AEATF II Aerosol Application Scenario: Rationale for Study Design and A Study for Measurement of Potential Dermal and Inhalation Exposure During Application of a Liquid Antimicrobial Pesticide Product Using a Pressurized Aerosol Can for Indoor Surface

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AEATF II Aerosol Application Scenario Rationale
for Study DesignandA Study for Measurement of
Potential Dermal and Inhalation Exposure During
Application of a Liquid Antimicrobial Pesticide
Product Using a Pressurized Aerosol Can for
Indoor Surface Disinfecting
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Status Summary

• AEATF II submitted an IRB-approved scenario
  design and study protocol dated August 4, 2009,
  for an aerosol spray exposure study
• The EPA Science and Ethics Review of September 21
  reflects review of the August 4 proposal, and was
  informed by the Governing Document and SOPs of
  the AEATF II

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Regulatory Context

• This is a proposal for research involving
  scripted exposure, and thus intentional exposure
  of human subjects, with the intent to submit the
  resulting data to EPA under FIFRA
• The following regulatory requirements apply
• 40 CFR 26.1125 requires prior submission of the
  protocol and supporting documentation
• 40 CFR 26.1601 requires review of the protocol
  by EPA and the HSRB

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Completeness for Review

• The August 4 submission contains all elements
  required by 40 CFR 26.1125
• EPA believes this proposal is ready for HSRB
  review

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Organization of Presentations

• Background and Context
• John Carley
• Science Assessment
• Tim Leighton
• Ethics Assessment
• Kelly Sherman

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Background and Context for AEATF II Aerosol
Scenario John M. CarleyHuman Research Ethics
Review OfficerOffice of Pesticide Programs
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Background for Exposure Monitoring

• In early 1990s individual pesticide handler
  exposure studies were combined in a shared
  databasethe Pesticide Handlers Exposure
  Database, or PHED
• PHED has supported meta-analyses across studies,
  and demonstrates the value of approaching
  exposure generically
• PHED has been the basis for most subsequent OPP
  exposure assessments
• Additional exposure monitoring for antimicrobials
  was conducted in the CMA study

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Limitations of PHED/CMA Data

• PHED/CMA remain the best data available, but have
  clear limitations especially for antimicrobials
• Spotty coverage of antimicrobial use patterns
• Studies had been conducted for different
  purposes inconsistent methods increase
  uncertainty of inferences

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New Exposure Studies are Needed

• A new generation of exposure monitoring is needed
• To address the limitations of PHED/CMA data
• To maximize the utility of generic data
• To standardize study design and methods
• FIFRA SAP (Jan 2007) concurred in
• Need for new studies
• Soundness of the generic principle
• General methods and study designs

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Formation of AEATF II

• EPA imposed requirements for new exposure studies
  in re-registration of antimicrobials
• In response to EPA requirements, members of the
  antimicrobials industry joined together beginning
  in 2004 to share technical and financial
  resources in the design and execution of a new
  antimicrobial exposure monitoring program

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Primary Objective of AEATF II

• To generate handler exposure monitoring
  studies to estimate and characterize exposures
  distributions for a multitude of
  occupational/industrial and consumer exposure
  scenarios involving antimicrobial products

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Scope of AEATF II Program

• Defined through extensive consultation with EPA,
  Health Canada, and CDPR (California)
• Focuses on handler exposure first, with
  monitoring of post-application exposures to
  residues on hard and soft surfaces to follow
• Covers the most common categories of
  antimicrobial pesticide use sites and the most
  common antimicrobial handler tasks

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Antimicrobial Handler Tasks
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Additional Simplifications

• Some scenarios are defined to include common
  combinations of tasks
• In some scenarios only higher-exposure variants
  are tested
• Subjects wear minimum required Personal
  Protective Equipment (PPE)

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The Generic Principle

• Exposure depends more on the characteristics of
  the use pattern than on the specific chemical
• Physical form and properties of the pesticide
• Method of application
• Amount of pesticide used
• User behaviors
• Data obtained by monitoring exposure from use of
  one chemical can be used, with appropriate
  adjustments, to estimate likely exposure from
  similar uses of other chemicals

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AEATF II Exposure Scenarios

• A set of similar uses of physically similar
  chemicals is an exposure scenario
• The unit in a scenario is a handler-day
• A Monitoring Event (ME) is a dataset fully
  describing a monitored handler-day
• The target population is the universe of future
  handler-days
• EPA wants to be able to characterize future
  exposures likely to result from use of a specific
  amount of an antimicrobial product in a
  well-defined exposure scenario

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Each Monitored Handler-Day is a Monitoring Event
(ME)

• Each ME characterizes dermal and inhalation
  exposure for a single subject over at least half
  a day
• The set of MEs for a scenario should characterize
  the range of expected exposures
• Measured exposures from each set of MEs will be
  used to represent future handler-day exposures to
  antimicrobial pesticides used in a particular
  scenario

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AEATF II Sampling Design

• Overall purposive sampling to characterize a
  broad range of exposures with a small sample size
• In guestrooms at 3 hotels/motels in Fresno area,
  differing in kitchen facilities
• At different times
• With a wide range in quantity of pesticide
  handled
• With different subjects (each subject monitored
  only once)
• Incorporating these random elements
• Sequence of screening hotels/motels
• Sequence of contacting janitorial services
  providers
• Assignment of enrolled subjects to sites and ME
  slots

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EPA Provisos

• EPA decided in November 2007, after considering
  the recommendations of the HSRB and others, to
  accept an overall purposive sampling design for
  the AEATF II monitoring program, with these
  provisos
• The AEATF II must
• Describe in detail their sampling design for each
  scenario
• Incorporate random elements whenever it is
  feasible
• Document their rationale for using a particular
  approach, including all decisions regarding the
  feasibility of randomization of specific elements
  in the design

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Diversity Sampling Maximizes Regulatory Utility

• Maximizeswith a small samplediversity in
  conditions expected to influence exposure
• Ensures that different MEs differ with respect to
  factors likely to affect exposure
• Increases the chance that the range of conditions
  expected to affect exposure in future
  handler-days is reflected in the set of MEs
  collected

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Consequence of Diversity Sampling

• As noted by the HSRB in earlier reports, the
  resulting distribution is not statistically
  representative of exposures to the target
  population, and statistical inferences cannot be
  drawn from results of AEATF II monitoring
• Distribution is deemed by EPA to adequately
  characterize for regulatory purposes the middle
  and larger exposure values for the target
  population of future handler-days

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AEATF II Study Participants

• Experienced professional handlers of
  antimicrobial pesticides
• Recruited through flyers and newspaper adsnot
  through employers
• Qualified volunteers are enrolled in the order of
  their response to recruiting efforts
• Enrolled subjects are assigned randomly to
  monitoring sites and specific ME slots

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AEATF II Study Results

• Study results will be reported to EPA in a
  monograph of each completed scenario
• Scenario monographs will be reviewed by EPA and,
  for scenarios involving scripted exposure, by the
  HSRB
• Upon acceptance, data for each scenario will be
  posted to the Biocide Handlers Exposure Database
  (BHED)

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EPA Science Assessment of AEATF II Aerosol
Scenario and Protocol

• Tim Leighton
• Antimicrobials Division
• Office of Pesticide Programs

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Overview Aerosol Scenario/Protocol

• Scenario Definition
• Study Objectives
• Selection of Surrogate Material for Testing
• Toxicity of Selected Surrogate Test Material
• Study Design
• Site location selection
• Sample characteristics
• Amount to be handled
• Allocation of subjects
• Spraying procedures
• Measurements
• Compliance with Scientific Standards

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Aerosol Application Scenario Definition

• Hand-held pressurized aerosol-based application
  of an end-use formulation containing an
  antimicrobial chemical
• Includes spraying a ready-to-use aerosol product
  until the treated surface is wet
• Excludes wiping treated surfaces

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Objectives

• To develop more accurate information on worker
  exposures to antimicrobials to support exposure
  assessments for aerosol spray applications
• To satisfy a requirement for new data imposed by
  EPAs Reregistration Eligibility Decision (RED)
  documents
• To support Registration Review as well as pending
  and future registrations for various
  antimicrobial aerosol products and uses

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Criteria for a Surrogate Aerosol Product

• Stable
• Appropriate vapor pressure
• Robust and sensitive analytical method
• Exposure at the high end of the range for
  different aerosol product types
• Hard surface disinfectant spray
• Soft surface disinfectant spray
• Foaming aerosol spray
• Air fresheners/sanitizers

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Variables Affecting Exposure from Aerosols

• Amount of material used
• Release rate
• Particle size distribution
• Nozzle technology
• Pressure in the can
• Temperature/humidity at time of use
• Surface on which product is used
• Orientation of the can during use

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Surrogate Selection

• Followed long and complex discussion with
  regulatory agencies
• Analysis of the variables affecting exposure
  showed hard-surface aerosols are likely to
  provide highest exposures and are appropriate
  surrogates for other aerosol types and uses
• Details are reported in Volume 1, Appendix A

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Selected Surrogate Test Material

• Commercial Solutions Clorox Disinfecting Spray
• EPA Reg. No. 67619-03
• Active Ingredients
• 0.252 ADBAC n-Alkyl dimethyl benzyl ammonium
  chloride
• 0.0945 DDAC Didecyl dimethyl ammonium chloride
  
• 0.189 ODAC Octyl decyl dimethyl ammonium
  chloride
• 0.0945 DODAC Dioctyl dimethyl ammonium chloride

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Toxicity of Test Materials ADBAC

• ADBAC dermal NOAEL reported in EPA RED is
  20 mg/kg/day (333 ug/cm2) for dermal irritation
• No dermal toxicity data available for low
  concentrations
• No systemic effects observed, only irritation
• ADBAC inhalation NOAEL reported in EPA RED is
  3 mg/kg/day, based on an oral study
• Based on the ADBAC RED, predicted dermal and
  inhalation MOEs will not be of concern

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Toxicity of Test Materials DDAC

• EPA relies on toxicity data on DDAC for all AIs
  in the DDAC cluster, including ODAC and DODAC
• DDAC dermal NOAEL reported in EPA RED is
  1000 mg/kg/day at 0.13 ai (the highest dose
  tested)
• No systemic effects no irritation observed
• Proposed concentration of DDAC in the test
  product is low (0.38 ai)
• DDAC inhalation NOAEL reported in EPA RED is
  10 mg/kg/day, based on an oral study
• Based on the DDAC RED, predicted dermal and
  inhalation MOEs will not be of concern.

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Study Design Cluster Location

• Fresno County
• Indoor aerosol spraying tasks do not vary
  geographically
• Efficient analytical lab is in Fresno
• Hotel/Motel Facilities
• Sufficient appropriate surfaces to be sprayed
• Readily available with varying configurations
• Full kitchen
• Kitchenette
• No kitchen

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Method for Site Selection

• List all hotels/motels in Fresno County yellow
  pages
• Screen properties in random sequence against
  criteria
• 20 or more units
• Management willing to cooperate with research
• Room configuration provides diversity of surfaces
• Functioning HVAC and electric systems
• Does not require cleaning or maintenance before
  use
• Select first qualifying property with each
• Full kitchen
• Kitchenette
• No kitchen

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Sample Characteristics

• Professional janitorsto ensure exposures are
  long enough to obtain usable data with exposure
  gtLOD
• 24 subjects will be enrolled 18 will be
  monitored
• 3 clusters/sites
• 6 subjects plus 2 alternates at each site
• EPA finds this sample size acceptable
• Rationale is consistent with all available
  aerosol data
• Size exceeds requirements of EPA and OECD
  Guidelines
• No existing data can substitute for any proposed
  new MEs

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ME Stratification by Amount Handled

• Constant concentration of test material exposure
  varies with amount handled and subject-specific
  behaviors
• Minimum amount sprayed is 1 can to ensure
  detectable residues
• Maximum amount sprayed is consistent with amount
  sprayed per room (AEJV, 113 g/room) and upper
  bound of 20 rooms cleaned/day
• One ME at each site at each pre-defined range of
  amount sprayed

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Allocation of Subjects to MEs

• Eight enrolled subjects at each site are ordered
  randomly the last two are alternates
• The first subject in order is assigned to the ME
  with highest number of cansi.e., Tier 6
• Each subsequent subject is assigned to the
  available ME with the highest remaining number of
  cans

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Spraying Procedure

• Subjects will follow label directions
• Spray 6-10 inches above surface until surface is
  thoroughly wet (3-4 seconds)
• Each subject will spray as they normally would on
  the job
• Subjects will not wipe surfaces after spraying

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Field Measurements

• Air temperature relative humidity
• Hotel/motel design and materials
• Characteristics of HVAC system
• Amount of material applied
• Observations/Video/Photographs

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Measurement of Dermal ADBAC Residues

• Whole body dosimeters
• Inner dosimeters
• Long-johns
• provide estimate of dermal exposure
• Outer dosimeters
• Normal work clothing consistent with label PPE
• provide estimate of protection provided by a
  single layer of clothing
• Hand wash before breaks and at end of task
• Face/neck wipe at end of task

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Measurement of Inhalation Exposure

• Personal Air Samplers include both OVS tubes and
  RespiCon filters
• OVS tube will be run at 2 L/min
• RespiCon filter will be run at 3.1 L/min and will
  size particles
• lt2.5 microns
• lt10 microns
• lt100 microns

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Analytical Phase

• Collected samplesdosimeters, hand/face washes,
  and air samplersare shipped on dry ice to the
  lab and frozen within 4 hours
• Method validation
• QA/QC plan
• Field recovery analysis
• Travel recovery analysis
• Storage stability studies
• Break-through analysis

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Compliance with Scientific Standards

• This protocol has addressed the technical aspects
  of applicable exposure monitoring guidelines
• EPA Series 875 Group A - Applicator Monitoring
  Test Guidelines
• OECD Applicator Guidelines
• Good Laboratory Practices (GLPs) (40 CFR Part
  160)
• Previous comments by EPA and JRC have all been
  satisfactorily addressed
• No scientific deficiencies requiring correction
  have been identified by EPA

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Summary Conclusion

• This protocol is likely to yield scientifically
  reliable information, satisfying the following
  criteria
• It would produce important information to fill an
  identified regulatory need
• This need cannot be addressed except by research
  with human subjects
• It has a clear scientific objective
• The study design should produce data adequate to
  achieve the objective

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EPA Ethics Assessment of AEATF II Aerosol
Scenarioand Protocol AEA-04

• Kelly Sherman
• Human Research Ethics Reviewer
• Office of Pesticide Programs

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Value to Society

• Reliable exposure data for aerosol antimicrobial
  products are needed to support EPA exposure
  assessments
• Existing data are inadequate
• Knowledge likely to be gained will be usable in
  exposure assessments for
• Both professional users and consumers
• Wide variety of aerosol products and use patterns

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Recruiting Process

• Subjects will be recruited from professional
  janitorial workers of Fresno County
• Workplace flyers in English and Spanish
• Advertisements in three Fresno newspapers
• Calls from individuals responding to flyers or
  ads will be received by a field researcher
• One field researcher is identified on the flyers
  and in ads as bilingual in English and Spanish

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Recruiting Process 2

• Callers are informed about the study using an
  IRB-approved script
• Callers are screened for janitorial experience
  and other eligibility factors, and then scheduled
  for informed consent meetings at the callers
  convenience

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Consent Process

• Essentially the same for English and Spanish
• Investigator meets with interested candidate
• Provides information about study design in
  candidates preferred language
• Applies eligibility criteria
• Reviews Informed Consent Document and
  Experimental Subjects Bill of Rights
• Provides label and MSDS
• Answers questions
• Principal Investigator confirms understanding and
  solicits consent to participate

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Change in Consent Process

• Unlike earlier AEATF II Mop and Wipe studies, the
  list of candidates responding to flyers or ads
  will not be randomized before scheduling consent
  interviews
• AEATF II has learned from Mop and Wipe studies
  that delaying informed consent meetings to allow
  randomization of lists leads to significant
  attrition
• EPA has agreed to this change, and considers this
  proposal still to comply with direction to
  incorporate random elements whenever feasible

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Recruiting and Consent

• Equitable subject selection
• Fully informed choice
• Fully voluntary choice

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Respect for Participants

• Participant privacy will be maintained
• Photographs and videos will be altered to protect
  subjects identities
• Proposed remuneration is reasonable
• Participants will be free to withdraw at any
  time, for any reason

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Risks and Risk Minimization

• Irritant response to test material or to solvents
  used to obtain residues from hands and face/neck
• Discomfort or heat-related illness due to extra
  layer of clothing and air pump
• Embarrassment while changing
• Surprise at results of pregnancy test

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Benefits

• No direct benefits to subjects
• Potential indirect benefit to subjects who learn
  individual results and how their exposure
  compares to that of others
• Sponsors will benefit by maintaining regulatory
  compliance
• Likely societal benefit is higher quality
  exposure and risk assessments for aerosol
  antimicrobial products

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Risk-Benefit Balance

• Risks have been effectively minimized
• Residual risks to subjects will be low
• Risks to subjects are reasonable in light of
  potential societal benefits

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Independent Ethics Review

• Independent Investigational Review Board, Inc.,
  of Plantation FL (IIRB, Inc.) reviewed and
  unanimously approved the protocol and supporting
  documents in English and Spanish
• IIRB-approved protocol was re-dated prior to
  submission to EPA
• AEATF II has confirmed that the version submitted
  to EPA is identical to the version approved by
  IIRB, notwithstanding that it was re-dated after
  IIRB approval
• In future submissions, the AEATF must maintain a
  version date as a permanent attribute of the
  file, to maintain the integrity of the record

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Applicable Ethical Standards

• This is a proposal for third-party research
  involving intentional exposure of human subjects
  to a pesticide, with the intention of submitting
  the resulting data to EPA under the pesticide
  laws
• The primary ethical standards applicable to this
  research are 40 CFR 26, Subparts K and L

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Corrections Called For by EPA

• Clarify compensation for research-related
  injuries
• Change We will pay for needed medical treatment
  that is not paid for by your own insurance or by
  someone else.
• To by your own insurance or by the insurance
  of a third party under which you are covered.
• Institute version control in all study documents

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Compliance with Ethical Standards

• All requirements of 26.1111, 26.1116, and
  26.1117 are met
• All requirements of 26.1125 are met
• Requirements of 26.1203 are met
• If requested corrections are made, the AEATF II
  Aerosol Scenario and Protocol will likely meet
  the applicable requirements of 40 CFR part 26,
  subparts K and L

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Charge Questions

• If the proposed AEATF II aerosol application
  scenario and field study protocol AEA04 is
  revised as suggested in EPAs review and if the
  research is performed as described
• Is the research likely to generate scientifically
  reliable data, useful for assessing the exposure
  of handlers who apply antimicrobial pesticides
  formulated as aerosol sprays?
• Is the research likely to meet the applicable
  requirements of 40 CFR part 26, subparts K and L?