October 23rd, 2018 EPA Human Studies Review Board Meeting Report


EPA-HSRB-19-1
Office of the Science Advisor
1200 Pennsylvania Avenue, NW
Washington, DC 20460
Subject: October 23rd, 2018 EPA Human Studies Review Board Meeting Report
Dear Dr. Orme-Zavaleta,
The United States Environmental Protection Agency requested that the Human Studies Review
Board (HSRB) provide scientific and ethics review of a protocol submitted by the Antimicrobial
Exposure Assessment Task Force (AEATF II) entitled^ Study for Measurement of Potential
Dermal and Inhalation Exposure During Antimicrobial Applications Involving Immersion, Dip,
and Soak. The Board's responses to the charge questions and detailed rationale and
recommendations for their conclusions on this study are provided in the enclosed final meeting
report.
Signed,
Liza Dawson, PhD
Chair
EPA Human Studies Review Board
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Advance notice of the meeting was published in the Federal Register as "Human Studies Review
Board; Notification of a Public Meeting" (EPA, FRL-9984-60-ORD) This Final Report of the
meeting describes the HSRB's discussion, recommendations, rationale and consensus in
response to the charge questions on ethical and scientific aspects of the Antimicrobial Exposure
Assessment Task Force (AEATF II) protocol, A Study for Measurement of Potential Dermal and
Inhalation Exposure During Antimicrobial Applications Involving Immersion, Dip, and Soak.
Agency staff presented their review of scientific and ethical aspects of the study, with each
presentation followed by clarifying questions from the Board. The HSRB solicited public
comments and then took up the charge questions under consideration. The Board discussed the
science and ethics charge questions and developed a consensus response to each question in turn.
For each of the charge questions, the Chair called for the Board to vote to confirm concurrence
on a summary statement reflecting the Board's response.
For their evaluation and discussion, the Board considered presentations given by EPA staff at the
meeting, oral comments from Agency staff and from the investigators during the meeting
discussions, and the Agency's written reviews which were provided to the Board prior to the
meeting.
Charge to the Board- Science:
Is the protocol "A Study for Measurement of Potential Dermal and Inhalation Exposure During
Antimicrobial Applications Involving Immersion, Dip, and Soak" likely to generate scientifically
reliable data, and is useful for assessing the exposure of those who use products containing
antimicrobial pesticides for sanitizing surfaces and equipment?
Response to the charge question:
The protocol "A Study for Measurement of Potential Dermal and Inhalation Exposure During
Antimicrobial Applications Involving Immersion, Dip, and Soak" is likely to generate
scientifically reliable data, and is useful for assessing the exposure of those who use products
containing antimicrobial pesticides for sanitizing surfaces and equipment provided the changes
requested by EPA and the changes requested by the HSRB below are taken into account and
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implemented. The Board also has specific recommendations and clarifications to be made in the
study protocol, and additional minor points which are described in the discussion below.
HSRB Detailed Recommendations and Rationale:
HSRB reviewed information provided in advance of the meeting, as well as the EPA scientific
and ethics presentations provided at the meeting. The Board noted and agreed with the changes
in the protocol requested by the EPA. In addition, the Board identified further details that need to
be added to the protocol. Specifically, the Board suggests that the temperature of the water being
used in each scenario be measured and captured. The rationale is that attention to air temperature
is given for the volatility and movement of the chemical in air, and this might also be affected by
water temperature. Water temperature also has the potential to damage or open pores of the skin.
Additional recommendations
The Board recommends clarifying the following issues in the study protocol.
Height of air sampler. The height of the air sampler on the participant and the height of the
participant should be recorded. This may have implications on the overall air exposure as
participant height will dictate distance from the exposure source.
Surface area cleaned during bucket and sponge/rag scenario. In determining the location
where the study is to be performed, we recommend that the site has a large enough amount of
surface with (i.e. enough chairs, counters, tables, etc) to allow a participant to perform the task
for a full 1 hour.
Protocols to account for loss during drinking and other activities: The primary measures of
exposure are dermal and inhalation, but the subject might also be instructed to avoid drinking,
eating, or smoking during the activity. And if they do, the protocol should be specific as to how
to account for loss due to this activity (e.g., similar to the description of rest room use by the
participant). Similarly, as the face and head are not being measured, any wiping of the face with
hands or arms could result in loss.
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Statistical review. In general, the proposed statistical design and analysis of the protocol are
appropriate for EPA's intended use of the data. In particular, the following comments were
made.
• Reasonable justification was provided for restricting subject selection to commercial
workers based on the risk being driven by larger amounts of the active ingredient handled
compared to typical consumers. Although the results could still be extrapolated to the
general population, this would represent a study weakness in doing so.
• For each of the three scenarios, multiple configurations would be used to get a range of
diverse situations. However, as noted by the Science reviewers, more specifics on the
actual ranges should be stated at the study design phase.
• According to EPA, there is not enough power to discover proportionality of concentration
and exposure for the 3-compartment sink and COP scenarios. The EPA recommendation
for those two scenarios is to increase the range of the concentrations of the test substance
in the treatment solution in order to increase the statistical power. Justification of
proposed sample sizes as amended by EPA should meet the accuracy goals. In addition, it
was stated that if these goals were not met based on the data collected in the study, follow
up actions would be taken, including possible additional sampling.
EPA would follow previously established statistical procedures for data analysis of these types of
studies. The statistical analysis of data collected on 54 monitoring events (MEs),18 MEs per
scenario, is adequate. A simple linear regression model for the logarithm of the exposure with an
intercept term and with a slope coefficient multiplied by the logarithm of the concentration is
utilized. Confidence intervals for the slope can be utilized in order to examine whether the slope
is different from 1 or from 0. Q-Q plots of the normalized exposures can be utilized to measure
the lognormality assumption. The studentized residuals can be utilized to measure the model
performance of the final model. These statistical procedures were deemed appropriate.
In addition, should simple linear regression not provide an adequate fit to the data, EPA would
consider other regression models and probability distributions as alternatives to the standard
procedures. Data values less than the limit of quantitation (LOQ) would be assigned a value of
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one-half of the LOQ for calculating total exposure. This choice is one of several commonly used
substitutions.
In general, the Board deemed the statistical procedures to be appropriate, with modifications as
requested by EPA's review.
Charge to the Board—Ethics:
Is the research likely to meet the applicable requirements of 40 CFR part 26, subparts K and L?
Response to the charge question:
EPA staff have made a number of ethics and privacy comments and recommendations. The
Board has reviewed these and agrees with recommendations EPA staff have made. With the
changes recommended by EPA staff the Board believes this study complies with the applicable
ethical standards [40 CFR 26, subparts K and L, as well as FIFRA 12(a)(2)(P)].
HSRB detailed recommendations and rationale:
The proposed study will assess worker exposure to an antimicrobial applied via three methods:
(1) bucket & sponge/rag, (2) 3-compartment sink, and (3) Clean-Out-of-Place (COP). The
protocol is well written and generally clear. The objectives of this study cannot be achieved via
studies in vitro or in vivo in animals, so the study must be conducted with humans. Minors
(under 18) and women who are pregnant or lactating are appropriately excluded, in accordance
with EPA human subjects standards for intentional exposure studies. With the addition of
recommendations by EPA staff, including differences for each experimental condition, inclusion
and exclusion criteria are appropriate. EPA staff have also made recommendations with regard
to the range of ADBAC concentrations to be tested (Table 1 of EPA review) and the sample size
to increase the statistical power of the study. Insofar as these recommendations strengthen the
science of this trial, they also contribute to the ethics, since sound science that benefits society is
the foundation of an ethical study. There are no direct benefits to the individuals participating in
this study, though the knowledge gained may benefit them and others using these agents. Risks
appear no more than those that the subjects would be exposed to on a daily basis in their
workplaces. The benefit/risk balance is favorable as the knowledge gained will benefit society
generally and those applying antimicrobials in multiple settings.
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Subjects will be recruited and participation is voluntary with informed consent of the subjects.
Subjects will receive a payment $20 for attending the consent meeting, and a payment of $100 to
$200 depending on subject experience and which antimicrobial application method they will be
involved with. As noted by EPA staff, these amounts are appropriate as compensation for the
subjects' transportations expenses, time and varying levels of skills/experience required for the
different methods. They are not so large as to provide an undue inducement to participate.
Both English and Spanish versions of the informed consent forms will be available. Staff will be
available to translate, or potential subjects may bring a family member or friend.
This protocol has been reviewed and approved by Advarra's IRB and will be reviewed again
once changes recommended by EPA staff and the EPA HSRB are made. The Board does not see
any ethical barrier to the conduct of the study and believes it will meet the applicable
requirements of 40 CFR part 26, subparts K and L.
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