1 of 104 July 25, 2006 Minutes of the United States Environmental Protection Agency ( EPA) Human Studies Review Board ( HSRB) June 27 30, 2006 Public Meeting Docket Number: EPA HQ ORD 2006 0384 Committee Members: ( See Roster  Attachment A)

Dates and Times: Tuesday, June 27, 2006; 1: 00 PM   6: 00 PM Wednesday, June 28, 2006; 8: 30AM   5: 30 PM Thursday, June 29, 2006; 8: 30AM   5: 30 PM Friday, June 30, 2006; 8: 30AM   3: 00PM ( See Federal Register Notice   Attachment B)

Location: EPA, One Potomac Yard ( South Building), 2777 Crystal Drive, Arlington, VA 22202 Purpose: The EPA Human Studies Review Board ( HSRB) provides advice, information, and recommendations on issues related to the scientific and ethical aspects of human subject research.

Attendees: Chair: Celia B. Fisher, Ph. D.

Board Members: David C. Bellinger Ph. D. William Brimijoin, Ph. D. * Alica Carriquiry, Ph. D. Gary L. Chadwick, PharmD, MPH, CIP Janice Chambers, Ph. D. D. A. B. T.* Richard Fenske, Ph. D. MPH Susan S. Fish, PharmD, MPH Suzanne C. Fitzpatrick, Ph. D. D. A. B. T. Kannan Krishnan, Ph. D. Michael D. Lebowitz, Ph. D. FCCP Lois D. Lehman McKeeman, Ph. D. Jerry A. Menikoff, M. D. Robert Nelson, M. D., Ph. D. Sean M. Philpott, Ph. D.

Consultants: Col. Raj Gupta, Ph. D. Daniel Strickman, Ph. D.

* Recused from carbofuran discussion and deliberation 2 of 104 Meeting Summary: Meeting discussions generally followed the issues and general timing presented in the Meeting Agenda, unless noted otherwise in these minutes ( Attachment C). 3 of 104 April 27, 2006 Introductory Remarks and Meeting Administrative Procedures Dr. Celia Fisher, ( HSRB Chair) began the meeting by thanking the Board members for their hard work in preparing for the meeting and invited them to introduce themselves. Following Dr. Fisher's introduction, Dr. George Gray, ( Science Advisor, EPA) thanked the Board for its work at this and previous meetings. Dr. Gray commented that at this meeting, the Board would be reviewing both completed and proposed pesticide human exposure studies. In addition, the Board would review guidelines for the efficacy of insect repellents. Dr. Gray remarked that Dr. Peter Preuss, as Director of the National Center for Environmental Assessment, also served as the Agency's Human Studies Research Review Official ( HSRRO). However, the Agency was pleased to announce that it had selected a full time HSRRO. That person would be joining the Agency shortly. Finally, Dr. Gray thanked his EPA colleagues and said that he was looking forward to hearing the Board's deliberations.

Next, Mr. Jim Jones ( Director, Office of Pesticide Programs [ OPP], EPA) welcomed the Board to OPP's new facility for this and future HSRB meetings. When the HSRB was formed, EPA faced statutory deadlines set by the Food Quality Protection Act ( FQPA). The Agency asked a lot of the HSRB to meet this deadline and was now confident that the deadline would be met, largely due to the support of the Board. Mr. Jones said the Board's advice has been valuable and that after this meeting, would establish a more regular schedule for meetings.

Dr. Fisher asked Mr. Jones for clarification on existing Agency time pressures since there are statutory deadlines, seasonal limitations on testing, and time limits set by applicant submissions for license. Mr. Jones responded that commonly, new registrations had time limits. In addition, OPP expected to announce the HSRB meeting schedules and hoped that applicants would factor this into their protocol review cycle. Dr. Fisher asked Mr. Jones for OPP to provide all background documents to the HSRB at least three weeks before a meeting in addition to providing a summary to the Board regarding prioritization of documents for Board review. For the April meeting, there was a linking for review documents. This type of linking would be helpful for review documents for future meetings. Dr. Fisher remarked that while the Board would deliberate on issues at an HSRB meeting, and the Chair's minutes would attempt to capture points raised at the meeting, the Board recommendations are not final until the Board had completed and approved its meeting report. Mr. Jones responded that he agreed with Dr. Fisher's conclusion.

Dr. Paul Lewis, ( Designated Federal Officer [ DFO], HSRB, Office of the Science Advisor [ OSA], EPA) thanked the Board and EPA in preparing for this meeting. He explained that the HSRB is a federal advisory board and is subject to the Federal Advisory Committee Act ( FACA) guidelines. As the DFO, he said that he serves as a liaison between HSRB and EPA, stating that HSRB meetings are public and all materials were available at the public docket. Concerning the insect repellent efficacy studies and protocols, Drs. Raj Gupta and Daniel Strickman would act as consultants to the HSRB. Drs. Chambers and Brimijoin were recused from all discussions on carbofuran. The informational presentation on the Proposed Workshop on Best Practices for EPA, National Exposure Research Laboratory Observational Human 4 of 104 Exposure Measurement Studies by Dr. Roy Fortmann ( NERL, Office of Research and Development, EPA) was moved to Friday morning on the meeting agenda.

Dr. Fisher asked EPA for clarification on the Board process, specifically some sense of the time pressures EPA is under with respect to receipt of Board recommendations. The Agency understood that if the applicant begins studies without a final Agency decision on the protocol, the applicant proceeds at its own risk and that the protocol may be rejected. Similarly OPP has proceeded with risk assessments based on what it understood the Board's recommendation to be  prior to approval of the final report by the Board. OPP took into consideration that it was proceeding without the Board's recommendations as outlined in its report.

Mr. John Carley ( OPP, EPA) gave an update on EPA follow up to HSRB recommendations. Mr. Carley reported that action had been taken on 4 of the 8 compounds discussed at the April meeting. All actions taken were consistent with Board recommendations. One of these actions included a follow up on the study conducted on hexavalent chromium by Chemrisk. Attempts to investigate, in more detail, the conduct of the study, were not successful. The principle investigator, Dr. Nethercutt, was deceased, and Chemrisk had declared bankruptcy in 2000, being reconstituted as Exponent.

Dr. Fisher reviewed the process for meeting operations. HSRB review would begin with a presentation by EPA on the scientific and ethical considerations of the studies under review. These presentations would be followed by public comments and the Board's discussion of the scientific and ethical considerations of the principle studies. Scientific considerations would precede ethical considerations because if a study wasn't scientifically sound, ethical deficiencies within the study would be raised. Scientific considerations would include dose selection, endpoint selection, participant selection, methodology, and statistical analyses. At previous meetings, the Board found single dose level studies to have limited utility except when interpreted in the context of other studies conducted under comparable conditions or when they showed evidence of toxicity at a lower dose than other studies conducted under comparable conditions. Dr. Fisher also reviewed the dose criteria established by the Board at its May meeting. In response to an EPA written comment on the Board's draft May 2006 meeting report, Dr. Fisher asked the Board if this dose criteria were applicable to all studies reviewed and to be reviewed by the Board. Members agreed that it did. The Board's ethics evaluation from completed studies would include an assessment of whether the study met prevailing ethical standards. If it did not, the study would be considered fundamentally unethical.

Science and Ethics of Chloropicrin Human Studies Dr. Elissa Reaves ( OPP, EPA) provided a summary of the Agency's analysis of the chloropicrin human study. Chloropicrin is a non selective soil fumigant whose primary toxic effect is sensory irritation. Chloropicrin is a unique soil fumigant, in that it is also used as an indicator chemical, or warning agent. The Agency is developing an assessment to estimate inhalation risk to bystanders and workers from acute exposures to chloropicrin.

Chloropicrin is one of several soil fumigants currently under review. It has a variety of uses: agricultural settings, on telephone poles, and empty grain and potatoes storage facilities. 5 of 104 Dr. Reaves reported a robust database for chloropicrin inhalation studies but limited port of entry details from acute studies. The chloropicrin human study was a 3 phase study with 127 individuals. Since the ability to detect chloropicrin induced irritation declines with age, exposed subjects were young adults ( ages 18 35). Odor detection, eye feel and nasal feel were assessed following brief exposures. During Phase 1, the duration of exposure for odor detection was 1 2 seconds, eyes were exposed for 25 seconds, and nose irritation exposures lasted 7 seconds in one nostril. Some subjects could not detect chloropicrin at the levels tested. Overall strengths of the study included the determination of pertinent odor and eye thresholds with similar responses among males and females. Phase 2 was conducted in a walk in chamber. Severity of feel was not a parameter in Phase 2. Subjects were asked to make a confidence of response judgment. The walk in chamber was considered a more appropriate exposure scenario for acute bystander exposure. For all phases, the doses were low to high and included both sexes. For Phases 1 and 2 there were no severity scores, no physiological parameters, and the durations of exposure were not equal. Phase 3 was designed for occupational exposure and was also conducted in the walkin chamber. Exposure duration was 60 minutes/ day for 4 days. Phase 3 included clinical examination of the eyes, nose and throat, before, during and after exposure. Perceptual effects, the time required to feel irritation, decreased with increasing concentration. Study strengths included subjective and objective measures and repeated dosing. Study weakness included lower concentrations, as studied in Phase 2, and not being examined ( i. e. 100 ppb) in Phase 3.

Dr. Reaves concluded that Phase 3 provided physiological parameters for eye irritation and was used as the point of departure ( POD) for chloropicrin. The BMDL10 of 73 ppb was based on eye irritation noted during Phase 3. The Agency's Weight of Evidence ( WOE) document and Data Evaluation Records ( DER) for chloropicrin described the study design of the acute inhalation human toxicity study. In addition, the Agency had concluded that the human toxicity study was appropriate for developing a POD for extrapolation of inhalation risk to bystanders and workers exposed to chloropicrin.

The Board began its initial discussion questioning the lack of confidence intervals. Dr. Reaves said that OPP also had trouble interpreting the data and had to call the chloropicrin study director and requested the Excel spreadsheets of the data. Dr. Fenske said that it was impossible for the Board to assess the study without this information. The study report indicated an estimate of central tendency but gave no measure of variability. Dr. Fisher asked what impact the human study had on limit setting and whether there was an alternative to human dosing. Dr. Reaves responded that the use of the human study data raised the POD one order of magnitude because a 10X uncertainty factor was eliminated. In terms of animal studies, rodent odor studies were not useful. While animals could be trained, this would be expensive and would not follow Agency guidelines. However, chloropicrin does have a solid animal toxicity data base. Mr. Jones explained that a decision on chloropicrin was needed by 2008, but that there were other time pressures, including an international interest to eliminate methyl bromide ( a fumigant), and an EPA commitment to move through decisions on all soil fumigants quickly. Historically, chloropicrin has been used for its detection properties, but pesticidal use is on the rise as the use of methyl bromide has been more restricted.

Dr. Fenske asked why Phase 2 was not used to inform the POD for chloropicrin since Phase 3 was designed for occupational purposes. The Phase 3 assessment included a benchmark 6 of 104 of eye irritation to be protective of the inhalation exposure. Dr. Lowit ( OPP, EPA) asked the Board to recall the MITC eye irritation study. The chloropicrin study was a stronger study because it utilized a walk in chamber. Dr. Lowit stressed that the use of this study was not solely to reduce the POD but also to assess physiological parameters and reduce risk to workers. Dr. Lebowitz stressed that you cannot estimate inhalation risk from any other route of exposure besides inhalation exposure. Dr. Fenske followed by clarifying that in Phase 2, there were 20 30 minute exposure intervals. He was concerned that a lower dose was not included in Phase 3 given the results of Phase 2 at the lower dose. Dr. Reaves clarified that for Phase 2, there was no measure of the severity of effects. Dr. Brimijoin asked how the Agency intended to address acute versus chronic effects since the human studies all dealt with short term exposure. Dr. Reaves said that the animal data would be used to assess chronic effects but chronic exposures were not expected given chloropicrin's use as a soil fumigant.

Mr. John Carley ( OPP, EPA) provided a review of the ethics of the chloropicrin human study. Mr. Carley explained that when the study was received, it did not include sufficient information to allow for an ethics review. Supplemental information was disorganized and did not address key ethical considerations. Mr. Carley summarized the framework for the study starting with the study's value. The study explored the lower threshold of human sensitivity to chloropicrin and the relationship between sensory awareness of chloropicrin and potential effects of exposure to the pesticide. As such, the study provided information of potential value in assessing bystander and worker risks associated with chloropicrin exposure. Subject screening factors were well documented and consistent with the scientific goals of the study. The racial make up of the subject group closely matched the demographics of the student population at UCSan Diego. No noteworthy ethical deficiencies were apparent when this study was reviewed against the standards of the Common Rule or the requirements of FIFRA § 12( a)( 2)( P). Remaining gaps in the record were not clear and convincing evidence that the research was fundamentally unethical.

Public Comments Dr. Robert Sielkin, Jr., of Sielkin and Associates Inc., and Dr. John Butala, of Toxicology Consultants, on behalf of the Chloropicrin Manufacturers Task Force Dr. Sielkin began the discussion stating that prior to any human exposures, a statistical analysis of the proposed human sample sizes was done to assure that the study had sufficient power. This analysis was done to determine the sample size such that the sample proportion detecting a chloropicrin concentration was sufficiently close to a true population proportion that would detect it. Phase 3 had 80% power of observing at least one respiratory irritation in 32 individuals. The study design did involve repeated exposures over a number of days. Assuming 50% correlation between first day and each subsequent exposure day, the Phase 3 study had 80% power of observing at least one respiratory irritation in 32 individuals. It was assumed that each individual's probability of a respiratory irritation following an exposure session at 0.1 ppm chloropicrin is at least 0.008 and the individual probability of a respiratory irritation following an exposure session at 0.15 ppm is 1.5 times that at 0.10 ppm. 7 of 104 Dr. Butala commented that the animal data base for inhalation of chloropicrin is fairly extensive and follows EPA guidelines. The human study demonstrated that humans could detect chloropicrin at levels far below the NOAEL thresholds based on human studies. Phases 1 and 2 informed the selection of dose levels for Phase 3. The BMD calculation does allow for the derivation of a threshold below the lowest dose tested. Dr. Fenske asked how one could account for subject selection that excluded subjects with eye irritation from any other source. Statistics could not overcome other limitations placed on the subject population. Subject selection of the younger adult group was biased to find sensitive subjects. The public commenter indicated that the concept of eliminating people with previous occupational exposure or other physiological irritation made the study more sensitive.

Dr. Jennifer Sass of the Natural Resources Defense Council Dr. Sass stated that NRDC had concerns that the chloropicrin study violated several ethical standards. The study report did not admit that students experienced any adverse effects beyond slight eye or nose irritation. In addition, there was no medical follow up. Existing studies showed effects at low doses. Thus Dr. Sass wondered how this study was beneficial for society. Participants must be fully informed, free to withdraw and receive compensation even if they withdrew. The study wasn't scientifically valid and did not have sufficient statistical power. Precise adverse effects and risk were not disclosed. Finally, exposure at up to 10x the occupational limit was not justified.

Charge to the Board 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.

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.

Board Response to the Charge Dr. Lebowitz began Board discussion by noting that Phase 1 considered very short term exposures discussed in terms of the NIOSH PEL. The methods used are considered state of the art. There was a feeling detected in the eyes of subjects. Phase 2 considered 20 30 minute 8 of 104 exposures in a chamber and included repeated, albeit short exposures. Some subjects did respond at the lowest dose ( 50ppb). Phase 3 investigated eye, nose and throat irritation for several days. One limitation was no lower dose level. By selecting healthy subjects, subjects with existing inflammation were excluded. The study included good subjective and objective measures of exposure and reasonable statistical analysis. Consecutive exposures did not seem to matter since there was no day to day increase in response. Most of the standards were plus or minus 3% of the measure and no lower airway effects were noted. The nasal passage cytology did not show significant irritation. Dr. Lebowitz concluded that the study was reasonably sound from a scientific perspective but he did not think the most sensitive subjects were included.

Dr. Fenske said he could not review the study as presented because the data were not presented in a decipherable fashion. There were no column headings and the Board was left with graphs of average responses over time. There was no way to check the Agency's analysis because the data were not available. It is clear that certain populations were excluded because those with eye problems, chemical hypersensitivity, or previous occupational exposure were excluded. Subject selection did introduce some bias. It was his understanding that Phase 2 was more relevant to by stander exposure. Almost 25% of the study population expressed confidence about being exposed to chloropicrin, but this may or may not be an adverse effect. Phase 3 was designed to address occupational exposure but he did not understand why a lower dose was not included. The investigators focused on Phase 3 for risk assessment which included 30 minute exposures for 4 days.

Dr. Chambers said that the study was well designed, went from short term to longer term exposures, and identified eye irritation as the most sensitive endpoint. She shared concerns that a lower dose was not included in Phase 3 and felt that some more credence might be given to Phase 2 for limit setting.

Dr. Fisher commented that the study might be well designed but did not provide enough supporting data. Board discussion noted that the lack of chronic data was considered less important because chronic exposure to chloropicrin was not expected. There are custom applicators who start in Florida and move north with the seasons but even they were not expected to be exposed for 180 days per year. Soil fumigants are typically used once a year. The human study is only being used to inform the acute threshold limit setting. Given the selective population used in the study, some additional factor might be needed to protect for bystander populations. Discussion on the charge to the Board followed and Dr. Fisher asked for some clarification on whether a human study was required to answer the question at hand. Dr. Lebowitz said that in most cases, the same effects at the same doses in an animal study would not be seen. Also, subjective responses were difficult to assess with animal subjects.

Dr. Fisher summarized the Board findings as follows: the study was well designed and provided information on acute exposure and interspecies variability. There was Board concern about the lack of one to one correspondence with the levels used in Phase 2 and Phase 3. The study did provide useful information for occupational exposures. The study may be used for bystander populations but consideration should be given to the fact that bystander populations may include more sensitive individuals. 9 of 104 Charge to the Board 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?

Board Response to the Charge Dr. Menikoff said that the study met prevailing ethical standards, exposed subjects to relatively low risk and was ethically appropriate. Informed consent for Phase 3 may have been deficient because it characterized side effects as minor. Exposure at greater amounts was characterized as completely reversible. A publication, " Chemicals in War", described chloropicrin as a lethal compound that acts primarily as a lung irritant. It was the major toxic gas used in WWI and can kill people at high levels.

Dr. Nelson stated that the study was almost contemporary but was judged as a retrospective study. In terms of exculpatory language in the informed consent document, the language was more exclusionary than what is typically used. Dr. Nelson did not believe that language regarding chloropicrin's use in war should have been included in the informed consent documents. Dr. Menikoff said that if there were screening procedures, subjects should have been asked for consent before screening. During screening studies, subjects should have been asked to complete a full health history. If consent was not given until after screening, this would have been an ethical flaw. Dr. Fenske commented that the MSDS for chloropicrin said that the OSHA limit for immediately dangerous to life and health was 2000 ppm. The TLV/ TWA excursion limits were never exceeded by the study. While there was momentary exposure at 1200 ppm during Phase 1, this was a graded exposure.

Dr. Fisher summarized the Board's conclusions indicating that the Board would have appreciated informed consent documents to include additional information on adverse effects at higher concentrations, different exculpatory language, and more information on whether screening subjects were given informed consent. However, there was no clear and convincing evidence that the study was fundamentally unethical or ethically deficient.

Agency Clarifying Remarks on Chloropicrin Mr. Jones provided clarification on the Agency's intention to raise or lower the levels of protection based on human studies. For all the compounds considered under the FQPA, the Agency was raising the level of protection. The question was, how much more protective did the Agency need to be. All the compounds presented so far to the Board were older compounds that had been in use for many years. 10 of 104 Insect Repellent Product Performance Testing Guideline Mr. Jones' comments were followed by a presentation of the science and ethics of insect repellent product performance testing guidelines by Mr. Kevin Sweeney ( OPP, EPA), Dr. Clara Fuentes ( OPP, EPA) and Mr. John Carley ( OPP, EPA). Mr. Carley explained that the Agency generally only published guidelines for required studies and was committed to harmonization with other offices within EPA and with NAFTA partners. One important point to keep in mind about guidelines was that they were not rules. Instead they are advisory. Deviations from guidelines was possible but needed to be justified. Likewise, following guidelines was no guarantee that a study would be accepted. The context for the repellants could be found in OPPTS Guidelines 810 3000, 3300, 3400, 3500 and 3700. EPA classifies repellants as public health products, therefore product safety performance data are required. In the DEET Reregistration Eligibility Decision ( RED), EPA proposed to require efficacy data for each registered product containing DEET. In 2001, EPA decided to postpone further work on guidelines until human testing issues were resolved. In 2006, the final human subject rule was published, making research involving intentional exposure, include insect repellent efficacy testing, subject to HSRB review.

Mr. Sweeney reviewed key issues to be addressed beginning with the purpose of the guideline for topically applied repellants. There were no alternative hosts and no good substitutes to evaluate efficacy of insect repellants. Thus, human subjects were needed. Products were developed for use on human subjects to prevent disease transmission. Since this was an intentional exposure, ethical requirements covered by the guidelines included: subject selection, risk minimization, independent oversight, voluntary participation and fully informed consent. Risks included allergic reaction to the repellent, allergic reaction to insect bite, and disease transmission. Most repellants did not have a toxic mode of action and are of low toxicity. The primary route of exposure was dermal. Developing an effective repellant involves complex computerized modeling beginning with chemical properties, host triggers and acute toxicity studies. Full scale efficacy testing would likely occur only late in the development cycle. The Agency would like to have single and multiple dose human toxicity studies, dermal absorption studies, pharmacokinetics, structure activity relationship studies and lab studies with disease free biting arthropods before a repellant was tested in the field.

Dr. Fuentes discussed advice from the 2000 Science Advisory Panel ( SAP) starting with the recommendation that only field studies be used to determine efficacy of skin applied repellants. She said that tick and chigger studies were hard to conduct. In addition, exposure to tick and chigger bites was hard to avoid and Rocky Mountain Spotted Fever and Lyme disease were risks associated with tick and chigger bites. In many areas of the U. S., mosquitoes transmit West Nile Virus and it was difficult to differentiate between mosquito vectors. West Nile virus is wide spread and has moved from east to west, Lyme disease is more focused in the northeastern US while Rocky Mountain Spotted Fever is more sporadic. Dr. Fuentes provided a definition of terms describing arthropod behavior. 11 of 104 Following Dr. Fuentes' presentation, Mr. Sweeney demonstrated the method used to test repellant efficacy in laboratory studies as described in the Agency's guidelines. Mr. Sweeney was assisted by Dr. Robin Todd and Mr. Nick Spero of Insect Repellent and Control, Inc.

The Chair adjourned the meeting for the day. 12 of 104 April 28, 2006 The Chair reconvened the meeting the following morning beginning with comments on the insect repellent product performance testing guidelines.

Public Comments Dr. Scott P. Carroll on behalf of Carroll Loye Biological Research Dr. Carroll began by saying that he is a proponent of insect repellents, including DEET alternatives. Over time he has seen less new product development. He was involved with the Armed Forces Pest Management Board tasked with searching for alternatives to DEET and he had previously commented on the insect repellent guidelines. The spread of West Nile Virus had made public interest in repellants high and had increased the military's need for such products. Dr. Carroll's research puts emphasis on probes and landings with intent to bite ( LIB). The Agency should consider a LIB approach compared to relative protection ( RP) since RP could result in an overexposure of bites. LIB is a possible alternative to reduce subject risk. The Agency should consider six as the minimum number of subjects. This is a small number of subjects and may promote excessive exposure to fewer subjects. The Agency's guideline asked researchers to use consumer dosing but this requires dosimetry data which may require additional HSRB review.

Following his public comments, the Board asked Dr. Carroll about how field studies were conducted. Dr. Carroll said that field studies were conducted with the goal of zero bites. Dr. Carroll served as an untreated control. Dr. Carroll was asked how effective trained subjects were in terms of getting mosquitoes before they bite. Dr. Carroll said that there was little data to quantify this but that in his field studies, after a few exposure periods, subjects tried to attract mosquitoes. Dr. Brimijoin asked why DEET alternatives were needed. Dr. Carroll explained that DEET causes rashes, has an unpleasant taste and odor and leaves an oily residue. Repellant efficacy varied among test subjects and mosquito species, so there were good reasons to seek alternatives. Tests were conducted in areas where you would expect one bite per untreated limb per minute. Dr. Lebowitz asked how Dr. Carroll's metric LIB compares to EPA metrics and whether studies had been conducted under a variety of temperatures and humidities. Dr. Carroll commented that his testing regime would not work in tropical environments because mosquito behavior is different in these environments. Dr. Carroll said that they had not attempted night time work and that most studies were conducted with a reliable biting rate so most studies were conducted at between 80 100 oF with high humidity. One would expect repellant failure at lower temperatures but there had been little systematic work done to look at these parameters.

Dr. Lehman McKeeman said that dose is critical to the interpretation of repellant studies and asked Dr. Carroll how dose was determined. Dr. Carroll said that based on the history of repellant use, a standard dose of 1ml/ 600 cm2 was used. This comes from military studies that measured an area of the forearm in many subjects. Dr. Carroll said that an n= 20 would be nice but expensive, an n= 10 would be more affordable. Dr. Carroll said that EPA was not requiring field studies for ticks because there was tremendous variation within tick populations. Dr. Fisher inquired about the risk of vector borne disease in field studies. Dr. Carroll said that there were 13 of 104 statistical measures for evaluating risk in a given area. While epidemiologists could study the risk of disease in a population, field studies should specifically avoid areas with any significant West Nile Virus and was assessed using sentinel chicken flocks.

Dr. Fitzpatrick asked if some subjects were more susceptible to bites and how do you address controls. Dr. Carroll explained that he acts as the control and feels he is average with respect to susceptibility to bites. Dr. Carriquiry expressed concerns with using Dr. Carroll as the average control. Dr. Carroll explained that he wanted to minimize the number of subjects potentially exposed to vector borne diseases. He said that he would be uncomfortable with a high number of untreated controls. Dr. Carriquiry said that the appropriate number of controls needed could be calculated. Dr. Carroll said that this was easy with a large number of subjects, but in the field it was more difficult. Dr. Fisher asked about statistical power and said that the methodological framework seemed limited. Dr. Carroll said that the method was flexible and that a sample size of six is more common than an n= 10 because it is the minimum number allowed by the Agency's draft guidelines. Dr. Carriquiry questioned that since there was a risk to subjects from vector borne disease, why could not all the tests be conducted in the laboratory? This would enable greater flexibility with the number of subjects. Dr. Carroll responded that the laboratory model might be appropriate in many instances, but field testing still needed to be done. He commented that the risk of vector borne disease transmission is lower than expected. Dr. Nelson asked what the scientific objective was for conducting field tests; the need for negative controls in the field was unclear to Dr. Nelson. Dr. Carroll said that negative controls were used to assess biting pressure. While there are efficacy data from the laboratory, the behavior of wild animals was being observed in the field. Negative controls in the field quantified repellant efficacy over time.

Consultants to the Board Dr. Daniel Strickman Dr. Strickman began his remarks by indicating that the purpose of such discussion should focus on truth in labeling. When a manufacturer claims eight hours protection from mosquitoes, ticks and chiggers we want to know whether this is true. There are huge differences between the 4000 species of mosquitoes, 28 stable flies, etc. In addition, considering a 5 10 fold difference between individuals and label claims for efficacy can be subjective. Variations in temperature and humidity have been tested in the laboratory and do have a large impact on efficacy; repellant efficacy can be significantly reduced. Product formulation may be as important as active ingredient. Experimental repellants with liposomes may provide 24 hours protection by binding with the upper layer of skin. The other complication in dosing is just how much faith you can put on following label directions. Dr. Strickman also commented on the laboratory and field studies. Comparing field studies is difficult but the difference between the laboratory and the field is key. A repellant is intended to reduce bites, but to the insect, a repellant can do many things. The insect has to find the subject using multiple chemical signals. Quantification of repellant protection can be represented with a sigmoidal curve. We are up at the top where the curve starts to flatten out. On the ends of the curve, precision is very low which is why we look at LD50s. Dr. Strickman said that one could be better served to look at 90% repellency rather than 95% acceptable for disease control. 14 of 104 Dr. Fisher said that truth in labeling is important, but subject protection is also important. Dr. Nelson said that rather than using a negative control, a measure of biting pressure was needed. A measure of efficacy in the laboratory needed to be compared to a measure of product efficacy in the field under varying conditions. The first step for IRB review was to minimize risk. The PI needed to explain study objectives and why a negative control was needed. Traps might be adequate to assess biting pressure. Dr. Chadwick asked whether some repellants were stronger than others. Dr. Strickman said that percent active ingredient were not being tested, formulations were being tested.

Col. Raj K. Gupta, Ph. D.

Dr. Gupta stated that repellency can vary both day to day and by the time of day. Feeding behaviors were based on complex chemical signaling so product registration was always complex. More products provide consumers with more choices, but required consumers to be more educated. Soldiers had been the target population for many studies but while they were doing research and development, the armed services followed the same rules as commercial product sponsors. Research began with the discovery phase to answer basic science questions. Next, the concept phase asked what would be better than what was already available. During the exploratory phase, the study would be designed. This was followed by the laboratory or field phase. Field studies were used to validate laboratory studies and should simulate actual conditions for product use. The studies were designed to address concerns or meet objectives. Each study should be independently designed and conducted. The average person used repellant products differently to the application procedure in a laboratory. There were numerous studies that provided adequate information on efficacy, but most of these studies were done from a pharmaceutical perspective.

Meeting Process Dr. Fisher introduced the subject of the amount of material received for this meeting, 10,000 pages of material with less than 2 weeks for review. Several Board members expressed concerns about being a deliberative body with so much information to review and so little time. Board members needed advance notice of what to expect and an annotated bibliography so that materials could be organized and accessible; similarly to the way the Board materials were organized for the April 2006 meeting.

Dr. Fisher made some comments on the specifics of the meeting. This included: greater time needed for Board discussion of their draft science and ethics criteria of proposed human studies research; she asked for clarification from OPP for the need for the urgency of the chloropicrin review since Agency decisions were not needed until 2008, and the need for the EPA NHEERL presentation since no background materials were provided. Dr. Fisher asked that unless there was a critical reason that the Board hear the EPA NHEERL presentation, that it be removed from Friday's agenda. Dr. Fisher remarked that the HSRB Chair sets the agenda for the meeting, in consultation with the Agency. Several other Board members shared Dr. Fisher's concern regarding the primary role of the Chair in setting the agenda. Dr. Fisher asked for 15 of 104 clarification of OPP's view on whether the Board, with the leadership of the Chair, set the agenda or whether OPP set the agenda.

Mr. Jones responded that although chloropicrin is not subject to the FQPA deadline of August 30, 2006, review was needed. As a soil fumigant, decisions on chloropicrin affect methyl bromide and there is global interest in reducing the use of methyl bromide. In terms of review materials and time, the Agency was willing to work with the Board and that the Board sets the agenda. Several Board members asked that in recognizing that the Chair, neither EPA nor EPA/ OPP set the agenda, that prior to the Agency organizing materials for each Board meeting, the Chair would convene a discussion about the agenda with HSRB DFO, EPA OSA, and the Agency relevant program office ( e. g. EPA/ OPP) requesting review by the Board. Mr. Jones agreed that there needed to be a 3 way dialog on the agenda. It would provide the tools needed to make reviews easier. Dr. Fisher said that EPA needed to establish priorities for each meeting. For example, it would have been helpful for OPP to provide a rationale for why the Board was asked to advise on insect repellants when it was also looking at protocols for agricultural handlers? Dr. Lehman McKeeman said that with respect to the May report, the Board was told that OPP was doing some calculations for carbofuran. The Board would like to see these BMD calculations and the confidence intervals around this value. EPA agreed to deliver the materials to the Board during the meeting. The Board wanted to know why they were issued generic protocols for insect repellants and agricultural handlers. Mr. Carley explained that the Board needed to look at protocols before decisions were made. The generic repellant protocols were provided for specific discussion on subject selection and the agricultural handler protocol was provided as a blank workbook. This should have been explained. The Emanuel approach was intended for protocol review, so the structure fit nicely but the Agency is receptive to another approach. Dr. Fisher noted that the Board had expressed concern at previous meetings about applying the Emanuel approach for review of protocols, it may not be appropriate for this purpose. Dr. Fisher suggested the Agency consider a different model; especially one that placed greater emphasis on evaluating the risks and benefits of the research. Finally, Dr. Fisher expressed concern that EPA was asking the Board for tacit approval of the generic protocols, when the Board was not asked to specifically advise on this. She added that the Board should not be perceived to provide review of generic protocols. Instead its charge is to provide advice and recommendations on specific protocols, the focus of this meeting.

Dr. Fisher asked for Board discussion on the meeting agenda moving forward. Dr. Nelson felt that the guideline discussion should go first. Dr. Fish seconded this order and said that it would be wrong to look prospectively. Dr. Preuss' presentation was informational regarding protocol review so this presentation may be premature. Dr. Preuss might present later at the meeting. Mr. Carley said there has been an Agency order in place since 1999 describing the policy and procedures on protection of human subjects in EPA conducted or supported research, including the role of the HSRRO. The Agency was contemplating a revision of this order, including further defining the role of the HSRRO. The Board concluded that while Dr. Preuss' presentation might be helpful, it was not urgent. The Chair they requested that the Board begin discussion of the criteria for review of human study protocols. This discussion began with a brief background presentation by Mr. John Carley on human studies research proposals. 16 of 104 EPA Background on Human Studies Research Proposals Mr. Carley began the discussion commenting that the final rule for testing with human subjects, which were effective April 1, 2006, expanded Common Rule protections to third party research and forbid EPA from using data that was collected by unethical means. Mr. Carley provided a brief summary of the subparts of the rule. One of the challenges of conducting intentional exposure studies was that the risk benefit analysis may not provide benefits to the subjects. Intentional exposure studies with pesticides were not designed to treat disease, so risks to subjects must be minimized and be reasonable in relation to anticipated benefits and the importance of the knowledge gained.

Mr. Carley said that the NAS recommendations for human studies were a place to start deliberations but not an ending point. Repellent efficacy studies involved intentional exposure; thus IRB approved protocols and supporting materials must be submitted for EPA and HSRB review. An important point was that there is scientific validity of human studies research; studies seeking to improve the accuracy of EPA decisions. Payment for participation should not be so high as to be undue influence or so low that it is only attractive to economically distressed subjects. Human studies should provide compensation for research related injuries. Mr. Carley then presented a list of considerations concerning science criteria for review of human studies protocols for HSRB consideration.

Review of HSRB Protocol Criteria Dr. Fisher stated that she had assigned several Board members to either an ethics or science workgroup to help identify issues for the Board to discuss with respect to Ethics and Science criteria for evaluating protocols.

Ethical Criteria Dr. Fisher asked the Board for its thoughts on a guide for how to evaluate new studies coming to the Board. Board criteria would be helpful for both the Agency and study investigators to understand the Board's approach for the review of proposed human studies. Dr. Nelson said that you start with general principles, than you define them in the context of a study. The Board may not recommend for approval a study that does not comport to the Agency's final human studies rule. Dr. Nelson said that the Board needed to specify what information needed to be submitted in order for the Board to make a decision under its criteria.

Dr. Fitzpatrick said that the roles of the IRB review needed to be separated from HSRB review. The HSRB could have additional criteria. Mr. Carley clarified that the FDA rules were identical to Subpart K of the Agency final human studies rule and as noted previously, its review occurred after IRB review. The Board was to interpret what these rules meant for EPA studies and needed to be cognizant of the difficulties of interpreting these rules. Subpart K of the rule describes what information needs to be submitted. With respect to the insect repellent product performance testing guidelines, Mr. Carley said that the document was submitted by Dr Carroll. EPA took the IRB records and compared them to Subpart K requirements. Pending more experience, Dr. Carroll's summary was a good starting place. The Agency would need to be 17 of 104 provided guidance on how the materials should be organized. Dr. Fisher said that the Board appeared to be in agreement about what was expected and that the onus was on the investigator to present the information. Mr. Carley felt a summary document might be helpful, especially with respect to risk minimization, but Dr. Fisher said that this was no different from current IRB review. Dr. Fisher introduced Dr. Peter Preuss as the Agency HSRRO.

One of the questions that emerged during Board discussion was the subject of payment. This was not considered a benefit from an ethics perspective. Compensation or inducement should not be considered in the benefits analysis. The Board would be looking at equity in terms of subject payments. In addition it might be considered coercive if workers believed they obligated to perform a research task that otherwise would not be asked of them. In such circumstances informed consent could not be evaluated as voluntary. Issues related to employee subjects would apply to insect repellent guidelines and the agricultural handler's protocol. There was also a need for monitoring both during and after the study, and to assess adverse effects. The Board decided that intentional exposure was exposure that would not have occurred if the worker or participant had not participated in the research. It does not matter if the exposure is to a product that the worker or participant may be ordinarily exposed to. What does matter is if the timing, extent of exposure, and/ or dosage of the compound is in addition to or different from what the participant would have been exposed to on the day of the testing.

Dr. Lebowitz said that improving accuracy was not a valid justification for a human study. Human studies must be used to reduce exposure or risk. Dr. Fish commented that if a study was being done solely to improve accuracy, it must do no harm. Dr. Lebowitz said that this was not his concern. He was concerned about science for the sake of science. Dr. Fenske said a study that would not be valuable unless it reduced exposure would be wrong. Dr. Lehman McKeeman said that improving accuracy was a frank benefit to society and could warrant the use of human studies, as long as no one was at risk. Studies that improved accuracy should not be excluded but research for basic data gathering should be avoided. If there was risk, the researcher should have a sliding scale of benefits. Dr. Lehman McKeeman said that a very clear statement of study objectives was needed. Dr. Nelson said the Board was calling for a rationale for research, not saying that new products shouldn't be developed. Researchers need to explain what was wrong with the existing products, and what the benefits of new research would be. Dr. Philpott noted that since the Final Rule required exclusion of pregnant women, registrants now need to describe in the ethics section and IRB proposal how pregnancy would be identified and how the pregnancy status of women recruited and or excluded from the study would be protected.

Dr. Fitzpatrick asked whether there would be a screening procedure for what the Board would review and was told that EPA would serve as the gatekeeper for information that came to the Board and also the final decision maker as to whether the Board's recommendations would be followed.

Summarizing the Board's discussion, Dr. Fisher listed the following criteria for protocols: 18 of 104 1. Provide all information required in Agency human studies rule including risks, measures to minimize risks, benefits, and to whom they accrue, alternative means of obtaining data, and balance of risks and benefits.

2. Describe the benefits of the study as they might relate for example to: ° More stringent regulatory standard ° New public health measure adopted ° New product that protects public health ° Improved scientific accuracy of risk assessment with statement of the potential benefit of improved accuracy.

3. Incentives or remunerations cannot be included in risk benefit analysis.

4. Informed consent must include all information required in Section 26.1116 of the Agency's human studies rule.

5. Provide justification that subject recruitment and incentives/ remunerations are not unduly coercive or could result in a retaliatory response.

6. Describe the rational for the safety monitoring plan during and post trial.

7. Describe procedures to reverse experimentally induced harms.

Dr. Fisher added if a researcher had difficulty obtaining IRB records, this needed to be explained. Compensation was not unethical, but should not be considered a benefit in a risk benefit analysis; monitoring after research was required. Dr. Menikoff commented that the word " compensation" should not be used. Instead incentives or remuneration were more appropriate.

Scientific Criteria Dr. Fenske said that there was overlap between scientific and ethical considerations. Empirical evidence supporting estimations of risks to participants should be provided. The researcher needs to state what scientific question would be answered by the study. Study benefits should be clearly defined. Specific objectives or hypotheses should be identified. The following questions were presented as science criteria for review of human studies protocols:

1) What is the scientific question addressed by the study? 2) Are existing data adequate to answer the scientific question? 3) Are new studies involving human subjects necessary to answer the question? 4) What are the potential benefits of the study? 5) What is the likelihood that the benefits will be realized? 6) What are the risks? Are they serious or irreversible? 7) Is the purpose of the study clearly defined? 8) What are the potential benefits of the study? What is the likelihood that the benefits would be realized? 9) Are there specific objectives/ hypotheses? 19 of 104 10) Can the study as described achieve these objectives or test these hypotheses? 11) What is the sample size and how is it derived? 12) What is the basis for the proposed dose levels and formulations in the study? 13) Is there a plan allocating individuals to treatment? 14) Can the findings from this study be generalized beyond the study sample? 15) Is there a justification for the selection of target population? 16) Are participants representative of the population of concern? If not, why not? 17) Are the inclusion/ exclusion criteria appropriate? 18) Is the sample a vulnerable group? 19) Will the measurements be accurate and reliable? 20) Are measurements appropriate to the question being asked? 21) Are adequate quality assurance procedures described? 22) Can the data be statistically analyzed? 23) Is the statistical method appropriate to answer the question? 24) Point estimates must be accompanied by measures of uncertainty? 25) Do laboratory conditions simulate real world conditions? 26) Are field conditions representative of intended use? 27) Does the protocol include a stop rule plan, medical management plan, and a safety monitor?

The Board then proceeded to respond to the charge for the insect repellent product performance test guidelines.

Insect Repellent Product Performance Testing Guideline Charge to the Board 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?

Board Response to the Charge Dr. Chambers responded that repellant efficacy testing can only be done with human subjects. Because repellants would be used at relatively high doses and used repeatedly, toxicological data are needed including the possibility of a developmental toxicity study. Any information from inadvertent exposures or historical use should be gathered. Laboratory tests should precede field tests with disease free insects. Subjects should not be taking any drugs that may result in adverse interaction during exposure. Formulations should be the same as that proposed for use. Laboratory results should show a good degree of repellency before going out to the field. The location of field tests should have a low frequency of disease bearing insects. It would be appropriate to empirically define areas with a low level of disease bearing insects. Dr. 20 of 104 Gupta, Consultant to the HSRB, commented that medical monitoring should be added as an additional step to reduce risk. Subjects need not be exposed for the entire test duration but intermittently throughout the period of warranty. Dr. Strickland, Consultant to the HSRB, said that it was not safe to assume that laboratory populations were not disease vectors; confirmatory testing would be needed. Defining allergic reaction to bites would be helpful. There should be a medical plan to respond to adverse effects such as anaphylaxis. Dr. Strickland said that the human studies should exclude populations that are particularly sensitive to vector borne disease such as West Nile Virus. Dr. Gupta said that the subject population should be from the local area because local populations are better acclimated to local insect populations. Dr. Fisher said that this could raise some ethical issues.

Dr. Fisher summarized some of the additional points made by the Board in order to document an evaluation of risk:

  Overall toxicity of the test material in the database, including all animal and reproductive studies should be considered.   Any human data from controlled or unintentional exposures or usage and allergic reactions.   Comparisons to comparable database( s).   Interactions with drugs an individual might be taking   Lab tests prior to field tests  need to have confidence in repellency in laboratory studies first.   In vitro models when appropriate.   Exclusion of subjects who are sensitive to insect bites, allergens, or vulnerable to diseases in the area.   Use of trained personnel for adverse events and medical monitoring.   Selection of field sites with documented lowest level of vector borne diseases.   Pilot study of insect to empirically define vector borne disease risk.   Continuous testing of insects.   Lowest number of control subjects to ensure statistical power.

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

Board Response to the Charge Dr. Lehman McKeeman began the discussion by recommending that, while not always correct, a structural analysis, in particular computer models for teratogenesis, was a good starting point. Acute toxicology studies should be mandatory and dermal exposure would be critical. Additional studies should be required for dermal and ocular toxicology, dermal sensitization and dermal absorption including modes of metabolism and excretion. There was a need for early screening for mutagenesis since this would be an irreversible effect, and also an in vitro analysis of clastogenicity. It would be ideal to have some assessment of repeat dosing. These are the kinds of studies that would be essential, but there should be a tiering of information. Subchronic 21 of 104 studies, reproductive toxicology and a study of human metabolism as it compares to rodent metabolism studies would be appropriate given the high rates of exposure. Some knowledge of what the human dose would be is needed to assess the margin of safety which becomes part of the equation. Dr. Krishnan added that the section on dose selection should be based on how the product would be used. This information would need to be bridged to the toxicology studies. The dose typically used is 1 ml/ 600 cm2 which equates to 15mg/ kg. Guidelines should include some relationship between the dose used and NOAEL/ LOAEL.

Mr. Carley responded that the Agency needed to know if the Board required a minimal research data set before beginning field testing on human subjects. Dr. Lehman McKeeman believed that there should be some early indication of whether the compound had teratogenic potential. This could be a quick assessment of informed structure relationships or in vitro metabolism. Dr. Chadwick said repellant studies were looking for no toxicity which is the opposite of most pesticide testing. Dr. Lehman McKeeman said that the Board was looking for toxicity as a hazard identification step. Mr. Carley said that what is being described is what the Agency refers to as acute toxicity testing.

Charge to the Board 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?

Board Response to the Charge Dr. Fish began the discussion by saying that she could think of no situation where research participation would be an ethical requirement for employment. Dr. Chadwick said that this may be the case in some military assignments. Dr. Gupta said that the military was no different than the commercial sector, and that all human subject research was done with fullyinformed subjects who have given consent. Dr. Fish continued that untreated controls should be asked to sign a study specific or generic consent form and be included as study subjects, not as non participants. The risk benefit analysis for untreated controls could be removed when controls are described as non participants. If the principle investigator ( PI) enrolls himself into a study, there must be some assurance that the PI can be determined to meet all inclusion criteria, without exerting undue influence on a co researcher. The book, " Who Goes First?", describes several benefits of self participating PI research. However, study oversight would have to be assigned to someone else. PI participation would be acceptable if the study was approved by the IRB prior to testing, the investigator was the only subject, and there was a plan for safety, integrity and oversight should the PI become incapacitated. Dr. Carriquiry stated that under no circumstances can we have a single control, whether this is the PI or not, unless the PI can prove that he/ she was randomly drawn from the study population. Repellant research, where multiple controls are exposed to multiple bites, may be more acceptable. A single source for biting pressure control may be appropriate, and the PI may be best at knowing the intent of the mosquito. Dr. Chadwick believed that the PI research opened the door to bias. The onus was on 22 of 104 the investigator to demonstrate that bias had not been introduced. PI participation in research was not a priori unethical but did require some specific guidelines.

Charge to the Board 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.

Board Response to the Charge Dr. Chadwick identified risks including allergic reaction to the insect bite and the transmission of vector borne disease. Assuming the study was well designed, there was no ethical objection to the use of negative control groups. Dr. Fenske supported this and said that evidence of insect biting pressure was needed, which most likely required negative controls. Dr. Fitzpatrick added that informed consents for negative controls were essential, along with a stopping rule and freedom to leave the study. Dr. Nelson was not convinced that risks to the negative controls would be trivial. There was a significant burden of proof for sending a negative control out into the field. While vaccines for vector borne diseases were available, there was an associated risk. Dr. Nelson suggested seeking information on the use of prophylactic antibiotics. The Board pointed out that controls were needed to demonstrate that the vectors were present and biting; one treated and one control could be used for this purpose. Trapping was also effective for knowing whether mosquitoes were present. Dr. Fisher said that there might be situations where a negative control would be needed. In these situations the onus would be on the investigator to demonstrate that alternative means of investigation were not suitable. The Board had some mixed opinions on what the threshold for using a negative control would be. The guidelines seem to assume that a negative control will be used in field studies. Dr. Strickland said that generally, a negative control is used in the field. These are parametric studies: yes or no, the subject was protected. You could do an epidemiological study, find an area without a high disease frequency, treat half the subjects and not the other half. This has been done but it is expensive. Dr. Fisher said at some point, the Board may need to issue a statement regarding cost and ethics. For efficacy testing in the laboratory, multiple controls are needed; in the field, negative controls to show biting pressure may, or may not be needed. If there was a scientific need for negative controls, this should be included in the guidelines. The Board may not want negative controls to be the default.

Charge to the Board 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).

Board Response to the Charge Dr. Nelson led the discussion by saying that the FIFRA SAP recommended an RP method based on 95% fewer bites in treated subjects compared with controls. This method 23 of 104 exposed subjects to many bites. The proximity of a treated arm to the untreated arm might affect mosquito biting behavior. This should be considered in an experimental design. Aspirating the mosquitoes before they bite was a very good way of reducing risks to subject. Temperature and humidity within the laboratory should be examined to see how they affect efficacy. Dr. Lehman McKeeman agreed with Dr Nelson, but believed that the FCB and RP methods provided answers to different questions. TFCB is a yes or no whereas the RP method required a more rigorous statistical analysis. Dr. Carriquiry agreed that the TFCB and RP parameters measured different things and said that RP required more controls than TFCB. Many untreated individuals were needed in the field to calculate the second metric. Dr. Gupta differed, stating that not many controls were needed, and that for statistical design, at some point, there was a diminishing benefit to adding additional subjects. Dr. Carriquiry said that because mosquito biting was variable, a well designed study needed controls for integration purposes.

The Chair adjourned the meeting for the day 24 of 104 June 29, 2006 The Chair opened the meeting with the Board responding to question F of the insect repellent product performance test guidelines.

Charge to the Board 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.

Board Response to the Charge Dr. Carriquiry said that the guidelines proposed six as a minimum number of subjects. However, one number does not fit all studies. Different experimental designs required different sample sizes, depending on the outcome of interest, confounding factors, heterogeneity of the sample population and heterogeneity of the environment in which the product would be tested. There was no magic number but there were procedures that should be followed. Dr. Bellinger added that the issue of replicates needed clarification. Were these different people or the same person multiple times? If the same data were repeatedly collected on the same person with different treatments, power calculations were needed to assess variability between individuals. The lack of power calculations must not be ignored. Dr. Strickman said that there was a 4 6 fold variability in the attractiveness of people to mosquitoes. Biting pressure also influenced the power of the study. Dr. Carriquiry commented that both the TFCB and RP were difficult to deal with when calculating confidence intervals. Dr. Nelson questioned whether inter personal variability affected power calculations. Dr. Carriquiry responded that variability among test subjects meant a large sample size was needed to achieve a certain power.

Charge to the Board 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.

Board Response to the Charge Dr. Menikoff said that historically other groups had looked into this question and they all agreed that subjects should be compensated for medical costs or other losses. The NAS addressed this issue and said justice, fairness and gratitude should prevail in this matter. The question to the Board suggested that insurance be provided which may be an administrative burden. If insurance was provided, the research sponsor, and not the researcher, should pay for this. Dr. Nelson agreed with Dr. Menikoff and added that there was an evidentiary issue that may at times be controversial. Dr. Nelson said that exculpatory language in the informed consent ( IC) materials should be examined and suggested that language should not refer to compensation, but medical care. 25 of 104 Charge to the Board 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.

Board Response to the Charge Dr. Fitzpatrick said that many of these studies were performed on experienced subjects so the IC materials were not very detailed. This is not what is expected based on provisions of the Common Rule. All procedures should be clear and it might help to have photos or a video to explain experimental procedures. Aspirator training should be provided. Subjects should be given an estimate of the number of bites they might encounter and all other experimental procedures. The consent process might include a quiz on the risks of vector borne disease, the risk of being bitten and sensitivity reactions. Subjects need to understand what type of medical support would be provided. They need to know the stopping rules and where medical personnel would be available. Confidentiality of records and the element of undue pressure should be examined. The voluntary nature of the experiment should be made clear and compensation for time provided. Dr. Menikoff agreed and said that the two consent forms that he reviewed were not sufficient. EPA may want to develop a generic consent form for studies of this type. Dr. Nelson said that the IC form should be clear, short and simple. Seasonality of risks should be highlighted but a quiz for comprehension probably was not needed. Dr. Fisher suggested that the IC form should state whether the product was experimental or approved. Dr. Gupta added that the IC form should be translated into the subject's native language.

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

Board Response to the Charge Dr. Fisher commended the Agency on the first draft of the insect repellent product performance testing guideline but said that revisions were needed. Dr. Nelson said that historically the emphasis seemed to be on field testing over laboratory testing, but the Board's discussions seemed to put more emphasis on the laboratory. Dr. Gupta replied that laboratory testing would be helpful and may replace some field testing. Protection in the field was generally longer than that in the laboratory and most exposures to mosquitoes occurred in the field. Dr. Chadwick said that the public may apply the product more often than was needed to be protected. Dr. Strickland said that some labels do limit the number of times the insect repellent could be applied. Most people do not reapply insect repellent by the time elapsed, but by when they start to be bitten. 26 of 104 Research on the Efficacy of Insect Repellents Protocol CL 001 Generic Template for Repellant Efficacy Testing Mr. Carley began the protocol discussion commenting that protocol CL 001 was developed to submit annually to the California Department of Pesticide Regulation and is intended to cover both laboratory and field studies of repellent performance against mosquitoes, biting flies, fleas, and ticks. CL 001 contains general background information, especially concerning recruiting practices. It is not a template for executable studies and cannot support full review. Because of the attraction of biting arthropods to humans and their role in disease transmission, there is potential societal benefit in developing additional safe and effective personal repellents. EPA requires testing with human subjects to establish repellant efficacy. CL 001 includes well documented methods for subject selection with no indication that subjects would be subject to any coercion or undue influence, or be recruited or enrolled for reasons inconsistent with the goals of the research. Exclusion factors ensure exclusion of children and pregnant or lactating women and students of investigators. There was some concern evident for risk reduction since a risk benefit assessment cannot be performed in the generic case. The CL 001 was unanimously approved by the Florida based IRB " as a template for future research." The protocol describes adequate procedures for IC but did not provide a generic consent form. The applicable standards for this protocol are: 40 CFR 26, Subparts K and L, FIFRA § 12( a) ( 2) ( P), and if conducted in California, then California Code of Regulations Title 3, Section 6710.

Deficiencies in CL 001 noted included a statement that subjects were orally informed of the risks of disease contraction. The risk of contracting disease and treatment available should have been discussed in writing in the pre consent information package. Section 4( H) stated that there was no plan for compensation for injury due to the low levels of risk involved. The risk of contracting an arthropod borne disease through participation in a field test may be low, but it is not zero. Planning for the possibility that subjects may be bitten by a disease carrying insect was essential both to risk minimization and to fully informing potential subjects. The generic protocol should have acknowledged the applicable standards of ethical conduct and the obligation of the investigators to inform the IRB of any amendments to or deviations from the approved protocol.

Study EMD 003 from Carroll Loye Biological Research Mr. John Carley began the Agency's presentation on the EMD 003 by stating that the study was a laboratory assay utilizing human subjects to evaluate the efficacy against ticks of three skin applied formulations of the insect repellent IR 3535. The protocol was similar in many aspects to the draft EPA guideline for tick testing, specifically to the 2000 version. IR 3535 has been registered in the US for six years and used in Europe for over 20 years. Three formulations were to be tested: 20% lotion, 20% aerosol and a 10% pump spray liquid. Formulations would be administered by pipette to the limb of the test subject as a liquid at the rate of 1 gram of formulation per 600 cm2 of skin surface. Five treatments groups would be used, including a DEET positive control and an untreated negative control. A line of IR 3535 is drawn across the wrist of each subject and a tick is placed on the hand, oriented toward the wrist. If a tick crosses the line in 3 minutes it is not repelled. Only one species of tick would be tested even though the guideline recommended testing three species from three different genera. The 27 of 104 protocol used liquid formulations applied by pipette when the guideline called for testing formulations as they are to be registered. The qualification of ticks before use, handling of ticks after qualification, and disposition of ticks after use were inadequately specified.

Mr. Carley reviewed the Emanuel Framework in relation to the protocol. Mr. Carley said that the purpose of the study was poorly described. The intention was to gather information to support development of personal repellents for future commercial marketing which do have a potential societal benefit. This was not described in the protocol. Recruiting methods were well described in CL 001 generic protocol and there was no indication that subjects would be subjected to any coercion or undue influence, or be recruited or enrolled for reasons inconsistent with the goals of the research. The protocol did not include a risk/ benefit assessment. The Florida based IRB gave unanimous approval of the protocol. Written consent was received from all subjects and was adequate but deficiencies in IC materials should be corrected. The applicable standards for this research are: 40 CFR 26, Subparts K and L, FIFRA § 12( a) ( 2) ( P), and California Code of Regulations Title 3, Section 6710.

Several deficiencies were noted for IC materials including a statement that subjects would be randomly assigned to treated or control groups while the CL 001 states that only investigators would serve as controls. Test procedures were inadequately described to subjects in IC materials and there was vague language in the IC regarding how far ticks would be allowed to travel before they were removed. The IC form also needed to make clear that the ticks used in this test are captive bred and free of disease. The word " not" is missing from the IC discussion of " Pregnancy Risks" which should read ". . . it is important that you do not participate in this study if you are, or think you may be pregnant." The IC promised to cover costs of " treatment required for injury resulting from being in the study," but then excluded injuries " resulting from normal work activities", and then further excluded compensation for " such things as lost wages, disability, or discomfort due to injury." This is unacceptable exculpatory language. The IC materials inappropriately discussed compensation to the subjects as a benefit, but did not discuss expected societal benefits and how they were weighed against risks to subjects. The California Department of Pesticide Regulation should be added to the list of parties to whom personal information may be disclosed. The protocol should acknowledge the applicable standards of ethical conduct and the obligation of the investigators to inform both the cognizant IRB and the California Department of Pesticide Regulation of any amendments or deviations from the approved protocol Mr. Carley concluded by saying that the Agency requested some additional information and Dr. Carroll was very responsive but there were still gaps. Failure to get the requested materials from the IRB was unexpected.

Dr. Nelson asked whether the Agency interpreted the language in its human studies rule as meaning that incomplete protocols for HSRB review need not be submitted to the HSRB. Mr. Carley said that the initial review was an evaluation for the completeness of the documentation. Then the protocol was reviewed for contents. Dr. Fisher asked if the Agency felt obligated to pass onto the Board protocols it believed were inadequate or incomplete. Mr. Carley said that this had not yet been addressed. Dr. Chadwick said that these protocols should not have been advanced to the Board until the package was complete. Mr. Carley acknowledged that this would be strived for by the Agency. Board members noted that it was no always necessary or a good use of Board time for EPA to present protocols to the Board that the EPA judged to be scientifically or ethically inadequate. 28 of 104 Study EMD 004 from Carroll Loye Biological Research Mr. Carley provided background on this protocol, commenting that study EMD 004 is a field test with human subjects designed to evaluate the efficacy against mosquitoes of three skinapplied formulations of the insect repellent IR 3535. The protocol was similar in many aspects to the draft 2000 version of the EPA guideline for mosquito testing. The protocol tests three formulations: 20% lotion, 20% aerosol and a 10% pump spray liquid. Formulations delivered by pipette or syringe to the limb of the test subject at a dose rate of 1 gram of formulation per 600 cm2 of skin surface. Tests may be conducted in Central California or the Florida Keys. Exposure of treated subjects is continuous and evaluation intervals differ for control and treated subjects. The study included a single untreated control which was inconsistent with EPA recommendations and compromises RP calculations. Mosquitoes were aspirated upon landing to minimize bites. No information about specimen handling, identification, and storage were provided. Product formulations should be applied and tested as they are to be registered. The protocol did not include an example of the data recording sheet.

Protocol EMD 004 poorly described the purpose of the study which was to gather information to support development of personal repellents for future commercial marketing. Recruiting methods were well described in CL 001 and gave no indication of subject coercion or undue influence or recruitment for reasons inconsistent with the goals of the research. Materials were tested for acute toxicity and candidates sensitive to mosquito bites were excluded. The aspiration of landing mosquitoes reduced bites and risk and tests would be conducted where disease carrying mosquitoes were not known to be present. The protocol was unanimously approved by the Florida based IRB. The procedures for IC were adequate but deficiencies noted in the IC materials should be corrected. Subject privacy would not be compromised and subjects would be free to withdraw. The applicable standards for this protocol are: 40 CFR 26, Subparts K and L, FIFRA § 12( a) ( 2) ( P), and California Code of Regulations Title 3, Section 6710.

Deficiencies noted included a statement in the IC materials telling subjects that they would be randomly assigned to treated or control groups while the CL 001 stated that only investigators would serve as controls. Separate consent documents for treated and control subjects may be needed. IC materials should be clarified to better explain the responsibility of the subjects to aspirate landing mosquitoes and the risks of being bitten. The word " not" is missing from the IC discussion of pregnancy risks. Given the possibility of a subject contracting a serious vector borne disease, the IC form was inadequate and unacceptably exculpatory. The IC materials inappropriately discussed compensation to the subjects as a benefit, but did not discuss expected societal benefits and how they were weighed against risks to subjects. The California Department of Pesticide Regulation should be added to the list of parties to whom personal information may be disclosed. The protocol should acknowledge the applicable standards of ethical conduct and the obligation of the investigators to inform the IRB of any amendments to or deviations from the approved protocol. 29 of 104 Board Discussion of Study EMD 004 from Carroll Loye Biological Research Scientific Considerations Dr. Chambers questioned the dose. The protocol said 1 ml/ 600 cm2 while the Agency said 1 gram/ 600 cm2. This would be clarified with Dr. Carroll, ml was probably the error. Dr Chambers wondered, since this protocol had been used for years, why Board review was needed. Dr. Philpott asked about the need to avoid multiple cycles of EPA review for protocols. Mr. Carley responded that presenting this protocol to the Board could help expedite future protocol reviews. Dr. Fisher questioned why the Board was being asked to evaluate the protocol when Mr. Sweeney's presentation of the science for this protocol, the previous day, was negative? Dr. Chadwick said that evaluating the protocol could be very informative, particularly in the early days of protocol review. This was a chance to apply the Board's criteria to a case study. Dr. Fish agreed, and said that this may take more than one meeting and more than one protocol but the Board could use this as an illustration. Dr. Krishnan said that this was a blind study but that the control may know whom he or she is. Blinding was not critical to the study design but was important for IC.

Dr. Lehman McKeeman encouraged EPA to interpret the protocol literally if it says 1 ml/ 600 cm2 . The Board should not be spending significant amounts of time reviewing protocols that were erroneous. However, the Board may be able to abridge the discussion for this one protocol. Dr. Fisher replied that the Board did not need to see bad studies but that its goal was to provide advice on studies that the Agency believed would go forward. Dr. Fish said that in the biomedical world, the control would have been treated with the vehicle without the active ingredient. Mr. Sweeney said that this would be dependent on whether the vehicle had any repellency properties. Dr. Chambers said that the guidelines were not mandatory but that deviations might be justified. Dr. Fisher did not see the role of the Board as giving advice for protocol improvement. While the Board was advisory, it could not, in good faith, approve a study if revisions were needed. Mr. Carley said to bear in mind that these protocols had already been approved by the IRB. If the HSRB recommended changes, the study would go back to the IRB. Dr. Fisher said that Board decisions were not dictated by IRB approval and that the onus was on the researcher to comply with the rules.

Ethical Considerations The Board raised general issues for consideration. All of the counties in central California have a history of West Nile virus. The risk of vector borne disease was assessed based on sentinel chicken flocks. The IC materials said subjects would be randomly assigned when untreated controls were affiliates of the research. Procedures needed to be more detailed. The word " not" was missing from the IC language regarding pregnancy. The language related to normal work activities, if this meant that the study would cover costs not covered by workman's compensation, this needed to be made clearer. Finally, the IC discussed compensation as a benefit but did not discuss societal benefits. 30 of 104 Public Comments Dr. Scott Carroll on behalf of Carroll Loye Biological Research, Inc Dr. Carroll began by stating that he sensed that the protocols were viewed by the Board as inadequate. The Agency had reviewed past protocols as a courtesy and CalEPA review had been mandatory since 1996. These protocols were narrative and were accepted and CalEPA personnel had acted as co principal investigators for some of these studies. CalEPA suggested the Florida based IRB be used for these studies. Supplemental material was requested by EPA and was provided quickly. The protocols and supplemental material were evaluated by Mr. Sweeney and Dr. Fuentes of EPA. Dr. Fuentes said that the materials provided met the requirements with minor changes. Mr. Sweeney provided pages of criticism which had been responded to online. The revised IC document was five pages long and was read less carefully by subjects. The major point that Dr. Carroll was concerned with was that we were getting to a point where the IC could be improved further, but would be 15 pages long and may not impact relative risk.

Dr. Chadwick wanted to know whether UC Davis personnel or IRB were used. Dr. Carroll said that other faculty had participated in the studies but there was no official UC Davis involvement. Dr. Chambers asked about clarification of dose. Dr. Carroll said the standard 1 gram/ 600 cm2 was used.

Mr. Nicketas Spero of Insect Control and Research Inc.

Research protocols are modeled after EPA guidelines for product registrations with considerations going into the field for the species present. He was concerned about the TFCB method and two negative untreated controls. Tests were conducted in an untreated area, counted landings and removal of insect with a pen. Bites were minimized but there was an active population of mosquitoes in the field. The 95% protection was a concern because when repellents breakdown, subjects may be exposed to more bites. The sole purpose of testing was for efficacy. The company has limited research until the guidelines are approved by the Agency.

Mr. Dan Giambattisto of EDM Chemicals, Inc.

Mr. Giambattisto said that IR3535 is a registered trademark repellant that has been tested against a wide variety of mosquitoes and ticks. IR3535 has an excellent safety and efficacy record against a variety of arthropods. IR3535 is EPA approved and WHO recommended. IR3535 is the best selling DEET alternative in the U. S. Sales of insect repellent products are seasonal so timely approval of the EMD protocols was essential for products to be on the market in 2007.

Charge to the Board Study EMD 004 from Carroll Loye Biological Research Scientific Considerations 31 of 104 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?

Board Response to the Charge Dr. Chambers began the discussion by saying that since efficacy had already been established in the laboratory, perhaps additional human studies were not needed. The greatest risk would be disease transmission. Sample size was derived consistently with guidelines but dose was not correctly stated and this was a clear deficiency. Study findings could be generalized to other areas. There was partial justification for subject selection. Inclusion/ exclusion criteria were adequate. Measurements would be adequate and the LIB approach minimized risk. The statistical method seemed to be appropriate, field conditions were representative of real world conditions and there was a stopping rule in place. Dr. Brimijoin added that there seemed to be a variety of opinions regarding the adequacy of a single untreated control and viewed this as a weakness of the protocol. Dr. Fitzpatrick believed that the protocol needed to state precisely what they intended to accomplish and the perceived benefit. Dr. Bellinger was confused about the statistical methods; this needed to be clarified to be appropriate for a continuous variable. Dr. Carriquiry said that the protocols needed to clarify the outcome: TFCB or RP. If it was RP, the use of one control was insufficient. Dr. Fish asked why the formulations intended for public use were not tested; especially when three products were being used. There might be substantial differences in dose with these three methods of application.

In summary, Dr. Fisher said that there were some strengths in the study, especially incorporation of the LIB approach. However, problems included repellant application, identifying the number of subjects and the use of a single untreated control. There might be a legitimate justification for sample size but it wasn't in the protocol. Given the deficiencies of the protocol, as presented, the Board did not feel that the study was likely to produce useful information. Dr. Chambers said that there were deficiencies but no fatal flaws. Dr. Carriquiry said that without power calculation it was impossible to know whether or not the study would generate useful information. Dr. Nelson did not agree that relative protection was an appropriate endpoint for this study. He would have preferred TFCB with a single untreated control. Dr. Lehman McKeeman's concern was that another researcher could not duplicate the study using the protocol provided. Product formulations were a critical area lacking detail. Dr. Carriquiry clarified that even if testing TFCB, power calculations were required. Dr. Chadwick remarked that this discussion was exactly why this type of protocol should not be reviewed by the Board. The Board should not be discussing the details. Instead the focus should be on whether the protocol conformed with the Agency's human studies rule   a yes or no answer. Dr. Fisher said that individuals must justify why they are not using a preferred method and asked whether there was a consensus on whether to reject this protocol. Dr. Fenske said that as an advisory board, it should keep in mind that the protocol was developed using draft guidelines. If the Board rejects this protocol they are providing EPA with recommendations on revisions to the guidelines. Dr. Fisher said that as an advisory board, it could not approve a protocol contingent upon revisions being made. Dr. Menikoff agreed with Dr. Fenske, procedurally the Board needed to understand 32 of 104 what the consequences of rejecting the protocol were. Dr. Brimijoin said that there may be consensus that the protocol, as submitted, was not acceptable, but to the extent that we can make recommendations that point toward a solution would be helpful. The Board should consider that approach. Dr. Brimijoin would not approve the protocol in its current form but he did not feel that the flaws were unrecoverable. Dr. Fish agreed and proposed that the first charge question could not be answered. Dr. Fisher recommended that the Board state that the protocol was deficient. If the deficiencies were met, EPA could approve the protocol without returning it to the HSRB. Dr. Fisher was concerned that there might be the perception that researchers could send anything to the HSRB and the Board would identify and solve the problems. Dr. Fish said that the Board agreed that in the future this type of protocol should not be submitted to the Board.

Charge to the Board Ethical Considerations 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?

Board Response to the Charge Dr. Nelson stated that the trouble with the protocol was that the information was scattered among several documents. There need not have a 20 page consent form. A brief IC document or a brief film could be constructed that will facilitate rather than impede IC. Dr. Philpott recommended a separate consent form for women that addresses the confidentiality issues pertaining to pregnancy. If a woman is excluded due to pregnancy, and this is uncovered by a research associate, this could be problematic. It is important to know what the affiliation with UC Davis is because the university IRB may have concerns. It would be helpful to see what the IRB said regarding the IC statement about treatment provided for experimental exposure but not exposures as part of work. Dr. Nelson again said that the IRB contract should include access to these types of document. If IRB minutes were not available, or if they did not provide them when requested by EPA, this made the IRB deficient. Dr. Philpott added that this did not mean that the protocol was deficient. Dr. Fisher said that explanations could be presented orally or by video, but that risk should be specified in writing. Dr. Fisher also stated that the Board has concluded that the protocol did not comport with the Agency's human studies rule.

Charge to the Board Study EMD 003 from Carroll Loye Biological Research Scientific Considerations 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 33 of 104 ( together with other data) assessing the potential levels of pesticide exposure received by people when mixing, loading or applying a pesticides]?

Board Response to the Charge Dr. Lehman McKeeman evaluated EMD 003 for ticks. There were several typos but the compound itself had been approved and had demonstrated low human toxicity. There was no rationale for why the study was needed. Another deficiency was that there was no characterization of compound stability. Dr. Bellinger said that the experimental design required manual dexterity and a training video might help with this. Without this, experimental data might be subjective. Dr. Fish added that all relevant comments on the previous protocol should be applied here. There was no clear rationale or dose justification, no measure of how biting pressure would be assessed, no clear explanation of negative controls and some concern about the manipulation of subjects, asking them to aspire mosquitoes.

Charge to the Board Ethical Considerations 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?

Board Response to the Charge Dr. Philpott agreed with the deficiencies noted by Mr. Carley and added that a separate consent form should be used for women. Dr. Philpott stressed that compensation should never be listed as a benefit. Dr. Menikoff believed that the consent form was written like a protocol. A brief description of the rationale for testing this product and of the study design would be helpful. Major risks should be identified in the IC document. Dr. Fish added that in the IC documents, study duration was unclear and that the language should be appropriate for the reading level of the target group. Dr. Fisher said that the relationship of the subject to the PI needed to be disclosed. While confidentiality was important, and conflicts of interest, in and of themselves are not unethical, these need to be disclosed in the IC documents. This was not a new requirement but may be new to repellent testing. The Board concluded that the protocol does not comport to the Agency's human studies rule.

Carbofuran: BMD Analysis Dr. Anna Lowit ( OPP, EPA) provided the Board with an update of the Agency's BMD calculation for carbofuran. The Agency is in the process of deciding BMDs for AChE inhibitors and there are 10 compounds in this common endpoint group. Dr. Lowit noted that in the Board's draft May 2 3, 2006 HSRB meeting report, the Board had some issues on the carbofuran study and requested supplemental information on this analysis. For carbamates, rapid recovery makes the AChEI analysis confusing. For BMD calculations, all the data points were used, including the controls. Dr. Lowit asked Dr. Rick Reese ( Exponent, Inc.) representing FMC Corp. to 34 of 104 provide additional explanations of the BMD analysis. Dr. Lehman McKeeman asked about changes in AChEI in controls. Dr. Lowit explained that individual changes over time did result in greater variability and uncertainty in the findings and the materials provided to the Board were still draft. Dr. Lehman McKeeman said that the question was how robust could this analysis be with such a small sample size. Dr. Carriquiry said that the model was underestimating at one end of the curve, but with such a small sample size, it was difficult to know which end. Dr. Fisher requested that Dr. Lehman McKeeman review the new material presented by the Agency and provide a summary of her analysis during the Board's final review of its May 2 3, 2006 report, occurring at this week's meeting.

Agricultural Handler Exposure Monitoring Studies Scientific Consideration for Agricultural Handler Protocols Mr. Jeff Dawson ( OPP, EPA) and Mr. Jeff Evans ( OPP, EPA) explained that the Agricultural Handlers Exposure Task Force ( AHETF) had submitted five protocols for pesticide exposure studies that are part of a larger research program the AHETF is conducting. The premise of the AHETF research program was that data could be used generically by various stakeholders ( e. g., applicants, registrants, EPA, and others) for calculating exposures for the agricultural handlers of pesticides. The scope of the AHETF research program was very broad in that it intended to address exposures related to many job functions in agriculture and also to assess 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 described studies to measure exposures for five specific scenarios.

The Agency believed that these studies improved EPA's ability to assess the risks of using pesticides because the data would reflect current agricultural practices, equipment and techniques leading to more refined exposure estimates. Further, the monitoring techniques to be used for these studies have been standardized for use across the AHETF research program. These more refined and reliable data would allow the Agency to better estimate how worker exposure levels were 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 ( PPE). It should be noted, however, that the use of the data generated in this study by the U. S. EPA and other stakeholders would depend upon the nature of the results.

There are limited exposure data for agricultural workers due to the cost and variability between studies. This led to the formation of AHETF with the objective of evaluating current practices and factors impacting worker exposure. The AHETF includes all but one major pesticide manufacture. The data generated would be used in a surrogate fashion and has been a 4 5 year, iterative, joint process. The overall goal was to create a database to assess handler exposures categorized by specific tasks performed. The AHETF was interested in evaluating the effectiveness of PPE evaluating trends in exposure, and what caused these trends to change. A list of AHETF protocols were summarized to date. Replicates are exposure events. The AHETF used a multi faceted approach for exposure analysis. There were two basic scenarios for dosimetry  pesticide handlers and farm labourer. Exposure scenarios were defined by job 35 of 104 function and other factors including: ( 1) equipment ( e. g. ground boom, aircraft); ( 2) physical nature of product, ( e. g. liquid, powder); ( 3) packaging ( open bottle, bag, closed system); ( 4) vehicle type ( tractor with cab or no cab) and; ( 5) clothing or PPE worn ( e. g. long pants, coveralls, respirator). A key factor was that handler exposures were proportional to the amount of pesticide used, not the identity of the pesticide ingredient.

Dr. Fisher asked whether participants were required to wear PPE. Mr. Dawson responded that if their clothing did not meet label requirements, they were not allowed to participate in the study. If compliant clothing was not routinely worn, was the AHETF concerned about this? Was there a safety factor calculation to account for failure to wear appropriate clothing? Mr. Dawson replied that the AHETF develops risk estimates under a variety of exposure scenarios. Basic inputs to calculations included application rates ( lbs active ingredient/ acre), area treated ( acres) and unit exposure ( how much someone gets on them per the amount that they handle). The margin of exposure was the ratio of the hazard endpoint to daily exposure. Unit exposure estimates were to be obtained from proposed AHETF studies. Mr. Dawson presented a list of EPA guidelines that were used to guide study design. Whole body dosimetry using a long underwear suit would be used to monitor deposition on the skin. Risks would be calculated assuming 100 percent absorption. The hand rinse technique estimated residues on a hand using a solvent rinse but he acknowledged that this technique was currently under review for suitability. The exposure estimates may be slightly lower than anticipated but not by an order of magnitude. The face wipe technique would be used to assess deposition on the face. A personal sampling pump was used to estimate inhalation exposures and breakthrough was possible. Dr. Krishnan asked about passive dosimetry, since this was all these studies evaluated. Dr. Fisher asked if these studies were to be done to update the agricultural handlers database, and if so, would be surprised that the Agency did not ask for preliminary testing of the collection devices. Mr. Dawson said that all the sampling devices had limitations. Mr. Dawson agreed that validation would be nice but the AHETF methods were still better than the existing 1993 data. More quantitative data could be used to adjust underestimation or variability. Dr. Carriquiry said that it must be difficult to collect this data, and asked about biomarkers. Board members also raised questions about the independence of the AHETF and EPA in designing and evaluating the studies.

Mr. Evans then reviewed the key components of the study. Quality assurance was based on good laboratory practice requirements. The studies were done on individuals that would routinely be doing these activities. Scenario based surrogate design had to do with the data generated. Board members asked if the exposure events would be done on the job or if this would be an additional exposure with the experimental compound at experimentally defined levels. If so, this wasn't strictly an observational study. There were three possibilities for exposure: 1) monitoring existing exposures with measurement devices; 2) monitoring exposure with altered compounds or concentrations; or 3) monitoring additional exposures that meet the requirements of the study. The protocol needed to define this. Mr. Dawson said that an attempt would be made to find applicators that would already be doing this nature of work. The exposure scenarios were scripted but the experimental exposures were part of the applicators' routine job duties. Application may need to be altered to meet the needs of the study but these would not be additional exposure. Thus, the Board considered this protocol an intentional exposure study. 36 of 104 Mr. Dawson said that the AHETF is collaboration between pesticide manufacturers and EPA that coalesced on their own and consults with EPA, CalEPA, and Health Canada. There was a process of working with the task force to make sure that the data generated were generalizable to AHETF purposes. What was the probability that a worker exposed under certain conditions would exceed a given threshold? The studies tried to characterize the entire distribution. Dr. Carriquiry supported the Agency's efforts but said that the Agency should perform replicate sampling on a different day. Mr. Dawson said that the compounds were selected with a broad range of uses. Mr. Carley added that these compounds were already in use. Mr. Dawson commented that the existing data were not collected in a uniform fashion and did not allow an estimation of variability and distributions of exposure. Dr. Fenske said that the documents provided to the Board did not make it clear that the existing data were inadequate. Mr. Dawson commented that the existing data were not fatally flawed, but not consistently collected. Existing data were being used in the database and new methods would be used to advise the AHETF. Dr. Lebowitz asked and Mr. Dawson responded that the agricultural handler Standard Operating Procedures ( SOPs) were final.

Ethical Considerations for Agricultural Handler Protocols Mr. Carley discussed the ethical considerations for the agricultural handler protocols. Subjects for the AHETF studies are workers with specific experience in the tasks to be performed. The IRB asked for extra care to avoid undue influence in subject selection. There was a negligible increase in pesticide exposure to workers because pesticides would be intercepted by the sampling device; however, there was increased risk due to heat exposure. There was IRB review and the protocols promised to obtain IC in the subjects' native language. Deviations from the protocol must be reported to the IRB. There was reference to excluding subjects with conflicts of interest but this was unclear. The IC materials should describe pesticide use patterns and pesticide labels should also be made available. The Board was troubled by the provisions in the protocols that there might be alteration of the application rates to meet the design time requirements of the study. The protocols failed to document ethical conduct of research consistent with the Agency's human studies rule. Subjects should have been told the exclusion criteria. Description of payment to participate was unclear. Compensation for injuries excluded those that would occur as part of routine activities. The words " replicate" and " worker" were used interchangeably. The IC form was not provided in Spanish and was not signed.

Dr. Fisher said that she understood that there was a group of employers that encouraged employees to participate. What did the employers receive? Mr. Carley could not answer this but said that this varied greatly across the country. Dr. Fish did not see IRB minutes as part of the submission, but noted that Western Research agreed to translate the IC form into Spanish. 37 of 104 Public Comments Dr. Elliot Gordon on behalf of the Agricultural Handlers Exposure Task Force, Mr. Curt Lunchick and Dr. Victor Canez of Bayer Crop Science on behalf of the Agricultural Handlers Exposure Task Force and Mr. Larry Smith of the Agricultural Handlers Exposure Task Force Dr. Gordon explained that there are several defining characteristics of the AHETF protocols. They monitor workplace exposure under normal agricultural product use conditions, in contrast to clinical toxicology studies. They address USEPA, PMRA and Cal DPR regulatory data requirements and utilize consensus derived regulatory exposure monitoring methods and standards and individual studies are part of an integrated industry task force effort. AHETF studies monitor professional farm workers who mix, load, and apply pesticides during their normal job activities, in standard, agricultural settings at appropriate times during the year. Products handled in AHETF studies are widely used USEPA registered products. The study participants comply with all product label requirements and the USEPA Worker Protection Standard ( WPS). An IRB reviews and approves all AHETF protocols prior to initiation of work and the IC document is issued by the IRB. AHETF data are generic rather than product specific. AHETF has conducted or initiated 14 exposure studies. In addition, an IRB had reviewed and approved the five protocols currently before the HSRB. Approximately 40 additional studies will be conducted over the next several years. North American regulatory agencies will use the data in risk assessments applicable to crop protection products and uses. AHETF studies conform to established Agency and OECD guideline methods and procedures. These have evolved for over 40 years and incorporate advances in both science and ethics. Pesticides can be mixed, loaded and applied in numerous ways that account for differences in equipment, product formulations, crops and regions. The Task Force has focused on 33 use scenarios with the goal of developing a comprehensive, integrated database rather than a series of stand alone studies, which pesticide handlers exposure database reflects. To summarize, the AHETF study schedules are time sensitive and would benefit from an expedited HSRB review. AHETF is interested in working with the HSRB and USEPA to develop ways to streamline this new review process.

Mr. Lunchick explained that the recruitment process began months before a study was initiated. Growers notified AHETF as to when they were ready to apply. Applicators did have access to the label. It is conceivable that an applicator may be asked to modify application rates but this was not normally done. There was a need to script application to allow for meta analysis conducted across scenarios. The Task Force was looking at what are typically maximum label application rates. The AHETF studies were being designed to capture variability of exposure at lower application rates. In the existing studies, the number of dosimeters were inconsistent and the data were old.

Dr. Philpott asked what the incentive were to the growers. The AHETF supplied free pesticides. Dr. Canez answered questions regarding improper handling of pesticides. For the AHETF studies, application rates were kept at label limits, and one person assigned to each handler to observe techniques. The labels have not been made available in Spanish but handlers must be able to understand the applications they are performing. If a subject wanted to withdraw, they could still receive the $ 100 payment. 38 of 104 Dr. Menikoff asked how one could ensure that there were no changes in application rates by contacting growers ahead of time. The researchers were familiar with application patterns for the region and whether the grower needed this product. There could be a variety of products that would suit their needs. Most applicators objected to wearing the long underwear as opposed to not applying the product. Dr. Fisher said that since the products were not viewed as hazardous, it could be assumed that a grower was more likely to choose the experimental product since it was provided free. The Task Force said they were monitoring pesticide applications that would exist and that the free pesticide was not that big of an incentive. Some growers believed that the pesticides did not meet their integrated pest management ( IPM) needs so they would not participate. There was a local site coordinator that identified growers that met the study criteria. After growers were identified, the applicators were contacted to work out the logistics of study execution. Applicators were allowed to drop out at any time and the growers were not told why a subject withdrew. Dr. Fenske asked that since there were no biomarkers, and the active ingredient did not make a difference, why not do the studies using an inert ingredient? Mr. Lunchick responded that it was easier to get growers to agree to apply a compound they were going to use anyway. None of the products tested were dermal irritants and it would have been difficult to separate product formulations from toxic ingredients.

There has been some replicate testing and this was of interest from the perspective of intrapersonal variability. The Task Force would not use subjects that worked for member companies or the industry, they were licensed applicators or commercial applicators that did this for a living. All materials would have to be read to them. Dr. Lehman McKeeman asked how the AHETF derived the subject numbers. AHETF would use the number of applicators needed to apply the material. AHETF had data where the same individual was tested twice. If there was a difference, the methods would be modified to include more duplicate testing to get a better handle on the intra variability. Heat illness resulted from the study but there was not a written plan for a response. However, the study director was aware of this risk and would address this concern.

Ms. Shelly Davis of the Farm Worker Justice Fund Ms. Davis commented that in the scenarios that these protocols covered, they did not address a real workday. Workers would have increased exposure because the grower would have them finish the job after the study was completed. The products were toxic and these exposures are cumulative. Ms. Davis was not sure whether this was an increase over what they would normally be exposed to but the exposures are cumulative. There was no care of the workers in the protocols. There was acknowledged risk due to heat stress and lab directors said that they would respond but why put participants at risk in the first place? The IC documents did not include health risks associated with the products they were applying. Labels were available but they were not in Spanish. Applicators were told how to apply the products but they did not know the health risks associated with the products. Health risk should have been specified in a language the subjects understood and should have been be supplied by the research sponsors. If a farm hand refused to participate, they would be sent home and would lose a day's pay. This was coercive. The small number of replicates raises doubts about the scientific validity of the studies. If this cannot be done in an ethical and scientifically valid manner then it shouldn't be done. Finally, the Farm Worker Justice Fund was never invited to comment on the study design. 39 of 104 The Chair adjourned the meeting for the day. 40 of 104 June 30, 2006 The Chair opened the meeting with Board discussion of the agricultural handler protocol change questions.

Charge to the Board 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 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? 41 of 104 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?

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? 42 of 104 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?

Board Response to the Charge Scientific Considerations Dr. Fisher began the Board's discussion reminding the Board to focus on similarities between each protocol, followed by the consideration of specifics. Dr. Fisher also discussed the Board's process for review of the five protocols and decided that due to the previous discussion on the Agency's presentation, the Board would discuss the protocols together, with the Board's lead discussants for each protocol serving as the primary respondents for all five protocols.

Dr. Fenske initiated the discussion of the AHETF protocols with comments on the generic database design. The generic database is a valid approach and has the advantage of allowing focus on key parameters affecting exposure. Dr. Fenske believed that not including the participation of labor in protocol design decisions was a deficiency because independent review was important at the beginning or design stage of the project. Dr. Fenske was supportive of a plan to present the guideline to the FIFRA SAP first. This would encourage more transparency with subsequent joint EPA endeavors. EPA ( not OPP) should be providing some oversight of the endeavor. While the Agency was calling this a third party study, the submitter has collaborated with the Agency. It may be too late to ask whether there was even a need for the new data since the project is already on going. Dr. Fenske believed not including farmworker community representation into the taskforce development process was a deficiency. To base the justification of the study on outdated software was not convincing. In contrast, stating that the pesticide handlers' database used the patch technique, which gives higher estimates of exposure, and questioning the compatibility of the two databases might have been a more persuasive argument for the justification of the study. The proposed comparison between passive dosimetry and biological monitoring might allow validation of results. In addition, several Board members raised questions on how the term replicate was used. Dr. Fenske said that a replicate means an exact copy, which is not what this was so the word replicate should not have been used to describe the test subjects. The same person doing the same activity two times are repeated measures. Different people doing the same job are test subjects. The sample sizes for subscenarios were small and the lack of repeated measures could overestimate exposure. Statistical consultation would have been helpful. The methods used to estimate dermal exposure could underestimate exposure and could allow breakthrough. Two layers of the cotton garment could 43 of 104 be used to assess quality of breakthrough data. The face and neck wipe method underestimates exposure and is not a standard method. Hand washing also underestimates exposure. A removal efficiency study could be conducted to correct for this. Dr. Fenske believed that the 4 hour exposure duration was reasonable and allowed investigators the time they needed to set up and take measurements. Dr. Fenske also raised issues on over and underestimation of exposure, based on the study design and estimates of exposure from hand and neck wipes, and hand rinsing. The Agency could develop an uncertainty factor ( UF) to account for underestimates but there was no way to do this type of research without uncertainty.

Dr. Lebowitz added that the characteristics of the workers were insufficient in terms of representativeness and generalizability. In addition, the protocols did not follow SOPs . Since there were problems with the monitoring of exposures, biomarkers would be helpful to validate measurements. The individuals measured used pesticides and there were ways to use PBPK for exposure monitoring.

Dr. Chambers stated that exposure data were always the weakest part of any risk assessment. Dr. Chambers was impressed with the efforts taken to quantify exposure in a variety of settings in an uncontrolled field environment. She objected to the use of " replicate" and believed that one subject was insufficient. With dosimeters taking up some of the compound, the biomarker approach would require a large number of individuals and might be an untenable effort. She was impressed with study design and execution and stated that whole body sampling data is better than patch data. She concluded that it was unfair to criticize the lack of justification because the criteria were just developed.

Dr. Bellinger agreed with Dr. Chambers and commended the study's quality assessment. Statistical methods were boilerplate but it was not clear how the data would ultimately be used. Environmental variables such as wind speed, temperature, etc. were recorded but it wasn't explained how this data would be combined into the final estimation. This was also true for hand rinsing and individual mixing scenarios. The issue of sample size was problematic. Information was sought from three handlers under a variety of exposure conditions but this estimate would take more than three subjects.