Human Studies Review Board Chairs Summary of Board

Human Studies Review Board Chair’s Summary of Board Recommendations* June 24 -25, 2009 Human Studies Review Board Meeting * The Chair’s summary of this public meeting reflect diverse ideas and suggestions offered by Board members during the course of deliberations within the meeting. Such ideas, suggestions, and deliberations do not necessarily reflect definitive consensus advice from the Board members. The reader is cautioned to not rely on this summary to represent final, approved, consensus advice and recommendations offered to the Agency. Such advice and recommendations may be found in the final report prepared, approved and transmitted to the EPA Science Advisor following the public meeting.

Nolan et al. (1982) pre-Rule study Charge Question 1: Are the blood and urine measurements of chlorpyrifos and/or TCP from the Nolan et al. oral and dermal studies reliable? Board Recommendations: Measurement of chlorpyrifos at the limit of detection are not useful. Measurement of TCP in urine is generally reliable. It is unclear, however, if the measurement of TCP in blood is useful because of concerns about the ability of the methods used to detect the appropriate TCP conjugate.

Nolan et al. (1982) pre-Rule study Charge Question 2: Are the measurements of cholinesterase activity/inhibition from the Nolan et al. oral and dermal studies reliable? Board Recommendations: Plasma Ch. EI measurements are generally reliable but the Board expressed some concern about laboratory variability and the lack of control group. The Board expressed concern about RBC assay variability but concluded that data appear to support the conclusion that there is no detectable RBC Ch. EI effect.

Nolan et al. (1982) pre-Rule study Charge Question 3: Is there clear and convincing evidence that the conduct of the Nolan et al. study was fundamentally unethical, or significantly deficient relative to the standards of ethical research conduct prevailing when it was conducted? Board Recommendations: Although concerned about the lack of a protocol for Board review, the Board concluded that there was no clear and convincing evidence that the study was fundamentally unethical or significantly deficient according to the standards of the time.

Honeycutt & De. Geare (1993) pre. Rule study Charge Question 1: Are the blood and urine measurements of chlorpyrifos and/or TCP from the Honeycutt & De. Geare worker biomonitoring study reliable? Board Recommendations: The Board concluded that the data are likely reliable but of limited value. Board members expressed concerns about: 1) the small sample size; 2) the background chlorpyrifos exposure not being properly accounted for; 3) the likely incompleteness of urine collection; and 4) the high degree of variation seen in the daily measurements.

Honeycutt & De. Geare (1993) pre. Rule study Charge Question 2: Are the measurements of cholinesterase activity/inhibition from the Honeycutt & De. Geare worker biomonitoring study reliable? Board Recommendations: The Board felt that the laboratory data are likely accurate and reliable but raised concerns about their utility. Some of the Board’s concerns included: 1) the lack of an untreated control; 2) the reliance on a single post-exposure time point; 3) the small sample size; and 4) the likely irreproducibility of the data.

Honeycutt & De. Geare (1993) pre. Rule study Charge Question 3: Is there clear and convincing evidence that the conduct of the Honeycutt & De. Geare study was fundamentally unethical, or significantly deficient relative to the standards of ethical research conduct prevailing when it was conducted? Board Recommendations: There were concerns about volunteers being coerced or unduly influenced to participate, as well as concerns about participant confidentiality, but the Board concluded that there was no clear and convincing evidence that the study was fundamentally unethical or significantly deficient relative to the standards of the time.

Kisicki et al. (1999) pre-Rule study Charge Question 1: Are the blood and urine measurements of chlorpyrifos and/or TCP from the Kisicki et al. oral study reliable? Board Recommendations: Questions about the analytic procedures used, the lack of an appropriate gluconamide control, and apparent discrepancies in the absorption data when compared with the data from Nolan et al. (1982), raise concerns about the reliability and utility of these data for risk assessment purposes.

Kisicki et al. (1999) pre-Rule study Charge Question 2: Are the measurements of cholinesterase activity/inhibition from the Kisicki et al. oral study reliable? Board Recommendations: The Board felt that these measurements represent a reliable set of data, but cautioned the Agency about relying on data from the incomplete profile for the one responder at the highest dose level. The Board also cautioned against relying on the statistical analyses as presented in the report.

Kisicki et al. (1999) pre-Rule study Charge Question 3: Is there clear and convincing evidence that the conduct of the Kisicki et al. study was fundamentally unethical, or significantly deficient relative to the standards of ethical research conduct prevailing when it was conducted? Board Recommendations: There was considerable concern about the informed consent process, but following the submission of additional material from MDS-Harris and presented at the June 24 th meeting, the Board concluded that there was no clear and convincing evidence that the study was fundamentally unethical or significantly deficient relative to the standards of the time.

LNX-002 protocol Charge Question 1: Is the research likely to generate scientifically reliable data, useful for assessing the efficacy of the tested materials in repelling biting flies in the field? Board Recommendations: To ensure the likelihood that the study will obtain scientifically reliable data, the Board recommends significant changes to the protocol as summarized on the following slide. The revised protocol, however, does not need to come before the Board for review prior to study execution.

LNX-002 protocol Board Recommendations for LNX-002 Protocol Revisions: • The study should be conducted at a site and time with sufficient biting pressure of black flies and/or biting midges. The protocol must be modified to consider how to accurately measure one and/or both of these species. • The choice of a 5’ every 30’ exposure time should be clarified, particularly as it raises questions about sufficient biting pressure and the probability of erroneous CPT results. • Mean protection time versus the duration of the study should be clarified, particularly as it affects the prevalence of censored data. • The protocol needs to be revised to clarify how the analysis will proceed in the presence of censored data (Maximum-likelihood or Kaplan-Meier).

LNX-002 protocol Charge Question 2: Is the research likely to meet the applicable requirements of 40 CFR part 26, subparts K and L? Board Recommendations: If revised in accordance with the EPA’s recommendations, along with a clarification of what “ 3 rd party” medical coverage means, the study will likely meet the applicable requirements of 40 CFR 26, subparts K and L.

ICR A-382 completed study Charge Question 1: Is the ICR study A-382 sufficiently sound, from a scientific perspective, to be used to assess the repellent efficacy of the tested formulations against stable flies in the laboratory? Board Recommendations: The Board concluded that the data were sufficiently sound to assess repellent efficacy against stable flies in the laboratory but raised some concerns about the data analysis and presentation, such as incorporating the assumed standard error estimate from the power and sample size calculation into the results.

ICR A-382 completed study Charge Question 2: Does available information support a determination that study A 382 was conducted in substantial compliance with subparts K and L 40 CFR Part 26? Board Recommendations: The Board concluded that the study was conducted in substantial compliance with the appropriate subparts of 40 CFR 26, although several board members raised concerns about the quality of IRB review and the qualifications of IRB members.

AHETF water soluble packing mixing/loading protocol Charge Question 1: Is the research likely to generate scientifically reliable data, useful for assessing the exposure of handlers who mix and load soluble or wettable powder pesticides in water-soluble packaging? Board Recommendations: The Board concluded that the proposed research is likely to generate some scientifically reliable data. The Board recommended, however, that the Agency acknowledge the limitations of the data that will be obtained, perhaps by developing an explicit statement on the utility of the data relative to the proposed study design and statistical limitations. The Board also recommended that the Agency and Task Force deemphasize statistical analyses of the data in future protocols and reports. The revised protocol does not need to come before the Board for review prior to study execution.

AHETF water soluble packing mixing/loading protocol Charge Question 2: Is the research likely to meet the applicable requirements of 40 CFR part 26, subparts K and L? Board Recommendations: The Board concluded that the proposed study will likely meet the applicable requirements of 40 CFR 26, subparts K and L. The Board also recommended that the Task Force implement the proposed protocol changes designed to address issues of representativeness and language. With respect to concerns about the release of individual exposure data, the Board recommended delaying release of individual data until all analyses of representative MUs are complete, expect in those instances where individual data suggest unusually high level of exposure.