Dr. Brimijoin was more critical of the protocols. He believed that since the Agency had a consultative role with the project, they should have been aware of such limitations as outlined by the Board in relation to the human studies rule. Almost all the studies included a single subject under some specific exposure conditions and the statistics were elementary. Plans to group the data were not described.

Dr. Lehman McKeeman believed this type of data was needed but struggled with the study design. If there had been a justification of the study this would affect study design. One replicate was not adequate for inclusion. She could see how this data could be used, but it was not described in the protocol. The Board needed to understand precisely how the data would be used.

Dr. Krishnan was concerned with dose selection. Minimization of risk could not be achieved without this understanding. Using the maximum application rate specified on the label 44 of 104 was problematic in the context of multiple and aggregate exposures. The study needed built in flexibility with application rates so maximum application rates specified on product labels were not exceeded.

Dr. Fitzpatrick saw a need for the data but believed it would have been nice to see why the newer estimate of exposure would be more reliable than other methods used and how this data would be used.

Dr. Fisher summarized Board discussion as follows: ( 1) there were advantages to having a generic data base and the efforts to do a field study of this complexity were admirable; ( 2) the protocols were deficient with respect to compliance with Subpart K of the human studies rule for third party studies; ( 3) not enough was said about the quality of existing exposure data or how the new data would be used or combined with old data; ( 4) the term subject should be used instead of replicate; ( 5) more information was needed on the proposed statistical approach; ( 6) worker interests needed to be taken into account; ( 7) sample size should be explained and when there were single subjects this needed to be justified; ( 8) accuracy would only be as good as the measurements taken; ( 9) clarification needed to be provided on agricultural handler work hours and the set up hours; ( 10) there was concern that the Agency's SOPs were not followed; ( 11) the generic data base included environmental factors but the study design did not describe how this information would be accounted for; ( 12) protocols needed to clarify who the subjects were and their level of authority; ( 13) baseline biomedical and biomarker data might be helpful and; ( 14) the protocols stated that label instruction would be followed but exposure rates were not detailed. There are 40 studies planned but Dr. Fisher did not see a critical health need to have these data immediately. While the Board discussed the draft science and ethics criteria for review of study protocols at this week's meeting, the task force should have acknowledged consideration of these criteria, at least as part of their oral remarks. She felt that the protocol lacked clear articulation of the study justification.

Dr. Lebowitz stated that aggregate exposure and biomarkers are critical. The database would be given to EPA statisticians so it was important to know how unusually high exposures during accidents would be reported. Dr. Chadwick said that the protocols were all done over 3 4 days with one person in a treatment group so how useful was this database. Dr. Nelson responded that the purpose of exposure scripting was to allow meta analysis and combination of studies into the database. Dr. Lehman McKeeman believed that these data could be very useful but the nature of the overarching purpose and execution of study did not seem to come through study execution. Exposure data was what was critical and collecting biomarker data could compromise this measure. The Board should take biomarkers off the table and focus on exposure data. Thus, the focus should be on exposure data, not biomarkers.

Dr. Fenske said that it would not be practical to combine biomonitoring and exposure data. Combining exposure data collected by various means could be utilized to get total dermal dose but there was a lot of uncertainty with this. Patch studies overestimated exposure but the methods used for the AHETF protocol included a systematic bias that underestimated exposure because absorbed dose was lost. There was no data analysis plan in the protocol and details were needed. Fourteen studies have already been initiated but it was not explained how wind speed and other environmental variables would be incorporated into the statistical analysis. It was up 45 of 104 to EPA to take the lead on this to ensure the quality of the database. Meta analysis refers to a specific method for data across studies. If there are different scenarios across protocols, we may not be able to combine the data generated. Dr. Brimijoin was supportive of collecting a large database but expressed concern about integration between study designs and the use of a metaanalysis

Dr. Fisher summarized by concluding that there was some agreement and some disagreement about the use of biomarkers, sampling methods and the study justification but there is no doubt that a study like this should be performed. The intent to do meta analysis was good but with so many variables being collected, it was difficult to know how the data would be used. Without a statistical design plan, what the Board would be approving was not clear. How do you approve five studies out of 40 when meta analysis is planned? There needed to be discussion whether the common parts of protocol should move forward, then see whether any of the individual studies had assets or deficiencies and whether they should also be initiated. Since the Board had concerns about use of the data moving forward, the Board needed to make a decision as to whether it wanted to see this protocol again. What the Board has not seen is the overarching study and analytical plan for how the data base would be used.

Ethical Considerations Dr. Philpott began the Board's discussion indicating that he was not supportive of the protocol. He was disappointed with the lack of clear validation of the methods and failure to follow some of the NAS recommendations. Although this study was described as observational, it was not strictly observational, nor a clear justification for why the data was needed. Whether or not there truly was a negligible increase in risk, given the scripted protocols for application, needed to be evaluated. Confidentiality needed to be examined in term of excluding pregnant women and illegal immigrants since this may have impacted the voluntariness of participation. There was a need to address the risks of pesticide handling. If the subjects did not speak English as their primary language, ways to reduce their potential exposure needed to be explained, and this may have impacted the collection of exposure data. The protection of subjects was primary even if it compromised exposure data. The risk of heat related illness also needed to be considered. Heat index data should have been used to assess this condition because the symptoms of heat related illnesses are vague and heat stress and heat stroke can have sudden onset. The growers were incentivized with free pesticides. Freedom to withdraw needed to be explicit. The fact that there were no withdrawals from previous studies raised a concern regarding subjects' perceptions regarding voluntary withdrawal. Defining appropriate compensation for time without getting into undue influence is tricky. Dr. Philpott recommended that additional compensation be added for preparation time. Dr. Philpott expressed concerns about language in the IC document, the reading level, and possible illiteracy of subjects. The IC also needed to describe heat related illnesses.

Dr. Nelson started with minimization of risk. The scripted nature of exposures was important because if there was additional exposure to pesticides, this would be unethical. Even if the duties performed were the worker's routine job duties, this was not minimal risk. It would be a good thing if, as part of the study, the workers learned better ways to handle pesticides and reduce exposure. Dr. Nelson would be inclined to share the data with workers but not if the 46 of 104 study was underestimating exposure. There was little documentation from the IRB, but the IRB appears to be a typical biomedical IRB. The IRB did not include an expert on pesticide application so this may not be the right group of people to use for the IRB.

Dr. Fish added that although what would be done on a given day was scripted, it would be one of the usual choices of what the worker was asked to do. The Board appeared to be struggling with the research. The protocols needed statistical consultation and the IC form require clarity that compensation would be received even if the subject withdrew. Whatever the IRB approved number of subjects was, this should have been followed. The IC needed to be changed to address heat stress. If the worker's day was extended due to participation in the research, this needed to be made clear. Pregnancy language also needed to be clarified.

Dr. Chadwick confirmed that there was a need to demonstrate comprehension of IC materials. There was also a need to understand whether this was strictly a dosimetry study or whether exposures would be altered. Workers' names should not have been recorded unless it was needed for the study and assistance with donning cotton garments should have been provided by a same sex individual. Amendments to the protocol are permissible but require approval by the IRB, not just the study director. Boilerplate language should have been removed from the IC form. Use of the word sponsor to describe Western Research may be misleading since the task force was the sponsor. The protocol needed to be more explicit with respect to safety. The IC appeared to authorize the release of medical records which did not respect the right to privacy.

Dr. Fisher said that the risk benefit ratio relies on the science. The risks were only acceptable if the benefits to science were clear and the Board was not clear as to what the risks were. If the pesticide tested was no more toxic than what it is being substituted for, then additional risk may not be great. Heat exposure was a critical risk that was not adequately addressed with respect to starting rules, IC, or medical intervention. If the compound to be applied was different, raising concerns regarding participation, the impact on compensation needed to be clearly stated. Working on a farm as a pesticide handler but not wanting to participate in the study should have resulted in other work being assigned. The study designers purposely selected lower toxicity compounds so that if two insecticides with equal toxicity and efficacy were used, the participants' risk would be no greater than that experienced with routine work. Heat related illness was a more critical risk but the study team commented the risk should be manageable.

Dr. Menikoff said that it is not about increased risk, it is about manipulating exposure without fully informed consent. This may not be coercive but the consequences of withdrawing from the study needed to be made clear. Dr. Fisher said that if there were a number of comparable products, the grower would select the one that was free because the grower would always select the product they could get the most cheaply. The grower made the decision about which pesticide would be used. The individuals in the research needed to agree to apply the subject pesticide and participate in research. A worker advocate might be helpful. The protocol needed to address medical concerns for illegal immigrants, subject names should be coded for privacy and a separate consent may be needed if pictures are taken. Part of the problem with heat exhaustion and heat stroke were sudden onset. This needed to be clarified and a statement 47 of 104 that all medical conditions would be treated needed to be included. The protocol lacked adverse event planning. Growers should not have been penalized if a worker failed to participate. The protocols should have included an explanation of the $ 100/ day compensation. A field study with this degree of complexity requires a long day for staff. The protocols needed to clarify whether extra time needed for subjects to participate would be compensated. Biomarkers might not make any sense based on the compound being tested. In addition, biomarkers are likely to give an underestimate of exposure.

Dr. Fisher asked the Board whether the five studies should proceed given the inadequacies noted. Dr. Brimijoin responded that if the studies were to proceed they would do so at the risk of not being approved. There was a need to see the parent protocol. There was sufficient uncertainty about the science and the purpose. Thus the Board could not respond to the charge question positively. Many Board members indicated agreement with Dr. Brimijoin's conclusion.

B oard Review of May 2 3, 2006 HSRB Meeting Report Dr. Fisher continued the meeting by leading the Board in review of the draft May 2 3, 2006 meeting report and opened the review by inviting public commenters to respond to the report.

Public Comments Dr. Donald Carlson and Ms. Jane McCarty of FMC Corp. and Dr. Rick Reiss of Exponent, representing FMC Corp.

FMC submitted written comments on the scientific and ethical issues concerning the carbofuran oral study and procedural issues. Ethical considerations included: no evidence that the study failed to meet ethical standards prevalent at the time, no evidence that deficiencies in the ethical procedures could have resulted in serious harm, nor was information provided that impaired their informed consent. Procedural issues included the recusal of two HSRB members, issues covered in the written comments, and incomplete BMD analysis available for the HSRB May meeting. FMC appreciated the HSRB interest in revisiting BMD analyses and wished to expand the Board's June 29th discussion. Scientific limitations were acknowledged including small sample size, the lack of control subjects, and highly variable RBC results. Nevertheless, FMC, EPA, and prior peer reviewers recommended use of the oral study for BMD modeling. The statistical procedure was used to estimate the dosage that caused a specified response level ( e. g., 10% ChEI). This method was superior to NOAEL/ LOAEL because it accounted for sample size and variability in the data. EPA typically regulates based on the statistical lower limit of BMD ( BMDL) and the difference between BMD and BMDL increases with greater variability and fewer samples. The BMD fit for carbofuran agreed well with actual data. Use of human data to inform the risk assessment for carbofuran reduced uncertainty in interspecies extrapolation. The rat BMDL10 estimated by EPA was similar to human values so EPA could use the BMDL10 from the human data for risk assessment. In addition, it had the discretion to add a database uncertainty factor to account for limitations in the dataset. In conclusion, the FMC human oral study was ethical, enhanced the data set and should be utilized. Dr. Lehman 48 of 104 McKeeman questioned that when the study was initially conducted, it was done to characterize exposure symptoms. This was confirmed by FMC.

Board Discussion Dr. Fisher led the review of the May 2006 report and highlighted comments received, specifically from EPA. Concerning hexavalent chromium, the HSRB concluded that the 1994 Nethercott chromium dermal toxicity study was sufficiently sound for use in the risk assessment. From the ethical perspective, the HSRB concluded that the study decision was hampered by a lack of supporting documentation but that these deficiencies did not meet the threshold of fundamentally unethical. The weaknesses of the carbofuran oral studies far outweighed their strengths so the HSRB did not recommend their use for risk assessment. The BMD calculations round out some of the study deficiencies but the accuracy and reliability of these calculations were limited by the technical shortcomings noted for the oral study. There was no evidence that the study failed to meet prevalent ethical standards nor was the study fundamentally unethical. The HSRB found deficiencies in both dermal toxicities studies with respect to risk minimization and the administration of the antidote. For MITC, the Board concluded that the eyes were a sensitive surrogate endpoint with respect to respiratory data. The HSRB determined that there were minor deficiencies with respect to ethical standards but that the study was not fundamentally unethical. Dr. Krishnan recommended an additional modification for the carbofuran discussion. Dr Fisher then asked the Board to accept the May meeting report with EPA comments.

Nelson  Accept the report as modified. Chadwick Accept the report as modified. Menikoff Accept the report as modified. Lebowitz Accept the report as modified. Menikoff Accept the report as modified. Fitzpatrick Accept the report as modified. Fish Accept the report as modified. Fenske Accept the report as modified. Lehman McKeeman Accept the report as modified. Philpott Accept the report as modified. Fisher Accept the report as modified.

Dr. Lewis announced that the next HSRB meeting is tentatively scheduled to occur October 17 20, 2006 at One Potomac Yard, South Building.

The meeting was adjourned by the Chair. 49 of 104 Respectfully submitted:

Paul I. Lewis, Ph. D. Designated Federal Officer Human Studies Review Board United States Environmental Protection Agency Certified to be true by:

Celia B. Fisher, Ph. D. Chair Human Studies Review Board United States Environmental Protection Agency NOTE AND DISCLAIMER: The minutes of this public meeting reflect diverse ideas and suggestions offered by Board members during the course of deliberations within the meeting. Such ideas, suggestions, and deliberations do not necessarily reflect definitive consensus advice for the Board members. The reader is cautioned to not rely on the minutes to represent final, approved, consensus advice and recommendations offered to the Agency. Such advice and recommendations may be found in the final report prepared and transmitted to the EPA Science Advisor following the public meeting. 50 of 104 Attachments Attachment A HSRB Members and Consultants Attachment B Federal Register Notice Announcing Meeting Attachment C Meeting Agenda Attachment D May 2 3, 2006 Draft HSRB Meeting Report 51 of 104 Attachment A EPA HSRB Members and Consultants Chair Celia B. Fisher, Ph. D. Marie Ward Doty Professor of Psychology Director, Center for Ethical Education Fordham University, Bronx, NY Vice Chair William S. Brimijoin, Ph. D.* Chair and Professor, Molecular Pharmacology and experimental Therapeutics Mayo Foundation, Rochester, MN Members David C. Bellinger Ph. D. Professor of Neurology Harvard School of Medicine, Boston, MA.

Alicia Carriquiry, Ph. D. Professor, Department of Statistics Iowa State University, Ames, IA.

Gary L. Chadwick, PharmD, MPH, CIP Associate Provost, Director, Office for Human Subjects Protection University of Rochester, Rochester, NY Janice Chambers, Ph. D. D. A. B. T.* Director, Center for Environmental Health Sciences, College of Veterinary Medicine Mississippi State University, Mississippi State, MS Richard Fenske, Ph. D. MPH Professor, Department of Environmental and Occupational Health Sciences University of Washington, Seattle, WA Susan S. Fish, PharmD, MPH Professor, Biostatistics & Epidemiology Boston University School of Public Health, Boston, MA Suzanne C. Fitzpatrick, Ph. D. D. A. B. T. Senior Science Policy Analyst U. S. Food and Drug Administration, Rockville, MD. 52 of 104 Kannan Krishnan, Ph. D. Professor Département de santé environnementale et santé au travail Faculté de médicine Universite' de Montreal Montreal, Quebec, Canada KyungMann Kim Ph. D., FCCP ** Professor and Associate Chair, School of Medicine and Public Health University of Wisconsin Madison, Madison, WI Michael D. Lebowitz, Ph. D. FCCP Professor of Public Health & Medicine University of Arizona, Tucson, AZ Lois D. Lehman McKeeman, Ph. D. Distinguished Research Fellow, Discovery Toxicology Bristol Myers Squibb Company, Princeton, N. J.

Jerry A. Menikoff, M. D. Associate Professor of Law, Ethics & Medicine Director Institute for Bioethics, Law and Public Policy University of Kansas, Kansas City, KS Robert Nelson, M. D., Ph. D. Associate Professor of Anesthesiology University of Pennsylvania School of Medicine, Philadelphia, PA.

Sean Philpott, PhD, MS Bioethics Associate Director Alden March Bioethics Institute Albany Medical Center, Albany, NY 53 of 104 Consultants to the Board Col Raj K Gupta, Ph. D. BCE Director, Science, Technology and Strategy Headquarters, Walter Reed Army Institute of Research Silver Spring, MD Daniel Strickman, Ph. D. National Program Leader Veterinary, Medical, and Urban Entomology United States Department of Agriculture Agricultural Research Service, Beltsville, MD * Recused from carbofuran discussion and deliberation ** Not in attendance at meeting 54 of 104 Attachment B Federal Register Notice Announcing Meeting Human Studies Review Board; Notice of Public Meeting [ Federal Register: June 6, 2006 ( Volume 71, Number 108)] [ Notices] [ Page 32536 32538] From the Federal Register Online via GPO Access [ wais. access. gpo. gov] [ DOCID: fr06jn06 53]

ENVIRONMENTAL PROTECTION AGENCY [ EPA HQ ORD 2006 0384; FRL 8081 6]

Human Studies Review Board; Notice of Public Meeting AGENCY: Environmental Protection Agency ( EPA). ACTION: Notice.

SUMMARY: The U. S. Environmental Protection Agency's ( EPA or Agency) Office of the Science Advisor ( OSA) announces a public meeting of the Human Studies Review Board ( HSRB) to advise the Agency on EPA's scientific and ethical reviews of human subjects' research.

DATES: The public meeting will be held June 28 30, 2006 from 8: 30 a. m. to approximately 5 p. m., eastern time. Location: One Potomac Yard, 2777 Crystal Drive, Arlington, VA 22202. Meeting Access: Seating at the meeting will be on a first come basis. Individuals requiring special accommodations at this meeting, including wheelchair access and assistance for the hearing impaired, should contact the Designated Federal Officer ( DFO) at least 10 business days prior to the meeting using the information under FOR FURTHER INFORMATION CONTACT so that appropriate arrangements can be made.

[[ Page 32537]]

Procedures for Providing Public Input: Interested members of the public may submit relevant written or oral comments for the HSRB to consider during the advisory process. Additional information concerning submission of relevant written or oral comments is provided in Unit I. D. of this notice.

FOR FURTHER INFORMATION CONTACT: Any member of the public who wishes further information should contact Paul I. Lewis, Designated Federal Officer ( DFO), EPA, Office of the Science Advisor, ( 8105R), Environmental Protection Agency, 1200 Pennsylvania Ave., NW., 55 of 104 Washington, DC 20460; telephone number: ( 202) 564 8381; fax: ( 202) 564 2070; e mail addresses: lewis. paul@ epa. gov.

ADDRESSES: Submit your written comments, identified by Docket ID No. EPA HQ ORD 2006 0384, by one of the following methods: http:// www. regulations. gov : Follow the on line instructions for submitting comments. E mail: ORD. Docket@ epa. gov. Mail: ORD Docket, Environmental Protection Agency, Mailcode: 28221T, 1200 Pennsylvania Ave., NW., Washington, DC 20460. Hand Delivery: EPA Docket Center ( EPA/ DC), Room B102, EPA West Building, 1301 Constitution Avenue, NW., Washington, DC 20460, Attention Docket ID No. EPA HQ ORD 2006 0384. Deliveries are only accepted from 8: 30 a. m. to 4: 30 p. m., Monday through Friday, excluding legal holidays. Special arrangements should be made for deliveries of boxed information. Instructions: Direct your comments to Docket ID No. EPA HQ ORD 2006 0384. EPA's policy is that all comments received will be included in the public docket without change and may be made available online at http:// www. regulations. gov , including any personal information provided, unless the comment includes information claimed to be Confidential Business Information ( CBI) or other information whose disclosure is restricted by statute. Do not submit information that you consider to be CBI or otherwise protected through http:// www. regulations. gov or e mail. The http:// www. regulations. gov Web site is an    anonymous access'' system, which means EPA will not know your identity or contact information unless you provide it in the body of your comment. If you send an e mail comment directly to EPA, without going through http:// www. regulations. gov , your e mail address will be automatically captured and included as part of the comment that is placed in the public docket and made available on the Internet. If you submit an electronic comment, EPA recommends that you include your name and other contact information in the body of your comment and with any disk or CD ROM you submit. If EPA cannot read your comment due to technical difficulties and cannot contact you for clarification, EPA may not be able to consider your comment. Electronic files should avoid the use of special characters, any form of encryption, and be free of any defects or viruses.

SUPPLEMENTARY INFORMATION:

I. Public Meeting A. Does This Action Apply to Me?

This action is directed to the public in general. This action may, however, be of interest to persons who conduct or assess human studies on substances regulated by EPA or to persons who are or may be required to conduct testing of chemical substances under the Federal Food, Drug, and Cosmetic Act ( FFDCA) or the Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA). Since other entities may also be interested, the Agency has not attempted to describe all the specific entities that may be affected by this action. If you have any questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT. 56 of 104 B. How Can I Access Electronic Copies of This Document and Other Related Information?

In addition to using regulations. gov, you may access this Federal Register document electronically through the EPA Internet under the Federal Register listings at http:// www. epa. gov/ fedrgstr/ Docket: All documents in the docket are listed in the http:// www. regulations. gov index. Although listed in the index, some information is not publicly available, e. g., CBI or other information whose disclosure is restricted by statute. Certain other material, such as copyrighted material, will be publicly available only in hard copy. Publicly available docket materials are available either electronically in http:// www. regulations. gov or in hard copy at the ORD Docket, EPA/ DC, EPA West, Room B102, 1301 Constitution Ave., NW., Washington, DC. The Public Reading Room is open from 8: 30 a. m. to 4: 30 p. m., Monday through Friday, excluding legal holidays. The telephone number for the Public Reading Room is ( 202) 566 1744, and the telephone number for the ORD Docket is ( 202) 566 1752. EPA's position paper( s), charge/ questions to the HSRB, and the meeting agenda will be available by mid June 2006. In addition, the Agency may provide additional background documents as the materials become available. You may obtain electronic copies of these documents, and certain other related documents that might be available electronically, from the regulations. gov website and the HSRB Internet Home Page at http:// www. epa. gov/ osa/ hsrb/. For questions on document availability or if you do not have access to the Internet, consult the person listed under FOR FURTHER INFORMATION.

C. What Should I Consider as I Prepare My Comments for EPA?

You may find the following suggestions helpful for preparing your comments: a. Explain your views as clearly as possible. b. Describe any assumptions that you used. c. Provide copies of any technical information and/ or data you used that support your views. d. Provide specific examples to illustrate your concerns. e. To ensure proper receipt by EPA, be sure to identify the docket ID number assigned to this action in the subject line on the first page of your response. You may also provide the name, date, and Federal Register citation.

D. How May I Participate in This Meeting?

You may participate in this meeting by following the instructions in this section. To ensure proper receipt by EPA, it is imperative that you identify docket ID number EPA HQ ORD 2006 0384 in the subject line on the first page of your request. a. Oral comments. Requests to present oral comments will be accepted up to June 21, 2006. To the extent that time permits, interested persons who have not pre registered may be permitted by the Chair of the HSRB to present oral comments at the meeting. Each individual or group wishing to make brief oral comments to the HSRB is strongly advised to submit their request ( preferably via email) to the DFO listed under FOR FURTHER INFORMATION CONTACT no later than noon, eastern time, June 21, 2006, in order to be included on the meeting 57 of 104 agenda and to provide sufficient time for the HSRB Chair and HSRB DFO to review the agenda to provide an appropriate public comment period. The request should identify the name of the individual making the presentation, the [[ Page 32538]]

organization ( if any) the individual will represent, and any requirements for audiovisual equipment ( e. g., overhead projector, LCD projector, chalkboard). Oral comments before the HSRB are limited to 5 minutes per individual or organization. Please note that this limit applies to the cumulative time used by all individuals appearing either as part of, or on behalf of an organization. While it is our intent to hear a full range of oral comments on the science and ethics issues under discussion, it is not our intent to permit organizations to expand these time limitations by having numerous individuals sign up separately to speak on their behalf. If additional time is available, there may be flexibility in time for public comments. Each speaker should bring 25 copies of his or her comments and presentation slides for distribution to the HSRB at the meeting. b. Written comments. Although you may submit written comments at any time, for the HSRB to have the best opportunity to review and consider your comments as it deliberates on its report, you should submit your comments at least 5 business days prior to the beginning of the meeting. If you submit comments after this date, those comments will be provided to the Board members, but you should recognize that the Board members may not have adequate time to consider those comments prior to making a decision. Thus, if you plan to submit written comments, the Agency strongly encourages you to submit such comments no later than noon, Eastern Time, June 21, 2006. You should submit your comments using the instructions in Unit 1. C. of this notice. In addition, the Agency also requests that person( s) submitting comments directly to the docket also provide a copy of their comments to the DFO listed under FOR FURTHER INFORMATION CONTACT. There is no limit on the length of written comments for consideration by the HSRB.

E. Background EPA will be presenting for HSRB review the results of a completed study involving intentional exposure of human subjects to the pesticide active ingredient, chloropicrin. In addition, EPA will be seeking the Board's advice on: Draft guidelines for conducting research on the efficacy of insect repellent products; insect repellent human studies protocols and pesticide agricultural handler human studies protocols. EPA will also be providing an informational presentation of its proposed workshop on Best Practices for EPA, National Exposure Research Laboratory Observational Human Exposure Measurement Studies. Finally, the Board may be reviewing draft HSRB reports for subsequent Board approval.

Dated: June 1, 2006. George Gray, Science Advisor. [ FR Doc. E6 8725 Filed 6 5 06; 8: 45 am] BILLING CODE 6560 50 P Federal Register: June 12, 2006 ( Volume 71, Number 112)] [ Notices] 58 of 104 [ Page 33747] From the Federal Register Online via GPO Access [ wais. access. gpo. gov] [ DOCID: fr12jn06 84]

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ENVIRONMENTAL PROTECTION AGENCY [ EPA HQ ORD 2006 0384; FRL 8183 4]

Human Studies Review Board; Notice of Public Meeting AGENCY: Environmental Protection Agency ( EPA).

ACTION: Notice.

SUMMARY: On June 6, 2006 ( 71 FR 32536), the U. S. Environmental Protection Agency's ( EPA or Agency) Office of the Science Advisor ( OSA) announced a public meeting of the Human Studies Review Board ( HSRB) to be held June 28 30, 2006 from 8: 30 a. m. to approximately 5 p. m., Eastern Time. Please be advised that the Board will also be meeting on June 27, 2006, beginning at 1 p. m. to approximately 5 p. m., Eastern Time. For further information contact Paul I. Lewis, Designated Federal Officer ( DFO), EPA, Office of the Science Advisor, ( 8105), Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: ( 202) 564 8381; fax: ( 202) 564 2070; e mail addresses: lewis. paul@ epa. gov.

Dated: June 6, 2006. George Gray, EPA Science Advisor. 59 of 104 Attachment C June 27 30, 2006 Meeting of the HSRB Meeting Agenda 6/ 26/ 06 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY HUMAN STUDIES REVIEW BOARD ( HSRB) JUNE 27 30, 2006 * PUBLIC MEETING Tuesday, June 27, 2006 One Potomac Yard ( South Building) 2777 Crystal Drive Arlington, VA 22202 703 305 7090 HSRB WEB SITE http:// www. epa. gov/ osa/ hsrb/ Docket Telephone: ( 202) 566 1752 Docket Number: EPA HQ ORD 2006 0384 C 1: 00 PM Introduction and Identification of Board Members   Celia Fisher, Ph. D. ( HSRB Chair)

C 1: 15 PM Welcome   George Gray, Ph. D. ( EPA Science Advisor)

C 1: 25 PM Opening Remarks   Mr. Jim Jones ( Director, Office of Pesticide Programs [ OPP], EPA)

C 1: 35 PM Meeting Administrative Procedures  Paul Lewis, Ph. D. ( Designated Federal Officer [ DFO], HSRB, OSA, EPA)

C 1: 40 PM Meeting Process   Celia Fisher, Ph. D. ( HSRB Chair)

C 1: 55 PM Update on EPA Follow up of HSRB Recommendations   Mr. John Carley ( EPA, OPP) Chloropicrin C 2: 05 PM Science and Ethics of Chloropicrin Human Studies   Elissa Reaves, Ph. D. ( OPP, EPA) and Mr. John Carley ( OPP, EPA)

C 3: 00 PM Break C 3: 15 PM Public Comments C 3: 45 PM Board Discussion Chloropicrin is a non selective soil fumigant whose primary toxic effect is sensory irritation in which stimulated free nerve endings mediate sensations and clinical signs in the nose, eyes, throat, and upper respiratory tract. Chloropicrin is a unique soil fumigant in that it is also used as an indicator chemical or warning agent ( 2% or less by weight in formulations). The Agency is developing an assessment to estimate inhalation risk to bystanders and workers from acute exposures to chloropicrin. 60 of 104 1. Scientific considerations:

The Agency's " Weight of Evidence" ( WOE) document and Data Evaluation Records ( DER) for chloropicrin describe the study design of the acute inhalation, human toxicity study. The Agency has concluded that the human toxicity study is appropriate for developing a point of departure for extrapolation of inhalation risk to bystanders and workers exposed to chloropicrin.

Please comment on whether the study is sufficiently sound, from a scientific perspective, to be used to estimate a safe level of inhalation exposure to chloropicrin.

2. Ethical considerations:

The Agency requests that the Board provide comment on the following:

a. Is there clear and convincing evidence that the conduct of the Cain study was fundamentally unethical?

b. Is there clear and convincing evidence that the conduct of the study was significantly deficient relative to the ethical standards prevailing at the time the research was conducted?

Insect Repellent Product Performance Testing Guideline C 4: 30 PM Science and Ethics of Insect Repellent Efficacy Guidelines   Mr. Kevin Sweeney ( OPP, EPA), Clara Fuentes, Ph. D. ( OPP, EPA), Roger Gardner, Ph. D. ( OPP, EPA) and Mr. John Carley ( OPP, EPA)

C 6: 00 PM Adjournment 61 of 104 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY HUMAN STUDIES REVIEW BOARD ( HSRB) JUNE 27 30, 2006 * PUBLIC MEETING Wednesday, June 28, 2006 One Potomac Yard ( South Building) 2777 Crystal Drive Arlington, VA 22202 703 305 7090 HSRB WEB SITE http:// www. epa. gov/ osa/ hsrb/ Docket Telephone: ( 202) 566 1752 Docket Number: EPA HQ ORD 2006 0384 C 8: 30 AM Convene Meeting   Celia Fisher, Ph. D. ( HSRB Chair)

C 8: 40 AM Follow up From Previous Day's Discussion   Mr. John Carley ( OPP, EPA)

Insect Repellent Product Performance Testing Guideline C 8: 50 AM Public Comments C 9: 15 AM Board Discussion The U. S. EPA Office of Pesticide Programs requests that the HSRB review and comment on the draft " Product Performance of Skin Applied Repellents of Insects and Other Arthropods" Testing Guideline in order to determine what changes, if any, are necessary for the guideline to be made consistent with the requirements for protection of human research subjects set forth in 40 CFR part 26. Below is a list of questions that focus on these topics.

a. What actions should an investigator routinely take to minimize the risks to human subjects exposed during laboratory and field research on the efficacy of repellents?

b. What types of toxicity data should be routinely generated before an investigator conducts repellent efficacy testing on human subjects with a new product?

C 10: 15 AM Break C 10: 30 AM Board Discussion c. In private and university research laboratories, investigators themselves have sometimes served as research subjects when assessing chemicals for insect repellent activity. What scientific and ethical issues would such a practice raise? Under what conditions, if any, would such a practice be acceptable? 62 of 104 d. Please comment on the scientific and ethical issues arising from the use of ( or decision not to use) negative controls groups in repellent efficacy studies, in both laboratory and field studies.

e. Please comment on the scientific and ethical issues raised by the design of studies to collect data sufficient to support assessment of repellent efficacy using the two different efficacy metrics: time to first confirmed bite ( TFCB), and time providing x% protection of treated subjects from bites relative to untreated controls ( RP).

f. Please comment on appropriate approaches for estimating the minimum number of subjects needed to evaluate the level of efficacy of a repellent in laboratory and field studies.

g. Please comment on whether or not investigators should have an ethical obligation to provide subjects of repellent efficacy research with insurance to cover possible future medical costs or other losses that result from injury or illness experienced by the subjects as a consequence of their participation in the research.

C 12: 30 PM Lunch C 1: 30 PM Board Discussion h. Please comment on any special considerations that should be addressed in the informed consent materials provided people who are candidates to become subjects in insect repellent efficacy research.

i. Does the HSRB recommend that the draft guideline be revised? If so, please explain what aspects or sections might improve with revision.

Human Studies Research Protocols C 2: 15 PM Introduction   Peter Preuss, Ph. D. ( Director, National Center for Environmental Assessment, Office of Research and Development, EPA)

HSRB Review of Protocol Criteria C 2: 45 PM HSRB Science and Ethics Criteria of Human Studies Protocols   Celia Fisher, Ph. D. ( HSRB Chair)

C 3: 30 PM Break C 3: 45 PM HSRB Science and Ethics Criteria of Human Studies Protocols   Celia Fisher, Ph. D. ( HSRB Chair) 63 of 104 Research on the Efficacy of Insect Repellents C 4: 15 PM Science and Ethics of Research on the Efficacy of Insect Repellents   Mr. Kevin Sweeney ( OPP, EPA), Clara Fuentes, Ph. D. ( OPP, EPA), Roger Gardner, Ph. D. ( OPP, EPA) and Mr. John Carley ( OPP, EPA)

C 5: 15 PM Adjournment 64 of 104 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY HUMAN STUDIES REVIEW BOARD ( HSRB) PUBLIC MEETING Thursday, June 29, 2006 One Potomac Yard ( South Building) 2777 Crystal Drive Arlington, VA 22202 703 305 7090 HSRB WEB SITE http:// www. epa. gov/ osa/ hsrb/ Docket Telephone: ( 202) 566 1752 Docket Number: EPA HQ ORD 2006 0310 C 8: 30 AM Convene Meeting   Celia Fisher, Ph. D. ( HSRB Chair)

C 8: 40 AM Follow up From Previous Day's Discussion   Mr. John Carley ( OPP, EPA)

Research on the Efficacy of Insect Repellents C 8: 50 AM Public Comments C 9: 20 AM Board Discussion Study EMD 003 from Carroll Loye Biological Research a. Does the proposed research described in [ name / designation of the protocol] appear likely to generate scientifically reliable data, [ useful for assessing the efficacy of the repellent] / [ useful ( together with other data) assessing the potential levels of pesticide exposure received by people when mixing, loading or applying a pesticides]?

b. Does the proposed research described in Study EMD 003 from Carroll Loye Biological Research appear to comport with the applicable requirements of 40 CFR part 26, subparts K and L?

C 10: 15 AM Break C 10: 30 AM Board Discussion Study EMD 004 from Carroll Loye Biological Research a. Does the proposed research described in Study EMD 004 from Carroll Loye Biological Research appear likely to generate scientifically reliable data, useful for assessing the efficacy of a test substance for repellent ticks? 65 of 104 b. Does the proposed research described in Study EMD 004 from Carroll Loye Biological Research appear to comport with the applicable requirements of 40 CFR part 26, subparts K and L?

C 11: 45 AM Lunch Research on Agricultural Handlers' Exposure to Pesticides C 12: 45 PM Science and Ethics of Research on Agricultural Handler's Exposure to Pesticides  Mr. Jeffrey Dawson, ( OPP, EPA), Mr. Jeffrey Evans ( OPP, EPA) and Mr. John Carley ( OPP, EPA)

C 1: 45 PM Public Comments C 2: 15 PM Board Discussion The Agricultural Handlers Exposure Task Force ( AHETF) has submitted protocols for five pesticide exposure studies that are part of a larger research program the AHETF is conducting. The premise of the AHETF research program is that data can be used generically by various stakeholders ( e. g., applicants, registrants, EPA, and others) for calculating exposures for the occupational handlers of pesticides. The scope of the AHETF research program is very broad in that it intends to address exposures related to many job functions in agriculture and also to assess generally the impacts of various parameters on exposure ( e. g., How do changes in the pounds of pesticide handled or acres treated affect exposure levels?). The protocols submitted for HSRB review describe studies to measure exposures for five specific scenarios ( i. e., closed or open system mixing/ loading , airblast applications to trellis and orchard crops, or pilot exposures from fixed wing agricultural aircraft).

The Agency believes these studies improve EPA's ability to assess the risks of using pesticides because the data will reflect current agricultural practices, equipment and techniques and will allow for more refined exposure estimates. Further, the monitoring techniques to be used for these studies also have been standardized for use across the AHETF research program.. These more refined and reliable data will allow the Agency to estimate better how worker exposure levels are affected by changes in various factors such as the amount of active ingredient handled, type of application equipment used, application rate used, volumes handled, and personal protective equipment used.

It should be noted, however, that the use of the data generated in this study by the U. S. EPA and other stakeholders will depend upon the nature of the results. For example, the adequacy of the field or laboratory quality control data may dictate that correction factors are applied to adjust monitored exposure levels to account for losses from field samplers or low performing analytical methods.

1. AHETF Closed System Mixing/ Loading of Liquids Protocol a. Does the proposed research described in Study No. AHE34 from the Agricultural Handlers Exposure Task Force appear likely to generate 66 of 104 scientifically reliable data, which will be useful, together with other data, for assessing the potential levels of pesticide exposure received by people when mixing, loading or applying a liquid pesticide with closed systems? [ Note: In a few cases, corresponding application events are also to be monitored; the same question applies to those elements of the study.]

b. Does the proposed research described in Study No. AHE34 from the Agricultural Handlers Exposure Task Force appear to comport with the applicable requirements of 40 CFR part 26, subparts K and L?

C 3: 15 PM Break C 3: 15 PM Board Discussion 2. AHETF Airblast Application to Trellis Crops in the West Protocol a. Does the proposed research described in Study No. AHE36 from the Agricultural Handlers Exposure Task Force appear likely to generate scientifically reliable data, which will be useful, together with other data, for assessing the potential levels of pesticide exposure received by people when making an airblast application of a pesticide to a trellis crop under conditions found in the western United States? [ Note: In a few cases, corresponding mixing/ loading events are also to be monitored; the same question applies to those elements of the study.]

b. Does the proposed research described in Study No. AHE36 from the Agricultural Handlers Exposure Task Force appear to comport with the applicable requirements of 40 CFR part 26, subparts K and L?

3. AHETF Airblast Application to Trellis Crops in the East Protocol a. Does the proposed research described in Study No. AHE37 from the Agricultural Handlers Exposure Task Force appear likely to generate scientifically reliable data, which will be useful, together with other data, for assessing the potential levels of pesticide exposure received by people when making an airblast application of a pesticide to a trellis crop under conditions found in the eastern United States? [ Note: In a few cases, corresponding mixing/ loading events are also to be monitored; the same question applies to those elements of the study.]

b. Does the proposed research described in Study No. AHE37 from the Agricultural Handlers Exposure Task Force appear to comport with the applicable requirements of 40 CFR part 26, subparts K and L?

C 5: 00 PM Adjournment 67 of 104 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY HUMAN STUDIES REVIEW BOARD ( HSRB) PUBLIC MEETING Friday, June 30, 2006 One Potomac Yard 2777 Crystal Drive Arlington, VA 22202 703 305 7090 C 8: 30 AM Convene Meeting   Celia Fisher, Ph. D. ( HSRB Chair)

C 8: 40 AM Follow up From Previous Day's Discussion   Mr. John Carley ( OPP, EPA)

Research on Agricultural Handlers' Exposure to Pesticides C 9: 00 AM Board Discussion 4. AHETF Closed Cab Airblast Application to Orchards Protocol a. Does the proposed research described in Study No. AHE38 from the Agricultural Handlers Exposure Task Force appear likely to generate scientifically reliable data, which will be useful, together with other data, for assessing the potential levels of pesticide exposure received by people when making an airblast application of a pesticide to orchard crops? [ Note: In a few cases, corresponding mixing/ loading events are also to be monitored; the same question applies to those elements of the study.]

b. Does the proposed research described in Study No. AHE38 from the Agricultural Handlers Exposure Task Force appear to comport with the applicable requirements of 40 CFR part 26, subparts K and L?

5. AHETF Fixed Wing Aerial Application Protocol a. Does the proposed research described in Study No. AHE42 from the Agricultural Handlers Exposure Task Force appear likely to generate scientifically reliable data, which will be useful, together with other data, for assessing the potential levels of pesticide exposure received by people making an aerial application of a pesticide from fixed wing aircraft? [ Note: In a few cases, corresponding mixing/ loading events are also to be monitored; the same question applies to those elements of the study.]

b. Does the proposed research described in Study No. AHE42 from the Agricultural Handlers Exposure Task Force appear to comport with the applicable requirements of 40 CFR part 26, subparts K and L? 68 of 104 C 10: 30 AM Break Proposed Workshop on Best Practices for EPA, National Exposure Research Laboratory Observational Human Exposure Measurement Studies C 10: 45 PM Informational Presentation of Proposed Workshop on Best Practices for EPA, National Exposure Research Laboratory Observational Human Exposure Measurement Studies  Roy Fortmann, Ph. D. ( NERL, Office of Research and Development, EPA)

C 11: 30 AM Lunch May 2 3, 2006 HSRB Meeting Report C 12: 30 PM HSRB Review of May 2 3, 2006 HRSB Meeting Report   Celia Fisher, Ph. D. ( HSRB Chair)

C 12: 45 PM Public Comments C 1: 15 PM Board Discussion and Decision on Report Chromium Methyl Isothiocyanate Carbofuran C 2: 45 PM Summary and Next Steps   Celia Fisher, Ph. D. ( HSRB Chair) and Paul Lewis, Ph. D. ( HSRB DFO)

C 3: 00 PM Adjournment * Agenda dates and times are approximate For further information, please contact the Designated Federal Officer for this meeting, Paul Lewis, via telephone: ( 202) 564 8381 or email: lewis. paul@ epa. gov 69 of 104 Attachment D May 2 3, 2006 Draft HSRB Meeting Report EPA HSRB 06 02 George Gray, Ph. D. Science Advisor Office of the Science Advisor 1200 Pennsylvania Avenue, NW Washington, DC 20460 Subject: May 2 3, 2006 EPA Human Studies Review Board Meeting Report Dear Dr. Gray:

The United States Environmental Protection Agency ( EPA or Agency) requested the Human Studies Review Board ( HSRB) to review scientific and ethics reviews of chromium, carbofuran and methyl isothiocyanate. The enclosed HSRB report addresses the Board's response to EPA charge questions for the Board's consideration at its May 2 3, 2006 meeting.

A summary of the Board's conclusions on the scientific and ethical considerations of the human toxicity studies for the three pesticides are provided below.

Chromium Scientific Considerations   The Board concluded that the 1994 Nethercott et al. dermal sensitization study was sufficiently sound, from a scientific perspective, to be used to estimate a safe level of dermal exposure to hexavalent chromium.

  The study was properly designed, well conducted, and employed appropriate scientific and clinical methods to determine a minimum elicitation threshold for dermal sensitization due to hexavalent chromium. The MET10 reported in the study provided a reasonable point of departure for risk assessment.

Ethical Considerations   The HSRB concluded there was insufficient information to determine whether the study failed to fully meet specific ethical standards prevalent at the time the research was conducted.

  The Board concurred with the assessment of the Agency that there was no clear and convincing evidence that the conduct of the research was fundamentally unethical in that the deficiencies did not result in serious harm, nor seriously impair the informed consent of the research subjects and; 70 of 104   The Board determined that there was not clear and convincing evidence that the conduct of the study was significantly deficient relative to the ethical standards prevailing when the study was conducted.

Carbofuran Scientific Considerations   The HSRB concluded that there were numerous technical issues regarding the conduct of the oral and dermal studies with carbofuran and that overall, the weakness of the studies far outweigh the strengths. Accordingly, the HSRB did not recommend any of the oral or dermal studies conducted with carbofuran in human subjects for the single chemical assessment or in informing the interspecies uncertainty factor for the cumulative assessment.

Ethical Considerations   For the oral study, there was no evidence that the study failed to fully meet specific ethical standards prevalent at the time the research was conducted.

  For the oral human toxicity study, there was no clear and convincing evidence of significant deficiencies in the ethical procedures that could have resulted in serious harm ( based on the knowledge available at the time the study was conducted) nor that information provided to participants seriously impaired their informed consent.

  For the oral study there was no clear and convincing evidence that the research was fundamentally unethical ( e. g., intended to seriously harm participants or that informed consent was not obtained).

  The HSRB found deficiencies in both dermal human toxicity studies relative to specific ethical standards prevalent at the time the study was conducted.

  For both dermal human toxicity studies, there was clear and convincing evidence of significant deficiencies in the ethical procedures for minimizing risk that could have resulted in serious harm ( based on the knowledge available at the time the study was conducted). The first dermal toxicity study was significantly deficient given the delay in the administration of atropine to more than one subject experiencing the signs and symptoms of carbamate toxicity. The second dermal toxicity study was considered significantly deficient in that the lack of information provided about the results from the initial dermal toxicity study seriously impaired their informed consent.

  However, for both dermal human toxicity studies, there was no clear and convincing evidence that the research was fundamentally unethical ( e. g., intended to seriously harm participants or that informed consent was not obtained).

Methyl Isothiocyanate 71 of 104 Scientific Considerations   The Board concluded that air concentrations of methyl isothiocyanate sufficient to produce eye irritation would lead to a conservative and prudent point of departure for inhalation risk ( i. e., eyes were a sensitive endpoint in relation to the respiratory system). The Board reached it decision based on eye irritation LOAELs are often lower than respiratory irritation LOAELs for irritant gases. While the use of eye irritation data as a surrogate for respiratory data is reasonable in this situation, one must be cautious as only appropriate controlled human studies of the respiratory system can provide a final and definitive respiratory point of departure, if ever determined.

Ethical Considerations   The HSRB determined there were minor deficiencies in the ethical procedures relative to those prevalent at the time, however:

  There was no clear and convincing evidence that the conduct of the research was fundamentally unethical ( e. g., the research was intended to seriously harm participants or failed to obtain informed consent) and;

  There was no clear and convincing evidence that the conduct of the study was significantly deficient relative to the ethical standards prevailing when the study was conducted.

The Board also provided commentary of its scientific criteria for review of human dosing studies. The Board's criteria encompassed the following: ( 1) justification; ( 2) dose selection; ( 3) endpoint selection; ( 4) participants; ( 5) method; and ( 6) statistical analyses. In addition, the Board established criteria for evaluating the utility of single dose level studies.

In conclusion, the EPA HSRB appreciated the opportunity to advise the Agency on the scientific and ethical aspects of human subjects research and looks forward to future opportunities to continue advising the Agency in this endeavor.

Sincerely,

Celia Fisher, Ph. D. Chair EPA Human Studies Review Board 72 of 104 NOTICE This report has been written as part of the activities of the EPA Human Studies Review Board, a Federal advisory committee providing advice, information and recommendations on issues related to scientific and ethical aspects of human subjects research. This report has not been reviewed for approval by the Agency and, hence, the contents of this report do not necessarily represent the view and policies of the Environmental Protection Agency, nor of other agencies in the Executive Branch of the Federal government, nor does mention of trade names or commercial product constitute a recommendation for use. Further information about the EPA Human Studies Review Board can be obtained from its website at http:// www. epa. gov/ osa/ hsrb/. Interested persons are invited to contact Paul Lewis, Designated Federal Officer, via e mail at lewis. paul@ epa. gov.

In preparing this document, the Board carefully considered all information provided and presented by the Agency presenters, as well as information presented by public commenters. This document addresses the information provided and presented within the structure of the charge by the Agency. 73 of 104 United States Environmental Protection Agency Human Studies Review Board Chair Celia B. Fisher, Ph. D. Marie Ward Doty Professor of Psychology, Director, Center for Ethics Education, Fordham University, Department of Psychology, Bronx, NY Vice Chair William S. Brimijoin, Ph. D., Chair and Professor, Molecular Pharmacology and Experimental Therapeutics, Mayo Foundation, Rochester, MN * **

Members David C. Bellinger, Ph. D., Professor of Neurology, Harvard Medical School Professor in the Department of Environmental Health, Harvard School of Public Health Children's Hospital, Boston, MA Alicia Carriquiry, Ph. D., Professor, Department of Statistics, Iowa State University Snedecor Hall, Ames, IA Gary L. Chadwick, PharmD, MPH, CIP, Associate Provost, Director, Office for Human Subjects Protection, University of Rochester, Rochester, NY Janice Chambers, Ph. D., D. A. B. T., William L. Giles Distinguished Professor, Director, Center for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State University, Wise Center, Mississippi State, MS *

Richard Fenske, Ph. D., MPH, Professor, Department of Environmental and Occupational Health Sciences, University of Washington, Seattle WA Susan S. Fish, PharmD, MPH, Professor, Biostatistics & Epidemiology, Boston University School of Public Health, Co Director, MA in Clinical Investigation Boston University School of Medicine, Boston, MA Suzanne C. Fitzpatrick, Ph. D., DABT, Senior Science Policy Analyst, Office of the Commissioner, Office of Science and Health Coordination, U. S. Food and Drug Administration, Rockville, MD Kannan Krishnan, Ph. D., Professor, Département de santé environnementale et santé au travail, Faculté de medicine, Université de Montréal, Montréal, Canada KyungMann Kim, Ph. D., CCRP, Professor & Associate Chair, Department of Biostatistics & Medical Informatics, School of Medicine and Public Health, University of Wisconsin Madison, Madison, WI ** 74 of 104 Michael D. Lebowitz, Ph. D., FCCP, Professor of Public Health & Medicine. University of Arizona, Tucson, AZ Lois D. Lehman Mckeeman, Ph. D., Distinguished Research Fellow, Discovery Toxicology, Bristol Myers Squibb Company, Princeton, NJ Jerry A. Menikoff, M. D., Associate Professor of Law, Ethics & Medicine, Director of the Institute for Bioethics, Law and Public Policy, University of Kansas Medical Center, Kansas City, KS Robert Nelson, M. D., Ph. D., Associate Professor of Anesthesiology and Critical Care, Department of Anesthesiology and Critical Care, University of Pennsylvania School of Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104 Sean M. Philpott, Ph. D., Research Scientist, David Axelrod Institute, Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany, NY Human Studies Review Board Staff Paul I. Lewis, Ph. D., Designated Federal Officer, United States Environmental Protection Agency, Washington, DC * Recused from carbofuran discussion and deliberation ** Not in attendance at May 2 3, 2006 Public Meeting 75 of 104 TABLE OF CONTENTS INTRODUCTION.................................................................................................................... 76 REVIEW PROCESS................................................................................................................. 77 CHARGE TO THE BOARD AND BOARD RESPONSE......................................................... 78 1. Chromium......................................................................................................................... 78 2. Carbofuran ....................................................................................................................... 84 3. Methyl Isothiocyanate ....................................................................................................... 94 COMMENTARY ON SCIENTIFIC STANDARDS FOR HUMAN DOSING STUDIES....... 101 REFERENCES....................................................................................................................... 103 76 of 104 INTRODUCTION On May 2 3, 2006, the United States Environmental Protection Agency's ( EPA or Agency) Human Studies Review Board ( HSRB) met to review scientific and ethical issues concerning human toxicity studies involving two pesticide active ingredients, carbofuran and methyl isothiocyanate ( MITC), and chromium, a constituent of wood preservative products ( wood preservatives are regulated as pesticides under the Federal Insecticide, Fungicide, and Rodenticide Act).

The Pesticide Registration Improvement Act ( PRIA) requires that EPA complete its decision making process on certain types of applications to register a pesticide product within specified amounts of time after receiving the application for registration. In addition, PRIA established deadlines for EPA to complete " reregistration" of pesticide active ingredients that are contained in pesticide products initially registered before 1984. Reregistration involves the systematic reexamination of older pesticides, applying contemporary scientific and regulatory standards. When a pesticide active ingredient is approved for use on food, EPA combines reregistration with the tolerance reassessment process mandated by the Food Quality Protection Act of 1996 ( FQPA).

Both MITC and carbofuran are undergoing reevaluation in the reregistration process. EPA is considering the human health risks of chromium both in its reregistration program and as part of its review of an application for registration pending under FIFRA and PRIA.

For each of the human studies under consideration, the Agency provided the Board with the complete study report and any supplements available to the Agency. Each of these studies was assigned a unique identifier, the Master Record Identifier or MRID, which the EPA, Office of Pesticide Programs ( OPP) uses to manage documents in its archive. When a company submits multiple documents pertaining to a single study, each document is assigned a unique MRID as it is received and catalogued. Thus a study with several supplements, such as the MITC study discussed at the meeting, may be associated with several MRIDs.

For each study, the Agency had provided a review of the ethical conduct of the study. Each ethics review identified any deficiencies noted in the conduct of the specific study compared to both current ethical standards and the ethical standards prevailing at the time the research was performed. EPA has intentionally deferred making a final determination of whether an individual study satisfies the ethical standards for acceptability in 40 CFR sections 26.1704   26.1706, pending the advice of the Board.

For most studies, the Agency develops documents, called Data Evaluation Records ( DERs), containing a scientific review of the study; the Board was provided with one or more DERs for carbofuran and MITC. DERs contain summaries of the study design, methods and results, describe potential deficiencies, and provides conclusions about the usefulness of the study in risk assessment.

In addition to the DERs, the Agency had prepared a Weight of Evidence ( WOE) memorandum for carbofuran and MITC discussing the differences and similarities between the 77 of 104 human and animal responses to each chemical and characterizing the usefulness of the human toxicity studies for human health risk assessment. The WOE memos expressed the Agency's current scientific conclusions on which the Agency was soliciting the Board's comments. To maintain the historical record of review, the Agency may, in some cases, include a DER for a study that expressed scientific conclusions differing from those in the WOE document.

For chromium, the Agency provided a set of documents which contained similar information to DERs and WOEs, but which had a slightly different format and presentation, due to the procedural history of the EPA's review of this chemical. As noted above, chromium is a constituent in wood preservative products. The Agency has concern about the potential for chromium to elicit an allergic response in sensitized individuals who come in contact with residues remaining in products made from wood that has been treated with chromium containing wood preservatives. To assess the risk of potential dermal exposure, the Agency reviewed, among other information, a study involving intentional exposure of sensitized subjects to different levels of chromium, ( Nethercott et al. 1994). This assessment was one of the first assessments of this kind performed by the Agency, and it raised significant scientific issues. Accordingly, the Agency prepared a background document for its independent, peer review advisory committee, the FIFRA Scientific Advisory Panel ( SAP). The SAP is a federally chartered advisory committee of scientific experts who provide advice to the Agency on pesticides and pesticide related issues as to their impact on human health and the environment of regulatory actions. The Agency provided a copy of the materials given to the SAP for its review, as well as a copy of the SAP's final report. After receiving the SAP's recommendations, the Agency sought review and comment from other Agency scientists through the steering committee of the Agency's internal Science Policy Council ( SPC) to ensure consistency across programs in the approach to regulating substances that are skin sensitizers. Using the advice of the SAP and the steering committee of the SPC, the Agency developed a memorandum describing how it intended to use the results of the Nethercott study to derive a sensitization Reference Dose.

The HSRB has reviewed studies on which the Agency proposes to rely in actions under the pesticide laws and studies that the Agency has decided not to use in its risk assessments, either for scientific reasons or because they do not meet the standards in EPA's final human studies rule, 40 CFR Part 26. The Agency asked the HSRB to advise the Agency on a range of scientific and ethics issues and on how the studies should be assessed against the provisions in 40 CFR sections 26.1701   26.1704 of EPA's final human studies rule. This report transmits the HSRB's comments and recommendations from its May 2 3, 2006 meeting.

REVIEW PROCESS On May 2 3, 2006 the Board had a public face to face meeting in Arlington, Virginia. Advance notice of the meeting was published in the Federal Register " Human Studies Review Board: Notice of Public Meeting ( 71 Federal Register 19725). At the public meeting, following welcoming remarks from Agency officials, Celia B. Fisher, HRSB Chair, proposed a set of scientific and ethics criteria consistent with the language of 71 Federal Register 6137 to guide Board evaluation of each protocol. The Chair's scientific criteria asked the Board to consider the following two questions: ( 1) did the research design and implementation meet scientific 78 of 104 standards and ( 2) Did the data generated by the study have implications for the Agency's Weight of the Evidence ( WOE) review and when applicable aspects of the risk assessment? The Chair's ethics criteria asked the Board to consider three questions: ( 1) did the study fail to fully meet specific ethical standards prevalent at the time the research was conducted; ( 2) was the conduct of the study fundamentally unethical ( i. e., specifically was there clear and convincing evidence that the research was intended to seriously harm participants or failed to obtain informed consent); and ( 3) was the conduct of the study significantly deficient relative to the ethical standards prevailing at the time ( i. e., was there clear and convincing evidence that identified deficiencies identified could have resulted in serious harm based on knowledge available at the time the study was conducted or the information provided to participants could seriously impair informed consent). The Board then heard presentations from the Agency on the following topics: science and ethics of chromium human studies, science and ethics of carbofuran human studies and science and ethics of methyl isothiocyanate human studies. The Board heard oral public comments from the following individuals:

Chromium Jennifer Sass, Ph. D. representing the Natural Resources Defense Council Carbofuran Donald Carson, Ph. D. and Ms. Jane McCarty on behalf of FMC Corporation Jennifer Sass, Ph. D. representing the Natural Resources Defense Council In addition, the Board received written public comments from CRLA Foundation, FMC Corporation, and the Natural Resources Defense Council. Following Agency presentations and public comments, the Board deliberated on the charge questions. For their deliberations, the Board considered the materials presented at the meeting, written public comments and Agency background documents on each individual pesticide ( i. e., pesticide human study, Agency data evaluation record ( DER) of the pesticide human study, weight of evidence review, risk assessment and ethics review).

CHARGE TO THE BOARD AND BOARD RESPONSE 1. Chromium Charge to the Board Hexavalent chromium is a component of a pesticide product intended to be used as a wood preservative. Members of the general public may experience dermal exposure to residues of hexavalent chromium remaining on wood treated with a wood preservative. Because chromium has caused allergic contact dermatitis ( ACD) in occupational settings, EPA has determined that it should assess the potential for ACD in the general public resulting from the use of wood preservatives containing chromium.

In a meeting of the FIFRA Scientific Advisory Panel ( SAP) in May 2004, EPA obtained independent peer review of scientific issues related to the assessment of the potential dermal risk 79 of 104 resulting from exposure to chromium. See www. epa. gov/ scipoly/ sap/ 2004/ final. doc The Agency had carefully considered the report of the SAP, as well as the advice of EPA scientists through the steering committee of the Agency's Science Policy Council. Taking all of this into account, EPA had derived a " sensitization reference dose" ( RfD) based on the 10% Minimum Elicitation Threshold ( MET 10) and use of a 10 fold uncertainty factor for potential variability within the human population and other uncertainties. See ADTC Memorandum, " Hexavalent Chromium  Finalization of Issues related to Quantitation of Dermal Risk from exposure to treated wood containing hexavalent chromium," August 31, 2004.

Scientific considerations EPA had identified a study performed with subjects who had documented sensitivity to chromium ( Nethercott, et al., 1994). The study was conducted to identify a level of exposure to chromium below which dermal exposure did not appear to elicit an ACD response. Regarding the Nethercott human study, the Agency had concluded that the study contains information sufficient for assessing human risk resulting from potential dermal exposure.

Please comment on whether the Nethercott study was sufficiently sound, from a scientific perspective, to be used to estimate a safe level of dermal exposure to hexavalent chromium.

Board Response to the Charge Introduction Hexavalent chromium ( CrVI) is known to cause allergic contact dermatitis ( ACD). CrVI is a component of a pesticide product used as a wood preservative, and members of the general public may be exposed through contact with treated wood. ACD is a delayed, immunologically mediated, inflammatory skin disease consisting of various degrees of erythema, edema, and vesiculation. ACD is typically characterized by two phases, termed induction and elicitation. Induction occurs when there was an exposure of sufficient magnitude and/ or duration to activate specific immune mechanisms resulting in the acquisition of sensitization, while elicitation occurs from a subsequent exposure to the same chemical allergen. In general, the amount of allergen exposure needed to produce induction is greater than that needed to produce elicitation in previously sensitized individuals. Thus, the study of elicitation can provide an appropriate critical endpoint for risk assessments. One approach to estimate an acceptable area dose for protection against elicitation is the determination of a minimum elicitation threshold, or MET. The concept behind the MET is that there was an elicitation threshold below which no sensitization reaction is expected.

The EPA FIFRA Scientific Advisory Panel met in May 2004 to review human and animal studies related to CrVI ( SAP, 2004). In August, 2004 the Agency's Antimicrobials Division Toxicity Endpoint Selection Committee issued a memorandum that summarized its assessment of dermal risk from CrVI ( ADTC, 2004). The Agency identified a study performed with human subjects who had documented sensitivity to chromium ( Nethercott et al., 1994). The study was conducted to identify a level of exposure to chromium below which dermal exposure did not appear to elicit an ACD response. Regarding the Nethercott et al. study, the Agency had 80 of 104 concluded that the study contained information sufficient for assessing human risk resulting from potential dermal exposure. The Agency had asked the HSRB to comment on whether this study was sufficiently sound, from a scientific perspective, to be used to estimate a safe level of dermal exposure to hexavalent chromium.

Critique of the 1994 Nethercott et al. Study The purpose of the study was to determine the MET as mass of allergen per skin surface area for CrVI by a patch testing technique. The study also included response to CRIII, but these data were not discussed here. Five concentration levels of CrVI ( 4.4, 0.88, 0.18, 0.088, 0.018 µ g/ cm2) was used in the patch test, and " TRUE Test" patches were manufactured specifically for use in the study to reduce the variability inherent in earlier patch preparation methods. The highest concentration ( 4.4 µ g/ cm2) were used as a screening concentration to identify those who were sensitized to CrVI. This first round of testing involved 102 volunteers ( 78 men and 24 women) previously shown to be sensitive to developing allergic contact dermatitis ( ACD) in response to an allergen. CrVI elicited ACD in 54 ( 39 men and 15 women) of these 102 subjects. Two lower concentrations ( 0.018 and 0.088 µ g/ cm2) were tested in these 54 volunteers in round two. Those who had no ACD response during round two were tested with the next two higher concentrations ( 0.18 and 0.88 µ g/ cm2) in round three. These concentrations were chosen to provide a maximal ACD response. The study was double blind as to concentration, and each concentration was matched with a control ( placebo) concentration within each volunteer. Patch concentrations were validated analytically and found to be within Contract Laboratory Procedure criteria for acceptability. The serial escalation of patch concentration level permitted the authors to determine a dose response relationship and to calculate MET values. The authors calculated a 10% minimum elicitation threshold ( MET10) of 0.089 µ g/ cm2.

This study had a number of strengths. It involved both sexes, the study concentrations were selected carefully based on previous studies, and the investigators determined a priori what sample size and dosing group size were needed to establish statistical accuracy for the MET10. Many elements of the experimental protocol ( e. g., employment of the control patch, serial increase of the concentration until manifestation of ACD, double blinding of patch concentration levels) were thoughtfully developed. The study was designed in accordance with current scientific standards to address a clearly defined research question, included representative study populations for the endpoint in question, and met requirements for adequate statistical power. It appears to have been conducted in accordance with recognized good clinical practices, including appropriate monitoring for safety. Finally, the study authors reported the design, conduct and analysis very comprehensively.

There are several questions that can be raised regarding the scientific validity of this study. First, the authors developed a cumulative response curve that included subjects who did not respond to any of the doses presented in rounds two and three. These subjects were assigned a minimum elicitation threshold value of 4.4 µ g/ cm2, although none were tested at doses between 0.88 and 4.4 µ g/ cm2. The assignment of this MET value appeared arbitrary, and potentially distorts the shape of the cumulative response curve. However, this use of the high MET value does not affect the calculation of the MET10, and so it was of no consequence to the study's primary conclusion. Second, a recent study by Hansen et al. ( 2003) reported a MET10 of 0.03 81 of 104 ug/ cm2 for 18 subjects, a value substantially lower than that reported by Nethercott et al. However, these two studies differed with respect to the reading scale employed. The reading of the tests in the Nethercott et al. study followed rules adopted for the diagnostic patch test; that is to say, the definition of a positive reaction was the appearance of erythema infiltration and papules. This approach was consistent with current international clinical standards. For the Hansen et al. study, the investigators used the same reading scale for diagnostic patch testing, but for definition of thresholds they used any degree of reaction, including erythematous and follicular reactions. The logic for this approach was that at very low concentrations irritation was not an issue, so that the question of threshold was not a diagnostic decision. This more sensitive reading approach, which at present was considered experimental, accounts for the difference in MET10 values reported in these two studies. Third, Nethercott et al. ( 1994) used patches that covered a very small area of skin ( 0.81 cm2). Workers, and presumably members of the public, would typically be exposed over a much larger skin surface area than that used in this study. In their article Nethercott et al. discussed the potential importance of patch surface area, and described an additional experiment with four of the study subjects who had exhibited MET values at 0.88 µ g/ cm2. In this experiment five patches were used for each subject, and the exposure level of CrVI was reduced to 0.18 µ g/ cm2 for each patch. The data that resulted from this experiment were not presented, but the authors stated that " sub MET concentrations of CrVI applied over a larger skin surface area did not elicit the positive responses seen when the MET concentration was applied in the standard patch." Current evidence indicated that the dose per unit area was the most important parameter for studies of this kind. But there was no doubt that if an extended area was exposed, such as the full arm, there may be an effect from absorption of an ACD producing compound. This type of exposure could lead to a systemic contact dermatitis reaction with spreading of the dermatitis to a vesicular palmar eczema, and eventually flexural eczema. Such systemic spreads are well known in relation to major contact dermatitis reactions, as occur in occupational exposures. The Nethercott et al. study, where relatively small skin surface areas were exposed, does not exclude that such effects could happen if larger areas were exposed.

HSRB Consensus and Rationale The Board concluded that the 1994 Nethercott et al. dermal sensitization study was sufficiently sound, from a scientific perspective, to be used to estimate a safe level of dermal exposure to hexavalent chromium.

The 1994 Nethercott et al. study was properly designed, well conducted, and employed appropriate scientific and clinical methods to determine a minimum elicitation threshold for dermal sensitization due to hexavalent chromium. The MET10 reported in the study provided a reasonable point of departure for risk assessment.

Charge to the Board Ethical considerations The Agency requested that the Board provide comment on the following: 82 of 104 a. Is there clear and convincing evidence that the conduct of the Nethercott study was fundamentally unethical?

b. Is there clear and convincing evidence that the conduct of the study was significantly deficient relative to the ethical standards prevailing at the time the research was conducted?

Board Response to the Charge Brief Overview of the Study A previously published study involving dermal exposure of 102 healthy volunteers to increasing doses of CrVI was evaluated, hereinafter referred to as Nethercott et al. 1994. he study sponsor was unknown, but is likely to be either the Chem Risk Division of McLaren/ Hart Environmental Engineering, Alameda CA, or a client of McLaren/ Hart. The study was conducted in 1992 at five U. S. and one Canadian academic institution: the Cleveland Clinic Foundation ( Cleveland, OH), Johns Hopkins University ( Baltimore, MD), Pennsylvania State University ( Hershey, PA), Stanford University ( Palo Alto, CA), the University of British Columbia ( Vancouver, BC), and the University of Louisville ( Louisville, KY). The study was conducted after the promulgation of federal protections for the protection of human participants in research ( i. e. Common Rule) ( § 45CFR46; adopted by the EPA in 1991 and published at § 40CFR26), so the regulatory requirements of the Common Rule were applicable. Furthermore, all five US academic institutions participating had a valid Multiple Project Assurance of Compliance with U. S. Department of Health and Human Services ( DHHS) Regulations for Protection of Human Research Subjects at the time the study was performed. The University of British Columbia, in contrast, held a Cooperative Project Assurance at that time, allowing its participation in DHHS recognized research programs and documenting the University of British Columbia's commitment to the protection of human research subjects in accordance with § 45CFR46.

Critique of Study The Board concurred with the factual observations of the strengths and weaknesses of the study, as detailed in USEPA ( 2006a). However, further comments were raised regarding: 1) whether the documentation and process of study subject enrollment was sufficient to meet prevailing standards of voluntary informed consent and 2) whether the repeat high dose oralexposure protocols used were designed to minimize risks to study participants.

1) Voluntary Informed Consent The Common Rule provides a comprehensive framework for initial and continuing review of research involving human subjects. In order to ensure that a study like Nethercott et al. was performed ethically, the Common Rule requires that: 1) people who participate as subjects in research are selected equitably and give informed and voluntary written consent; and 2) research involving human subjects be reviewed and approved by an independent oversight group such as an Institutional Review Board ( IRB). As published, however, the Nethercott et al. study did not contain sufficient information for the Board to adequately determine whether or not the 83 of 104 informed consent process used to enrolled study participants met the standards outlined in § 45CFR46. All that is known about the informed consent process is that " all volunteers provided their doctors with written consent to participate in the study" ( Nethercott et al. 1994).

Given the paucity of documentation, the Board concluded there was no evidence that the voluntary informed consent process used failed to meet the regulatory and ethical standards applicable to research conducted in the United States and Canada in 1992. All six academic institutions participating in this study had an assurance of compliance with DHHS Regulations for Protection of Human Research Subjects at the time, requiring independent review of the research protocol and consent documents by IRBs. These review boards were expected to approve a study involving human subjects only if: 1) the risks to subjects were minimized by using procedures which were consistent with sound research design and which do not unnecessarily expose subjects to risk; and 2) the risks to subjects were reasonable in relation to anticipated benefits to subjects, if any, and the importance of the knowledge that may reasonably be expected to result ( see, e. g., § 45CFR46.111). The HSRB believed that it was unlikely that all six of these IRBs would overlook deficiencies in the consent process that would seriously impair the voluntary informed consent of the research subjects.

2) Minimization of Risks to Study Participants The Nethercott et al. study employed a three step exposure protocol. Initially, 102 volunteers were screened for hexavalent chromium sensitivity by dermal exposure using a chromium concentration equivalent to the standard dose used in patch testing for skin allergies ( 4.4 µ g Cr( VI)/ cm2). Pregnant women, individuals receiving immunosuppressive or steroid medications, and patients with recent or concurrent dermatological conditions were excluded from study participation. 54 chromium sensitive subjects were identified by Nethercott et al. These chromium sensitive subjects then participated in up to two rounds of additional testing. In the first round, subjects were exposed to 0.018 and 0.088 µ g CrVI/ cm2 using a skin patch approach. Five subjects developed allergic contact dermatitis to one or both of these lower doses; these subjects were excluded from further testing. Subjects who failed to respond to either the 0.018 or 0.088 µ g dose, however, were subsequently exposed to ten fold higher doses ( 0.18 or 0.88 µ g Cr( VI)/ cm2. 27 subjects developed allergic contact dermatitis to one or both of these higher doses.

In sensitized individuals, chromium exposure elicits an allergic contact dermatitis similar to a poison oak or poison ivy rash. The result typically is an itching, red rash with bumps or blisters; these transient symptoms usually are mild and can be treated with calamine lotion and hydrocortisone cream. The use of patch testing, even when it knowingly results in allergic contact dermatitis, thus meets the generally accepted definition of minimal risk. Furthermore, Dr. Torkil Menne, a consultant to the HSRB, commented that most studies designed to determine the minimum elicitation threshold to a dermal sensitizing agent like chromium have used a singlestep protocol in which study subjects were exposed to the entire range of dermal concentrations in a single round of testing. The study exclusion criteria and the use of a three step exposure protocol, involving initial screening of subjects for chromium sensitivity followed by additional rounds of testing, using doses significantly smaller than those routinely employed for allergy testing and excluding reactive study participants from further exposure, seems designed 84 of 104 specifically to minimize the risk of serious harm to research participants. Thus, the Board believed that there was not was clear and convincing evidence that these studies could have resulted in serious harm based on the knowledge available to the investigators at the time.

HSRB Consensus and Rationale The Board concurred with the assessment of the Agency that there was no clear and convincing evidence that the conduct of the research was fundamentally unethical in that the deficiencies did not result in serious harm, nor seriously impair the informed consent of the research subjects.

The Board determined that there was no clear and convincing evidence that the conduct of the study was significantly deficient relative to the ethical standards prevailing when the study was conducted.

The Board based these two determinations on its conclusion that this study appeared to have not deviated significantly from the ethical standards prevailing when the study was conducted. However, this conclusion was based, in part, on a process that was hampered by a lack of supporting documentation concerning independent ethical review by the study investigators' home institutions. The Board strongly recommended that for all studies submitted to the HSRB, the Agency make a good faith effort to obtain such documentation in the future.

2. Carbofuran Charge to the Board Carbofuran is an N methyl carbamate ( NMC) pesticide whose primary toxic effect is neurotoxicity caused by the inhibition of the enzyme, acetylcholinesterase, via carbamylation followed by rapid recovery. Carbofuran can, at sufficiently high doses, lead to a variety of clinical signs. The Agency is conducting acute, aggregate ( single chemical, multi route) and worker risk assessments of carbofuran. In addition, carbofuran is a member of the N methyl carbamate common mechanism group and is thus included in the cumulative ( multi chemical, multi route) risk assessment for the NMCs.

Scientific considerations:

The Agency's WOE document and DERs for carbofuran described the study design and results of a carbofuran human oral study and two human dermal toxicity studies. The WOE document also discusses the Agency's conclusions that these studies were useful in establishing points of departure, both oral and dermal, for the single chemical assessment and in informing the interspecies uncertainty factor for the cumulative assessment.

Please comment on the scientific evidence that supports these conclusions. 85 of 104 Board Response to the Charge Study Overview Three separate studies ( one oral, two dermal) were carried out with carbofuran in human subjects. The study details are described separately below.

Overview of Oral Study The oral study conducted with carbofuran was carried out in nine healthy male volunteers using an ascending dose schedule and single doses of 0.05, 0.1 and 0.25 mg/ kg ( 1976). The goal of this study was to determine the threshold for toxicity following a single oral dose. Initially, the study was conducted in an open design ( subject and investigator knew that carbofuran was ingested) until a dose level produced symptoms determined to be intolerable ( described below). Once the intolerable dose was achieved ( 0.25 mg/ kg), the study was completed in a randomized, double blind manner. Carbofuran was administered as a single dose in a capsule immediately following breakfast, after which subjects remained under observation for 24 hours. Blood samples were collected for analysis of plasma and RBC cholinesterase activity at 0.5, 1, 2, 3, 6 and 24 hours after dosing. The baseline level of RBC cholinesterase activity was established from a predose sample collected immediately prior to dosing. For each subject, additional physiological parameters including ECG, blood pressure, pupil size and accommodation and the Fukuda step test were collected, and subjects were monitored continuously for additional symptoms of toxicity, including sweating, salivation, headaches and nausea and vomiting throughout the 24 hour post dosing period. A complete clinical chemistry profile was performed predose and at 24 hours. The next highest dose was not initiated until data from the 24 hour post treatment period were evaluated. Plasma and RBC cholinesterase levels were determined using a modification of the Ellman colorimetric method with propionylthiocholine as substrate. Subjects were allowed to smoke during the 24 hour sample collection period.

After administration of the 0.05 mg/ kg dose ( 2 subjects), no symptoms were noted and RBC cholinesterase activity was decreased by 11 or 22% from baseline ( plasma cholinesterase was decreased by 32 and 36%, respectively). Accordingly, the dose was escalated to 0.1 mg/ kg ( 2 subjects). In this leg of the study, one subject exhibited an abnormal vestibular mechanism prior to dosing and showed further deterioration after exposure to carbofuran. This subject also showed changes in cardiovascular parameters including sinus bradycardia and sinus arrhythmia. Two subjects presented with mild symptoms including headache ( 1 subject) or lightheadedness ( the other subject). RBC cholinesterase activity decreased 33 and 31%, respectively, whereas plasma cholinesterase activity was more variable ( decreased 56 and 35%, respectively). Based on these results, the dose was escalated to 0.25 mg/ kg ( 2 subjects) where marked symptoms, including drowsiness, nausea, vomiting, headache, salivation, and sinus bradycardia were noted. Accordingly, this dose level was considered to have achieved the level of intolerable symptoms, and an additional 2 subjects were exposed to this level along with one control subject in a double blinded manner. At this dose level, RBC cholinesterase inhibition ranged from 46 63% and plasma cholinesterase inhibition ranged from 33 100%.

Overview of Dermal Studies 86 of 104 The dermal studies conducted with carbofuran ( 1977 and 1978) involved application of the compound to the backs of subjects for 4 hours. The two studies were similar in design, but differed with respect to the commercial formulations tested and the mass applied per unit area of skin.

The 1977 dermal study ( i. e., first dermal study) was carried out as a single, ascending dose study and was designed to determine the threshold for toxicity under conditions of normal and elevated temperatures. Carbofuran was provided in labeled capsules containing 75.4% carbamate powder or placebo. This powder was applied to the backs of each subject over an area described by a paper template and was then mixed with either water, an artificial sweat medium, or normal saline to insure adhesion. Under normal temperature conditions ( approximately 70 ° F and 35% humidity), the doses evaluated were 2, 4, 8 and 32 mg/ kg ( 2 subjects per dose level), whereas under elevated temperature conditions ( approximately 90 ° F and 68 89% humidity), the doses evaluated were 0.5, 1 and 2 mg/ kg ( 2 subjects per dose level). A control group ( 2 subjects) was included in the high temperature leg of this study. For the high temperature conditions, subjects were also made to exercise by riding a stationary bicycle ( 5 minutes of exercise followed by 15 minutes of rest) throughout the entire 4 hour exposure period. The parameters outlined above under the overview of the oral study were performed on all subjects in this study.

Under normal temperature conditions, no symptoms were noted at any dose level, and changes in RBC and plasma cholinesterase were variable. RBC cholinesterase inhibition did not exceed 24% ( observed at 32 mg/ kg). Plasma cholinesterase activity was highly variable, with a maximal inhibition of 33% noted at the 4 mg/ kg dose, whereas only 0 or 2 % inhibition was reported in the 2 subjects dosed with 32 mg/ kg.

Under conditions of high temperature and humidity, symptoms were observed in the two subjects dosed at 2 mg carbofuran/ kg. One subject at this level exhibited severe symptoms ( including hazy vision, vomiting, defecation with muscle cramps and chills) and required atropine ( at 3 separate times) to ameliorate symptoms. Maximal inhibition of RBC cholinesterase activity at this dose level was 45 and 65% in the 2 subjects ( 4 hours), whereas plasma cholinesterase inhibition was maximal at 24 hours ( 12 and 16 %, respectively).

The 1978 dermal study ( i. e., second dermal study) was carried out as a single, ascending dose study and was conducted under conditions of elevated temperature and humidity as described above. The carbofuran used in this study was a formulation containing 44% active ingredient and was applied at a concentration of approximately 0.5 mg/ cm2 using a 50% dilution of the formulation. The doses evaluated were 0.5, 1, 2 and 4 mg/ kg ( 2 subjects per dose level). There was no control group. The same parameters outlined above under the overview of the oral study were performed on all subjects in this study.

One subject dosed at 0.5 mg/ kg reported nausea after treatment and the other subject noted burning at the application site. In contrast, neither subject dosed with 1 or 2 mg/ kg experienced any symptoms. A dose of 4 mg/ kg resulted in symptoms of nausea, dizziness and weakness in both subjects, and atropine was administered to these subjects. Inhibition of RBC cholinesterase activity showed some evidence of dose dependence but was variable, ranging 87 of 104 from 22 and 7% to 61 and 49% in the 2 subjects treated with 0.5 and 4 mg/ kg, respectively. Plasma cholinesterase levels were highly variable, with 33 and 46% inhibition observed at 0.5 mg/ kg and 6 and 9% at 4 mg/ kg, respectively.

Critique of the Oral and Dermal Studies Conducted with Carbofuran In the three studies described above, the major strength of the work was that the experimental design included the evaluation of at least three dose levels from which dose response relationships could be evaluated. Furthermore, the study outcomes were generally consistent with fundamental principles of xenobiotic disposition including observations that exposure from the oral route likely exceeded that from the dermal route ( reflected by the observation of toxicity at much lower oral doses) and that dermal exposure was increased in an environment of increased temperature and humidity. However, in evaluating all of the studies, numerous weaknesses were noted by the HSRB. These weaknesses included:

1) There was no justification or rationale for the selection of doses used in any of the three studies.

2) The sample size was very small ( typically two subjects per dose or condition) with few or no controls ( no more than two control subjects in any study). Such a design prevented evaluation of statistical significance for any parameter measured in the studies.

3) The values obtained for RBC and plasma cholinesterase levels were highly variable. Factors that contributed to this variability included the small sample size, the inclusion of only a single baseline sample collected immediately prior to dosing used to compare all post dosing samples, the small number of control subjects, and an uncommon method for analytical determination of cholinesterase activities. The contribution of potential laboratory error cannot be ruled out.

4) Plasma cholinesterase levels were highly variable in all studies so as to preclude any useful interpretation. In general, plasma cholinesterase levels were not consistent with changes in RBC cholinesterase activities.

5) One subject who presented with abnormal vestibular mechanisms in the pre dose evaluation was used in the oral study and showed serious symptoms after treatment.

6) Subjects were allowed to smoke during the study period.

While the oral and dermal studies shared these common weaknesses, there were also serious limitations regarding the application of carbofuran in the conduct of the dermal studies. In particular, it is known that dermal absorption is influenced by the concentration of compound applied per unit surface area of skin, and it was clear that the studies were extremely different in this regard. For example, as shown in the Table 1 below in the first dermal study ( high temperature/ humidity), the mass loading range was 6,000 to 12,000 µ g carbofuran/ cm2. These extremely high loading levels were not appropriate for evaluating potential dermal absorption from occupational or environmental exposure to carbofuran. In the first dermal study, the 88 of 104 greatest skin surface area treated in the normal temperature leg of this study was 40 cm2; a mass of 3,264 mg was applied to this area, equivalent to a loading of 81,600 µ g carbofuran/ cm2. In contrast, mass loading was controlled to achieve approximately 500 µ g carbofuran/ cm2 at all dose levels in the second dermal study.

Table 1. Calculation Of Loading Levels For Carbofuran For Subjects In The First Dermal Study ( High temperature/ humidity conditions)

Subject Dose Body Wt Mass Template Loading ( mg/ kg) ( kg) ( mg) ( cm2) ( ug/ cm2)

1 0 63 0 2 0 65 0 3 0.5 72 36 6 6,000 4 0.5 66 33 5.72 5,769 5 1 74 74 8.55 8,655 6 1 64 64 7.94 8,060 7 2 74 148 12.16 12,171 8 2 78 156 12.49 12,490 A primary deficiency of the first dermal study was that it did not provide a realistic worker exposure scenario; that is, the exposures of the subjects in these experiments did not correspond to exposures likely to be seen among workers. Large amounts of carbofuran ( up to 3,000 mg) were applied to a relatively small skin surface area ( 6 40 cm2) in the experiments, whereas we typically see much larger skin surface areas exposed to smaller amounts among workers ( e. g., 1 10 µ g/ cm2). For example, the hands, a skin surface commonly exposed to pesticides, have a total surface area of 990 cm2 ( EPA Exposure Factors Handbook, 1997). Dermal dosing studies require careful consideration of three factors: mass applied to the skin, surface area treated, and the duration of exposure. Therefore, the skin loadings and skin surface areas exposed in both carbofuran dermal studies were not appropriate for determination of a NOAEL or a LOAEL for risk assessment purposes.

HSRB Consensus and Rationale The EPA concluded that the oral and dermal studies conducted with carbofuran in human subjects were useful in establishing points of departure, both oral and dermal, for the single chemical assessment and in informing the interspecies uncertainty factor for the cumulative assessment.

However, while these studies were informative, the HSRB concluded that there were numerous technical issues regarding the conduct of the oral and dermal studies with carbofuran and that overall, the weakness of the studies far outweigh the strengths. The weaknesses included the small sample size, the lack of control subjects, the highly variable results for RBC cholinesterase activity and the inappropriate application methods used in the dermal studies. Accordingly, the HSRB did not recommend any of the oral or dermal studies conducted with 89 of 104 carbofuran in human subjects for the single chemical assessment or in informing the interspecies uncertainty factor for the cumulative assessment.

Additional Considerations: Potential For The Carbofuran Human Studies Data The Board provided additional analysis in response to the Agency's charge to the Board concerning the potential for the data in human subjects for carbofuran to be applied to: ( 1) the calculation of a benchmark dose ( BMD10) and identification of the BMD10L ( lower confidence limit); ( 2) the identification of a NOAEL or LOAEL for effects or ( 3) the comparison to other species for possible adjustments to uncertainty factor for the cumulative assessment.

The HSRB provided the following additional perspective relative to the Agency's question:

The utility of the human studies with carbofuran was limited by the very small sample size used in all of the studies. The Agency proposed to use the RBC cholinesterase data for determination of the BMD10L. However, under conditions where the group size was only two, it would be imperative to have highly accurate, valid, reliable and consistent measures of RBC cholinesterase activity in both control and carbofuran treated subjects. This rigor was simply not achieved in the human studies. Rather, RBC cholinesterase activities were compared to a single baseline value, were highly variable across subjects, including controls, and did not show any consistency with plasma cholinesterase levels. As such, although a BMD10L could be calculated, the magnitude of the error in the derived values would preclude a reliable, meaningful assessment. Therefore, the HSRB reiterated its recommendation that the human data should not be used for calculation of the BMD10.

In a similar manner, the small sample size, compounded by the lack of consistent changes in cholinesterase activities in all studies, the inappropriate methods used for dermal application of the compound in the dermal studies and the inclusion of at least one subject who presented with abnormal vestibular function in a pre dose assessments limited the general utility of the data. Collectively, the weaknesses in the carbofuran human studies conduct and outcomes cast doubt on the utility of the data for identifying a NOAEL or LOAEL or for comparing across species in consideration of the interspecies uncertainty factor for the cumulative risk assessment. Thus the HSRB recommended that the human data should not be used for these evaluations.

Charge to the Board Ethical Considerations The Agency requested that the Board provide comment on the following:

Oral Toxicity Study: Is there clear and convincing evidence that the conduct of the human oral study conducted with carbofuran was fundamentally unethical? 90 of 104 Is there clear and convincing evidence that the conduct of the oral study was significantly deficient relative to the ethical standards prevailing at the time the research was conducted?

Dermal Toxicity Studies: Is there clear and convincing evidence that the conduct of either of the human dermal studies conducted with carbofuran was fundamentally unethical?

Is there clear and convincing evidence that the conduct of the dermal studies was significantly deficient relative to the ethical standards prevailing at the time the research was conducted?

Board Response to the Charge Study Overview There were three studies involving either oral or dermal administration of carbofuran: an oral toxicity study performed in 1976 ( IRB Review dated March 31, 1976; Final Report dated September 17, 1976); a dermal toxicity study performed in late 1976 and early 1977 ( IRB Review dated August 25, 1976; Final Report dated March 18, 1977); and a second dermal toxicity study conducted in late 1977 ( REC Review date unknown; Final Report dated February 15, 1978).

The location for the research was the Quincy Research Center in Kansas City, Missouri. All three studies were under the direction of a single principal investigator, John D. Arnold, MD. The research appeared to have been performed under contract to the Midwest Research Institute, also located in Kansas City. The responsible institutional review board was the Community Review Committee, Inc., again located in Kansas City. The research sponsor was FMC Corporation, located in Philadelphia, Pennsylvania with the manufacturing facility apparently located in Middleport, New York.

No ethical or regulatory standards were mentioned in any of the study documents. Given the dates of the research studies, Section 12 of FIFRA applied to the research. In addition, the 1975 version of the Declaration of Helsinki was available at the time.

Critique of Studies The following comments apply to all three studies.

1) The fact that these studies have never been published should not be used as the sole criterion to determine whether the purpose of the research was to obtain generalizable knowledge. Publication is neither a necessary nor sufficient criterion of whether or not the research was designed to allow for either a descriptive or causal inference.

2) The risks were minimized by the study design ( setting aside the actual conduct), assuming that there was a valid scientific purpose in escalating the dose until achieving a " lowest observable adverse effect level" ( LOAEL). Examples of the procedures that were incorporated to 91 of 104 minimize risk included the presence of a supervising physician who was readily available for 24 hours after dosing, confinement of the subjects for 24 hours, abstinence from alcohol during the study, the exclusion of other drugs within two weeks of performing the study, the availability and administration of atropine ( discussed further below), and a delay in dose escalation ( at least in the oral toxicity study) until the 24 hour clinical data was available. In addition, subjects only received the active compound once during each research study.

3) Measurements of RBC cholinesterase inhibition should serve as an adequate surrogate measure of toxicity, obviating the need to induce clinical signs and symptoms of cholinergic toxicity. The question however in judging these three studies was whether this standard was either appreciated or applicable in 1976 and 1977. The fact that the research was designed to cause clinical signs and symptoms of cholinergic toxicity as the study endpoint does not, in and of itself, establish that the interests of the subjects did not prevail over other interests. The Common Rule allows for the balancing of the risks of research against the knowledge that may reasonably be obtained. The central question then was whether the risks were reasonable, not whether the research was designed to elicit clinical toxicity.

4) With respect to informed consent, the list of signs and symptoms of cholinergic toxicity found in the consent documents was fairly complete. The consent documents were fairly straightforward about the fact that the testing involved a pesticide and that the research would be of no benefit to the subject. The freedom to withdraw was emphasized, along with the fact that additional testing to ensure the safety of subjects would be requested by the supervising physician. In spite of these strengths, the consent documents failed to provide a description of the study design ( i. e., dose escalation) and the anticipated endpoint of clinical toxicity. The phrase " we do not expect any serious complications" is clearly open to interpretation. Some would and some would not consider the clinical signs and symptoms of cholinergic stimulation " serious." Regardless, the phrase does introduce a framing of these stated risks as " non serious." Given the research design, the consent documents would have been improved if they had been explicit about the dose escalation, the place of the specific subject within that dose escalation, and the fact that someone would eventually have a 100% chance of experiencing clinical toxicity. Although these changes are an admirable standard going forward, the consent documents used for the oral and first dermal toxicity study met ( and some might argue exceeded) the standards prevalent in 1976 and 1977. However, as discussed below, the consent document for the second dermal toxicity study was seriously deficient.

The Board had specific comments about the conduct of each of the studies that can be addressed under the general topic of the reasonableness of the risks ( and the efforts to reduce those risks) that the subjects experienced in the conduct of this research.

1) Was it appropriate to expose additional subjects, in the oral toxicity study, to a dose which had already been shown to cause clinical toxicity if the scientific purpose was to establish a LOAEL? Given the criticism of attempting to determine a " no observable adverse effect level" ( NOAEL) using a small sample size, the design chosen in these three studies to elicit a LOAEL may be more reliable. However the small sample size, when combined with the variability and unreliability of the RBC cholinesterase measurements, undermine confidence that the study was designed to establish the real LOAEL. The repeat administration of the test substance absent 92 of 104 dose escalation was used in other cholinesterase inhibitor studies, but the endpoint driving the decision to not escalate dosing was the more sensitive endpoint of the degree of RBC cholinesterase inhibition.

2) There was documentation ( in a letter dated October 26, 1976) of the decision to start at the 2.0 mg/ kg dose in the low temperature and low humidity phase of the first dermal toxicity study. Although the responsible IRB was not consulted ( for which there were no procedural guidelines in 1976), was the decision to bypass the 16 mg/ kg dose in favor of a 32 mg/ kg dose in the low temperature and humidity phase of the dermal toxicity study reasonable? If the doseresponse relationship based on the percent RBC acetyl cholinesterase inhibition was linear, yet the onset of clinical signs and symptoms reflects a threshold response, this decision could have placed the subjects given the higher dose at greater risk even though, in retrospect, the 32 mg/ kg dose was well tolerated.

3) The administration of atropine as an antidote to cholinergic toxicity may have been delayed for one or more of the subjects in the high temperature and high humidity phase of both dermal toxicity studies. Although mention was made of written instructions for the administration of atropine, these instructions were not included in the submitted documentation. The question then was whether there could be any justification for the delay in the administration of atropine. Two possible justifications might be: ( 1) the signs and symptoms were from nonmuscarinic cholinergic receptors and thus would not be responsive to atropine ( which was not the case); or ( 2) the supervising physician was concerned that any resulting tachycardia or other side effects from the administration of atropine would be of greater risk ( highly unlikely). After considerable reflection, the Board could find no scientific or clinical reason to delay the administration of atropine.

4) Study participants were not fully informed of the risks of the study. It should have been clear to study investigators that the escalating dose design used was likely to result in serious harm to some research subjects. For example, several participants who received a 2.0 mg/ kg dose of carbofuran during the high temperature and high humidity phase of the first dermal toxicity study exhibited clear clinical signs and symptoms of carbamate poisoning, requiring administration of atropine as an antidote. Plasma and red cell cholinesterase inhibition data also was obtained from these individuals, with participants demonstrating 46% and 65% peak red cell inhibition respectively. In the subsequent second dermal toxicity study, however, the data from the first dermal toxicity study were not used either to develop clear stopping criteria or to modify the dosing protocol, thus exposing study participants to an unacceptable level of risk. The two participants in the high temperature and high humidity second dermal toxicity study who received a 2.0 mg/ kg dose of carbofuran did not exhibit any clinical symptoms of carbamate poisoning. These individuals did, however, exhibit peak red cell cholinesterase inhibition of 40% and 42% respectively, similar to the level of inhibition seen in one of the symptomatic participants in the first dermal toxicity study. These data suggest that the LOAEL for carbofuran was at or near 2.0 mg/ kg. Nevertheless, the decision was made to expose two subjects to a dose of 4.0 mg/ kg carbofuran, once again resulting in severe clinical symptoms indicative of carbamate poisoning and requiring administration of atropine as an antidote. In light of the clinical and biomarker data obtained from the first dermal toxicity study, it should have 93 of 104 been obvious to study investigators that exposure of additional research subjects to a dose of 4.0 mg/ kg carbofuran was likely to have resulted in serious harm to these two study participants.

This conclusion, coupled with the observation that the consent documents from the second dermal toxicity study explicitly stated study investigators "[ did] not expect a serious complications" raises serious questions about the informed consent process. At least some study participants were likely to experience clinical signs indicative of carbamate toxicity. To imply otherwise in the informed consent documents suggests that the consent process was severely flawed. Study participants were denied access to information that might have influenced their decision to voluntarily enroll in the second dermal toxicity study.

HSRB Consensus and Rationale Oral Toxicity Study For the oral study, there was no evidence that the study failed to fully meet specific ethical standards prevalent at the time the research was conducted.

There was no clear and convincing evidence that the research was fundamentally unethical ( e. g., intended to seriously harm participants or that informed consent was not obtained).

There was no clear and convincing evidence of significant deficiencies in the ethical procedures that could have resulted in serious harm ( based on the knowledge available at the time the study was conducted) nor that information provided to participants seriously impaired their informed consent.

Dermal Toxicity Studies The HSRB found deficiencies in both dermal human toxicity studies relative to specific ethical standards prevalent at the time the study was conducted.

The majority of the Board concluded there was no clear and convincing evidence that the research was fundamentally unethical ( e. g., intended to seriously harm participants or that informed consent was not obtained). In light of the results obtained from the first dermal toxicity study, one Board member concluded that the second dermal toxicity study was fundamentally unethical in design. The Board member believed that this study was neither designed to minimize the risk of serious harm to participants nor to ensure an adequate informed consent.

For both dermal toxicity studies, there was clear and convincing evidence of significant deficiencies in the ethical procedures for minimizing risk that could have resulted in serious harm ( based on the knowledge available at the time the study was conducted). The first dermal toxicity study was significantly deficient given the delay in the administration of atropine to more than one subject experiencing the signs and symptoms of carbamate toxicity. The second dermal toxicity study was considered significantly deficient by a majority of Board members in 94 of 104 that the lack of information provided about the results from the initial dermal toxicity study seriously impaired their informed consent.

3. Methyl Isothiocyanate ( MITC)

Charge to the Board MITC is an irritating compound that has a limited animal database for toxicity via inhalation, the key route of exposure. MITC can be used as a pesticide directly to treat wood poles, but the major pathway of exposure to MITC is from degradation of several fumigant pesticides ( i. e., metam sodium, metam potassium, and dazomet). Due to its volatility, MITC has the potential to move off site, which can result in exposure to bystanders near treated areas and, through ambient air, to people far away from treated areas. Use of the soil fumigants also results in exposure to those handling the pesticides or working in treated fields.

Scientific considerations The Agency's WOE document and DER for MITC describe the study design and results of the MITC odor threshold and eye irritation human studies. The WOE document also discusses the Agency's conclusions that the eye irritation study is useful for the assessment of potential effects on bystanders and workers from exposures to MITC during acute ( 1 day) intervals. The Agency had concluded that the odor threshold study is less useful than the eye irritation study for assessing the human health effects of MITC, since the odor detection threshold for humans is higher than the level that causes eye irritation. The Agency had decided, however, to use the results of the eye irritation study for assessing the inhalation exposure of MITC.

Please comment on the scientific evidence that supports this conclusion.

Board Response to the Charge Introduction MITC is the primary and key degradate of these fumigant pesticides ( i. e., metam sodium, metam potassium and dazomet). As a gas injected into soil, it can kill soil borne pests, such as insects, microorganisms, weeds, and nematodes. The fumigant dissipates from the soil in a few days to a couple of weeks.

According to the EPA Weight of Evidence ( WOE) document ( USEPA 2006b) " The mode of toxic action for MITC is not known at this time. MITC is primarily an irritating compound that produces non specific systemic effects in oral toxicity studies such as changes in body weight, food consumption, and hematological parameters. Following air exposures to MITC, consistent effects are observed in rats and humans. For example, clinical signs and pathological changes of the respiratory tract consistent with an irritant have been observed in laboratory studies in rat. Humans exposed to MITC complain of symptoms such as itchy and burning eyes, rash and burning skin, nausea, scratchy throat, salivation, coughing, and shortness 95 of 104 of breath. In acute toxicity testing with animals, MITC is considered Acute Toxicity Category I ( corrosive) for skin and eye irritation." Since the animal studies were either long term inhalation or oral studies, they were not considered for a point of departure and therefore would be less protective of human health. Thus, the Board recommended the eye irritation LOAL as a point of departure.

Brief Overview of Study The EPA WOE extracted a description of the odor and eye irritation study ( Russell and Rush 1996) directly from the Risk Characterization Document for MITC of the Department of Pesticide Regulation, Cal EPA ( July 25, 2003, pp 53 59), which was considered accurate and quoted herein.

" In order to determine the NOEL for human eye irritation produced by MITC vapors, as well as its odor threshold, human volunteers were exposed to air concentrations of MITC in a laboratory setting ( Russell and Rush, 1996). The study specifically focused on assessing these parameters at different times of exposure. An olfactometer was used which permitted the operator to dispense the test material through a manifold system. The test material could thus be diluted over a 100 fold concentration range. The material was dispensed by diffusion from a glass vessel which could be maintained at any temperature ± 0.1 ° C over a range of 30 to 70 ° C. A Total Hydrocarbon Analyzer ( THA) was used to monitor the flow of test material during the exposure period. In addition, carbon tube samples were drawn once the system was equilibrated prior to exposure, and at the end of the exposure. The test material was desorbed from the carbon and analyzed by gas chromatography. Every effort was undertaken to minimize the reaction of the test material with the tubing and other equipment used in the delivery system".

" In the olfactory threshold study, 33 individuals ( 16 males, 17 females) with a mean age of 25 years ( range, 18 to 34 years) were tested. They were exposed to three positive control odorants, pyridine, acetic acid, and n butyl alcohol as well as to MITC. The technician chose the odorant and concentration level. The odorant was dispensed in double blind fashion from one of three presentation ports. The subject was responsible for identifying from which of the presentation ports the odorant was dispersed. A 30 second rest period between exposures was permitted in order to allow the subject to recover prior to the next exposure. The operator tested each subject over the range of concentrations for each odorant until he was assured that the threshold had been adequately ascertained. A standard procedure was employed in order to make this determination."

" In the NOEL determination for eye irritation, the olfactometer was modified by attaching goggles to the presentation line. This permitted the test material to be directed only to the eyes. Five parameters were used to ascertain an irritation response: 1. the subjects' subjective estimation of irritation ( using the " Likert" scale); 2. photographs of the subjects' eyes prior to and after exposure; 3. blink rate as measured by electromyography; 4. effect upon visual acuity; 5. tear production. Both a positive control ( acetic acid) and a negative control ( air) were employed. Baseline responses for each of the assessment parameters were determined under preexposure conditions (" zero time controls") and upon exposure to the negative control (" air only controls") for the prescribed period. A positive irritation response was based on three criteria: 1. 96 of 104 the average response must be quantitatively greater than the pre exposure response; 2. the average response must be greater than pre exposure and greater than could be expected statistically from individual to individual differences within the group; 3. the average treated response must be greater than the air only group's response and greater than could be expected from individual differences observed within the group. Seventy individuals ( 38 males, 32 females) with a mean age of 32 years ( range, 18 67 years; median age, 28 years) were exposed to air, MITC, and/ or acetic acid. Between 9 and 16 subjects were examined under each dose/ time period combination. Three exposure periods, 14 minutes, 4 hours and 8 hours were used. In the eight hour test, subjective responses, blink rates and tearing were assessed at 0, 1.5, 3, 3.5, 6 and 8 hours ( tearing was not measured at 3.5 hours). Two 15 minute rest breaks and a 30 minute lunch break were permitted during the 8 hour period. In the four hour test, these same parameters were assessed at 0, 1, 2, 3 and 4 hours ( tearing was not measured at 0, 2 and 3 hours). In the 14 minute exposure protocol, subjective responses and blink rates were measured at 0, 1, 4 and 14 minutes after the start of exposure. Tearing was measured at 14 minutes only. Visual acuity and ocular morphology were assessed at the beginning and end of each exposure period. All analyses were performed in a double blind manner." T tests were used to compare responses at each computed concentration level for each time period to both air control results and zero time results. Both were significant and positive but responses to the control substance were not as dramatic.