c potential. Therefore, human subjects are unlikely 35 to be at risk of experiencing adverse effects relative to exposure to the proposed formulations. 36 37 The HSRB recognized three major limitations to the protocol as submitted to the HSRB 38 for review. These limitations include: ( 1) the lack of a clear rationale underlying the conduct of 39 the study; ( 2) the lack of identification and characterization of the formulations to be tested and 40 ( 3) the scientific design of the study. Of these issues, which are discussed in more detail below, 41 the design of the study was seen as the most significant shortcoming of the proposed work. 42 43 With respect to the clear rationale for the conduct of the study, the HSRB understood that 44 all new formulations must be evaluated for efficacy, and that such studies must be conducted in 45 human subjects to be valid. However, the investigators failed to identify what was new about the 46 Proposed Final Draft v. 1 Dated August 28, 2006; Do Not Cite or Quote 44 of 67 formulations being studied and failed to identify the potential benefit of the formulations. This 1 shortcoming was considered to be minor and could readily be addressed by providing such 2 additional information in the study protocol. 3 4 With respect to the formulations to be evaluated, the investigators provided tables listing 5 the percent of active ingredient along with incipients used to formulate the spray, aerosol and 6 lotion to be used in the study. However, there was no additional information regarding when the 7 formulations would be prepared relative to study execution, whether the formulations would be 8 characterized analytically to confirm active ingredient composition, and whether the stability of 9 the formulations was to be determined. This information is critical to the overall valid execution 10 of the study and could be remedied by providing such detail in the protocol. 11 12 The major limitation with the scientific conduct of the study concerned the study design 13 and data collection. In particular, the protocol outlined a study using six test subjects for each 14 product formulation, with two additional subjects serving as a negative and a positive control. 15 No information was provided to justify the group sizes used in the research. Given the nature of 16 these studies to evaluate tick repellency, the HSRB considered that a test in which each subject 17 served as his own control ( using one arm for the untreated, negative control and one arm for the 18 test) was a more appropriate design that would also be more powerful statistically and more 19 likely to generate reliable results. 20 21 Additional questions were raised by the HSRB concerning how subjects would be trained 22 to accurately and consistently collect information regarding the number of ticks crossing or 23 repelled from the arm skin. The protocol defined that a crossing is scored by the movement of a 24 tick by at least two centimeters toward the elbow starting from a line at the wrist, and that 25 subjects select a new tick from a pool of unused, prescreened ticks every 15 minutes. There was 26 no information made available to the Board as to how subjects were trained and qualified to 27 establish that they could collect accurate data on tick movement. The Board agreed that such 28 information was important for establishing good quality control of the data collection concerning 29 repellency. 30 31 HSRB Consensus and Rationale 32 33 Overall, the HSRB concluded that there were numerous technical deficiencies in protocol 34 EMD 003, and the information provided in the general protocol ( CL 001) did not make up for 35 the deficiencies in the specific protocol. Therefore, the Board concluded that the available 36 protocol did not warrant moving forward with the study. 37 38 Charge to the Board 39 b. Does the proposed research described in Study EMD 003 from Carroll Loye Biological 40 Research appear to comport with the applicable requirements of 40 CFR part 26, subparts K and 41 L? 42 43 Board Response to the Charge 44 45 Background 46 Proposed Final Draft v. 1 Dated August 28, 2006; Do Not Cite or Quote 45 of 67 1 The study proposed was to evaluate the efficacy of a compound known as IR3535 as a 2 tick repellent in human subjects. The study is to be conducted by Carroll Loye Biological 3 Research, a private research laboratory in Davis, California by using healthy volunteers and a 4 controlled laboratory environment. Two protocols were submitted for review, a general protocol 5 ( CL 001) that provided considerable background information about tests of insect repellency in 6 general, and the protocol for analysis of the efficacy of IR353 as a tick repellent evaluated here. 7 8 For this protocol, the efficacy of IR3535 as a tick repellent would be determined by 9 placing Western black legged ticks ( Ixodes pacificus) on IR3535 treated and   untreated forearms 10 and measuring the speed and distance that moving insects would penetrate into the treated area. 11 12 Strengths and Limitations 13 14 The Board concurred with the factual observations of the strengths and weaknesses of the 15 study, as detailed in the EPA's Initial Ethics Review ( USEPA 2006b). This study, it was argued, 16 would provide critical data on the efficacy of IR3535 as a tick repellent. IR3535 is commercially 17 available and has been used as a repellent in Europe for years with no evidence of toxicity, so the 18 subjects enrolled in this study were unlikely to be at increased risk of experiencing adverse side 19 effects upon exposure. The ticks used for the study also were bred and raised in a laboratory 20 environment and are considered to be pathogen free, minimizing the risk of vector borne 21 diseases. 22 23 The Board concluded, however, that given the deficiencies noted by the Agency, the 24 proposed research described in Protocol EMD 003 did not comport with the applicable 25 requirements of § 40CFR26, particularly subpart K. Carroll Loye Biological Research and the 26 IRB of record also failed to obtain or to provide all of the documents necessary to be in 27 compliance with the requirements of § 40CFR26, subpart M. The IRB, for example, refused to 28 release copies of the minutes documenting the discussion of EMD 003 protocol, preventing the 29 Board from evaluating whether or not they considered fully the issues listed under the EPA's 30 Final Human Studies Rule as part of their review. Furthermore, the protocol and supplementary 31 documents submitted to the Board were poorly written which, while not a fatal flaw in and of 32 itself, should have precluded IRB and HSRB review and approval. 33 34 The HSRB recognized several significant limitations to the protocol, as submitted to the 35 Board for review. There was, for example, lack of a clear rationale justifying the conduct of the 36 study as designed. The Board's concerns about this are discussed in detail with respect to the 37 companion protocol submitted by Carroll Loye, EMD 004, but it was felt that absent any clear 38 scientific rationale for conducting such a study, exposure of human subjects to the risks inherent 39 in this protocol would be unnecessary and unjustifiable. 40 41 Additional limitations of the study protocol provided to the Board can be grouped into 42 two broad categories: ( 1) concerns about equitable study subject selection and recruitment; and 43 ( 2) questions about whether or not the documentation and process of study subject enrollment 44 was sufficient to meet prevailing standards of voluntary informed consent. 45 46 Proposed Final Draft v. 1 Dated August 28, 2006; Do Not Cite or Quote 46 of 67 Subject Recruitment 1 2 The Board expressed concern about the potentially coercive nature of study subject 3 recruitment. Although the study is to be conducted by Carroll Loye Biological Research, a 4 private research laboratory in Davis, California, the Principal Investigator of the study and Co 5 Owner of the research laboratory, Dr. Scott P. Carroll, also is an adjunct faculty member of the 6 Department of Entomology at the University of California, Davis. As the majority of research 7 participants will be recruited from the University's student population, including from Dr. 8 Carroll's own department, the protocol and consent documents need to be altered to define 9 clearly the mechanisms in place to prevent any coercive enrollment, as well as the additional 10 concerns listed below. 11 12 Voluntary Informed Consent 13 14 The Board believed that the protocol and consent documents, as provided, lacked 15 sufficient information to ensure that all study participants were adequately informed about the 16 risks, benefits and alternatives to participation in the study. It was unclear, for instance, that 17 participation in the study would have no direct benefit for volunteers or that the study was being 18 conducted solely for marketing research. The major risks of participation in the study also 19 needed to be more clearly identified in the informed consent form and in supplementary 20 documents provided to study subjects. For example, one additional risk that the study 21 investigators may have failed to consider arises from the plan to pre screen female volunteers in 22 order to exclude any subjects who may be pregnant. In accordance with the newly promulgated 23 provisions in the EPA's final human studies rule ( § 40CFR26.1701  26.1704), minors and 24 pregnant women are explicitly excluded from participation, the latter being confirmed by 25 requiring all female volunteers to undergo a self administered over the counter pregnancy test on 26 the day of the study. Because many of the volunteers are undergraduate or graduate students at a 27 nearby college, the unexpected revelation that a subject may be pregnant could have a profound 28 psychological or social impact; Dr. Carroll also may have a professional relationship with these 29 students through his affiliation with the University. These risks should be specifically addressed, 30 and the Board recommended that a separate consent document for female volunteers be prepared 31 that addresses these risks as well as the safeguards established by study investigators to ensure 32 that the results of over the counter pregnancy tests would be kept private. 33 34 Study investigators also may wish to provide either a more detailed explanation of the 35 study protocol   including a detailed method for manipulating the ticks used in the experiment 36 and a clear description of the study's duration. 37 38 Finally, it was felt that the informed consent documents should be re written to: ( a) 39 comport with the reading and comprehension level of the likely subject population; and ( b) 40 clarify the section on compensation for research related injury. 41 42 HSRB Consensus and Rationale 43 44 Proposed Final Draft v. 1 Dated August 28, 2006; Do Not Cite or Quote 47 of 67 The Board concurred with the initial assessment of the Agency that the study submitted 1 for review by the Board failed to meet the ethical requirements established in the Agency's final 2 human studies rule ( § 40CFR26). 3 4 The Board determined the proposed research described in this study did not comport with 5 the applicable requirements of § 40CFR26, subparts K and L. The study documents submitted for 6 review also failed to comply with the requirements of § 40CFR26, subpart M. However, the 7 deficiencies noted, while significant, were not irreparable. 8 9 Study EMD 004 from Carroll Loye Biological Research 10 11 Charge to the Board 12 13 a. Did the proposed research described in Study EMD 004 from Carroll Loye Biological 14 Research appear likely to generate scientifically reliable data, useful for assessing the efficacy of 15 a test substance for repellent ticks? 16 17 Board Response to the Charge 18 19 Introduction 20 21 The Board began its review noting that this protocol addresses repelling insects, not ticks. 22 The Board concluded that the proposed research should generate scientifically useful data for 23 assessing efficacy. Protocol EMD 004 describes a test of the efficacy of 3[ N butyl N acetyl] 24 aminopropionic acid, ethyl ester ( IR3535) to repel mosquitoes in field experiments. It describes 25 the formulation and dose of the repellent and the number of replications ( 6 10 for each 26 formulation). The components of the three formulations were provided by the Agency. There 27 would be one to two untreated controls and one to two positive ( DEET treated) controls. Two 28 locations would be used, in or adjacent to the Central Valley in California and the Florida Keys. 29 The experiment would be double blinded. The compound has a very low toxicity profile in 30 animal tests and has been used in Europe for over 20 years as a repellent for many years without 31 reports of adverse effects in humans. 32 33 General Scientific Criteria 34 35   The scientific question was stated ( i. e., to test the efficacy of IR3535 in repelling 36 mosquitoes). 37   It was not clear whether existing data were adequate to answer the question. 38   It was not clear whether new studies involving human subjects were necessary; however, 39 if the repellency had never been tested with North American mosquitoes, the tests may be 40 necessary. 41   The potential benefits of the study were clear, i. e., that an effective repellent would be 42 available that would have either greater efficacy and/ or fewer drawbacks than what was 43 currently approved. 44   It was likely that the benefits would be realized ( i. e., efficacy as a repellent) because there 45 was a long positive history on this compound from its European use. 46 Proposed Final Draft v. 1 Dated August 28, 2006; Do Not Cite or Quote 48 of 67   The risks were not specifically noted. 1   The most likely relevant risk would be disease transmitted by the mosquitoes, if the 2 mosquitoes carried pathogens, and some mosquito borne diseases ( e. g., West Nile virus 3 mediated disease) were serious. The protocol did not indicate the likelihood of the 4 mosquitoes in the two test areas to be carriers of disease organisms that could be 5 transmitted to humans. However, using the fewest number of untreated controls would 6 provide the least risk of disease to the participants. The protocol did not indicate whether 7 all the inert ingredients in the formulations are GRAS compounds or have documented 8 lack of toxicity at the exposure levels anticipated. 9 10 Study Design Criteria 11   The purpose of the study was clearly defined ( i. e., efficacy testing). 12   There were specific objectives/ hypotheses ( i. e., that IR3535 is an effective repellent). 13   The study as described can test this hypothesis. 14   The sample size and how it was derived was not clear, but seems to have been taken from 15 the guidelines. The number of subjects listed in section 9.1.3 of the protocol listed 16 potentially more subjects than in the table in section 8.3.2. It was not clear if the stated 17 number of subjects would be repeated in both locations. The basis for the dose levels and 18 formulations were not provided. There were no controls with just the formulation matrix 19 without the repellent. 20   There was a plan allocating individuals to treatments. 21   The findings from this study can probably be generalized beyond the study sample. 22 23 Participation Criteria 24   There was partial justification for the selection of the target population. 25   The participants were representative of the population of concern. 26   The inclusion/ exclusion criteria were appropriate. 27   The sample was not a vulnerable group. 28 29 Measurement Criteria 30   The measurements were expected to be accurate and reliable. 31   The measurements were appropriate to the question being asked. 32   Quality assurances issues did not appear to be addressed. 33 34 Statistical Analysis Criteria 35   The data should be able to be analyzed statistically if the efficacy with time was the 36 subject of the analysis and the comparisons are made across time. However, if there is 37 only one untreated control ( which would be more protective against possible disease 38 transmission), then there would be difficulties with statistical analysis with comparisons 39 to the untreated control. 40   The statistical method seems to be appropriate. 41   Measures of uncertainty were not addressed. 42 43 Laboratory and Field Conditions 44 Proposed Final Draft v. 1 Dated August 28, 2006; Do Not Cite or Quote 49 of 67   No laboratory experiments were proposed in this protocol, probably because of the data 1 already available due to the compound's long previous use. 2   The field conditions were representative of the intended use. 3   The protocol did not include a stop rule plan, medical management plan, and a safety 4 monitor. 5 6 HSRB Consensus and Rationale 7 8 It was not clear whether new studies involving human subjects were necessary. If the 9 repellency had never been tested with North American mosquitoes, however, the tests were 10 probably necessary. The potential benefits of the study were clear, i. e., that an effective repellent 11 would be available that would have either greater efficacy and/ or fewer drawbacks than what 12 was currently approved. However, empirical evidence or procedures to determine risks to 13 subjects ( e. g., risks of contracting a vector borne disease) were not adequate. It was not clear if 14 the stated number of subjects would be repeated in both testing locations. The basis for the dose 15 levels and formulations were not provided. There were no controls with just the formulation 16 matrix without the repellent. Therefore, the Board concluded that some of the more critical 17 deficiencies in information identified above would have to be adequately addressed before this 18 protocol could receive a positive recommendation. 19 20 Charge to the Board 21 22 b. Did the proposed research described in Study EMD 004 from Carroll Loye Biological 23 Research appear to comport with the applicable requirements of 40 CFR part 26, subparts K and 24 L? 25 26 Brief Overview of the Study 27 28 The proposed study would evaluate the efficacy of three different skin applied 29 formulations of an already registered and marketed ( in Europe) insect repellent IR3535. There 30 would be two study sites, one located in central California and the other located in the Florida 31 Keys. The test compounds would be administered to a standardized skin surface area, with a 32 comparison to one positive control and one negative control. The subjects allocated to the 33 intervention groups would be blinded to the treatment. The chosen outcome measures are 34 " percent reduction in the rate of alightments" and " complete protection time." The protocol 35 stated that there would be 6 to 10 subjects per treatment group, with one subject per control 36 group. However there was no discussion of sample size justification. As discussed below, the 37 protocol lacked any discussion of risks. 38 39 Ethics and Regulatory Compliance 40 41 Subpart K of the Agency's final human studies rule requires that the investigator submit 42 to the EPA all information that pertains to the IRB review of proposed research ( 40 CFR 43 26.1115a) as well as additional information specified in 40 CFR 26.1125, if not already included 44 in the IRB documentation. The information requested under 40 CFR 26.1125 includes a 45 discussion of the potential risks to human subjects, the measures proposed to minimize these 46 Proposed Final Draft v. 1 Dated August 28, 2006; Do Not Cite or Quote 50 of 67 risks, expected benefits if any and to whom, alternative means to obtain comparable information, 1 and the balance of risk and benefits of the research. In addition, subject information sheets and 2 approved written informed consent agreements should be provided, along with any information 3 about recruitment and the presentation of this subject information. Finally, the investigator 4 should provide copies of all correspondence with the IRB, including official notification of IRB 5 review and approval. 6 7 In the case of this protocol, the principal investigator made a request to the reviewing 8 IRB ( Independent Investigational Review Board Inc. located in Plantation, Florida) for the 9 documents required under 40 CFR 26.1125. The response from the IRB, dated May 12, 2006, 10 did not include the minutes of IRB meetings at which the protocol was discussed. As a result, 11 the Board was unable to assess whether the IRB discussed or was even aware of the controversial 12 issues raised by this protocol. The IRB did provide templates of two different forms, the EPA 13 Protocol Checklist and Research Evaluation Form. Although these forms were fairly 14 comprehensive, the Board was not provided with copies of the forms used for the specific 15 protocol review and thus cannot assess whether or not the forms were used or the content of the 16 IRB analysis and discussion. The membership roster of the IRB was included. Although the 17 membership was diverse and meets the regulatory requirements, there was no scientific member 18 that appears to have sufficient expertise in the scientific issues involved in field testing of insect 19 repellents to assure that the IRB was qualified to make an adequate assessment of this protocol. 20 The scientific and ethical assessment may have been adequate, but the lack of IRB minutes made 21 this determination impossible. In effect, the IRB response was to provide procedural 22 documentation of the IRB's compliance with 40 CFR 26.1115 but to withhold any substantive 23 documentation that this procedural compliance resulted in an adequate ethical and scientific 24 review of the submitted protocol. As such, the proposed research failed to meet the requirements 25 of 40 CFR part 26, subpart K. 26 27 The investigator, to his credit, remedied some of these deficiencies in a supplementary 28 document submitted to the EPA as part of the Board's review. This undated document was 29 presumably written after the IRB review. In this document, the investigator addressed the 30 potential risks to human subjects, the measures proposed to minimize these risks, the nature and 31 magnitude of all expected benefits of the proposed research and to whom they would accrue, the 32 balance of risks and benefits of the proposed research, and alternative means of obtaining 33 information comparable to what would be collected through the proposed research. 34 35 Several observations are in order. First, none of this material, including the discussion of 36 risks and benefits can be found in the protocol submitted to the IRB. The absence of this 37 information in the protocol further compounds the uncertainty created by the absence of minutes 38 showing how the IRB made the determinations required under 40 CFR 26.1111. The 39 information about the potential risks to human subjects, the measures proposed to minimize these 40 risks, the nature and magnitude of all expected benefits of the proposed research and to whom 41 they would accrue, and the balance of risks and benefits of the proposed research should be part 42 of the research protocol submitted for initial IRB review. Otherwise, the IRB lacked sufficient 43 information to make an appropriate assessment of the proposed research. This was not to say 44 that the protocol would fail to meet the criteria for IRB approval, only that there was no evidence 45 that the IRB had sufficient information or expertise to make these determinations. Second, the 46 Proposed Final Draft v. 1 Dated August 28, 2006; Do Not Cite or Quote 51 of 67 protocol did minimize the risk of vector borne diseases by limiting the untreated control group to 1 a single subject who was experienced in field biology or entomology. The risk was minimized 2 further by using an outcome measure that does not require biting, but rather preparatory activities 3 on the part of the mosquito after lighting on the subject followed by aspiration and removal of 4 the mosquito. However, this approach raised concerns about the scientific adequacy of the 5 protocol design. Third, the investigator addressed the question of alternative means of obtaining 6 information by arguing that the protocol was designed in compliance with previous EPA 7 guidelines for registration of these products. The Board did not take a position on whether the 8 protocol was indeed in compliance with these previous guidelines. However, there was 9 sufficient discussion by the Board of the new draft EPA guidance on " Insect Repellent Product 10 Performance Testing" to cast doubt on the scientific adequacy and necessity of the approach 11 taken in this protocol. 12 13 Finally, the Board agreed with the ethical deficiencies noted by the EPA ( USEPA 2006c) 14 With the exception of amending the protocol to include the applicability of additional standards 15 of ethical conduct and the process of informing appropriate regulatory authorities of any 16 amendments or deviations from the approved protocol, all of these deficiencies related to the 17 informed consent discussion and document. These included a more accurate discussion of 18 subject assignment, a more extensive discussion of the risks ( with specific information about the 19 risk of vector borne diseases), the correction of an important typographical error in the 20 pregnancy section, a clarification of the section on compensation for research related injury, a 21 clarification of the lack of direct benefit to research subjects and additional information under the 22 heading of confidentiality. The Board also discussed the topic of pregnancy testing and whether 23 there should be a separate consent for such testing. As many of the research subjects may be in a 24 professional relationship to the principal investigator ( such as graduate students or colleagues), a 25 protocol and consent document needs to discuss how the confidentiality of such pregnancy 26 testing would be protected. 27 28 HSRB Consensus and Rationale 29 30 The Board thus concluded that the proposed research described in Study EMD 004 from 31 Carroll Loye Biological Research did not comport with the applicable requirements of 40 CFR 32 part 26, subpart K. The proposed research does comport with subpart L, as pregnant women and 33 children were excluded. Although the ethical concerns identified by the Board could be 34 remedied, there were sufficient questions raised about the adequacy of the research design to cast 35 doubt on whether the proposed research would meet the criteria for IRB approval found under 40 36 CFR 26.1111( a) ( 1). In other words, absent a sound research design, any exposure of human 37 subjects to risk would be unnecessary and unjustifiable. 38 39 Board Response to the Charge 40 41 Occupational Handler Exposure Monitoring Studies 42 43 Charge to the Board 44 45 Proposed Final Draft v. 1 Dated August 28, 2006; Do Not Cite or Quote 52 of 67 The Agricultural Handlers Exposure Task Force ( AHETF) had submitted protocols for 1 five pesticide exposure studies that are part of a larger research program the AHETF is 2 conducting. The premise of the AHETF research program is that data can be used generically by 3 various stakeholders ( e. g., applicants, registrants, EPA, and others) for calculating exposures for 4 the occupational handlers of pesticides. The scope of the AHETF research program was very 5 broad in that it intends to address exposures related to many job functions in agriculture and also 6 to assess generally the impacts of various parameters on exposure ( e. g., How do changes in the 7 pounds of pesticide handled or acres treated affect exposure levels?). The protocols submitted 8 for HSRB review described studies to measure exposures for five specific scenarios. 9 10 The Agency believed these studies had the potential to improve EPA's ability to assess 11 the risks of using pesticides because the data would reflect current agricultural practices, 12 equipment and techniques and would allow for more refined exposure estimates. Further, the 13 monitoring techniques to be used for these studies have been standardized for use across the 14 AHETF research program. These more refined and reliable data would allow the Agency to 15 estimate better how worker exposure levels are affected by changes in various factors such as the 16 amount of active ingredient handled, type of application equipment used, application rate used, 17 volumes handled, and personal protective equipment used. 18 19 It should be noted, however, that the use of the data generated in this study by the EPA 20 and other stakeholders would depend upon the nature of the results. For example, the adequacy 21 of the field or laboratory quality control data may dictate that correction factors are applied to 22 adjust monitored exposure levels to account for losses from field samplers or low performing 23 analytical methods. 24 25 1. AHETF Closed System Mixing/ Loading of Liquids Protocol ( AHE34) 26 27 a. Does the proposed research described in Study No. AHE34 from the Agricultural Handlers 28 Exposure Task Force appear likely to generate scientifically reliable data, which would be 29 useful, together with other data, for assessing the potential levels of pesticide exposure received 30 by people when mixing, loading or applying a liquid pesticide with closed systems? [ Note: In a 31 few cases, corresponding application events are also to be monitored; the same question applies 32 to those elements of the study.] 33 34 b. Does the proposed research described in Study No. AHE34 from the Agricultural Handlers 35 Exposure Task Force appear to comport with the applicable requirements of 40 CFR part 26, 36 subparts K and L? 37 38 2. AHETF Airblast Application to Trellis Crops in the West Protocol ( AHE36) 39 40 a. Does the proposed research described in Study No. AHE36 from the Agricultural Handlers 41 Exposure Task Force appear likely to generate scientifically reliable data, which would be 42 useful, together with other data, for assessing the potential levels of pesticide exposure received 43 by people when making an airblast application of a pesticide to a trellis crop under conditions 44 found in the western United States? [ Note: In a few cases, corresponding mixing/ loading events 45 are also to be monitored; the same question applies to those elements of the study.] 46 Proposed Final Draft v. 1 Dated August 28, 2006; Do Not Cite or Quote 53 of 67 1 b. Does the proposed research described in Study No. AHE36 from the Agricultural Handlers 2 Exposure Task Force appear to comport with the applicable requirements of 40 CFR part 26, 3 subparts K and L? 4 5 3. AHETF Airblast Application to Trellis Crops in the East Protocol ( AHE37) 6 7 a. Does the proposed research described in Study No. AHE37 from the Agricultural Handlers 8 Exposure Task Force appear likely to generate scientifically reliable data, which would be 9 useful, together with other data, for assessing the potential levels of pesticide exposure received 10 by people when making an airblast application of a pesticide to a trellis crop under conditions 11 found in the eastern United States? [ Note: In a few cases, corresponding mixing/ loading events 12 are also to be monitored; the same question applies to those elements of the study.] 13 14 b. Does the proposed research described in Study No. AHE37 from the Agricultural Handlers 15 Exposure Task Force appear to comport with the applicable requirements of 40 CFR part 26, 16 subparts K and L? 17 18 4. AHETF Closed Cab Airblast Application to Orchards Protocol ( AHE38) 19 20 a. Does the proposed research described in Study No. AHE38 from the Agricultural Handlers 21 Exposure Task Force appear likely to generate scientifically reliable data, which would be 22 useful, together with other data, for assessing the potential levels of pesticide exposure received 23 by people when making an airblast application of a pesticide to orchard crops? [ Note: In a few 24 cases, corresponding mixing/ loading events are also to be monitored; the same question applies 25 to those elements of the study.] 26 27 b. Does the proposed research described in Study No. AHE38 from the Agricultural Handlers 28 Exposure Task Force appear to comport with the applicable requirements of 40 CFR part 26, 29 subparts K and L? 30 31 5. AHETF Fixed Wing Aerial Application Protocol ( AHE42) 32 33 a. Does the proposed research described in Study No. AHE42 from the Agricultural Handlers 34 Exposure Task Force appear likely to generate scientifically reliable data, which would be 35 useful, together with other data, for assessing the potential levels of pesticide exposure received 36 by people making an aerial application of a pesticide from fixed wing aircraft? [ Note: In a few 37 cases, corresponding mixing/ loading events are also to be monitored; the same question applies 38 to those elements of the study.] 39 40 b. Does the proposed research described in Study No. AHE42 from the Agricultural Handlers 41 Exposure Task Force appear to comport with the applicable requirements of 40 CFR part 26, 42 subparts K and L? 43 44 Board Response to the Charge 45 46 Proposed Final Draft v. 1 Dated August 28, 2006; Do Not Cite or Quote 54 of 67 For the Board's review of the agricultural handler protocols, the Board decided to focus 1 its analysis addressing the common strengths, limitations and overall conclusion of the five 2 protocols. 3 4 5 Scientific Considerations 6 7 Study Overview 8 9 The pesticide handler exposure study protocols submitted to the HSRB were part of a 10 larger project that was initiated in December 2001 by the Agricultural Handler Exposure Task 11 Force ( AHETF). The project will produce a generic agricultural handler exposure database 12 ( AHED   ) . EPA and other regulatory agencies would use this database to calculate pesticide 13 handler exposures across a wide range of work conditions. All of the protocols follow a similar 14 pattern. They involve personal measurements of inhalation and dermal exposure among a group 15 of workers who conduct what is referred to as a " scenario"; that is, the study participant would 16 conduct a specified job task with specified equipment, handling a particular product formulation 17 that contains one of six pesticides. 18 19 These studies can be referred to as scripted, so as to distinguish them from purely 20 observational studies. Workers are asked to conduct their work activities under a set of scripted 21 conditions similar, but maybe not identical, to those they experience in their normal work 22 activities. The overall plan for the exposure database had been discussed with regulators from 23 EPA, California EPA, and Health Canada on a regular basis. The presentation of these protocols 24 to the HSRB is the first independent scientific review of the task force project. 25 26 The task force had proposed 33 handler exposure scenarios, distinguished by equipment 27 type, work task, and pesticide formulation. The task force has already conducted or initiated 14 28 exposure studies, and has sponsored four studies. In addition to the five protocols presented to 29 the HSRB, the task force planned to conduct approximately 40 additional studies over the next 30 several years. 31 32 Each of the protocols focuses on one primary exposure scenario, but all of the protocols 33 include more than one scenario. The five protocols reviewed by the HSRB are summarized in 34 Table 1. 35 36 Proposed Final Draft v. 1 Dated August 28, 2006; Do Not Cite or Quote 55 of 67 Table 1. Exposure Scenarios Included In The Five AHETF Protocols ( N = anticipated number of 1 independent observations for a particular scenario) 2 3 AHE34 AHE 36 AHE37 AHE38 AHE42 Scenario 1 Closed system mixload of a liquid Open cab trellis crop airblast application Open cab trellis crop airblast application Closed cab orchard crop airblast application Closed cockpit fixed wing aircraft application N 10 5 5 8 7 Scenario 2 Open or closed cab airblast application Closed cab trellis crop airblast application Closed cab trellis crop airblast application Open pour mix load of a liquid Open pour mix load of a liquid N 0 3 4 4 not specified 0 3 Scenario 3 Closed cockpit fixed wing aircraft application Open pour mix load of a liquid Open pour mix load of a wettable powder Closed system mix load of a liquid N 0 3 0 4 4 0 3 Scenario 4 Closed cockpit rotary wing aircraft application Closed system mixload of a liquid N 0 3 0 4 Total N 13 13 13 not specified 10 Chemical Malathion 8 ( 80% a. i.) Malathion 8 ( 80% a. i.) Diazinon 50% WP Carbaryl 4lb a. i./ gal Chlorothalonil 6lb a. i./ gal Location CA West ( CA) East ( NY) FL and GA Pacific NW 4 The task force studies are using six different pesticides: three organophosphorus 5 insecticides ( acephate, diazinon, malathion), one carbamate insecticide ( carbaryl), one 6 organochlorine fungicide ( chlorothalonil), and one triazine herbicide ( simazine). A description of 7 the selection criteria for these compounds was provided as a part of the task force documentation 8 package. These selection criteria did not include the toxicity of the compounds, and toxicity was 9 not discussed in the Agency reviews of the protocols. However, oral comments from task force 10 representatives at the June HSRB meeting indicated that the formulations of these pesticides 11 have been selected such that all fall into EPA toxicity categories III or IV; i. e., relatively low 12 toxicity formulations. It was also stated that all workers in these studies wear long sleeve shirts, 13 long legged pants, as well as socks and shoes. Protective equipment, such as chemical resistant 14 gloves and eye protection, are provided to the workers if required by the pesticide label. 15 16 The database to be developed from the task force studies is intended to supersede an 17 existing database   the Pesticide Handler Exposure Database ( PHED). This database was 18 Proposed Final Draft v. 1 Dated August 28, 2006; Do Not Cite or Quote 56 of 67 developed in the late 1980' s and early 1990' s through the compilation of existing data. These 1 data were drawn from both registrant sponsored studies and studies published in the scientific 2 literature. The studies included in PHED used a different method for measuring dermal exposure. 3 This method, known as the " patch technique" ( deposition coupons distributed over body regions 4 attached to the outer layer of clothing), has served as the standard method for such studies since 5 the 1960' s. When coupled with a hand rinse technique, it provides an estimate of exposure to all 6 body surfaces. 7 8 The documents submitted by the AHETF in support of the proposed exposure studies 9 consisted of the following: 10 11   Cover letter dated May 24, 2006 12   Analytical method validation reports for 5 of the 6 pesticides ( missing simazine) 13   List of 33 exposure scenarios 14   Description of selection requirements for surrogate compounds 15   32 standard operating procedure ( SOP) documents 16   A generic field exposure monitoring protocol 17   5 exposure study protocols: AHE34, 36, 37, 38, and 42 18   IRB documents related to each protocol 19 20 In addition, the HSRB received an EPA review for each protocol, EPA, Office of Pesticide 21 Program guideline documents, and several general documents on pesticide handler exposure. 22 Finally, the AHETF provided public comments ( AHETF 2006) containing comments on the 23 EPA review of the five protocols. 24 25 Critique of Study 26 General Scientific Criteria 27 28 The primary aim of these studies is to generate personal measurement data on pesticide 29 handlers suitable for use in an agricultural handler exposure database. The notion that such a 30 generic database for pesticide handlers can be developed is supported by substantial scientific 31 evidence. This evidence indicated that occupational pesticide exposure in agriculture is largely 32 process rather than chemical dependent ( excluding chemicals with high volatility). Thus, if 33 sufficient data can be collected on the key variables that influence exposure, then a database can 34 be developed to estimate exposure for a wide range of exposure scenarios. A major concern of 35 the HSRB was that these protocols included too many variables, and that, even when combined 36 with the full complement of studies proposed, the database would be inadequate for meaningful 37 exposure estimates. 38 39 The process that has guided the exposure database project had some significant 40 limitations. The database project has been developed over the past 5 years by a pesticide industry 41 task force with the input of regulatory staff from EPA, California, and Canada. Such an 42 ambitious undertaking would have benefited from an initial independent scientific peer review, 43 particularly of the study design and statistical plan, as the HSRB finds itself raising some 44 fundamental questions mid stream in the project. Input from the labor community would also 45 Proposed Final Draft v. 1 Dated August 28, 2006; Do Not Cite or Quote 57 of 67 have enhanced the project regarding procedures such as subject recruitment, selection of 1 pesticides to be used in individual studies, and informed consent. The purpose of the project, 2 after all, is to develop data to estimate worker risks. It seems reasonable to give those who would 3 be taking the risks an opportunity to contribute to the design of the project. 4 5 In regard to justification for new human studies, the Agency currently uses an existing 6 generic pesticide handler exposure database, known as PHED. It is recognized that new data 7 have not been added to PHED in a number of years, and that the existing data have a number of 8 scientific limitations. However, the inadequacy of PHED was not documented in the protocols. 9 The Agency had not provided a compelling justification for these new human studies in the 10 materials provided. 11 12 Benefits of the study were not described in the protocols. However, the AHETF 13 comments ( AHETF 2006) and the EPA review documents provided some general information 14 regarding the role of a handler exposure database in EPA's regulatory process. It was not 15 possible to determine the likelihood that the benefits would be realized, since the protocols did 16 not include a description of the full database and how it would be used. 17 Study Design Criteria 18 The purpose of these studies was clearly defined. The objective was to collect high 19 quality personal measurement data for use in a generic exposure database. The protocols 20 reviewed by the Board should be able to produce such data. 21 22 Approximate sample sizes were presented in the protocols and discussed in more detail in 23 the Agency reviews of the protocols. Within each protocol, the sample sizes for particular 24 scenarios were quite small. All of the protocols contained multiple scenarios, with sample size 25 per scenario ranging from 1 10 ( see Table 1). The inability to define exactly how many samples 26 would be collected in each proposed study was understandable, since the task force was 27 attempting to take advantage of ` real world' conditions. Weather, logistical challenges, and 28 grower decisions regarding pest management can all affect the number of workers available for a 29 given study. The effort to study exposures under realistic conditions required expenditure of 30 significant resources, and was viewed by the HSRB as highly commendable. The HSRB 31 understood that these protocols should not be viewed as " stand alone" studies, since data from 32 these studies would be combined with other similar studies. Presumably all of the data collected 33 in these five studies would be allocated to one of the 33 exposure scenarios outlined by the task 34 force. Under these circumstances, there was insufficient information for the HSRB to evaluate 35 the adequacy of the sample size. 36 37 In regard to dose levels, participants would be handling varying amounts of pesticides 38 under variable exposure conditions. The HSRB presumed that the conditions outlined in the 39 protocols and reviewed by the Agency all fall within parameters on the label. Actual dose during 40 these studies would likely be lower than normal, due to the wearing of a whole body cotton 41 garment, and strict observance of label instructions. 42 Proposed Final Draft v. 1 Dated August 28, 2006; Do Not Cite or Quote 58 of 67 Participation Criteria 1 2 Participants are referred to as ` replicates' both in the AHETF protocols and in the Agency 3 reviews. This term is problematic from a scientific perspective, since it is used to refer to both a 4 series of independent observations ( e. g., three persons doing the same thing one time) and a 5 series of repeated measures ( e. g., one person doing the same thing three times). This language 6 needs to be altered such that different terms are used for repeated measures on one person as 7 compared to observations on unique individuals. The AHE34 protocol, for example, indicated 8 that " ten different mixer/ loader workers ( or replicates) will be monitored . . . each mixer/ loader 9 replicate should be performed by a separate worker." This type of awkward description could be 10 eliminated through use of unambiguous terminology. 11 12 The protocols indicated that the participants would be " experienced workers" recruited 13 through their employers, but there was no detailed description of the recruitment procedures, nor 14 were there clear inclusion/ exclusion criteria other than age and pregnancy status. It was hard to 15 tell whether the workers who volunteer for a protocol exposure study would be representative of 16 the typical worker. Random sampling from a group of eligible workers would improve this 17 aspect of the protocols. 18 Measurement Criteria 19 AHETF investigators are using three different methods to measure skin exposure: cotton 20 garments ( whole body dosimeters), hand rinse, and face/ neck wipes. The cotton garments should 21 be able to capture pesticide that would normally be deposited on skin. However, no method for 22 preventing or monitoring garment breakthrough was presented. If breakthrough occurs, the 23 dermal exposure measurements would underestimate true exposure. The hand rinse method and 24 face/ neck wipe both measure the amount of material that can be removed from the skin at the 25 particular time of the sampling. This amount is some fraction of the total material deposited on 26 the skin, since some of the material would have been absorbed into the skin. This method is 27 likely to underestimate the true exposure. Published laboratory and field studies have indicated 28 that the fraction of the amount deposited on skin that can be removed by rinsing or wiping can be 29 quite variable, depending on the nature of the chemical, its formulation, skin characteristics, and 30 the length of time the chemical has been in contact with the skin. In particular, the face/ neck 31 wipe method may seriously underestimate exposure to these surfaces. This method was not 32 among the methods presented by the Agency in its 875 guidelines ( Occupational and Residential 33 Exposure Test Guidelines: OPPTS 875.1100 Dermal Exposure   Outdoor), and has not been 34 validated. The accuracy of these measurements could be improved through the conduct of 35 laboratory removal efficiency studies. The 875 guidelines do not require removal efficiency 36 studies, but they do indicate that investigators should address this concern. If such method 37 validation studies are contemplated, the HSRB recommended that they be conducted as 38 independent scientific studies published in the peer reviewed literature. 39 40 In summary, all of the methods for dermal exposure measurements have the potential to 41 underestimate exposure. The study investigators should acknowledge this problem in the 42 protocols, and explain what steps, if any, they have taken to improve or verify the accuracy of 43 the measurements. 44 Proposed Final Draft v. 1 Dated August 28, 2006; Do Not Cite or Quote 59 of 67 1 The protocols stated that hand rinse and wipe samples may be collected multiple times 2 during the work period ( e. g., prior to eating, whenever a worker would normally wash hands), 3 and that this would vary from worker to worker. The protocols did not explain how multiple 4 measurements from a single worker would be combined. They also did not discuss whether or 5 not samples across workers with different rinse/ wipe regimens can be considered comparable. 6 For example, can the amount of pesticide recovered in a single hand rinse from a worker at the 7 end of the study period be put in the same database as that from a worker who had four hand 8 rinses across the study period? The answer would seem to be " no" from a sampling perspective, 9 given the nature of dermal absorption processes. 10 11 The quality assurance components of the protocols are of high quality. There was 12 substantial documentation regarding the reliability of analytical methods available for each of the 13 sampling media to be used. There were detailed standard operating procedure documents for 14 field and laboratory quality assurance activities. 15 Statistical Analysis Critera 16 An inadequate statistical analysis plan was provided in the protocols. The HSRB 17 identified this deficiency as the most critical scientific limitation for these protocols. There was 18 a need for a more professional and comprehensive treatment of statistical issues in the analysis of 19 data, and in the design of individual protocols. Chief among these issues was the question of 20 statistical power. It is critical to address the HSRB's concern that the present design calls in most 21 cases for a single observation per experimental condition. In other words, it appears that the 22 present studies are intended to be parsed in terms of formulation, container size, frequency of 23 worker activity, equipment, air temperature, wind speed, relative humidity, amount of cloud 24 cover, rainfall, crop, amount of material handled, rate of application, acreage treated, and 25 geographic location ( along with other possible qualifiers). As a result, the number of variables to 26 be evaluated appears to approach or even exceed the total number of subjects for a given 27 scenario. One may hope that some useful information might yet emerge from a properly 28 performed analysis of the full data set coming from studies involving different chemicals, sites, 29 and conditions. What is needed now, however, is a cogent and thoughtful discussion, in the 30 protocol, of just what can be accomplished along these lines, and an explanation of how it can be 31 accomplished. Further thought may lead to the conclusion that the current data gathering plan is 32 in fact overly optimistic in regard to the issue of statistical power. It would then be essential to 33 restructure the plan and change the study design to ensure that the enormous effort in this large 34 and important project would not be wasted. 35 36 If the goal of these studies was to estimate the distribution of exposures across a variety 37 of application scenarios, it would be important to include true repeated measures for at least 38 some of these scenarios to assess the extent of within worker variability. 39 Laboratory and Field Conditions 40 41 The protocol states that the field conditions were selected to be representative of real 42 world use of pesticides. In this regard, participants are experienced workers, are allowed to wear 43 Proposed Final Draft v. 1 Dated August 28, 2006; Do Not Cite or Quote 60 of 67 their own clothing, and conduct normal work activities in an actual agricultural setting. Studies 1 are distributed across the U. S. and across the year in an attempt to develop a range of exposure 2 conditions. While laudable in scope, it is important to restate the concern that the large number 3 of variables included in these studies may prove extremely problematic for analysis. 4 5 The issue of potential heat stress was discussed at length at the HSRB public meeting. 6 The HSRB concluded that the protocols should include explicit criteria for halting a study due to 7 heat stress risk. 8 The protocols stated that workers would be monitored " during a period of time 9 representative of a full day's work". The protocols also indicated that monitoring times would 10 conform to a " typical" workday. However, none of the protocols defined the typical work period 11 for the specific tasks to be studied. Instead, the protocols stated that monitoring time " will 12 involve work periods with a target of 4 hours." This language suggested that even four hours of 13 monitoring might not be achieved in some cases, and there was no indication that workdays as 14 long as 8 or 9 hours would ever be monitored. It was not clear to the HSRB that these studies 15 would necessarily reflect a full workshift or a " typical" workday. Many factors can influence the 16 length of the workday, including weather conditions, and the need to " get the job done" due to 17 pest pressures or the stage of crop development. Fatigue is an important factor that can affect 18 exposure, and usually inattention occurs at the end of the day. The HSRB recommended that the 19 protocols document the time of a typical workday ( or the range of these times) for each scenario, 20 and that the monitoring time be based on this information. 21 22 Special Concerns Regarding Use of Diazinon in Protocol AHE37 23 24 Protocol AHE37 involves handling a wettable powder ( 50WP) formulation of diazinon. 25 Workers would be monitored during open cab trellis crop airblast applications and open pour 26 mixing loading operations. The HSRB was concerned that these practices are not consistent with 27 current Agency policy. The Agency's May 2004 interim registration eligibility document 28 ( IRED) for diazinon stated that engineering controls are required during handling. The " IRED 29 Facts for Diazinon" states, " All application equipment must use lock and load engineering 30 controls. All wettable powder formulations must be packaged in water soluble bags. Closed cabs 31 are required for all ground equipment, except for applications to apples." The IRED Executive 32 Summary further stated, " Occupational exposure to diazinon is of concern to the Agency. For 33 agricultural uses of diazinon, most mixer/ loader/ applicator risk scenarios currently exceed the 34 Agency's level of concern ( i. e., MOEs are less than 100 for dermal exposure and MOEs are less 35 than 300 for inhalation exposure). Taking into consideration both the risks and benefits of these 36 uses, EPA has determined that most agricultural uses may continue with the adoption of the 37 following mitigation measures: . . . engineering controls for mixers and loaders and closed cabs 38 for applicators for all application scenarios . . ." The above statements indicate that open pouring 39 of diazinon is not permitted, and that open cab airblast applications are not permitted in trellis 40 crops. 41 42 43 44 45 Proposed Final Draft v. 1 Dated August 28, 2006; Do Not Cite or Quote 61 of 67 HSRB Consensus and Rationale 1 2 The five studies presented for HSRB review were components of a large scale exercise to 3 create a contemporary database on occupational exposure to agricultural pesticides. The 4 undertaking is in itself likely to be worthwhile in quantifying and improving our understanding 5 of the exposures of and risks to pesticide handlers. The potential benefits are large and the risks 6 appear to be relatively modest. However, the materials supplied for HSRB review failed to deal 7 adequately with risks and benefits. None of these protocols can be properly evaluated in regard 8 to scientific validity because they lacked: ( 1) a developed rationale documenting the need for 9 new data; ( 2) a clear and appropriate plan for the handling of the data ( including its statistical 10 analysis), and ( 3) an explanation of the uses to which the data would be put and adequate sample 11 sizes and protocols for repeated measures to appropriately estimate exposures within individuals 12 and between scenarios. These points need to be addressed, at least briefly, in each specific 13 protocol and, more fully, in a separate and new " governing document" that is not simply a 14 generic description of the planned activities. 15 16 Additional validation studies are recommended to determine the extent to which dermal 17 exposure measurements may underestimate true exposure. Laboratory based removal efficiency 18 studies or field based biomonitoring studies could be conducted to achieve this goal. Such 19 studies should be published in the peer reviewed literature. Broader participation of the scientific 20 community and of parties with a direct interest in the database project, such as the labor 21 community, would likely improve the quality of the database and enhance the credibility of its 22 use in risk assessments. 23 24 The HSRB recommended that specific criteria for cessation due to heat stress be included 25 in these worker exposure protocols, and that the protocols included a heat stress management 26 plan. In addition, the HSRB recommended that the length of each study should be truly 27 representative of a full workday, and that each protocol should document the basis for the 28 proposed duration of the study. 29 30 The HSRB was gratified to receive the Agency's response to its query regarding the use 31 of diazinon in the AHE37. It is the understanding of the HSRB that the Agency would inform the 32 AHETF that it needs to identify a pesticide other than diazinon in this protocol to evaluate 33 exposures associated with open pour activities and applications using open cabs, and that the 34 Agency would ensure that future protocols comply with the most current risk mitigation 35 measures specified in IREDs and REDs. 36 37 Board Response to the Charge 38 39 Ethical Considerations 40 41 Background 42 43 These five studies are part of a series of studies that are to be conducted by the AHETF, a 44 coalition of 19 pesticide registrants that was formed in December 2001 to share resources in the 45 Proposed Final Draft v. 1 Dated August 28, 2006; Do Not Cite or Quote 62 of 67 design, evaluation, and development of a proprietary agricultural mixer/ loader and applicator 1 exposure database for use in regulatory risk assessments. 2 3 The study protocols were designed by AHETF investigators after joint discussions with 4 the US EPA, Health Canada, and the California Department of Pesticide Regulation, in 5 accordance with the recommendations of such guidance documents as: 1) US EPA, Occupational 6 and Residential Exposure Test Guidelines, Series 875.1000 through 875.1600 ( 1996); and 2) US 7 EPA, Working Draft  Occupational and Residential Exposure Test Guidelines, Series 875 8 Group B, Postapplication Exposure Monitoring Test Guidelines Version 5.4 ( 1998). The 9 supporting and supplementary study documents also assert compliance with the Good 10 Laboratory Practice ( GLP) Standards established by the 1972 amendment to the Federal 11 Insecticide, Fungicide, and Rodenticide Act ( FIFRA) ( § 40CFR160). Finally, these protocols 12 were reviewed and approved by the Western Institutional Review Board ( WIRB) of Olympia, 13 Washington, prior to submission to the Agency. 14 15 The aims of these studies are to provide critical exposure information for individuals who 16 mix, load, and apply agricultural pesticides. Agricultural producers (" growers") would be 17 recruited by the study coordinators several months prior to initiation of the study; in exchange 18 for their participation in the study, each grower would receive, free of charge, an amount of 19 liquid pesticide equivalent to the normal quantity mixed and loaded into closed mixing systems 20 and spray rigs for the duration of the study ( expected to be a single day). Participating growers 21 also may be asked to recruit other growers and pesticide applicators into the research study. 22 23 Study investigators would recruit agricultural handlers on site; volunteers would receive 24 $ 100/ day for their participation in addition to their regular pay. Voluntary informed consent 25 would be solicited by study investigators, and will be documented using a standardized informed 26 consent form. Because the study participants would be recruited from a pool of experienced 27 agricultural workers who routinely mix and load liquid pesticides as part of their normal duties, 28 the AHETF had argued that participation in this study presents a negligible increase in pesticide 29 exposure risk to volunteers. In accordance with the newly promulgated provisions in the EPA's 30 Final Human Studies Rule ( § 40CFR26.1701  26.1704), minors and pregnant women are 31 explicitly excluded from participation, the latter being confirmed by requiring all female 32 volunteers to undergo a self administered over the counter pregnancy test on the day of the 33 study. 34 35 Dermal exposure to pesticides would be ascertained through hand rinses and face/ neck 36 wipes, as well as the use of long cotton underwear   as a surrogate for skin   to be worn under 37 the study participant's clothing. In addition to the long underwear, all participants would be 38 required to wear long sleeved shirts and long pants, shoes plus socks, in accordance with 39 accepted worker protection standards. Volunteers may wear their own clothing provided they are 40 freshly laundered; alternatively, the AHETF would provide freshly laundered clothing. Any 41 personal protective equipment ( PPE) that may also be required, such as chemical resistant gloves 42 and protective eyewear, will be provided. At the conclusion of the four hour study observation, 43 the long underwear would be removed and subjected to laboratory analyses to estimate whole 44 body dermal pesticide exposure. Study participants would also be asked to wear OSHA Versatile 45 Samplers ( OVS) outfitted with glass filters, XAD 2 sorbent, and tygon tubes to measure 46 Proposed Final Draft v. 1 Dated August 28, 2006; Do Not Cite or Quote 63 of 67 inhalation exposure. The tubes would be attached to the volunteer's collars with the openings 1 positioned in their breathing zones. By using such state of the art monitoring techniques, the 2 AHETF argues, this study would provide critical exposure information for individuals who 3 mix/ load liquid agricultural pesticides. 4 5 Strengths and Limitations 6 7 These studies would provide critical exposure information for individuals who mix/ load 8 and apply agricultural pesticides. It is also believed that the monitoring techniques proposed for 9 these studies represent the current state of the art. However, the Agency also recognized that use 10 of the data resulting from this studies would take careful scrutiny and may require a number of 11 adjustments depending upon the results. Finally, the overall design of these studies should be 12 considered in the context of the goals of the AHETF which are to develop a broad based 13 database that can be generically used as a predictive tool for estimating exposures to pesticide 14 handlers and that the interpretation of the results of these studies may or may not necessitate the 15 need for additional monitoring data. 16 17 The Board concurred with the factual observations of the strengths and weaknesses of the 18 studies, as detailed in the EPA's Initial Ethics Review of the AHETF Template Protocol and 19 each individual study protocol. The Board concluded that, given the deficiencies noted by the 20 EPA, the proposed research described in the AHETF Template Protocol and each individual 21 study protocol do not comport with the applicable requirements of § 40CFR26, subparts K and L. 22 Furthermore, the AHETF and WIRB failed to provide all of the documents necessary to be in 23 compliance with the requirements of § 40CFR26, subpart M. 24 25 Although public comments from several members of the AHETF helped assuage some of 26 the Board's concerns, the members of the HSRB believed that further comments about this 27 protocol were warranted. The comments below are grouped into four broad categories: ( 1) 28 whether the study was designed to adequately minimize risk to study participants; ( 2) whether 29 the documentation and process of study subject enrollment was sufficient to meet prevailing 30 standards of voluntary informed consent; ( 3) whether study participants would be adequately 31 compensated in the event of a study related injury; and ( 4) whether appropriate alternatives to 32 participation are provided. 33 34 Minimization of Risks to Study Participants 35 36 This study proposes to measure dermal and inhalation exposure to liquid pesticides by 37 agricultural handlers who usually perform pesticide mixing, loading, and application as part of 38 their daily routine. However, it was unclear to Board members, given the semi scripted nature of 39 the protocol provided, as to whether or not study participants would be exposed to greater 40 quantities of these compounds than would normally occur. Are the studies proposed purely 41 observational in nature, or are study investigators intervening by requesting that study 42 participants use different types and quantities of pesticide, or different mixing, loading, and 43 application methods, than they normally would? If the latter is true, the assumption that this 44 study represents a negligible increase in pesticide exposure risk to volunteers may be unfounded. 45 Several Board members also expressed concern that the additional requirements for donning and 46 Proposed Final Draft v. 1 Dated August 28, 2006; Do Not Cite or Quote 64 of 67 removing the equipment used to measure pesticide exposure may inadvertently lengthen the 1 participant's normal work day. If so, this should be clearly described during the consent process, 2 as should the question of whether the $ 100 paid for study participation is expected, in whole or 3 in part, to compensate for the extension of the work day. 4 5 The protocol failed to detail the approach taken to ensure that agricultural handlers are 6 adequately trained in the proper mixing, loading, and application of these compounds. Although 7 pesticide mixing instructions and Material Safety Data Sheets are made available to study 8 participants, given that many agricultural workers may not be fluent in English ( or may even be 9 illiterate), a clear plan for ensuring that volunteers are properly educated in minimizing their 10 exposure to these compounds should be included. Furthermore, study investigators may want to 11 make arrangements to provide volunteers with the results of the study following completion. 12 13 One of the greatest risks to study participants is heat related illness, given that dermal 14 exposure to pesticides will be determined by asking volunteers to wear long underwear in 15 addition to their normal protective equipment ( e. g., long sleeved shirts and long pants, and other 16 applicable protective gear). Although study coordinators are expected to be vigilant for signs of 17 heat related illness among volunteers, in order to minimize the risks posed to the study 18 participants the protocol also should include: a) explicit starting and stopping criteria based on a 19 quantifiable measure like ambient temperature or heat index; and b) a clear description of the 20 symptoms of heat related illness in the informed consent documents. There should also be a clear 21 plan for reporting any heat related illness ( or, for that matter, any other adverse event) to the 22 study investigators, Western IRB, and the EPA. 23 24 Because some of the study participants may be undocumented immigrants, measures to 25 ensure strict confidentiality should be developed. Many undocumented workers, for example, 26 may be loathe to report any adverse study related event requiring medical attention or 27 hospitalization if they believe that their illegal status will be reported to immigration authorities. 28 Alternatively, study investigators may wish to require documentation of citizenship or 29 immigration status as part of the inclusion criteria for recruiting study participants. In addition, 30 because many pregnant day laborers may fear job loss in the event that their employer learns of 31 their condition, extra care should be taken to keep the results of over the counter pregnancy tests 32 private. 33 34 Voluntary Informed Consent 35 36 Several Board members felt that the AHETF protocol, as provided, lacked sufficient 37 safeguards to ensure that all study participants were adequately informed about the risks, benefits 38 and alternatives to participation in the study. For example, it was felt that the informed consent 39 documents provided were written at too high of a reading and comprehension level. Given the 40 sociodemographic characteristics of the farm worker population, many of the study participants 41 may have limited education, may speak English as a second or even a third language, or may 42 even be illiterate. Study investigators should develop a clear consent document which   in 43 addition to including a more detailed description of risks ( including the risks of the pesticides 44 being handled) as described previously, as well as a clear distinction between what comprises 45 research versus normal activities   is written at a lower grade level and translated into the 46 Proposed Final Draft v. 1 Dated August 28, 2006; Do Not Cite or Quote 65 of 67 various languages likely to be spoken by study participants. A brief oral test of comprehension 1 should also be developed, with volunteers required to demonstrate a clear understanding of the 2 purposes and the risks of the study prior to enrollment. 3 4 The Board also expressed concern about the potentially coercive nature of the study, 5 given the potential for study participants to believe that there is a direct relationship between 6 study investigators and growers. Absent additional safeguards, the " gift" of study pesticide to the 7 growers may contribute to undue influence on employees to participate in the research. Western 8 IRB, in its initial review of several of the AHETF protocols, recommended that " extra care" be 9 taken during the recruitment and consent process to minimize coercion or undue influence on 10 study participants. However, no documentation was provided to the HSRB as to how the AHETF 11 addressed WIRB's concern. For example, there was no evidence to suggest that AHETF 12 researchers solicited the help of the farm workers themselves or other community leaders to 13 ensure that study participants would not be covertly or overtly coerced into participating in the 14 study. The rights of participants to withdraw from the study at any time also should be 15 emphasized. It is unclear from the informed consent or other study documents, for instance, as to 16 whether volunteers are entitled to receive monetary payment even if they chose to withdraw 17 during the course of the study. Although the Board was reassured during the discussion that 18 sufficient alternate work was available, the protocol also failed to specify that workers would 19 still be paid for a day's labor even if they refused to participate in the research. 20 21 Compensation for Injury to Study Participants 22 23 The study protocol and informed consent documents state that: " If [ a study participant is] 24 injured as a result of being in this study, treatment will be available from a health professional at 25 a nearby medical facility. The costs of such treatment will be covered by the AHETF. This does 26 not cover any injuries resulting from [ the volunteer's] normal activities." Given the nature of the 27 study design, however, it is unclear whether a distinction between injuries resulting from normal 28 work activities versus participation in this study can be made. Two of the symptoms of heat 29 exhaustion, for example, are dizziness and loss of coordination   will study coordinators be able 30 to distinguish between an accidental injury caused by clumsiness versus an injury resulting from 31 potentially unrecognized symptoms of heat related illness? In light of these concerns, the Board 32 recommends that the AEHTF cover medical treatment for all participant illness and injury 33 occurring during the study period ( i. e., the day of the test). 34 35 Alternatives to Participation 36 37 As noted above, the design of this study involves collaboration between the researchers 38 and growers in which the growers receive, free of charge, a particular pesticide that they are 39 required to apply to their fields on the day of the study. That arrangement will lead in many 40 circumstances ( except of the few coincidental instances when the grower had already planned to 41 use that chemical on that day) to a change in the pesticide being applied by the grower. 42 43 The following question thus arises: What alternatives are offered to agricultural handlers 44 working for that grower who choose not to participate in the study? One option is that they could 45 be offered the choice of applying that pesticide that day, but not needing to participate in any 46 Proposed Final Draft v. 1 Dated August 28, 2006; Do Not Cite or Quote 66 of 67 other study procedures ( such as wearing the long underwear). Some members of the Board 1 believed that if that is the only alternative to participation, then this aspect of the study would not 2 comply with 40 C. F. R. Part 26, Subpart K. A primary purpose of the EPA rule is to prevent a 3 person from being intentionally exposed to a pesticide without their voluntary informed consent. 4 The EPA emphasized this point when it promulgated the final version of its rule, commenting 5 that the term " research involving intentional exposure" covers " any research on a substance, 6 unless the subjects of the research retain complete control over whether, when, and how they are 7 exposed to the substance." 71 Fed. Reg. 6138, 6146 ( 2006). 8 9 Some members of the Board accordingly concluded that for agricultural workers who had 10 pre existing expectations of earning money working for the grower on the day of the study 11 ( either as employees or as independent contractors with contractual expectations of working that 12 day), the protocol must provide them alternatives for earning that same amount of money that do 13 not require them to apply the pesticide used in the study. Acceptable alternatives could include 14 applying some other pesticide they have in the past applied, performing some other task they 15 regularly perform, or being paid their expected earnings without needing to work. Absent such 16 alternatives, the protocol would appear to be inappropriately coercing such persons into applying 17 the study compound or else losing the money they expected to earn that day. 18 19 20 HSRB Consensus and Rationale 21 22 The Board concurred with the initial assessment of the Agency that the studies submitted for 23 review failed to meet the ethical requirements established in the 40CFR26. 24 25 The Board determined the proposed occupational handlers exposure studies do not comport 26 with the applicable requirements of 40CFR26, subparts K and L. However, the deficiencies 27 noted, while significant, were not irreparable. 28 29 Proposed Final Draft v. 1 Dated August 28, 2006; Do Not Cite or Quote 67 of 67 REFERENCES 1 2 AHETF 2006. Comments to the Human Studies Review Board ( HSRB) Regarding Five 3 Protocols Submitted for Review. June 20, 2006. 4 5 NAS 2004. Intentional Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical 6 Issues. National Academy Press. 7 8 NBAC 2001. Ethical and Policy Issues in Research Involving Human Participants. National 9 Bioethics Advisory Commission. www. bioethics. gov 10 11 Prentiss AM. 1937. Chemical in War: A Treatise on Chemical Warfare. McGraw Hill Book 12 Company, Inc. New York. 13 14 USEPA 2006a. Human Studies Review Board. Weight of Evidence Determination for 15 Chloropicrin. June 7, 2006 16 17 USEPA 2006b. Ethics Review of Protocol for Human Study of Tick Repellent Performance. 18 June 9, 2006. 19 20 USEPA 2006c. Ethics Review of Protocol for Human Study of Mosquito Repellent Performance 21 June 9, 2006. 22 23 USGPO. 1949. Trials of War Criminals before the Nuremberg Military Tribunals under Control 24 Council Law No. 10, Vol. 2, pp. 181 182. Washington, D. C. 25 26 27


[Federal Register: November 26, 2008 (Volume 73, Number 229)]
[Proposed Rules]
[Page 71955-71957]
[DOCID:fr26no08-29]

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DEPARTMENT OF TRANSPORTATION

Federal Aviation Administration

14 CFR Part 39

[Docket No. FAA-2008-1242; Directorate Identifier 96-SW-13-AD]
RIN 2120-AA64

Airworthiness Directives; Bell Helicopter Textron Canada Model
206L, 206L-1, and 206L-3 Helicopters

AGENCY: Federal Aviation Administration, DOT.

ACTION: Notice of proposed rulemaking (NPRM).

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SUMMARY: This document proposes to revise an existing airworthiness
directive (AD) for Bell Helicopter Textron Canada (BHTC) Model 206L,
206L-1, and 206L-3 helicopters with certain part-numbered tailbooms.
That AD currently requires a visual inspection of the tailboom skin in
the areas around the nutplates and in the areas of the tailboom drive
shaft cover retention clips for cracks and corrosion using a 10-power
or higher magnifying glass until the tailboom is replaced with an
airworthy tailboom. This action would require the same actions as the
existing AD but would allow a longer interval for the repetitive
inspections if the tailboom is modified. Replacement with an airworthy
tailboom other than a part-numbered tailboom affected by this proposal
would constitute terminating action for the requirements of this AD.
The existing AD was prompted by an accident and several reports of
fatigue cracks in the tailboom skin in the areas around the nutplates
for the tail rotor fairing and in the areas of the tail rotor drive
shaft cover retention clips. These proposed actions are intended to
prevent failure of the tailboom and subsequent loss of control of the
helicopter.

DATES: Comments must be received by January 26, 2009.

ADDRESSES: Use one of the following addresses to submit comments on
this proposed AD:
     Federal eRulemaking Portal: Go to http://
www.regulations.gov. Follow the instructions for submitting comments.
     Fax:<PHONE_NUMBER>.
     Mail: U.S. Department of Transportation, Docket
Operations, M-30, West Building Ground Floor, Room W12-140, 1200 New
Jersey Avenue, SE., Washington, DC 20590.
     Hand Delivery: U.S. Department of Transportation, Docket
Operations, M-30, West Building Ground Floor, Room W12-140, 1200 New
Jersey Avenue, SE., Washington, DC 20590, between 9 a.m. and 5 p.m.,
Monday through Friday, except Federal holidays.
    You may get the service information identified in this proposed AD
from Bell Helicopter Textron Canada, 12,800 Rue de l'Avenir, Mirabel,
Quebec J7J1R4, telephone<PHONE_NUMBER> or<PHONE_NUMBER>, fax (450)
433-0272, or at http://www.bellcustomer.com/files/.
    Examining the Docket: You may examine the docket that contains the
proposed AD, any comments, and other information in person at the
Docket Operations office between 9 a.m. and 5 p.m., Monday through
Friday, except Federal holidays. The Docket Operations office
(telephone<PHONE_NUMBER>) is located in Room W12-140 on the ground
floor of the West Building at the street address stated in the
ADDRESSES section. Comments will be available in the AD docket shortly
after receipt.

FOR FURTHER INFORMATION CONTACT: Sharon Miles, Aviation Safety
Engineer, FAA, Rotorcraft Directorate, Regulations and Guidance Group,
Fort Worth, Texas 76193-0111, telephone<PHONE_NUMBER>, fax (817) 222-
5961.

SUPPLEMENTARY INFORMATION:

Comments Invited

    We invite you to submit any written data, views, or arguments
regarding this proposed AD. Send your comments to the address listed
under the caption ADDRESSES. Include the docket number ``FAA-2008-1242,
Directorate Identifier 96-SW-13-AD'' at the beginning of your comments.
We specifically invite comments on the overall regulatory, economic,
environmental, and energy aspects of the proposed AD. We will consider
all comments received by the closing date and may amend the proposed AD
in light of those comments.
    We will post all comments we receive, without change, to http://
www.regulations.gov, including any personal information you provide. We
will also post a report summarizing each substantive verbal contact
with FAA personnel concerning this proposed rulemaking. Using the
search function of our docket Web site, you can find and read the
comments to any of our dockets, including the name of the individual
who sent or signed the comment. You may review the DOT's complete
Privacy Act Statement in the Federal Register published on April 11,
2000 (65 FR 19477-78).

Discussion

    On August 22, 1996, we issued AD 96-18-05, Amendment 39-9729 (61 FR

45876, August 30, 1996), to require, before further flight, and
thereafter at intervals not to exceed 50 hours time-in-service (TIS), a
visual inspection of the tailboom skin in the areas around the
nutplates and in the areas of the tailboom drive shaft cover retention
clips for cracks and corrosion using a 10-power or higher magnifying
glass. That AD requires the 50-hour TIS inspection regardless of
whether the tailboom has been modified in accordance with Bell
Helicopter Textron Alert Service Bulletin No. 206L-87-47, Revision C,
dated October 23, 1989 (ASB). That AD also requires repeating those
inspections until the tailboom is replaced with a tailboom, part number
(P/N) 206-033-004-143 or -177. That action was prompted by an accident
and several reports of fatigue cracks in the tailboom skin in the areas
around the nutplates for the tail rotor fairing and in the areas of the
tail rotor drive shaft cover retention clips. That condition, if not
corrected, could result in failure of the tailboom and subsequent loss
of control of the helicopter.
    Since issuing that AD, we have re-evaluated our AD determination
that modified tailbooms should be inspected at intervals not to exceed
50 hours TIS. Therefore, we have issued several alternate method of
compliances (AMOCs) to allow owners and operators to conduct 100 hours
TIS repetitive inspections, as described in the ASB, instead of the 50
hours TIS repetitive inspections required by the existing AD for those
tailbooms modified in accordance with Part I of the ASB. We have
determined that increasing the inspection interval for modified
tailbooms does not compromise the safety of this helicopter. To provide
this relief to all operators, we have decided to propose to revise the
AD.
    This helicopter model is manufactured in Canada and is type
certificated for operation in the United States under the provisions of
14 CFR 21.29 and the applicable bilateral agreement. When AD 96-18-05
was issued, the type certificate for these affected model helicopters
was in the U.S. and the FAA had oversight responsibility for these
model helicopters. Transport Canada issued an AD following the FAA AD,
except that Transport Canada required modifying the tailboom in
accordance with the ASB and increasing the inspection interval to 100
hours TIS. Subsequently, these type certificates were transferred to
Canada.
    Therefore, the proposed AD would revise AD 96-18-05 to allow an
increased inspection interval to 100 hours TIS for a tailboom modified
in accordance with the ASB. The inspection interval for an unmodified
tailboom would remain at 50 hours TIS. The visual inspection of the
tailboom skin in the areas around the nutplates and in the areas of the
tailboom drive shaft cover retention clips for cracks and corrosion
using a 10-power or higher magnifying glass would still be required.
The proposed AD would also require repeating the 50-hour TIS
inspections until the tailboom is modified per the requirements of the
AD. Once modified, repeating the 100 hour TIS inspection until the
tailboom is replaced with a tailboom, part number (P/N) 206-033-004-143
or -177, or a tailboom not affected by this AD, would be required.
    We estimate that this proposed AD would affect 551 helicopters of
U.S. registry, and the proposed actions would take approximately 0.8
work hour per helicopter to inspect and 8 work hours per helicopter to
modify, at an average labor rate of $80 per work hour. If a helicopter
is modified to increase the inspection intervals, required parts would
cost approximately $385. Based on these figures, we estimate the total
cost impact of the proposed AD on U.S. operators to be $423,168 per
year, assuming all the helicopters are unmodified and 12 50-hour TIS
inspections per helicopter. If we assume that all helicopters are
modified at the beginning of the year, the cost impact of the proposed
AD on U.S. operators would be $776,359 for the first year, assuming
there are 6 100-hour TIS inspections the first year, and $211,584 for
each year thereafter.

Regulatory Findings

    We have determined that this proposed AD would not have federalism
implications under Executive Order 13132. Additionally, this proposed
AD would not have a substantial direct effect on the States, on the
relationship between the national Government and the States, or on the
distribution of power and responsibilities among the various levels of
government.
    For the reasons discussed above, I certify that the proposed
regulation:
    1. Is not a ``significant regulatory action'' under Executive Order
12866;
    2. Is not a ``significant rule'' under the DOT Regulatory Policies
and Procedures (44 FR 11034, February 26, 1979); and
    3. Will not have a significant economic impact, positive or
negative, on a substantial number of small entities under the criteria
of the Regulatory Flexibility Act.
    We prepared a draft economic evaluation of the estimated costs to
comply with this proposed AD. See the AD docket to examine the draft
economic evaluation.

Authority for This Rulemaking

    Title 49 of the United States Code specifies the FAA's authority to
issue rules on aviation safety. Subtitle I, Section 106, describes the
authority of the FAA Administrator. Subtitle VII, Aviation Programs,
describes in more detail the scope of the Agency's authority.
    We are issuing this rulemaking under the authority described in
Subtitle VII, Part A, Subpart III, Section 44701, ``General
requirements.'' Under that section, Congress charges the FAA with
promoting safe flight of civil aircraft in air commerce by prescribing
regulations for practices, methods, and procedures the Administrator
finds necessary for safety in air commerce. This regulation is within
the scope of that authority because it addresses an unsafe condition
that is likely to exist or develop on products identified in this
rulemaking action.

List of Subjects in 14 CFR Part 39

    Air transportation, Aircraft, Aviation safety, Incorporation by
reference, Safety.

The Proposed Amendment

    Accordingly, pursuant to the authority delegated to me by the
Administrator, the Federal Aviation Administration proposes to amend
part 39 of the Federal Aviation Regulations (14 CFR part 39) as
follows:

PART 39--AIRWORTHINESS DIRECTIVES

    1. The authority citation for part 39 continues to read as follows:

    Authority: 49 U.S.C. 106(g), 40113, 44701.

Sec.  39.13  [Amended]

    2. Section 39.13 is amended by removing Amendment 39-9729 (61 FR
45876, August 30, 1996), and by adding a new airworthiness directive
(AD), to read as follows:

Bell Helicopter Textron Canada: Docket No. FAA-2008-1242;
Directorate Identifier 96-SW-13-AD. Revises AD 96-18-05, Amendment
39-9729.

    Applicability: Model 206L, 206L-1, and 206L-3 helicopters, with
tailboom, part number (P/N) 206-033-004-003, -011, -045, or -103,
installed, certificated in any category.
    Compliance: Required as indicated.
    To prevent failure of the tailboom and subsequent loss of
control of the helicopter, accomplish the following:
    (a) Before further flight, unless accomplished previously, using
a 10-power

or higher magnifying glass, inspect the tailboom for cracks or
corrosion in accordance with the Accomplishment Instructions, Part
II, steps (1) through (7), of Bell Helicopter Textron Alert Service
Bulletin No. 206L-87-47, Revision C, dated October 23, 1989 (ASB).
    (b) For a tailboom that has not been modified in accordance with
the Accomplishment Instructions, Part I of the ASB, using a 10-power
or higher magnifying glass, inspect the tailboom for a crack at
intervals not to exceed 50 hours time-in-service (TIS) in accordance
with the Accomplishment Instructions, Part II, steps (1) through
(7), of the ASB.
    (c) For a tailboom that has been modified in accordance with the
Accomplishment Instructions, Part I, of the ASB, using a 10-power or
higher magnifying glass, inspect the tailboom for a crack or
corrosion at intervals not to exceed 100 hours TIS in accordance
with the Accomplishment Instructions, Part II and Part III of the
ASB, except you are not required to contact the manufacturer.
    (d) If a crack or corrosion is detected that is beyond the
repairable limits stated in the applicable maintenance manual,
remove the tailboom and replace it with an airworthy tailboom.
    (e) Replacing the tailboom with a tailboom, P/N 206-033-004-143
or -177, or an airworthy part-numbered tailboom that is not listed
in the Applicability section of this AD, constitutes a terminating
action for the requirements of this AD.
    (f) To request a different method of compliance or a different
compliance time for this AD, follow the procedures in 14 CFR 39.19.
Contact the Manager, Safety Management Group, FAA, ATTN: Sharon
Miles, Aviation Safety Engineer, FAA, Rotorcraft Directorate,
Regulations and Guidance Group, Fort Worth, Texas 76193-0111,
telephone<PHONE_NUMBER>, fax<PHONE_NUMBER>, for information about
previously approved alternative methods of compliance.
    (g) Special flight permits will not be issued.

    Issued in Fort Worth, Texas, on November 18, 2008.
Mark R. Schilling,
Acting Manager, Rotorcraft Directorate, Aircraft Certification Service.
[FR Doc. E8-28113 Filed 11-25-08; 8:45 am]

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