1 1 AEATF II Aerosol Application Scenario: AEATF II Aerosol Application Scenario: Rationale for Study Design Rationale for Study Design and and A Study for Measurement of Potential Dermal and A Study for Measurement of Potential Dermal and Inhalation Exposure During Application of a Liquid Inhalation Exposure During Application of a Liquid Antimicrobial Pesticide Product Using a Pressurized Antimicrobial Pesticide Product Using a Pressurized Aerosol Can for Indoor Surface Disinfecting Aerosol Can for Indoor Surface Disinfecting
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AEATF II Aerosol Application Scenario: AEATF II Aerosol Application Scenario: Rationale for Study DesignRationale for Study Design
andandA Study for Measurement of Potential Dermal A Study for Measurement of Potential Dermal and Inhalation Exposure During Application of and Inhalation Exposure During Application of a Liquid Antimicrobial Pesticide Product Using a Liquid Antimicrobial Pesticide Product Using a Pressurized Aerosol Can for Indoor Surface a Pressurized Aerosol Can for Indoor Surface
DisinfectingDisinfecting
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Status SummaryStatus 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 ContextRegulatory 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 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 PresentationsOrganization of Presentations
Background and Context• John Carley
Science Assessment• Tim Leighton
Ethics Assessment• Kelly Sherman
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Background and Context Background and Context for AEATF II for AEATF II
Aerosol ScenarioAerosol Scenario
John M. CarleyJohn M. CarleyHuman Research Ethics Review OfficerHuman Research Ethics Review Officer
Office of Pesticide ProgramsOffice of Pesticide Programs
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Background for Exposure Background for Exposure MonitoringMonitoring In early 1990’s individual pesticide handler
exposure studies were combined in a shared database—the 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 DataLimitations 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 NeededNew 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 IIFormation 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 IIPrimary 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 ProgramScope 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
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 PrincipleThe 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 ScenariosAEATF 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 Each Monitored Handler-Day is a Monitoring Event (ME)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 DesignAEATF 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
Maximizes—with a small sample—diversity 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 SamplingConsequence 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 ParticipantsAEATF II Study Participants
Experienced professional handlers of antimicrobial pesticides
Recruited through flyers and newspaper ads—not 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 ResultsAEATF 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™)
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 EPA’s 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
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 janitors—to ensure exposures are long enough to obtain usable data with exposure >LOD
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: Tier Spray
1 1 to 1.5 cans
2 1.5 to 2 cans
3 2 to 2.5 cans
4 2.5 to 3 cans
5 3 to 3.5 cans
6 3.5 to 4 cans
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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 cans—i.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:
washes, and air samplers—are 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 ShermanHuman 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 caller’s 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 candidate’s
preferred language
Applies eligibility criteria
Reviews Informed Consent Document and “Experimental Subject’s 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 EPA’s 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?
