Antimicrobials ExposureAssessment Task Force (AEATF) IIIntroduction and BackgroundINTRODUCTION•AEATF’sprimary purpose is to generate exposuredata to support EPA’s development of improvedexposure assessments for antimicrobial (biocide)risk analyses and associated regulatory decisionmaking•Asecondary objective is to provide data to otherregulatory agencies (Canada PMRA, EU, BPD) fortheir assessments and decision-makingsOctober 20072INTRODUCTIONAEATF overview:•Represents a coordinated effort between ACC andEPA•Preliminary talks in 2003•Development talks starting in 2004•Includes multinational regulatory authority input andinvolvement (EPA, CDPR, PMRA, EU, OECD)October 20073INTRODUCTIONAEATF overview:•$10 Million program (initial estimate)•43 participating companies representing theantimicrobials value chain (active producers toend-user formulators)•Addresses 19 different exposure scenariosOctober 20074New Antimicrobial Exposure DataAre Needed•Existing antimicrobial exposure data are very limited•In response to a 1986 EPA Antimicrobial Data Call-In, ACC Task Force(AEATF I) conducted the “CMA Antimicrobial Exposure Assessment study”•The CMA study provided the first exposure data for antimicrobials, but hasmany limitations (low numbers of individuals monitored, high detection limitsand only 8 activities monitored)•EPA currently uses the CMA study data in conjunction with PesticideHandlers Exposure Database (PHED) to conduct most risk assessments formost registered antimicrobial active ingredients•Paucity of existing data prompted the EPA request for new data•In more than 8 Re-registration Eligibility Decision documents issued since2005, EPA has requested replacement data for the CMA study•The need for additional exposure data was confirmed by the EPA’s ScientificAdvisory Panel (SAP) in January 20075Key Role of AEATF DataDevelopment Effort•AEATF II is a state-of-the-art exposure assessmentprogramthatwillprovideexceptionaldataforregistrant and EPA decisions•Cost overruns and delays threaten the scope and theviability of this program•AEATFII wants tocontinue working with the EPA tofind workable solutions to maintain the viability of thisvaluable program6Introduction•Antimicrobial pesticides have two major uses:–Protect inanimate objects (for example material preservativesin floors and walls), industrial processes or systems, surfaces,water, or other chemical substances from contamination,fouling, or deterioration caused by bacteria, viruses, fungi,protozoa, algae, or slime–Disinfect, sanitize, reduce, ormitigate growth or developmentof microbiological organisms78Examples of Antimicrobial UsesAEATF Program ScopeUse PatternsApplicationMethods1.AgriculturalPremisesandEquipment1.AerosolSpray2.FoodHandling/StorageEstablishments PremisesandEquipment2.HighPressureSpray3.Commercial,Institutional &IndustrialPremisesandEquipment3.LowPressureSpray4.ResidentialandPublicAccessPremises4.PourLiquid5.MedicalPremisesandEquipment5.PumpLiquid6.HumanDrinkingWater Systems6.PourSolid7.IndustrialProcessWater Systems7.PlaceSolids8.MaterialPreservatives8.Mop9.AntifoulantCoatings9.Wipe10.WoodPreservatives10.Fogging11.SwimmingPools11.Brush12.AquaticAreas12.Roller13.AirlessSpray14.Flood15.Immersion16.Dip17.Soak18.Impregnated19.PressureTreatmentOctober 20079Data Needs -Brief History:AEATF I –CMA “PopendorfStudy”•Response to the 1986 U.S. EPA Antimicrobial Data Call-In;•1988 –1992 sponsored by 20 companies under the auspices ofCMA Biocides Panel•How have the data been used?–Exposure data from this study, combined with PHED data and models,enabled continued registration andre-registration of over 120antimicrobial active ingredients and many end-use products•Strengths–Provided first generic data for antimicrobials–Generic data served as the foundation for handler unit exposures•Limitations–High detection limits (0.002 to 3 μg/cm2; AEATF II target 0.003 μg/cm2)–Low number of monitoring units (min = 3)–Limited number of representative antimicrobial scenarios (applicationmethods) studied (n = 8)10Data NeedsIdentified by EPA•In various Re-Registration Eligibility Decisions issued during 2005and 2006, EPA has stated:“...the risk assessment noted deficiencies in the surrogate dermal andinhalation exposure data available from the Chemical ManufacturersAssociation (CMA) data base.Therefore, the Agency is requiringconfirmatory data to support the uses assessed with the CMA exposuredata within this risk assessment.”–PHMB.September 2005.EPA739-R-05-003–Benzisothiazoline-3-one.September2005.EPA739-R-05-007–Para-Tertiary-Amylphenol, Potassium Sodium Salt.January 2005.EPA738-R05-001–Azadioxabicyclooctane.September 2005.EPA739-R-05-010–Chlorine Dioxide and Sodium Chlorite.August 2006.EPA738-R-06-007–Pine Oil.October2, 2006.(publication numberunavailable)–Aliphatic Alkyl Quaternaries (DDAC).August 2006.EPA739-R-06-008–Alkyl DimethylBenzyl Ammonium Chloride (ADBAC).August2006.EPA7389­R-06-00911EXPOSURE DATA NEEDS (cont.)Antimicrobial exposure-related data needs havebeen clearly identified and justified by OPP/AD•Confirmatory and new data requirements indicated in many EPARegistration Eligibility DecisionDocuments(RED)•Need confirmed by the EPA’s Science Advisory Panel (SAP)•Data needs for “next generation”generic exposure database veryapparent with antimicrobial chemicalsand more pronounced thanwith most agricultural scenariosOctober 200712Antimicrobials Are Unique•Many of the exposure scenarios for antimicrobials are not sharedwithAHETF (Agricultural Handlers Exposure Task Force) (e.g., moppingorwiping, etc.)•Even similar (shared) scenarios havedifferent exposure potential asexplained later (e.g., pour liquid)•The selection process forantimicrobial surrogate active ingredients(a.i.s)to be used for generating genericdata has special considerations:–High reactivity and/or low concentrations of antimicrobials requirethat sensitive analytical methods be available for surrogatechemicals.This limits the number of a.i.sthat can be studied.•Opportunitiesfor conducting antimicrobial studies are limited–e.g., Limited access toin situlocations, limited opportunities whereselected surrogate chemicals are being usedOctober 200713Quantitative Objective•Primary quantitative objective isthe same for both Task Forces:–Reasonable (practical) estimates ofthe ‘middle’and ‘upper’values ofnormalized exposure (e.g., arithmetic mean, 95th percentile of areferencedistribution)–These values are then compared to critical toxicology endpoints for agiven unique antimicrobial chemical (i.e., risk is function of hazard &exposure)•Some users of these data might alsowish to explore the relationshipbetween exposure and the amount ofAI handled (or components suchas “duration of task”). While such relationships can alwaysbeexamined, the range of AaiHfor mostanti-microbial scenarios is toosmall to guarantee statistical power.Thus, no such objectives areformally included in the program design.October 200714AEATF Study Design Considerations•Categories of antimicrobial exposure scenarios:–Indoor studies involving simple, repetitive tasks•e.g., mop application, wipe application, aerosol application,immersion/dip/soak, spray application, liquid pouring, solid pouring•some of these scenario tasks are similar for both Task Forces, e.g.,open pouring of liquids, albeit with different environmental andproduct use conditions, i.e., outdoors versus indoors, large versussmall quantities•commonality of environmental and task conditions permits the useofsimulated environments and semi-scripted (or synthetic) monitoringevents to ensure diversity–Indoor studies involving more complex, multi-tasking•e.g., wood treatment, metal working fluids•unique environmental and task conditions requirein situstudies,albeit with semi-scripted study designs to ensure diversityOctober 200715Application Scenario has the GreatestImpact on Exposure•Many AEATF scenarios (e.g., mopping, wiping) occurin various indoor locations (e.g., hospitals, hotels,residences), wherein repetitive tasks are performed,with a similar range of environmental conditions(surface types and configurations, temperature,humidity, air exchange rate)•The existing CMA antimicrobial exposure monitoringstudy involving nine application methods (largelyrepetitive task scenarios) concluded that:– “the hypothesis was validated that exposures for a givenapplication method would not vary significantly among enduse settings;therefore, theapplication method is a greaterdeterminant of exposure than is the setting”October 200716Environmental andProduct Use Considerations•Reasons for proposed semi-scripted,simulated AEATF study designs:–Existing antimicrobial exposure data have a large number of non-detectson inner dosimeters, despite upper-bound usage; therefore it is notfeasible to use significantly less product to extend the range lower.–Limiting upper-bound usage are ergonomic considerations e.g., heatstress, limits of endurance and the practical upper limits of area coveredby an individual using hand-held equipment in a day.These factors takentogether dictate a range of ~5-fold for amount used in a particular usescenario.–The large number of non-detects on inner dosimeters further dictates thatto meaningfully estimate dermal exposure, the outer dosimeter valuesmust be used with an appropriate data-derived clothing penetration factor.October 200717‘Sampling’Methods•The most recent HSRB issue is the necessity of incorporating randomsampling in the program design.–This requires careful consideration of the appropriateness, practical feasibility, andcost implicationsfor AEATF studies.•Very large monitoring costs result in relatively small numbers of monitoringevents per scenario (e.g., 15-20)•As much diversity as possible is needed among the set of monitoring events•Sampling is not from an existing population of handler-days–Synthetic handler-days in simulated environments are used to obtain a broadrepresentation offuture exposure conditions.–Adiverse selection of volunteersare needed perform scenario-related tasks–Diversity is also (potentially) increasedby using multiple experimental locations(e.g., buildings & monitoring dates)•This is viewed as a set of synthetic handler-days that represent futureexposures under a set of diverse conditionsOctober 200718Random Sampling•Issue: Should subjects (and even buildings used forsimulated environments) be a probability sample?–Is there much advantage in a small random sample of subjects from alocalized population when the environments and monitoring conditionsare synthetic?–Random + SyntheticÆSynthetic–Listing activities are costly and random sampling could result in lesssubject diversity–Increased time required for conduct of random sampling-based studies19Random Sampling•Incremental cost and time requirements versus realizedbenefits•Previous 875-series guideline cost (study phase only) = 15K perME•Previous 875-series guideline total cost (includes analytical methoddevelopment, database development, quality assurance,development of SOPs, legal and program management costs,etc.)= 30K per ME•Revised purposive-diversity based sampling total cost = 45K perME•Random sampling based total cost = 63K per ME20Participation/Volunteer Rates•Review of previousstudies and task force expertise suggests thatsite/subject participation rates (from the entire population) would beextremely small–For example, less than 5% response rate was observed forpotential study site selection in previous CMA study.This lowresponse rate was also observed in a recently conducted AEATFsurvey re: information and cooperation for the brush/roller “paintingscenario study.•Even if a random sample of subjectswere desirable, small participationrates and self-selected volunteers lessen its ability to represent thesubject population•In addition, ethical issues arisewhen incentives are provided toovercome refusal to participateOctober 200721Purposive ‘Sampling’is a Commonly EmployedCharacteristic of Regulatory Studies•Exposure monitoring studies are typically not designedas random samples for cost and other practical reasons(time requirement, response rate issues).•Purposive-type (non-random sampling-based) studieshave routinely served as the basis for applied pesticideexposure and risk analyses (worker and consumer)conducted by EPA, CA EPA, PMRA, Europeanregulatory authorities and the regulated community overthe past 30 years.•EPA 875 Series and OECD exposure monitoringguidelines support purposive sampling study designs.October 200722Purposive Studies:Role in Regulatory AgencyRisk Analysis & Decision-Making•Purposive sampling has often been necessary in exposuremonitoring studies for regulatory purposes:–Precedence (purposive-type pesticide exposure monitoring studies):•CA DPR sponsored-studies measuring worker exposure•Studies conducted in Europe•Industrial hygiene studies sponsored by OSHA, NIOSH and privateindustry•Pesticide registrant-sponsored studies measuring worker exposure•But, for large scale studies and surveys, probability-basedsampling is necessary:•National Human Exposure Assessment Survey (NHEXAS)•Product use and activity pattern surveys (e.g., REJV, NHAPS, NOPES)•Dietary intake surveys (e.g., USDA’s CSFII)October 200723Re-Cap of Study Monitoring Methodsand Design Elements•Studies will be conducted in accordance with U.S. EPA GLPs, 875 SeriesGuidelines, and regulations providingfor the protection of human subjectsinvolved in research, 40 CFR Part 26•Protocols are also consistent with OECD guidelines and are reviewed by EUcompetent authorities•Key antimicrobial study design considerations:–Allocation of resources to address diverse array of use patternsandapplication methods–Scenarios often involve indoor environments–Some scenarios involve handling small amounts (e.g., mopping, aerosolspraying)–Use of surrogate a.i.swith analytical methods that minimize non-detects–Use of semi-scripted tasks in an appropriate indoor location provides ameans of ensuring diversity–Low site/participant response rate requires substantial effort to achievedesired diversity and sample size24