I have concerns with. There are some 

### 11 additional papers that have occurred since the 2008 SAP. In 

### 12 2009 Hanslick et al., was basically looking at neuronal 

### 13 apoptosis following developmental exposure to DMSO and on PND 7 

### 14 a single dose of as low as .3 mills per kilogram increase the 

### 15 incidents of neuronal apoptosis and that was DMS alone. 

### 16 Also there has been several studies in zebra 

### 17 fish to demonstrate that DMSO has a neurotoxic effect, which 

### 18 alter behavior following acute exposure but more importantly in, 

### 19 I think it was 2-TN on Turner et al., basically found that if 

### 20 you could expose zebra fish embryos to levels as low as .0025 

### 21 percent, which is 25 ml/l. It induces gene expression in those 

### 22 embryos.

### Page 441 1 And that kind of suggests that if you put DMSO 

### 2 into a developing system, it does have the potential to interact 

### 3 on its own and, in addition, probably could potentiate the 

### 4 effect of other chemicals in that system. 

### 5 DR. KENNETH PORTIER: Any additional comments? 

### 6 Dr. Anna Lowit does that look like an accepted answer. I will 

### 7 not even attempt to summarize this stuff. 

### 8 DR. ANNA LOWIT: It is pretty clear actually, 

### 9 so yes. 

### 10 DR. KENNETH PORTIER: We are going to move on 

### 11 then to Question 2.1. 

### 12 LIEUTENANT AARON NIMAN: Question 2.l. As 

### 13 discussed in Section 3.2.1, although there are numerous 

### 14 mechanistic studies in the scientific literature, the research 

### 15 on different hypotheses does not provide sufficient data to 

### 16 establish causal linkages among different levels of biological 

### 17 organization to show how effects lead to adversity. 

### 18 As such, a mode of action or adverse outcome 

### 19 pathway leading to effects on the developing brain cannot be 

### 20 established at this time. Moreover, although multiple 

### 21 biologically plausible hypotheses are being pursued by 

### 22 researchers, based on the current state of the science, no one

### Page 442 1 pathway has sufficient data to be considered more credible than 

### 2 the others. 

### 3 Please comment on the Agency's preliminary 

### 4 conclusion that although there are multiple biologically 

### 5 plausible hypotheses being evaluated by research scientists, the 

### 6 mechanistic experimental toxicology data does not yet support a 

### 7 coherent set of key events in a mode of action/adverse outcome 

### 8 pathway. 

### 9 DR. KENNETH PORTIER: Dr. Harry. 

### 10 DR. JEAN HARRY: I think we all pretty much 

### 11 agree your answer to this is yes. We agree with the Agency. I 

### 12 would like to say I think the Agency has done an excellent job 

### 13 of pulling together the data, not only just on chlorpyrifos but 

### 14 with the processes of the mechanism, the potential for there to 

### 15 be ChE activities other that the normal way of thinking about 

### 16 them, the cellular responses that could be associate, and to 

### 17 really sort of set up the fact that there may be a diverse role 

### 18 during development and possibly during other life stages of the 

### 19 organism. 

### 20 I really think it is an excellent put together 

### 21 package. A lot of work went into it. A lot of expert thought 

### 22 process went into it.

### Page 443 1 What I found interesting as I was reading 

### 2 through it I sort of got to the point and said, "This is 

### 3 starting to look like all the old lead literature or the mercury 

### 4 literature where there are a lot of little pieces but yet have 

### 5 not really identified from a lot of those little pieces to be 

### 6 able to have a pathway to stay with." 

### 7 So I think that it seems like what you have in 

### 8 the literature and what you put forward very well is that you 

### 9 have got the starting point of some studies that if they are 

### 10 expanded pass a descriptive stage by the investigators, that you 

### 11 may start to look at some bases for other dynamics of how they 

### 12 may be happening, how you may be having developmental effect but 

### 13 right now they are very speculative on any sort of mechanism and 

### 14 your data is not really there to identify another pathway or 

### 15 even something that you do not know that is not secondary to an 

### 16 already known mechanism process mode of action. 

### 17 I think the Agency laid out very well that 

### 18 there really needs to be that next step follow-through on some 

### 19 of those findings but that it is not there yet. But I think 

### 20 that some of that in the way that they worded the report really 

### 21 nicely demonstrated that to be able to get there the benefit is 

### 22 going to come from not just looking at chlorpyrifos alone but at

### Page 444 1 looking at a lot of the genetic and pharmacological data that 

### 2 may start to support some of the dynamics. 

### 3 So I think that is a long way of saying yes I 

### 4 agree with you but I agree with you on the basis of the Agency 

### 5 really laid out well an open and unbiased looking at what the 

### 6 data was out there and I thought they really did a very good job 

### 7 of pulling it together, of possible mechanisms and other aspects 

### 8 of expanding outside just limited data framework for 

### 9 chlorpyrifos. So I think there is a strong basis for my yes, I 

### 10 agree with the Agency. 

### 11 DR. KENNETH PORTIER: Dr. Carr. 

### 12 DR. RUSSELL CARR: I concur with Dr. Harry. 

### 13 DR. KENNETH PORTIER: This could be really 

### 14 easy. Dr. Collier. 

### 15 DR. ABBY COLLIER: I agree with Dr. Harry and 

### 16 Dr. Carr and I have nothing to add. 

### 17 DR. KENNETH PORTIER: Dr. Pope. 

### 18 DR. CAREY POPE: Yes, me too. 

### 19 DR. KENNETH PORTIER: Well what is all of this 

### 20 stuff written on your screen? Dr. Terry. 

### 21 DR. ALVIN TERRY: Maybe I will be the 

### 22 troublemaker here. In essence I also agree with Dr. Harry's

### Page 445 1 conclusion but when I was reading the white paper and thinking 

### 2 about this I guess all in context and looking at that statement 

### 3 these data do not yet support a coherent set of key events. 

### 4 Then I look on page 36, the other report when 

### 5 discussions of lead, meth, mercury and ethanol are being sort of 

### 6 summarized even today with thousands of published papers on 

### 7 these accepted developmental neural toxicants no coherent 

### 8 adverse outcome pathway can be constructed. 

### 9 So when I'm reading all this I sort of felt 

### 10 like I was painted into a corner that it is very difficult to 

### 11 meet these criteria and if you look at domoic acid, the real 

### 12 idealized pathway, very very few times we ever encounter a 

### 13 compound like that. So having said that it seems like a very 

### 14 difficult thing for me to do but as it stands right now looking 

### 15 at all the literature, I would also agree with the central 

### 16 premise. 

### 17 DR. KENNETH PORTIER: I will open it up to the 

### 18 rest of the panel, any additional comments? Going twice. Okay. 

### 19 So those were the easy questions, alright? And I think that is 

### 20 another pretty clear short response. Let's go on to Question 

### 21 2.2. 

### 22 LIEUTENANT AARON NIMAN: Question 2.2.

### Page 446 1 Although a mode of action/adverse outcome pathway has not been 

### 2 established, qualitatively, the growing body of mechanistic 

### 3 studies does demonstrate that chlorpyrifos and/or its oxon are 

### 4 biologically active on a number of processes that affect the 

### 5 developing brain. 

### 6 Some mechanistic studies provide evidence of 

### 7 possible effects which are similarly sensitive or more sensitive 

### 8 than AChE inhibition (e.g., neurite outgrowth, binding to 

### 9 muscarinic receptors, axonal transport; serotonergic nervous 

### 10 system development). Some of these comparisons must be 

### 11 considered with caution since the amount of change in the in 

### 12 vitro systems required to elicit an adverse effect in vivo is 

### 13 unknown. Moreover, extrapolation from in vitro perturbations to 

### 14 in vivo effects has not been established, which introduces 

### 15 additional uncertainties. 

### 16 Given the doses/concentrations evaluated in 

### 17 the in vitro and in vivo mechanism studies, please comment on 

### 18 the degree to which these studies suggest that endpoints 

### 19 relevant to evaluating potential neurodevelopmental outcomes may 

### 20 or may not be more sensitive than AChE inhibition. 

### 21 Please include in your comments a discussion 

### 22 of the strengths and uncertainties.

### Page 447 1 Please also include in your comments a 

### 2 discussion of the scientific understanding of dose response 

### 3 relationships for biological perturbations and the magnitude, 

### 4 frequency and/or duration of such perturbations that can lead to 

### 5 adverse effects at higher levels of biological organization to 

### 6 support characterization of the likelihood of adverse outcomes 

### 7 in a human health risk assessment. 

### 8 DR. KENNETH PORTIER: Yes, it is a lot. The 

### 9 only thing I would point out, I think on the second line you 

### 10 said "does not" and it reads does, right? So it does 

### 11 demonstrate chlorpyrifos and/or its oxon are biologically 

### 12 active. DR. Harry. 

### 13 DR. JEAN HARRY: The longer the question the 

### 14 longer the answers. I think this is where we are not getting to 

### 15 just the yes but you have asked a lot of questions here and I 

### 16 think it is trying to filter through to give you back the 

### 17 comments that you really want. 

### 18 While it is not exactly in the question, I may 

### 19 do these in bullet forms. A lot within the document was asking 

### 20 that you were expecting eventually for these things to be linked 

### 21 to a functional or structural change. And I think again you 

### 22 need to come back and define what you are asking for from that

### Page 448 1 because are you asking for eventually any of these in vitro 

### 2 systems to be able to translate over to a behavioral 

### 3 manifestation? Is that what you are taking as a functional or 

### 4 do they have to translate over into a histopatholgical change 

### 5 that you can see within an H&E stain on a guideline study? 

### 6 That might be expecting way too much because 

### 7 they are relatively crude endpoints. So I think there just 

### 8 needs to be a definition of exactly what your expectations are 

### 9 going to be for it to be translated in your mind over, because 

### 10 the functional change could end up being a change in 

### 11 self-physiology; that is as much function as a behavioral 

### 12 manifestation. 

### 13 A structural change could be a structural 

### 14 configuration change of a synapse and that is as much as a cell 

### 15 depth change could be. So it is going to be within that 

### 16 framework where you are starting to look at what your 

### 17 requirements will be for that. 

### 18 Again, like I said, this is sort of coming in 

### 19 bullets because there are lots of questions here and hopefully 

### 20 when we write this up it will be much more integrated for you. 

### 21 I think some of your other concerns are that you are looking at 

### 22 whether something is more sensitive or not and there seems to be

### Page 449 1 this concern about whether any of the in vitro methods could 

### 2 manifest and give you the dose response that you are looking 

### 3 for. 

### 4 Some issues were raised as in some studies you 

### 5 would find nothing at a couple of doses or you might find 

### 6 something at two doses but no does response. 

### 7 I think you are going to have to look at the 

### 8 systems that people are using and look outside of their further 

### 9 sensitivity within either a genetic component or at a 

### 10 pharmacological component because you may not get those same 

### 11 type of linear dose response that you really want to see to be 

### 12 able to do your point of departure from. These types of studies 

### 13 may never provide that type of data. They just may not be 

### 14 sensitive enough to do it yet as in the type of numbers it is 

### 15 giving you. 

### 16 So I'm not real sure that you are going to get 

### 17 a number of the things that you are going to get magnitude dose 

### 18 response, you are going to get that nicely laid out like you are 

### 19 getting with ChE inhibition at times. 

### 20 I think the other thing that was not brought 

### 21 out in any of the papers in trying to evaluate those 

### 22 concentration in vivo, in vitro, any type of translation there

### Page 450 1 is the fact that in all of the in vitro systems you are looking 

### 2 at a cell in isolation and that is not the way a cell is going 

### 3 to be in vivo. 

### 4 So you can be looking at a neuron in isolation 

### 5 but that is not the way it is going to exist in the brain. I'll 

### 6 take the example of looking at neural stem cells or progenitor 

### 7 cell populations. There is some data that is available on those 

### 8 as to whether it is stimulating proliferation, those aspects, 

### 9 but we know that the niche that those cells live in tightly 

### 10 regulates those cells within the brain. 

### 11 So looking at them in isolation is going to be 

### 12 another problem for you to try to do the translation over 

### 13 because it may be that trying to recapitulate in vitro what you 

### 14 see in vivo is going to be very very difficult. And I know that 

### 15 there is a lot of effort of saying that, "If I look at a neural 

### 16 stem cell it will give me a more current development." But it 

### 17 is a cell in isolation and even when you look at the 

### 18 differentiation the distribution of the cell that the stem cell 

### 19 will differentiate into is not recapitulating what you would 

### 20 have in the brain. 

### 21 Not real sure I'm answering your question but 

### 22 it is more concerns of considerations as you are looking at

### Page 451 1 that. Again, I found the document excellent in going through 

### 2 some of the underlying biology even for the in vitro systems. 

### 3 It did not seem to me that they were being dismissed; it seem to 

### 4 me that the Agency was really looking at them to see what type 

### 5 of data that they could provide them and I think that that is 

### 6 going to be exactly how you are going to have to look at that 

### 7 data. 

### 8 And in models that you develop for looking at 

### 9 any other compound to look at how do you take the in vitro data, 

### 10 again the linear model for the domoic acid is like the one 

### 11 clean-cut model. I think you can probably find a couple of 

### 12 other models out there that you could look at to see how they 

### 13 follow out, that there is enough data available, but it is going 

### 14 to be a rare occasion that you are going to be able to go in 

### 15 those box sequences. You are going to have to look at how a 

### 16 number of different modifying events will change those. 

### 17 You were asking about the magnitude or 

### 18 frequency, it is going to be somewhat difficult to try to relate 

### 19 in vitro to in vivo. Again, as I said I am not sure you are 

### 20 going to find the dose response but if you think about it the 

### 21 reason that you go in vitro is you are going in there because 

### 22 you are trying to ask a very specific question as to how it

### Page 452 1 relates to your hypothesis of a mechanism that may be affected. 

### 2 And you might go in and do in essence a dose 

### 3 response looking at what you might find and equivalent to a 

### 4 functional observational battery you do in the adults. It is 

### 5 that first tier observation, "What do I see at any dose." And 

### 6 then you come back in and when you find something you hope that 

### 7 at that point that you can address that deeper. You find an 

### 8 effect; you can go after the effect. What is the mechanism 

### 9 underlying the effect. 

### 10 I think where the data falls short for the 

### 11 Agency is that it has done the descriptive and it has not gone 

### 12 further into detail in mechanism and then once it has identified 

### 13 a mechanism, has not necessarily gone back to do your dose 

### 14 response to see if that mechanism could hold up to a dose 

### 15 response effect. Although on the other end, some of these 

### 16 studies in the future may offer you that robustness that Dr. 

### 17 Moser was asking for, that you need a robust endpoint at which 

### 18 to be looking at. 

### 19 So as it comes back I'm not real sure that I 

### 20 would set a demand of these studies that they have to show a 

### 21 dose response. Nor would I set a demand that they have to show 

### 22 a very robust pronounce severity of response because it can be

### Page 453 1 subtle changes that can happen. So it is going to be putting a 

### 2 whole package together of all of the individual in vitro data 

### 3 and how does one aspect support the other. 

### 4 I think the other aspect is when you are 

### 5 talking about, again, staying on the relationship across the 

### 6 exposure and the biological outcome and will that cross over to 

### 7 what would happen in vivo and to maybe a human health event. I 

### 8 think one of the things that you need to look for or hopefully 

### 9 that investigators will provide you is to actually take their 

### 10 data and translate from in vitro to in vivo. 

### 11 So if you have something that is implying that 

### 12 you have an alteration in neurite outgrowth as a developmental 

### 13 component in a dish, there are ways that you can design that 

### 14 next study to say does this happen in the developing animal. It 

### 15 is not going to be a standard study but it will be a study 

### 16 designed to do that. So you can see if these effects translate 

### 17 over. If they have got any predictive validity at all to help 

### 18 you out that will help you both with chlorpyrifos but would also 

### 19 help you in the long run about whether you would look at these 

### 20 things if they have any predictive validity for developmental 

### 21 neurotoxic that are not. 

### 22 I think the other aspect; one of the other

### Page 454 1 areas that were shown to be affective was in the area of axonal 

### 2 transport. There is a lot of information in chemical exposure 

### 3 and alteration and axonal transport at which you could take what 

### 4 may be found in vitro and test that hypothesis again to whether 

### 5 that predicts what would happen in vivo with a very targeted 

### 6 approach. 

### 7 I guess if we come down to all of that is I 

### 8 think you have got a lot of data out there but I do not think it 

### 9 is getting to the point of where you can use it because the 

### 10 investigators are not taking it where you need to have it taken. 

### 11 And to do that predictive validity so you can know which one of 

### 12 these in vitro tests would actually be a good one to predict 

### 13 that you would have a developmental outcome in any way, shape, 

### 14 or form. 

### 15 If you think I have talked long, I know the 

### 16 others have got longer and more specific comments that they want 

### 17 to go after. 

### 18 DR. KENNETH PORTIER: And with that hopefully 

### 19 Dr. Carr will not say ditto, right? Dr. Carr. 

### 20 DR. RUSSELL CARR: Basically I agree with Dr. 

### 21 Harry. I think that the uncertainties we face in this situation 

### 22 are enormous. A lot of the problem with the in vitro studies is

### Page 455 1 they are looking for basically a molecular target where we are 

### 2 talking about a chemical that has an established molecular 

### 3 target that could modify things downstream that will have 

### 4 effects in a different manner for which we really cannot find 

### 5 looking at it in in vitro system because you know in the central 

### 6 nervous systems there are so many different systems connected 

### 7 that one can communicate with others and disrupt one and you can 

### 8 have effects in the other. 

### 9 And so as we progress from in vitro to in vivo 

### 10 we are going to have to start trying to utilize our PBK 

### 11 knowledge to try to get an estimate of target site and dosage 

### 12 because that is what is important here is target site and 

### 13 dosage. Will we get enough of the active compound at the target 

### 14 site to cause a biological perturbation; and then how can we 

### 15 measure that such that we can use it for human risk assessment? 

### 16 And I think that is probably our biggest difficult step there is 

### 17 moving from these mechanistic studies into human risk assessment 

### 18 because like Dr. Terry mentioned with lead and other things we 

### 19 are still looking for that magic box in those but we do know 

### 20 those are developmental toxicants. 

### 21 I was very impressed with the paper. I was 

### 22 very impressed with the amount of detail that went into it and I

### Page 456 1 think that we are hopefully moving in the right direction and I 

### 2 do hope that we can start taking more advantage of the 

### 3 technologies that we have especially with the PBK model and 

### 4 where we can actually try to estimate and connect what we think 

### 5 we find in a plate what actually occurs in the body. 

### 6 DR. KENNETH PORTIER: Dr. Collier. 

### 7 DR. ABBY COLLIER: Well, I agree with Dr. 

### 8 Harry and Dr. Carr. I have a few additional comments. I really 

### 9 do believe that the oxon in protein adducts seem to be a 

### 10 potentially important pathway and the oxon seem to have an 

### 11 incredibly rapid half-life despite its relatively high affinity 

### 12 for ChE. 

### 13 The law of averages indicates that sooner or 

### 14 later it is going to bind to another cellular component and I 

### 15 really think the criticality of both components can mediate the 

### 16 magnitude of the effects so I think the oxon should not be 

### 17 discounted but clearly the weight of the evidence is that ChE 

### 18 inhibition is what is going on. 

### 19 You asked about a scientific understanding of 

### 20 dosage response relationships for biological perturbations. My 

### 21 understanding is that PK and PD should not be uncoupled too far, 

### 22 that PK can inform PD because pharmacokinetic differences can

### Page 457 1 affect active site concentrations and, therefore, can affect 

### 2 pharmacodynamics effects. 

### 3 And to this end, I think TCPy and DETP 

### 4 conjugation by the sulfotransferases and glucanotransferase is 

### 5 actually an important thing to consider. 

### 6 According to Dr. Bartels' submission from DOW, 

### 7 the glucuronides and the sulfonates are equally prevalent but we 

### 8 do not know the relative affinities. And I would remind you 

### 9 that since you are interested in pregnancy and pediatrics, human 

### 10 fetuses, a UGT null as far as activity goes, until at or around 

### 11 the time of birth. Therefore, the glucuronidation is being done 

### 12 by the maternal liver and the placenta and we are just about the 

### 13 only mammal where the fetus does not have UGT active in the 

### 14 liver. 

### 15 And so what that means is that despite the 

### 16 acetylcholinesterase abducting oxon not really getting 

### 17 conjugated if glucuronidation is the right limiting path, then 

### 18 other metabolites could accumulate to the un-toxic levels or you 

### 19 could interfere with your own biomarker analysis and cause 

### 20 errors in your dosimetry calculations. 

### 21 I do think that the strengths of the 

### 22 approaches that have been taken so far are that much is known

### Page 458 1 about the P450s and PON1 and has been integrated into the 

### 2 analyses that have been done, and I think that is really 

### 3 fantastic. I think some of the efforts toward PB/PK and 

### 4 PB/PK/PD modeling have been really well presented and really 

### 5 thoughtfully done, especially the attempts by Dr. Hattis with 

### 6 the pregnancy model. We all talk about that as something we 

### 7 would like to see and I see you are moving forward with it so 

### 8 that is fantastic. 

### 9 I think the weaknesses are that there is a 

### 10 lack of knowledge of conjugation in humans with chlorpyrifos; 

### 11 Phase II is really high capacity. sulfotransferase and UGTs are 

### 12 really high capacity and we keep talking about that chlorpyrifos 

### 13 is a high extraction drug and high face past metabolism; and 

### 14 despite that P450s are important, I really think that 

### 15 conjugation may be playing a role in this. 

### 16 The other weakness that I seem to keep coming 

### 17 back to is the species differences and sulfotransferases. So 

### 18 some of the UGTs particularly the 2B family, but many of the 

### 19 sulfotransferases non-orthologous between rodents and humans. 

### 20 And I think this might explain why Dr. Hattis said when he was 

### 21 modeling rat clearance data it was very different to what he 

### 22 started doing with human clearance data.

### Page 459 1 So too much reliance on a rodent model without 

### 2 reference to whether or not the enzymes we are looking at are 

### 3 really truly representative of the human situation can cause 

### 4 problems and it could start interfering with your ability to 

### 5 look at your endpoints I think. 

### 6 So those are mostly my points about PK and 

### 7 about metabolism. I do also think that pregnancy is a very 

### 8 specific state and it is not just a case of changes in blood 

### 9 flow or changes in volume of distribution. We also need to 

### 10 start considering that there may actually be metabolic changes 

### 11 specific to pregnancy as well as related to steroid metabolism. 

### 12 13 And finally, specific developmental periods in 

### 14 which perturbation may occur in the human still appear to be 

### 15 ill-defined, and also to some extent in rodent species. One 

### 16 discussion that I had with somebody else was that "What is a 

### 17 postnatal day 10, meaning birth." And I have to agree with 

### 18 that; that if we have really good data saying when developmental 

### 19 periods arise then we can have better translation of results to 

### 20 human given that much of these data cannot be generated in 

### 21 humans. But I think that there is a consensus at a broad level 

### 22 at the moment that we are studying the right developmental

### Page 460 1 periods if we are looking at pregnancies and pediatrics. 

### 2 So those are what I think are the weaknesses 

### 3 at the moment when you ask about the scientific understanding of 

### 4 dose response relationship and the magnitude and frequency or 

### 5 the duration of these effects. 

### 6 However, I really would like to congratulate 

### 7 you because what we have seen is some really positive movement 

### 8 in a direction that is very difficult to study, so thank you. 

### 9 DR. KENNETH PORTIER: Thank you. Dr. Pope. 

### 10 DR. CAREY POPE: So changes in neurite 

### 11 outgrowth or dendritic spine expansion on transport of these 

### 12 other cellular responses that have been reported in sub-studies 

### 13 with chlorpyrifos or chlorpyrifos oxon exposure in vitro, 

### 14 sometimes report at level remarkably low in the picomolar range, 

### 15 studies by Shu et al. and some of Pam Lyon's (phonetic) work. 

### 16 But being an in vivo person I tend to think 

### 17 that these kinds of comparisons must be made with caution. For 

### 18 example, adding chlorpyrifos oxon directly to some hippocampal 

### 19 neurons in vitro in two Shu culture mediums is kind of 

### 20 unrealistic for how the oxon could potentially reach one of 

### 21 those neurons. 

### 22 The more simplified or isolated and biological

### Page 461 1 system is, the less macromolecules around that system and 

### 2 available for interacting with the toxin. And many detoxifying 

### 3 binding proteins are obviously not included in these kinds of in 

### 4 vitro conditions potentially modifying the interaction of the 

### 5 chemical with the cell. 

### 6 Kind of similarly, if an acetylcholinesterase 

### 7 in a disrupted tissue is looked at for its sensitivity to 

### 8 chlorpyrifos oxon, it may show a certain level of sensitivity. 

### 9 If you pull that enzyme or any other sensitive enzyme out of 

### 10 that tissue and study it in idle isolation, you are going to see 

### 11 it is a lot more sensitive to chlorpyrifos oxon based on 

### 12 concentration of the chemical. 

### 13 Such effects of tissue components in the 

### 14 relative potency of these chemical makes, for me, extrapolation 

### 15 of in vitro effects to an in vivo setting a very difficult one. 

### 16 In general, the collective data suggested changes in neural 

### 17 developmental endpoints required relatively higher exposure in 

### 18 the in vivo animal models than in a number of these in vitro 

### 19 preps. 

### 20 An important factor in these types of in vivo 

### 21 studies, which has been raised by the panel previously, is the 

### 22 time that acetylcholinesterase is evaluated. In particularly in

### Page 462 1 developing animals, the timing may be even more critical to make 

### 2 sure that you are looking at the right time and there is a 

### 3 window of opportunity that could be very short and that kind of 

### 4 definition of that opportunity to see inhibition has to be 

### 5 demonstrated under some conditions. For example, with higher 

### 6 exposure levels to make sure that if there is inhibition in a 

### 7 particular study then you are going to see it. To me 

### 8 neurobehavioral studies that are conducted without 

### 9 acetylcholinesterase tagging along should be avoided. 

### 10 While neurobehavioral changes following early 

### 11 chlorpyrifos exposure may not be potentially causally related to 

### 12 acetylcholinesterase inhibition, I think it is reasonable to 

### 13 conclude with the existing data that we have got, that 

### 14 neural-developmental disruptions following chlorpyrifos in 

### 15 general occurs at levels of exposure at, near or around those 

### 16 associated with significant inhibition. 

### 17 DR. KENNETH PORTIER: Thank you. Dr. Terry. 

### 18 DR. ALVIN TERRY: I just have a few comments. 

### 19 I would first like to mention I agree with Dr. Harry and others 

### 20 about how well written this white paper was in covering all 

### 21 these potential mechanisms. I would like to add one area that 

### 22 was not covered and that is the potential of chlorpyrifos and

### Page 463 1 the oxon affecting growth factor receptor levels. 

### 2 I know the Slotkin group has shown effects on 

### 3 FGF in neonatal animals I believe. Dr. Carr published a paper a 

### 4 few years ago and I think it was in neonates also showing 

### 5 effects on nerve growth factors, and then those were in neonate. 

### 6 And our group has shown effects on nerve growth factor related 

### 7 receptors. So I would like to see that added or at least 

### 8 thought about. 

### 9 Just a few other comments and certainly I have 

### 10 never been a regulatory person so I do not envy being in your 

### 11 shoes when it comes to making these kinds of decisions. And I 

### 12 would be very remised to make any regulatory decisions based on 

### 13 in vitro data. 

### 14 And I agree with Dr. Pope and others that 

### 15 extrapolating from in vitro studies all the way to whole animal 

### 16 and human is very problematic. But I do think they can educate 

### 17 us on potential mechanisms other than cholinesterase that are 

### 18 very important and you, in the paper, have certainly highlighted 

### 19 some of those. 

### 20 I do agree with the idea that most of the 

### 21 studies in vitro tend to look at fairly high concentration, but 

### 22 this is not always the case, whether it be the parent compound

### Page 464 1 or the oxon. And so if you look at some of the neurite 

### 2 outgrowth, that is at least three or four of those they are 

### 3 looking at either, you know, low nanomolar levels of the oxon or 

### 4 low micromolar levels of the parent compound in many cases you 

### 5 do not detect cholinesterase inhibition at those levels, at 

### 6 least we do not. 

### 7 One of the things that also was not mentioned 

### 8 in the white paper is effects of mitochondrial morphology in 

### 9 transporting oxon. So that is something we have seen its levels 

### 10 as low as five nanomolar of oxon -- this is in vitro again -- 

### 11 primary cultures, and as low as a micromolar of the parent 

### 12 compound. So that is another of the mitochondrial morphology 

### 13 issue would be another one to add. 

### 14 And then if you think about all of this in 

### 15 context, and this was brought up earlier about potential 

### 16 covalent modification of multiple proteins other than a 

### 17 cholinesterase and many of you know that the Lockridge group has 

### 18 done a lot of this work. 

### 19 If you think about covalent modification of 

### 20 things like kinesin tubulin and the effect in tubulin 

### 21 polymerization, you know, motor proteins involved in axonal 

### 22 transport, these are fundamental processes that could affect a

### Page 465 1 lot of downstream pathway. 

### 2 And again getting back to the -- you will 

### 3 never fit the domoic acid paradigm to this type of thing, but 

### 4 those are not trivial effects I would argue and I think that 

### 5 this should be stated again. 

### 6 So collectively you look at things, neurite 

### 7 outgrowth, mitochondrial morphology, covalent modification of 

### 8 proteins that are involved in axonal transport, and on and on, 

### 9 collectively this is a lot of stuff and I think that it should 

### 10 not be trivialized by just saying that in vitro studies do not 

### 11 predict what happens in the real world. And I think that is 

### 12 pretty much what I had to say. 

### 13 DR. KENNETH PORTIER: Thank you, anybody want 

### 14 to add anything? Dr. Harry. 

### 15 DR. JEAN HARRY: I guess the one thing I would 

### 16 like to add is that in looking at the whole body of data that is 

### 17 out there I think the Agency is taking a very conservative and 

### 18 safe approach by going with looking at the ChE inhibition for 

### 19 regulating and determining risk. I think you have got a good 

### 20 basis for that; you have got really good data for that. 

### 21 You have got a lot of things that are 

### 22 happening in vitro and I guess I'm just going to raise this one

### Page 466 1 caution because it does come back up in thinking about the lead 

### 2 and the mercury and a number of other compounds. Is that, if I 

### 3 have a compound that is going to affect neurite outgrowth and I 

### 4 have a compound that is going to affect axonal transport and I 

### 5 have a compound that is going to affect cross linking of other 

### 6 proteins and I have a compound that is going to affect neural 

### 7 stem cells, if I'm seeing this at even the levels that are about 

### 8 what you see the inhibition happening in vivo, I would expect 

### 9 that I would have a really messed up animal. 

### 10 So we see a lot of these processes that are 

### 11 maintained, they are critical to every cell of the brain yet we 

### 12 usually find some sort of specificity within at least pathology 

### 13 or within a functional outcome. And that has always been where 

### 14 the disconnect has been between neural toxicants in vitro and in 

### 15 vivo. Is that if you get these generalized responses, how do 

### 16 you adjust those now to specificities that can happen in vivo. 

### 17 So that sort of plagued us through a lot of 

### 18 compounds over the years is that type of pivot point and I think 

### 19 until we have some really good studies that target something and 

### 20 say, "If I do a neurite outgrowth study and I do it this way in 

### 21 vitro, I can look at that compound and this dose and I can 

### 22 predict that this is what I would see in vivo and I can show

### Page 467 1 it." 

### 2 Until you have that data you really just have 

### 3 a lot of experiments looking at different endpoints that are 

### 4 affecting directly in a dish, not necessarily translating over 

### 5 in vivo, at least within a range where human health risk 

### 6 assessment is concerned. Having done both in vivo and in vitro 

### 7 it is like they each serve a purpose but you use the data to the 

### 8 best benefit that you can. 

### 9 DR. KENNETH PORTIER: Any additional comments? 

### 10 Dr. Aschner. 

### 11 DR. MICHAEL ASCHNER: What I would like to do 

### 12 is actually to break it into the individual points; I may be a 

### 13 little bit redundant. The first question is essentially what is 

### 14 the degree to which these studies, in vitro and in vivo, 

### 15 evaluating potential neurodevelopmental outcomes and may or may 

### 16 not be more sensitive than AChE inhibition. 

### 17 I think the answer for that is that we really 

### 18 do not know. I think these studies are generally predictive and 

### 19 they can be used to come up with some ideas in terms of 

### 20 mechanistic effects that might be taking place but again I would 

### 21 be very cautious and it has been said before in terms of how you 

### 22 extrapolate from the in vitro to the in vivo because it is a

### Page 468 1 sort of reductionist kind of approach. 

### 2 I'm also not sure how you compare cell 

### 3 differentiation if you collect cells from an animal on day one 

### 4 and you look at the axonal growth for example, how you would 

### 5 equate that with exposure that might be occurring later on in a 

### 6 completely different system of neurotransmitters. So again you 

### 7 might get some hints in terms of some of the mechanisms that 

### 8 might take place but how these translate to the in vivo system I 

### 9 think would have to be followed up. 

### 10 One thing that I did not find in the document, 

### 11 and I want to actually reiterated what was said before. It is a 

### 12 wonderfully written document and I commend you on that but I 

### 13 think what was missing for me in terms of what is the next step 

### 14 is that we do have actually a lot of techniques that can be 

### 15 incorporated to look at some of these issues that you are 

### 16 raising in the in vivo animals. 

### 17 There is wonderful imaging types of systems 

### 18 where you can look at cell differentiation, migrations, and up 

### 19 to genesis and none of that has been done. I do not think 

### 20 anybody is willing to pay for it but I think the kinds of 

### 21 questions that you are asking might be derived from these types 

### 22 of studies.

### Page 469 1 In terms of question number two, please 

### 2 include in your comments a discussion of the strengths and 

### 3 uncertainties. I think I have touched upon that. In terms of 

### 4 the third question, it says dose response and again when you do 

### 5 dose response in vitro it is obviously nice to see that you get 

### 6 one in the first place but not all the dose responses are always 

### 7 linear or curbed; they can be "U" shaped. And that again raises 

### 8 different issues in terms of how you are going to extrapolate 

### 9 the data from these findings. 

### 10 The kind of dose response that you will get 

### 11 might also depend on the composition of the cells that you have 

### 12 in a plate so if you do these types of studies only with neurons 

### 13 you may get one type of effect. If you do it in the presence of 

### 14 microglia and astrocytes, the effects may go away. And once you 

### 15 get to all these complicated issues and once you incorporate it 

### 16 into the dish, it is very hard to take these data and say X 

### 17 happens in vitro and have some certainty or whatever percent 

### 18 certainty you may assign to it, in terms of this is going to 

### 19 happen in vivo as well. 

### 20 So I agree pretty much with everything that 

### 21 was said. I agree with the presentation of Dr. Mundy I think in 

### 22 terms of biological organization, which is question four, this

### Page 470 1 can be very informative in terms of what is happening but in 

### 2 terms of coming up with a risk assessment, I think there are so 

### 3 many shortcomings and I can go on and on, that one would have to 

### 4 look at all these data very cautiously before making any 

### 5 decisions. 

### 6 DR. KENNETH PORTIER: Thank you. Any 

### 7 additional comments? I think that was pretty clear. What I'm 

### 8 going to do right now is we are going to go ahead and take our 

### 9 15 minutes midafternoon break. 

### 10 I would like to see briefly Question 3 

### 11 discussants in the break room. I'm hoping we can maybe get 

### 12 through all of Question 3 today; it has three parts to it and we 

### 13 had one part scheduled for tomorrow. I'm hoping we can just go 

### 14 ahead and tackle that today. Thank you. 

### 15 BREAK 

### 16 DR. KENNETH PORTIER: I think our game plan is 

### 17 we are going to try to get through all of Question 3 today. We 

### 18 had scheduled part of Question 3 to be tomorrow morning but I 

### 19 think it would be nice if we could kind of wrap up the Question 

### 20 3 discussion and then start fresh tomorrow morning with the EPI 

### 21 Question 4. And I understand Question 3 is probably going to 

### 22 take the rest of the afternoon just so everybody knows.

### Page 471 1 So I think we wrapped up Question 2.2, no more 

### 2 questions, so why don't we go ahead and read Question 3.1. 

### 3 DR. ANNA LOWIT: Dr. Portier, we have had a 

### 4 request at the break for a document. I just want to make sure 

### 5 that while we are chasing it down behind the scenes that we are 

### 6 chasing down the right thing. Dr. Sandy asked that we find the 

### 7 EPA review for the Marson et al., 2000. We will have a review 

### 8 of the guideline version of the same study but not Marson, which 

### 9 would be a shorter version of the guideline study. So we can 

### 10 find you the review of the guideline study but it will not be 

### 11 Marson per se although it is the same information. 

### 12 DR. MARTHA SANDY: This is the study that has 

### 13 the lowest BMDL for inhibition of acetylcholinesterase according 

### 14 to one of the tables, I guess on page 19 or 20 of your 

### 15 background documents. We are just looking for a description a 

### 16 little bit more description of that study and its study design 

### 17 for measuring the time points of dosing and measuring AChE. 

### 18 DR. ANNA LOWIT: Okay, I'm glad I clarified 

### 19 because that is different from what I was just asked for. Okay, 

### 20 we will find that. 

### 21 DR. MARTHA SANDY: Thank you. 

### 22 DR. KENNETH PORTIER: Thank you.

### Page 472 1 DR. GINGER MOSER: Question 3.1. As discussed 

### 2 in Section 3.2.2, the experimental toxicology data in laboratory 

### 3 rodents show neurobehavioral effects following developmental 

### 4 exposure with changes in a number of neurological domains. In 

### 5 2008, the SAP agreed to this preliminary conclusion, and the 

### 6 nine additional studies available since 2008 add further 

### 7 support. 

### 8 Please comment on the degree to which these 

### 9 studies show changes in a number of neurological domains and 

### 10 support the qualitative conclusion that chlorpyrifos exposure 

### 11 during gestation and/or early post-natal period may result in 

### 12 long-term adverse effects on the developing nervous system. 

### 13 What evidence does or does not support this conclusion? 

### 14 Please also include in your comments a 

### 15 discussion of the strengths and uncertainties. 

### 16 Please also include in your comments a 

### 17 discussion of the scientific understanding of dose response 

### 18 relationships for biological perturbations and the magnitude, 

### 19 frequency and/or duration of such perturbations that can lead to 

### 20 adverse effects at higher levels of biological organization to 

### 21 support characterization of the likelihood of adverse outcomes 

### 22 in a human health risk assessment as articulated in NRC 2007.

### Page 473 1 DR. KENNETH PORTIER: So that looks like five 

### 2 questions. Dr. Vorhees. 

### 3 DR. CHARLES VORHEES: That is a very 

### 4 complicated question to which I have a somewhat complicated 

### 5 answer. It seems to me in looking this question over and 

### 6 reviewing the studies involved, it seems to me, unless others 

### 7 see it differently, that they are asking for an independent 

### 8 evaluation of the strengths and weaknesses of those 21 studies 

### 9 that are cited in Appendix 3. 

### 10 Now, in order to do that, I'm not going to go 

### 11 through every study and bore you with the design and the 

### 12 findings because if I did that we would not finish even today. 

### 13 What I would like to do, however, is step through some of the 

### 14 studies to the extent of bringing up some issues that I do not 

### 15 think that the Agency highlighted as potential concerns in some 

### 16 of these studies. To just bring to your attention issues that a 

### 17 developmental behavior neuroscientist would think about as 

### 18 issues in these kind of study design. 

### 19 So, I'll take them kind of in the order that 

### 20 Appendix 3 lays them out just for convenience. So that I can do 

### 21 this systematically, although many of the studies in the EPA 

### 22 table appear more than once I will not do them more than once.

### Page 474 1 There is an Abou-Donia study that I just would 

### 2 like to point out a few things about. They used a supplier 

### 3 supplied timed pregnant animal shipped from the supplier for 

### 4 doing a prenatal study. Now, I have worked for the last 15 

### 5 years with a stress HPA access, a neuroscientist, and I can just 

### 6 tell you that I think that is a really bad experimental decision 

### 7 because prenatal stress is known to have long-term effects on 

### 8 behavior. 

### 9 Now, the defense of that would be, well you 

### 10 are ordering in all the animals as timed pregnant but how do you 

### 11 know that the compound does not interact with the stressor, 

### 12 because there will be no control within the study that would 

### 13 allow you to determine that since the controls would be exposed 

### 14 to the vehicle, and I'm learning a lot about the bad things 

### 15 about DSMO but aside from that, I think it is a serious problem 

### 16 and it arises over and over in this particular literature. 

### 17 Another thing I would like to point out in 

### 18 this study, and this is a problem that you see in a number of 

### 19 these studies and I think we have alluded to it and I would just 

### 20 like to emphasis it here, that people who worked in 

### 21 developmental animal studies, multi-verse species animals for 

### 22 many years know. and Dr. Moser brought it up yesterday. Is that

### Page 475 1 it is very important that you look at litter. You look at the 

### 2 unit analysis as it sometime is called by litter, and in this 

### 3 study they only have five litters in the principle treated 

### 4 group; it actually has multiple treated groups. And I think 

### 5 that is a major problem. This study is seriously deficient in 

### 6 sample size. 

### 7 In addition to that they did something which 

### 8 is another, I think, big problem in developmental studies, and 

### 9 this has been talked about in the literature for many years I 

### 10 always refer people back to the Holsen and Pearce study that 

### 11 looked at this and simulated it, and that is the problem of 

### 12 oversampling within a litter. And this study severely 

### 13 oversamples the number of offspring that are evaluated per 

### 14 litter. 

### 15 So when you take the combination of a small 

### 16 number of litters per group and you oversample the number of 

### 17 offspring per litter, what you do is you set yourself up; the 

### 18 risk of type one errors goes way up as Dr. Holsen simulations 

### 19 show the more you do that. And I do not know why but in this 

### 20 whole field we have been going around and around on this for 

### 21 years and yet the lesson does not seen to be learned as 

### 22 indicated by the fact that this study is 2006; and this

### Page 476 1 information has been known to those of us who do research in 

### 2 this area since, I think it has been settled since the 70's but 

### 3 that is maybe just my view of it. 

### 4 But I know all agencies' regulatory studies 

### 5 recognize this issue and set things up so that those are not 

### 6 problems. So when you get on to, for example, the Icengole 

### 7 study you run into that same sort of problem; they used timed 

### 8 pregnant animals shipped in. 

### 9 Another thing that they do and this particular 

### 10 laboratory does, which is a completely unproven method, and that 

### 11 is what they do is shortly after birth they randomize the pups 

### 12 among the dams. I think the goal of that is to try to randomize 

### 13 genetic and intrauterine effects. We know that air variance 

### 14 clusters within litters. They are trying to break that 

### 15 association so that they do not have to pay much attention to 

### 16 the litter variable as they go along. 

### 17 And this laboratory does this and they not 

### 18 only will randomize one shortly after birth, they will randomize 

### 19 every three days. And I think their goal is to try to break 

### 20 that genetic or maybe epigenetic intrauterine effect. The 

### 21 problem is you do not change the dam factor. So, the dam factor 

### 22 is still going to produce a clustering effect as the animals are

### Page 477 1 reared. 

### 2 There is not a single published scientific 

### 3 paper that I know of where anyone has actually tested, whether 

### 4 or that procedure breaks litter clustering. Nobody wants to do 

### 5 that study because it is a giant pain in the neck, for which you 

### 6 will get a very ho-hum answer. So, nobody does it. It is a 

### 7 completely unproven method and I think it is a problem. 

### 8 I will just point out another problem that I 

### 9 do not know whether other people would be sensitive to, but it 

### 10 bothered me. They run a test called spontaneous alternation in 

### 11 this experiment. I do not know how many of you know what his 

### 12 test is about, but the concept behind is that if you put a rat 

### 13 in a T maze with no reinforcement whatsoever, they will go down 

### 14 and they will choose an arm. Then, you put them back in at the 

### 15 beginning. What will tend to happen about 67 percent of time on 

### 16 that second trial, they will choose the alternate arm. That 

### 17 indicates that they remember the arm they went down, and are now 

### 18 interested in exploring the other choice. 

### 19 You run this test. The idea behind the test 

### 20 is to run it under low anxiety conditions. It is a novel 

### 21 environment already. The goal is not to increase anxiety to a 

### 22 higher level. This laboratory runs this test in an elevated T

### Page 478 1 maze. I have never seen this before. What you are basically 

### 2 doing is running the elevated plus maze as a T maze. 

### 3 So, for those of you who are not into this 

### 4 that may not seem like you are like, wow, who cares, believe me, 

### 5 this is not the way you want to run it. It is counter to one of 

### 6 the basic premises of the test of what you are trying to 

### 7 measure. You are not trying to measure anxiety. You are trying 

### 8 to measure memory. If you increase the anxiety level to a high 

### 9 level, you can potentially interfere with what you are trying to 

### 10 measure. I would also point out that every finding in this 

### 11 study, whether statistically significant or not, is in fact 

### 12 quite small. 

### 13 Another thing I would like to bring up about 

### 14 the radial arm maze, which I think is a very serious problem in 

### 15 this whole literature. It is not just the chlorpyrifos 

### 16 literature; it is really a problem throughout neuroscience. I 

### 17 had to put is so bluntly, but I think a lot of people who run 

### 18 the radial arm maze do not really know what they are doing. 

### 19 So, the problem that you have is that you have 

### 20 to think what you are trying to measure, short-term memory. How 

### 21 do you measure short-term memory? Short-term memory is a 

### 22 phenomenon that depends on recent events and it decays very

### Page 479 1 rapidly over time, like trying to remember a telephone number. 

### 2 In a rat, you put him in the radial maze, the 

### 3 idea is that all the bated arms, they have to go down that arm 

### 4 and remember that they just visited it so that they do not go 

### 5 back and visit it again having forgotten that they already went 

### 6 down that arm. 

### 7 It is absolutely essential in such a test that 

### 8 you have a delay between their first arm choice and their 

### 9 second, third, fourth arm choice. If you do not have a delay in 

### 10 between, rodents are just like people. They figure out the 

### 11 simplest way to solve the problem without relying on short-term 

### 12 memory, because that is harder to do than it is to just learn a 

### 13 phenomenon called chaining. In chaining, the rat learns a very 

### 14 simple strategy to defeat the test. 

### 15 All I have to do to maximize the number of 

### 16 rewards I get, which is what the rat wants, it to go out of each 

### 17 arm and turn right. If I turn right on every option that I get, 

### 18 I will go around the maze and collect the maximum number of 

### 19 reinforcements, and I do not have to use any memory whatsoever. 

### 20 All I have to learn is a habit. Habit learning is much easier 

### 21 than relying on short-term memory. 

### 22 None of these experiments do the appropriate

### Page 480 1 controls to rule out that what they are really measuring is 

### 2 habit formation rather than short-term memory. I will come 

### 3 later to the one study that actually seems to have controlled 

### 4 for it. When we come to it, we will come to the conclusions 

### 5 that it reached. 

### 6 There is another study, I do not know if I can 

### 7 pronounce the authors' names. It is done in mice. It is kind 

### 8 of an interesting study. It is Billauer-Haimovitch, and there 

### 9 were some good features in this study. The fostered some of the 

### 10 litters and they did not foster other litters. Then, they 

### 11 looked to see whether fostering or not fostering made any 

### 12 difference. They report without showing the data that it did 

### 13 not make a difference. Then they pooled the data. 

### 14 I would like to comment on an issue that comes 

### 15 up in the morris water maze. There are a number of things, and 

### 16 Dr. Harry has alluded to some of these. One of the things that 

### 17 people do not often pay very much attention to, this is spacial 

### 18 task. The idea is to measure spacial mapping, which is a 

### 19 hippocampally-dependent form of learning and is homologous in 

### 20 humans to declarative memory. Declarative memory is memory for 

### 21 people, places, things and events. 

### 22 What becomes essential if you are going to use

### Page 481 1 this as a rodent version of declarative memory is that you have 

### 2 a spacial component that is really spacial. What these people 

### 3 do is they use a very tiny maze. It is 87 cm in diameter. For 

### 4 mice, the standard size that is considered appropriate for mice 

### 5 is 122 cm. Not only that, you can use a small maze if you want 

### 6 to adjust the size of the goal proportionately. But what you do 

### 7 not want to do is use a small maze and a very big target, 

### 8 because then it is not very difficult. If the platform is large 

### 9 and the maze is small, the animal is going to find it rather 

### 10 easily. There is no much demand on hippocampal place cells. 

### 11 So, what they do is use a pretty large 

### 12 platform and a pretty small maze. It produces a search area 

### 13 ratio of 74 to 1. 74 to 1 is not an adequate test of spacial 

### 14 mapping. We need ratios that are above 200 to 1. Many mazes 

### 15 are 300 to 1 or 400 to 1. So, it is just not a good test for 

### 16 what they were trying to get at. 

### 17 A strength of this paper is that they have 3 

### 18 separate experiments in there. They find an effect each time, 

### 19 but they use latency. We know that latency in the morris maze 

### 20 can be confounded by a number of factors, but obviously swim 

### 21 speed is one of them. Now, they measured swim speed and they 

### 22 say that there is no effect. That is good, but they did not

### Page 482 1 report path length. We know path length is the principle index 

### 2 of spacial mapping, and they do not report it. They also did 

### 3 not do a probe trial, which is if you are going to say you are 

### 4 looking at spacial learning and reference memory, you have to do 

### 5 a probe trial or you have not measured it. They also say they 

### 6 ran the qued version as a control procedure, but they do not 

### 7 tell us what they found. So it is another example. 

### 8 The next study is by them as well, Turgeman, 

### 9 and they use the same maze, have the same issues. So I will not 

### 10 belabor that one as if I have no belabored these. So, this will 

### 11 get easier as I go along. 

### 12 Laviola did kind of an interesting thing. 

### 13 They tested and they used reeler knockout mice. They bread 

### 14 hets. They took out of each litter the knockouts and the wild 

### 15 types and tested them. So, it ends up being kind of a 

### 16 complicated study. But my problem with the study is not that 

### 17 they used reelers, because I thought that was sort of an 

### 18 interesting idea given what we know about reelers and early 

### 19 brain development, but they do some very strange statistical 

### 20 things. 

### 21 One of the things that is very strange is to 

### 22 test animals, and for example, by the way they test the axon in

### Page 483 1 this study, it is odd in that way. But when you do a 

### 2 statistical analysis on 45 minute locomotor data and you do not 

### 3 find an effect and you go in and just say, well I am going to 

### 4 look at the last 25 minutes because I want to, I just sort of 

### 5 becomes rather strange. That is exactly what they do. They 

### 6 just say well, it looked to us like there was an effect in the 

### 7 last 25 minutes, so we will do a separate additional analysis on 

### 8 the last 25 minutes. Because that is significant, is everything 

### 9 okay? 

### 10 They did not do their subjects by litter, so 

### 11 it has that potential confound in it. In fact, they did not 

### 12 appear to use sex as a factor in the analysis. This study is 

### 13 just full of problems in the design, in the way the study was 

### 14 conducted and in the analysis. So, it did not leave me with a 

### 15 lot of confidence. 

### 16 There is a whole series of studies by an 

### 17 Italian group, Venerosi in 2010 as one example. They use an 

### 18 interesting statistical approach. What they tell you is that 

### 19 they ran most of the outcome data by analysis of variance, which 

### 20 would appear to be pretty appropriate, but in some cases, they 

### 21 did not run the analysis of variance. They simply used a Tookie 

### 22 test selectively without an ANOVA finding, without a significant

### Page 484 1 F test. 

### 2 Well, I guess I do not have a problem if you 

### 3 can justify doing selective testing by some, say a priori 

### 4 prediction. When you get to the results, you should at least 

### 5 tell us which of the data are in fact significant by ANOVA 

### 6 followed by Tookie and which are significant by Tookie without 

### 7 ANOVA. They do not tell you. 

### 8 Haviland study I found to be a problematic 

### 9 study. There is no mention of litters that litters were used. 

### 10 There is no mention of the number of litters taken from each 

### 11 litter. There is no mention of how sex was handled in the 

### 12 design. The results are not well described statistically. They 

### 13 are done in a very sort of sweeping general sort of style. 

### 14 There is no mention of how they do pair-wise comparisons. They 

### 15 do mention it for the thyroid assay, but they do not mention it 

### 16 for the behavioral outcomes, whether the use the Fisher LSD for 

### 17 the behavior, but it would have been nice if they had said so. 

### 18 Alright, enough. 

### 19 The Levin studies with Dr. Slotkin have an 

### 20 interesting feature. They report that they use this randomized 

### 21 litter. Even though they are randomizing the pups in the litter 

### 22 to break litter factor, they still go ahead and select one out

### Page 485 1 of each artificial litter, one male and one female, for testing. 

### 2 I do not quite understand the logic there. It seems a little 

### 3 circular. So, I am going to break the litter effect, but I am 

### 4 going to treat the litter effect as though it is important. But 

### 5 they say that they use analysis of variants set at 0.05 to look 

### 6 at main effects, but at interactions they are going to look at 

### 7 anything that is P less than 10%. 

### 8 I do not understand that and I do not 

### 9 understand the rationale for it, but their biostatistician is 

### 10 here. If they want to defend this, you know, I will let them. 

### 11 They use an animal in their studies that concerns me. They do 

### 12 not use the most common and well-understood animal for learning 

### 13 and memory tests, Sprague Dawley from Charles River or Harlan. 

### 14 They use the Zivic-Miller Sprague Dawley. If you go into the 

### 15 older experimental psychology literature on learning and memory 

### 16 and you look at the learning of the Zivic-Miller Sprague Dawley. 

### 17 If you go into the older experimental psychology literature on 

### 18 learning and memory and you look at the learning of the 

### 19 Zivic-Miller Sprague Dawley, what you find is, it is the worst 

### 20 performer of all the stocks of Sprague Dawley rats. It is 

### 21 particularly bad in shock avoidance tasks, which means it is a 

### 22 terrible in active avoidance. It is great in passive avoidance

### Page 486 1 because when they get shocked, they will not move. 

### 2 So, when you take an oddball animal and you 

### 3 use it in a setting like this, you produce data that are then 

### 4 difficult to fit in, I think, with other studies in the 

### 5 literature. It is interesting to me that eventually they 

### 6 dropped in some of their later studies, they stopped using the 

### 7 Zivic-Miller. I do not know why, but I could guess. 

### 8 We talked about some of the difficulties in 

### 9 the Levin and Slotkin studies about dose response. I will not 

### 10 go back over those. So, that covers the dam study and its 

### 11 essential features because the same design considerations are 

### 12 used. I thought that the Aldridge study was one of the stronger 

### 13 studies because of the use of ketanserin. I think when they use 

### 14 ketanserin as a challenge to look at 5-HT2 receptor involvement, 

### 15 they were actually onto something. I hope at some point they 

### 16 choose to follow that up. 

### 17 The Ricceri study is very similar to the other 

### 18 studies from the Italian group. One of the things about several 

### 19 of the Italian studies is they do a extremely complex design, in 

### 20 which they have 3 prenatal groups crossed by 3 postnatal groups 

### 21 producing a 9 group study. My experience with large, and I 

### 22 guess a lot of us have tried those, is you start losing control

### Page 487 1 over the study. There are practical problems with trying to do 

### 2 extensive behavioral analyses, keep all other factors constant 

### 3 when you have the enormous number of animals going through your 

### 4 protocol. You inevitably end up with large numbers of 

### 5 interaction terms in your analysis of variance that become very 

### 6 difficult to sort. They really have some major problems in 

### 7 sorting these data. 

### 8 I will just say that when it comes to the 

### 9 Johnson study, again, I think that that study would benefit from 

### 10 control over in the radial arm maze for the phenomenon of 

### 11 chaining. I am not saying that chaining actually happened in 

### 12 their animals, but without some description or assurance that 

### 13 chaining did not happen, it remains an open question. 

### 14 I think in the Carr study of 2001, one of the 

### 15 concerns there in that design is the number of litters they used 

### 16 was relatively modest. They did very slightly over sample per 

### 17 litter. They took 2 per litter per sex in order to get up to 

### 18 their sample size that they wanted of 10 per sex per treatment 

### 19 group. It is a little shy on the ends. 

### 20 The Jett study is an interesting study. It 

### 21 could have been a very important study, but I think the 

### 22 experimenters made some mistakes. What made it interesting is

### Page 488 1 that they tested 2 doses, 0.3 which is an area where we would 

### 2 like to have some data, and a high dose of 7. Unfortunately, I 

### 3 do not understand their exposure protocol, which is postnatal 

### 4 day 7, 11 and 15. It is not clear and there is no justification 

### 5 for how those days were chosen. 

### 6 They also test in the morris water maze at 24 to 28 days. That 

### 7 is not an optimal time to look at spacial learning. Spacial 

### 8 learning is just merging at that stage of development. 

### 9 Some labs do not get very good learning at 

### 10 that age because it is not a fully developed capacity. Their 

### 11 statistics are not described properly. They leave a lot to be 

### 12 guessed at. The statistical model is unspecified. They do no 

### 13 report path length data for the morris maze. They report that 

### 14 there were no differences on Q trials, but they do not show us 

### 15 any data. They report that there are no effects on speed. That 

### 16 is good. 

### 17 Their sample looks okay when you just glance 

### 18 at it, 10 males and females in the control group, 10 and 9 in 

### 19 the low dose and 9 and 8 in the high dose, but you do not know 

### 20 how many litters that came from. Then, you get to this very 

### 21 problematic sentence that it could have been selected from as 

### 22 little as 2 litters. You know, it is hard to know, but it does

### Page 489 1 not look promising. 

### 2 I think that the strongest design study in 

### 3 this whole group is the Morrison study because it was done, I am 

### 4 guessing, as a guideline kind of study. So, the sample sizes 

### 5 are bigger and it is a nice feature that they include a 0.3, a 1 

### 6 and a 5 mg/kg group. They expose for, what I would suggest, is 

### 7 a more reasonable exposure time. They do not try to just pick 

### 8 out of the air random developmental periods to do their 

### 9 exposure. They expose from implantation to postnatal day 10. I 

### 10 would fault them for giving the postnatal exposure to the Dams. 

### 11 There are several studies that do that. I know regulatory 

### 12 guideline studies do this. I strongly disagree with it. I do 

### 13 not think it is an appropriate design. They seldom document how 

### 14 much of the compound is getting through lactation to the pups. 

### 15 I think it is a poor choice, and I have said so before in other 

### 16 contexts, and I have written about this. Nobody listens. 

### 17 Another thing they do that statistically, they 

### 18 do sort of an interesting thing. They know they are going to be 

### 19 doing a lot of ANOVAs, so to try to control for that, they set a 

### 20 higher P value of 0.02. That is kind of an interesting way to 

### 21 try to protect against false positives. They are very strict 

### 22 about it. They get a number of 0.03 and 0.05 effects, and they

### Page 490 1 just say they are not significant. Now, one could look at those 

### 2 and say well maybe there is something there, but they basically 

### 3 do not get anything. 

### 4 This study is largely null, but one of the 

### 5 strengths of it is they used a delayed spacial alternation test. 

### 6 One of the nice things that they did is they actually tested 

### 7 different delays between trial 1 and trial 2, actually testing 

### 8 working memory. They actually did working memory as you are 

### 9 supposed to do working memory. So, they actually do not find a 

### 10 working memory effect. It remains an open question. I think in 

### 11 the animal studies whether there are working memory deficits, it 

### 12 sort of seems like there are from the radial maze, but the 

### 13 radial maze, they way they have been run, have some problems. 

### 14 The study that ran a strong paradigm, at least for working 

### 15 memory, does not find an effect. You cannot exactly compare 

### 16 delayed spacial alternation to radial arm, so there is always 

### 17 that. By and large, this looked like a strong study. 

### 18 Now I am going to sort of get to my bottom 

### 19 line. First, I would just like to say that there are many 

### 20 effects seen in these studies. Whatever their deficiencies, 

### 21 there are many long-term effects documented at doses in the 

### 22 range of 1 to 5 mg/kg per day. It has already been shown to us

### Page 491 1 ad nauseam that these doses significantly inhibit 

### 2 cholinesterase. Let's just make that clear right there. 

### 3 There are only 3 studies that I could identify 

### 4 of the 21 that used doses below 1 mg/kg. Two used 0.3 and 1 

### 5 used 0.2. Those studies are the Jett study, the Braquenier 

### 6 study and the Morrison study. Of these, 2 found no effects at 

### 7 that lower dose and only 1, the Jett study which is deeply 

### 8 flawed, found an effect at 0.3. Because that study contains, I 

### 9 think among the most serious methodological flaws, it is very 

### 10 difficult to know whether any weight should be put on it or not. 

### 11 So, I do not think that the studies and the data from the Jett 

### 12 study should be relied upon. It would require a replication in 

### 13 a properly designed and analyzed study. In the absence of that, 

### 14 I think that study has to be heavily discounted. 

### 15 I think in the remaining studies, 1 mg/kg and 

### 16 above, there are many difficult interpretational and 

### 17 methodological limitations. There are many inconsistencies as 

### 18 been discussed across the different tests. Some of the tests 

### 19 that are used transplanted, as I said yesterday from 

### 20 neuroscience, are transplanted without apparent full 

### 21 appreciation for what they were designed to do. 

### 22 For example, an anxiety test picked up and put

### Page 492 1 down into a neurotoxicology setting. What does it mean if an 

### 2 animal show an increase or a decrease in anxiety? Which one of 

### 3 those is a toxic manifestation? Which is bad for us? I mean, 

### 4 we know that in human beings, high anxiety is detrimental to 

### 5 performance and so is low. People perform best in a mid range 

### 6 of moderate anxiety. Is that true for rodents? Well, we think 

### 7 it is. So, if you give them a test of anxiety and they are up a 

### 8 bit or they are down a bit, but they are not extremely high or 

### 9 extremely low, just because it is significantly different from 

### 10 baseline, is that a toxicological end point just because it is 

### 11 an end point that has changed? I do not know, but I can tell 

### 12 you that there is no data that I know of that establishes that 

### 13 it is a neurotoxic outcome. 

### 14 I think the same should be said about the 

### 15 social tests. They are very interesting and they have a place 

### 16 in neuroscience. As I think I alluded to, they have a place in 

### 17 autism modeling where the disorder that you are trying to model 

### 18 is a social disorder. If you are knocking out a candidate gene 

### 19 in looking for a social deficit because you believe that you 

### 20 knocked a gene out that is important to social behavior, and in 

### 21 that context, you can interpret a change in anxiety, I think, 

### 22 within the context in an appropriate way.

### Page 493 1 But, how do you move that over into a 

### 2 toxicological setting? I think the cognitive test for that 

### 3 reason. I do not think that many people would say that impaired 

### 4 learning is a good thing. When you have impaired learning, you 

### 5 do not have the same interpretational issues that you have with 

### 6 social interactions. If a Dam goes out to her pups and licks 

### 7 them more or less, I do not know which of those is the toxic 

### 8 outcome, and that is a problem to understanding a lot of these 

### 9 data. A lot of the Italian data are like that. 

### 10 Question 3.1. I think the evidence support 

### 11 that developmental neurobehavioral study, show an adverse 

### 12 effects of CPF exposure, they show long-term effects. The 

### 13 strengths and weaknesses of these studies are outlined above, 

### 14 and are the principle findings and the study designs that are 

### 15 independently summarized in the things I have said and in the 

### 16 EPA table. Adequately summarize the key features of these 

### 17 studies. In general, the studies fall into 2 major categories, 

### 18 those that have adequate group sizes, in which control for 

### 19 litter effects by sampling only 1 offspring per litter 

### 20 stratified by sex, or only barely oversampled per litter by 

### 21 using 2 of each sex per litter. It think those are in the 

### 22 acceptable range. Analyze the data using appropriate

### Page 494 1 statistical models, ANOVA models with factors of group and sex, 

### 2 optimally using litters of blocking factor and a completely 

### 3 randomized block design, in which treatment and sex are fixed 

### 4 effects within the blocks. Using repeated measure factors where 

### 5 you have trials, days or intervals when you have a repeated 

### 6 measure on the same subject. 

### 7 Then, I think there is another set of studies 

### 8 that failed to control for litter effects. They tested too few 

### 9 litters. They were underpowered. They were very prone to type 

### 10 1 errors. They should be significantly discounted in 

### 11 determining the weight of evidence for or against 

### 12 neurobehavioral effects for developmental exposure to CPF. 

### 13 Some of the studies include appropriate 

### 14 downstream statistical analyses and some did not. In general, 

### 15 most studies appropriately use factorial ANOVA or ANOVA models 

### 16 with follow-up methods, although the follow-up methods vary 

### 17 quite widely. Some of the models used further step down slice 

### 18 techniques or simple effect ANOVAs and some do not. I think 

### 19 that can be an issue. 

### 20 I think in this literature, some of the a 

### 21 posteriori techniques that are used are, my guess I could say 

### 22 is, sort of out of date. I think Fisher's LSD test has been

### Page 495 1 discussed in many statistical textbooks for its limitations are. 

### 2 It can be used when you only have 3 groups, but above 3 groups, 

### 3 it does not control for Alpha and therefore is not recommended. 

### 4 5 I have gone over, I think, the significant 

### 6 problems with the interpretation of some of the learning and 

### 7 memory tests. I think that these are by and large appropriate 

### 8 methods. The radial arm maze and the morris water maze are 

### 9 appropriate tests for inclusion in studies of this kind, but the 

### 10 caveat is of course when they are done appropriately with 

### 11 appropriate controls, appropriate size mazes, appropriate 

### 12 trials, appropriate safe guards for confounding factors, the use 

### 13 of appropriate additional methods like Dr. Harry mentioned 

### 14 yesterday. One of the things that you would want to do is do a 

### 15 reversal phase. Reversal is a very fundamental aspect of 

### 16 spacial mapping that is neglected in most of these studies. 

### 17 Dose response. Although a number of 

### 18 experiments reviewed here and had 2 or 3 doses, linear or even 

### 19 curvilinear or even monotonic dose response relationships were 

### 20 frequently not seen. This was clearly troubling to the agency 

### 21 and certainly troubled to me as a reviewer. It is difficult to 

### 22 understand some of these effects. We can conjecture

### Page 496 1 explanations as has gone on in the biological literature forever 

### 2 about curvilinear, inverted U-shaped curves, but do we have any 

### 3 evidence that that happens with this particular compound? I do 

### 4 not actually know of any such evidence. I did not see any. I 

### 5 did not see much discussion of the issue in these papers either, 

### 6 though I have to say I discounted authors' discussion sections 

### 7 rather heavily as I was just mostly focused on their methods and 

### 8 results. 

### 9 Persistence of effects. One of the aspect of 

### 10 my review of these papers to me stands out. That is that at the 

### 11 doses of 1 mg and above, there are many studies which find 

### 12 long-term effects. I do not think that there is any evidence to 

### 13 suggest that these effects stem in any way from 

### 14 acetylcholinesterase inhibition, but they are there. What the 

### 15 mechanism is, is entirely unclear. Many of these studies 

### 16 exposure prenatally, test the offspring as juveniles, 

### 17 adolescents or even adults, weeks and months after the exposure 

### 18 is over when there is no more cholinesterase inhibition, and 

### 19 these effects still show up. They show up in a large number of 

### 20 studies. It is hard to discount that those are all type 1 

### 21 errors. So, I think there is something going on there. I think 

### 22 the agency comes to that same conclusion, but what it is, is a

### Page 497 1 very difficult thing to pin down. 

### 2 So, it does look like that there is a 

### 3 developmental vulnerability to this compound based on these 

### 4 data. It would be interesting of someone would figure out what 

### 5 that was. Should I stop right there before I go to 3.2? 

### 6 DR. KENNETH PORTIER: Let's let some of the 

### 7 other panelists figure out if there is anything left unsaid. 

### 8 That was very good though. I was thinking about the statistical 

### 9 issues you brought up. I tend to concur. There is no reason to 

### 10 use and unprotected Fisher's test, unless what you are really 

### 11 doing is searching for significance. You want a bunch of 

### 12 significant effects, so you have something to report in the 

### 13 journal, but it is really not supported anymore without doing 

### 14 comparison-wide control, which is what you do not have. Dr. 

### 15 Aschner, I think you are next. 

### 16 DR. MICHAEL ASCHNER: Michael Aschner. There 

### 17 is not much that I could say after Chuck. I am not really in a 

### 18 position to evaluate the studies individually, but I think what 

### 19 I just heard actually helps me to explain or understand better 

### 20 why there are such big discrepancies between the studies. You 

### 21 know, I always have difficulty when same doses are used in the 

### 22 same genders, and you get bidirectional effects. The assertion

### Page 498 1 that no matter direction the effect occurs is indicative that 

### 2 there is some effect, which seems to be the EPA conclusion, and 

### 3 something that did bother me. 

### 4 I guess when you take into account all of 

### 5 these flaws in all of these studies, that might explain actually 

### 6 why they are getting at times inconsistent results. I do agree 

### 7 with what Chuck said about persistent effects. I am not sure 

### 8 though, that any of these animal studies actually have been 

### 9 carried out far enough. I would think that there are probably 

### 10 some other domains that need to be looked at. 

### 11 We heard earlier today for example that 

### 12 dopaminergic systems might be affected. A lot of these systems, 

### 13 other neurotransmitter systems, have a tremendous redundancy in 

### 14 terms of the clinical manifestations of the deficits that occur 

### 15 within these systems. For example, with a dopaminergic system, 

### 16 if you wipe out 60% or 80% of the neurons, you would not expect 

### 17 to see any effects that manifest clinically or behaviorally in 

### 18 these animals. If you do these studies early on after the 

### 19 exposure, postnatal months 2 and 3, it might be that many of 

### 20 these effects are still unmasked because they do not show up 

### 21 until a much later life stage periods. 

### 22 In terms of the doses, I think some of these

### Page 499 1 studies have been done at different doses, very few of them 

### 2 actually. It comes back to some of the other issues that we 

### 3 mentioned earlier about, I think Dr. Lu mentioned them. It is 

### 4 very hard to equate these studies in terms of the exposures, 

### 5 because many of them use subcutaneous exposures. Others use 

### 6 oral exposures. We know very little about how much of these 

### 7 compounds are transferred to the pups under the different 

### 8 conditions. We did not see anything about this. 

### 9 My overall conclusion is that indeed there are 

### 10 some effects that seem to persist and there are some effects, 

### 11 whether they occur at doses that are lower than the 1 mg/kg per 

### 12 day, I do not think I could say with any high level of 

### 13 confidence, but I think clearly some of the effects are 

### 14 persistent. They do occur and I will close with that. There is 

### 15 not really much else that I could add to what Chuck said before. 

### 16 17 DR. KENNETH PORTIER: Thank you. Dr. Carr? 

### 18 DR. RUSSELL CARR: I will have to concur with 

### 19 Dr. Aschner that there is not much else I can say, except to 

### 20 speak to that I agree with the point that this chemical does 

### 21 exert long-term effects and it tends to be that everybody stops 

### 22 at 1 mg/kg. At that dose and above, we do see effects. Below

### Page 500 1 that dose, so far there have been no effects observed, but that 

### 2 kind of speaks to what the does response relationship, it may 

### 3 possibly, that U-shaped dosage curve may start to occur at that 

### 4 low dose where maybe effects at that low dose are not indicative 

### 5 or similar to the effects at the higher doses because it is such 

### 6 a low dose. 

### 7 So until we can figure out what we can test to 

### 8 pick up that, then we are kind of stuck in a quandary of are the 

### 9 low doses really having an effect, because the effects may be 

### 10 totally different than what we are used to observing at the 

### 11 higher doses. 

### 12 DR. KENNETH PORTIER: Dr. Harry? 

### 13 DR. JEAN HARRY: Jean Harry. So, I totally 

### 14 appreciate everything you went through, for going through those 

### 15 papers. I think it really represents how peer review data does 

### 16 not necessarily mean that it is a correct study. I think that 

### 17 that was a great presentation about going through, but also 

### 18 coming into the fact that a lot of things are falling out, even 

### 19 in the face of some fatal flaws in the studies that need to be 

### 20 considered. 

### 21 I want to support the caution that was raised 

### 22 for starting to integrate in some new test methods into

### Page 501 1 toxicology, the social behavior I am sure is coming over because 

### 2 of the autism work. That is a difficult assessment. I have 

### 3 done it. You can skew it in a lot of different ways. It is 

### 4 maybe applicable to the animal models for autism, but even that 

### 5 is somewhat in question. It is about all there is there, so it 

### 6 relies on that. The anxiety question, again, that is an 

### 7 elevated T maze and it is talking about looking at changes that 

### 8 would happen because they would be responsive to antianxiety 

### 9 drugs. So, is it anxiety or is it a behavior that is responsive 

### 10 to an antianxiety pharmacological agent. Again, we do not 

### 11 really know. 

### 12 So, I think investigators are going to start 

### 13 pulling those in because they are coming up in the literature 

### 14 more and more. How you interpret them, what they mean, is it 

### 15 good or bad? If you have 3 contacts with a stranger mouse, is 

### 16 that worse than having 6 contacts with a stranger mouse? I 

### 17 mean, we really do not know those answers. I think trying to 

### 18 translate that over into the toxicology field needs to be done 

### 19 with extreme caution. 

### 20 The learning and memory is a different 

### 21 component. If we have a deficit in learning, whether it is an 

### 22 attention deficit, as long as we are not just measuring a

### Page 502 1 performance and motor deficit rather than a learning and memory 

### 2 deficit, do those studies and they are done correctly, we can 

### 3 interpret what would be adverse there. 

### 4 So, I think overall, the data suggests there 

### 5 is something there that is happening at 1 and above. Whether it 

### 6 is due to cholinesterase inhibition, we really do not know that. 

### 7 It is associated with it, and that gives you a good marker. I 

### 8 think that is pretty much it. I agree with everybody else's 

### 9 comments that have been made. 

### 10 DR. KENNETH PORTIER: This is Ken Portier. I 

### 11 have a question, something that Dr. Aschner said about long-term 

### 12 effects. I wonder, Dr. Vorhees, can you expand a little bit 

### 13 more on long-term, what does it mean in these animals for 

### 14 long-term effects on learning and memory? Did these studies 

### 15 really address long-term, or this deficits that show up in a 

### 16 juvenile that may or may not be something that affects an adult? 

### 17 If I am making sense. 

### 18 DR. CHARLES VORHEES: It makes sense. There 

### 19 is virtually no data in this set where anyone tried doing the 

### 20 same learning tests at 2 different ages to try to answer that 

### 21 question, so I cannot really say that there is anything here 

### 22 that speaks to it. With other neurotoxins, it has been done and

### Page 503 1 people can demonstrate the effects that show up during say, 

### 2 adolescences, it will appear then in adulthood and a few of us 

### 3 have gone out and tested again at a year, which in a rat is a 

### 4 pretty long interval and middle age. Yeah, those effects with a 

### 5 real neurotoxin, will show up again. Whether they would show up 

### 6 in this case, I do not know. 

### 7 Let me just add a comment. I do think that 

### 8 the issue that I did not emphasize but others have emphasized 

### 9 that I think is real important is this route of administration 

### 10 for this compound. I mean, that was not something I was 

### 11 particularly sensitive to coming from the world of giving drugs 

### 12 where you give them subcutaneously. 

### 13 In fact, with this compound, it seems to be 

### 14 for a lot of reasons, the route is going to play a very 

### 15 important role in how various tissues are going to see the 

### 16 compound. Of course, the brain being the one I am particularly 

### 17 interested in, how much it is going to see it, how long it is 

### 18 going to see it, are critical things. Of course, I mentioned 

### 19 the vehicle used. I think there is now, I am hearing since I 

### 20 have been here, some serious concerns about potential 

### 21 interactions between the compound and the vehicle used in the 

### 22 DMSO studies.

### Page 504 1 There are studies in here that use oil, which 

### 2 seems like a better way to go. There are some of those that are 

### 3 pretty well designed, in which we found some long-term effects. 

### 4 There are a number that you might now discount because of the 

### 5 DMSO to some extent. 

### 6 DR. KENNETH PORTIER: Yes, Dr. Aschner? 

### 7 DR. MICHAEL ASCHNER: Michael Aschner. I 

### 8 agree with what Chuck has said. I think the early 

### 9 manifestations in terms of behavior would probably persist into 

### 10 adulthood. The point that I was trying to make is that there 

### 11 might be some behaviors, and correct me if I am wrong on that, 

### 12 that you might not pick up at 2 or 3 months of age, which may 

### 13 show up later on in life. So, that may not obviously occur with 

### 14 lower doses. It is just that they take much longer to manifest 

### 15 because of redundancies within those neurotransmitter systems. 

### 16 That has not been looked at. 

### 17 DR. KENNETH PORTIER: This is Ken Portier. 

### 18 Yes, I noticed that none of these are multigen studies for 

### 19 example. So, maternal behavior in an exposed child that then 

### 20 moves on to try to breed, it could affect that kind of behavior. 

### 21 We have not seen any of that when we do see that in some other 

### 22 studies. Dr. Carr, did you want to jump in here? I thought you

### Page 505 1 were getting ready. 

### 2 DR. CHARLES VORHEES: Can I comment on that? 

### 3 I think most of the literature shows that in rodents, cognitive 

### 4 capacity in rodents is crystalized by 60 to 90 days. 

### 5 DR. KENNETH PORTIER: Dr. Harry? 

### 6 DR. JEAN HARRY: Jean Harry. I would like to 

### 7 say something about route of administration. While I think it 

### 8 is important when you are doing your final assessment for risk 

### 9 on the route, if you are doing that initial study or you are 

### 10 trying to test something to see if it is possible, I would not 

### 11 automatically rule out the subcutaneous route. But if you did 

### 12 find something in the subcutaneous, which would be more likely, 

### 13 then to try an oral route, but I do not think I would 

### 14 automatically dismiss it. Just put it within the framework with 

### 15 what know about route of exposure if at all possible. I am not 

### 16 sure I would toss out papers that did that. 

### 17 DR. CHARLES VORHEES: I do not know that I 

### 18 would toss them out entirely, but I would say that we know from 

### 19 the ethenol literature that you really cannot give ethanol 

### 20 subcutaneously. If you do, you will get spurious findings all 

### 21 over the place. I do think with every drug or agent that you 

### 22 test, you really do have to be sensitive to the route of

### Page 506 1 administration as an issue. How it modulates your 

### 2 interpretation is another thing, but we know that you can give 

### 3 it wrong sometimes and really skew the findings. 

### 4 DR. KENNETH PORTIER: Dr. Carr? 

### 5 DR. RUSSELL CARR: I think there also is 

### 6 another issue where your vehicle comes into play, how it behaves 

### 7 in that subcutaneous route. We had a paper a few years ago 

### 8 where we did oil subcutaneous and oil oral, and they were really 

### 9 similar as far as cholinesterase inhibition, same dosages, but 

### 10 DMS was totally different. 

### 11 DR. KENNETH PORTIER: Dr. Pope? 

### 12 DR. CAREY POPE: Yes, I guess also whether you 

### 13 want to ignore, so to speak, studies that used a subcutaneous 

### 14 route for example. I am thinking somebody was showing data that 

### 15 suggest that oral dosing is not the only thing going on here. I 

### 16 mean, a kid could get exposed by dermal dosing and possibly, I 

### 17 think Dale Hattis was saying inhalation exposures may be 

### 18 relevant. So, that oral doses is important, but it is not the 

### 19 only thing. Subcutaneous may capture some of these other 

### 20 routes. 

### 21 DR. CHARLES VORHEES: Well that is a good 

### 22 point. I am glad you reminded me of it because it seems to me

### Page 507 1 that one of things that would be valuable in this area is to 

### 2 have an inhalation study where someone looked at neurobehavioral 

### 3 outcomes after inhalation exposures. There are many inhalation 

### 4 tox labs that could do such a study. If they would just 

### 5 collaborate with someone who does the neurobehavioral, I think 

### 6 you could get a very interesting and maybe useful study out of 

### 7 something. 

### 8 DR. KENNETH PORTIER: That was Dr. Vorhees. 

### 9 My only issue was that every time I have seen the animal 

### 10 inhalation studies, it seems like they are so controlled and 

### 11 stressful for the animal, I do not know if anything you would 

### 12 get would be a stress response. Dr. Terry? 

### 13 DR. ALVIN TERRY: Dr. Alvin Terry. So, I had 

### 14 a few questions for Dr. Vorhees. I heard a lot of weaknesses 

### 15 and not many strengths when it comes to these behavioral studies 

### 16 that were overviewed. One criticism with a water maze study 

### 17 that I did not feel that was particularly valid is the issue of 

### 18 not reporting path lengths if they reported latency and swim 

### 19 speeds because path length is factored in to swim speed. So, it 

### 20 is centimeters traveled per second that was one thing. And then 

### 21 with the radial arm maze study and this issue of chaining, and I 

### 22 did not review these papers individually, so do you know for a

### Page 508 1 fact if the ones you reviewed did not have a central hub so that 

### 2 was prevented with the chaining effect? 

### 3 DR. CHARLES VORHEES: Charles Vorhees. They 

### 4 have a hub, but they did not confine them to the hub between 

### 5 trials. Not one of these studies discussed confinement. So you 

### 6 have to have that delay. There is published data that showed 

### 7 that if you do not do that, you do not get a working memory. 

### 8 DR. ALVIN TERRY: Okay, are these the Levin 

### 9 papers or, which? 

### 10 DR. CHARLES VORHEES: Nobody who used the 

### 11 radial maze included a delay interval in the central region. 

### 12 DR. ALVIN TERRY: One argument I would make 

### 13 there, and it is not semantics, but if an animal adopts a 

### 14 chaining strategy and you see in acquisition over time, there is 

### 15 still a lot for me to learn. It stops the strategy. It is a 

### 16 form of learning. If the 2 groups are different, then they are 

### 17 different. 

### 18 DR. CHARLES VORHEES: It is habit learning. I 

### 19 am just trying to point out that they probably are not measuring 

### 20 working memory. They are probably measuring habit learning. 

### 21 DR. ALVIN TERRY: Some other kind of learning. 

### 22 DR. CHARLES VORHEES: I am not saying there is

### Page 509 1 not an effect there. I was trying to actually say there is an 

### 2 effect there. I just would not describe it as a working memory 

### 3 effect. Unless someone is willing to go in and rule out this 

### 4 alternate interpretation that it could be habit, that is what I 

### 5 am saying. 

### 6 Now, to your morris maze, and I did try to 

### 7 point out that several of these papers have stated that there is 

### 8 no swim speed effect, but another control that you need in that 

### 9 situation is the probe trial. It seems to be that if you do not 

### 10 demonstrate the animals shows adequate spacial bias, you really 

### 11 have not gone all the way to showing that it is a reference 

### 12 memory deficit. So, they might show that there is the spacial 

### 13 learning deficit, but they have not shown a reference memory 

### 14 deficit. Some of these authors are a little broad stroke in the 

### 15 way the talk about what they found. So, I am just faulting them 

### 16 for that. There are studies in here that are strong. I guess I 

### 17 over emphasize the negative probably. That is what reviewers 

### 18 tell me. 

### 19 DR. ALVIN TERRY: I thought I was on NI Study 

### 20 Section for a minute there. Another question I had too about 

### 21 the overview of the radial arm maze studies, and you mentioned 

### 22 working memory errors, which is the typical wind shift version,

### Page 510 1 I know that on some occasions, and I am not speaking 

### 2 specifically to these studies because I do not know and you 

### 3 could clarify, if this is a 12 arm or 16 arm maze and they have 

### 4 some arms bated and some not bated. It breaks the chain, so 

### 5 that would not be necessarily a valid argument, or are they 

### 6 reporting always just working memory errors or are they also 

### 7 report reference memory errors in some of these studies? 

### 8 DR. CHARLES VORHEES: Charles Vorhees. Most 

### 9 of those studies do report that there is some increase. Well, 

### 10 some of the studies got a significant effect on reference memory 

### 11 errors and that is true. It is very difficult to know if an 

### 12 animal was using a training strategy. It is very difficult to 

### 13 know whether a reference memory, for example, what is the cost 

### 14 to the animal to go down the wrong arm and make a reference 

### 15 memory error. What is that cost? The very next arm probability 

### 16 wise is going to be a bated arm. It really costs the animal 

### 17 very little to do down the unbaited arm, even if they know it is 

### 18 unbaited, it does not really cost them. The way rats move 

### 19 through these mazes, it costs them probably 6 to 10 seconds to 

### 20 go down there. 

### 21 Without the confinement procedure, chaining 

### 22 could be going on even in the reference memory errors, and you

### Page 511 1 would not know it unless you also say video tape the animals and 

### 2 watch them for the pattern that they are using. That is 

### 3 something that they should be doing. If you are not going to 

### 4 confine them in some sort of system that closes gates or 

### 5 something, then what you should be doing instead is videotaping 

### 6 them. 

### 7 The Barnes maze is an example. The maze is 

### 8 very similar. What the Barnes maze scoring, which is done all 

### 9 pretty much manually, looks at is the strategy that the animal 

### 10 uses because they do the same chaining thing in the Barnes maze, 

### 11 which is an open arena with a lot of holes. They have to find 

### 12 the hole that has the escape. So, it is very similar 

### 13 conceptually. What you see is that animals go through stages, 

### 14 but when you finally get to spacial learning, they go from the 

### 15 start straight to the goal. 

### 16 So, what you want to see is a strategy in 

### 17 which the animal demonstrates that they are going to arms and 

### 18 not repeating, but they are not going sequentially. That is 

### 19 what you need to see. These studies are just mute on that 

### 20 point. There is no way to tell whether they did or did not 

### 21 because the investigators, I do not think, ran those analyses. 

### 22 So, you have an interpretational issue and I

### Page 512 1 do not know how to resolve it based on what is presented. 

### 2 DR. KENNETH PORTIER: I think Dr. Lowit would 

### 3 like to jump in on this. 

### 4 DR. ANNA LOWIT: I did have one question for 

### 5 thought. It occurred to me yesterday listening to the 

### 6 conversation. There are times when we will go to investigators 

### 7 of academic research in any area, whether it is tox studies or 

### 8 exposures studies or epidemiology studies. We do it on a 

### 9 regular basis. We contact the authors and we ask them questions 

### 10 about their study. Sometimes we get a lot of information. Some 

### 11 people do not give us a lot of information. It is a personal 

### 12 choice that. 

### 13 This body of data is not one of those areas 

### 14 where we have done that where we have gotten on the phone and we 

### 15 have gotten emails and we started bugging people about answering 

### 16 our questions or providing additional details. Listening to 

### 17 you, I am getting the sense of some of the critiques, some 

### 18 information may exist in some of these laboratories that help 

### 19 produce some of these critiques. It sort of came back to my 

### 20 mind that this may be an area that we would have to wait the 

### 21 resources to do that given the conclusions of the panel. We 

### 22 would sort of have to wait how much effort that would take and

### Page 513 1 what would be the value added to the analysis. It is certainly 

### 2 something that we could be something that we could think about. 

### 3 Certainly, if there were certain studies or particular studies 

### 4 that seem to be lack in their details. Let's say they may have 

### 5 promise or may have interesting information but are lacking in 

### 6 details, if there are a handful of those, you can certainly 

### 7 suggest. That is something that we could think about is 

### 8 pursuing talking to the investigators and getting additional 

### 9 details. 

### 10 DR. KENNETH PORTIER: I would start by asking 

### 11 how many Dams. I really appreciated what he was saying because 

### 12 I have done these kinds of reviews before. It is very 

### 13 frustrating to read the methods. They will not even tell you 

### 14 how many Dams were used in the study. That is critical to all 

### 15 the analysis. If I had to ask one question that would be the 

### 16 first one I would ask. It drives a lot. It tells you a lot 

### 17 about the study. Dr. Harry? 

### 18 DR. JEAN HARRY: Jean Harry. Just based upon 

### 19 that comment and I do not know if anybody around the table could 

### 20 do it or just depose it, but there is a number of neuroscience 

### 21 journals that now have, and they are sharing this list. Journal 

### 22 of Neurochemistry is one that does it. They have had so much

### Page 514 1 trouble in some of the behavioral studies of people being able 

### 2 to replicate findings. I get a lot of this is probably coming 

### 3 up much more in the transgenic animals, that they actually have 

### 4 before you submit a paper. They have a list of everything they 

### 5 want to know about the experimental design. You have to include 

### 6 it before the Journal will even consider the paper. It is 

### 7 almost a check off. It is things like litter. It is things 

### 8 like chaining. It is these types of things that what are the 

### 9 critical features that have to be mentioned so that somebody 

### 10 could replicate it. A number of them are putting it in their 

### 11 supplemental information so it is not taking up a lot of the 

### 12 Journal, but it is accessible for reproducibility. 

### 13 I have yet to see that come up in a tox 

### 14 journal, but yet it seems to be the area that needs that 

### 15 information so much. It might be something you could propose to 

### 16 some of the journals or editors or bring up at SOT, is it 

### 17 something that any of the tox journals would consider following 

### 18 through on as some of the neuroscience journals are doing. 

### 19 There is a precedent for basically demanding a certain type of 

### 20 information prior to even a manuscript being considered. 

### 21 DR. KENNETH PORTIER: Okay, he promised me it 

### 22 would be at least an hour, and it was a little over an hour,

### Page 515 1 thank you. Any additional comments on this question before we 

### 2 move to question 3.2, which has 2 parts? Yes, Dr. Vena. 

### 3 DR. JOHN VENA: I am not sure after listening 

### 4 to all of this, if I have a good sense of the last question in 

### 5 the charge question. What it the bottom line in terms of the 

### 6 accumulated evidence of the animal studies, and is there any 

### 7 sense of a dose response relationship for these perturbations in 

### 8 the magnitude? I do not know if I clearly heard that. 

### 9 DR. CHARLES VORHEES: Maybe I did not make 

### 10 that very clear. The dilemma is that there are a few studies, 

### 11 which have dose response relationships. There are many studies 

### 12 that do not show dose response. There are many studies that 

### 13 would look like they are dose response, but they have so many 

### 14 methodological issues it is not clear whether you want to put 

### 15 much weight on them. So, I am a little torn about the 

### 16 interpretation on that. 

### 17 I would say that it is quite unclear to me 

### 18 whether there is a linear or anywhere close to linear dose 

### 19 response for neurobehavioral effects. I just do not see going 

### 20 across studies that that looks very strong. I really appreciate 

### 21 the other panel members commenting on this because I found this 

### 22 a very difficult issue to try to deal with in these 21 studies

### Page 516 1 because it is so problematic here. I cannot explain why someone 

### 2 would get an effect at 1 and not at 5, or they would get an 

### 3 effect at 1 and 3 and then not at 5 mg/kg. It is very difficult 

### 4 to make sense out of to me. 

### 5 DR. KENNETH PORTIER: Dr. Carr? 

### 6 DR. RUSSELL CARR: I concur in the fact that 

### 7 there are select studies that do show dose response, but then I 

### 8 think the methodological problems come into play sometimes. I 

### 9 do not think right now that there is a clear understanding of 

### 10 whether or not there is or not a dose response. It is like 

### 11 Chuck said, if you are not getting effects at 5 and you are 

### 12 getting effects at 1 in one study and the next study is the 

### 13 reverse, it is really difficult to make a clearcut across the 

### 14 board this is what is happening. 

### 15 DR. KENNETH PORTIER: This is Ken Portier. I 

### 16 get the feeling here that there is just not a confidence in 

### 17 replicability of that dose response at this point. So, you see 

### 18 some hints, but it is not to that point where you feel that if 

### 19 somebody replicated that study they would get exactly that same 

### 20 dose response until we get to that point. It may just be a 

### 21 function of just not enough studies, not enough good studies. 

### 22 Dr. Lu?

### Page 517 1 DR. CHENSHENG LU: Maybe the rodents are not 

### 2 an ideal model for this type of testing. I mean, people use 

### 3 primates for neurobehavioral testing on lead and other metals. 

### 4 I am not promoting primate research, but with this discussion 

### 5 about those inconsistencies, so it kind of leads to the 

### 6 question, would the agencies further consider data from rodent 

### 7 models in this neurobehavioral testing and just completely not 

### 8 using it. 

### 9 DR. KENNETH PORTIER: Okay, I think we have 

### 10 kind of done this one. Why don't we move onto question 3.2, 

### 11 part 8. 

### 12 DR. GINGER MOSER: Question 3.2 much of which 

### 13 has been discussed. The dose response data in the in vivo 

### 14 experimental neurodevelopmental toxicity studies are not 

### 15 amenable to empirical dose response modeling. As many studies 

### 16 use only 1 or 2 doses, and in some cases the lower dose but not 

### 17 the higher dose level produce significant effects. Many studies 

### 18 report effects at a dose of 1 mg/kg per day. A dose that 

### 19 produces some amount of brain cholinesterase inhibition when 

### 20 given directly to the pups postnatally, but may or may not alter 

### 21 fetal brain cholinesterase activity given to the Dams 

### 22 gestationally, 1 study Braquenier et al., 2010, using lower

### Page 518 1 doses administered to the Dam on GD 15 to lactational day 14 

### 2 reported a NOEL of 0.2 mg/kg per day. Comparing the NOEL of 0.2 

### 3 mg/kg per day to a repeated dosing acetylcholinesterase 

### 4 inhibition, BMDL10 of 0.03 mg/kg per day suggests that 

### 5 cholinesterase inhibition is a sensitive and protective 

### 6 endpoint. Please comment on the scientific quality and 

### 7 robustness of the animal neurodevelopmental toxicity studies. 

### 8 Please comment on the degree to which studies that measure 

### 9 acetylcholinesterase inhibition and those that measure 

### 10 neurodevelopmental outcomes could be integrated to evaluate 

### 11 whether points of departure based on 10% acetylcholinesterase 

### 12 inhibition provide more sensitive endpoints than endpoints 

### 13 measured in the experimental neurodevelopmental studies. Please 

### 14 include in your comments of consideration the strengths and 

### 15 uncertainties associated with this assessment. 

### 16 DR. KENNETH PORTIER: Dr. Vorhees, it is up to 

### 17 you whether you take these separately or as a group. 

### 18 DR. CHARLES VORHEES: Okay, I think it might 

### 19 make more sense to break them apart and have the Panel comment. 

### 20 I promise this is going to get shorter as we do along. 

### 21 So, this may not be the most satisfactory 

### 22 answer, but here goes. So the quality of the studies in this

### Page 519 1 category varies. There are some of high quality. Overall, the 

### 2 studies by Slotkin and Levin, and those of Carr and the one by 

### 3 Morrison, and several of the Ricceri and Venerosi studies are 

### 4 the better ones because they generally use multiple doses. They 

### 5 had adequate sample size. They controlled for litter effects, 

### 6 some in a little bit of unorthodox ways, and they in general 

### 7 used pretty sound behavioral methods. They used appropriate 

### 8 statistical methods to analyze their data. Because all of these 

### 9 studies find some long-term neurobehavioral effects, these data 

### 10 collectively may be regarded as a robust set of findings, but 

### 11 only at doses of 1 mg/kg and above. 

### 12 The data are mute or negative concerning 

### 13 affects below 1 mg/kg of CPF. Among these studies however, 

### 14 there are some concerns. In the Slotkin and Levin experiments, 

### 15 the use of commercially supplied time pregnant animals is a 

### 16 concern as was the use of Zivic-Miller Sprague Dawley's and a 

### 17 number of their studies, some of their statistical methods. So 

### 18 for that reason, there are a few doubts about some of their 

### 19 findings. 

### 20 As people have talked about before, they find 

### 21 some inverse findings in males and females, for example in the 

### 22 radial arm maze. That is sort of a puzzling effect. For

### Page 520 1 studies I think with regulatory implications, preferable to use 

### 2 mainstream stock such as the Charles River Sprague Dawley or 

### 3 Harlan as I mentioned before. 

### 4 There were some concerns about what is being 

### 5 measured in the radial arm mazes. Not that there is not a 

### 6 finding there. I acknowledge there is a finding. I think that 

### 7 the question is what is the finding? What does it mean? It is 

### 8 a working memory or reference memory effect as the authors 

### 9 present it as, or is it habit formation? 

### 10 The weight of evidence for the neurobehavioral 

### 11 studies is that no effects are reliably or convincingly 

### 12 demonstrated below 1 mg/kg per day. 

### 13 DR. KENNETH PORTIER: Dr. Aschner? 

### 14 DR. MICHAEL ASCHNER: I agree with everything 

### 15 that was said. The only comment that I have to offer here is 

### 16 that perhaps the only way that we might get at some of these 

### 17 issues is to do a cross laboratory study. Given the lack of 

### 18 doses in most of these studies and the other deficiencies, if we 

### 19 could come up with a unifying design for experiments to be 

### 20 conducted in those laboratories that are considered to be the 

### 21 leading laboratories in this area, then perhaps doing these 

### 22 studies carefully designed taking care of all of these issues

### Page 521 1 methodological issues, dosing issues, if we came up with a 

### 2 series of studies that can be done on 3 or 4 labs and then look 

### 3 at the data, we might get some answers as to how reliable those 

### 4 findings are. I think with what we have right now, there are so 

### 5 many uncertainties that we really do not know. 

### 6 DR. KENNETH PORTIER: Dr. Carr? 

### 7 DR. RUSSELL CARR: I will just concur to the 

### 8 previous statements. I find that I agree that anything below 1 

### 9 mg/kg per day, we do not see anything. I think probably future 

### 10 studies need to maybe focus on those dosages a little bit more, 

### 11 although we do run the problem, as Ginger said that other day, 

### 12 of not wanting to publish negative data. There may be a lot of 

### 13 negative data out there, effects at those dosages that did not 

### 14 make it to the literature because it was negative data. That is 

### 15 just the way it is. 

### 16 DR. KENNETH PORTIER: Dr. Harry? 

### 17 DR. JEAN HARRY: I really have nothing to add 

### 18 other than the comments that have just been made that any future 

### 19 efforts should try to focus on the 1 and below, because you know 

### 20 what is happening above that, link the 2 together and really 

### 21 just do a really good study, but that is hoping that the 

### 22 investigators out there will do that.

### Page 522 1 DR. KENNETH PORTIER: Anyone else? Dr. 

### 2 Vorhees, they pull out in this statement this one 2010 study 

### 3 Braquenier, I did not hear you say anything particular about 

### 4 that one? What was your finding on that particular study? If 

### 5 you could go back one slide just so he can see. 

### 6 DR. CHARLES VORHEES: I can go back and talk 

### 7 about that one. 

### 8 DR. KENNETH PORTIER: Just because they kind 

### 9 of pointed it out, I thought maybe you had looked at that one 

### 10 particularly. I did not get a feeling for whether, I guess I 

### 11 need a clear reading, is that a good study or a poor study or an 

### 12 in between study? 

### 13 DR. CHARLES VORHEES: Okay, this is a mouse 

### 14 study in CD1 mice. They use 0.2, 1 and 5 mg/kg administered on 

### 15 E14 to P14 as I have it. Again, they give it postnatally to the 

### 16 mother, not directly to the pups. It is a pretty carefully done 

### 17 study. They call their litters to a standard size. The 

### 18 stratify for sex using a random selection. They find effects, 

### 19 but the effects are not dose dependent. That was one of the 

### 20 things about the effects that they found. They also probed 

### 21 rather hard on effects, which I think we would question whether 

### 22 or not you would do follow-up analyses on. For example, they

### Page 523 1 said well, they saw a trend in the light dark test in side 

### 2 preference at 0.08. They said well that is sufficient to go on 

### 3 and dot a posteriori testing using Dunnetts. I do not think I 

### 4 would do that. They made quite a bit out of an elevated plus 

### 5 maze finding where the trend was at point less than 10. They 

### 6 went ahead and did Dunnetts tests anyway saying that they saw 

### 7 significantly reduced time in open in these mice at a 

### 8 significant level in Dunnetts, even though the ANOVA was at 

### 9 0.10. 

### 10 So, I think this study has some problems. I 

### 11 mean, I think my reading of what the EPA was saying was that 

### 12 there are effects reported in the paper at 1 mg and there are no 

### 13 effects at that dose 0.2. That is what they are saying, well 

### 14 that is then the no effect level. I do not think that the study 

### 15 is very strong in some of its features. The study design was 

### 16 okay, but they did some, can I use this word, squirrelly things 

### 17 statistically, some sort of unorthodox things that I am not sure 

### 18 are easily defended. Yet if you accept their interpretation, 

### 19 there are findings. Again, I do not know what the elevated plus 

### 20 maze means in this context. I do not know what the light dark 

### 21 test means in this context. Those are the tests. There is also 

### 22 locomotor test. They did not find anything there.

### Page 524 1 All the effects are marginal. I think that is 

### 2 a generous description of the findings. 

### 3 DR. KENNETH PORTIER: Dr. Carr, you were going 

### 4 to add something? No? Okay. Dr. Lowit? 

### 5 DR. ANNA LOWIT: I am sensing a slowing of the 

### 6 comment that had a clarification. Before you close, and I do 

### 7 not think you are ready, but before you close, I have heard a 

### 8 lot of details on certainly a subset of the poorer quality. We 

### 9 have talked quite a bit about dose to the extent that that is 

### 10 possible. But, there was a short exchange that I did not feel 

### 11 like it came full circle about the age of the testing. There 

### 12 was a comment from 1 or 2, and I do not remember who the 

### 13 individuals were, about the onset of behaviors later than the 

### 14 testing happened. We just want clarity around what those ideas 

### 15 and what the science behind those ideas or if this just creative 

### 16 thinking or if there is science behind behaviors that would 

### 17 begin or brain development that would occur I think up to age 

### 18 60, where you are testing, let's say age, 50 if that is a 

### 19 systematic problem or the relationship. I guess I beg a little 

### 20 conversation around the age of the testing versus the age of the 

### 21 onset of the behavior, if that makes any sense at all. 

### 22 DR. KENNETH PORTIER: Can we come back to

### Page 525 1 that? Because we still have B to do. I think that is where we 

### 2 were going to move next is to the 3.1B. If you could click the 

### 3 slide one more just so people can remember what we are talking 

### 4 about in B. I will ask Dr. Vorhees. 

### 5 DR. CHARLES VORHEES: Let me just try to wrap 

### 6 that one up. There is that last sentence. I guess I really did 

### 7 not really address as Dr. Vena pointed out, which is part of 3.2 

### 8 is asking us to compare, comparing the NOEL of 0.2 to a repeated 

### 9 measuring of acetylcholinesterase inhibition, BMDL10 of 0.03 

### 10 suggests that it is the most sensitive. I guess they are asking 

### 11 do we agree with that. I would say yes. That is my read of 

### 12 that. Just to make sure that that is clear, my understanding of 

### 13 that is the answer to that is yes. Ready to go on? Okay. 

### 14 So, B is about doses at which 10% 

### 15 acetylcholinesterase inhibition was assessed compared to the 

### 16 neurobehavioral effects after CPF. Of the neurobehavioral 

### 17 effects reported in the reviewed experiments that assessed 

### 18 acetylcholinesterase inhibition, I could find no studies that 

### 19 were identified that should affects on behavior below 10% 

### 20 inhibition, which was approximately, and this very approximate. 

### 21 I am just using what is presented in those papers, not drawing 

### 22 on other data on that the Agency has, I think, drawn on. In

### Page 526 1 those behavioral papers using approximately 1 mg/kg. Doses 

### 2 below 1 mg/kg do not show convincing evidence as I understand it 

### 3 of neurobehavioral effects combined with significant inhibition 

### 4 of acetylcholinesterase. 

### 5 So, that is about as far as I can comment on 

### 6 that issue. I found myself sort of constrained in the 

### 7 behavioral studies because many of them do not do the 

### 8 acetylcholinesterase in the same study. So, there were very few 

### 9 that did, but it looks like you do not get any behavioral 

### 10 effects below 1 mg/kg. There is a dose at which you do get 

### 11 acetylcholinesterase inhibition. 

### 12 So, by inference, you can say that nothing 

### 13 below that is going to produce as far as we know today, a 

### 14 neurobehavioral effect. At least, nobody has been able to show 

### 15 it with the 3 studies that have a lower dose. In those 3 

### 16 studies, 2 are negative, 1 is positive and seriously flawed. 

### 17 That is the dilemma. When you get down to those doses, that 

### 18 literature is so thin that it is very difficult to draw much in 

### 19 the way of inferences, at least for me. I just could not make 

### 20 strong statements about such a very tiny data set. 

### 21 We have, I would bet, there are probably at 

### 22 least 1000 studies now on candidate genes for autism spectrum

### Page 527 1 disorder, behavioral studies in mice. Do we know what the 

### 2 mechanism of autism is? Are we close? I think not. So, here 

### 3 you have 21 studies on a compound. 

### 4 I think one has to think about this in 

### 5 perspective. This is a very small data set. The fact that 

### 6 there are inconsistencies in it, when I look back at the lead 

### 7 literature when it was starting, the fetal alcohol literature 

### 8 when it was at this stage of development, methamphetamines, 

### 9 cocaine, go down the list of prenatal thought to be established 

### 10 developmental neurotoxins, and they were a mess in the early 

### 11 going. I do not find that terribly surprising. People got 

### 12 better and better at doing experiments, at looking at the right 

### 13 things as time went on. People made mistakes and they went back 

### 14 and they persisted. There were more and more perspective 

### 15 epidemiological studies and then very gradually over about 25 

### 16 years for cocaine it took before the data began to really come 

### 17 into some kind of convergence. I do not know that the animal 

### 18 data on this compound are any more close to what we know about 

### 19 alcohol, lead, methylmercury, methamphetamine, cocaine. 

### 20 So, we are trying to look at this from the 

### 21 larger sort of perspective. This is a very tiny data set. When 

### 22 you are looking at the low dose, it is even tinier 3 studies.

### Page 528 1 So, I do not feel like I can make strong statements, just that 

### 2 there is not anything persuasive below 1 mg. 

### 3 DR. KENNETH PORTIER: Dr. Aschner? 

### 4 DR. MICHAEL ASCHNER: I agree. There is 

### 5 nothing below 1 mg/kg per day. So, I cannot add much to this. 

### 6 Since Chuck started talking about some of the things that can be 

### 7 done, again I think there are a lot of genetic issues that have 

### 8 not been considered in any of these studies. There are 

### 9 different variants of acetylcholinesterase, the R type and the S 

### 10 type, which might affect synaptic plasticity if we talk about 

### 11 development. If you consider other issues, I have not seen a 

### 12 single study that has done stereology, looking at point volume, 

### 13 for example. I mean, there is a whole laundry list and I know 

### 14 it is unrealistic on my part to suggest those kinds of studies. 

### 15 Again, to reiterate what Chuck said in terms of our knowledge, I 

### 16 think the number of studies that have looked at many of these 

### 17 mechanisms, mode of actions and outcomes, and specifically 

### 18 related them to cholinesterase inhibition, we can count them in 

### 19 one hand, the careful studies. 

### 20 DR. KENNETH PORTIER: Dr. Carr? 

### 21 DR. RUSSELL CARR: I really cannot add much 

### 22 more to that. I mean, Chuck pointed out the obvious. It is

### Page 529 1 very small. It is very new. As we progress, hopefully it will 

### 2 get stronger and we can do a better job at this. 

### 3 DR. KENNETH PORTIER: Dr. Harry? 

### 4 DR. JEAN HARRY: I think in answering directly 

### 5 to your question, which pretty much says if you do the point of 

### 6 departure based upon the cholinesterase inhibition, not only is 

### 7 it more sensitive endpoint, but it is more reliable endpoint in 

### 8 which you can get consistency across a lot of your studies, so 

### 9 much more than the neurobehavioral endpoints are. 

### 10 DR. KENNETH PORTIER: We are going to throw in 

### 11 a ringer, Dr. Popendorf. 

### 12 DR. WILLIAM POPENDORF: Good description. I 

### 13 agree particularly with the last statement in terms of 

### 14 cholinesterase being an important historic measure in something 

### 15 that we find to be very reliable. The other endpoints would be 

### 16 based on dose. Then we get into issues of different animal 

### 17 systems. I think we are just opening an can of worms should we 

### 18 get to the point where we have data or an endpoint that we could 

### 19 justify below. I am just going to comment on the value of that 

### 20 PBBK, as I think that will come up numerous times. As we get 

### 21 into the levels below 10% or using the measure other than 

### 22 acetylcholinesterase, I think that PBBK type model is going to

### Page 530 1 be a virtually essential tool to relate dose to outcome, and 

### 2 particularly the dose to the target site and facilitate the 

### 3 linkages that we need between animals and again, going back a 

### 4 step further to the in vitro and in vivo tests. So, overall, I 

### 5 agree with everything that has been said. 

### 6 DR. KENNETH PORTIER: Anyone else? Dr. Harry? 

### 7 8 DR. JEAN HARRY: This did not have to do with 

### 9 this question, but I did want to mention that we asked to 

### 10 discuss a point. 

### 11 DR. KENNETH PORTIER: We will come back to 

### 12 that question. Anyone else on this part B? Yes, Dr. Buckley? 

### 13 DR. BRIAN BUCKLEY: I just have a question. I 

### 14 am not hearing sort of strong feelings about the values below 1. 

### 15 Does that mean there just are not enough studies does at this 

### 16 point in time to make that definitive statement so we really 

### 17 want to leave that as sort of an unknown classification as 

### 18 opposes to weakly no effect? I am trying to get a feel from 

### 19 everybody. 

### 20 DR. CHARLES VORHEES: I think there is just 

### 21 not enough data. So, I think that the studies just do not speak 

### 22 to this issue. The 2 studies that seem pretty well done do not

### Page 531 1 find anything. So, to the extent that you would want to put 

### 2 weight on 2 studies showing no effects, that is what we have. 

### 3 That is my sense is 2 studies is kind of inadequate. Proving 

### 4 that null is hard enough and of course never can be proven 

### 5 really, but 2 studies? That is really terrible. 

### 6 DR. RUSSELL CARR: At least, may I add that we 

### 7 also maybe we have not seen the effects yet. Maybe it is there. 

### 8 We just have not found it. Right now as far as what we know, 

### 9 we have not observed the effects. 

### 10 DR. KENNETH PORTIER: I think at this point, 

### 11 let's come back to Dr. Lowit's question about the long-term 

### 12 behaviors versus the age of testing. Dr. Harry, did you want to 

### 13 start that discussion? 

### 14 DR. JEAN HARRY: I can start a part of it. 

### 15 One would be to address it as a question. On the last paper 

### 16 that was looking at the mice and, as I do not remember, looking 

### 17 at the light dark place preference and the elevated T maze, so 

### 18 in mice, the light dark place preference is often considered an 

### 19 equivalent in the adolescent, in the very early postweaning 

### 20 animal to the elevated T maze in the adult. So there are 

### 21 certain tests that would be applicable to use in those young 

### 22 animals, and others that you really need to take up to be about

### Page 532 1 50 to 60 days of age to get a fully integrated system if you 

### 2 were going to test for alterations within it. I have to default 

### 3 on some other timing, and I do not remember the rat data. I am 

### 4 much more knowledgeable of the mouse data now developmentally. 

### 5 You were saying that for learning and memory, 

### 6 for cognitive functioning that you would pick up on a morris 

### 7 water maze or a radial arm maze type thing, you should pretty 

### 8 much have it crystalized by about 60 days of age. 

### 9 DR. CHARLES VORHEES: So, it is not going to 

### 10 change after that. It is fully formed. It is at full capacity. 

### 11 It is not going to get better if you test them at 180 days. In 

### 12 rodents when you get past a certain age, then you start getting 

### 13 into the aging issue and performance starts to deteriorate 

### 14 again. They usually have to get out to 18 months to 2 years to 

### 15 start seeing that. I am not sure what Dr. Lowit is driving 

### 16 toward here. 

### 17 DR. JEAN HARRY: I think one of her questions 

### 18 was if you tested the animals at day 50, are you now testing 

### 19 them a little too young? You are not testing at the appropriate 

### 20 time. Are there cautions about age of testing that they should 

### 21 be looking at in some of these data sets. 

### 22 DR. ANNA LOWIT: There was an exchange, I do

### Page 533 1 not remember who the individuals were, around the maturation and 

### 2 the testing. I just wanted to ensure that what we are talking 

### 3 about are true uncertainties and no speculation. The 

### 4 uncertainty is based in good science and not just throwing out 

### 5 ideas for the sake of throwing out ideas. I wanted to close 

### 6 that piece. 

### 7 DR. MICHAEL ASCHNER: It may be something that 

### 8 I mentioned in terms of dopaminergic system where I said if you 

### 9 lose 80% or 90% functional capacity, you will see some effects. 

### 10 Those may not manifest until much later on in life, not 

### 11 specifically the behavioral changes. This comes back to what 

### 12 Dr. Carr said. I do not think these kinds of domains have even 

### 13 been looked at. So, I am not commenting specifically about the 

### 14 behavior. What Dr. Vorhees says if you see something at 60 

### 15 days, you will probably see it at 90 days. I accept that, but I 

### 16 am saying that if you have either functional deficits, which are 

### 17 motor related, if you tested 60 days and it is related to the 

### 18 dopaminergic system, you might not see them until the animals 

### 19 are 18 months old. 

### 20 DR. CHARLES VORHEES: So, cognitive effects, I 

### 21 think the other thing that may have triggered that thought that 

### 22 you had, which I was talking about some concerns about one of

### Page 534 1 the morris water maze tests where they tested them at 24 to 28 

### 2 days. We know that spacial learning and reference memory are 

### 3 not fully developed at that age. By the time you get to 60 days 

### 4 of age, it is. 

### 5 When you are doing developmental testing, you 

### 6 just have to be sensitive to the fact that that particular type 

### 7 of learning and memory is not fully mature at that age. There 

### 8 might be things that you would learn at those ages that maybe 

### 9 you would benefit from that you would not see when they are 60 

### 10 days of age. But it is also possible that an effect that you 

### 11 see at 24 to 28 days will in fact disappear when the animals are 

### 12 older. It can go either way. 

### 13 So, I do not mean to throw that out to 

### 14 disparage the fact that they were testing at that age. I am 

### 15 just saying that it is unclear that that kind of an effect, just 

### 16 as if in children you tend to do Bayleys at a certain age. 

### 17 Bayleys are not very predictive of waist data and why is that? 

### 18 They have partial prediction, WAIS, Wechsler Adult Intelligence 

### 19 Scale. So, how do you interpret that? 

### 20 It is a developmental marker that has some 

### 21 cognitive components in it. Because children's intelligence is 

### 22 not crystalized until later, it can change because that is still

### Page 535 1 a developing function. I am just trying to say that the same 

### 2 thing goes on in animals that developmental psychologists I 

### 3 think would tell you about the Brazelton to the Bayley, from the 

### 4 Bayley to the WPPSI, from the WPPSI to the WISC, and from the 

### 5 WISC to WAIS. They have various predictive correlations, but 

### 6 the earlier ones are the poorest predictors of the adult ones. 

### 7 DR. KENNETH PORTIER: Dr. Harry? 

### 8 DR. JEAN HARRY: So I think the one comment 

### 9 that Dr. Aschner was making was we also know that in a number of 

### 10 different types of studies that sometimes you do not see things, 

### 11 especially at low dose effects, you may not see things unless 

### 12 the animal or organism is challenged in some way. That could be 

### 13 represented either on your pharmacological challenges that you 

### 14 have seen done. Other people have proposed that that challenge 

### 15 could come in with aging. As the process of aging, as the 

### 16 process of the dynamics that happen within the brain and the 

### 17 stress that is put on is over time that you may start to unmask 

### 18 changes as a function of aging, not necessarily the young adult, 

### 19 but as aging. It is a continuum up and down. You may unmask 

### 20 different things at different times. 

### 21 DR. KENNETH PORTIER: In my comments earlier, 

### 22 that is kind of what I was trying to get at. I was trying t

### Page 536 1 elicit that kind of discussion that some things may not show up 

### 2 early. A deficit may only show up later. I was thinking in 

### 3 terms of some of the other studies that I have seen, not 

### 4 chlorpyrifos, but some of the others for example, where you see 

### 5 gender switching very early that could have implications for the 

### 6 whole life cycle of the animal that may not show up very clearly 

### 7 early on, but it will be obvious later on. That is all that I 

### 8 was trying to get at. 

### 9 Any additional comments on question 3, 

### 10 neurodevelopmental discussion? Yes, Dr. Pope? 

### 11 DR. CAREY POPE: So, if I understood what you 

### 12 were saying Dr. Vorhees, that there were 3 studies that actually 

### 13 go down into below the 1 from the experimental animal 

### 14 neurobehavioral studies, yes 2 negative and 1 positive. The 1 

### 15 positive you said there are a lot of difficulties with the 

### 16 design. But, did you mention that one of these also was a 

### 17 well-conducted study that looked at delays in response to kind 

### 18 of focus more on working memory? The Morrison study? 

### 19 DR. CHARLES VORHEES: The Morrison study did 

### 20 not find an effect. 

### 21 DR. CAREY POPE: Was that also the study that 

### 22 you said was kind of enforcing POO2 cutoffs?

### Page 537 1 DR CHARLES VORHEES: Yes, absolutely that is 

### 2 true. 

### 3 DR. CAREY POPE: Just for fun, were any of 

### 4 those findings in that study between 0.02 and 0.05 show 

### 5 statistical significance? 

### 6 DR. CHARLES VORHEES: I do not remember off 

### 7 the top of my head exactly what. I have to find that one. I do 

### 8 not have these memorized, not my area. Well for example, he 

### 9 found a point 0.03 effect on acoustic startle response latency, 

### 10 not amplitude. The principle measure in that test is in fact 

### 11 amplitude not latency. I do not know what it means. He found 

### 12 some delays in developmental landmarks. Vaginal patency was 

### 13 delayed in the high dose group, pinna detachment and preputial 

### 14 separation were delayed at 0.03 and 0.05, but they did not reach 

### 15 the 0.02 cutoff, so he dismissed those. I have nothing on the 

### 16 spacial delayed alternation test of working memory at any level. 

### 17 So, those are sort of physical landmark developmental delays 

### 18 more than anything. The startle effect, I would not put much 

### 19 weight on. He discusses that at some length, which is why he 

### 20 does not think that that is a particularly important 

### 21 observation. I sort of buy his argument that a change in 

### 22 startle latency without a change in amplitude is of questionable

### Page 538 1 significance biological meaning. Did that answer your question? 

### 2 3 DR. CAREY POPE: Yes. 

### 4 DR. GINGER MOSER: Just to add one thing about 

### 5 that with the Morrison paper. Just to point out that that 

### 6 delayed spacial alternation was done at weaning. As we have 

### 7 already heard, weaning may be a bit early for some of these 

### 8 spacial tasks. The adult testing was done in the same animals. 

### 9 So, it is unfortunate in a way because that means that adult 

### 10 animals were not tested in that task naEve. That is a confound 

### 11 that we have no idea how that would have come out otherwise. I 

### 12 think that was an important thing to point out with that paper. 

### 13 14 DR. CHARLES VORHEES: I agree. I think that 

### 15 is worth pointing out, but I would defend it in the sense that 

### 16 while they would not be naEve to the task, the decay function 

### 17 that you see with progressively longer delays intervals, should 

### 18 map pretty much the same in the adult as in the juvenile animal. 

### 19 I do not think that you disrupt the fundamental integrity of 

### 20 that test because of its nature. You do not really disrupt it 

### 21 by testing an animal multiple times. That is one of those tests 

### 22 that you can do multiple times. You should still get the same

### Page 539 1 decay function each time you do it. The curve will not look 

### 2 exactly the same as they have more practice, but it will look 

### 3 largely the same because the working memory does not show large 

### 4 practice effects. It is inherent in its nature that it does not 

### 5 show large practice effects. 

### 6 DR. KENNETH PORTIER: I think we have run out 

### 7 of juice here. Again, the Panel is sitting back. They are not 

### 8 engaged anymore. I think we are to the point where we have kind 

### 9 of worried the neurodevelopmental data to death. We have to 

### 10 apologize to the epidemiologist for having to sit through it, 

### 11 but that is the nature of this panel. You learn a lot, but you 

### 12 spend a lot of time sitting waiting for your turn. Your turn 

### 13 will come tomorrow morning. 

### 14 At this point, I think we are going to end the 

### 15 Panel deliberations for today. We will start again tomorrow 

### 16 morning at 9 o'clock with the question 4 issues on epidemiology. 

### 17 Okay? 

### 18 19 DR. KENNETH PORTIER: So Good morning. This 

### 20 is day 3 of the FIFRA Scientific Advisory Panel Meeting on 

### 21 scientific issues associated with chlorpyrifos health effects. 

### 22 I am Ken Portier, Chair of the FIFRA SAP and Chair of this

### Page 540 1 session, and we are in the middle of the panel discussion on 

### 2 the agency questions. As we normally do, we are not going to 

### 3 go around the room and introduce all the panel again. By this 

### 4 point, everybody in the audience and everybody here are good 

### 5 friends. We all know each other. So we are going to move 

### 6 forward. 

### 7 Before we start with question 4, I wanted to 

### 8 double check to make sure if anybody had any leftover issues 

### 9 with question 3. And I know that Dr. Vorhees wanted to make a 

### 10 comment about some of his material. Dr. Vorhees? 

### 11 DR. CHARLES VORHEES: After we adjourned 

### 12 yesterday, Dr. Moser was kind enough to bring to my attention 

### 13 an error I made, so I just want to correct it for the official 

### 14 record. In the Javelin study I said that they did not analyze 

### 15 the data by litter, but in fact, they did. So I just want to 

### 16 make that clarification. Thanks. 

### 17 DR. KENNETH PORTIER: So any additional 

### 18 clarifying remarks from the panel? Okay. It looks like we are 

### 19 ready to go on and talk about the epidemiology question, which 

### 20 should be fun. Dr. Christensen? 

### 21 DR. CAROL CHRISTENSEN: Carol Christensen. I 

### 22 will read question 4.1. Section 4 in appendixes 5 and 6

### Page 541 1 provide the agency's review of the available epidemiology 

### 2 studies from the Columbia Mothers and Newborn study, the Mount 

### 3 Sinai Child Development Study and the Center for Health 

### 4 Assessment of Mothers and Children of Salinas, or the CHAMACOS 

### 5 Study. 

### 6 Consistent with the 2008 SAP recommendations 

### 7 the agency has considered information offered in each of these 

### 8 three cohort investigations. However, EPA acknowledges the 

### 9 privacy of the Columbia Cohort data for the purposes of 

### 10 informing risk assessment because researchers measure 

### 11 chlorpyrifos parent compound directly. 

### 12 Please comment on the sufficiency, clarity 

### 13 and quality of the agency's epidemiology review as contained in 

### 14 Section 4 in appendixes 5 and 6 of the draft issue paper with 

### 15 respect to identifying major strengths and limitations of each 

### 16 study. 

### 17 DR. KENNETH PORTIER: Thank you. And our 

### 18 lead discussant is Dr. Gold. 

### 19 DR. ELLEN GOLD: Good morning, Ellen Gold. 

### 20 So the panel believes that the epidemiology section of the 

### 21 draft issue paper is very well written clear, accurate and 

### 22 fairly complete. We commend the agency on the inclusion of the

### Page 542 1 epidemiologic evidence and its risk assessment and its staff on 

### 2 the thorough review of the epidemiology literature and putting 

### 3 their epidemiology review in the context of the modified 

### 4 Bradford Hill criteria, as recommended by the 2010 SAP. In 

### 5 addition to reviewing the potential for selection and 

### 6 information biases in each of the studies reviewed. 

### 7 Epidemiologic studies such as these are very 

### 8 difficult to conduct, because they require large numbers of 

### 9 mothers and infants, or children to be followed longitudinally 

### 10 for an extended period with extensive data collection at 

### 11 regular intervals to ascertain exposure measures, data on 

### 12 potential confounders and assessment of health outcomes, all of 

### 13 which can change over time. 

### 14 These studies are logistically difficult to 

### 15 implement and require great commitment and potentially large 

### 16 burden in terms of time and effort on the part of the study 

### 17 participants over a lengthy period of time, often with little 

### 18 or no specific benefit or return to themselves. 

### 19 So the agency's review adequately summarizes 

### 20 the challenges and scientific contributions of each of these 

### 21 studies, so I am just going to hit the high points of what we 

### 22 agree with and some additions that we would suggest.

### Page 543 1 So, all three studies have the significant 

### 2 strength of being longitudinal prospect of designs. The most 

### 3 effective design for establishing the temporal sequence in 

### 4 relating exposure to health outcomes, specifically in these 

### 5 studies relating exposure measures obtained prenatally or at 

### 6 delivery to outcomes measured at six months up to nine years of 

### 7 age. 

### 8 Regarding the exposure assessment as the 

### 9 draft paper points out, only the study by the Columbia 

### 10 investigators measured a biomarker of the parent compound in 

### 11 cord blood as well as in mother's milk, and conducted an 

### 12 exposure validation study and looked at correlations of cord 

### 13 blood measures with mother's blood and meconium and used the 

### 14 cord blood as the measure of exposure in relationship to scores 

### 15 on standard neurodevelopmental test batteries for children of 

### 16 ages seven years in the 2011 publication, at early time periods 

### 17 for the earlier publications. 

### 18 We agree with that agency that because this 

### 19 study included the most specific exposure measure, particular 

### 20 attention should be focused on its results. We would disagree 

### 21 with some of the comments that were made the first day or so 

### 22 that, because the observed associations occurred at level below

### Page 544 1 those required for acetylcholinesterase inhibition, results 

### 2 should be discounted. Instead, we believe that these findings 

### 3 come from well-designed and conducted study, and thus, instead 

### 4 suggest that the mechanism may be other than 

### 5 acetylcholinesterase inhibition. 

### 6 Furthermore, the very large effect measures 

### 7 observed in this study for the relation of exposure to 

### 8 attention deficits reduced birth weight prior to the voluntary 

### 9 withdrawals of chlorpyrifos, reduced mental and psychomotor 

### 10 development and reduced IQ are unlikely to be due to important 

### 11 misclassification, or bias in assessing exposure or to 

### 12 uncontrolled confounding. 

### 13 The two other studies used nonspecific 

### 14 metabolites as markers of exposure, although all three studies 

### 15 used TCPy, which is in relationship to the exposure, and then 

### 16 looked at it in relationship to the outcomes. So this is a 

### 17 better measure than the DAPs, the other indirect biomarker, but 

### 18 it does have some limitations. 

### 19 So we thought that the potential 

### 20 misclassification of exposure might be more explicitly stated, 

### 21 and the value of using TCPy as a biomarker also hinges on the 

### 22 mode of action, which is not really well established with

### Page 545 1 certainty yet. 

### 2 As the epidemiology review appropriately 

### 3 notes, all three studies were strengthened and decided by using 

### 4 biomarkers of exposure instead of relying on self reports, 

### 5 which would be more likely to result in much greater 

### 6 misclassification of exposure. All three studies also use 

### 7 similar standard validated measures of non-verbal and general 

### 8 intelligence, behavior and home environment, which enhance the 

### 9 quality of the outcome assessments and the ability to assess 

### 10 the consistency of the findings regarding these outcomes across 

### 11 studies. 

### 12 In addition, as appropriately noted in the 

### 13 agency's review, all three studies collected extensive data on 

### 14 potential confounding variables, used appropriate 

### 15 multi-variable statistical methods to control for confounding 

### 16 effects of socioeconomic factors, lifestyle and behavioral 

### 17 factors as well as additional environmental exposures, and 

### 18 conducted sensitivity analyses to determine if assumptions made 

### 19 about missing data, for example, were appropriate. Those are 

### 20 all strengths. 

### 21 One concern is that, in general, the sample 

### 22 sizes of the three studies were only moderately large, ranging

### Page 546 1 from just over a hundred to slightly under five hundred, 

### 2 depending on which subset of the data mothers and children was 

### 3 being analyzed. 

### 4 So the epidemiology review correctly notes 

### 5 that the modest sample sizes were a limitation in having 

### 6 sufficient statistical power to detect as statistically 

### 7 significant possible modest relations of exposure to outcomes 

### 8 or interactions with other variables. But the limited sample 

### 9 sizes were possibly one of the important limitations of these 

### 10 studies, which is reflected in the wide confidence intervals 

### 11 for some of the effect measures -- and I don't think enough was 

### 12 made of this -- of moderate or large increases in exposure to 

### 13 see statistically significant affects, in IQ for example. 

### 14 However, some evidence of interaction with 

### 15 paraoxonase 1, either genotype of phenotype was provided in 

### 16 some of the studies, and some examinations of interactions with 

### 17 other exposures were presented and summarized in the review. 

### 18 So two items that might be added to the 

### 19 review are, first of all, in that table 10 which we thought was 

### 20 a good table -- this is in light of some of the comments that 

### 21 were made -- replacing the null and positive non-significant 

### 22 with actual point estimates in 95 percent confidence intervals.

### Page 547 1 For effect estimates, to the extent possible, we realize that 

### 2 there's a lot of detail there and you will have to pick and 

### 3 chose a little bit, but we think that would be more 

### 4 informative. 

### 5 And also, secondly, noting in the text of 

### 6 other interactions, such as with the sex of the child, 

### 7 gestational age at the measurement of exposure, length of 

### 8 breast-feeding, use of alcohol, et cetera, were not 

### 9 consistently described in the three studies. And in most 

### 10 cases, the sample sizes were inadequate to have sufficient 

### 11 statistical power to detect meaningful effect modification as 

### 12 statistically significant. 

### 13 And this later point is important, because it 

### 14 means that the potential for stronger associations or larger 

### 15 affects in subgroups with potentially enhanced susceptibility 

### 16 could not be or were not adequately examined or reported. 

### 17 In addition, the review in the draft paper 

### 18 mentions that the restriction of some of the study samples by 

### 19 race, ethnicity or to low-risk pregnancy, such as non-smokers 

### 20 or women without comorbidities reduce the potential for 

### 21 confounding, which is a plus, but also reduce the generalized 

### 22 ability of the results.

### Page 548 1 And perhaps the review did not sufficiently 

### 2 emphasize that this limitation also meant that affect 

### 3 modification by race or ethnicity, or other risk factors could 

### 4 not be examined with these study sample restrictions, or the 

### 5 sample sizes in general were inadequate to examine such 

### 6 interactions. So differential affects for subgroups with other 

### 7 risk factors or characteristics really could not be determined. 

### 8 The review also examined potential for a 

### 9 misclassification and bias in each of the studies and mentions 

### 10 that the likelihood is that any such misclassification, or 

### 11 biases that operated were non-differential and thus likely to 

### 12 result in an under estimation of the affect. And for example, 

### 13 for chlorpyrifos exposures, the assessment of that was unlikely 

### 14 to be differential with respect to the outcomes that were 

### 15 measured, and thus would have resulted in bias to the null or 

### 16 under estimation of affect measures. 

### 17 Similarly, although not explicitly stated in 

### 18 the publications, it was unlikely that those who were assessing 

### 19 the outcomes using standard instruments knew the exposure 

### 20 levels of the participants, which could have biased their 

### 21 assessments. Thus, again, the misclassification of outcomes 

### 22 could have occurred but were likely to be non-differential,

### Page 549 1 with respect to the exposure levels, and thus were likely to 

### 2 have resulted in bias to the null or underestimation of 

### 3 effects. 

### 4 We also thought that we ought to respond to 

### 5 the issue that was raised about multiple comparisons that came 

### 6 up in the public comments. We feel it is important to note 

### 7 that all the comparisons made in the three studies were 

### 8 hypothesis-driven and dealt with related outcomes rather than 

### 9 reflecting "fishing expeditions" that would have been likely to 

### 10 result in significant findings by chance, due to multiple 

### 11 comparisons. So, we feel that the multiple comparisons issue 

### 12 is not an important concern regarding the findings of these 

### 13 three studies over the years. 

### 14 We also felt that the agency's review 

### 15 reflects the author's views from the three studies that among 

### 16 the statistically significant effects seen most appeared to 

### 17 have a linear relationship with exposure and have no evidence 

### 18 of threshold. But when we looked at some of the graphs and 

### 19 other results presented in some of the papers, it would appear 

### 20 that this point actually requires some further data and 

### 21 examination. 

### 22 I will just say, when I was at graduate

### Page 550 1 school, my biostatistician and faculty said, look at the data. 

### 2 And when you look at the data, for example, the graphs in the 

### 3 Columbia study seemed to suggest no threshold for the effect on 

### 4 working memory but do suggest a threshold for full-scale IQ. 

### 5 In the California sample, the graphs in the 

### 6 most recent paper suggest a drop in IQ that begins usually in 

### 7 the second quintile. It depends which outcome they were 

### 8 looking at, and then doesn't seem to get worse with increasing 

### 9 dose. So with increasing quintiles of exposure, this would 

### 10 also be suggestive of a threshold effect. And the graphs in 

### 11 the recent publication from the Mount Sinai Study seem to 

### 12 indicate no threshold when using tertiles, but the confidence 

### 13 in the roles are quite wide. 

### 14 So the review appropriately notes that, due 

### 15 to the modest sample sizes, statistical power may have been 

### 16 inadequate to detect departures from linearity with logged 

### 17 transformed exposures or outcomes. It might also be mentioned 

### 18 that the modest sample sizes limited statistical power to 

### 19 really assess dose response adequately, which is one of the key 

### 20 criteria promulgated by Bradford Hill. 

### 21 And also, through the quartiles -- see, their 

### 22 tertiles or quintiles weren't comparable across study, so it

### Page 551 1 makes comparing them a little bit difficult. 

### 2 In conjunction with the modified Bradford 

### 3 Hill criteria, the review states that the biologically 

### 4 plausible role for chlorpyrifos in relationship to adverse 

### 5 neurodevelopmental outcomes is believed to involve inhibition 

### 6 of acetylcholinesterase. While this is a reasonable 

### 7 assumption, both papers by Rauh and the one by Bouchard, recent 

### 8 ones, note that neurodevelopmental deficits associated with 

### 9 prenatal and early postnatal exposure to chlorpyrifos in 

### 10 rodents were seen at exposure levels well below the threshold 

### 11 for systemic toxicity caused by cholinesterase inhibition in 

### 12 the brain. And they both note that other mechanisms should be 

### 13 considered involving disruption of neural cell development, 

### 14 neural transmitter symptoms, synaptic formation in different 

### 15 brain regions and others may play roles. 

### 16 In addition, the observed effect modification 

### 17 also suggests other mechanisms, including oxidative stress and 

### 18 lipid peroxidation. The mode of action is discussed in more 

### 19 detail elsewhere in the draft paper, but these additional 

### 20 potential mechanisms might be added in the epidemiology portion 

### 21 of the review. And as noted before, just because the 

### 22 significant effects are observed at exposure levels below which

### Page 552 1 acetylcholinesterase inhibition occurs does not mean that the 

### 2 effects are not real, but rather that the mechanisms in humans 

### 3 are likely to be different, perhaps, other than 

### 4 acetylcholinesterase inhibition. So we think that more 

### 5 mechanistic work needs to be done to clarify this issue. And 

### 6 that is all I have. I will stop there. 

### 7 DR. KENNETH PORTIER: Thank you very much. 

### 8 That was actually very clear. I was able to follow everything. 

### 9 That was good. Dr. Koutros? 

### 10 DR. STELLA KOUTROS: Hi. I concur with all 

### 11 the points that Dr. Gold made, but I also wanted to add an 

### 12 additional comment about the analysis of effect modification by 

### 13 PON1. Although we have noted the limited statistical power to 

### 14 detect interactions, I still think there is significant added 

### 15 value of these findings. It is not really a common thing to 

### 16 have so much functional information for a gene or a set of 

### 17 variants and to know that the exposures of interest are 

### 18 metabolized through this pathway. So the fact that there are 

### 19 several observable associations that were modified by PON1 

### 20 bolsters the finding that the given exposures that we are 

### 21 looking at are related to the outcomes assessed, in my opinion. 

### 22 DR. KENNETH PORTIER: Good point. Dr. Lu?

### Page 553 1 DR. CHENSHENG LU: I have to say that this is 

### 2 probably the most hard-working panel that I ever attend. We 

### 3 meet at lunch, dinner, and last night we exchanged emails by 11 

### 4 o'clock. So the other girl has stated pretty much summarize 

### 5 our comments. So I have nothing to add. 

### 6 DR. KENNETH PORTIER: Dr. Vena? 

### 7 DR. JOHN VENA: Yes. I'd like to commend Dr. 

### 8 Gold for integrating all of the comments from each member of 

### 9 the team, so I think she really nicely summarized our 

### 10 deliberations. I would also like to just mention that I 

### 11 thought Appendix 6, provided by EPA -- the detailed review of 

### 12 each of the studies -- was really well done. I thought that it 

### 13 was really helpful in going through each of the studies and 

### 14 then going back to the review paper to really kind of 

### 15 understand what were all of the strengths and limitations. 

### 16 We did note in our review that there were 

### 17 some areas though that maybe were in the appendix that were not 

### 18 in the text of the actual document, and so we made 

### 19 recommendations about where those additional things could be 

### 20 added to clarify the issues. So I agree that the review is 

### 21 clearly written, generally accurate, provides very thorough 

### 22 review in the context of the criteria. And we have made notes

### Page 554 1 where those additions would really help clarify the issues. 

### 2 DR. KENNETH PORTIER: Dr. Young? 

### 3 DR. HEATHER YOUNG: I concur with the rest of 

### 4 the panel. Again, I just want to commend the EPA on the 

### 5 thoroughness of the review. I have been on several of these 

### 6 panels and this is the best review that I have seen yet. And 

### 7 so you all did a wonderful job summarizing all of the 

### 8 literature. And a lot of it was very detailed literature, so I 

### 9 think it was very well done. 

### 10 DR. KENNETH PORTIER: So, Dr. Carr? 

### 11 DR. RUSSELL CARR: I have two points. The 

### 12 first is the rodent data reported in the introduction of the 

### 13 Rauh and Bouchard paper. This all comes from one laboratory. 

### 14 And the dosages they used in those studies were never below 1 

### 15 mg per kg, and they claim that it was non-cholinesterase 

### 16 inhibiting but we know, in fact, that dosages of 1 mg per kg 

### 17 will lead to cholinesterase inhibition. They did not 

### 18 adequately measure cholinesterase inhibition in a lot of those 

### 19 papers. 

### 20 The second thing I have is, in the 2011 Rauh 

### 21 paper, they found decreased IQ in 7-year-olds from the Columbia 

### 22 cohort, and the paper was very well written. They accounted

### Page 555 1 mathematically for possible confounders such as PAHs and 

### 2 environmental tobacco smoke. 

### 3 However, if you go back to 2009, in that same 

### 4 cohort of kids they found decreased IQ and working memory 

### 5 scores in five-year olds and they attributed that to exposure 

### 6 to polycyclic aromatic hydrocarbons. And again, they did 

### 7 mathematical calculations and said it wasn't due to 

### 8 interactions with the chlorpyrifos that it was due to PAHs. 

### 9 I am at a quandary here, because I have got 

### 10 the same cohort of kids who had decreased IQ at 5-years-olds 

### 11 and decreased IQ at 7-year-olds, but they are being caused by 

### 12 different things. I can understand how you can mathematically 

### 13 account for these things in any model. And the more you know 

### 14 about what you are working with, the stronger the model 

### 15 becomes. But the brain, especially the developing brain, is 

### 16 very dynamic, is very intricate. There is so much that we 

### 17 don't know. And I am just having a hard time biologically 

### 18 separating out that PAHs are present; chlorpyrifos is present, 

### 19 but yet they are having the same effect simultaneously through 

### 20 two different routes and no interactions. And basically, that 

### 21 is what these papers say, is that I just cannot biologically 

### 22 separate that.

### Page 556 1 I mean, you can do it mathematically and 

### 2 statistically but, as far as a biological function, if those 

### 3 two compounds are there and they both claim that they both 

### 4 caused decreased IQ, how can you separate that? I mean, I just 

### 5 want to just state that that is a quandary for me right now. 

### 6 DR. KENNETH PORTIER: Dr. Gold? 

### 7 DR. ELLEN GOLD: I would have to go back and 

### 8 check the paper, in particular. I mean I looked carefully at 

### 9 the more recent one and less carefully at the older one. So 

### 10 setting aside for a moment the biological piece -- we can come 

### 11 back to that, but mathematically, I think that when they are 

### 12 adjusting one for the other, they can see independent effects. 

### 13 So it is like saying what happens when you look only at one and 

### 14 when you look only at the other and when you look at both. 

### 15 And then what they don not see is what we 

### 16 call enhancement or interaction or in fact modification, when 

### 17 both are there together. So they are seeing independent 

### 18 effects of each. 

### 19 So I would have to go back and check the 

### 20 older paper about the PAHs, because that one I actually do not 

### 21 recall. 

### 22 In the more recent one, though, what they are

### Page 557 1 saying is this was an independent effect of chlorpyrifos, 

### 2 independent of the PAHs, because when they adjusted for it and 

### 3 they checked for effect modification they didn't see it, so 

### 4 they saw an independent effect. Biologically, it's a separate 

### 5 issue with it. Probably you are more qualified to comment on 

### 6 it than I am. 

### 7 DR. RUSSELL CARR: Dr. Carr. I understand 

### 8 mathematically, you have to separate that. But even with that 

### 9 assessment, is, they selected out the chlorpyrifos kids for 

### 10 kids who had residues of chlorpyrifos in their umbilical cord. 

### 11 They selected the PAH by kids who had residues of PAHs, or 

### 12 through environmental monitoring or PAH adducts in their 

### 13 umbilical cords. 

### 14 There is a potential for a kid who has a low 

### 15 IQ to fall in both those categories. And so, if at 5 years old 

### 16 he falls into the PAH category and they claim that it is 

### 17 through the PAHs, then he possibly could fall into the 

### 18 chlorpyrifos category because he is still living in the same 

### 19 environment exposed to all the same things. And so that is one 

### 20 thing. 

### 21 I understand that mathematically they can 

### 22 correct for that, but just the dynamics of the situation

### Page 558 1 puzzles me a little bit. 

### 2 DR. ELLEN GOLD: So I think what we can say 

### 3 is, there are kids who have only one or the other exposure or 

### 4 who have both exposures. And that could be different at 

### 5 different time points. Okay? And mathematically, what you are 

### 6 saying is when they measured it, what did they see when they 

### 7 only had one or when they only had the other or when they had 

### 8 both. 

### 9 DR. RUSSELL CARR: Well the exposure occurred 

### 10 prenatally. And so the authors did not identify if the kids -- 

### 11 we include just the chlorpyrifos kids but we excluded the kids 

### 12 that had the PAHs exposure, or that they include just the PAH 

### 13 kids and excluded them if they had a chlorpyrifos exposure. I 

### 14 mean, you understand, those kids were exposed prenatally and 

### 15 that the environmental air monitoring picked up both chemicals. 

### 16 DR. ELLEN GOLD: But not in all of them. 

### 17 That is my point, is that some of them are going to have one or 

### 18 the other and some will have both. 

### 19 DR. RUSSELL CARR: But we do not know that. 

### 20 That was not differentiated in any of these papers whether they 

### 21 used that as criteria for selecting those children. I mean, 

### 22 some of those kids could have been exposed to both of them.

### Page 559 1 DR. ELLEN GOLD: Yes. 

### 2 DR. RUSSELL CARR: So that kind could have 

### 3 fallen into that low IQ group and then picked out in the PAH 

### 4 paper as having a low IQ to the exposure of PAHs, but then turn 

### 5 around and picked out in the chlorpyrifos paper as having the 

### 6 low IQ due to exposure to chlorpyrifos just because he has a 

### 7 low IQ and was exposed to both. 

### 8 I mean, I understand what you are saying, but 

### 9 because it wasn't delineated, I don't see how we can just say, 

### 10 "You got a low IQ at 5-year-old and it's due to your exposure 

### 11 of PAHs, but your IQ is still low at 7, but now it's due to 

### 12 your exposure to chlorpyrifos. 

### 13 DR. KENNETH PORTIER: Dr. Carr, I think you 

### 14 got it backwards though, because you are looking from the 

### 15 outcome back. I am thinking of this as a biostatistician. And 

### 16 the analysts knows the cord blood level for both of these 

### 17 chemicals, all right? So when they looked at 5-year-olds and 

### 18 they analyzed the effect as a function of that two-by-two table 

### 19 of plus or minus/plus or minus chlorpyrifos and a PAH they were 

### 20 able to show that the combination didn't add. But if you 

### 21 looked at plus/minus chlorpyrifos there was an effect 

### 22 plus/minus PAHs, there is some effect and no interaction.

### Page 560 1 And then when they did it again at seven the 

### 2 probably found the same thing, but now it's stronger with the 

### 3 chlorpyrifos than the PAH side. The PAH change was probably 

### 4 stronger at five. I think that is what I hear you saying in 

### 5 that analysis. 

### 6 DR. RUSSELL CARR: And I understand that. 

### 7 But still, how can you separate the two? If you know that at 

### 8 five, this one caused it, how can the effects at five due to 

### 9 that one causing a low IQ not still be present at seven? 

### 10 Biologically you can't do that. 

### 11 DR. JOHN VENA: I don't know if they are 

### 12 saying it's not there. 

### 13 DR. RUSSELL CARR: They said it's not 

### 14 correlated. 

### 15 DR. JOHN VENA: Well they don't have to be 

### 16 correlated. It's just that in the 7-year-olds the effect was 

### 17 bigger -- 

### 18 DR. RUSSELL CARR: Due to chlorpyrifos. 

### 19 DR. JOHN VENA: -- on the chlorpyrifos side. 

### 20 Did they actually say there isn't a PAH effect? 

### 21 DR. RUSSELL CARR: They said the effect 

### 22 wasn't correlated, that the correlation was not significant

### Page 561 1 between the PAHs and the chlorpyrifos. They are independent. 

### 2 DR. JOHN VENA: Yeah, they are independent 

### 3 effects. That is what they found. That is in their model. 

### 4 DR. RUSSELL CARR: See, my point is -- I 

### 5 understand that, but biologically they are not. 

### 6 DR. JOHN VENA: It doesn't mean that both 

### 7 could be related to the outcome. It's just that each one 

### 8 individually is related to the outcome. But there was no 

### 9 interaction. 

### 10 DR. RUSSELL CARR: So there is an 

### 11 interaction. So they are having separate biological effects 

### 12 leading to the same outcome. 

### 13 DR. KENNETH PORTIER: Dr. Young? 

### 14 DR. HEATHER YOUNG: I mean, I think it's 

### 15 important to remember we are talking about an EPI study, so we 

### 16 are looking at associations. They are not saying there is a 

### 17 causal pathway here. And so it is reasonable to believe that 

### 18 there could be an association independently with PAHs, with 

### 19 these neurodevelopmental outcomes, and also chlorpyrifos plays 

### 20 a role. 

### 21 And so, I think -- this is kind of leading 

### 22 into 4.2 -- but the agency's conclusion wasn't that

### Page 562 1 chlorpyrifos was the sole actor but that it plays a role. And 

### 2 so, I mean, I find it reasonable that there could be a whole 

### 3 mix of stuff that these kids are exposed to that may have 

### 4 independent effects on these neurodevelopmental outcomes. And 

### 5 so it's not saying, "Okay, we are pointing to one thing at age 

### 6 5 and now we are saying it's another thing at age 7. We are 

### 7 just saying that there were associations and they showed up at 

### 8 these different time points because of the way that the kids 

### 9 fell into the tertiles or the quartiles, however they were 

### 10 analyzed at those time points. 

### 11 DR. KENNETH PORTIER: I think we are going to 

### 12 probably continue this discussion in the next session, but -- 

### 13 Dr. Harry? 

### 14 DR. JEAN HARRY: Jean Harry. So I have a 

### 15 little concern with the strength of the statement you read. So 

### 16 you read from what's going to be in the reports so that is why 

### 17 I am responding to it. And in trying to associate the effects 

### 18 that we are seeing in non-enzyme inhibition activity -- and I 

### 19 don't really think that you can say that. 

### 20 When you went through the mechanistic data 

### 21 and we went through the animal data, I mean we raised enough 

### 22 issues in the fact that you have to look at that at very

### Page 563 1 specific times to really get a handle on when that really 

### 2 happens, and that's going to be very difficult in a human study 

### 3 to do. 

### 4 The issue was the strength in saying that 

### 5 these effects are likely due to non-cholinesterase inhibition 

### 6 effects, and I don't think that can be said. And I think, if 

### 7 it is written in that format, it is inconsistent with 

### 8 yesterday's conversation of how we were looking at the 

### 9 mechanistic studies, their possibilities. 

### 10 And I think what's interesting is, a number 

### 11 of things in the report raised that, as we are understanding 

### 12 more and more about the cholinergic system during development, 

### 13 we are realizing that a lot of these effects that we think are 

### 14 specific to development may also still be related to that 

### 15 transmitter activity. So we are getting a better understanding 

### 16 of the system and I don't think we can rule it out quite that 

### 17 much. 

### 18 So, I guess, bottom line -- I think the 

### 19 strength of that statement is inconsistent with the discussion 

### 20 that we had yesterday. 

### 21 DR. KENNETH PORTIER: Dr. Gold, did you want 

### 22 to --

### Page 564 1 DR. ELLEN GOLD: I thought I understood, but 

### 2 now I'm not sure I do. All I think we are saying is don't rule 

### 3 out the possibility that there might be another mechanism. I 

### 4 think that is all we are saying. 

### 5 DR. JEAN HARRY: That wording is fine. The 

### 6 wording as it was written was a lot stronger and that is what I 

### 7 was concerned about. 

### 8 DR. KENNETH PORTIER: The other thing I 

### 9 thought I heard you say is that, as our understanding of 

### 10 mechanisms increase, when we expect to see certain effects show 

### 11 up might be incorporated in when we test for them in the 

### 12 epidemiology. I mean I thought you were saying some of the Epi 

### 13 testing may be occurring at the wrong time based on maybe our 

### 14 understanding of how the cholinergic system develops. Dr. 

### 15 Harry? 

### 16 DR. JEAN HARRY: I'm not sure that it's going 

### 17 to drive when we should test in the children, but I think what 

### 18 we may find is, the specific roles that we have given to this 

### 19 enzyme, we may learn that it does more than that or activities. 

### 20 The oxon may do more. 

### 21 So we have to keep in mind that we are 

### 22 limiting our knowledge-base, of the enzyme of where we were a

### Page 565 1 number of years ago and we may actually be starting to learn 

### 2 that it does more in the subtly. So that association may stay 

### 3 there in many more things than we think it is, right now. 

### 4 That is speculative, but I think it does put that caution in of 

### 5 there is no association between the two simply because you 

### 6 can't measure something at the time you chose to try to measure 

### 7 it. 

### 8 You know you have got the issue of timing, as 

### 9 we have raised quite often, but we have also got the issue that 

### 10 we may start understanding that this enzyme is actually doing a 

### 11 lot more than what we credited it for doing 10 years ago. 

### 12 DR. KENNETH PORTIER: Dr. Pope? 

### 13 DR. CAREY POPE: This is Carey Pope. I agree 

### 14 with some of the points that Dr. Harry is making, but I think 

### 15 Dr. Gold, in her comments used the words "well below those 

### 16 eliciting systemic toxicity or something along those lines, not 

### 17 that these were well below those elicit in the 

### 18 acetylcholinesterase inhibition. And to me there is a 

### 19 distinction there in wording that you could -- in my mind, you 

### 20 can have some degree of acetylcholinesterase inhibition in some 

### 21 systems, not saying in all systems, without eliciting systemic 

### 22 toxicity. So those things need to be kept kind of separate.

### Page 566 1 DR. KENNETH PORTIER: Dr. Popendorf? 

### 2 DR. WILLIAM POPENDORF: Yes. I have two 

### 3 additional comments. One is related to the misclassification 

### 4 that was talked about in the review paper and you mentioned in 

### 5 your report. 

### 6 I am concerned -- and I don't have particular 

### 7 references to point to, but the issue paper in particular 

### 8 consistently quotes R values. And my interest is always on 

### 9 R-squared. And its importance, so the R-squared explains the 

### 10 fraction of a variance attributable to the outcome, and this 

### 11 gong to come out in some other comments as well, but most of 

### 12 the significant R-squared values are really very small. We are 

### 13 talking in the order of .1, little less, little more. That 

### 14 means 90 percent of the variance of the outcomes is 

### 15 attributable something else. 

### 16 So I am little concerned on the one hand of 

### 17 causation in the likely statement, and I appreciate as well. 

### 18 But in terms of misclassification, my concern here is that if 

### 19 you have an R-squared of .1 and you have misclassification, 

### 20 what effect would that have on the result? 

### 21 I think the comments about the effect is 

### 22 always going to be an underestimate, would be true if you had a

### Page 567 1 very strong association, really only had one direction to go. 

### 2 But if you've got an R-squared of .1, misclassification has 

### 3 almost as likely effect to go in positive as a negative 

### 4 direction. So I would like some comment on that. 

### 5 DR. ELLEN GOLD: If I can comment on that. I 

### 6 think, again, we are getting a little bit into 4.2. But what I 

### 7 will say is two things. One is, in epidemiology, what they 

### 8 have reported a lot of are odds ratios, which is the typical 

### 9 measure, and most of these are much stronger than 1. 

### 10 I mean, some of them are on the order of 3, 

### 11 4, 5, 6, and those kids of odds ratios, it would be very 

### 12 difficult for misclassification to overcome. So that's point 

### 13 number one. 

### 14 And point number two is, I think 

### 15 neurodevelopment, like most outcomes of chronic conditions that 

### 16 we look at don't have one attributable factor that is 

### 17 associated with it that we call the multifactorial. And so 

### 18 it's not uncommon to see that one particular factor doesn't 

### 19 explain all of the variance or even a lot of the variance, 

### 20 because there are lots of things that affect neurodevelopment 

### 21 just like there are lots of things that affect a lot of other 

### 22 health outcomes that we look at.

### Page 568 1 But I think it would be unlikely that the 

### 2 odds ratios -- and I think Dr. Young has done a report on these 

### 3 in her section -- the magnitude that we are seeing would be 

### 4 unlikely to be overcome, even if you discovered some -- and 

### 5 undoubtedly there is some misclassification, undoubtedly. It 

### 6 always happens. But I think in this case, it would be unlikely 

### 7 to overcome the magnitude, the associations that are seen and 

### 8 reported. 

### 9 DR. WILLIAM POPENDORF: I mean I am more of 

### 10 the regression type person in the environment because my second 

### 11 point is also related to that, but I am more of a regression 

### 12 portion, so I take your point on the odds ratio that that may 

### 13 be true. I don't appreciate that as much. But on the 

### 14 regressions, I don't see the same strength there. 

### 15 DR. ELLEN GOLD: Actually it is quite similar 

### 16 because the odds ratio come from regressions. And in many of 

### 17 these papers, the affects are using data values, and so the 

### 18 betas are quite strong. And, again, I think I would make the 

### 19 same comment about unlikely to be overcome by 

### 20 misclassification. 

### 21 And again, the misclassification is probably 

### 22 in one direction so that these are likely to be underestimates.

### Page 569 1 I mean, it could be in both directions but the most likely is 

### 2 that it's -- is it non-differential misclassification, which 

### 3 would tend to bias things towards the null. 

### 4 DR. WILLIAM POPENDORF: If it's a two-way 

### 5 classification, it would have probably a different effect than 

### 6 if it had multiple different classifications, in which it would 

### 7 fall and then things get a little more complicated, but maybe 

### 8 we can have some further discussion as that develops. 

### 9 My second point, I guess, kind of reflects my 

### 10 first in being an environmental oriented person. I'm more 

### 11 comfortable with looking at values and not sort of changes and 

### 12 nonparametric. 

### 13 And particularly, in looking at the data 

### 14 subsequent to 2001, you get a lot more nondetext (phonetic). 

### 15 And I would just suggest that there are ways of dealing with 

### 16 nondetext that use the environmental measures more directly 

### 17 than nonparametric tests that, at least some people would be 

### 18 more comfortable with. That was addressed in the July 2010 SAP 

### 19 meetings. Some methods were presented. 

### 20 There was some article that was used, one by 

### 21 Richardson. There was an Epi referenced Richardson and Company 

### 22 2003 is another reference where they are accounting. And

### Page 570 1 basically you can do regression on missing data. In fact, you 

### 2 can even do it if you have no data at all. If it is all 

### 3 nondetext, you can set some upper bound limits using that, and 

### 4 that just makes some recommendations that -- I think there are 

### 5 more useful tests that could be done on some of those data with 

### 6 missing values. 

### 7 DR. KENNETH PORTIER: Dr. Sandy? 

### 8 DR. MARTHA SANDY: I just have a question for 

### 9 Dr. Harry. When you were talking about the things that we may 

### 10 learn about the activity of the acetylcholinesterase enzyme, as 

### 11 I read the draft background paper and listened to the 

### 12 discussions, I understood that it was this protein. Not the 

### 13 enzymatic activity, but the protein in neurodevelopment may 

### 14 have other functions that are distinct from its enzymatic 

### 15 function. Is that correct? And were you also suggesting that 

### 16 the enzymatic activity might do other things that we don't 

### 17 know? 

### 18 DR. JEAN HARRY: So basically, what you said 

### 19 is correct. But what I was thinking in a sense, that you've 

### 20 got the protein but you've also got the enzymatic activity, 

### 21 which is going to drive potentially the amount of the protein 

### 22 and the activity, so they are linked in a dynamic fashion. But

### Page 571 1 in a sense, we appear to be learning more about what the system 

### 2 can contribute to the development of the brain, and that may be 

### 3 a combination of -- I mean, it's going to be a synthesis of the 

### 4 protein degradation, the protein level of the protein. So I 

### 5 think we are sort of talking in the same way. 

### 6 Basically, that system, as we learn more 

### 7 about that, we may learn more about what might happen if we 

### 8 start to alter the level of the available protein to the system 

### 9 during critical times of development. 

### 10 We seem to be learning more about it as our 

### 11 interest have been geared toward it. And I think, with the 

### 12 interest and all the Alzheimer's diseased-based drugs that they 

### 13 are trying to do, we may actually learn much more about this 

### 14 than we would have before. 

### 15 DR. KENNETH PORTIER: I think what I'd like 

### 16 to do is just go on to 4.2 and we can kind of continue the 

### 17 discussion on the agency's take on the chlorpyrifos. So why 

### 18 don't we go ahead and read question 4.2? 

### 19 DR. JEAN HARRY: Similar to the initial 

### 20 conclusions from 2008, the agency has preliminarily concluded 

### 21 that, qualitatively, chlorpyrifos likely played a role in the 

### 22 neurodevelopmental outcomes reported in the epidemiologic

### Page 572 1 studies. 

### 2 And that information available since 2008 

### 3 including both new epidemiologic investigations as well as 

### 4 epidemiologic method's papers strengthens this conclusion. 

### 5 Please comment on the agency's preliminary qualitative 

### 6 conclusion that chlorpyrifos likely played a in the 

### 7 neurodevelopment outcomes observed in the epidemiology studies. 

### 8 9 Please include in your comments a discussion 

### 10 on the strengths and uncertainties associated with this 

### 11 preliminary conclusion. 

### 12 DR. KENNETH PORTIER: Dr. Young? 

### 13 DR. HEATHER YOUNG: So, overall, the panel 

### 14 reiterates the 2008 SAP's conclusion and the agency's 

### 15 concurrence with the statement that chlorpyrifos likely plays a 

### 16 role in neurodevelopmental outcomes in the three cohorts. 

### 17 The qualitative conclusions of the 

### 18 epidemiology review seems quite well-justified. The panel 

### 19 agrees with the agency that, although exposures to other 

### 20 acetylcholinesterase, inhibiting compounds cannot be ruled out 

### 21 as contributing to neurodevelopmental outcomes and the 

### 22 potential combination and/or added effects of these compounds

### Page 573 1 does not rule out the role of chlorpyrifos. However, it should 

### 2 be noted that it cannot be stated that chlorpyrifos is the sole 

### 3 contributor to the observed outcomes. 

### 4 With regard to the strengths of the three 

### 5 studies, specifically they all have perspective longitudinal 

### 6 designs which permit clear indication of a temporal 

### 7 relationship of the exposure to the adverse neurodevelopmental 

### 8 outcomes. 

### 9 There is relative consistency of findings in 

### 10 different populations but using similar standardized exposure 

### 11 and outcome measures, strength of the associations, use of 

### 12 objective measure of exposure and standardized validated 

### 13 measures of outcomes, controlled multiple confounding 

### 14 variables, suggestion of a dose response effect, minimization 

### 15 in bias in assessing outcomes and exposure the likelihood that 

### 16 the basis is a misclassification of exposures and outcomes 

### 17 resulted in a bias of the null, an underestimation of the 

### 18 effect. And then there were attempts to investigate genetic 

### 19 and phenotypic effect modification and dose response effects. 

### 20 We also went through and did an analysis of 

### 21 some of those points. Some of these details were previously 

### 22 presented in the 2008 SAP report, but we have reiterated them

### Page 574 1 here so that we have all of our Epi evidence in one place. 

### 2 It should be noted that the studies published 

### 3 since 2008 have continued to show associates between the 

### 4 neurodevelopmental outcomes and potential exposure to 

### 5 chlorpyrifos and have only strengthened the available Epi 

### 6 evidence. 

### 7 Recently, analysts have looked at 

### 8 neurodevelopmental outcomes in older children and addressed 

### 9 some of the issues of confounding by a socioeconomic status of 

### 10 other pesticides, and issues of exposure measurement 

### 11 validation. 

### 12 So if we look at strength of association we 

### 13 focused mainly on the Columbia cohort, as this cohort 

### 14 specifically measures the chlorpyrifos directly from the cord 

### 15 blood, and therefore had the most robust exposure measurement. 

### 16 Although the results from the other cohorts 

### 17 are useful, even if you would decide to negate those studies 

### 18 due to nonspecific exposure measurement, the Columbia cohort 

### 19 provides a number of strong associations. 

### 20 We see effects as early as fetal growth and 

### 21 continue to see them through early childhood with the recent 

### 22 evidence of neurodevelopmental effects seen at age 7.

### Page 575 1 To summarize with fetal growth, there were 

### 2 statistically significant deficits in birth weight and birth 

### 3 length with infant neurodevelopmental, statistically 

### 4 significant and very strong deficits on the Bayley Psychomotor 

### 5 Development Index at three years when comparing high to low 

### 6 exposure groups. And in a more recent analysis, that these 

### 7 decrements persisted even when they adjusted for the group in 

### 8 individual level by socioeconomic variables, which was one of 

### 9 the concerns that we had in 2008. 

### 10 Earlier studies also saw strong increased 

### 11 odds of mental delay 2.4 in psychomotor delay of almost 5 at 

### 12 age 3 when comparing high to low exposure groups. One of the 

### 13 concerns in 2008 was that would these associations possibly go 

### 14 away when we controlled for diazinon and propoxur exposures. 

### 15 In Appendix 4 there is an unpublished analysis that show that 

### 16 the chlorpyrifos still showed significant increased odds. In 

### 17 fact, the measures were stronger when you controlled for the 

### 18 diazinon and propoxur exposures. 

### 19 Looking at attention problems, the Columbia 

### 20 Cohort showed extremely large odds ratios 11 for attention 

### 21 disorder, 6.5 for ADHD and 5.4 for PDD when comparing high to 

### 22 low chlorpyrifos exposure groups. So these are really large

### Page 576 1 and not likely to be affected by any sort of residual 

### 2 confounding. 

### 3 And then looking at the more recent study 

### 4 with intelligent measures we saw significant decreases of 1.4 

### 5 percent in full scale IQ and approximately 3 percent in working 

### 6 memory among 7-year-olds for each standard deviation increase 

### 7 in chlorpyrifos exposure. 

### 8 And the interesting thing to note is that 

### 9 they did sensitive analyses and the results persisted even when 

### 10 they looked at only those with detectable chlorpyrifos levels, 

### 11 so getting rid of the ones where they imputed the values below 

### 12 the LOD. In addition, they found no evidence of mediation by 

### 13 child behavior when they looked at the working memory 

### 14 instrument. 

### 15 When looking at consistency of association, 

### 16 we compared the results from the Berkeley and Mount Sinai 

### 17 Cohorts and found that there were several areas in which they 

### 18 were consistent with or supportive of the conclusions from the 

### 19 Columbia Cohort. 

### 20 It should be noted again that the Berkeley 

### 21 and Mount Sinai Cohorts did not replicate the results on fetal 

### 22 growth that we see in the Columbia Cohort. Although they are

### Page 577 1 similar in composition and design, they did not measure 

### 2 specific chlorpyrifos exposure, but instead used nonspecific 

### 3 measures. But the internal validity of the cohorts gives us 

### 4 confidence in the consistency of the results. 

### 5 With the neonatal neurodevelopmental, this 

### 6 was not measured in the Columbia study, but we saw consistently 

### 7 in both the Berkeley and Mount Sinai Cohorts that there were 

### 8 increased abnormal reflexes in the neonates associated with 

### 9 maternal DAPS. 

### 10 In infant natal development in the Mount 

### 11 Sinai Cohort, we found that prenatal DAP was significantly 

### 12 associated with deficits in the Bayley MDI at 12 months among 

### 13 Blacks and Hispanics. And notably, the association was 

### 14 enhanced among children that had maternal carriers of the 

### 15 PON1QR and RRR, so the fast metabolizers. 

### 16 The Berkeley Cohort also showed significant 

### 17 decreases in MDI at 24 months associated with increased 

### 18 prenatal and infant urinary DAP measures, and also showed 

### 19 evidence of poor MDI scores at two years among those children 

### 20 that had the PON1 allele, so similar results to what the Mount 

### 21 Sinai Cohort showed. 

### 22 The Berkeley Cohort, with regard to attention

### Page 578 1 problems showed total urinate prenatal and postnatal DAP 

### 2 measures associated with significantly increased odds of PDD at 

### 3 age 2. And in addition, prenatal DAP was associated with ADHD 

### 4 in the child behavior, and checklist problems at 5 years. 

### 5 Child concentrations at DEP were also 

### 6 adversely associated with a composite measure of attention in a 

### 7 recent study by Marks, et al. 

### 8 With regard to intelligent measures, the 

### 9 Berkeley Cohort showed a similar effect to what we saw in 

### 10 Columbia, which was a significant deficit of 7 points in full 

### 11 scale IQ among the 7-year-olds when comparing with highest 

### 12 quintile child maternal DAP to the lowest level. 

### 13 The Mount Sinai Cohort showed slight but not 

### 14 significant decrease in full scale IQ perceptual reasoning and 

### 15 working memory that was associated with prenatal maternal 

### 16 urinary DAP in 6- to 9-year-olds. 

### 17 They also showed increased prenatal and 

### 18 maternal urinary DAP associated with decreases in perceptual 

### 19 reasoning and maternal QQ characters. And this association did 

### 20 show a monotonic trend. 

### 21 One more point that I want to make and it's 

### 22 about the crude exposure response relationship. We thought

### Page 579 1 this was notable that when you looked at the pre/post 

### 2 cancelation analysis in the Columbia Cohort -- they had not 

### 3 meant to test this and it was a unique natural experiment that 

### 4 occurred. 

### 5 And when thinking in Epi terms, the 

### 6 effectiveness of a prevention measure is generally when you 

### 7 remove the potential exposure, the outcome goes away and you 

### 8 see the exposure measure is decreased. And we thought that it 

### 9 was unique in this study that it does argue for a crude dose 

### 10 response relationship because the study show that post 

### 11 cancellation, there was a significant reduction in chlorpyrifos 

### 12 and maternal personal air samples when you looked at the pre 

### 13 and post cancellation levels. 

### 14 And then we also see an improvement in the 

### 15 3-year MDI and PDI scores looking at pre and post cancellation, 

### 16 so that you see an association in the pre-cancellation group 

### 17 and no association in the post cancellation group. So although 

### 18 it wasn't designed to test that, it does provide evidence of a 

### 19 crude dose response relationship. 

### 20 With regard to the uncertainties, we said 

### 21 that you should note that the relatively modest sample sizes 

### 22 limit the statistical power to detect some meaningful

### Page 580 1 differences that may be statistically significant, also limits 

### 2 the ability to look at effect modification by rate of ethnicity 

### 3 in some of the genetic characteristics. 

### 4 Relatively moderate to large exposure 

### 5 differences were needed to see significant effects due to the 

### 6 modest sample sizes. 

### 7 There is a lack of clarity regarding the 

### 8 linear dose response relationship instead of the potential 

### 9 threshold effect. The other concern was use of a single or 

### 10 average sample in the Berkeley Cohort for exposure. 

### 11 Whyatt did note in the 2009 paper that there 

### 12 were moderate but significant correlations between Meconium and 

### 13 quart of maternal blood in average urine TCPy but it is still 

### 14 unclear the representative of the single point of exposure. 

### 15 Obviously time varying exposures with the ability to define 

### 16 cumulative exposures would have been preferable. 

### 17 Another uncertainty is lack of a specificity 

### 18 of a window of affect and potential for misclassification of 

### 19 individual exposure measures. External generalized ability of 

### 20 the cohorts, given their unique racial ethnic and socioeconomic 

### 21 characteristics is another uncertainty. However, it should be 

### 22 noted that their exposures are within the range of those seen

### Page 581 1 in NHANES, and that kind of gets into another question later 

### 2 on. 

### 3 Questions about the biologic plausibility are 

### 4 also an uncertainty due to the lack of clarity on the mechanism 

### 5 of action, particularly at the low exposure level seen in the 

### 6 cohorts and limited and mixed animal studies showing there are 

### 7 developmental effects. 

### 8 So in conclusion, although the three studies 

### 9 were not exactly comparable, more similarities than 

### 10 discrepancies were found across them. And the panel concluded 

### 11 that the additional literature since the 2008 SAP continues to 

### 12 support and strengthens the evidence for the conclusion that 

### 13 chlorpyrifos plays a likely role in the adverse effects in 

### 14 child neurodevelopment. 

### 15 And I believe there was some late night 

### 16 comments that some of my other discussants had, so I will leave 

### 17 those for them because I didn't get them incorporated. 

### 18 DR. KENNETH PORTIER: Thank you. Dr. Gold, 

### 19 do you want to add anything? 

### 20 DR. ELLEN GOLD: No. Dr. Young has 

### 21 incorporated all of my comments. I have nothing to add. 

### 22 DR. KENNETH PORTIER: Dr. Harry?

### Page 582 1 DR. JEAN HARRY: I will safely say no. I 

### 2 concur with the discussions that have happened. I think, 

### 3 between the last two we've covered, we've covered this one 

### 4 well. 

### 5 DR. KENNETH PORTIER: Dr. Koutros? 

### 6 DR. STELLA KOUTROS: I also agree with all 

### 7 the points made by Dr. Young. I did make some comments, which 

### 8 she was referring to late last night. I think she did cover 

### 9 some of the major points, so I don't really want to go into too 

### 10 much detail about some of the things I said. I think we can 

### 11 add it to the text later. 

### 12 But I did want to make a comment about one 

### 13 aspect of a confounding assessment that I found particularly 

### 14 compelling in the data. The author's made efforts to present 

### 15 data on co-exposures to several top candidate environmental 

### 16 exposures that could have accounted for the observed 

### 17 associations like lead and mercury and PCBs and environmental 

### 18 tobacco smoke, PHs, organochlorine pesticides and some other OP 

### 19 insecticides. 

### 20 So the authors showed that none of the 

### 21 exposures likely explain the observed associations. This sort 

### 22 of directly speaks to the it-must-be-something-else argument

### Page 583 1 that was made the other day, I think. 

### 2 So I think we have to remember that, in 

### 3 order for the observed effect to be attributable to something 

### 4 else that it would have to be related to chlorpyrifos exposure. 

### 5 So the authors did not show that to be the case, or not 

### 6 necessarily a chlorpyrifos exposure in the metabolites of 

### 7 interest, as well, that were explored in the other studies. 

### 8 But also from my own experience in the 

### 9 agricultural setting, we find, where many pesticides are 

### 10 applied at the same time, we have found low to moderate 

### 11 correlations between pesticides, so this suggests that it's not 

### 12 unreasonable to consider the effects of the each pesticide 

### 13 independent. Not that, that is true in all settings, but I 

### 14 think this also leads me to believe that confounding due to 

### 15 some of these other chemicals is unlikely. And so, I think 

### 16 that's it. 

### 17 DR. KENNETH PORTIER: Dr. Vena? 

### 18 DR. JOHN VENA: I concur with what was said. 

### 19 I don't have anything to add right now. 

### 20 DR. KENNETH PORTIER: Dr. Lu? 

### 21 DR. CHENSHENG LU: Well again, kudos to Dr. 

### 22 Young. I think my email stamp is 10:04 p.m. We finalized that

### Page 584 1 version that Dr. Young has reported. 

### 2 I have one thing to add to this comment. 

### 3 Again, I think the group concur with agency's preliminary 

### 4 conclusion that chlorpyrifos is likely to play a role. 

### 5 However, in order to prove or add confidence to this 

### 6 preliminary conclusion, I would suggest to the agency to look 

### 7 at other pesticide measurements in the data. That's why I 

### 8 asked the agency yesterday -- or Tuesday that, in addition to 

### 9 chlorpyrifos or TCPy, what else pesticide data do you have, 

### 10 especially from Columbia study. 

### 11 So for example, if you look at this pre and 

### 12 post phase-out period and you see the changes from association 

### 13 to no association to chlorpyrifos residue in cord blood 

### 14 samples, do you see the same trend for, say for example 

### 15 malathion or diazinon or the other way around, and that 

### 16 analyses will somehow strengthen or weaken your preliminary 

### 17 conclusion whether chlorpyrifos is likely to play an important 

### 18 role. And I think that in essence should be very easy to do, 

### 19 but I think definitely worth it to sort of double check your 

### 20 conclusion using other data. 

### 21 DR. KENNETH PORTIER: Dr. Koutros? 

### 22 DR. STELLA KOUTROS: Dr. Lu and I had a short

### Page 585 1 discussion about that this morning and I think what he is 

### 2 suggesting is that we always have this question in Epi that it 

### 3 could be something else. This happens all the time, and so 

### 4 there is a huge burden on us to try and show that these other 

### 5 exposures are not causing the effect. 

### 6 So additional analyses that I think he was 

### 7 suggesting, and I really don't recall from the study what they 

### 8 did -- although they did do some of this work -- if there is 

### 9 any other measured pesticide exposure, it would be very easy to 

### 10 put them in a model at the same time and see if the effects of 

### 11 chlorpyrifos remain. But again, I don't recall what 

### 12 measurements were from what particular study, so I don't know 

### 13 if that makes it a little bit more clear, and not necessarily 

### 14 just -- I mean, I don't really think just looking at malathion 

### 15 and saying that -- you know, just whatever they have measured. 

### 16 Of course, I wouldn't suspect you would want to do a new 

### 17 analysis just to look at that, or a new biomarker analysis just 

### 18 to look at that. 

### 19 But this actually made me wonder -- you know, 

### 20 I wasn't at the last SAP, so it sounded, from some of the 

### 21 material that I read, that there had been some communication 

### 22 with the cohort authors in the past. And I am not sure what

### Page 586 1 available biological samples are still there and how, if at 

### 2 all, they've considered pulling any of their data. So I didn't 

### 3 know if anybody knew anything about that. 

### 4 DR. KENNETH PORTIER: Dr. Aschner? 

### 5 DR. MICHAEL ASCHNER: I mean, if you did this 

### 6 actually and you showed for example that you're using a lot 

### 7 more malathion, I mean would you be able to conclude that 

### 8 malathion improves the IQ? I mean I'm having problem with this 

### 9 kind of -- 

### 10 DR. STELLA KOUTROS: Can you repeat the 

### 11 question? 

### 12 DR. MICHAEL ASCHNER: Yeah. If, at the same 

### 13 time, you had a tremendous increase in the amount of malathion 

### 14 that is being used post the removal of chlorpyrifos, would your 

### 15 conclusion be that malathion increases the IQ? 

### 16 DR. STELLA KOUTROS: I'm not sure exactly 

### 17 what you are driving at but -- go ahead. 

### 18 DR. CHENSHENG LU: I guess you have to make 

### 19 the comparison at pre and post phase-out. Yes; if, say for 

### 20 example, during the phase-out period, malathion use this 

### 21 increase by 50 percent and then all show up in the cord blood 

### 22 sample, and that -- yes, maybe that's the case. And that's

### Page 587 1 what I'm saying, that if you need to look at this additional 

### 2 analysis and ask themselves whether chlorpyrifos is likely to 

### 3 play a role. 

### 4 DR. KENNETH PORTIER: Dr. Koutros? 

### 5 DR. STELLA KOUTROS: So, in order for 

### 6 whatever this is to play a role, it would have to be related to 

### 7 prenatal chlorpyrifos exposure, which I think is highly 

### 8 unlikely. But I do think a limitation of the studies, and 

### 9 actually one of the major potential confounders that could be 

### 10 at play is postnatal exposure, which is likely to be related to 

### 11 chlorpyrifos and may also be related to the outcome. So that, 

### 12 I think, is unknown and probably will be unknown. 

### 13 DR. KENNETH PORTIER: Dr. Popendorf? 

### 14 DR. WILLIAM POPENDORF: I've got a statement 

### 15 and a half, I suppose, but one would be about the weaknesses 

### 16 that I'm going to talk about in a the future response with the 

### 17 DAP and TCP as indices of exposure. But the other is, 

### 18 certainly I think that the strength of that crude dose response 

### 19 is very good for the Columbia data, and I think there is future 

### 20 opportunities to see more differences as you have more 

### 21 separation in time. 

### 22 Again, it seems like the -- the one that I'm

### Page 588 1 looking at, the environmental residues were certainly still 

### 2 there in the 2002, 2003, maybe even 2004 timeframe. So the 

### 3 more time that separates them, I think, the more opportunities 

### 4 there will be with that data or that type of study to look for 

### 5 effects, opportunities to detect differences. 

### 6 DR. KENNETH PORTIER: That's only if they are 

### 7 continuing to recruit into the cohort, right? They are not 

### 8 doing that anymore. The cohort stops. So that would only be 

### 9 if you were getting some new children into the cohort today at 

### 10 extremely low level. 

### 11 DR. WILLIAM POPENDORF: I would certainly 

### 12 except that. And I guess I'm sort of potentially encouraging 

### 13 that type of study to be reinitiated with all the similarities 

### 14 and measurements, cohort or socioeconomic factors, et cetera. 

### 15 DR. KENNETH PORTIER: Dr. Terry? 

### 16 DR. ALVIN TERRY: This sort of goes back to 

### 17 question 4.1. And I was sort of sitting here scratching my 

### 18 head about a comment or two that Dr. Harry made and I wanted to 

### 19 get clarification, and it relates to her asking Dr. Gold to 

### 20 sort of tone down the comments about the possibility that these 

### 21 detected neurobehavioral effects were non-cholinesterase 

### 22 related.

### Page 589 1 And I'm thinking about some of the 

### 2 presentations yesterday. I think it was one of the public 

### 3 presentations, and correct me if I'm wrong; in the Columbia 

### 4 cohort, the only real measurements of chlorpyrifos were in cord 

### 5 blood and they were something only worth pg/g per mil, very low 

### 6 but detectable. So why is it not a fair statement to suggest 

### 7 that these effects may be non-cholinesterase related? I don't 

### 8 know of anyone who has ever detected cholinesterase inhibition 

### 9 with a pg/g per mil concentration. Did I misinterpret what you 

### 10 said? 

### 11 DR. JEAN HARRY: I wasn't digging heals into 

### 12 the sand. What I was cautioning about was in the wording. And 

### 13 I think it's just going to -- to back and look, because it was 

### 14 stated that in the absence of clinical science, again, you're 

### 15 at lower levels. 

### 16 It almost seemed to take us right back to 

### 17 say, "Well, if it's not that then it's got to be due to all 

### 18 these other things that we know happened during development." 

### 19 And I just thought that the wording of that paragraph -- and 

### 20 again, it was the subtleties of the wording was inconsistent 

### 21 with the discussion that we had around the table yesterday. 

### 22 Not that there are not potential effects, but since we cannot

### Page 590 1 say timing, we cannot say when during gestation -- I mean we 

### 2 really can't say that what you're looking at is not due to that 

### 3 activity. 

### 4 Such a strong paragraph that took a quote out 

### 5 of a paper in the discussion, which was great, I mean, it sort 

### 6 of set it up. And I think that that issue needs to be there. 

### 7 But in order to outgrow other types of things that -- to take 

### 8 the mechanistic studies and bring them over as possibility of 

### 9 what might be causing that I think is inconsistent with their 

### 10 discussion yesterday that sort of says, "Yes, we have a lot of 

### 11 things there but there is a lot of questions in the in vitro 

### 12 data about applying them over." 

### 13 So, in a way it's a matter of semantics of 

### 14 the wording of that paragraph, not that you have to rule out, 

### 15 that other things are happening. It's a consideration. It was 

### 16 just more in the editorial style of the paragraph. 

### 17 DR. KENNETH PORTIER: Dr. Gold once again. 

### 18 DR. ELLEN GOLD: I just have a quick comment. 

### 19 I did go back and look at the paragraph, and it just says that 

### 20 these other things may play a role, so I hope that addresses 

### 21 the concern. But the other part of it was a direct quote from 

### 22 the article by the authors, which we can removed. But I'm just

### Page 591 1 saying that these other things should be considered as maybe 

### 2 playing a role. 

### 3 DR. JEAN HARRY: It might be the direct quote 

### 4 coming into the discussion because some of that is speculative. 

### 5 And when you bring it over into a report like this it gives it 

### 6 a little more credibility. 

### 7 DR. KENNETH PORTIER: The way I heard this is 

### 8 that -- what you're saying is it doesn't take cholinergic 

### 9 effects off the table. It makes them less likely and increases 

### 10 the likelihood that we need to look at some of these other 

### 11 mechanisms. And I think you were worried that it was taking 

### 12 cholinergic effects off the table, and I thought that's what 

### 13 you were getting at. A bunch of hands went up. I think Dr. 

### 14 Vena, and then -- 

### 15 DR. JOHN VENA: I would just recommend taking 

### 16 the quote out and just paraphrasing what they meant to say. I 

### 17 agree it may be better. 

### 18 DR. KENNETH PORTIER: I see a lot of heads 

### 19 shaking. Dr. Sandy? 

### 20 DR. MARTHA SANDY: And I'll just say that 

### 21 question 4.3(a) is going to get to this discussion again, so 

### 22 stay tuned.

### Page 592 1 DR. KENNETH PORTIER: Dr. Koutros? 

### 2 DR. STELLA KOUTROS: I'm sorry to ask again, 

### 3 but has any pooling of data or samples been considered? Does 

### 4 anybody know? 

### 5 DR. CAROL CHRISTENSEN: I can respond for the 

### 6 sake of clarity. I believe those efforts are ongoing. I don't 

### 7 know what stage they are ongoing but I had asked that question 

### 8 and those efforts are underway to do some type of pooling 

### 9 analysis across the three with biological samples, but I don't 

### 10 know a lot of details about it. 

### 11 DR. KENNETH PORTIER: So it was not reported 

### 12 before the panel. It's not in any material and you missed it. 

### 13 DR. STELLA KOUTROS: No. Yeah, I just wanted 

### 14 to make the point that that would be really useful to see that 

### 15 data because -- I mean, I don't know if it's pooling of data or 

### 16 pooling of biological samples for a new effort, but either way, 

### 17 it could add some additional clarity having a bigger sample 

### 18 size to look at some of these questions. 

### 19 DR. KENNETH PORTIER: I think that's not an 

### 20 unreasonable recommendation for the panel to include that says 

### 21 that kind of pooling would be the logical next step for the 

### 22 analysis to move forward, and hopefully you'll get that in the

### Page 593 1 report. 

### 2 I have 10:15. I think it's a good time to 

### 3 take a break before we move onto questions 4.3, which is two 

### 4 parts. Dr. Vena, some closing remarks? 

### 5 DR. JOHN VENA: Yeah. Just one point of 

### 6 clarification for Alex Lu that -- in the write-up, she did have 

### 7 that, describing Whyatt and Rauh's recent report of the control 

### 8 for diazinon and propoxur exposures and dichlorpyrifos still 

### 9 showed significant odds ratios. So there was some stuff that 

### 10 was done to control for that but I don't think they had 

### 11 malathion in there though, but I'm not sure. 

### 12 DR. KENNETH PORTIER: Let's go ahead and take 

### 13 a 15-minute break. We'll be back 10:30 by this clock. 

### 14 (BREAK) 

### 15 DR. KENNETH PORTIER: Unless someone has 

### 16 pressing issues on 4.2, I'd like to go ahead and move on to 

### 17 question 4.3. It's continued discussion of the Epi stuff, so I 

### 18 don't think it limits the panel's conversation. It just brings 

### 19 in another dimension. So why don't we read 4.3? It's a long 

### 20 one. 

### 21 DR. CAROL CHRISTENSEN: Question 4.3. As 

### 22 discussing question 2.0, a mode of action or adverse outcome

### Page 594 1 pathway has not yet been fully elucidated for the potential 

### 2 neurodevelopmental outcomes as a result of prenatal 

### 3 chlorpyrifos exposure. 

### 4 Although this does not undermine the 

### 5 qualitative interpretation of these studies and the preliminary 

### 6 conclusions stated above, the identification of a dose response 

### 7 for neurodevelopmental effects based upon a mode of action is 

### 8 not possible. Further, given the urine and cord blood sampling 

### 9 frequency in the study, there is a large degree of uncertainty 

### 10 in estimating absolute exposure response relationships, as 

### 11 opposed to establishing relative exposure groups for evaluating 

### 12 associations. 

### 13 With respect to dose response, critical 

### 14 durations of exposures and windows of susceptibility are 

### 15 unknown. In 2008, the SAP cautioned against using the Columbia 

### 16 Cohort data for deriving points of departure for risk 

### 17 assessment due, in part, to only measuring biomarkers at one 

### 18 point in time and because they could not exclude the 

### 19 possibility that effects seen were due to chlorpyrifos in 

### 20 combination with other pesticides. 

### 21 In 2008, the SAP advised against using data 

### 22 from the epidemiology studies for deriving POD due to

### Page 595 1 limitations and exposure for the purpose of risk assessment. 

### 2 I'm just going to go on to Part A. Due to 

### 3 the limitations of exposure assessment performed in the 

### 4 epidemiologic investigations, for the purpose of quantitative 

### 5 risk assessment, the agency has concluded that the 

### 6 epidemiologic data are not sufficient for deriving points of 

### 7 departure for quantitative risk assessment. 

### 8 The agency proposes that acetylcholinesterase 

### 9 inhibition data from lab animals remains the most appropriate 

### 10 data to use for dose response modeling and the derivation of 

### 11 points of departure. 

### 12 Please comments on the scientific evidence 

### 13 that does and does not support this conclusion, as well as the 

### 14 strengths and limitations of the evidence. 

### 15 DR. KENNETH PORTIER: Dr. Sandy, would you 

### 16 start the discussion? 

### 17 DR. MARTHA SANDY: Sure. I would like to 

### 18 commend the EPA. I thought the draft document very well 

### 19 summarized the data and laid it out. I'd like to start by 

### 20 describing the multiple lines of evidence that suggests that 

### 21 adverse effects may be attributed to doses lower than those 

### 22 which illicit 10 percent inhibition of acetylcholinesterase.

### Page 596 1 There are evidence that comes from the 

### 2 epidemiological studies that we've just heard about. These are 

### 3 the three longitudinal children's cohorts. These studies 

### 4 indicate that chlorpyrifos likely play a role in 

### 5 neurodevelopmental outcomes. The Columbia study has the most 

### 6 direct measure of exposure for chlorpyrifos, measuring the 

### 7 compound and cord in material blood. 

### 8 Overall, the levels of chlorpyrifos measured 

### 9 in this study were within the range of levels measured in the 

### 10 general U.S. population at that time, based on the NHANES data. 

### 11 So they are not exceptionally high levels. 

### 12 And while we do not have data on 

### 13 acetylcholinesterase inhibition in either the Columbia study 

### 14 participants or the NHANES participants, we would not 

### 15 anticipate that acetylcholinesterase inhibition would be 

### 16 associated at these levels of chlorpyrifos. 

### 17 Specifically as noted in the draft document, 

### 18 effects seen in the Rauh, et al 2006 paper reported 

### 19 chlorpyrifos, the main level at 6.07 peak-o-grams per gram of 

### 20 blood. And these peak-o-grams per gram blood levels are 

### 21 unlikely to illicit acetylcholinesterase inhibition based on 

### 22 the Noland 1984 study in male adults where they see peak levels

### Page 597 1 of chlorpyrifos in the 10 to 30 ng per mil level that results 

### 2 in inhibition of acetylcholinesterase. 

### 3 Evidence also comes from the Animal 

### 4 Neurodevelopmental Studies. And I'll refer back to the 

### 5 discussion we had yesterday of the neurobehavioral studies that 

### 6 were the focus of the discussion for charge question three and 

### 7 the conclusion that there were only three of those 

### 8 neurobehavioral studies that evaluated doses below the 1 mg/kg 

### 9 and also assessed acetylcholinesterase inhibition where two of 

### 10 those studies were negative and one was positive but flawed, as 

### 11 discussed yesterday. 

### 12 But as discussed in Dr. Mundi's (Phonetic) 

### 13 presentation and in the draft document, there are additional 

### 14 neurodevelopmental studies conducted in vivo. There's two 

### 15 additional studies in rates that reported effects at doses 

### 16 below those in which acetylcholinesterase inhibition was 

### 17 detected. One study was the Ray, et al 2010 study that 

### 18 reported an increase in oxidative stress genes in the CNS. No 

### 19 effect was seen on acetylcholinesterase inhibition in this 

### 20 study. Specifically, they dosed the animals by gavage. They 

### 21 were 7-day-old rat pups and they got doses of either 0.1, 0.51 

### 22 or 2 mg/kg. And they saw changes in rat or brain gene

### Page 598 1 expression. And among the changes they saw that oxidative 

### 2 stress genes were affected by this treatment. 

### 3 As noted on page 30 of the draft document, it 

### 4 has been suggested that oxidative stress can result in 

### 5 disregulation of signaling pathways, controlling no progenitor 

### 6 cell function. So the study is suggestive of an effect that 

### 7 needs to be investigated further. 

### 8 The second study is a rat study that has 

### 9 reported effects on serotonergic tone of the adult CNS with no 

### 10 effect on the adult CNS with no effect on the 

### 11 acetylcholinesterase inhibition. But this study administered 

### 12 chlorpyrifos in DMSO and the acetylcholinesterase activity was 

### 13 measured 24 hours after the last dose, so there are doubts 

### 14 about this finding and whether it was seen at a level where you 

### 15 didn't have inhibition. So we've got one additional study from 

### 16 those discussed yesterday in vivo in animals. 

### 17 There is also evidence that comes from 

### 18 several in vitro mechanistic studies that have been summarized 

### 19 in this draft document that EPA provided us that demonstrate a 

### 20 variety of effects at the molecular and cellular levels. In 

### 21 addition to the effect summarized in the draft document, there 

### 22 are additional studies looking at other effects, as mentioned

### Page 599 1 yesterday by Dr. Terry, such as the effects of chlorpyrifos and 

### 2 their growth factor and mitochondrial morphology. 

### 3 Many of these effects have been observed at 

### 4 very low concentrations in vitro. Levels below which 

### 5 acetylcholinesterase inhibition would be predicted in a couple 

### 6 of cases they actually tried to measure it in the in vitro 

### 7 system and didn't see any inhibition. 

### 8 So these lines of evidence suggests that 

### 9 chlorpyrifos at levels below which acetylcholinesterase 

### 10 inhibition occurs can effect neurodevelopmental. And they 

### 11 indicate that the use of acetylcholinesterase inhibition may 

### 12 not be the most appropriate data for dose response modeling and 

### 13 derivation of a point of departure for chlorpyrifos. 

### 14 I urge the EPA to work to use the 

### 15 epidemiology studies to inform the dose response assessment 

### 16 with chlorpyrifos, perhaps put some bounds on the possible 

### 17 concentration responses observed. I suggest that using the 

### 18 Columbia cohort, since that cohort had the measures of the 

### 19 parent compound chlorpyrifos admittedly at one time point 

### 20 birth, measuring it in the cord blood and the maternal blood. 

### 21 But I encourage the EPA to work with folks that are doing 

### 22 pharmacokinetic modeling, as we heard from Dr. Hattis and from

### Page 600 1 others, to predict exposure levels and get some sense of the 

### 2 levels that were experience in utero, and again, put some 

### 3 bounds on the concentration responses that you might expect. 

### 4 I do understand that the animal data that we 

### 5 do have for dose response is the best at this time and it's for 

### 6 another endpoint. It's for inhibition of acetylcholinesterase. 

### 7 Some of the limitations of using those data include the data 

### 8 that are being proposed for the points of departure in the rat. 

### 9 It's based on a repeat dosing study in pregnant rats. It's 

### 10 based on measurement of red blood cells acetylcholinesterase 

### 11 activity at a single point in time. 

### 12 Four to five hours after that last dose was 

### 13 administered, the dose -- so I'm not sure how certain we are 

### 14 that that time point, four to five hours after the last dose is 

### 15 an optimal time point for measuring acetylcholinesterase 

### 16 inhibition. The draft EPA document on page 17 says that the 

### 17 time of peak effect is typically within one to several hours 

### 18 after dosing. 

### 19 The dosing in this study was from gestation 

### 20 day 6 to 20, and so we have to think about how confident we are 

### 21 that inhibition of acetylcholinesterase had reached steady 

### 22 state in this experiment. These were pregnant dams.

### Page 601 1 Looking across the other studies that the EPA 

### 2 has reviewed, it looks like we can have some confidence that 

### 3 the inhibition had reached steady state. Since a companion 

### 4 studied that dosed dams from gestation day 6 through lactation 

### 5 date 10 gave a similar BMDL 10 for the red blood cells 

### 6 acetylcholinesterase inhibition. 

### 7 We have to ask how confident we are that the 

### 8 dose response for acetylcholinesterase inhibition in the 

### 9 pregnant rat is predictive of acetylcholinesterase inhibition 

### 10 in the human fetus, so that's another unknown. 

### 11 So, going back to the Columbia human cohort, 

### 12 I think there are some strengths in the exposure assessment 

### 13 that was done, as discussed in previous parts of this question 

### 14 4. It's rare to have that much information, actual measurement 

### 15 of air, levels of chlorpyrifos of blood, levels of 

### 16 chlorpyrifos, levels of metabolite TCPy in different 

### 17 substrates, meconium and urine. So I really encourage the EPA 

### 18 to use that information to come up with some assessment of 

### 19 integrated exposure and look at that. And I'll turn it over to 

### 20 my fellow discussants. 

### 21 DR. CHENSHENG LU: Again, Dr. Sandy's email 

### 22 stem at 10:54 p.m. last night. But I concur with what she said

### Page 602 1 in terms of these specific questions. I do have something to 

### 2 add in question 4.3 in terms of what we can do. 

### 3 Basically I agree that, so far, the data from 

### 4 the three studies is not sufficient to be used to come up with 

### 5 the point of departure, mainly because those studies are more 

### 6 focused on measuring the health outcome than doing the exposure 

### 7 assessment. 

### 8 DR. KENNETH PORTIER: Dr. Popendorf? 

### 9 DR. WILLIAM POPENDORF: And I think I overall 

### 10 concur with the general comments that are being made. I will 

### 11 touch on the timing issue in a human study at a later question, 

### 12 which also affects that in steady state. My sense is that it 

### 13 might not be as important the timing of the blood sample. It 

### 14 might not be as important as the single dose. And I also 

### 15 concur with the value of the PBPK. That, I think, keeps coming 

### 16 up to be used in a lot of different ways, and I certainly 

### 17 encourage that in addition to the animal studies. 

### 18 One other point that I'll make again at a 

### 19 later question, but the reliability of cholinesterase 

### 20 measurement, in particularly trying to detect small changes in 

### 21 any animal, cholinesterase is a challenge. And the 

### 22 methodologies that are used to -- the issue is one of

### Page 603 1 repeatability of the analytic measure from run to run or day to 

### 2 day, and that has been well known in human studies. There's no 

### 3 reason that it doesn't apply to animal studies as well. 

### 4 And that issue really hasn't been discussed 

### 5 in any form here within the issue paper. I'll bring that up 

### 6 again later in another human-related question. But it just 

### 7 kind of brings into question the overall reliability needs to 

### 8 be looked at carefully of small changes in cholinesterase, even 

### 9 in animal data. 

### 10 DR. KENNETH PORTIER: Any additional comments 

### 11 from the panel? Dr. Collier? 

### 12 DR. ABBY COLLIER: I caution agency about 

### 13 using rat and mouse data for points of departure based on 

### 14 acetylcholinesterase inhibition, using that to extrapolate to 

### 15 human neonates in fetuses and I'm going to tell you why. 

### 16 The cytochromes p450 that are absolutely 

### 17 required to create the active oxon includes CYPs 182384, 2C19 

### 18 and 2C9, and there's a 2B isoform in there as well. I'm not 

### 19 certain of which is the dominant pathway. 2C19 and 2C9 are 

### 20 highly polymorphic in humans but may not have the same 

### 21 polymorphisms in rats and mice. 

### 22 Secondly, there are different homologs and

### Page 604 1 orthologs in the rats compared to the humans, and so the 

### 2 relative amounts of metabolism you may receive from a rodent 

### 3 species compared to a human neonate are going to be different. 

### 4 Thirdly, in human neonates and/or fetuses, 

### 5 some of these CYPs are not present at birth or in the fetus and 

### 6 they rise after birth; notably, CYP 1A2, but there are others. 

### 7 Whereas, we know that they are present in the fetal mouse and 

### 8 rat. So if you go right back to the top of this metabolic 

### 9 pathway from chlorpyrifos activating to the oxon, which is the 

### 10 oxon that everybody's talking about with acetylcholinesterase 

### 11 inhibition. The activation of the oxon may be significantly 

### 12 different, what you would get from a mouse or rat to what you 

### 13 see in human studies. 

### 14 Having said that, I'm well aware, personally 

### 15 and professionally, of how hard it is to do these studies in 

### 16 human fetal and neonatal and pediatric tissue. But given the 

### 17 trouble with this type of extrapolation, there's a lot of good 

### 18 data out there as to when these turn out. And I do refer you 

### 19 to the work from Professor Ron Hines' lab. I refer you to the 

### 20 work from Professor J. Stephen Leeder's lab that has been 

### 21 looking at the ontogeny of these cytochromes p450. 

### 22 But I think there's been so much emphasis on

### Page 605 1 acetylcholinesterase inhibition. And when you look at the 

### 2 metabolic pathway for activation, the cytochrome p450 come 

### 3 first to activate and make the oxon. And there may not have 

### 4 been enough consideration of that with respect to inter-species 

### 5 extrapolation. Thank you. 

### 6 DR. KENNETH PORTIER: Want to make sure we 

### 7 get that to Dr. Sandy to include in the minutes. Any 

### 8 additional comments? I just wanted to kind of make sure I 

### 9 understood what you're basically saying. So in terms of 

### 10 answering the specific question that EPA ask, you're saying 

### 11 that the animal data is only one part of the data that they 

### 12 need to look at. It is not the only part of data. 

### 13 You're suggesting the Epi data can inform the 

### 14 dose response assessment that PK modeling can inform, and that 

### 15 all of those, in addition to understanding some of the 

### 16 biochemistry, is going to be necessary to establish a points of 

### 17 departure. Is that pretty much a summary? 

### 18 DR. ABBY COLLIER: Yes, with the addition 

### 19 that -- I'm saying there's multiple lines of evidence 

### 20 suggesting there are effects that are likely to occur below the 

### 21 level of acetylcholinesterase inhibition, therefore those rat 

### 22 data on acetylcholinesterase inhibition -- well the best data

### Page 606 1 available to do quantitative dose response assessment are not 

### 2 directly -- we have a lot of uncertainty in linking them to a 

### 3 conclusion that that will be protective against what we are 

### 4 observing in the Epi studies. And I'm suggesting that they 

### 5 really work hard to use those epidemiological studies in 

### 6 exposure concentration response associations to develop some 

### 7 dose response or bounding on how well that rat data, what 

### 8 confidence you're have that that's going to be in the same 

### 9 range. 

### 10 DR. KENNETH PORTIER: So Dr. Christensen or 

### 11 Dr. Lowit, do you understand the panel's answer on this, and 

### 12 the additional clarification question? I'll give you the 

### 13 opportunity here because I'm hearing they don't necessarily 

### 14 agree with you on this particular statement. 

### 15 DR. ANNA LOWIT: I guess, when I put my light 

### 16 on it -- because I had heard Dr. Sandy a little bit different 

### 17 than I think maybe the way that you heard Dr. Sandy, and so I 

### 18 think maybe it's worth clarifying to make sure the way I heard 

### 19 Dr. Sandy's suggestion, and I thought it was largely a very 

### 20 good one -- that, largely consistent with what was said 

### 21 yesterday, with respect to the dose response data and the 

### 22 reliability of that data, the rat cholinesterase data is still

### Page 607 1 the best starting point, for example. 

### 2 But if you remember from a couple of days 

### 3 ago, several of the EPA speakers talked about thinking about 

### 4 ranges of risk and ranges of uncertainty in areas of strength 

### 5 and uncertainty. And what I heard Dr. Sandy suggest was to 

### 6 take those other datasets and to use them in a bounding 

### 7 analysis to get a handle on what those bounds of uncertainty 

### 8 and ranges of risk that would help characterize the relative 

### 9 confidence in that cholinesterase data that would provide that 

### 10 reliable starting point, and that's the way I heard it. And it 

### 11 sounds like you heard it a little bit differently, so I think 

### 12 maybe a little bit more conversation about that would help. 

### 13 DR. MARTHA SANDY: In essence, I think what 

### 14 you just said is correct. I'm acknowledging that it's 

### 15 difficult to do dose response on anything but the animal data. 

### 16 But I'm not sure the response that you're assessing is truly 

### 17 protective. And that's why I'm asking for the use of the Epi 

### 18 to do the bounding to get some sense of -- so it's all about 

### 19 how we phrase this, but to get some level of how much 

### 20 uncertainty there is in using that rat data with a different 

### 21 endpoint; is it protective against the neurodevelopmental 

### 22 effects that we are seeing.

### Page 608 1 DR. KENNETH PORTIER: Dr. Lu? 

### 2 DR. CHENSHENG LU: I would suggest Dr. 

### 3 Portier wait until we finish 4.3(b) before making any 

### 4 conclusion. I think there are some comments for 4.3(b) which I 

### 5 think is more relevant to the whole question of 4.3, instead of 

### 6 just 4.3(a). 

### 7 DR. KENNETH PORTIER: Good suggestion. So 

### 8 let's move on to 4.3(b) and see what we find. 

### 9 DR. CAROL CHRISTENSEN: Question 4.3(b): The 

### 10 agency does, however, believe that the epidemiologic data are 

### 11 useful to informing other key aspects of the chlorpyrifos risk 

### 12 assessment, including hazard characterization, exposure 

### 13 characterization and quantitative uncertainty characterization 

### 14 analysis. 

### 15 Please suggest approaches and/or analyses for 

### 16 potentially using the epidemiology data in different parts of 

### 17 the chlorpyrifos risk assessment, including those noted above. 

### 18 Some of these may also be covered in question 5.4 below. 

### 19 DR. KENNETH PORTIER: And Dr. Meek has been 

### 20 very quiet in the corner there and now she has her chance to 

### 21 address the panel. 

### 22 DR. BETTE MEEK: Thanks very much. So,

### Page 609 1 firstly, because I haven't said very much today, I wanted to 

### 2 recognize the contribution of the agency, particularly in the 

### 3 contribution of the framework for integrative analysis to 

### 4 evaluate multiple lines of evidence in the context of 

### 5 understanding of the AOP/MOA. I think it's excellent construct 

### 6 by which to think about weight of evidence. And of course, 

### 7 it's an excellent construct to think about weight of evidence 

### 8 in the context as we move forward to incorporate increasingly 

### 9 varied types of information from evolving technologies. 

### 10 So in relation to the epidemiological data 

### 11 informing the key aspects of the chlorpyrifos risk assessment, 

### 12 I'd like to expand this somewhat beyond hazard 

### 13 characterization, exposure characterization and quantitative 

### 14 uncertainty characterization analysis because the 

### 15 epidemiological data do provide information relative also to 

### 16 dose response, though again, not necessarily as the basis for 

### 17 the point of departure, but I think that they do inform us. 

### 18 First of all, in relation to exposure 

### 19 characterization, I think that the environmental monitoring and 

### 20 biomonitoring data in the epidemiological studies contribute to 

### 21 the overall database on estimation of exposure, including 

### 22 particularly population variability, and to some degree,

### Page 610 1 inter-individual variability. But again, to the extent that 

### 2 those cohorts weren't very large, they at least provide us some 

### 3 information on those aspects. 

### 4 In particular, they provide insight into 

### 5 perhaps more generalizable observations on temporal trends in 

### 6 exposure of the general population following the impact of 

### 7 withdrawal of the domestic uses of chlorpyrifos, and I think 

### 8 that's an important contribution. I think they also provide 

### 9 unique opportunity to investigate the relationship between 

### 10 environmental levels and biomonitoring, since for some studies 

### 11 there're both types of data available. 

### 12 And I guess, to some degree they can also 

### 13 provide some insight into the suitability of the various 

### 14 biomarkers as measures of short and/or long-term exposure to 

### 15 chlorpyrifos. 

### 16 So in relation to the hazard 

### 17 characterization, clearly, the epidemiological data contributes 

### 18 strongly to an evolving database on potential hazard in humans, 

### 19 and that's critical. They have and continue to contribute to 

### 20 hypothesis generation for targeted investigations of 

### 21 developmental mental toxicity in animal studies. And to some 

### 22 degree, they confirm expectations concerning potentially

### Page 611 1 susceptible subgroups based on mode of action; so the PON1 

### 2 genotypes. They do provide some information on the extent of 

### 3 impact of other factors which, in combination with 

### 4 chlorpyrifos, may impact on observed effects. 

### 5 An emulation of the quantitative uncertainty 

### 6 characterization analysis; again, I wanted to address this 

### 7 particularly in the context of dose response analysis. 

### 8 So EPA has concluded that the current 

### 9 epidemiological database strengthens the 2008 conclusion that 

### 10 chlorpyrifos likely plays a role in the observed adverse 

### 11 effects on child neurodevelopmental, specifically those 

### 12 reported by Columbia University. I think that we've heard that 

### 13 as a recurring theme this morning in the discussions of the 

### 14 epidemiological data. 

### 15 So given that this is the case, it seems 

### 16 important then to maximally utilize the available data on dose 

### 17 response from these studies, again, as Dr. Sandy indicated, to 

### 18 at least bound referenced doses developed on the basis of 

### 19 animal data. 

### 20 And I'm encouraged by, for example, the work 

### 21 that Dr. Hattis is doing, and also the developments in the 

### 22 physiologically based pharmacokinetic modeling.

### Page 612 1 I wanted to add something here though. In 

### 2 addition, though, given the potential significance of the 

### 3 observations in the epidemiological studies, I think it's also 

### 4 clearly desirable to consider the potential, at least 

### 5 semi-quantitative impact of factors of study design 

### 6 interpretation to bound the dose response relationship from the 

### 7 human studies. And probably, there needs to be systematic 

### 8 consideration, again, at least semi-quantitatively of the 

### 9 potential impact on reported dose response analysis of exposure 

### 10 measurement or outcome ascertainment in impact to confounding 

### 11 variables and statistical analysis. 

### 12 We heard this morning that, in fact, clearly 

### 13 -- you know, we can't attribute the observed effects solely to 

### 14 chlorpyrifos, but what can we do additionally to understand 

### 15 what's the potential contribution from other pesticides? I 

### 16 think that's really key. And that's the end of what I have to 

### 17 say, and I'd invite my co-discussants to address the question. 

### 18 DR. KENNETH PORTIER: Dr. Lu? 

### 19 DR. CHENSHENG LU: So my point of view for 

### 20 this question is that, Epi data, especially Columbia data 

### 21 actually offer a great opportunity for the agency to derive to 

### 22 the POD for neurodevelopmental effects in infants and to

### Page 613 1 determine whether the chlorpyrifos level that they were 

### 2 measured in the, the cord blood sample, could inhibit either 

### 3 red blood cells or acetylcholinesterase. And I think this can 

### 4 be easily done in either EPA laboratory or other laboratories 

### 5 as well. And even better if EPA can use the already published 

### 6 PBPK models specifically for cord blood. And then use those 

### 7 levels that Columbia study measured and can extrapolate to see 

### 8 whether there could be a range of chlorpyrifos level during the 

### 9 pregnancy over the period of 9 months. So you actually can 

### 10 have a range of the chlorpyrifos level in cord blood samples 

### 11 and then see whether those levels actually inhibit or not 

### 12 inhibit to the extent that we can measure. 

### 13 So why this is important? I think the 

### 14 results of the laboratory testing will answer a critical 

### 15 question that I raised yesterday after The Dow Group, their 

### 16 presentation in terms of whether there is an association 

### 17 between chlorpyrifos and neurodevelopmental effect in the 

### 18 absence of acetylcholinesterase inhibition is plausible or not 

### 19 for humans. 

### 20 And to answer this question, since it has 

### 21 been raised by the Dow research team over and over again, I 

### 22 think the easiest and most readable answer would be to look

### Page 614 1 into this Columbia data. 

### 2 So my opinion is that this is two separate 

### 3 observations in which the cholinesterase results from acute 

### 4 exposure scenario, whereas the neurobehavior is likely to be 

### 5 caused by chronic low levels of chlorpyrifos exposure. 

### 6 The Columbia study along with the other two 

### 7 studies were all designed to examine the neurobehavior outcome 

### 8 from in utero or chronic chlorpyrifos exposures, not just acute 

### 9 response from the recent event. 

### 10 However, I think the cord blood data would be 

### 11 ideal to test this hypothesis, whether my personal opinion is 

### 12 valid. Thank you. 

### 13 DR. KENNETH PORTIER: Dr. Sandy? 

### 14 DR. MARTHA SANDY: As I indicated in the 

### 15 previous question, the levels of chlorpyrifos measured in the 

### 16 cord blood in the Columbia Cohort are within the range of what 

### 17 was observed in children and the general population in NHANES 

### 18 at the time. And we have no indication that the general 

### 19 population was experiencing any inhibition of 

### 20 acetylcholinesterase. 

### 21 So I would start with the premise that, 

### 22 likely, these children and their mothers were not experiencing

### Page 615 1 inhibition of acetylcholinesterase inhibition. They were 

### 2 exposed to fairly low levels. 

### 3 The additional work proposed by Dr. Lu to use 

### 4 pharmacokinetic modeling and look at that and actually do some 

### 5 tests would be helpful in confirming that assumption. 

### 6 But given the severity of the effects that 

### 7 are being observed in these three longitudinal cohorts in euro 

### 8 exposure to chlorpyrifos, effects seen from birth throughout 

### 9 age 7, especially the IQ deficits, I would suggest that the EPA 

### 10 consider using -- if they must rely on, for a point of 

### 11 departure, the rat data on inhibition of acetylcholinesterase 

### 12 for point of departure, I would seriously recommend considering 

### 13 retaining the 10-fold FQPA factor because of all the 

### 14 uncertainty in vulnerable populations, other exposures that 

### 15 have occurred in these cohorts, as well as to just the polation 

### 16 in general that may contribute to lower levels of 

### 17 acetylcholinesterase activity and vulnerability of the system 

### 18 of the no developmental system to the action of chlorpyrifos. 

### 19 DR. KENNETH PORTIER: Dr. Young? 

### 20 DR. HEATHER YOUNG: I concur with everything 

### 21 that's already been said. I just want to reiterate that I 

### 22 think it's important to view that Epi data at least for some

### Page 616 1 sort of bounding. I realize it's not there and it's not the 

### 2 best data for the point of departure at this point, but at 

### 3 least to start to us it similar to what Dr. Hattis was showing 

### 4 yesterday and at least some of the human data is then being 

### 5 used in the PBPK models and in doing some bounding with it. 

### 6 DR. KENNETH PORTIER: Anyone else on the 

### 7 panel has a comment on this question? Dr. Popendorf? 

### 8 DR. WILLIAM POPENDORF: Just an observation, 

### 9 following up on Dr. Lu's suggestion of looking at cord blood; I 

### 10 was looking at the relationships between cord blood and 

### 11 maternal blood, and there was a discrepancy that I haven't 

### 12 really investigated the origin. 

### 13 Whyatt in all 2004 showed a correlation 

### 14 regression model, basically. And if you run the median values 

### 15 you'll see a difference of about a 50 percent difference 

### 16 between cord and maternal. Whyatt 2005 shows mean values that 

### 17 are within 10 percent of each other, closer to five percent, 

### 18 almost equal. And I don't know why that discrepancy is. I 

### 19 know within the PBPK model, they use one assumption. Other 

### 20 people use a different assumption. So I think that particular 

### 21 point needs to be investigated and clarified for uses between 

### 22 material and cord, in particular.

### Page 617 1 DR. KENNETH PORTIER: Anyone else? Dr. 

### 2 Christensen? 

### 3 DR. CAROL CHRISTENSEN: Just on that point 

### 4 between the Whyatt 2004 paper and the 2009 paper; you meant 

### 5 2009 or 2005? 

### 6 DR. WILLIAM POPENDORF: 2005. 

### 7 DR. CAROL CHRISTENSEN: So between 2004 and 

### 8 2005? 

### 9 DR. WILLIAM POPENDORF: Right, two 

### 10 publications. It could be 9 but I wrote 4 on my note. 

### 11 DR. CAROL CHRISTENSEN: Okay. I will look 

### 12 into that. I was just going to note they are slightly 

### 13 different subsets of the population in that validation work 

### 14 performed in Whyatt 2009 than that was performed in the earlier 

### 15 paper, which could result in that discrepancy. 

### 16 DR. WILLIAM POPENDORF: Right. Which could 

### 17 explain the difference. But then you have a question of why is 

### 18 there a difference and how are you going to use those two for 

### 19 future extrapolations. 

### 20 DR. CAROL CHRISTENSEN: Okay. We'll note 

### 21 that. 

### 22 DR. KENNETH PORTIER: Dr. Lowit, Dr.

### Page 618 1 Christensen, I heard a number of approaches for analysis and 

### 2 suggestions for initial analysis to this question, so I think 

### 3 it's adequately answered. Your comments? 

### 4 DR. ANNA LOWIT: No. I think that, for the 

### 5 most part it's very clear and largely inline of what I think we 

### 6 were thinking. 

### 7 I'd just like to comment on -- if we can keep 

### 8 the conversation about the strengths and the weaknesses of the 

### 9 science and where the uncertainties are and where there is 

### 10 ability to quantify those uncertainties and where they are 

### 11 largely qualitative, and using bounding kind of things to get a 

### 12 handle on the magnitude of that, that is largely the most 

### 13 useful thing that we can do, that you can do to help us take 

### 14 the next steps in our analysis of putting all the pieces 

### 15 together. 

### 16 Because, if you remember, as Dr. Popendorf 

### 17 pointed out yesterday, you have actually only seen a slice of 

### 18 what is a very complicated, very large risk assessment that 

### 19 includes exposure assessment for multiple pathways in different 

### 20 groups of populations throughout the country. 

### 21 So as we get further into these media 

### 22 questions about uncertainty, if we can focus on the science and

### Page 619 1 less so on the policy, that's the most helpful thing for us. 

### 2 DR. KENNETH PORTIER: So what I'll do is ask 

### 3 Dr. Meek and Dr. Sandy to kind of make sure that A and B are 

### 4 separated, because A deals with the uncertainties and the 

### 5 scientific evidence, and B kind of addresses the additional 

### 6 analyses and moving forward kind of things. So we'll just kind 

### 7 of try to make sure in our report that we have those as well 

### 8 separated as we can get them. Okay? Any additional comments 

### 9 on all of question 4? Dr. Lu? 

### 10 DR. CHENSHENG LU: Well I understood what the 

### 11 agency mentioned about what Dr. Lowit just talked about. But 

### 12 my trouble is that, even as of today, there's very few new data 

### 13 in this field. And for the new data that we discussed 

### 14 yesterday in terms of neurobehavior in Rodan (phonetic) study, 

### 15 actually added a vision of uncertainty to this overall 

### 16 discussion. So I don't know how we are going to improve this 

### 17 subject without better data, and we cannot just look at those 

### 18 data over and over again hoping that there is going to be some 

### 19 new insight coming out from the same dataset. Again, the new 

### 20 insight doesn't help because the animal testing for the 

### 21 neurobehavior. So I think this is something very fundamental 

### 22 for the agency to think about it. That's how I would look at

### Page 620 1 it. 

### 2 DR. KENNETH PORTIER: And I think, in 

### 3 question 4.1 there's a lot of opportunity to talk about data 

### 4 needs because there is strengths and limitations discussed 

### 5 there. And my notes indicate there are a number of places 

### 6 where we indicated some data needs that would help clarify. 

### 7 Because you asked the issue of clarification and there are a 

### 8 lot of places where it's not very clear, and additional data, 

### 9 additional analysis will pay off on that. Dr. Lowit? 

### 10 ANNA LOWIT: And, yeah, the chlorpyrifos is 

### 11 certainly one of those chemicals where the -- I'm sure their 

### 12 publications have come out in the last week since we've been 

### 13 sitting here that the science is constantly evolving and very 

### 14 rapidly. I think at this point people are really getting 

### 15 smarter and smarter doing these things. 

### 16 So to the extent that we -- there is a forum 

### 17 to encourage people to be moving in certain directions, I would 

### 18 concur with that, as long as there is a balance between that 

### 19 and understanding that we've got some very difficult decisions 

### 20 to make and real time for which a lot of new data is not inform 

### 21 too much. So if you can just balance those two needs. 

### 22 DR. KENNETH PORTIER: Dr. Sandy?

### Page 621 1 DR. MARTHA SANDY: Just a follow-up on that. 

### 2 It seems that we are spending a lot of time trying to figure 

### 3 out, based on just a few studies that measured 

### 4 neurodevelopmental effects and acetylcholinesterase one or two 

### 5 or three, it would be great if EPA can encourage somehow or 

### 6 fund or conduct themselves studies on key observed effects in 

### 7 whatever system you need, and at the same time, do a nice dose 

### 8 response and look at acetylcholinesterase inhibition. That 

### 9 would probably not take more than six months to actually do the 

### 10 work, and that would greatly improve the database, I believe. 

### 11 This is for the animal in vivo studies. 

### 12 DR. KENNETH PORTIER: I'd like to see that in 

### 13 4.1. Okay. Any additional comments? That was a good 

### 14 discussion, I thought. I'd like to move on with question 5.1 

### 15 and begin the discussion on exposure profile and biomonitoring 

### 16 research with the recognition that we will try to break around 

### 17 noon or 12:15, so we have about an hour to begin that 

### 18 discussion with 5.1. 

### 19 LIEUTENANT AARON NIMAN: Section 5 of the 

### 20 draft issue paper presents an overview of the principle 

### 21 chlorpyrifos biomarkers and the comparison of biomonitoring 

### 22 studies that measured urinary TCPy levels in a range of study

### Page 622 1 populations involving both the general population and 

### 2 potentially vulnerable populations, including children, workers 

### 3 and farm families. 

### 4 Please comment on the degree to which the 

### 5 agency identified the primary chlorpyrifos biomarkers of 

### 6 exposure. Appropriately discuss the strengths and limitations 

### 7 of such biomarkers and how the strengths and limitations effect 

### 8 the interpretation of chlorpyrifos biomonitoring data. 

### 9 DR. KENNETH PORTIER: Thank you. And Dr. 

### 10 Buckley tells me that this group has been working very hard, so 

### 11 I expect a nice coherent report at this point. 

### 12 DR. BRIAN BUCKLEY: You are going to 

### 13 definitely get a report. The coherency is in the eye of the 

### 14 beholder. I will tell you that what I have is both a 

### 15 distillation of the comments that we share with one another as 

### 16 well as some individual comments that were forwarded to me 

### 17 directly. So with that in mind, I'm going to read the comments 

### 18 that I have so far. 

### 19 Considering the availability of standard 

### 20 methods, the specificity of the biomarker, the number of 

### 21 laboratories capable of making the measurement in the relative 

### 22 concentration levels, the first choice for a biomarker would be

### Page 623 1 chlorpyrifos in blood, followed by TCPy in urine and then DETP, 

### 2 DEP in urine. The total DAPs as DMP and DEP are not selective 

### 3 enough to be a true biomarker for chlorpyrifos, although it may 

### 4 be more appropriate in a risk consideration or calculation 

### 5 model because all of the acetylcholinesterase inhibiting 

### 6 chemical should be considered together when evaluating risk. 

### 7 8 The panel recognizes the inability of urinary 

### 9 TCPy to distinguish between exposures of chlorpyrifos, 

### 10 chlorpyrifos-methyl and trichlopyr as well as direct exposure 

### 11 to TCPy as a chlorpyrifos degradate. It is more selective, 

### 12 however, than the DAPs and currently is the most selected for 

### 13 urinary metabolites, but questions remain. 

### 14 There should be more emphasis placed on the 

### 15 direct intake of the environmental degradate TCPy mainly 

### 16 present in foods. 

### 17 As early as the late 1990s, the Ryan Group 

### 18 (phonetic) had identified an anomaly in the amount of TCPy 

### 19 found in urine was substantially greater than the measured 

### 20 intake of chlorpyrifos. This work has continued with papers by 

### 21 Morgan et al, Wilson et al, Lu et al, indicating the presence 

### 22 of degradates in foods.

### Page 624 1 Ryan et al have continued this work with a 

### 2 recent PhD student focusing on the kinetics of this process. 

### 3 While this work has not yet been published, and the other works 

### 4 are mentioned, insufficient emphasis has been placed on 

### 5 observation, putting into question the utility of urinary TCPy 

### 6 as a useful measure of exposure to the parent compound. 

### 7 The panel also recognizes the ability to 

### 8 measure acetylcholinesterase and butyrylcholinesterase and 

### 9 their inhibition as biomarkers of exposure, but they are even 

### 10 less specific than the DAPs. They are, however, more 

### 11 indicative of potential health risk and rather, are more than 

### 12 just a biomarker of exposure. 

### 13 In addition, the ability to measure the 

### 14 anilities is likely to vary widely from laboratory to 

### 15 laboratory and they are difficult to calibrate, as has already 

### 16 been noted by Dr. Popendorf. I just want a point of my own 

### 17 personal comment. 

### 18 While these measurements are key potentially 

### 19 within the biomarker -- not necessarily the biomarker, but the 

### 20 folks doing the research on the in vivo and in vitro studies, 

### 21 their ability to be compared from laboratory raises some 

### 22 doubts, especially for very small changes because of the

### Page 625 1 difficulty in calibration. So when we consider 

### 2 acetylcholinesterase and butyrylcholinesterase inhibition and 

### 3 you're trying to compare a study to study, there is a lot of 

### 4 uncertainty, I think, that's included in that comparison. And 

### 5 they should probably be evaluated for changes after an exposure 

### 6 more within a laboratory than across laboratories or from study 

### 7 to study. 

### 8 Full consideration of conjunctive metabolism 

### 9 will assist in correct biomarker use, including interpretation 

### 10 of biomonitoring data and appropriate dissymmetry to with, 

### 11 despite the acetylcholinesterase adducting axon, won't be 

### 12 conjugated if glucuronidation or sulfonation are rate limiting 

### 13 or ontogenetically deficient. 

### 14 And other metabolites may accumulate due to 

### 15 the inadequacy of the metabolism. This includes the potential 

### 16 for error in biomarker analysis and may cause error in 

### 17 dissymmetry, estimations or recalculations due to overlarge 

### 18 estimations of exposure in the fetus or child. 

### 19 In the future, more selective biomarkers are 

### 20 expected, including direct measurement of the oxon in blood, as 

### 21 well as adducts in both blood and urine. These adducts include 

### 22 proteins, glucuronides, et cetera.

### Page 626 1 While the oxon is very short-lived, we 

### 2 believe it is possible to measure it in the blood and 

### 3 represents the true species that presents risk. It is also 

### 4 exclusive to exposure to chlorpyrifos as opposed to the 

### 5 chlorpyrifos degradate TCPy. 

### 6 When evaluating any of the other biomarkers 

### 7 in blood, the EPA will need to consider that some of these 

### 8 biomarkers will differ in concentrations between cord blood and 

### 9 material blood as they have different lipophilicity. 

### 10 There also needs to be more emphasis placed 

### 11 on urinary metabolites, glucuronides and sulfates. And in 

### 12 discussions with Dr. Collier, we both agree there has not been 

### 13 significant effort to look at either of the glucuronide or 

### 14 sulfate metabolites. And I believe the primary reason is that 

### 15 these metabolites have only recently been evaluated both from a 

### 16 physiological and analytical perspective, which, from the 

### 17 analytical perspective, they just haven't been looked at until 

### 18 recently when we've had to do it in some of the other 

### 19 compounds. 

### 20 Measuring multiple metabolites simultaneously 

### 21 and then taking ratios of metabolites, such as TCPy to DETP 

### 22 should provide greater discrimination between exposure to

### Page 627 1 chlorpyrifos rather than its degradate product. It may even be 

### 2 possible to do a source of apportionment and separate degradate 

### 3 exposure from exposure to the active. 

### 4 Okay. Other considerations. In the 

### 5 presentation, the agency suggested that meconium could be used 

### 6 as a biomarker for fetal chlorpyrifos exposure throughout 

### 7 pregnancy. This is not suggested to be a good idea for the 

### 8 following reasons: 1) no studies in chlorpyrifos and amniotic 

### 9 fluid have been performed; 2) the diffusion and/or transport of 

### 10 chlorpyrifos across the placenta in either direction is 

### 11 unknown. But since its rather fat soluble, equilibrium within 

### 12 the maternal serum might be postulated. 

### 13 This does not seem to be the case with at 

### 14 least one umbilical maternal serum study presented at this 

### 15 meeting, which is beyond 2010; 3) metabolism across the 

### 16 placenta is unknown; 4) the contribution of umbilical tissue, 

### 17 including any adducting of cord tissue, for example, by the 

### 18 oxon is likewise unknown. Fetal and maternal blood flow, 

### 19 umbilical cord tissue consists of a polymatrix, which is made 

### 20 up of uco-polysaccharides. It contains one vein to carry 

### 21 oxygenated blood and nutrients to the fetus and two arteries 

### 22 carrying the oxygenated blood and fetal waste back to the

### Page 628 1 placenta. These vessels are lined with endothelia. 

### 2 Occasionally, only two vessels, one vein and 

### 3 one artery are present in the umbilical cord, but this is not 

### 4 necessarily related to fetal defects or complications of 

### 5 pregnancy. 

### 6 Based on these characteristics and the very 

### 7 fat soluble natural chlorpyrifos, and it is relatively fat 

### 8 soluble metabolites, the umbilical cord would not be expected 

### 9 to function as a good reservoir of these. However, since it is 

### 10 so well profused, umbilical tissue may be expected to be a 

### 11 target for oxon binding. 

### 12 5) Meconium being comprised mostly of 

### 13 intestinal epithelia, lanugo, mucus, amniotic fluid, biowater 

### 14 is reasonably hydrophilic and thus should be also considered a 

### 15 poor matrix or reservoir for chlorpyrifos and other fat soluble 

### 16 xenobiotics to accumulate. 

### 17 It may be marginally better for the 

### 18 metabolites, TCPy and DETP, but these molecules would also have 

### 19 some net flow in the power cellular pathway. 

### 20 6) While placental studies are undetermined 

### 21 which is the limitation of data available to the agency, 

### 22 several important points in this respect are already known from

### Page 629 1 elicit drug literature and should be considered in light of 

### 2 attempting the same type of monitoring for chlorpyrifos or 

### 3 other antibiotics. 

### 4 For example, antipuradine (phonetic), an 

### 5 amphetamine derivative, is used in placental profusion 

### 6 experiments as a marker of pure diffusive transport with 

### 7 affectively no barrier. In contrast, coke, cocaine and 

### 8 cotinine showing differing slightly less fat soluble profiles. 

### 9 For example, cocaine is transferred across the placental at 

### 10 only 80 percent the rate of antipurine. And some studies have 

### 11 suggested that the placenta acts as a depo (phonetic) for 

### 12 cocaine accumulation preventing transfer to the fetus. 

### 13 Additionally, previous studies have indicated 

### 14 that while nicotine, again highly fat soluble, is transferred 

### 15 into the fetal compartment up to five times the concentration 

### 16 in maternal blood, cotinine concentrations in the fetal 

### 17 compartment were considerably lower than corresponding maternal 

### 18 serum levels. 

### 19 Again, it has been suggested that cotinine 

### 20 adducts, the placenta, preventing equilibrium of the 

### 21 concentrations between the maternal and fetal systems. These 

### 22 systems support the need for greater consideration of the

### Page 630 1 transplacental characteristics of chlorpyrifos. And since 

### 2 placental characteristics change drastically by term, leaky 

### 3 after about 36 weeks, placental studies need to consider each 

### 4 trimester in one trimester after eight weeks when placenta is 

### 5 profused, since prior to eight weeks, only active transported 

### 6 diffusion of the placenta can occur due to villi (phonetic) 

### 7 being blocked. 

### 8 Such studies would be ideally recommended 

### 9 before extrapolating fetal exposure and may be included as part 

### 10 of the longitudinal study of pregnancy. And we all agree that 

### 11 longitudinal studies of pregnancy are key in terms of 

### 12 determining what the fetal exposure is going to be overall. 

### 13 That's something that was discussed at great detail and 

### 14 represents a significant data gap. 

### 15 These points highlight the uncertainty of 

### 16 using meconium as a measure of exposure over the course of 

### 17 pregnancy at this time. And that's it. 

### 18 DR. KENNETH PORTIER: Thank you. Dr. 

### 19 Collier? 

### 20 DR. ABBY COLLIER: I'd like to thank Dr. 

### 21 Buckley for incorporating on my comments with those at the risk 

### 22 of the panel, and I have nothing further to add.

### Page 631 1 DR. KENNETH PORTIER: Dr. Lu? 

### 2 DR. CHENSHENG LU: To be consistent, I got 

### 3 the last draft on Dr. Buckley at 9:45 p.m. last night. I have 

### 4 nothing to add. 

### 5 DR. KENNETH PORTIER: Dr. Popendorf? 

### 6 DR. WILLIAM POPENDORF: Well I agree in a 

### 7 broad sense with that, but I will provide some comments with 

### 8 regard to the two middle priorities of the urinary biomarkers. 

### 9 Whether TCPy is better than DETP, there's pluses and minuses 

### 10 for both of them, and I think there's logic to put the sequence 

### 11 as he did. 

### 12 TCPy, probably it's biggest strength is that 

### 13 it has a lot of historical value. It's used in other studies 

### 14 so much. But I think the other data that was talked about 

### 15 through the actual amounts of TCPy in the environment, the 

### 16 potential for direct dosing with TCPy is actually 

### 17 quantitatively a lot bigger than the errors or uncertainties 

### 18 associated with DEP. So, if I had the choice, I would put DEP 

### 19 as the second and TCPy as the third. But I think there's no 

### 20 question that chlorpyrifos in blood is number and DAP is number 

### 21 4. 

### 22 DR. KENNETH PORTIER: Thank you. Hopefully

### Page 632 1 we can kind of capture that in the write-up. Dr. Ryan Barry? 

### 2 DR. BARRY RYAN: I'd just like to add to my 

### 3 support to what Dr. Popendorf just said that, you know, the 

### 4 ordering of TCPy versus the explicit DAPs can be problematic. 

### 5 You know. Clearly chlorpyrifos in serum is the way to go. And 

### 6 after that it's a little bit troublesome on what to pick next. 

### 7 I mean TCPy had some other problems associated with it. The 

### 8 dietary intake is one that we mentioned in this. So what the 

### 9 ordering is, I don't think is all that critical. We got the 

### 10 first one; we got the last one. The two guys in the middle, we 

### 11 are not quite so sure about. 

### 12 There was one other point that I wanted to 

### 13 make that I got sidetracked on. Oh, yeah, the longitudinal 

### 14 studies. I just want to reiterate and add some extra emphasis 

### 15 to the need for these longitudinal investigations during the 

### 16 pregnancy itself. 

### 17 What we are seeing really is 1 point, maybe 2 

### 18 points over the course of pregnancy where a measurement of some 

### 19 kind is made, whether it's cord blood, whether it's maternal, 

### 20 whether it's urine, whatever it might be. And of course, we 

### 21 are well aware that chlorpyrifos, in particular, and OPs in 

### 22 general have a biological half-life that's measured in days,

### Page 633 1 not months or years. So if we just happen to hit it, great, we 

### 2 did a good job; we got what we wanted. But there's really no 

### 3 way of knowing if we've gotten that unless we go through and do 

### 4 a longitudinal investigation. 

### 5 And I challenge the women around here to tell 

### 6 me whether it's likely that we could get women to participate 

### 7 throughout their entire pregnancy and give us urine samples and 

### 8 blood samples, say on a two-day cycle or something like that, 

### 9 which is really kind of what we need. Now, more realistically, 

### 10 if we could look at something on the order of a week perhaps 

### 11 would be much more likely to hit any exposures that might be 

### 12 there. 

### 13 It could very well be that we measure a cord 

### 14 blood level or meconium level -- notwithstanding what Dr. 

### 15 Collier is pointing out to us -- or whatever that indicates 

### 16 relatively low levels of exposure, but these may very well be 

### 17 intricative over the entire pregnancy. While one large hit at 

### 18 one time versus a very low level throughout the entire time 

### 19 period could give an entirely different effect, especially if 

### 20 it were at some critical point during the neurodevelopmental 

### 21 progress of a fetus. So I just wanted to add my extra impetus 

### 22 on the longitudinal investigation type idea. That concludes my

### Page 634 1 remarks. 

### 2 DR. KENNETH PORTIER: Dr. Collier? 

### 3 DR. ABBY COLLIER: In response to Dr. Ryan, 

### 4 I'm not speaking for the women on the panel. I am speaking as 

### 5 an investigator that works in pregnancy as well as pediatrics. 

### 6 7 Yes, it is possible to run trials where women 

### 8 are not going to stay on a two-day cycle. We'll give you blood 

### 9 and urine but we'll give you specifically urine across the 

### 10 course of the pregnancy. However, we tend to think about this 

### 11 as an individual-based kind of thing, and it doesn't have to be 

### 12 that way. 

### 13 If you want to think about using like a 

### 14 pharmacokinetic reference point, there's two stage, classical 

### 15 pharmacokinetics where you take medical samples from one 

### 16 person. But instead, we use a population-based study. So if 

### 17 we can collect amniotic fluid and fetal hair and placenta all 

### 18 the way across gestation from women who deliver early or from 

### 19 women who -- all the way across gestation all the way up to 

### 20 term. Then we can develop a population profile within the 

### 21 population we are studying. And those are very, very feasible 

### 22 studies. In fact, I know of a couple that are going on right

### Page 635 1 now in Hawaii in our OBGYN department. 

### 2 So one of the things that I see with using 

### 3 the epidemiology studies as a primary reference point is that 

### 4 Epi studies are fantastic and they tell us a lot about our 

### 5 population. And when we start to talk about some of the more 

### 6 basic science mechanisms we need to use a more basic science 

### 7 approach, like a longitudinal study that's repeatedly sampled. 

### 8 9 And people get stuck on the idea we 

### 10 repeatedly sample a single person. But if we take a 

### 11 population-based approach it can still be reasonably accurate 

### 12 within what its designed to do. Thank you. 

### 13 DR. KENNETH PORTIER: Dr. Buckley? 

### 14 DR. BRIAN BUCKLEY: Yeah. I just want to 

### 15 respond to Dr. Ryan's comments, and actually Dr. Popendorf's 

### 16 too. I completely agree at this stage of the game that the 

### 17 difference between chlorpyrifos in blood as a biomarker and any 

### 18 of the other urinary biomarkers is a huge, huge difference. 

### 19 I would, however, like to re-emphasize a 

### 20 point that I made just in a glancing fashion. I do think 

### 21 there's potential when you start looking at the ratios of some 

### 22 of these guys, DETP to TCPy, and see if we can get some sort of

### Page 636 1 relationship representing a true exposure to chlorpyrifos 

### 2 versus a secondary exposure to TCPy. Because if you're just 

### 3 exposed to TCPy you shouldn't produce DETP. Otherwise, you 

### 4 should have about, essentially, a one to one ratio. And if we 

### 5 can capture both of those, we have the potential, all of a 

### 6 sudden, with things we are already measuring to now do a much 

### 7 better job at differentiating exposure to TCPy versus 

### 8 chlorpyrifos directly itself. So I think there's some promise 

### 9 there. 

### 10 I don't think there's been any studies done 

### 11 it yet. To be honest and reflective of something else, I don't 

### 12 know how much future studies there will be done on it. I don't 

### 13 see this as a hot area at this point in time, and development 

### 14 of new biomarkers may be secondary. 

### 15 Hopefully, there are enough studies out there 

### 16 that this is one of the things that they could tack on without 

### 17 too much trouble. And we'll talk about some of those other 

### 18 studies when we talk about 5.1(b). 

### 19 DR. KENNETH PORTIER: Dr. Ryan? 

### 20 DR. BARRY RYAN: I would just like to add my 

### 21 support to what you've just said, Dr. Buckley, regarding 

### 22 getting both of those at the same time. I think the sum of

### Page 637 1 those two together is far superior to individual things. We 

### 2 would get information about how much TCPy is coming into the 

### 3 body as a degradator in the environment from some other way by 

### 4 looking at exactly that, and I think that's an excellent 

### 5 suggestion you've made. 

### 6 DR. KENNETH PORTIER: One of the questions 

### 7 asked was commenting on the Whyatt paper on the agency's 

### 8 discussion on these biomarkers, and I'm not quite sure I heard 

### 9 the panel's assessment of that. Was that job done well? I 

### 10 mean, I heard a lot of things you suggested but I didn't know 

### 11 if that was critical or supportive, and I need something a 

### 12 little more direct there. 

### 13 DR. BRIAN BUCKLEY: I think that the white 

### 14 paper did a good job describing the principle biomarkers out 

### 15 there and their limitations. I absolutely agree with that. I 

### 16 don't think they placed enough emphasis on looking toward blood 

### 17 measurements of chlorpyrifos. I think that that's something 

### 18 that we as discussants emphasize more greatly and I understand 

### 19 the reason. There weren't so many labs that could do that 

### 20 measure versus the number that could do the measurement of 

### 21 TCPy, so most of what they had to work with in terms of the 

### 22 agency has been based on TCPy measurements and urine as the

### Page 638 1 principle urinary metabolite. 

### 2 And because most of their discussion focused 

### 3 on existing papers and the weight of what was out there, I 

### 4 think they did a reasonable job at covering the bulk of the 

### 5 literature. But it's the use of the one or two papers where 

### 6 they're starting to measure chlorpyrifos in blood should get 

### 7 more emphasis in terms of a true biomarker of exposure. 

### 8 And while they discussed the confounders of 

### 9 the degradate TCBy in the environment, perhaps more focus 

### 10 should've been paid upon that as a serious confounder as 

### 11 opposed to just a recognition that it was one. 

### 12 DR. KENNETH PORTIER: Kind of like to see 

### 13 that assessment in there as well. Dr. Gold? 

### 14 DR. ELLEN GOLD: I'd like to go back to the 

### 15 point about the longitudinal studies during pregnancy, if I 

### 16 could for a moment. There already are existing studies. The 

### 17 National Children's Study, for example, is recruiting women 

### 18 before they become pregnant and following them with a number of 

### 19 biomarkers and certainly collecting samples and 

### 20 neurodevelopmental measures of outcome as well. 

### 21 And we too have studies ongoing in our 

### 22 department for women who become pregnant and have had a prior

### Page 639 1 child, say, with autism. And they've got three different 

### 2 groups. They're not just the high-risk women, but other women 

### 3 to compare them to, and doing serial measures through pregnancy 

### 4 with neurodevelopmental outcome measures. 

### 5 And so, tapping into some of those existing 

### 6 data sources, where maybe all that we needed would be measuring 

### 7 the biomarkers that you're interested in because you probably 

### 8 have a lot of the other data that you would need. So I would 

### 9 encourage the agency perhaps to look into those possibilities 

### 10 because, I think without too much more work, you could answer 

### 11 some other questions you're interested in. Again, I'm not 

### 12 speaking for women at the table though. 

### 13 DR. KENNETH PORTIER: Dr. Vena, do you want 

### 14 to speak for women at the table? 

### 15 DR. JOHN VENA: No. Just to clarify, Brian 

### 16 what you were saying in the last comment about TCPy being a 

### 17 confounder of the measurement of exposure, but I don't see it 

### 18 as that. I see it as a complimentary biomarker of the exposure 

### 19 to the parent compound, so I don't see it as a confounder but 

### 20 as an important exposure measure. Because, what I'm trying to 

### 21 grasp is the metabolism of the parent compound, how quickly it 

### 22 reacts -- you know, we've talked about those flowcharts and

### Page 640 1 where it goes. 

### 2 So when you go to measure these point 

### 3 measurements, it's a snapshot of what's there, so the exposure 

### 4 was there. It's already metabolized. So TCPy gives us a 

### 5 measure of the -- so it seems to me that you have to have both, 

### 6 that you have to have a parent compound and you have to have 

### 7 metabolite, because at one point in time, the parent compound 

### 8 is already metabolized and it's gone to the next phase. So I 

### 9 don't see it as a confounder. It's part of the measure of the 

### 10 total exposure pathway, it seems to me. 

### 11 DR. BRIAN BUCKLEY: The problem is, though, 

### 12 that TCPy is generated in the environment before the ingestion 

### 13 process. So the food that you're eating may contain 

### 14 chlorpyrifos. It may also contain TCPy directly. There's no 

### 15 metabolism done at that point in time. The oxon is not formed 

### 16 in the body. Potentially there's no damage done with the TCPy 

### 17 ingestion at that point in time. 

### 18 So, while you're measuring a total 

### 19 concentration of TCPy, it's two components or that which have 

### 20 done damage or potentially done damage through the oxon 

### 21 metabolism pathway, and that which is degraded in the 

### 22 environment before it's been ingested or inhaled or any other

### Page 641 1 exposure. 

### 2 DR. JOHN VENA: The question I have though is 

### 3 that -- and the reliance on the parent compound and the oxon is 

### 4 that that's what causes the acetylcholinesterase inhibition. 

### 5 But now, what we are talking about is not 

### 6 just acetylcholinesterase inhibition, we are talking about 

### 7 potentially other effects related to whatever exposure 

### 8 parameters are related to the parent compound. 

### 9 So, I guess my question is, is the metabolite 

### 10 -- if we are thinking about the mode of action and all these 

### 11 other effects that aren't related to the acetylcholinesterase 

### 12 inhibition -- is it potentially related to the TCPy? 

### 13 DR. BRIAN BUCKLEY: Right. But the TCPy 

### 14 doesn't represent the parent compound. Now is TCPy in and of 

### 15 itself a potential toxicant, for lack of a better term -- and I 

### 16 don't know that anyone studied that, per se. With all the 

### 17 literature out there, there's got to be some -- someone has 

### 18 looked at TCPy as opposed to just the chlorpyrifos. 

### 19 But because the exposure is not to the parent 

### 20 but to the TCPy directly, unless there's a link between TCPy 

### 21 and the toxicological endpoints that we've discussed, it's 

### 22 exposure doesn't make up part of the risk characterization. I

### Page 642 1 wouldn't think so anyway. 

### 2 DR. JOHN VENA: So the proportion of TCPy in 

### 3 urine -- what proportion would be related to chlorpyrifos 

### 4 related to the other? I guess that's the big question. Seems 

### 5 to me that the majority of it would be related to the parent 

### 6 chlorpyrifos versus these other pesticides. So the key is, if 

### 7 you do have measurements, like what a couple of folks have 

### 8 said, if you do have measurements of everything at the same 

### 9 time, then which I think the Columbia study does is, maybe 

### 10 you'll have a sense of how much of that TCPy is in measure and 

### 11 how sensitive it is to give you a measure of the exposure of 

### 12 the parent compound and as metabolites. That's just my 

### 13 question. I'm not an exposure assessment person but I'm just 

### 14 trying to get my head around this though. 

### 15 DR. BRIAN BUCKLEY: I'm going to turn that 

### 16 question to Dr. Ryan and Dr. Lu, who have actually done these 

### 17 studies and can tell you with greater certainty. 

### 18 19 DR. KENNETH PORTIER: Yeah. I saw Dr. Ryan 

### 20 and Dr. Popendorf kind of shaking their heads and -- "No, no, 

### 21 wait --." So one of you guys have to jump in here. Dr. Ryan? 

### 22 DR. BARRY RYAN: I'll jump off first. The

### Page 643 1 paper that we did in the late 1990s suggested, as much as 90 

### 2 percent of the TCPy that was excreted in urine came from 

### 3 someplace else. That is, if we took into account all of the 

### 4 chlorpyrifos that went into someone's body and we only came up 

### 5 with 10 percent of what came out the back end, I think that's a 

### 6 very, very high estimate. 

### 7 On the other hand, if it's even a third or 

### 8 equal amounts, that would be a significant problem. Those are 

### 9 the type of numbers I've got. But Dr. Lu has done some work in 

### 10 this area. Perhaps he has more recent data. I am currently 

### 11 doing some work in this area but I don't have the data analyzed 

### 12 at this point, so I can't give the numbers for that. 

### 13 DR. KENNETH PORTIER: Dr. Lu? 

### 14 DR. CHENSHENG LU: I was afraid to be 

### 15 considered as kind of self-promoting our paper, but since 

### 16 everybody point to me so I can talk about this. So we did 

### 17 identify this problem way back in early 2000. 

### 18 So we did a study in the laboratory in terms 

### 19 of buying a couple of juices from the supermarket and we take 

### 20 the sample to analyze the so-called environmental degradation 

### 21 portion of the metabolite in the juice. And then we also 

### 22 fortified the juice with known amount of chlorpyrifos and we

### Page 644 1 left the juice in the refrigerator for three days and five 

### 2 days, and then we take juice sample and sent it to the same 

### 3 laboratory for analysis of the degradation, the additional 

### 4 added to it. 

### 5 So anyway, in brief, we found that no matter 

### 6 how long you leave the fortified juice sample in the 

### 7 refrigerator, you always get 30 to 35 percent degradation. 

### 8 It's not a hundred percent. It's not one percent. It's always 

### 9 30, 35 percent degradation. Meaning that there could be just 

### 10 30, 35 percent of TCPy in the environment that actually 

### 11 degraded itself. And the rest of the 65 still remain as a 

### 12 parent compound. 

### 13 So how significant that is? We use a PBPK 

### 14 model, basically it's on a thing called ERDEM, which was peer 

### 15 reviewed all through the SAPs many years ago for carbaryl for 

### 16 the chlorpyrifos. And as you know that chlorpyrifos has 

### 17 abundant data that we can create some kind of PBPK model with 

### 18 great confidence. 

### 19 So we used a another study which is designed 

### 20 to look into the multi-exposure pathway and try to compare the 

### 21 estimated TCPy level to the TCPy that we physically measured in 

### 22 the urine that collect from the same kids in the study. Guess

### Page 645 1 what? The PBPK output, in terms of estimated TCPy, also 35 

### 2 percent higher than we physically measured in the urine sample. 

### 3 4 So I thought that we answered the question in 

### 5 terms of what is the degree of the environmental TCPy and how 

### 6 was that attributed to the dose estimate. So we quickly wrote 

### 7 a paper and published in 2010. 

### 8 DR. KENNETH PORTIER: Okay. I guess that 

### 9 answers that question. Any additional issues? Dr. Pope? 

### 10 DR. CAREY POPE: Dr. Lu, that last comment 

### 11 you made, or set of comments, I was confused whether you were 

### 12 talking about the amount of degradation that you were measuring 

### 13 or the amount of degradate that you were measuring? 

### 14 DR. CHENSHENG LU: I thought that's the same 

### 15 thing. 

### 16 DR. CAREY POPE: You were talking about 

### 17 putting chlorpyrifos in juice and waiting various times and 

### 18 measuring. Were you measuring the breakdown chlorpyrifos or 

### 19 attempting to into TCPy under those conditions, or just kind of 

### 20 like what is the level of the degradate in the juice? 

### 21 DR. CHENSHENG LU: Oh, we measured total 

### 22 amount of TCPy in the juice.

### Page 646 1 DR. CAREY POPE: Uh-huh. Were you expecting 

### 2 to see that chlorpyrifos was producing TCPy during those times? 

### 3 DR. CHENSHENG LU: Well that's what we 

### 4 suspect. The exposure data suggest that there is a known 

### 5 amount of TCPy is degradated itself in the environment or in 

### 6 food, and that's why we went to investigate that magnitude. 

### 7 DR. KENNETH PORTIER: Dr. Ryan? 

### 8 DR. BARRY RYAN: Just to address that same 

### 9 issue. I have a doctorial student who just finished up and her 

### 10 work was to look at various different types of foods and look 

### 11 at both at the same time. 

### 12 We spiked chlorpyrifos and a number of other 

### 13 things into the food, measured their degradation of the 

### 14 chlorpyrifos and the simultaneous increase in TCPy. So we are 

### 15 actually getting some of the kinetics back out, and our studies 

### 16 were done over a period of about two weeks in relatively simple 

### 17 matrices ranging from water up to orange juice, was probably 

### 18 the most complex matrix we have. 

### 19 We are also looking at data in other types of 

### 20 food, looking at the degradate versus a parent compound for a 

### 21 series of these things. Those data, you know, they're not 

### 22 published at this point. She's finished her doctorate so

### Page 647 1 she'll write the papers over the next couple of months and 

### 2 we'll submit them, but they're not available at this point. 

### 3 DR. CAREY POPE: It's kind of cyclical to me 

### 4 thinking like that, but yesterday someone presented some data 

### 5 about TCP being used in the field as opposed to the relative 

### 6 amounts of chlorpyrifos. Yes. And it looked like really good 

### 7 data, I mean, down to the pounds in a particular -- was at 

### 8 Selena Valley (phonetic) or -- that's very informative data. 

### 9 And the information I was commenting on was 

### 10 from an EPA publication 2011 that is more general and less down 

### 11 to the pounds. But it talks about triclopyr relative to 

### 12 chlorpyrifos. This is the group work of 2011. 

### 13 And they talk about roughly 17 to 44 percent 

### 14 on the nation basis of relative amounts of triclopyr compared 

### 15 to chlorpyrifos. So while it looks like it's predominantly 

### 16 chlorpyrifos in that dataset, around the country it looks like 

### 17 it's much more chlorpyr relative to chlorpyrifos being used. 

### 18 So this doesn't address degradation in food 

### 19 products, but just the application of triclopyr nationwide and 

### 20 other places besides Selena Valley. 

### 21 DR. KENNETH PORTIER: Dr. Lu? 

### 22 DR. CHENSHENG LU: Since we are on this

### Page 648 1 subject, although it kind of, somewhat, deviates what we are 

### 2 supposed to discuss, but I just want to emphasize or alert the 

### 3 panel, is that, even though the presence of environmental 

### 4 degradate TCPy or DEPs has been talked about for a long time, 

### 5 but we don't really have a systematic way to investigate it. 

### 6 And I have to say this; there is a great 

### 7 possibility -- I'm not discounting other investigator's papers 

### 8 that's published, but I have to alert that there is a great 

### 9 possibility -- when you are using the same method aiming to 

### 10 analyze either chlorpyrifos or other organophosphate there is a 

### 11 chance that an analytical method itself could degrade the 

### 12 parent compound to either TCPy or DEP. So that's why there is 

### 13 some discrepancy reported in the literature in terms of one 

### 14 paper published that is 95 percent of the degradation product 

### 15 in the samples. But the questions is that they never reported 

### 16 whether the analytical method itself degrade the parent 

### 17 compound in the process of laboratory analysis. 

### 18 So in our juice study, we actually spent 

### 19 almost a month to develop a method specifically for that 

### 20 purpose. And we have a great confidence that the method itself 

### 21 will not degrade parent compound to TCPy in the laboratory. So 

### 22 I think, again, there is a void in the science in terms of

### Page 649 1 whether the data that's reported are true or valid. 

### 2 DR. KENNETH PORTIER: We are handing out the 

### 3 slides that Dr. Dawson presented yesterday and I think that 

### 4 includes the data. Dr. Buckley? 

### 5 DR. BRIAN BUCKLEY: Just to address Dr. Lu's 

### 6 last comment. One would hope that the analytical laboratory 

### 7 would do the necessary spikes to ensure that they don't get 

### 8 compound degradation during sample preparation. There are ways 

### 9 to safeguard, but all labs don't do that. You are absolutely 

### 10 right. And that safeguard should be in place in any analysis 

### 11 to make sure that the degradation product is not the one that's 

### 12 actually measured or created, more importantly, during the 

### 13 sample preparation process. 

### 14 DR. KENNETH PORTIER: Dr. Sandy? 

### 15 DR. MARTHA SANDY: Can I ask a question since 

### 16 we are on to degradation? Is it anything known about the 

### 17 stability of DEP in samples? 

### 18 DR. KENNETH PORTIER: Who's going to jump in 

### 19 on this one? Dr. Buckley? 

### 20 DR. BRIAN BUCKLEY: I'll offer and say that, 

### 21 all of these compounds have sort of -- I hate to call it this, 

### 22 but sort of platforms stability. A lot has to do with how the

### Page 650 1 samples are maintained throughout the process. 

### 2 Photo degradates are always possible. 

### 3 Thermal degradates are always possible. DETP/DEP are sort of 

### 4 that next plane of stability that we think, as long as the 

### 5 samples are reasonably well-preserved you're not going to have 

### 6 an issue in terms of degradation. 

### 7 Having said that, I can make almost anything 

### 8 degrade just by treating it improperly, and you never know. 

### 9 Dr. Popendorf, I think, is probably going to offer comments. 

### 10 DR. WILLIAM POPENDORF: It was kind of an 

### 11 elaboration on the question because I think you were referring 

### 12 to -- I know my interest was just -- once it's formed in the 

### 13 environment, particularly if it's on surfaces and such, how 

### 14 stable would it be there? Not in a sample but just in the 

### 15 environment, home environment, workplace environment, possibly 

### 16 even in an agricultural environment. 

### 17 DR. BRIAN BUCKLEY: Are we talking about TCPy 

### 18 or DETP? 

### 19 DR. WILLIAM POPENDORF: It could be both. 

### 20 But I guess TCPy in particular, yeah. 

### 21 DR. BRIAN BUCKLEY: I think TCPy is pretty 

### 22 stable in the environment relative to other environmental --

### Page 651 1 it's more stable obviously than chlorpyrifos. 

### 2 DR. KENNETH PORTIER: Than DEP? 

### 3 DR. BRIAN BUCKLEY: DETP, I'm not aware of 

### 4 great environmental concentrations of this stuff. It's not the 

### 5 degradate product, as I understand it. It's a metabolite, 

### 6 which is a different process. 

### 7 DR. KENNETH PORTIER: Dr. Sandy? 

### 8 DR. MARTHA SANDY: My question was 

### 9 specifically stability of DEP in urine. 

### 10 DR. BRIAN BUCKLEY: It's one of the stable 

### 11 metabolites that we monitor pretty routinely. We try and 

### 12 preserve all samples because they, like everything else, things 

### 13 do degrade. But it is one of the more stable metabolites that 

### 14 we measure in urine. 

### 15 DR. KENNETH PORTIER: Dr. Lu? 

### 16 DR. CHENSHENG LU: I think one of the three 

### 17 cohort studies actually attempt to measure the stability of 

### 18 DEPs in their urine sample. And either they publish in the 

### 19 paper or make a presentation. I will not come up just without 

### 20 any evidence. I would look for it. 

### 21 But, again, going back to the degradation 

### 22 issue; I'm afraid that this magnitude of environmental

### Page 652 1 degradation of organophosphate pesticide has been blown out of 

### 2 proportion. 

### 3 Remember, the chemical will not degrade by 

### 4 themselves spontaneously. It has to be either through 

### 5 enzymatic metabolites or through hydrolysis in this case. It 

### 6 has to be one or both. It's almost impossible, say, you put a 

### 7 chlorpyrifos in the air and then you would just degrade it by 

### 8 itself. If that's the case, then what's the use of this 

### 9 chlorpyrifos for insect control? 

### 10 Again, that's what I'm saying. I have great 

### 11 doubt in seeing degradation in the air sample. Because if 

### 12 that's the case, then why we use chlorpyrifos to kill mosquitos 

### 13 and so on. 

### 14 Again, I'm not saying that our paper is a 

### 15 bible in this subject. But I think that magnitude, in terms of 

### 16 how much organophosphate can be degraded in the environment has 

### 17 been brought out of proportion. 

### 18 DR. KENNETH PORTIER: Dr. Buckley. 

### 19 DR. BRIAN BUCKLEY: To follow-up with Dr. Lu 

### 20 and place emphasis again, I agree. And we haven't looked at 

### 21 food products as much as anything else. But, you know, if it's 

### 22 35 percent we can count for, great. But when we did work back

### Page 653 1 in the 90s on application of the dorms, we were measuring 

### 2 chlorpyrifos readmission weeks after application, so it had not 

### 3 degraded to an extent that it was beyond measurement. In fact, 

### 4 it was quite stable and could be measured. So post 

### 5 application, it is stable for weeks. 

### 6 Having said that, you know, I don't know what 

### 7 the relative contributions of dose are, although it sounds like 

### 8 35 percent, roughly, is what you might get from an ingestion. 

### 9 DR. KENNETH PORTIER: And I think you finally 

### 10 came back to Dr. Vena's original question which had to do with 

### 11 intake, proportional intake. 

### 12 DR. JOHN VENA: Yes, but also I think it was 

### 13 a really good discussion to put into context the ranking of 

### 14 these biomarkers and how they'll be used and how they can be 

### 15 used in the context of these risk assessment procedures, et 

### 16 cetera, so this was helpful. 

### 17 DR. KENNETH PORTIER: Okay. I think at this 

### 18 point, we are going to go ahead and break for lunch. It's noon 

### 19 by this clock. We'll break for an hour. I'm not finished with 

### 20 this question. We'll come back and make sure we've got all the 

### 21 finished ideas before we move on to 5.2. 

### 22 (Lunch Break)

### Page 654 1 DR. KENNETH PORTIER: Let's continue the 

### 2 discussion on Question 5, Exposure Profile and Biomonitoring 

### 3 Research. I want to remind everybody who's dialed in, it turns 

### 4 out that we can't mute you out. You have to mute yourself. So 

### 5 please use *6 at this point to mute the line so we don't hear 

### 6 your breathing in the background. Thank you. 

### 7 Let's see. Dr. Buckley, you said you had a 

### 8 comment you wanted to make on 5.1a, as a continuation of the 

### 9 discussion? 

### 10 DR. BRIAN BUCKLEY: Yes. As a continuation 

### 11 of the discussion, I was asked about the degradation rates of 

### 12 the two potential degradates, DETP and chlorpyrifos in the 

### 13 environment. And I said I didn't recall any real studies on 

### 14 those and did a literature of lunch rather than eat lunch, and 

### 15 did not find anybody who studied the degradation of the 

### 16 degradates. 

### 17 So if we are able to use ratios of say, DETP 

### 18 to TCPy, we are going to have to have a better understanding of 

### 19 the degradation rates of the degradates in the environment. 

### 20 And looking at the molecules, I mean, I would believe there 

### 21 would be an inherent difference in those two, which would lend 

### 22 itself still, to potential use of the ratios to at least, you

### Page 655 1 know, predict exposure to the active as opposed to the 

### 2 degradate. But it's a more convoluted process at this point in 

### 3 time. 

### 4 DR. KENNETH PORTIER: Thank you, any 

### 5 additional comments on 5.1a? Dr. Popendorf, you had mentioned 

### 6 something? 

### 7 DR. WILLIAM POPENDORF: Yes, just to clarify 

### 8 when we were discussing the cholinesterase methods and their 

### 9 variability. We will provide some references on that. 

### 10 DR. KENNETH PORTIER: And then during the 

### 11 lunch break, Dr. Lu had a one page from an Environmental Health 

### 12 Perspectives paper copied out with some diagrams? Dr. Lu, did 

### 13 you want to say anything about this? 

### 14 DR. CHENSHENG LU: All this is pertaining to 

### 15 question 5.2. 

### 16 DR. KENNETH PORTIER: Then we'll get on to 

### 17 that. Okay. So why don't we move on to 5.1B? Go ahead and 

### 18 read the question. 

### 19 LIEUTENANT AARON NIMAN: Section 5 of the 

### 20 draft issue paper compares biomonitoring findings from the 

### 21 three children's health cohorts with other major observational 

### 22 exposures studies in the United States. Based on comparison

### Page 656 1 with NHANES 2001-2002, median TCPy levels in the CHAMACOS and 

### 2 Mount Sinai cohorts were slightly higher than the general 

### 3 population. It should be noted that exposures experienced by 

### 4 CHAMACOS and Mount Sinai cohorts overlapped the start of the 

### 5 residential chlorpyrifos phase-out. By contrast, median TCPy 

### 6 levels in the Columbia cohort, for which sampling occurred when 

### 7 chlorpyrifos use should have rapidly declined due to voluntary 

### 8 cancellation, were slightly lower than the levels measured by 

### 9 NHANES in the general population. Please comment on the 

### 10 adequacy of the Agency's comparison for the purposes of 

### 11 evaluating chlorpyrifos exposure levels in the three children's 

### 12 health cohorts. Are there any additional biomonitoring studies 

### 13 that should be included in the Agency's comparison? 

### 14 DR. KENNETH PORTIER: So Dr. Buckley, I see 

### 15 two questions here. A comment and anything additional. 

### 16 DR. BRIAN BUCKLEY: The studies discussed in 

### 17 this section are the best available and by consequence we 

### 18 believe that the EPA did a good job, at least evaluating those 

### 19 studies, and as a starting point for their criticality, or 

### 20 critical analysis of the larger risk component. They do, 

### 21 however, look at specific types of exposure: agriculturally 

### 22 based exposure, and exposures in city dwelling units likely

### Page 657 1 treated for insects on a regular basis. 

### 2 Further they span a range of times when 

### 3 chlorpyrifos use was ubiquitous through the phase out of indoor 

### 4 uses of the insecticide. Because of this, there are 

### 5 inconsistencies in the data, but these inconsistencies really 

### 6 are indicative of change of use patterns. Current use in 

### 7 indoor settings is dominated by parathyroid's, rather than 

### 8 chlorpyrifos. 

### 9 Agricultural settings, however, are still 

### 10 likely to see large exposures to chlorpyrifos. And that's 

### 11 important for a lot of the considerations of future 

### 12 populations, and evaluations of concentrations and exposure 

### 13 risk. 

### 14 There appears to be inconsistent recognition 

### 15 in this change, especially in light of the comparison with 

### 16 group norms, for example, the NHANES studies. 1999-2000 

### 17 NHANES, will indicate higher exposures to chlorpyrifos in 

### 18 residential settings than later data. But that should be to no 

### 19 one's surprise. 

### 20 Now with that in mind, we believe the next 

### 21 NHANES data set may be the most important, and is likely to 

### 22 reflect the decrease in exposure caused by the voluntary

### Page 658 1 removal from the home market. If the levels progress in a 

### 2 manner similar to those predicted by the decrease demonstrated 

### 3 in the Columbia study, the risk from chlorpyrifos may decline 

### 4 as rapidly. 

### 5 Even if this is true, chlorpyrifos is a model 

### 6 compound for a risk paradigm that includes EPI Dose 

### 7 reconstruction, PBPK modeling and exposure dose symmetry, 

### 8 requires a much broader consideration of the studies. The 

### 9 agency seemed to concentrate on studies that include a reported 

### 10 health outcome and we wonder why these studies were the 

### 11 principal focus, as many studies provide data on exposure and 

### 12 dose, but weren't the principal focus. 

### 13 For example, to be protective the agency 

### 14 should consider the NHEXAS study, because it represents the 

### 15 highest level at exposure and may contribute, or continue to 

### 16 represent direct or indirect agricultural exposure. And this 

### 17 sort of speaks to some of the general impressions that we got, 

### 18 which was chlorpyrifos may be a model compound in the sense 

### 19 that there is so much data available, relatively speaking. 

### 20 Now, clearly we spent the last day and a 

### 21 half, two days decrying how much data we don't have at this 

### 22 point in time. But relatively speaking, there are few

### Page 659 1 environmental agents that we have more data on. So if you're 

### 2 going to use all of the tools in the toolbox, the Epi data, the 

### 3 PBPK data, et cetera, et cetera, chlorpyrifos is not a bad 

### 4 model compound to work with. 

### 5 But because of that we think that you should 

### 6 use as much data as possible and not just focus on the data 

### 7 that's reflective of studies that provide outcomes for human 

### 8 health. And by that I mean, you've got data -- many studies 

### 9 that have measurement of environmental matrices, as well as 

### 10 urinary concentrations of the metabolites. 

### 11 And if you're going to do a dose 

### 12 reconstruction or the dose symmetry model based on those -- and 

### 13 we think that that's important -- then those studies should be 

### 14 included too. 

### 15 Many of the studies listed in the draft 

### 16 paper, but not directly discussed should be considered when 

### 17 establishing dose and subsequently risk. The New Jersey 

### 18 studies where cord blood measurements were used as the 

### 19 principal sample type is important, because there's likely to 

### 20 be a desirable biomarker and studies more frequently in the 

### 21 future. 

### 22 Farm worker studies are important, because

### Page 660 1 the farmer -- because their families are likely to be the ones 

### 2 of the remaining populations that see significant exposure. 

### 3 Again, to be validated by the next round of NHANES data. So 

### 4 you may see the general population across the country drop in 

### 5 terms of their metabolite level, but the farm worker families, 

### 6 or families near agricultural areas may remain high. 

### 7 The CPS study by Lu and CPPAES studies are 

### 8 important, because they provide data on multiple exposure 

### 9 vehicles media and will be especially useful in does 

### 10 reconstruction. Dose reconstruction will be paramount in 

### 11 validating PBPK models to be subsequently discussed. Among the 

### 12 current the studies that are those that look at both the 

### 13 urinary concentration and the media where the exposure is 

### 14 likely to occur, will provide the best models for closing the 

### 15 knowledge gap between exposure and dose. And studies where 

### 16 urine was collected within one half-life after a fresh exposure 

### 17 may provide the most useful information. 

### 18 Knowing when the exposure -- or knowing when 

### 19 they application of the pesticide occurred, is going to be key 

### 20 in any PBPK modeling, in any exposure dose reconstruction, et 

### 21 cetera, because you at least know the degradation rate of the 

### 22 pesticide; you know potentially the PBPK behavior.

### Page 661 1 Although not ready for this report, studies 

### 2 are now underway that are longitudinal in design affording a 

### 3 better understanding of actual exposure profiles when compared 

### 4 to cross sectional approaches. Due to the short biological 

### 5 half-lives of the metabolites of chlorpyrifos in the body, a 

### 6 spot check of a relatively small number of people may not give 

### 7 a good indication of the fraction of individual's exposure at 

### 8 some important level over the longest period. Say a year. 

### 9 Only a longitudinal investigation can get at this important 

### 10 data. 

### 11 Several new studies have been completed and 

### 12 will be published in the near future that are of interest to 

### 13 this group. The Children's Pesticide Exposure Study, lead by 

### 14 Dr. Alex Lu of Harvard School of Public Health, focuses on 

### 15 dietary intake of children and the related pesticide exposure. 

### 16 The Children Exposure to Environmental 

### 17 Pesticides, by Dr. Barry Ryan of Emory University, evaluates 

### 18 the utility of biomarkers of pesticide exposures. DAPs and 

### 19 pesticide specific markers of OPI and parathyroid exposure's 

### 20 environmental levels measured in soil, house dust, and food. 

### 21 Once again, getting back to the notion that we need that whole 

### 22 loop, not just what's in the body, but what the environment is

### Page 662 1 that's providing those exposures. And that will help us do the 

### 2 dose reconstruction. 

### 3 Dr. Stanebar (phonetic) and Barry Ryan of 

### 4 Emory University and Dr. Tapanawan (phonetic) of Chiang Mai 

### 5 University of Northern Thailand, examined pesticide biomarker 

### 6 concentrations in pregnant mothers and similar markers in their 

### 7 newborn children. Multiple measurements in both urine and 

### 8 serum had been made throughout pregnancy, giving a better 

### 9 longitudinal picture of exposure. 

### 10 Several smaller investigations are underway, 

### 11 designed to evaluate direct intake of pesticide degradates and 

### 12 to evaluate the kinetics of the degradation process in the 

### 13 environment, including food. That's going to be key in 

### 14 understand whether, or not the degradates themselves can be 

### 15 used as biomarkers. 

### 16 Data quality of some of the studies have been 

### 17 called into question due to the apparent changes in the limits 

### 18 of the detection associated with two methods used to evaluate 

### 19 serum chlorpyrifos concentrations, as developed by the CDC. 

### 20 The questions arise due to misunderstandings of the methods. 

### 21 There's an apparent 20-fold difference in the 

### 22 LODs (phonetic) between the two methods, and this can be

### Page 663 1 accounted for in three ways. First, the newer method uses a 

### 2 sample size of one half as large and the older method injects 

### 3 twice as much, thereby accounting for a factor of four 

### 4 differences in LODs. 

### 5 Second, although both methods are 

### 6 multi-contaminant, the newer method spans a much larger range 

### 7 of anolyte polarities. In order to obtain adequate recoveries 

### 8 for some of the less polar compounds, there's likely some 

### 9 sacrifice in sensitivity towards the more polar compounds, such 

### 10 as chlorpyrifos. 

### 11 The reason we are bringing this in is, as we 

### 12 start to evaluate exposure data and dose reconstruction, the 

### 13 ability to evaluate study to study and concentration to 

### 14 concentration, and studies where you have lots of non-detects 

### 15 versus lots of measured concentrations, are all going to be 

### 16 dependant upon and understanding of the methods used to perform 

### 17 the analysis. 

### 18 And it's those cross validations in comparing 

### 19 studies to study that are going to give you the most 

### 20 information in terms of whether, or not a biomarker is 

### 21 effective based on its ability to be quantified, or the percent 

### 22 detects.

### Page 664 1 DR. KENNETH PORTIER: Thank you. Dr. 

### 2 Collier? 

### 3 DR. ABBY COLLIER: I have nothing further to 

### 4 add at this time. Dr. Buckley summarized what we discussed 

### 5 nicely. 

### 6 DR. KENNETH PORTIER: Dr. Lu? 

### 7 DR. CHENSHENG LU: I have nothing to add 

### 8 either. Thanks. 

### 9 DR. KENNETH PORTIER: Dr. Ryan? 

### 10 DR. BARRY RYAN: All I would like to add is, 

### 11 Dr. Gold brought up earlier today a National Children's study 

### 12 as being one that may be providing useful information. The 

### 13 only problem I have with a National Children's study is we are 

### 14 not quite sure what kinds of things are going to be collected 

### 15 in that study in terms of biomarkers, environmental samples and 

### 16 so on. 

### 17 If indeed all of the things that we want to 

### 18 have collected are collected, I think that'll be an excellent 

### 19 study to follow. We'll see the kids from pregnancy until age 

### 20 21 and that is really what we want. We want that type of 

### 21 longitudinal investigation. Unfortunately, I think in the 

### 22 National Children's study the current protocols call for really

### Page 665 1 snap shots at relatively, widely, spaced time spans over the 

### 2 lifetime of the child. 

### 3 DR. KENNETH PORTIER: Anyone else want to add 

### 4 to this? So Dr. Buckley, as you right this up do you envision 

### 5 a priority on these additional studies, where EPA might get the 

### 6 most bang for their buck out of participation? Can you see 

### 7 adding that in? 

### 8 DR. BRIAN BUCKLEY: We'll certainly make an 

### 9 attempt. I think both the studies that we -- well, I think 

### 10 NHANES is going to be paramount obviously. It will tell us 

### 11 where our benchmarks are. But in terms of understanding the 

### 12 mechanism and looking for more of the criteria that we are 

### 13 looking for, I think the studies that we outlined -- both by 

### 14 Dr. Ryan and Dr. Lu -- are the types of studies that will 

### 15 provide a great deal of information. 

### 16 Whether or not EPA decides to take on dose 

### 17 reconstruction as a validation tool -- and we recommend that 

### 18 they do -- they may have a lot of the studies that they need 

### 19 for that. But I do believe the studies by Dr. Ryan and Dr. Lu 

### 20 are both going to provide a lot more of the information, but 

### 21 we'll have that reflected in a report. 

### 22 DR. KENNETH PORTIER: Any additional

### Page 666 1 comments? Dr. Lowit do you have any -- I mean I thought this 

### 2 was -- 

### 3 DR. ANNA LOWIT: No. That was a very clear 

### 4 answer. Thank you. 

### 5 DR. KENNETH PORTIER: Very good. Now we get 

### 6 to move on to question 5.2. 

### 7 LIEUTENANT AARON NIMAN: In Section 5.0 of 

### 8 the draft issue paper, the agency summarized the 2008 

### 9 preliminary findings on the association between urinary TCPy 

### 10 levels and acetylcholinesterase and butyrylcholinesterase 

### 11 inhibition and discussed two recent studies involving 

### 12 manufacturing workers in the U.S. and Egypt. 

### 13 Please comment on the scientific quality of 

### 14 these studies and their findings. Please include a discussion 

### 15 of their strengths and limitations. Please comment on the 

### 16 strengths and limitations of the evidence from this research to 

### 17 show an association between TCPy and acetylcholinesterase and 

### 18 butyrylcholinesterase inhibition at exposure levels experienced 

### 19 by occupational populations. 

### 20 DR. KENNETH PORTIER: Dr. Popendorf? 

### 21 DR. WILLIAM POPENDORF: Though I don't have 

### 22 my comments as finally written as some of the prior

### Page 667 1 respondents, but I think I have a lot of things to say. And 

### 2 I'd like to start with the Farahat study before going on to the 

### 3 Garabrant study. 

### 4 Both of these were occupational exposure 

### 5 studies, observational in nature. I think, from their positive 

### 6 side, both of them had a relatively large number of 

### 7 participants which, for an observational type study of this 

### 8 nature -- although compared to the Epi studies, I'm sure that 

### 9 would present a different perspective, because we are talking 

### 10 about 38 in the Farahat study in Egypt and 53 exposed in the 

### 11 manufacturing study. 

### 12 And I think from a broad perspective, these 

### 13 two studies provide very good justification for the PBPK 

### 14 models. That's probably their biggest value, because I think 

### 15 they are both exposures that are well beyond those that are 

### 16 applicable to the children and home exposures that we've been 

### 17 talking about. 

### 18 So what I'd like to do is just walk through 

### 19 some of the strengths and most of the weaknesses of the two 

### 20 studies. If I had a graph, I think there's a lot of parallels 

### 21 of their strengths and weaknesses. 

### 22 So again, I'll begin with the Farahat study

### Page 668 1 which involved 14 chlorpyrifos applicators. These are hand 

### 2 applicators walking through cotton fields applying 

### 3 chlorpyrifos, along with 24, sort of what they call engineers 

### 4 and technicians that are also getting exposed by not directly 

### 5 handling it. 

### 6 On the plus side, they were getting high 

### 7 exposures, which is easier to measure. And I think that they 

### 8 are also fresh chlorpyrifos, which probably means low levels of 

### 9 background TCPy, which would eliminate some of that 

### 10 contribution. 

### 11 The doses were high enough to illicit 

### 12 acetylcholinesterase responses. I mean, half of these folks -- 

### 13 there is a 210 article as well, which is a little more 

### 14 descriptive of the process that these -- you know, half of the 

### 15 applicators were walking through these fields barefooted. It's 

### 16 okay to do in cotton, I guess, but we certainly wouldn't -- you 

### 17 know, provide some high levels of exposures; the foliage in 

### 18 front of them and walking through the wet foliage, so you can 

### 19 imagine the levels. 

### 20 On the downside, that particular study had 

### 21 high levels of pre-exposure background of both TCPy -- and they 

### 22 took their cholinesterase measures before the official spring

### Page 669 1 season, but the high background of TCPy, which is about five 

### 2 times the level that we are going to see in the manufacturing 

### 3 workers means that there was a lot of prior exposure, which 

### 4 maybe has some pluses. They may have been closer to steady 

### 5 state than you might've otherwise expected because they were 

### 6 working for roughly two weeks, anywhere from 9 to 17 days of 

### 7 application. 

### 8 The urine samples ended up being mostly 

### 9 morning voids, which some of the Dr. Lu's results suggest that 

### 10 that's not the best time to collect a sample. But again, 

### 11 they're probably in steady state, so maybe that's not as bad as 

### 12 some of the other researchers have found. 

### 13 They took four blood samples within 30 days, 

### 14 but there was no unexposed control group for the blood sampling 

### 15 work. So the concerns about the run-to-run analyses of 

### 16 cholinesterase that we mentioned earlier should've affected 

### 17 these people. 

### 18 On the other hands, the cholinesterase 

### 19 results, some of these people had very high exposures and 

### 20 supposedly, looking at TCPy versus both butyrylcholinesterase 

### 21 and acetylcholinesterase, fairly good correlations. And 

### 22 interestingly, they did not report change in cholinesterase.

### Page 670 1 They reported actual cholinesterase activities. Probably 

### 2 reflects some of their baseline. They didn't really discuss 

### 3 why they didn't show change. They just showed valued compared 

### 4 to sort of the normal, if you will, of what they described as 

### 5 their background range. And they had one person down to 90 

### 6 percent ACH inhibition or below. The rest of the group 

### 7 reported no symptoms, which is interesting. 

### 8 Nonetheless, those results did fit the -- 

### 9 well, they didn't use the PBPK but they did have a similar 

### 10 pattern. In fact, the handout that we got -- I think Dr. Lu's 

### 11 going to talk about -- you can see the bimodal relationship 

### 12 with an inflection point that he'll address. 

### 13 And perhaps not surprisingly, both the TCPy 

### 14 and butyrylcholinesterase remain high for another 8 to 10 days, 

### 15 as far as they track these people afterward. Maybe that's not 

### 16 too surprising for those levels of exposure. And again, it 

### 17 might reflect continuing exposures outside of that study. 

### 18 The other large plus that I mentioned in the 

### 19 beginning is that the pattern of both butyrylcholinesterase and 

### 20 acetylcholinesterase match the kinds of expectations that you 

### 21 would expect from the PBPK model and I think that's very, very 

### 22 encouraging.

### Page 671 1 So overall it's interesting. If you 

### 2 understand what Lawrence of Arabia, he liked the desert because 

### 3 it's clean. And I wouldn't call this a clean study but it's 

### 4 interesting. 

### 5 The Garabrant study was a 2009, again, 

### 6 observational in nature. 53 manufacturers of chlorpyrifos, 60 

### 7 controls saran (phonetic) manufacturers studied over one year 

### 8 sort of as an opportunity of convenience with an ongoing 

### 9 occupational health monitoring. 

### 10 The background chlorpyrifos, again, contained 

### 11 high TCPy values because those workers were already being 

### 12 exposed. And in those cases, their exposures were high enough 

### 13 to elicit a change in butyrylcholinesterase but not in terms of 

### 14 acetylcholinesterase. 

### 15 One of the weaknesses of that study was their 

### 16 baseline blood values were supposedly pre-exposure since these 

### 17 were employees in a plant that -- they didn't state how long 

### 18 they gave the age of the participants, but not how long they'd 

### 19 been working there, so there's no telling how long those 

### 20 pre-exposure blood samples were taken. It could've been years. 

### 21 They really didn't have any other pre-exposure opportunities 

### 22 in that study.

### Page 672 1 Urine samples, again, morning; it's really 

### 2 only three samples collected. The urine samples and blood 

### 3 samples weren't exactly matched. And they chose urine samples 

### 4 that matched within seven days of the blood sample being taken, 

### 5 and so there's definitely some temporal disconnect between 

### 6 urine and bloods. The bloods were being collected as part of 

### 7 an ongoing occupational health survey. 

### 8 Again, there was no indication that, although 

### 9 they had that referenced population, the blood samples were not 

### 10 being used to matched their laboratory methods. And if you 

### 11 look at the variance and their cholinesterase of the controls, 

### 12 they were seeing some very high variations in 

### 13 acetylcholinesterase indicative of the method. 

### 14 Again, the fact that they weren't using it to 

### 15 control -- and what one does in the older studies -- and 

### 16 somehow we seem to know about that 20/30 years ago, but have 

### 17 forgotten that if you're going to do this kind of study, you 

### 18 use controls that are unexposed and don't even live in the same 

### 19 area, don't work in the same area. You collect their blood, 

### 20 analyze it intermixed with the exposed group, and you'll see 

### 21 the day-to-day or run-to-run changes in the cholinesterase. 

### 22 And you adjust the values of your exposed group to reflect the

### Page 673 1 changes in the unexposed. And that's how it should be done, 

### 2 and most of these studies don't do that, which is okay. You 

### 3 know. It's designed for a clinical diagnostic tool and it 

### 4 works fine for that. But when you're trying to measure 10 

### 5 percent or less, it gets somewhat unreliable. 

### 6 The other negative was there method for 

### 7 butyrylcholinesterase. That was the only real change that they 

### 8 found in terms of cholinesterase inhibition was on 

### 9 butyrylcholinesterase side. And they were using a -- I think 

### 10 that was a -- yeah, they were using a proprietary kit for that 

### 11 and, again, had a lot of variation. 

### 12 The ongoing occupational health program, a 

### 13 person would be -- there would be at least some investigation. 

### 14 They would be withdrawn from exposure, beginning at the 20 

### 15 percent butyrylcholinesterase inhibition. So during the year's 

### 16 time, 43 percent of the exposed group were pulled out from 

### 17 that, but 13 percent of the saran manufacturers also had a 20 

### 18 percent butyrylcholinesterase response. That's really -- and I 

### 19 think mostly indicative of the method and its variability. From 

### 20 a business case perspective, I think they really should look at 

### 21 what they're doing. They're probably a good portion of the 43 

### 22 percent. The exposed may not be really showing a real change

### Page 674 1 either. 

### 2 But again, the butyrylcholinesterase 

### 3 inflexion point, very similar to the Farahat study. The 

### 4 Garabrant study used the PBPK, the Timchalk PBPK model. The 

### 5 model pretty much paralleled the results and they both had an 

### 6 inflection point at the same, roughly 110 micrograms of TCPy 

### 7 per gram of urine adjusted for creatinine. So taken together, 

### 8 they both really do support that PBPK model. 

### 9 Beyond that, I think there are some 

### 10 significant methodologic issues if you try to use it too 

### 11 quantitatively. But the overall pattern -- again, I mentioned 

### 12 PBPK several times before. I think it supports the whole chain 

### 13 of events from in vivo, in vitro back on up to these types of 

### 14 human exposures. 

### 15 DR. KENNETH PORTIER: Okay. Dr. Buckley? 

### 16 DR. BRIAN BUCKLEY: I agree with everything 

### 17 that Dr. Popendorf said and I'm just going to add a few 

### 18 comments and observations about the studies. 

### 19 I think that this is as close as we'd be able 

### 20 to get to a human study mimicking the 1984 study. We couldn't 

### 21 do that anymore where people are just voluntarily ingesting 

### 22 chlorpyrifos. So in terms of in starting a PBPK model, you go

### Page 675 1 from -- at least the first time this season or whatever, you go 

### 2 from little or no exposure to this massive exposure and then 

### 3 it's how your body deals with it. 

### 4 I caution, though, two things. First, the 

### 5 Egyptian study. The concentrations were so much higher -- well 

### 6 they were higher enough than the U.S. study that I'm not sure 

### 7 how relevant they are to a lot of the risks that we are 

### 8 considering here. These are folks that had a huge exposure. 

### 9 And I don't think there's a lot of discrepancy about health 

### 10 effects above that acetylcholinesterase inhibition line. 

### 11 I think that, primarily, where all of the 

### 12 discussion is centered is in that region below, and whether or 

### 13 not there are health effects or risks that need to be 

### 14 considered. 

### 15 I also will caution that both of these 

### 16 studies, I think, are probably appropriate for PBPK models of 

### 17 adult men. And I don't think that we can create one PBPK model 

### 18 and have it applicable to all of the populations that we are 

### 19 considering when we are considering risks. And we talk a 

### 20 little bit further about this in 5.4. But there are vulnerable 

### 21 populations that a PBPK model derived for adult farm workers, 

### 22 or whatever, probably not appropriate for small children or

### Page 676 1 pregnant women. And I think that that's something that needs 

### 2 to be noted, that one size probably does not fit all in terms 

### 3 of the PBPK models. 

### 4 DR. KENNETH PORTIER: Dr. Collier? 

### 5 DR. ABBY COLLIER: I agree with Dr. Popendorf 

### 6 and also Dr. Buckley. And he took the words right out of my 

### 7 mouth about one-size fits all models, so thank you. 

### 8 DR. KENNETH PORTIER: Dr. Lu? 

### 9 DR. CHENSHENG LU: So that study from the 

### 10 Garabrant Study 2009. So I think this is well-documented in 

### 11 the literature as well, is that every time we look at the 

### 12 acetylcholinesterase or butyrylcholinesterase data we have to 

### 13 make sure that they are using the right assay, because the 

### 14 whole assay is very sensitive to many, many factors. 

### 15 I remember a couple of years ago we had an 

### 16 SAP involving Dr. Barry Wilson from UC Davis, and he actually 

### 17 have a very animated section, in terms of whole assay issues. 

### 18 So this 2009 study used assay that's fairly 

### 19 new. It's in the laboratory-based assay that don't really 

### 20 reference in terms of has been replicated or not or is a 

### 21 commonly used assay. But based on the description, it looks 

### 22 pretty new. So I have no way to judge whether the quality of

### Page 677 1 the cholinesterase enzyme activity is good or bad. 

### 2 But if you look at 2011 of Farahat's study, 

### 3 they used battery powered test kit, which is considered 

### 4 non-valid measurement. But we'll go to there later. 

### 5 So for the 2009 study, assuming the quality 

### 6 is good, the data that's presented in the paper actually 

### 7 deserve further close examination. And I'm actually talking 

### 8 about these two graphs here on slide 16. So on your right hand 

### 9 side, this is the acetylcholinesterase and this is the 

### 10 butyrylcholinesterase. 

### 11 So again, I want to highlight the variance of 

### 12 the measurement. If you look at both acetylcholinesterase and 

### 13 butyl, it varies from 140 percent inhibition to 70 percent 

### 14 inhibition, so that kind of tells you. But if you kind of draw 

### 15 the line and facilitate by the PBPK model -- actually if you 

### 16 look at acetylcholinesterase, doesn't matter how high the TCPy 

### 17 is measured in the urine. There's essentially no change of the 

### 18 acetylcholinesterase of this wide range of TCPy from, I would 

### 19 say 0.1 to 1000. Whereas, if you look at butyrylcholinesterase 

### 20 you would start seeing the inverse correlation in which TCPy 

### 21 increase from 100 and above, and you see a linear degration 

### 22 inhibition of butyrylcholinesterase.

### Page 678 1 So what does this mean? So one question 

### 2 that's put out to the panel is whether acetylcholinesterase is 

### 3 the most sensitive biomarker for organophosphate pesticide 

### 4 exposure. Well obviously the data shows that's not the case. 

### 5 Right? 

### 6 So what happened, actually butyl got 

### 7 inhibited but not acetylcholinesterase. I think this is some 

### 8 kind of a mechanism that has not yet been either identified or 

### 9 categorized. 

### 10 We just happened to have an animal study that 

### 11 actually sort of have a similar hypothesis of this, and I can 

### 12 kind of put it out here -- although the data has not been peer 

### 13 reviewed yet -- is that, it's very likely that when you have 

### 14 exposure to, say, chlorpyrifos, once the chlorpyrifos is 

### 15 absorbed in the body, it will interact with butyl first because 

### 16 butyl is a boundant. It's in the plasma. It can quickly bound 

### 17 to chlorpyrifos and got inhibited. And whatever is left, the 

### 18 residual will go into the secondary compartment, which is 

### 19 acetylcholinesterase, in a central nerve system. And then it 

### 20 will interact with enzyme and got inhibited. I'm not saying 

### 21 that this is true, but I mean, the speculation is, if this is 

### 22 true, then we are talking about totally different trajectory in

### Page 679 1 terms of how we are going to look at in vitro 

### 2 acetylcholinesterase as the mode of action without any 

### 3 butyrylcholinesterase enzyme inhibition data? So that's what I 

### 4 take from the 2009 study. 

### 5 And in terms of the 2011 study, in addition 

### 6 to the quality of the cholinesterase measurement, I really want 

### 7 to have this showed in front of the panel because some may not 

### 8 have the access to the paper. 

### 9 So this full graph shows before, during and 

### 10 after application event. If you just use your naked eye 

### 11 examination, those relationships are actually non-changed. It 

### 12 doesn't matter if it's before, during or after application. 

### 13 So the question is how good is this data, 

### 14 especially knowing that by looking at the TCPy measurement in 

### 15 the urine, some of the people in the study actually is exposed 

### 16 to extremely high level chlorpyrifos. I don't even see that 

### 17 kind of number before; 5000 microgram per gram of creatinine 

### 18 adjustment. I don't even know if there's any literature that 

### 19 documents this kind of level. But if you look at 

### 20 cholinesterase enzyme inhibition it barely changed, to some 

### 21 degree. So again, I question their cholinesterase enzyme 

### 22 measurements.

### Page 680 1 I mean, no doubt that this taking place in 

### 2 Egypt, they don't have that kind of facility, but again, I 

### 3 don't think that we should use this data from this study for 

### 4 further analysis. 

### 5 And something that's really concerning is, if 

### 6 you read the paper carefully -- I don't know how they passed 

### 7 this, but there's a couple of workers, their 

### 8 acetylcholinesterase enzyme inhibition actually reached to 

### 9 almost 90 percent. I don't know how these workers survived. 

### 10 90 percent of acetylcholinesterase inhibition will lead to 

### 11 death right away. But this paper got published without any IRB 

### 12 (phonetic) challenge. 

### 13 So, I guess the reason they have this such 

### 14 high inhibition of acetylcholinesterase is the poor quality of 

### 15 the measurement, is the poor quality of a test kit. But 

### 16 otherwise, I think that person or the couple of persons have 

### 17 this low, almost zero -- I mean some of the butyl is actually 

### 18 zero. I don't know how those people can survive. So that's 

### 19 just my comment. 

### 20 DR. KENNETH PORTIER: So, for the record, Dr. 

### 21 Lu was referring to the slides for RBC cholinesterase and 

### 22 plasma butyl cholinesterase in the Niman presentation before

### Page 681 1 the panel. 

### 2 DR. CHENSHENG LU: Slide number 16 and 17. 

### 3 DR. KENNETH PORTIER: Right, slide 16 and 17. 

### 4 And I don't know if you're going to want to include that in 

### 5 the report but at least we should make reference to that, and 

### 6 then make reference to the Farahat paper page 804. 

### 7 DR. BARRY RYAN: I just have two very minor 

### 8 points, additional point on this topic and then I'll shut up. 

### 9 Dr. Buckley, pointed out that we are talking about men 

### 10 exclusively in this. I would like to just add to the point 

### 11 that these are actually healthy men. And men overall may have 

### 12 a different effect, and certainly, overall, populations could 

### 13 have different effects as well. 

### 14 And secondly, I think Dr. Lu just pointed out 

### 15 more clearly to me and said more concisely, but I think that 

### 16 the exposure levels that are being shown here are occupational 

### 17 type levels, and there may be other pathways that are -- I 

### 18 don't want to say saturated, but are run-through with respect 

### 19 to this. 

### 20 And what Dr. Lu was just saying regarding 

### 21 butyrylcholinesterase inhibition versus acetylcholinesterase 

### 22 inhibition kind of supports that. That's all I have on this.

### Page 682 1 DR. KENNETH PORTIER: Dr. Vena and then Dr. 

### 2 Terry. 

### 3 DR. JOHN VENA: Just to add that, in the 

### 4 description here it does say that the Garabrant paper had 22 

### 5 percent female study participants in the study population and 

### 6 26 percent in the referenced groups, female. 

### 7 But for the most part, I agree that this is 

### 8 generalizable to adult men. And the doses in the populations 

### 9 really aren't relevant for generalized ability to many of the 

### 10 issues that we've been discussing here, which is the 

### 11 reproductive development effects and exposure to pregnant 

### 12 ladies and children. 

### 13 So although I guess it is informative, I 

### 14 guess the reason this question was asked is informative to the 

### 15 bigger issues of acetyl transfer cholinesterase inhibition and 

### 16 what doses create those effects. 

### 17 DR. KENNETH PORTIER: Dr. Terry? 

### 18 DR. ALVIN TERRY: Yes. I have one thing to 

### 19 clarify. It wouldn't change the overall interpretation of 

### 20 whether the Farahat study is worth utilizing or not, but there 

### 21 was the issue mentioned about 90 percent acetylcholinesterase 

### 22 inhibition.

### Page 683 1 We routinely do studies in animals where you, 

### 2 if you exposure animals intermittently, overtime you can easily 

### 3 approach 90 cholinesterase in this and see no cholinergic 

### 4 signs. So I just wanted to clarify that. I'm sorry, couldn't 

### 5 hear? Okay. 

### 6 Just wanted to clarify one point, and that 

### 7 was the statements you made about someone having cholinesterase 

### 8 inhibition approaching 90 percent and not having symptoms. If 

### 9 you are exposed intermittently -- and I'm basing this on adult 

### 10 rodent models -- you can routinely approach 90 percent 

### 11 cholinesterase inhibition without seeing any cholinergic signs. 

### 12 But this is a different type obviously, so that's rodents, 

### 13 adult rodents in its intermitted exposure overtime. 

### 14 DR. CHENSHENG LU: Just to clarify, is it 

### 15 butyrylcholinesterase or acetylcholinesterase at the 90 percent 

### 16 inhibition level? 

### 17 DR. ALVIN TERRY: Either or both. 

### 18 DR. WILLIAM POPENDORF: If you look back and 

### 19 some of the old Graub data (phonetic) from the 40s and early 

### 20 50s, there was one particular series where they took people 

### 21 down below, it was like down to one percent active in a 99 

### 22 percent inhibition. I don't remember the timeframe but they

### Page 684 1 took them down over some period of time. They've got 

### 2 decreasing levels of activity. They're down to 99 percent 

### 3 inhibition. If you do it slow enough, they didn't have 

### 4 symptoms either, so it is possible to do that with people as 

### 5 well. 

### 6 DR. KENNETH PORTIER: Dr. Pope? 

### 7 DR. CAREY POPE: Yeah, just to add to that. 

### 8 We don't even have to do it intermittently. We can do it with 

### 9 a single acute dose with chlorpyrifos given subcutaneously. 

### 10 Their brain cholinesterase will be dropped to 90 percent 

### 11 inhibition with very few signs of severe cholinergic signs. 

### 12 DR. KENNETH PORTIER: Dr. Carr? 

### 13 DR. RUSSELL CARR: What Dr. Pope said. 

### 14 DR. KENNETH PORTIER: Dr. Lu. 

### 15 DR. CHENSHENG LU: I just want to clarify 

### 16 this. I mean, this is hard to read the data because they don't 

### 17 provide detailed information. But if you look at these two 

### 18 graphs at the bottom of slide 17, one shows almost the end of 

### 19 application. The other shows this 14-day post-application. 

### 20 And over that 14-day period, I assume that those low numbers 

### 21 from the same individual -- which I cannot assure because the 

### 22 paper does not say so -- but if those are the same persons, how

### Page 685 1 can those persons survive 14 days with acetylcholinesterase 

### 2 inhibition at a 90 percent level? I agree that animal testing 

### 3 you could see nothing instantaneously. But what if you sustain 

### 4 that level of inhibition at 14 days? 

### 5 So again, what I'm trying to say in here is 

### 6 that there are some unanswered questions associated with these 

### 7 two studies. I think the Egyptian study has more problems than 

### 8 the 2009 study. 

### 9 But again, this kind of identifies something 

### 10 in terms of -- this could be true because, remember, 

### 11 acetylcholinesterase can be overly inhibited become H. So this 

### 12 could be the H symptoms, which we don't really see that in the 

### 13 previous literature. But also, just bear in mind that 

### 14 acetylcholinesterase can also reactivate it. So that's why I'm 

### 15 saying this does not really answer many questions that I have. 

### 16 DR. KENNETH PORTIER: Dr. Popendorf? 

### 17 DR. WILLIAM POPENDORF: I was just going to 

### 18 comment on butyrylcholinesterase side. You know the PBPK model 

### 19 actually -- I can't explain the mechanics of it but they do 

### 20 predict that the butyrylcholinesterase would be inhibited well 

### 21 before the acetylcholinesterase side. So I don't think that 

### 22 should be too surprising.

### Page 686 1 But on the other hand, we've not really 

### 2 discussed the value of acetylcholinesterase. Clearly it's 

### 3 getting inhibited more early. Should it be considered as an 

### 4 alternative biomarker, basically? Perhaps this has been 

### 5 discussed in literature but it hasn't been discussed here. 

### 6 DR. RUSSELL CARR: There's a lot of 

### 7 individual variability with butyrylcholinesterase, and so it's 

### 8 not as baseline stable as red blood cell cholinesterase is in 

### 9 humans. And there is age-dependent increases in 

### 10 butyrylcholinesterase, and so the variability kind of limited 

### 11 it out. We kind of hashed that out in 2008 that it was just 

### 12 too variable to be depended upon. It is a very good marker of 

### 13 exposure because it's more sensitive than red blood cell 

### 14 cholinesterase but it is just too variable. 

### 15 DR. KENNETH PORTIER: Well one of the 

### 16 questions I have, I guess, also a question here about the 

### 17 association is the existence of this breakpoint/inflection 

### 18 point in the relationship, as you can kind of see it in the 

### 19 handout, the Farahat paper or in the EPA presentations. And I 

### 20 wondered, do you think this fairly represents this kind of 

### 21 inhibition and then kind of a point at which the rate of 

### 22 inhibition increases? That kind of quantitative association,

### Page 687 1 is that that reasonable? I didn't hear anybody talking to 

### 2 that. Dr. Popendorf? 

### 3 DR. WILLIAM POPENDORF: I mean, for blood 

### 4 RBC, basically, is what you're looking at, and there are two 

### 5 mechanisms that would account for that. One is the temporal 

### 6 reversion, the disassociation, if you will, of the 

### 7 phosphorylation of that enzyme which occurs over a short period 

### 8 of time at a fairly high rate and something I think for 

### 9 chlorpyrifos, if a third or so of the initial inhibition is 

### 10 released in the first 24 hours. And then, of course, you're 

### 11 getting replacement RBCs. 

### 12 So up to the point between the plasma acting 

### 13 as sort of a buffer, if you will, for some of that dose, and 

### 14 then those other two mechanisms replacing the RBC, you see 

### 15 almost no change until those two mechanisms are sort of 

### 16 overwhelmed by the dose; and then you're going to see that 

### 17 drop-off. So I think there are some fairly, fairly well 

### 18 understood mechanisms. 

### 19 I mean, the figure 3 of the Garabrant study 

### 20 is basically a plot of just the results of the Timchalk model, 

### 21 and it shows the plasma, RBC and brain CHE all with those 

### 22 breakpoints. So it's predictable and it matches, so I think

### Page 688 1 the mechanisms are fairly well understood. 

### 2 DR. KENNETH PORTIER: Dr. Lu? 

### 3 DR. CHENSHENG LU: So the inflation point 

### 4 would determine basis on butyrylcholinesterase measurement. IN 

### 5 the 2011 study, I don't think that butyrylcholinesterase 

### 6 measurements are valid. Just this is on the graph. Whereas, 

### 7 on the 2009 study, the butyrylcholinesterase seems okay. But 

### 8 again, at that level, we don't see any acetylcholinesterase 

### 9 inhibition. So what is the implication of this inflection 

### 10 point, for butyrylcholinesterase related to 

### 11 acetylcholinesterase when there is essentially no change? 

### 12 So I think, you know, inflection point is a 

### 13 good idea but, you know, you're talking about a non-targeted 

### 14 cholinesterase enzyme activity and try to relate it to more 

### 15 specific, has toxicological meaning, which is 

### 16 acetylcholinesterase which we don't see any change. So what is 

### 17 good about this inflection point? 

### 18 DR. KENNETH PORTIER: Don't ask me. Dr. 

### 19 Popendorf? 

### 20 DR. WILLIAM POPENDORF: I was just thinking. 

### 21 When you say good you mean informative or beneficial? What do 

### 22 you mean by good?

### Page 689 1 DR. CHENSHENG LU: Well good means that you 

### 2 can find an inhibition at level start going up, exposure level, 

### 3 to kind of give an indication in terms of, at what exposure 

### 4 level you start seeing butyrylcholinesterase inhibited. But my 

### 5 point is that, yes, based on the 2009 study there's a clear 

### 6 distinction between non-inhibited versus inhibit. But if you 

### 7 look at acetylcholinesterase measurement from the same person, 

### 8 there's no information whatsoever what should be the inflection 

### 9 point. But we all use acetylcholinesterase as a toxicological 

### 10 endpoint, not butyrylcholinesterase, not just a variation 

### 11 perspective, also it's very general. There's no specific 

### 12 toxicological implication if butyrylcholinesterase are 

### 13 inhibited. 

### 14 DR. WILLIAM POPENDORF: So I think you're 

### 15 saying that it's not informative to know that there is an 

### 16 inflection. And I think if you look at that data -- I mean, I 

### 17 agree with you on that point. If you look at the figure 5 of 

### 18 that paper to reflect Dr. Buckley's point, I mean some of the 

### 19 people at just about that inflection point, they're up 80 

### 20 percent above their baselines. I mean, if you didn't have a 

### 21 line there you might almost think the inflection is going the 

### 22 other way. But, I think, obviously that line was generated not

### Page 690 1 just at random. There's physiologic reasons for that 

### 2 happening. But, yeah, I think I agree that it's not helpful to 

### 3 know that. Okay. It happens. We don't know how to interpret 

### 4 it. 

### 5 DR. KENNETH PORTIER: Any additional 

### 6 comments? Dr. Lowit, was that a clear enough -- I think 

### 7 they'll be able to write this up. 

### 8 DR. ANNA LOWIT: Yes. Thank you. 

### 9 DR. KENNETH PORTIER: Okay. Why don't we go 

### 10 on to 5.3, which at least has a short description. I don't 

### 11 know if the discussion is going to be short. 

### 12 LIEUTENANT AARON NIMAN: Question 5.3: 

### 13 Several approaches ranging from qualitative to the most 

### 14 sophisticated PBPK/PD modeling approach were introduced as 

### 15 potential options for analyzing the chlorpyrifos biomonitoring 

### 16 data. Please comment on the strengths and limitations of these 

### 17 approaches. In addition, please suggest, if appropriate, 

### 18 alternative approaches or analyses not identified by the 

### 19 agency. 

### 20 DR. KENNETH PORTIER: Dr. Meek? 

### 21 DR. BETTE MEEK: Thanks. Well, I really like 

### 22 the manner in which the agency's presented the options for

### Page 691 1 interpreting biomonitoring data, ranging from qualitative, 

### 2 non-comparative looking at trends or comparative, taking into 

### 3 consideration controlled human studies to semi-quantitative 

### 4 approaches estimating biomarker levels associated with 

### 5 regulatory exposure guidelines or estimating exposure from 

### 6 biomarker levels using reverse dosimeter PBPK model. 

### 7 I think that presentation of a number of 

### 8 options in an increasing data informed construct of this nature 

### 9 has the potential to maximize the use of biomonitoring data for 

### 10 different applications, accounting additionally for factors 

### 11 contributing to variability and external exposure estimates. 

### 12 But depending upon the quality, the 

### 13 availability and specific nature of the biomonitoring data and 

### 14 the intent of its use, the question is really, I think, what 

### 15 degree of uncertainty is acceptable for the intended purpose 

### 16 and in what population. 

### 17 So those approaches are necessarily dependant 

### 18 on the extent of the data available on toxicokinetics relevant 

### 19 to the population subset of interest and mode of action and 

### 20 their integration, so with the Cadillac being the PBPK/PD 

### 21 model. But again, that needs to be fit for purpose and needs 

### 22 to be carefully evaluated.

### Page 692 1 So the framing by the agency I think permits 

### 2 flexible use of biomonitoring data in this context, including 

### 3 that for chlorpyrifos. But for example, if the objective is 

### 4 media-specific assessment or management, there's a need for 

### 5 dose reconstruction or reverse dosimetry from the biomonitoring 

### 6 data. 

### 7 As a minimum, currently, I think the 

### 8 biomonitoring data on chlorpyrifos should be helpful in ground 

### 9 truthing the total external exposure estimates under various 

### 10 use conditions, which are necessarily based on many more 

### 11 assumptions, such as activity patterns and intakes in 

### 12 concentrations in various media. 

### 13 I'd also like to encourage the agency to 

### 14 seriously consider the development of a value of kin to a 

### 15 biomonitoring equivalent concurrently with the derivation of a 

### 16 referenced dose in the conduct of the assessment. 

### 17 So biomonitoring equivalent is a calculated 

### 18 level of a biomarker associated with exposure consistent with 

### 19 health protective guidance values for the general population. 

### 20 This would provide a valuable addition for interpretation of 

### 21 the biomonitoring data in a public health risk context. It 

### 22 would also draw efficiently on the existing process for review

### Page 693 1 and consultation for the regulatory assessment. So BEs are 

### 2 based on similar considerations as the reference dose but 

### 3 incorporating very few additional considerations. 

### 4 In relation to the PBPK model, I think that's 

### 5 been discussed extensively in a previous SAP and I won't go 

### 6 into that in any detail. Again, a PBPK model, which is fit for 

### 7 purpose and well verified would serve to reduce a lot of the 

### 8 uncertainty associated with some of the issues that we are 

### 9 struggling with, and I'll leave it at that. 

### 10 DR. KENNETH PORTIER: Dr. Buckley? 

### 11 DR. BRIAN BUCKLEY: One of the observations I 

### 12 made about these models is they are very much going to be 

### 13 data-dependent. In other words, the more data you have, the 

### 14 more you'll be able to progress through qualitative into 

### 15 quantitative approximations of dose. And I think that the 

### 16 further you can go from qualitative assessment to quantitative 

### 17 assessment the better the overall risk assessment is going to 

### 18 be in the long run. So the more data you have, the better your 

### 19 opportunity to work with things. 

### 20 But there are two things that I want to point 

### 21 out, and the first being much more important. The ability to 

### 22 use the quantitative model is only going to be as good as the

### Page 694 1 PBPK model. And I've discussed before the fact that the single 

### 2 PBPK model that we have is probably not appropriate across all 

### 3 populations, and especially not true for the vulnerable 

### 4 populations that we are going to consider. So those are things 

### 5 we -- and we discussed this a little bit more on Question 5.4 

### 6 as well -- that the quality of the PBPK model should be 

### 7 assessed directly. 

### 8 I am also going to recommend, both here and 

### 9 in 5.4, that we utilize all of the exposure media data; the 

### 10 soil, the air, the water, the food, et cetera, for creating a 

### 11 dose reconstruction or a potential dose reconstruction and 

### 12 utilizing that information to validate the PBPK model. In 

### 13 other words, if you know approximately what the concentration 

### 14 that someone would've been exposed to -- based on the media and 

### 15 based on all of the things that we discussed the other day 

### 16 about how much dirt do kids eat and how much do we breath and 

### 17 drink and put our hands on tables, et cetera -- if you can 

### 18 estimate the dose, you should be able to pull that through your 

### 19 PBPK model at that point in time and derivate at a theoretical 

### 20 concentration of metabolites in urine. Then you can compare 

### 21 those concentrations. You have lots of studies to work with at 

### 22 that point in time.

### Page 695 1 It's not just the Columbia study and the 

### 2 Mount Sinai and the CHAMACOS study. You have all of those 

### 3 other studies that didn't measure outcomes to work with. So 

### 4 there's a lot of data there that you can potentially validate 

### 5 your PBPK model. And we are going to discuss this a little bit 

### 6 more in 5.4 but I think that's key. 

### 7 On a minor note, the semi-quantitative 

### 8 information utilizing creatinine corrected urine. We don't do 

### 9 creatinine correction in our laboratory for a number of 

### 10 reasons, but one of them being that the creatinine that's 

### 11 excreted from individual to individual differs greatly based on 

### 12 lean body mass and other things, and it was discussed real well 

### 13 on a paper by Dr. Barr (phonetic). 

### 14 But more importantly, we utilize a specific 

### 15 gravity. And I think it's better for comparing study to study 

### 16 because it more accurately reflects the dilution, if you will, 

### 17 of the urine because it represents total dissolve solids rather 

### 18 than just a single component of creatinine. Those are my 

### 19 observations. 

### 20 DR. KENNETH PORTIER: Dr. Collier? 

### 21 DR. ABBY COLLIER: I'd like to agree with Dr. 

### 22 Meek about the quality of the data that agency has available to

### Page 696 1 it. And I have some very specific recommendations in terms of 

### 2 your PBPK modeling. 

### 3 When we use models we have a saying; junk in 

### 4 equals junk out, and I really do think that we are not putting 

### 5 junk into these models. It's very apparent over the last few 

### 6 days that agency has deemed really high quality data available 

### 7 to them, especially from the biomonitoring data. So therefore, 

### 8 the development of these models shouldn't present as much of a 

### 9 challenge as it would be if the field went as well developed. 

### 10 The presenter from Dell, Dr. Bartells 

### 11 (phonetic), indicated that life-stage specific modeling was 

### 12 available to the M3 via PBPK/PD method. However, when 

### 13 questioned directly, agency replied that they do not scale for 

### 14 pediatrics. 

### 15 In adult PK or PBPK modeling, we can simply 

### 16 use an allometric scaling variant such as a three quarter 

### 17 power, and that does give some sort of an indication of what's 

### 18 going on with children. 

### 19 Alternatively, Wang's (phonetic) modification 

### 20 of the Dubois and Dubois method can be used, and it's slightly 

### 21 more physiological and could easily be applied to adult PBPK 

### 22 data to try and get close to what we would see with children.

### Page 697 1 However, this is a very simplistic way of looking at improving 

### 2 prediction for pediatric populations. 

### 3 Another point is, when developing these 

### 4 models, it's come to my attention over the course of the last 

### 5 few days that chlorpyrifos is highly, highly protein bound. 

### 6 And a consideration in the models is that plasma proteins in 

### 7 children and in pregnancy differ drastically. So in developing 

### 8 such models, that's going to be very important. 

### 9 That may be least important for TCPy or DETP 

### 10 if these are endpoints rather than chlorpyrifos itself, 

### 11 although I'm not aware of the unbound fraction. I'm not aware 

### 12 of what the percentages of those are. 

### 13 A sophisticated PBPK model for children 

### 14 already exists. Okay? It belongs to Simsit (phonetic), which 

### 15 is a company in Sheffield, England. I am aware that it's 

### 16 expensive, but it is a very good model and it is flexible to 

### 17 allow input. 

### 18 Although, as was mentioned earlier by agency, 

### 19 developing a pregnancy PK or PBPK model, it's kind of 

### 20 challenging and ambitious. I was extremely gratified to see 

### 21 what Dr. Hattis has been doing. I thought that was very 

### 22 exciting and potentially very useful.

### Page 698 1 It is suggested for several of the reasons 

### 2 that I mentioned earlier, and reasons mentioned in 5.1, that a 

### 3 pregnancy model is developed as a multicompartment model with a 

### 4 fetal compartment including the fetus, the amniotic SEC/fluid 

### 5 and the placenta are modeled as a separate unit. I acknowledge 

### 6 that this will affect the outcomes from the data as presented 

### 7 by Dr. Hattis, especially for oral exposure, but less so 

### 8 effective against inhalational. 

### 9 However, to give you an example of why this 

### 10 may be important, at term the placenta is profused to around 

### 11 about 600 mils per minute, which means the mother's blood is 

### 12 exchanged to the placenta as little as every six to eight 

### 13 minutes before it presents an extremely important cardiac 

### 14 output and extremely important part of the total metabolic 

### 15 profile. 

### 16 Furthermore, the average surface area of a 

### 17 placenta at term is around about 11 meters squared. So we're 

### 18 talking about a very large, very rapidly profused and exchanged 

### 19 area. And most of the CYPs as well as the glucuronyl 

### 20 transferase, sulfotransferases that metabolized chlorpyrifos 

### 21 have been found in the placenta. So based on that, as a 

### 22 speculative argument, I suggest that it is considered that the

### Page 699 1 fetal compartment is a separate compartment in a model that's 

### 2 developed. 

### 3 Alternatively, if it can be shown that the 

### 4 placenta is not sufficiently metabolic or that changes from the 

### 5 fetal compartment is not sufficiently important, then you can 

### 6 leave the placenta in its compartment as part of liver 

### 7 metabolism, thus simplifying the model. 

### 8 One thing that I think I raised earlier in 

### 9 panel discussions is that this is an increasing interest not 

### 10 just for pesticides. There are several other compounds of 

### 11 interest that EPA will be looking at where this has come up 

### 12 over and over again. So the utility of a pregnancy specific 

### 13 model for toxicokinetics will not just be useful in respect 

### 14 with FIFRA, but other things the agency may be asked or desire 

### 15 to look at. Thank you. 

### 16 DR. KENNETH PORTIER: Dr. Lu? 

### 17 DR. CHENSHENG LU: I look over this question 

### 18 many times. I thought that the question should be framed this 

### 19 way, in terms of how can we utilize sophisticated PBPK/PD model 

### 20 to analyze chlorpyrifos exposure data so we can recreate a 

### 21 situation in which, under what exposure scenario, that lead to 

### 22 certain levels of chlorpyrifos residue in the cord blood

### Page 700 1 samples, because that's how PBPK has been utilized in terms of 

### 2 estimating or predicting urinary concentration based on what 

### 3 exposure scenario. 

### 4 So the way that the agency asked me this 

### 5 question, I'm confused. But I guess I sort of like interpreted 

### 6 in a way that, how can we use biomonitoring data in the PBPK 

### 7 model in a sense that we can lead to further knowledge? So I'm 

### 8 thinking about reverse dosimetry, which is possible. And I 

### 9 would say that there will be a paper published in General 

### 10 Toxicology in 2012 that basically expands the PBPK model and 

### 11 create a verse dosimetry, which actually use chlorpyrifos TCPy 

### 12 data as input and then back calculate and estimate what would 

### 13 be the original exposure, either injection dose or inhalation. 

### 14 I guess that's what the agency was asking. 

### 15 But, I think we also have a complete SAP 

### 16 either a year ago or two years ago that kind of delegate this 

### 17 subject. So I think I will encourage the agency to look into 

### 18 that report as well. 

### 19 I think the most important thing about the 

### 20 PBPK/PD model approach is that, there are several models out 

### 21 there that we can utilize. But keep in mind that models have 

### 22 to be validated using human data, not just animal data. Again,

### Page 701 1 I point out butyrylcholinesterase versus acetylcholinesterase. 

### 2 3 There's a huge gap that we don't know, in 

### 4 terms of in animals. So if you don't have human data that you 

### 5 can utilize and validate in the PBPK model, you always had to 

### 6 kind of ask yourself how good the model is. But I do believe 

### 7 that the PBPK or PD model is the way to go in terms of the 

### 8 future regulatory activity. Again, I would like to know under 

### 9 what kind of exposure scenario that the Columbia kids or the 

### 10 mother has such levels of chlorpyrifos in their cord blood. Is 

### 11 it predominately from oral injection from food or is it from 

### 12 inhalation of the contaminated indoor air as a result of a pass 

### 13 application. Those questions can be answered by the PBPK 

### 14 simulation. 

### 15 In terms of PD model, I think that could be 

### 16 complicated. Listening to what Dr. Morris' deliberation 

### 17 yesterday, it seems like there's really no good animal data 

### 18 that you can use to create a PD model that gives you some kind 

### 19 of degree of confidence that we can actually link exposure to 

### 20 some sort of neurobehaviors, and that part I think need to be 

### 21 further developed. But overall, I would say that they'll be 

### 22 more advantage than limitations in terms of using PBPK/PD model

### Page 702 1 in this specific subject. 

### 2 DR. KENNETH PORTIER: Dr. Ryan? 

### 3 DR. BARRY RYAN: I just had two minor 

### 4 comments on this section, but my two comments are much more 

### 5 eloquently displayed and talked about by, first, Dr. Buckley 

### 6 and then Dr. Collier, so I will refrain from taking the time of 

### 7 the committee here for that. 

### 8 DR. KENNETH PORTIER: Dr. Meek, you know, as 

### 9 I was reading and rereading the question, the word analyzing 

### 10 the biomonitoring data -- I kept saying what do they mean by 

### 11 using a PBPK model to analyze data? I always think of a model 

### 12 as a way of kind of describing the data. But to me, analyzing 

### 13 is looking at relationships and associations. And what are the 

### 14 other approaches that they're talking about? I mean we've 

### 15 concentrated on the PBPK/PD models, but do you get a feeling 

### 16 for what other approaches are? Did you cover that in your -- 

### 17 it's been so long since you did your presentation. I need to 

### 18 come back to the beginning to make sure we address the whole 

### 19 statement here. 

### 20 DR. BETTE MEEK: I mean, I introduced what 

### 21 the other approaches were. And in my view, I think that every 

### 22 single one of them has value, depending upon the context in

### Page 703 1 which you're using this. And I think of this in a risk 

### 2 assessment context. 

### 3 So, depending upon the level of 

### 4 sophistication of the analysis that you're doing, you can use 

### 5 the biomonitoring data, for example, to ground truth your 

### 6 external exposure estimates. You can use it to potentially, if 

### 7 you have -- and again, it depends very much on the data that 

### 8 you have available as well. So again, there isn't a specific 

### 9 -- I don't understand what the specific application is here and 

### 10 so I think there's been a little bit of confusion. That's why 

### 11 people have interpreted that slightly differently. For 

### 12 example, if we're talking about the PBPK model, how does that 

### 13 relate to the biomonitoring data? And I was thinking of it 

### 14 more on a broader risk assessment context as to how you can use 

### 15 the biomonitoring data. 

### 16 But what I'm encouraged about is the fact 

### 17 that the agency is looking into several approaches to using the 

### 18 biomonitoring data maximally in risk assessments. 

### 19 DR. KENNETH PORTIER: So you completed that 

### 20 first sentence by saying, for analyzing the biomonitoring data 

### 21 for risk assessment, and you're focusing on that. And I wanted 

### 22 to get back to Dr. Lowit and see is that exactly what you had

### Page 704 1 in mind in this question? I wanted to make sure we are going 

### 2 in the right direction here. 

### 3 DR. ANNA LOWIT: Well, if we can maybe push 

### 4 it just a touch, because the issue brought up, I just left 

### 5 myself a note about. 

### 6 So Bette, as she says, introduced the topic 

### 7 and there are a variety of approaches, and each in its own 

### 8 context has strengths and limitations. What we haven't heard 

### 9 outside of the pregnancy gestational PBPK modeling is the 

### 10 specifics about the strengths and the limitations of the 

### 11 alternatives. 

### 12 So I just relooked at my slides. Just to 

### 13 give you sort of a grounded example, there needs to be a risk 

### 14 mitigation decision in the order of 2015, which means the 

### 15 science analysis would need to be done a year'ish before that, 

### 16 and that's less than two years from now, and so, to run the 

### 17 experiments, the build the model, run some more experiments, 

### 18 probably, have a gestational model thoroughly reviewed and 

### 19 published and then available to the agency to do a full-blown 

### 20 risk assessment in less than two years. 

### 21 I'm all for big goals. I would beg you to -- 

### 22 and I agree with the idea of encouraging that science. I would

### Page 705 1 request that alternative, maybe a little bit less sophisticated 

### 2 approaches, get some more detailed discussion. That would also 

### 3 be very helpful. 

### 4 DR. KENNETH PORTIER: Dr. Collier? 

### 5 DR. ABBY COLLIER: I'd just like to reiterate 

### 6 that before I launched into a tirade about PBPK models, I did 

### 7 very directly say that you can take data from a simple PK model 

### 8 or even an adult PBPK model and use an allometric approach or 

### 9 even a partially physiologically-based approach, which is what, 

### 10 adding a couple of math equations if you want to be really 

### 11 blunt about it. And it's really approximate. But according to 

### 12 Anderson 2010 and Anderson in Hull (phonetic) for 2009, it's 

### 13 actually not a bad approach for pediatrics. So that's a simple 

### 14 way of getting it faster if the agency is concerned about 

### 15 timing. 

### 16 DR. ANNA LOWIT: That's an excellent example. 

### 17 And then I would ask if we could take the next step further. 

### 18 You know, that's a great example. That's something that can be 

### 19 done relatively quickly. If you could help us understand where 

### 20 those uncertainties would be, you know, because this is really 

### 21 about uncertainty analysis. If we were going to do a less than 

### 22 gold standard analysis, where would the uncertainties be and

### Page 706 1 what would be the direction of those uncertainties? And would 

### 2 there be a way to get a handle on the quantitative? Are we 

### 3 talking order of magnitude, just a few fold? Is it up? Is it 

### 4 down? That kind of sense would be very helpful, or a direction 

### 5 of where to go to find that, that kind of specifics would be 

### 6 very, very helpful. 

### 7 DR. ABBY COLLIER: How long is a piece of 

### 8 strength? So, the reason that we are moving from PK analysis 

### 9 to PBPK is not because we like playing with computers. It's 

### 10 because it's more sophisticated. But along with sophistication 

### 11 comes time, energy and things. 

### 12 But the basic PK model is relying on 

### 13 something like three quarter power. They do have a lot of 

### 14 uncertainty in it. And the one thing I think that's difficult 

### 15 with that type of approach is that you are going to end up 

### 16 missing some of your most vulnerable populations. So it's the 

### 17 same in that you're going to catch your most of the people, but 

### 18 it depends on what agency is really, really concerned about. 

### 19 And we're talking about vulnerable populations anyway; 

### 20 pregnancy pediatrics. 

### 21 The thing with the more blunt the model, the 

### 22 more likely you are to miss subtleties where toxicity is

### Page 707 1 important, and that's as much guidance as I can give you 

### 2 without sitting here and trying to build a model for you on the 

### 3 back of an envelop. 

### 4 DR. KENNETH PORTIER: Dr. Lu? 

### 5 DR. CHENSHENG LU: So I think, in my brain, I 

### 6 think I have things cut out for agency to do for the next year 

### 7 or two. I think that might be very interesting. So let's use 

### 8 Columbia study as example. 

### 9 Knowing that, what we believe is the indoor 

### 10 chlorpyrifos in the air contribute the majority of exposures, 

### 11 right? That's why you don't see anything after the phase-out. 

### 12 13 So each agency can use whatever the PBPK 

### 14 models have in the literature and then select one that you 

### 15 think that by focusing on inhalation exposure will be the most 

### 16 ideal and reliable pathway. And then the PBPK model estimate 

### 17 of urine concentration would be somewhat in the range of -- and 

### 18 you measure in the maternal urine. 

### 19 Then you can use that PBPK model and convert 

### 20 it to a verse dosimetry, in terms of whether the level that you 

### 21 see in the cord blood would be correlated with the indoor air 

### 22 concentration that was used as input parameters. And then you

### Page 708 1 can shut down the inhalation components because there is a 

### 2 phase-out period and see whether the reverse dosimetry would 

### 3 adequately describe what happened after the inhalation 

### 4 component got taken away from the model, and see whether you 

### 5 can get the same or close to the same level of the chlorpyrifos 

### 6 in cord blood. 

### 7 And if you're satisfied with the verse model, 

### 8 I think you have accomplished a great deal in terms of 

### 9 sensitivity analysis, because you can see how far off that 

### 10 manipulation in terms of inhalation-yes verses inhalation-no, 

### 11 and then to determine whether you're satisfied with the 

### 12 sensitivity analysis. 

### 13 But again we talk about three cohort study. 

### 14 But Columbia tend to stand out as the most valuable to this 

### 15 whole exercise because they have indoor air concentration 

### 16 measured both before and after the phase-out. And that could 

### 17 become a very important parameter for PBPK model exercise. 

### 18 The PBPK model we published in 2010 rely on a 

### 19 couple of measurements that we have on the food injection. 

### 20 Without that food injection, as we state in the paper, that the 

### 21 model actually grossly underestimate the true exposure. So I 

### 22 think Columbia study may behave [sic] the same pattern that the

### Page 709 1 study that we did way back in 1998. 

### 2 DR. KENNETH PORTIER: Dr. Buckley? 

### 3 DR. BRIAN BUCKLEY: I really want to echo 

### 4 what Dr. Lu just said. That's exactly what I was referring to 

### 5 in terms of using the exposure media data to validated your 

### 6 PBPK model. And no more studies need to be done. It's not the 

### 7 only study that you have both media data for and urine 

### 8 excretion. 

### 9 So if you have a rugged model you can move it 

### 10 past the Columbia study NHEXAS. You can move it into all sorts 

### 11 of other studies where you have environmental media and you 

### 12 have urinary output. And it shouldn't be a three-year project, 

### 13 you know? That should be something that you can accomplish 

### 14 fairly quickly and I encourage you to do it. 

### 15 But I think Dr. Lu sort of gave you a 

### 16 step-by-step-by-step as to how to valid that PK model, that's 

### 17 exactly what I was referring to in terms of utilizing the 

### 18 concentrations and the media to validate your exposure 

### 19 estimate, and therefore, your PBPK model. 

### 20 DR. KENNETH PORTIER: So I want to remind Dr. 

### 21 Lu, Dr. Buckley and Dr. Collier, make those notes and pass them 

### 22 on. And Dr. Meek then has the fun task of incorporating this

### Page 710 1 trying to answer that question. That's kind of why I asked the 

### 2 question, is, I felt that we concentrated too far on the PBPK 

### 3 side and not on the simple side. Any additional comments to go 

### 4 in here? 

### 5 DR. ANNA LOWIT: Can I just push one more 

### 6 question? 

### 7 DR. KENNETH PORTIER: Sure. 

### 8 DR. ANNA LOWIT: I'm sorry to keep being a 

### 9 pain, but this one is really, really important. So I love what 

### 10 I heard. I think that's excellent. But what I didn't hear is 

### 11 that one last connection. 

### 12 So, in theory, what you are proposing is to 

### 13 take something of one of the existing models, whether it's the 

### 14 Timchalk or Lu's adaption or the Hattis. All of these are good 

### 15 efforts but incomplete in their own pieces. 

### 16 To take one of those or all of them or any of 

### 17 them and to do these analysis -- and we are still going to be 

### 18 at the end and then they left with that, sort of 

### 19 elephant-in-the-room uncertainty of what about the fetal 

### 20 compartment, and how do we get a handle on the direction of 

### 21 that uncertainty? Are we over? Are we under? Does it wash 

### 22 itself out by doing multiple approaches or does the bounding

### Page 711 1 give you a handle on that? 

### 2 DR. KENNETH PORTIER: Dr. Lowit is looking at 

### 3 Dr. Carr and Dr. Collier for some insight here and they are 

### 4 kind of shaking their heads like, "Okay, you're opening a big 

### 5 box of --" 

### 6 DR. ABBY COLLIER: Dr. Collier was staring at 

### 7 Dr. Carr going, "Save me." I'm dying to tell you something 

### 8 that you won't like to hear. If you really want to sort out 

### 9 what's going on in the fetal compartment you need to study 

### 10 what's happening in the placenta and you need to see what's 

### 11 going on potentially as well in the amniotic fluid. 

### 12 It doesn't have to be a giant, you know, 

### 13 follow a thousand women over pregnancy, but you need some basic 

### 14 estimates to start building your model. There are people 

### 15 doing studies like this. There are labs that have them up and 

### 16 running. They are not studying chlorpyrifos. And to find out 

### 17 what's going on in the fetal compartment you need to understand 

### 18 the flow. It's more of a flow issue than a metabolism issue, I 

### 19 think, at this stage, so that you can find out whether or not 

### 20 you've got equilibration between the mom and the fetus, because 

### 21 that's not at all clear from the umbilical cord bloods and the 

### 22 maternal serum bloods.

### Page 712 1 So whether or not you've got equilibration, 

### 2 which makes everybody's life a lot easier, including Dr. 

### 3 Hattis' model, or whether or not there's something else going 

### 4 on, in which case you need that separate compartment. So it's 

### 5 potentially more about metabolism at this stage. That's how I 

### 6 would answer that question. 

### 7 DR. KENNETH PORTIER: Dr. Carr, do you have 

### 8 anything to add to this? Dr. Carr says no. Dr. Vena? 

### 9 DR. JOHN VENA: Just one question. Did any 

### 10 of the studies collect placenta or save any of the placenta? 

### 11 DR. KENNETH PORTIER: Dr. Christensen? 

### 12 DR. CAROL CHRISTENSEN: Not to my knowledge. 

### 13 But CHAMACOS study did make a measure in amniotic fluid though. 

### 14 DR. JOHN VENA: You may want to check with 

### 15 them because we did a study in Buffalo. There was 100 

### 16 perspective pregnancies and there was one guy that we had that 

### 17 did collect some placenta, a small group. But I know there are 

### 18 other studies throughout the nation where they've collected 

### 19 placenta. I would be surprised that they would not have 

### 20 attempted at least a subset to get some placenta. 

### 21 DR. KENNETH PORTIER: I think Dr. Lu and then 

### 22 Dr. Collier.

### Page 713 1 DR. CHENSHENG LU: I agree there is a 

### 2 gigantic elephant in the room. But I think, in terms of a 

### 3 fetal compartment, I don't think that's an uncertainty issue. 

### 4 It's a scientific issue because the science has not advanced to 

### 5 that level yet. 

### 6 But if we can get a good hold on the 

### 7 chlorpyrifos level in cord blood, I think it's a huge 

### 8 accomplishment. If the agency can describe 

### 9 pharmacokinetically, in terms of how chlorpyrifos levels change 

### 10 in the cord blood over that nine months of pregnancy period, 

### 11 that would lead to observable neurobehavioral change. I think 

### 12 that's a huge accomplishment in terms of the rest of the -- 

### 13 like, for example, placenta. You know. We don't even know 

### 14 should we collect the whole placenta or portions of the 

### 15 placenta. Which portion of placenta should we collect, and so 

### 16 on and so forth. 

### 17 We have a colleague that -- she actually 

### 18 collects her own placenta, and she says it's a pain in the neck 

### 19 to collect the whole thing. And where are you going to store 

### 20 it, right? So again, I don't think that's a sensitivity issue. 

### 21 I think it's more like a science issue that we don't really 

### 22 have that kind of capability yet. So I don't even thing that

### Page 714 1 we should stop right here. 

### 2 As far as I can tell, if I can understand the 

### 3 pharmacokinetics or the dynamics of chlorpyrifos levels in cord 

### 4 blood, I would be very satisfied with this whole exercise. 

### 5 DR. KENNETH PORTIER: Dr. Collier? 

### 6 DR. ABBY COLLIER: So, to follow up on that, 

### 7 Dr. Lu, how do you think it gets into the cord blood? Cord 

### 8 blood is a fetal exposure. It gets across the placenta. So if 

### 9 we can come up with some sort of equation that describes it 

### 10 without actually studying the placenta, that's fine. I mean, 

### 11 that's really good. 

### 12 I guess I should probably tell you this. 

### 13 The University of Hawaii has a placenta bank with 15,000 DNA 

### 14 samples. And it is eight and a half thousand mother/child 

### 15 peers with DNA. And we don't have placenta for all of them, 

### 16 but we do have placenta for about, I'm going to say 5,000 of 

### 17 them, as well as amnion and chorion rolls. We don't have 

### 18 amniotic fluid, and I'm the director of the biorepository. 

### 19 And that's actually been running for nine 

### 20 years now, so I think we may have missed the chlorpyrifos 

### 21 cut-off, is the problem. It's that the placentas that we do 

### 22 have, you wouldn't be able to necessarily do an environmental

### Page 715 1 study on it because I think it started in '02, maybe, maybe 

### 2 '03. But if you had a scientist that was running those 

### 3 studies, that may be something. 

### 4 So people are talking about how would you 

### 5 collect them and where would you store them, those are some 

### 6 issues that we've solved. I just maybe should mention that. 

### 7 And we're not the only one. There are other researches. I 

### 8 mean Roberto Ramirez (phonetic) has an amniotic fluid bank, 

### 9 although it's for his private research. It's not a 

### 10 biorepository. And there are several researchers nationwide 

### 11 that have these types of repositories but they are primarily 

### 12 for their own research and they don't make them available as a 

### 13 repository, so they do exist though. 

### 14 DR. KENNETH PORTIER: Dr. Sandy? 

### 15 DR. MARTHA SANDY: This is not quite as 

### 16 exciting as what we just heard. But I'm thinking, because it 

### 17 is so difficult to figure out what the pharmacokinetics are in 

### 18 the fetus and in the fetal compartment, can we step back and 

### 19 say, if we can just get a better handle on the maternal 

### 20 exposure? Because really that's what you would want in the end 

### 21 control for, how much of whatever substance we're worried 

### 22 about, in this case chlorpyrifos, is in the air and the diet in

### Page 716 1 the water, et cetera. What's a maternal exposure that results 

### 2 in effects in the fetus? So we still need some way to model 

### 3 better and predict over that 9-month time course based on one 

### 4 sample in cord blood and maternal blood what the exposures 

### 5 were. But I'll throw that out as another alternative. 

### 6 DR. KENNETH PORTIER: Dr. Buckley? 

### 7 DR. BRIAN BUCKLEY: I think you know this but 

### 8 the New Jersey study did do pesticides in cord blood, so 

### 9 certainly you have some of the data that potentially you could 

### 10 work with. 

### 11 DR. KENNETH PORTIER: I think what I'd like 

### 12 to do at this point is kind of take our 15-minute mid afternoon 

### 13 break. We'll come back and continue to discuss this before we 

### 14 go to 5.4. I see wheels turning, but maybe a little bit of 

### 15 coffee might speed those wheels up. We'll return, let's just 

### 16 say 10 till 3:00. 

### 17 (BREAK) 

### 18 DR. KENNETH PORTIER: As I expected, coffee 

### 19 works wonders, and we've gotten a lot of good conversation 

### 20 going on. I know Dr. Meek has talked with Dr. Lowit about 

### 21 restating the question so we know exactly what EPA wants us to 

### 22 answer. And I think there was a little bit of confusion on the

### Page 717 1 question. But before we get to that -- because Dr. Lowit spent 

### 2 so much time talking. She hadn't had a chance to take her 

### 3 break. While she's out of the room I'm going to ask Dr. 

### 4 Collier, who met with Dr. Lu and they've come up with another 

### 5 topic to discuss under this. Dr. Collier? 

### 6 DR. ABBY COLLIER: It's not so much another 

### 7 topic. In talking with Dr. Lu, Dr. Lowit was really concerned 

### 8 about how to move forward in a timely manner with a minimum 

### 9 level of uncertainty. And Dr. Lu and I sort of talked about 

### 10 how building these sophisticated models take a long time. They 

### 11 are very intensive. 

### 12 And we think that, perhaps the best way to 

### 13 move forward is to take the studies you have where you have 

### 14 maternal sera and fetal cord blood and to analyze those with 

### 15 respect to coming up with an equation that describes those 

### 16 studies, because they are all slightly different. 

### 17 Looking at the data that was presented and 

### 18 the data that we looked over before we arrived, there is a 

### 19 consensus. And so an equation could be built that models 

### 20 between those five or six studies, and that would give you your 

### 21 first basic idea of what the transfer to the fetus is. 

### 22 And as an initial starting point, I think

### Page 718 1 that would be very valuable and it would meet the objectives 

### 2 that you need to meet in the manner that you need to meet it, 

### 3 as long as the understanding was that it's a starting point. 

### 4 Alex, do you want to comment? 

### 5 DR. CHENSHENG LU: The only thing I would 

### 6 like to add too, which might introduce another layer of 

### 7 uncertainty, is that, because when we measure cord blood we 

### 8 measure at the birth, so we don't know what happened in the 

### 9 previous month. So if the interest is to look into this whole 

### 10 integrated exposure over that period of nine months then we do 

### 11 need to consider whether there will be a reliable PBPK model 

### 12 for just cord blood itself, independent from the chemical of 

### 13 interest, so we can extrapolate the level that we measure at 

### 14 birth in cord blood and to whatever month of your interest, the 

### 15 second month or third month. But knowing that, that could 

### 16 introduce additional uncertainty. 

### 17 But I think, you know, we agree that this 

### 18 might be the most immediate solution to tackle these issues 

### 19 without waiting for the new data or for new models. 

### 20 DR. KENNETH PORTIER: So the kind of model 

### 21 you're talking about is more an empirical one, right? A 

### 22 regression model, not a mechanistic model, right? So the first

### Page 719 1 link would be making that relationship between cord blood, 

### 2 maternal blood. Dr. Meek, did you learn? 

### 3 DR. BETTE MEEK: No, that's fine. I think 

### 4 the discussion has evolved since that. 

### 5 DR. KENNETH PORTIER: And Dr. Lowit, we 

### 6 decided to solve the problem while you were not in the room. 

### 7 Typically that works the best. No. I wanted to ask if you had 

### 8 any additional questions on this question, insights. I think 

### 9 we've tried to answer the question here. At the break, I got 

### 10 the feeling from most of the panel that the ultimate answer is 

### 11 still going to be an appropriate PBPK model, eventually. To 

### 12 answer the kind of questions that you need you're going to need 

### 13 to be -- and that's the message that we gave in 2008 and 

### 14 probably the same one in 2011 -- I forget when the last 

### 15 chlorpyrifos -- so the panel is at least consistent in it's 

### 16 messaging. That may not help you in the short-term but I think 

### 17 in the long-term we still feel that there's a lot of value in 

### 18 doing the right kind of integration of these biomonitoring data 

### 19 through a knowledge-build physiologically-based 

### 20 pharmacokinetic, pharmacodynamic model. 

### 21 DR. ANNA LOWIT: I appreciate the added 

### 22 addition, and I appreciate you letting me push you a little bit

### Page 720 1 to try to understand our needs, so thank you. 

### 2 DR. KENNETH PORTIER: So any additional 

### 3 comments on question 5.3? So why don't we move on to 5.4, 

### 4 which is another long one? 

### 5 LT. AARON NIMAN: Characterization of 

### 6 chlorpyrifos exposure experienced by women in the Columbia 

### 7 cohort, particularly during the pre-cancellation period, 

### 8 remains an important uncertainty in using these data and 

### 9 quantitative risk assessment. Exposure levels in the range 

### 10 measured in the cord blood data from the epidemiology studies, 

### 11 pg/g plasma are probably low enough that it is unlikely that 

### 12 the cohort mothers would experience acetylcholinesterase 

### 13 inhibition at the time of delivery. 

### 14 However, the biomonitoring data were taken 

### 15 after birth and not necessarily associated in time with an 

### 16 application in chlorpyrifos. As such, the actual of such 

### 17 exposure, particularly during any critical windows of 

### 18 susceptibility is not known, and a better understanding of the 

### 19 range of possible exposures and the degree to which they may or 

### 20 may not have elicited inhibition of acetylcholinesterase 

### 21 remains a key scientific question. 

### 22 In light of panel discussions of questions

### Page 721 1 4.3 and 5.3, please suggest approaches and/or analyses which 

### 2 would inform the understanding of the degree to which exposure 

### 3 levels experienced by the Columbia Cohort participants may or 

### 4 may not have been below doses which result in 10 percent 

### 5 inhibition of acetylcholinesterase in the most sensitive life 

### 6 stages. 

### 7 Please discuss the strengths and 

### 8 uncertainties associated with such analyses. Please include in 

### 9 your discussions approaches involving chlorpyrifos and its 

### 10 metabolites, and also chlorpyrifos plus other 

### 11 acetylcholinesterase inhibiting pesticides, for example, 

### 12 propoxur diazinon, which the cohort participants were exposed 

### 13 to. 

### 14 DR. KENNETH PORTIER: Dr. Buckley, not an 

### 15 easy set of questions. 

### 16 DR. BRIAN BUCKLEY: Well as per my other 

### 17 questions, I have a script but I'm going to deviate from it 

### 18 almost immediately because of the discussion we just finished 

### 19 having. 

### 20 I believe that PBPK modeling is one way to go 

### 21 about it. And even if it's something as simple as a single 

### 22 compartment, half life-based PBPK model, you can get a rough

### Page 722 1 idea of what mom might've been exposed to. 

### 2 You can certainly look at some of the 

### 3 equation modifications that Dr. Collier was talking about to 

### 4 get an estimate of what trial was exposed to. But in order to 

### 5 really get an idea of what the overall process is, especially 

### 6 since chlorpyrifos has such a short half-life, this is where 

### 7 you really need to do dose reconstruction. 

### 8 This is where you really need the information 

### 9 about when was the application made with respect to when was 

### 10 the samples taken. And then how many times the applications 

### 11 was made over the course of the pregnancy and how much was 

### 12 applied. That's the type of dose reconstruction that's going 

### 13 to give you as much a feel for whether or not the infant or the 

### 14 fetus was at risk as trying to back calculate a dose or a fetal 

### 15 cord blood concentration at birth projecting six and half or 

### 16 seven months ago. Okay? 

### 17 So if you have a rough idea of approximate 

### 18 does versus cord blood concentration, then you can reconstruct 

### 19 dose based on the surveys of the people and how often they 

### 20 applied the pesticides, et cetera, et cetera. All right? But 

### 21 you're going to need both, and it's the dose reconstruction 

### 22 that's going to tell you whether or not there was true risk

### Page 723 1 back in the day from the time it was applied. 

### 2 And that's off the cuff comments based on the 

### 3 discussions we just had. Now I'm going to go through the 

### 4 comments that were put together by the rest of the panelists 

### 5 here. 

### 6 It's important to realize the short half-life 

### 7 of chlorpyrifos and its metabolites in the body, and it calls 

### 8 into question any spot data that might be used. 

### 9 Large cross-sectional investigations may 

### 10 catch some exposures but did not put them into context. And 

### 11 longitudinal investigations clearly are going to be your best 

### 12 source of information in constructing a model. 

### 13 Understanding the limitations to the data 

### 14 within the context of a PK/PD model, having the potential to 

### 15 estimate dose at a given time since exposure may provide some 

### 16 information. But once again, go back to the dose 

### 17 reconstruction. 

### 18 Information that's been required for 

### 19 reasonable estimation of maximum dose would be whether the 

### 20 exposure dose was a steady-state or a bolus, and approximately 

### 21 how long after the bolus exposure was the sample collected. 

### 22 Once again, the best way to validate your PK/PD or any model

### Page 724 1 that you chose. 

### 2 With a very simple one-compartment model and 

### 3 time after exposure, reasonable estimate of the maximum dose 

### 4 delivered to mom and whether or not acetylcholinesterase 

### 5 inhibition threshold was reached, but a more sophisticated PBPK 

### 6 model may provide even better data assuming that PBPK model is 

### 7 realistic for the fetus. Okay? 

### 8 Previous panelists have noted that the 

### 9 decided lack of realistic PK/PD models for chlorpyrifos exist. 

### 10 You've gotten some more feedback as to better models, so 

### 11 hopefully you'll find one that's more effective. 

### 12 And effective PBPK model is one that is 

### 13 applicable to target populations such as pregnant women and 

### 14 small children. A lot of this stuff has been discussed so I'm 

### 15 going to bypass most of these comments because we've covered 

### 16 them already. 

### 17 Many of the studies discussed in 5.1 provide 

### 18 data on the concentration of chlorpyrifos and media. And 

### 19 market basket data exist. These are the primary tools for 

### 20 generating an effective exposure assessment and subsequent 

### 21 reconstruction of potential dose. It's a further to what Dr. 

### 22 Lu said earlier on and what I reiterated. But dose

### Page 725 1 reconstruction can be used to evaluate the efficacy of the 

### 2 PK/PD model as well as to predict how much the exposure was 

### 3 over the course of the pregnancy. Once again, most of these 

### 4 comments we've already offered, so I'm not going to re-read 

### 5 them. 

### 6 Now, the effect of mixtures of chlorpyrifos 

### 7 and diazinon, chlorpyrifos and propoxur, chlorpyrifos, propoxur 

### 8 and diazinon have not previously been considered. 

### 9 There's no easy way to approach this. PBPK 

### 10 models are tough enough with one component systems. We are 

### 11 just starting to get a feel for competitive inhibitions or 

### 12 additive effects or both. And like all mixtures, both 

### 13 constructive and destructive interferences can occur. 

### 14 Questions will have to be addressed: Do they 

### 15 affect each other's half-lives and distributions in clearance 

### 16 through the metabolic competition? Are there net 

### 17 acetylcholinesterase effects additive or multiplicative? Do 

### 18 they share mechanistic pathways? To address this, we recommend 

### 19 further studies describing 5.3 to improve estimates of effects 

### 20 when mixtures of antibiotics are used as compared to single 

### 21 agents. 

### 22 Probably not in enough time for you to get

### Page 726 1 your stuff done because you are looking at a two-year window. 

### 2 Mixture studies are difficult to do but there are mixture data 

### 3 out there that might be used for at least modifying your PBPK 

### 4 models if you think that the competitive pathways exist along a 

### 5 single metabolic pathway. All right? If they utilize the same 

### 6 enzymes for metabolism, you might be able to modify your PBPK 

### 7 to say two similar pesticides will actually compete for 

### 8 enzymatic metabolic processes and you won't have the same 

### 9 thing, or they may actually enhance one another in terms of 

### 10 their net effect. So both of which you're going to have to 

### 11 deal with data where people are studying the mixtures. 

### 12 Using currently available data other than 

### 13 improving in silico PK or PK/PD approaches, again, described in 

### 14 5.3, I'm not sure there is more the agency can do to reanalyze 

### 15 or transform the available data into meaningful studies. 

### 16 Once again, more discussion that will be 

### 17 included in the report that I don't need to cover here, but 

### 18 I'll just bullet point reiterating the need to potentially 

### 19 separate a 10 percent acetylcholinesterase inhibitory effect 

### 20 with any sort of other negative health outcomes should probably 

### 21 be considered, or should definitely be considered. They don't 

### 22 necessarily have to be tied to one another.

### Page 727 1 The 10 percent marker might just be a nice 

### 2 threshold upon which we've done things in the past. We should 

### 3 look to other potential biomarkers, other potential outcomes as 

### 4 drivers for creating risk assessment. And I think that that's 

### 5 about it. 

### 6 DR. KENNETH PORTIER: Dr. Collier? 

### 7 DR. ABBY COLLIER: I agree with Dr. Buckley. 

### 8 DR. KENNETH PORTIER: Dr. Lu? 

### 9 DR. CHENSHENG LU: So just to continue what I 

### 10 respond to the previous question, and also looking at this 

### 11 graph, is that, no matter what you're going to do, you won't 

### 12 see 10 percent inhibition of acetylcholinesterase in a Columbus 

### 13 study just because, at the level of 100 micrograms of TCPy per 

### 14 gram of creatinine, the acetylcholinesterase still remains 

### 15 uninhibited. 

### 16 Sure, this is et al. data. So let's put 

### 17 safety factor at 100 to the newborn babies. We're talking 

### 18 about 10 micrograms of TCPy and the urine still don't inhibit 

### 19 acetylcholinesterase and that 10 micrograms of TCPy happen to 

### 20 be the 95th percentile of the general population in this 

### 21 country. 

### 22 So again, I want to emphasize, just because

### Page 728 1 of this question, and also question number 6, to separate this 

### 2 whole regulatory activity by chronic and acute. I still 

### 3 believe that we are talking about two different things and it 

### 4 cannot be mixed together as one thing. You have to have an 

### 5 acute endpoint. You have to have a chronic endpoint. We are 

### 6 talking about two different things you cannot mix together. 

### 7 You know, the study that's recently published 

### 8 sort of reinforce my belief that you won't see 10 percent of 

### 9 acetylcholinesterase inhibition at the level that people 

### 10 exposed to. It doesn't matter if it's the adults or the kids. 

### 11 12 DR. KENNETH PORTIER: Dr. Ryan? 

### 13 DR. BARRY RYAN: The points I wanted to raise 

### 14 with respect to this question had been brought up in other 

### 15 questions, so I really have nothing to add at this point. Dr. 

### 16 Buckley summarized our points of view here. The group has 

### 17 worked together a little bit on this anyway, and I think we 

### 18 should just move on. 

### 19 DR. KENNETH PORTIER: Any additional 

### 20 comments? Yes, Dr. Carr? 

### 21 DR. RUSSELL CARR: The last part of it where 

### 22 it talks about the mixture of propoxur and diazinon, and it

### Page 729 1 says which of the cohorts participants were exposed to too, 

### 2 also, what we've got to consider there too is everything else 

### 3 they were exposed to. I mean, you've got PAHs in there which 

### 4 could balance the HR receptor, which could modify P450, 

### 5 manipulations of the organophosphates. You've got even 

### 6 piperonyl butoxide. And those had been listed in the 

### 7 epidemiology studies as leading to neurobehavioral, the 

### 8 deficits in these children in this cohort. 

### 9 And so, you know, we just got to make sure 

### 10 that we don't just narrow the focus on the OPs right here 

### 11 because we've got a lot of other actors here that could 

### 12 potentially come into play, and I know that's really difficult 

### 13 to handle. And I don't really have an answer but I just think 

### 14 we need to just keep that in the back of our mind. 

### 15 DR. KENNETH PORTIER: Do we have any 

### 16 conservative assumptions that can be made with regard to the 

### 17 mixture issue that would kind of simplify it down to 

### 18 chlorpyrifos equivalents, especially for the 

### 19 acetylcholinesterase inhibition outcome? Dr. Buckley? 

### 20 DR. BRIAN BUCKLEY: I've only recently delved 

### 21 into the whole mixture scenario. 

### 22 I don't think additives are protective

### Page 730 1 enough, but it probably gets you to the middle of the road, in 

### 2 terms of overall. And it's where people generally start. But 

### 3 the reality is, until you get in and study, you know, you don't 

### 4 know what's going to be more than additive at this stage of the 

### 5 game. 

### 6 At the same, this is a potential for being 

### 7 less than additive as well. You know. If you just take the 

### 8 concentration of the two and add the effects, that's somewhat 

### 9 protective. But there are certainly opportunities, as we 

### 10 discussed earlier on -- you know, DMSO (phonetic) not a big 

### 11 thing. Chlorpyrifos has it's known, but if DMSO makes 

### 12 chlorpyrifos much more bioavailable because it opens up 

### 13 transport mechanisms all of a sudden, you've got more than an 

### 14 additive effect at that point in time. 

### 15 And we'll continue to study more of these 

### 16 things with time. But up until now, people have been somewhat 

### 17 afraid to delve into -- well I shouldn't say that. People have 

### 18 been cautions in their approach to dealing with mixtures just 

### 19 because it's tough enough to study one component at a time 

### 20 versus the other. It's not a recommendation but they can start 

### 21 with additive effects and see what that does. 

### 22 DR. KENNETH PORTIER: Dr. Lu?

### Page 731 1 DR. CHENSHENG LU: I think the mixture is 

### 2 kind of a complicated subject. But I think in this case, not 

### 3 just the Columbia study, I think the NHANES study and our study 

### 4 as well, chlorpyrifos is frequently detected in the samples, 

### 5 whereas diazinon or other pesticides -- the frequency of 

### 6 detection is much, much lower. So in terms of the defect from 

### 7 the mixture of pesticides, it's very easy to tease out 

### 8 diazinon. And other pesticides because the frequency of 

### 9 detection is somewhere around 10 percent, whereas chlorpyrifos 

### 10 is somewhere 70/80 percent. 

### 11 DR. KENNETH PORTIER: Dr. Pope? 

### 12 DR. CAREY POPE: Dr. Lu, is the frequency of 

### 13 the detection based on the detectability of the diazinon, for 

### 14 example, or is it because of the levels of the diazinon 

### 15 relative to chlorpyrifos? The table handed out by EPA just 

### 16 this morning showed that, at least in the slimmest value, 

### 17 there's like more than twice as much diazinon being used there 

### 18 than chlorpyrifos. 

### 19 DR. CHENSHENG LU: I don't exactly know that 

### 20 they use these patterns, but I think diazinon is commonly used 

### 21 in agriculture where, before the phase-out, chlorpyrifos is 

### 22 commonly used in the residential setting, the pest control and

### Page 732 1 so on. 

### 2 I think you can look at the NHANES data 

### 3 somewhat. I agree that that's what I remember, that frequency 

### 4 detection for each pesticide used in those studies are 

### 5 dramatically different compared to chlorpyrifos. 

### 6 DR. KENNETH PORTIER: Dr. Popendorf? 

### 7 DR. WILLIAM POPENDORF: I've got a couple of 

### 8 comments. Just looking recently in the Whyatt 2007, actually 

### 9 air concentrations diazinon were about four times the air 

### 10 concentration of chlorpyrifos, in terms of mean values. It's 

### 11 an odd-looking distribution but the actual concentrations are 

### 12 quite a bit higher. 

### 13 My other comment though is combining sort of 

### 14 Dr. Buckley's and Dr. Lu's comments about using blood and 

### 15 modeling. And we don't really know what the last application 

### 16 was, but we not only have blood so we could do what you 

### 17 suggested Dr. Lu but we also have the array of air 

### 18 concentrations. And one could chose the highest value there as 

### 19 with the highest value in blood and find out does the highest 

### 20 blood value produce cholinesterase; does the highest air value 

### 21 give you a dose that would produce cholinesterase. 

### 22 And one can make the assumption or argument

### Page 733 1 that the highest air value may represent in fact the most 

### 2 recent application. 

### 3 DR. KENNETH PORTIER: Dr. Dawson? 

### 4 DR. JEFF DAWSON: Just a little clarity about 

### 5 chlorpyrifos use. Definitely, at the time it was in the 

### 6 residential market, this was and still is a major agricultural 

### 7 use pesticide kind of broadly used on a variety of crowds, so 

### 8 millions of pounds per year. 

### 9 DR. KENNETH PORTIER: Dr. Lu? 

### 10 DR. CHENSHENG LU: Just to clarify Dr. 

### 11 Popendorf's comment; we're talking about frequency of 

### 12 detection, not concentration, in terms of chlorpyrifos and 

### 13 diazinon. There's a frequency of detection. 

### 14 DR. WILLIAM POPENDORF: I think they were 

### 15 actually detected very close to -- 

### 16 DR. KENNETH PORTIER: One is in blood and one 

### 17 is in air. 

### 18 DR. WILLIAM POPENDORF: I'm talking air, 

### 19 yeah. 

### 20 DR. KENNETH PORTIER: You're talking air -- 

### 21 are you talking air or are you talking blood? 

### 22 DR. CHENSHENG LU: I'm talking about

### Page 734 1 concentration of urine, metabolites. 

### 2 DR. WILLIAM POPENDORF: Okay. I'm talking 

### 3 air, in terms of dose. 

### 4 DR. CHENSHENG LU: Okay. 

### 5 DR. WILLIAM POPENDORF: Environment versus -- 

### 6 7 DR. KENNETH PORTIER: So media matters here. 

### 8 Media matters. Dr. Buckley? 

### 9 DR. BRIAN BUCKLEY: Yeah. I just want to 

### 10 re-emphasize what Dr. Popendorf said but to bring it back 

### 11 again. The environmental media, their concentrations can be 

### 12 used to extrapolate or to project a max dose. And I would 

### 13 encourage you to use more than just air, but use the market 

### 14 basket survey information to estimate the contributions from 

### 15 diet, the dust. Anything else that you have matrix on, you use 

### 16 them all to reconstruct that dose. And that should give you an 

### 17 idea of what the max concentration was that the fetus might be 

### 18 exposed to. 

### 19 DR. KENNETH PORTIER: Yeah. Dr. Buckley, I 

### 20 think that was the major topic of the 2011 panel where we 

### 21 looked at linkage between the exposure modeling and the PBPK, 

### 22 right? I think we did that. Was that 2010?

### Page 735 1 DR. ANNA LOWIT: Just food though, just food. 

### 2 DR. KENNETH PORTIER: Oh, just food, that's 

### 3 right. Just the food part. But I think they've been working 

### 4 on that. 

### 5 DR. BRIAN BUCKLEY: Well it seems like a lot 

### 6 of the models are based primarily on an air exposure route and 

### 7 inhalation root, solely. And really, you've got to sum all the 

### 8 potential exposures. 

### 9 DR. KENNETH PORTIER: Jeff Dawson? 

### 10 DR. JEFF DAWSON: Just one other thing. I 

### 11 think this mentioned this yesterday, but in Appendix 1 of the 

### 12 document we gave a flavor of that. We took some of the 

### 13 scenarios of our risk assessment and put them in as a few 

### 14 representative ones to try to illustrate how we do that 

### 15 routinely in risk assessment, if you want to look at that. 

### 16 DR. KENNETH PORTIER: Dr. Sandy? 

### 17 DR. MARTHA SANDY: Yeah. And just to follow 

### 18 up on what you said, Dr. Portier, it was February 2011 that the 

### 19 panel looked at the PBPK/PD model. And one of the comments 

### 20 that was made by the panel at that time was you do need to take 

### 21 into account all routes of exposure, including the 

### 22 hand-to-mouth pathway, inhalation diet and others demo --

### Page 736 1 DR. KENNETH PORTIER: And barefoot in the 

### 2 house. Any additional comments on this question? Dr. Lowit? 

### 3 DR. ANNA LOWIT: I think we are good. 

### 4 Thanks. 

### 5 DR. KENNETH PORTIER: So Dr. Buckley, you got 

### 6 all the notes of all the discussion, right? Good. 

### 7 DR. ANNA LOWIT: So we're moving on to 

### 8 question 6? 

### 9 DR. KENNETH PORTIER: Do you want us to take 

### 10 a break while you guys reassess? 

### 11 DR. ANNA LOWIT: No. 

### 12 DR. KENNETH PORTIER: I think we are ready to 

### 13 go. 

### 14 DR. ANNA LOWIT: At the break we congressed, 

### 15 and I think the things that we heard didn't change our 

### 16 thoughts. So before we read question 6, Dr. Vicky Dallarco, 

### 17 Senior Advisor to our office director is just going to sort of 

### 18 lay out where we think what we've heard sort of at the 

### 19 thousandth, 10 thousandth foot level in order to setup question 

### 20 6. 

### 21 DR. VICKY DALLARCO: Thank you, Anna. Yeah. 

### 22 We were huddled during the breaking making sure that we had our

### Page 737 1 head around everything that was being said, and the discussion 

### 2 has been excellent. And over the last couple of days, you have 

### 3 really helped us in pointing out strengths and limitations and 

### 4 uncertainties around the lines of evidence. 

### 5 But the analysis that we'll do at this 

### 6 compound is going to be unique for us, and so clarity is really 

### 7 important. So we want to make sure we understand what you're 

### 8 saying, that's why we want to repeat it and make a couple of 

### 9 points. And what you're actually doing around these different 

### 10 questions, you're laying down our roadmap and we want to make 

### 11 sure we understand that roadmap. 

### 12 And so the points I'm going to make will get 

### 13 at some of the comments that we made today. So what we heard 

### 14 yesterday is, the rat is not an invalid model to use for a 

### 15 point of departure. But we heard today, there is uncertainty 

### 16 around that model. 

### 17 And we also heard the recommendation that, to 

### 18 look at the epidemiology in a quantitative way or a 

### 19 semi-quantitative way to characterize the uncertainty around 

### 20 the rat or the rat points of departure. And so, as we do that, 

### 21 Anna has emphasized in the remarks that she's made how 

### 22 important it is to understand as we look at the different

### Page 738 1 approaches that you're recommending -- like the idea approach 

### 2 to do that is that PK model for this susceptible population 

### 3 that we don't have. 

### 4 But we heard some other approaches that we 

### 5 could do that sort of comparison dose reconstruction. But as 

### 6 we look at these different approaches, and some of the 

### 7 uncertainties and limitations you've been discussing need to be 

### 8 put in the context of these approaches as we do these 

### 9 comparisons or this bounding. I actually thinks this helps 

### 10 sets up 6, so you want to make sure that you have uncertainty 

### 11 here with this rat model. You're using the human information 

### 12 or the Epi data to try to characterize that, and with these 

### 13 different approaches, to have a clear understanding of, well, 

### 14 what are the assumptions we're invoking as we do that. What 

### 15 are the uncertainties, because that's important to understand. 

### 16 In other words, you're not invoking so many assumptions. You 

### 17 have so much uncertainty here in trying to characterize the 

### 18 uncertainty there. 

### 19 So that clarity, kind of bringing that 

### 20 together will be helpful as you talk about the approaches in 

### 21 how we do this. And when we look at the observational findings 

### 22 in the epidemiology and where we see neurobehavioral effects in

### Page 739 1 the rodents, cholinesterase inhibition, if you look at that, 

### 2 we're talking around four orders of magnitude difference. And 

### 3 we understand that rats and humans, the dynamic process of 

### 4 neurodevelopment is different in terms of timing. We 

### 5 understand there're pharmacokinetic differences. You've done a 

### 6 very good job in pointing that out, but it would be helpful if 

### 7 you could provide some perspective about how the combined 

### 8 physiology between the rat and human could account for so many 

### 9 orders of magnitude difference to try to put that in a 

### 10 biological context or some biological plausibility around that. 

### 11 Or maybe some of these approaches that you're suggesting that 

### 12 we do can help maybe narrow that margin down a little bit so 

### 13 it's more plausible, more reasonable. So anyway, that's 

### 14 basically some of the points we heard and some of the 

### 15 connections. And I don't know if anybody wants to make any 

### 16 comments about that, but did I get it right? 

### 17 DR. KENNETH PORTIER: Dr. Meek? 

### 18 DR. BETTE MEEK: Yeah. I think it's a 

### 19 question not just of the biology as well, Vicky, but it's why I 

### 20 was pushing this morning to have some bounding, some 

### 21 semi-quantitative bounding on the estimates from the 

### 22 epidemiological studies. And the way that that's traditionally

### Page 740 1 done is that people who have a lot of experience in the area 

### 2 have some idea of how much impact one of these confounding 

### 3 variables might have, whether it's a two-fold or 10-fold or -- 

### 4 I was asked myself, for example, to look at 

### 5 uncertainty in the context of replacing the kinds of default 

### 6 assumptions that we normally use with kinetic and dynamic data 

### 7 for adjustment factors. And initially I said, "Well, I don't 

### 8 think I can easily do that." And then when I thought about it, 

### 9 I could because I had a pretty good idea of, you know, when we 

### 10 replace the default assumptions with relevant kinetic and 

### 11 dynamic data what the bounds on that were. You know. Was it 

### 12 10, 100, 1000? 

### 13 So I would challenge particularly the 

### 14 epidemiologist to think a little bit about what these 

### 15 uncertainties that we have in the epidemiological studies. For 

### 16 example, there could be exposure to other pesticides. But does 

### 17 that explain a forward or magnitude difference? I mean there 

### 18 needs to be some semi-quantitative thinking in that direction, 

### 19 so that's kind of what I was trying to get at this morning. 

### 20 DR. KENNETH PORTIER: Anyone else want to 

### 21 react? Dr. Buckley? 

### 22 DR. BRIAN BUCKLEY: Yes. Something you said

### Page 741 1 about not having a PBPK model. I know that we described one 

### 2 for kids, and I thought we had described at least one or two 

### 3 for adults. But more than anything else, what have been said 

### 4 now by three or four or five panelists, if you have a mechanism 

### 5 to validate your PBPK model, whichever one you chose. And we 

### 6 can't stress that enough in terms of importance with whether or 

### 7 not you want to utilize a PBPK model that you use the dose 

### 8 reconstruction to figure out whether or not the multiple 

### 9 studies that have environmental media and urine values, that 

### 10 you have the two components you need to decide whether or not 

### 11 the PBPK model that you want to use is valid. 

### 12 Now, we can argue about the fetal component 

### 13 and we can argue about whether or not the kid PBPK model is the 

### 14 one that you want to go with. But having the ability to 

### 15 validate is paramount in assessing whether or not a PBPK model 

### 16 can be utilized. 

### 17 DR. KENNETH PORTIER: I was sitting there 

### 18 thinking. I think we're all kind of processing. Dr. Collier? 

### 19 20 DR. ABBY COLLIER: So one of the things that 

### 21 I struggle with when you're talking about four orders of 

### 22 magnitude, and I've sort of been thinking about it the last few

### Page 742 1 days, is the way in which animal data are used to extrapolate 

### 2 to a whole in vivo person. 

### 3 And if you think about it from like a 

### 4 pharmacology drug development paradigm, we don't skip in vitro 

### 5 human, like metabolic studies and things. And perhaps some of 

### 6 the orders of magnitude are coming from -- interspecies 

### 7 extrapolation is well-recognized and has its uses, but in some 

### 8 cases I can be far, far out. And I'm wondering if, for 

### 9 chlorpyrifos, not so much the behavioral data which I cannot 

### 10 speak to, but more for things like the metabolic data, if we're 

### 11 not really missing something here, because we're trying to jump 

### 12 too far from your rat metabolism into a human outcome, and I do 

### 13 wonder if that's where some of your variability comes from, and 

### 14 I've been thinking about that pretty much since I got here. 

### 15 That's the suggestion that I can offer. 

### 16 DR. KENNETH PORTIER: Dr. Harry? 

### 17 DR. JEAN HARRY: So, totally different 

### 18 comment than anything that's been said. But one of the things 

### 19 you asked was, you were asking about how do you sort of deal 

### 20 with this animal difference to the human? And the thing that 

### 21 popped in my head is that, we could say timing. We could say 

### 22 length of time that it takes for the brain to develop is

### Page 743 1 shorter in one. But the problem is we are looking at the 

### 2 rodent brain as a rodent version of the human brain and there 

### 3 are a number of differences. I mean there are a number of 

### 4 things that are the same. There's the different regional 

### 5 differences and the structural comparisons, the different 

### 6 nuclei of neurons, the transmitters that control different 

### 7 things. So there's a lot of things that are very similar. 

### 8 But just as we mentioned in the in vitro 

### 9 study, if you start to take out a neuro and you look at it in 

### 10 isolation, it is going to perform, more than likely, very 

### 11 differently than when you look at it in its glee environment 

### 12 around it. 

### 13 So that made me think, you know, one of the 

### 14 different things, is, most of the things that you're looking at 

### 15 were intercepted as looking at a neuronal component. And in a 

### 16 rodent, the neurons and glee and atrocities are sort of split 

### 17 about 50/50. When you get to the human it's a much higher 

### 18 proportion of the cells within the brain or the atrocities, not 

### 19 the neurons. 

### 20 So, while you've got this whole dynamic -- 

### 21 and we have the timing -- we also have the fact that the brain 

### 22 is not just a smaller version of the human brain, which is

### Page 744 1 another whole dynamics that you wish you didn't have to go 

### 2 into. But if we do, and being a glee person, if we continue in 

### 3 the way that we look at things on a neuronal-centric type 

### 4 thing, we lose a large proportion of the cells within the human 

### 5 brain that have very dynamic roles. You know. The neurons are 

### 6 not going to work unless the atrocities are there. They have 

### 7 all the transmitters, all the receptors. You know. So there 

### 8 is a whole world out there that really hasn't gotten into any 

### 9 of these interpretations in even the in vitro models. So it's 

### 10 not helping you any but it was one thing that you asked that 

### 11 sort of popped in mind. That is something we now know within 

### 12 the last few years that's very different between the rodent 

### 13 brain in the human brain. 

### 14 DR. KENNETH PORTIER: Dr. Popendorf? 

### 15 DR. WILLIAM POPENDORF: Just following up on 

### 16 that a bit. The other day, yesterday perhaps, someone 

### 17 mentioned using primates as an example and I would imagine that 

### 18 would be a step in the right direction. Of course, we are 

### 19 adding years to your solution here, but I would be curious to 

### 20 follow-up. I mean how much more similar would a primate brain 

### 21 be than a rodent brain? 

### 22 DR. JEAN HARRY: A lot more similar. And a

### Page 745 1 lot of people have been proposing things like the African green 

### 2 monkey or a marmoset. So in a way it's almost what aspect of 

### 3 brain development you want to look at that might be closer and 

### 4 the distribution. So you don't always have to go to a higher 

### 5 order of the non-human primate. There are some other small 

### 6 primates that you could look at in a much more reasonable 

### 7 fashion, and at which there are colonies around the country 

### 8 that you could use those -- 

### 9 There was like an African green monkey colony 

### 10 at Wake Forest quite a while ago, but those are being 

### 11 incorporated a lot more into some of the neurodegenerative 

### 12 disease models and things like that. So I think they are 

### 13 starting to find that there is a lot of power by looking at 

### 14 something in the middle versus a Reeses or a rat. There are 

### 15 lots of things in the middle that could work. 

### 16 DR. KENNETH PORTIER: Dr. Buckley? 

### 17 DR. BRIAN BUCKLEY: One other thing, getting 

### 18 back to your floaters and magnitude; Dr. Lu said this with the 

### 19 last question but I want to re-emphasize. Don't underestimate 

### 20 the power of low-does long-term versus acute exposure. Big 

### 21 difference, especially over the developmental timeframe. 

### 22 DR. KENNETH PORTIER: I've been thinking

### Page 746 1 about that too. I don't know enough about the developmental, 

### 2 but I always wonder if one acute event at the right time could 

### 3 actually be potentiated and produce this big output, that full 

### 4 order of magnitude could be that one exposure, but we don't 

### 5 know what that time is. I haven't heard anybody say when in 

### 6 the developmental stage would we expect to see a perturbation 

### 7 that would impact IQ at 7 years old. That would be nice to 

### 8 know but I don't think anybody knows that. Dr. Harry? 

### 9 DR. JEAN HARRY: So, I don't know if you want 

### 10 to step back into it, but I guess if you go back and look in 

### 11 the LED (phonetic) literature. And I know over the many years 

### 12 of sitting on this panel at different things there's a lot of 

### 13 concern about the time for hand-to-mouth, so the exposure -- 

### 14 but if you look at some of the LED literature and -- I don't 

### 15 know if the Mercury does it or not, but the LED somewhat 

### 16 identifies age three as being very, very sensitive to 

### 17 perturbations that come in. And that's probably where some of 

### 18 the animal studies have been modified to try to look at 

### 19 postnatal day 10 in an animal, thinking that you might be 

### 20 catching about that age 3 in timing, to say if I disrupt 

### 21 homeostasis by this chemical on-board at this critical time, 

### 22 would I potentially have a long-term effect. And I think in

### Page 747 1 the developmental biology field, you're going to find people 

### 2 believe that that can be true. You could have that one little 

### 3 episode. 

### 4 And if you look at some of the drug of abuse 

### 5 literature you could probably follow and get supportive data on 

### 6 that, that one exposure just at that time, whether it's in the 

### 7 last trimester or second trimester when you know things are 

### 8 happening, that if you disrupt that, everything builds upon the 

### 9 time before. So you can have this huge accelerated and 

### 10 augmented type effect that you may not see if you have low dose 

### 11 exposure that's not enough to reach a threshold, and the system 

### 12 can change its homeostatic balance so it develops properly. 

### 13 Everything is sort of delayed together. 

### 14 DR. KENNETH PORTIER: I think now we're ready 

### 15 to go to question 6. 

### 16 DR. ANNA LOWIT: The 2009 NRC Report, Science 

### 17 and Decisions focused on improving the technical analysis 

### 18 through the development and use of scientific knowledge and 

### 19 information to promote more accurate characterizations of risk, 

### 20 and thus improving the utility of risk assessment for risk 

### 21 management decisions. 

### 22 The NRC Report also pointed out that

### Page 748 1 regulatory risk assessment does not routinely approach public 

### 2 health and environmental problems by arraying a wide range of 

### 3 options for dealing with them. 

### 4 In the case of chlorpyrifos, in light of the 

### 5 questions, discussions of question 1 through 5, please provide 

### 6 guidance for assessing and presenting the range of plausible 

### 7 responses at given doses in the effect of the overall 

### 8 uncertainty and variability around that range. 

### 9 DR. KENNETH PORTIER: Dr. Meek? 

### 10 DR. BETTE MEEK: Well this is a probably a 

### 11 continuation of the discussion we've initiated. 

### 12 So as I've indicated, in response to another 

### 13 question, I really think it's important to maximally utilizing 

### 14 the available data and dose response from the epidemiological 

### 15 studies as a basis at least to bound referenced doses developed 

### 16 in the basis of points of departure from animal data. And 

### 17 again to the extent possible, we are going to have to 

### 18 characterize around those different estimates our degree of 

### 19 uncertainty. And again, that's why I was kind of pushing for 

### 20 at least some semi-quantitative bounding of the dose response 

### 21 relationship from the human studies based on the impact of the 

### 22 uncertainties.

### Page 749 1 This would perhaps clarify the basis for a 

### 2 conclusion that the uncertainties associated with one or other 

### 3 are similar, hugely different. But it's a missing part of the 

### 4 equation from my perspective, currently, as to how we should be 

### 5 using the data on dose response in relation to predicted 

### 6 outcome here. 

### 7 So I think we lose important information in 

### 8 collapsing a huge database on dose response to even the single 

### 9 or a couple of points of departure. So, for example, for risk 

### 10 management purposes, it would be helpful to characterize the 

### 11 nature of the risk above the reference dose. And for that 

### 12 reason, I think that it's helpful to present an array of dose 

### 13 response data for different types of effect, again, bounded by 

### 14 their relative uncertainty. 

### 15 To me, it's much more informative and 

### 16 presents the point of departure for the referenced dose in the 

### 17 context of the range of effects reported in the broader 

### 18 database. 

### 19 I'm hopeful, as well, that it will also 

### 20 promote our relying on more certain rather than the most 

### 21 conservative data in every case. And as a minimum, I think 

### 22 it's helpful in communicating the relative degree of protection

### Page 750 1 provided by the selected point of departure. So I think 

### 2 there's been some confusion in some of the discussion around 

### 3 the table about whether we are confusing acute and chronic 

### 4 effects here or whether we are selecting the point of departure 

### 5 on the basis of it's expected to be protective for other types 

### 6 of effects. 

### 7 So since this last question is rather broad, 

### 8 I wanted to raise one other issue, and it relates to 

### 9 comparability within the agency across compounds, because since 

### 10 I tend to think of weight of evidence in this context -- and it 

### 11 was an issue that was raised by Steve on the first day, so by 

### 12 way of comparison with other datasets. 

### 13 So part of the value of the framework for 

### 14 integrative analysis to evaluate multiple lines of evidence is 

### 15 to enable us to draw inference on weight of evidence from the 

### 16 totality of the data. 

### 17 And so, for example, in the document it's 

### 18 stated that there is a number of known developmentally 

### 19 neurotoxic chemicals with well established relationships 

### 20 between exposure and neurological disorders in humans for which 

### 21 a definitive mode of action has not been established. For 

### 22 example, lead, methyl, mercury and ethanol.

### Page 751 1 So it seem to me that it might at least be 

### 2 helpful as a basis for characterizing our confidence in the 

### 3 results of the epidemiological studies for this dataset to 

### 4 compare the nature of the extent of the data as a basis to 

### 5 estimate dose response in humans with that of other substances, 

### 6 such as lead and mercury. So then you get at least a relative 

### 7 since of how confident you are in this dataset compared to 

### 8 other datasets that you've used for similar applications in the 

### 9 agency. And that's all that I had. 

### 10 DR. KENNETH PORTIER: Dr. Lu? 

### 11 DR. CHENSHENG LU: NRC like to draw big 

### 12 pictures and make recommendations. I was hoping that they 

### 13 would use chlorpyrifos as their case study to see whether they 

### 14 can come up with this kind of recommendation or not, which is 

### 15 very challenging. 

### 16 But regardless, though, previously NRC 

### 17 published a book that led to the passage of Food Quality 

### 18 Protection Act. So this may lead to something even more 

### 19 significant than just food quality protection that -- I don't 

### 20 know. 

### 21 But again, I want to re-emphasize my strong 

### 22 belief that, in the case of chlorpyrifos, I would suggest the

### Page 752 1 agency to separate the endpoint from chronic to acute. 

### 2 Mode of action is obviously a legitimate 

### 3 approach, looking into the toxicological endpoint. But knowing 

### 4 the animal data and the recent human study, it's obvious that 

### 5 in terms of acute and chronic does not match. 

### 6 The human study 2009 indicated that you have 

### 7 to reach certain amounts of exposure in which ordinary people 

### 8 will never experience, will have some sort of measurable 

### 9 acetylcholinesterase inhibition. However, we also see the 

### 10 outcome from the Columbia Study before and after the phase-out 

### 11 of the chlorpyrifos that those adverse neurobehavioral outcomes 

### 12 disappear. 

### 13 I mean, one of the questions we're asking is 

### 14 whether it's true for chlorpyrifos to likely play a role in 

### 15 those adverse neurobehaviors, if EPA can conduct further 

### 16 analysis to confirm with a certain degree of confidence that 

### 17 that's the case. 

### 18 Now the question is that, whether those 

### 19 neurobehavioral outcomes will be meaningful to, in terms of 

### 20 reflecting on acetylcholinesterase inhibition. Again, question 

### 21 number 5, I'd also say, for sure that you will not see any 

### 22 inhibition, again, because of the study that's recently

### Page 753 1 published. That leads to my belief that this is two different 

### 2 things. 

### 3 So in terms of point of departure, it's 

### 4 almost in evidence that agency needs to come up with two points 

### 5 of departure, one for the acute, one for the chronic and focus 

### 6 on neurobehavior. That's what I think will lead to a better 

### 7 outcome. Thank you. 

### 8 DR. KENNETH PORTIER: Dr. Sandy? 

### 9 DR. MARTHA SANDY: I'm going to focus on some 

### 10 broader issues related to the risk characterization. This 

### 11 Lanson (phonetic) decisions report is recommending that, as you 

### 12 do a risk assessment you take into account vulnerability of the 

### 13 populations, so vulnerability factors and background exposures, 

### 14 as well as mode of action. 

### 15 And as we have discussed over the last few 

### 16 days, we know that there are no developmental effects that are 

### 17 seen in the epidemiology studies, and the odds ratios measures 

### 18 of effect are pretty strong, so, as it was discussed, we think 

### 19 those are real effects. The levels at which they were seen 

### 20 appear to be levels that are not outside the range of levels of 

### 21 chlorpyrifos measured in the U.S. population based on NHANES 

### 22 data, so there are low level effects.

### Page 754 1 We have discussed the pharmacokinetic 

### 2 modeling needs to somehow come to a good estimate of what the 

### 3 exposure might've been during that prenatal period. But as we 

### 4 do the risk assessment, you're going to need to discuss in the 

### 5 risk characterization the uncertainty that would be due to -- I 

### 6 would say the major uncertainty as whether protecting against 

### 7 acetylcholinesterase inhibition is going to protect against 

### 8 neurodevelopment effects. 

### 9 Another major uncertainty is whether the dose 

### 10 response data for acetylcholinesterase inhibition in pregnant 

### 11 rats is relevant to pregnant humans and their fetus. Then of 

### 12 course there are other uncertainties. 

### 13 Variability would be discussed in terms of 

### 14 differences in biologic susceptibility, such as differences in 

### 15 health and disease status, genetics. And here we have talked 

### 16 about the metabolic polymorphisms related to chlorpyrifos 

### 17 metabolism. And life-stage, of course, is another important 

### 18 variability. So we don't know what the critical window is 

### 19 during the prenatal period for exposure to cause these adverse 

### 20 effects. It might be the entire period. It might be a certain 

### 21 period. So in looking at a cohort study and comparing one 

### 22 cohort to another, you might have some variability in the dose

### Page 755 1 response estimates from that. 

### 2 And then there's background exposures that 

### 3 could be other exposures to chlorpyrifos if we are looking, for 

### 4 example, at the Columbia study. And because we have air 

### 5 measures but we don't have dietary measures or other sources, 

### 6 in the dose reconstruction, there might be some variability due 

### 7 to, I guess that would be uncertainty, because we don't have 

### 8 definitive information and estimates of what each route 

### 9 contributed. 

### 10 Another source of background exposure could 

### 11 be, as we have just discussed, exposures to other chemicals 

### 12 that might compete for metabolic enzymes interfering with other 

### 13 stages in the proposed adverse outcome pathway. We don't 

### 14 really have adverse outcome pathways either. There is 

### 15 uncertainty there too. 

### 16 There is a lot to be discussed in the risk 

### 17 characterization, depending upon what you actually use to 

### 18 derive your point of departure and how you come to your health 

### 19 protective number, and these are just some of the things that 

### 20 should be covered. 

### 21 DR. KENNETH PORTIER: Dr. Sandy, one of the 

### 22 things that I think you missed is that, at least in this case,

### Page 756 1 we have the epidemiology in what we probably all agree is the 

### 2 most susceptible population, in the sense that it's done 

### 3 pregnant women who have likelihood of higher exposure. 

### 4 DR. MARTHA SANDY: I am aware of that. I 

### 5 don't know where the agency is going -- what information 

### 6 they're going to use to derive at dose response and a point of 

### 7 departure. Right now they are proposing to use the rat data, 

### 8 so I'm bringing up that. 

### 9 And in discuss just in risk characterization, 

### 10 you have a number you're going to discuss is it protective. 

### 11 You're going to say that we think the most vulnerable 

### 12 population is likely the fetus. And hopefully you'll be able 

### 13 to say with some confidence you think you're protecting the 

### 14 most vulnerable population. I'm just saying these are factors 

### 15 to be discussed in the risk characterization. 

### 16 DR. KENNETH PORTIER: Anyone else would like 

### 17 to add to this discussion? It's kind of a broad question, so 

### 18 anything you say kind of can get in here. It's your 

### 19 opportunity. Dr. Vena? 

### 20 DR. JOHN VENA: It seems to me that, at the 

### 21 beginning when you approached this, you said that you wanted to 

### 22 take each of these buckets, these pieces of information that

### Page 757 1 you've collected and that we've talked about separately. And 

### 2 now the task is the putting it together and saying, okay, 

### 3 what's the full picture of this and how can we interpret the 

### 4 plausible outcomes in humans, and what the epidemiology says in 

### 5 the context of the quality of the exposure measurements, the 

### 6 dose response measurements that we have, and in the human 

### 7 studies, what the animal evidence tells us with regard to what 

### 8 those potential exposure levels are or could be and how they're 

### 9 related to those outcomes in animals. And given that, what are 

### 10 the potential measures of risk. You said utility of the risk 

### 11 assessment for risk assessment decision, is then to put into 

### 12 context the epidemiology relative to all the other stuff. 

### 13 And I think you'd have a very difficult job 

### 14 because of the inconsistencies between some of what the 

### 15 epidemiology says, the issue of whether it's an acute or a 

### 16 chronic exposure, and in particular, what's the mode of action. 

### 17 18 You know. So to me, putting into context 

### 19 what the Epi means relative to the mode of action and the fact 

### 20 that it's likely, the findings appear to be not at doses that 

### 21 are related to the mode of action that you're seeing mostly in 

### 22 the animals and the acetylcholinesterase inhibition.

### Page 758 1 So you're in a tough spot, I think. But 

### 2 somehow, you have to do that with regard to taking the 

### 3 epidemiology and thinking about it with your best available 

### 4 evidence from each one of those buckets. And so I think each 

### 5 of these points provided you some very specific guidance into 

### 6 how to kind of gage that uncertainty, what's the variability 

### 7 around those uncertainties and then putting these things in the 

### 8 context with regard to making decisions about what's the best 

### 9 thing we can do to protect folks who are exposed at the levels 

### 10 that are in the environment and that maybe the NHANES will tell 

### 11 us what the current exposures are of some of these compounds, 

### 12 et cetera. So that's my view in terms of -- I'm not sure if 

### 13 that's what you're trying to get at with this question. 

### 14 DR. KENNETH PORTIER: As I read it again, I 

### 15 guess it was something Dr. Meek said about the -- once you're 

### 16 all said and one, your point of departure probably needs to be 

### 17 stated in something that the public health community can react 

### 18 against. So instead of as an internal dose, you really want a 

### 19 biomonitoring level below which you wouldn't want to keep the 

### 20 population. 

### 21 And I think part of what we're hearing here 

### 22 is them saying that it's nice to talk about a point of

### Page 759 1 departure that talks about cholinesterase level in the blood of 

### 2 a pregnant woman, but that's not going to help the public 

### 3 health people really protect -- you need to bring it back out, 

### 4 right? Sometimes we don't see those kinds of issues. Dr. 

### 5 Vena? 

### 6 DR. JOHN VENA: Just one thing to add also is 

### 7 that, there is also some information in the epidemiology that 

### 8 says there may be susceptible subgroups based on either their 

### 9 genetic background or makeup or ability to metabolize things, 

### 10 et cetera, so that also has to be considered as part of this as 

### 11 well, in terms of thinking about the variability around those 

### 12 dose ranges, et cetera. 

### 13 DR. KENNETH PORTIER: Dr. Lu? 

### 14 DR. CHENSHENG LU: Well the one thing I look 

### 15 at the question and I say that it has to be public health 

### 16 implications. So the question is, for example, I can rephrase 

### 17 this question and say, "Well, which one has more public health 

### 18 implications? The acute inhibition of acetylcholinesterase or 

### 19 the neurobehavior outcome that we've seen in Columbia study?" 

### 20 So obviously I will say I don't know. But most people would 

### 21 say, "It's the Columbia Study outcome that has more public 

### 22 health implication than the acetylcholinesterase inhibition."

### Page 760 1 So again, I think somewhere -- I couldn't 

### 2 remember which question. I make a suggestion that taking the 

### 3 data from Columbia study, in terms of what are the levels of 

### 4 chlorpyrifos residues in cord blood samples, and use those 

### 5 numbers to do a study to see whether those levels can cause any 

### 6 acetylcholinesterase inhibition. And I think EPA already sort 

### 7 of said it's highly unlikely it would have any inhibition at 

### 8 all, right? So again, that kind of paved the road into this 

### 9 so-called separation of POD from chronic to acute. Because, 

### 10 again, you don't see inhibition under those levels, but those 

### 11 levels does cause neurobehavior outcome. And that's my 

### 12 justification into this POD from acute to chronic. I think I 

### 13 can justify this. 

### 14 And until we have a better picture in terms 

### 15 of how to do this, I wouldn't worry about variability or 

### 16 uncertainty issues because, depending upon how you're going to 

### 17 look into the separated POD, you don't even know what kind of 

### 18 variation you're going to bring into this whole exercise. 

### 19 But I think the concept has to be agreed upon 

### 20 not just the panel, but the agency in terms of looking at this 

### 21 cholinesterase inhibit chemicals, do we need a POD look into 

### 22 acute versus chronic.

### Page 761 1 DR. KENNETH PORTIER: Dr. Buckley? 

### 2 DR. BRIAN BUCKLEY: In dealing with 

### 3 uncertainty, one thing that I hope didn't get glossed over, 

### 4 because it was only addressed in the very last question, which 

### 5 absolutely can't discount the role of multiple exposures to 

### 6 multiple chemicals and their potential effects. So whenever 

### 7 you decide where that protective line is and with the brain 

### 8 trust here, we're not going to give you a definitive number. 

### 9 But keep in mind that some of the effects that you may have 

### 10 seen may have been because of additive effects or even worse 

### 11 with some of the other co-exposures. And it's just something 

### 12 that you need to keep in mind when you decide on what 

### 13 uncertainties are going to be utilized in a protective fashion 

### 14 versus which are just uncertainties. 

### 15 DR. KENNETH PORTIER: I think we've squeezed 

### 16 the panel dry at this point. Any additional comments, Dr. 

### 17 Lowit? Typically what we do at the end of the meeting like 

### 18 this is we kind of do a go-around-the-room. If there are any 

### 19 additional issues or thoughts that you'd like to possibly get 

### 20 down on paper, when we do our final report, we certainly are 

### 21 going to address the six sets of questions that EPA has put 

### 22 before the panel and we have a lot of material for that.

### Page 762 1 But sometimes issues are raised that we just 

### 2 didn't get to that you'd like to at least put down at the end 

### 3 of the report and say, "Oh, maybe EPA should be thinking about 

### 4 this as well." So at this point, we'll just kind of go around 

### 5 the room and see if there's any additional issues for the next 

### 6 SAP. And I'll pick on Dr. Meek here. She's still warm from 

### 7 the last question. 

### 8 DR. BETTE MEEK: So, I actually have one, and 

### 9 this may exist and it may just be that I haven't seen this in 

### 10 the documentation for this meeting. But it would be extremely 

### 11 helpful at the outset of discussions of weight of evidence on 

### 12 particular types of effects to have a priori (phonetic) 

### 13 criteria for judging the adequacy of the studies so that those 

### 14 would be stated at the front end, because it would facilitate 

### 15 input, I think, of panel members, others in term of impacting 

### 16 on the discussion of all of the studies, as opposed to looking 

### 17 at each individual studies. 

### 18 In any case, I recognize well that not all 

### 19 factors can be taken into consideration in that manner, but it 

### 20 would at least be useful as a starting point. 

### 21 DR. KENNETH PORTIER: So this gets back to 

### 22 the issue of, you know, the report should at least say how many

### Page 763 1 dams did they use, sample size, little things like that that 

### 2 help us understand the design and be able to replicate this 

### 3 study. 

### 4 DR. BETTE MEEK: In fact, it came up in some 

### 5 of Jean's comments about, you know, these have been specified, 

### 6 for example, for publication in terms of actually just the data 

### 7 that needs to be presented to evaluate the adequacy of the 

### 8 study. And you weight some of those factors more than others 

### 9 if you are evaluating for risk assessment purposes, so I think 

### 10 we need to be a bit explicit about that up front. 

### 11 DR. KENNETH PORTIER: Dr. Popendorf? 

### 12 DR. WILLIAM POPENDORF: Well there was one 

### 13 thing that -- I guess this is my chance to add -- as I was 

### 14 going through talking about the Garabrant study in particular. 

### 15 I sort of paused and I'm trying to read my notes, but I was 

### 16 making the comparisons in the field study. The chlorpyrifos 

### 17 was fresh and we can make some reasonable assumptions that 

### 18 there wasn't TCPy in the environment. In the Garabrant Study 

### 19 it was an in-factory typesetting, so there is a very good 

### 20 chance that there was residual TCPy in the facility to which 

### 21 they were exposed and contributing to that TCPy, which just 

### 22 adds one more uncertainty to that study.

### Page 764 1 Other than that, I mean, I'm thinking that 

### 2 overall, you know, you've presented a lot of information. 

### 3 We've talked about a lot of things that leave a lot of -- and 

### 4 we can appreciate the uncertainty with which you're dealing. 

### 5 And if you conclude that at the end there is not enough 

### 6 evidence to judge that there was effects from this population, 

### 7 I hope that it wouldn't go away as an issue. 

### 8 There may not be enough evidence, but it 

### 9 doesn't mean that it doesn't happen. And that's part of your 

### 10 role as the EPA, is to protect us all from this. So I for one 

### 11 appreciate the continuing interest and continuing to ask the 

### 12 questions that you're asking us. 

### 13 DR. KENNETH PORTIER: Dr. Ryan? 

### 14 DR. BARRY RYAN: While I've made a number of 

### 15 suggestions along the way of modification or new studies that 

### 16 should be put together, or would actually add to this, I think 

### 17 the EPA has done an excellent job putting together this report. 

### 18 And what is out there is what is out there, and they've done a 

### 19 very good job of reviewing that. 

### 20 I would still like to say there are more 

### 21 things to be done. I think we've all said in our papers 

### 22 before, more research is needed, and I think this is a

### Page 765 1 continuing interest of all of us here. The work is good. 

### 2 There's more to be done. 

### 3 DR. KENNETH PORTIER: Dr. Terry? 

### 4 DR. ALVIN TERRY: There was this one thing I 

### 5 remember in discussions of Dr. Vorhees the other day that just 

### 6 sort of came back to my head, that we've seen very detailed 

### 7 critiques of the epidemiology of the rodent neurobehavioral 

### 8 data, the in vitro data. But what we didn't hear from was a 

### 9 neuropsychologist to critique the neuropsych data that's being 

### 10 used in this epidemiology. 

### 11 I think between now and the next couple of 

### 12 years, it would be nice to hear from -- or at least, you would 

### 13 probably want to hear from someone that -- 

### 14 DR. KENNETH PORTIER: Dr. Vena? 

### 15 DR. JOHN VENA: I just want to say that it 

### 16 was a pleasure to meet everyone here and work with you. And 

### 17 this is my first time in this group and SAP and I learned a 

### 18 lot. Thank you. 

### 19 DR. KENNETH PORTIER: Dr. Vorhees? 

### 20 DR. CHARLES VORHEES: Well I'd echo that. I 

### 21 did learn a lot myself. I was very impressed by the review of 

### 22 the epidemiological evidence, the Columbia study in particular,

### Page 766 1 and what the epidemiologist had to say about it. And I was 

### 2 impressed by the magnitude of some of those effects. 

### 3 And it seems to me, while I didn't particular 

### 4 find that the animal data was very helpful, it seems like the 

### 5 human Epi studies are very helpful. And so it seems to me that 

### 6 those could be relied upon, at least that was my take on it, to 

### 7 provide a great deal of guidance in how to set some kind of 

### 8 uncertainty or protection level. So thank you. 

### 9 DR. KENNETH PORTIER: Dr. Young? 

### 10 DR. HEATHER YOUNG: I'm just going to say 

### 11 ditto Dr. Vorhees. It's exactly what I wanted to say. 

### 12 DR. KENNETH PORTIER: Dr. Sandy? 

### 13 DR. MARTHA SANDY: I agree with that. And 

### 14 I'd add that the EPA consider getting some more animal data on 

### 15 dose response, reiterating what I've said before, looking at 

### 16 acetylcholinesterase inhibition in low-dose studies. We're 

### 17 also looking for some of the stronger neurodevelopment effects 

### 18 in animals, if you feel that you need to use the animal data as 

### 19 well as the Epi data. 

### 20 DR. STEVE CLANEY: I just want to echo the 

### 21 fine job by the agency. And hopefully this panel will help set 

### 22 a path forward. It seems like a lot of ground to cover.

### Page 767 1 DR. KENNETH PORTIER: Dr. Pope? 

### 2 DR. CAREY POPE: Well I guess I'm a little 

### 3 overwhelmed over the last few days thinking about the problems 

### 4 with behavioral studies, animal studies and the problems with 

### 5 all studies, I guess. 

### 6 I mean, from an extreme biologist 

### 7 perspective, you'd like to think that you can kind of confine 

### 8 variables and just look at the effect of one chemical, for 

### 9 example. But as we've discussed, I mean even under these kinds 

### 10 of conditions there are things that can go wrong that you can't 

### 11 think about ahead of time. 

### 12 And not being an epidemiologist and kind of 

### 13 listening to people talk about these studies, I mean there are 

### 14 all kinds of ways you can poke holes at places and think about, 

### 15 well, was this an interacting factor or not? Was this covered? 

### 16 Was this controlled for? And I think, the totality of it is 

### 17 that, no matter what the dataset is, there's always going to be 

### 18 some holes that are very unclear. And so the four orders of 

### 19 magnitude difference in responses, I mean that's a big hole to 

### 20 cover for me. 

### 21 And the only thing that keeps coming back to 

### 22 me is this idea of the single point analysis from the Epi study

### Page 768 1 it's in, and Dr. Lu's recurrent idea about chronic versus acute 

### 2 and whether there -- I mean, there can obviously be a chronic 

### 3 response from an acute insult, particularly in a developing 

### 4 system. 

### 5 So there's lots to think about. I'm glad I'm 

### 6 not a risk assessor working for EPA. 

### 7 DR. KENNETH PORTIER: Why don't we go to Dr. 

### 8 Lu? 

### 9 DR. CHENSHENG LU: I kind of wonder sometimes 

### 10 what if those three studies all have the same protocol. What 

### 11 if they all measure chlorpyrifos in cord blood? The discussion 

### 12 would be very different in this SAP. And that kind of 

### 13 highlights the deficiency in terms of -- you know, it takes a 

### 14 lot of resources and effort to conduct first cohort study. And 

### 15 I don't even know when will be the next time that we're going 

### 16 to have another three brand new cohort study plan. 

### 17 So the last hope is the National Children's 

### 18 Study. However, according to Dr. Ryan, the outlook is not very 

### 19 optimistic at this, based on our discussion. And also, I 

### 20 understand that National Children's Study is a multiagency 

### 21 study. But I do hope that EPA would exercise their inference 

### 22 at the study design level at this that the study should take

### Page 769 1 multiple samples, looking at long-term exposure and so on and 

### 2 so forth. Otherwise, I think we're wasting another perfect 

### 3 opportunity to tackle issues of not just chlorpyrifos but other 

### 4 environmental chemical issues related to health outcome. 

### 5 DR. KENNETH PORTIER: Dr. Koutros? 

### 6 DR. STELLA KOUTROS: I wanted to say that 

### 7 it's my understanding that it's relatively new for the Epi 

### 8 studies to be included in this kind of discussion, so I really 

### 9 appreciate that we have the opportunity to be here and do that. 

### 10 And I really commend the agency on their review of the 

### 11 epidemiologist studies. 

### 12 DR. JEAN HARRY: First I'd like to say, just 

### 13 to reiterate what we've all said, is, the report is a very 

### 14 excellent piece of work. It's very nice to see. 

### 15 I'll reiterate a couple of people's comments, 

### 16 and one is, it's very nice to see the Epi data be brought in. 

### 17 And I think that takes the sting somewhat out of the very 

### 18 detailed review that Dr. Vorhees did of the behavioral data in 

### 19 the animals. But it's looking at the two together, and it's 

### 20 the whole body of it that's very nice to see that the agency's 

### 21 trying to look at all of that for, and to consider the in vitro 

### 22 for biological plausibility of whether there's anything showing

### Page 770 1 up there, not just to dismiss it, even though we are very 

### 2 hesitant about how you would put it in, but if it does start to 

### 3 support anything that you're looking for. Again, I think it's 

### 4 just trying to pull everything together, and you just wish that 

### 5 those behavioral studies had been a little stronger when they 

### 6 were initially designed. 

### 7 DR. KENNETH PORTIER: Dr. Gold? 

### 8 DR. ELLEN GOLD: I'm not sure I have much to 

### 9 add except I would like to again congratulate the agency on a 

### 10 very careful review and for incorporating the epidemiologic 

### 11 data using the framework that we developed a couple of years 

### 12 ago. And I think making policy is the root. Virtually, what 

### 13 you're doing is trying to make your best decisions in the 

### 14 absence of perfect knowledge. And given how carefully you 

### 15 undertook this effort, you know, I have some confidence that 

### 16 you'll reach some conclusions. 

### 17 There is lots of uncertainty but that's sort 

### 18 of the nature of the best. So I also wish you lunch. 

### 19 DR. KENNETH PORTIER: Dr. Collier? 

### 20 DR. ABBY COLLIER: I'd like to reiterate what 

### 21 the rest of the panelists have said regarding the really high 

### 22 quality of the report that we got, because we can't make

### Page 771 1 comments unless we get something really good to start with. 

### 2 I would like to make a small suggestion that 

### 3 if agency is going to focus on pregnancy and pediatrics they 

### 4 include maybe a few more people that specialize in toxicology 

### 5 and pharmacology in pregnant women and pediatrics. I know 

### 6 there's not a huge number of us out there, but I think it would 

### 7 eliminate the discussion somewhat. But other than that, it's 

### 8 been very large undertaking, but I see where agency is trying 

### 9 to come from and I think it's really fantastic, so thank you. 

### 10 DR. RUSSELL CARR: I just want to 

### 11 congratulate the agency on a well written document. There was 

### 12 a lot of useful information and I learned a lot, like I do 

### 13 every time I come to one of these. 

### 14 I also agree with Dr. Terry in that I think a 

### 15 developmental neurobiologist would have assisted us in 

### 16 understanding what some of the scores in the epidemiology study 

### 17 meant, and how we could understand that better. Because I 

### 18 think those are impact things that we need to understand, is 

### 19 that the human effects are real. And I think we definitely can 

### 20 all agree that there are some serious issues that we have to 

### 21 address there. But we also have to recognize also that it's 

### 22 not a lab study. And there are so many things out there and so

### Page 772 1 many other chemicals and so many opportunities for one chemical 

### 2 to alter the physiology of another chemical and to just change 

### 3 its projection. And so we just have to make sure that we just 

### 4 kind of understand that. 

### 5 DR. KENNETH PORTIER: Dr. Buckley? 

### 6 DR. BRIAN BUCKLEY: I want to start by 

### 7 applauding the EPA for taking on a more comprehensive risk 

### 8 model than they've taken on in the past, including the Epi 

### 9 data, but also hopefully exposure reconstruction or dose 

### 10 reconstruction data as well. 

### 11 What was enlightening to me, and it's 

### 12 something that we need to think about from a study perspective 

### 13 is that we don't generally study things that have already been 

### 14 done before. In other words, we don't apply to validate a 

### 15 study and repeat a study, and we don't fund those studies 

### 16 either. And I think that represents a serious deficit in our 

### 17 approach because we get to a situation like this and we can't 

### 18 even compare two studies because they'd been tweaked or done 

### 19 something different. So from a scientific perspective, it's 

### 20 something that we need to keep in mind and maybe reconsider the 

### 21 way we've done these things or will do them in the future. 

### 22 At the same time, I think that the Columbia

### Page 773 1 study is very important. And if you make guidelines based on 

### 2 it, I think it will probably wind up being your most protective 

### 3 that you can be. 

### 4 I think you should consider it very, very 

### 5 carefully in your risk assessment just because it is a human 

### 6 population. Even though the animal data doesn't provide a 

### 7 mechanism of action, per se, at least it probably provides more 

### 8 data than some of the other things that we've considered. 

### 9 I also echo the notion that it was a very 

### 10 well written report. 

### 11 DR. KENNETH PORTIER: Dr. Aschner. 

### 12 DR. MICHAEL ASCHNER: I'm the last one maybe. 

### 13 I also want to echo the good job. As I said yesterday, I 

### 14 think that the document was very logic, very easy to follow. 

### 15 And I think it framed the problem in a very logic constructive 

### 16 way. 

### 17 Leaving this place I've learned actually 

### 18 quite a bit of terminology that I wasn't aware of before. I'm 

### 19 not sure I understand it all, but one thing that comes across 

### 20 is that this is one of the few compounds that we have where we 

### 21 have epidemiological data, three sets from different studies 

### 22 where there's some uncertainties, but certainly there's quite a

### Page 774 1 bit of data. And one thing that I heard today or yesterday was 

### 2 about the possibility of pulling some of this data and pulling 

### 3 them together, which I think is going to be very useful. 

### 4 In some ways, the data here appear to be much 

### 5 more consistent than some of the other literature. I think Dr. 

### 6 Meek brought in lead and mercury and some others. I would say 

### 7 that when mercury -- for example -- I don't think you could do 

### 8 a lot of the things that came up today in the discussions 

### 9 because, actually, the data are very contradictory, which 

### 10 doesn't seem to be the case with chlorpyrifos. 

### 11 And for those of us that do animal studies, I 

### 12 think what this does is, it's sort of putting in perspective 

### 13 that dose is important. So if you heighten the dose, you 

### 14 always get some kind of an effect. But I think, when you get 

### 15 the effect, what you need to do is put in perspective and think 

### 16 whether it really mimics and reflects physiological levels of 

### 17 exposure. But those of us that are doing animal studies with 

### 18 whatever it is, I think it's a good lesson that, when we do 

### 19 those studies, we need to keep in mind physiological levels of 

### 20 exposure. 

### 21 And I think, in terms of the human data, 

### 22 there have been a lot of suggestions about implementing some

### Page 775 1 new methodologies or refining methodologies. And I think this 

### 2 is going to be useful not just for the chlorpyrifos. I think 

### 3 when you are done with this model, overall, the new type of 

### 4 risk assessment that you may come up with might be very 

### 5 beneficial and looking at many other compounds. So again, I 

### 6 would encourage you to do that because I think it's going to 

### 7 transcend to many other compounds. 

### 8 DR. KENNETH PORTIER: I'm trying to capture 

### 9 all these comments so we can kind of write something up at the 

### 10 end. 

### 11 One thing that I heard that I would like to 

### 12 point out to EPA, I wasn't looking forward to this panel 

### 13 because I did chair the 2008 panel. And it's one of those 

### 14 panels that I remember very vividly because the epidemiologist 

### 15 weren't communicating with the toxicologists. I think we had 

### 16 some AG types in there, as well, and it was a big panel. 

### 17 And I think the big difference this time is 

### 18 that EPA has employed a professional epidemiologist, Dr. 

### 19 Christensen, to help them kind of get the interpretation and 

### 20 the integration correct. So I want it on record that I think 

### 21 that's a good move on EPA's part. It's helped us a lot in this 

### 22 panel. It's meant that we've been able to focus on the value

### Page 776 1 of the information on the epidemiology and not on the things 

### 2 that weren't helpful the last time around. 

### 3 And then finally, I'd like to say this is my 

### 4 last panel as a permanent panel member and as Chair. And I 

### 5 really have appreciated EPA's giving me the opportunity to do 

### 6 this. 

### 7 By my count, this is either the 61st or the 

### 8 62nd panel that I've sat on, starting in 1999. So you can see 

### 9 I've enjoyed this a lot and I'm going to miss it a whole lot. 

### 10 I encourage those of you who are new -- there 

### 11 are I think four newbies on the panel here, but I think they 

### 12 have proved their worth at this meeting. I'm sure you'll be 

### 13 invited back. And I can tell you, you learn more each time you 

### 14 come here, and you actually are of more use to EPA each time 

### 15 you come and participate. So when invited, I would encourage 

### 16 you to take up the opportunity, as I have. 

### 17 With that, I'm going to turn the meeting over 

### 18 to Fred Jenkins, the DFO, for some final comments. Dr. Lowit 

### 19 and Dr. Whitby? 

### 20 DR. KAREN WHITBY: 60 meetings? Wow, that's 

### 21 quite impressive. I'd like to thank the SAP staff for all that 

### 22 they've done to organize us for this meeting, particularly the

### Page 777 1 efforts of Fred Jenkins, Joe Bailey and Laura Bailey and others 

### 2 that have been working behind the scenes. 

### 3 I'd like to thank the team, the chlorpyrifos 

### 4 team, and I'd also particularly like to thank ORD for their 

### 5 contributions and support. We will continue to rely on them 

### 6 for their expertise as we move forward with the chlorpyrifos 

### 7 assessment. 

### 8 And I'd very much like to thank the SAP panel 

### 9 for being very helpful and productive with this meeting. We 

### 10 know how hard you've worked. There's a lot of material here to 

### 11 go through and it took a lot of time to prepare and to be here. 

### 12 I particularly recognize a level of effort 

### 13 with emails through midnight last night. Very thoughtful 

### 14 recommendations and feedback and I appreciate your talent. 

### 15 And again, finally, I'd like to thank Ken. 

### 16 And it's been great; 60 meetings, wow. Thank you for running 

### 17 such an efficient meeting here, my first as acting Division 

### 18 Director. You've really kept us on task and focused and I 

### 19 appreciate what great job you've done here. Thank you. 

### 20 DR. FRED JENKINS: Before I give my closing 

### 21 statements, I want to turn the floor over to Laura Bailey, the 

### 22 executive secretary to the FIFRA SAP.

### Page 778 1 LAURA BAILEY: Good afternoon. I am Laura 

### 2 Bailey and I am the FIFRA SAP Executive Secretary. And first I 

### 3 would like to say thank you to the panel. I'd also like to say 

### 4 thank you to the agency, Karen Whitby, Anna Lowit and the 

### 5 entire team and OPP, and to Fred Jenkins who served as the 

### 6 designated Federal official for this meeting, and to the entire 

### 7 SAP staff and all the participants who contributed to make this 

### 8 an outstanding meeting. 

### 9 And I personally think that the 

### 10 recommendations that had been provided at this meeting will 

### 11 play a significant role in the direction that the agency goes 

### 12 forward from this point. 

### 13 Well, I am before you today to recognize a 

### 14 very special individual, one who has served with tremendous 

### 15 dedication, competence and often perseverance. Undoubtedly a 

### 16 great deal of the SAP success can be attributed to his 

### 17 expertise as a statistician and his unique leadership skills. 

### 18 And I am referring to none other than Dr. Kenneth Portier. 

### 19 I mentioned to Dr. Portier on yesterday, I 

### 20 said, "Well this is a bittersweet experience for me and the SAP 

### 21 because this marks the last meeting that he will serve as Chair 

### 22 of the FIFRA SAP, as his tenure as a permanent panel member

### Page 779 1 expires this month. 

### 2 Now although he has promised that he will 

### 3 return as an ad-hoc member -- and we're going to hold you to 

### 4 that promise -- but Dr. Portier has provided exceptional 

### 5 service to the SAP. And he has served as a permanent panel 

### 6 member for eight years and he's already told you his remarkable 

### 7 record of the number of SAP meetings that he has participated 

### 8 in. And not only has he participated as a member but he also 

### 9 served as the SAP Chair for the past year. 

### 10 And on behalf of the agency, Dr. Portier, I 

### 11 want to publicly thank you for your tremendous service to the 

### 12 SAP and let you know that we are grateful for the contributions 

### 13 that you have made to advance in science here at the agency. 

### 14 And I want you to know that you have set the bar high for 

### 15 participation on the SAP. And it has been a joy and a pleasure 

### 16 having you on the panel and we wish you the best as you 

### 17 continue your illustrious career. 

### 18 And at this time we have a beautiful plaque 

### 19 of appreciation. And I'm just going to read to you what the 

### 20 plaque reads: "It is an appreciate award presented to Kenneth 

### 21 M. Portier, PhD for outstanding contributions and leadership of 

### 22 the FIFRA Scientific Advisory Panel 2004 to 2012" and it is

### Page 780 1 signed by James J. Jones, who is an acting Assistant 

### 2 Administrator for the Office of Chemical Safety and Pollution 

### 3 Prevention. Please join me in congratulating Dr. Kenneth 

### 4 Portier. 

### 5 DR. KENNETH PORTIER: Thank you very much. 

### 6 Charlene is going to take a picture here of us. One more, 

### 7 because Fred's got to finish the meeting. 

### 8 LAURA BAILEY: Okay. At this time, I'll turn 

### 9 the meeting back over to our designated Federal official, Fred 

### 10 Jenkins. 

### 11 DR. FRED JENKINS: I just have a few closing 

### 12 remarks. First I want to thank this entire panel for agreeing 

### 13 to participate in this meeting. I think you all did a great 

### 14 job. As I've told you in the beginning, on behalf of the 

### 15 agency, we appreciate your time, your talent and your expertise 

### 16 and willingness to participate. 

### 17 A special thanks to Dr. Portier. It's been 

### 18 truly an honor and a pleasure to work with you, and as we've 

### 19 shared these meetings and as serving as DFO along side of you. 

### 20 And I wish you the very best in all of your future endeavors. 

### 21 I hope to see you again soon. 

### 22 Thank you public for attending this meeting.

### Page 781 1 Special thanks to all those who are listening out on the World 

### 2 Wide Web via our webcast. Thank you to our oral public 

### 3 commenters, including DOW and its affiliates. Thank you to 

### 4 NRDC for their public comments and to Dr. Dale Hattis. 

### 5 I want to give a special thanks to the Office 

### 6 of Pesticide Programs team. Dr. Anna Lowit, thank you so much. 

### 7 It's been a lot of hard work working with you in preparing for 

### 8 this meeting. Thank you to the entire team. Dr. Whitby, thank 

### 9 you for your leadership in helping prepare for this meeting. 

### 10 Also, I have to say a special thanks to the 

### 11 EPA FIFRA SAP staff, my colleagues, who are tremendous support 

### 12 to me and other DFOs when we serve in these meetings. 

### 13 The meeting report will be available no later 

### 14 than 90 days after the close of this meeting. This meeting is 

### 15 official closed now. I just want to say to the panel we want 

### 16 to meet very briefly in the breakout room after the meeting. 

### 17 Thank you everyone, again. 

### 18 (Whereupon, the meeting was adjourned.) 

### 19 * * * * * 

### 20 21 22

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