1

Tim Leighton

Kelly Sherman

Office of Pesticide Programs

Jonathan Cohen, PhD

ICF International

January 17, 2013

EPA Review of Completed 

AEATF II Liquid Pour Study

Dermal and inhalation monitoring of 

Workers pouring a liquid antimicrobial product 

from various size containers packaged in 

conventional and reduced-splash containers
2

Organization of Presentation

 Science Assessment

 Ethics Assessment

2
Overview of Science Assessment

 Study Scope & Basics

 Study Objective

 Responsiveness to EPA and HSRB Comments

 Protocol Deviations

 Sectioning of WBD (Inner & Outer)

 QA/QC Results

 Summary of Key Study Parameters

 Statistical Analysis (3 main issues to highlight) 

 Conclusions 

3
Scope of Liquid Pour Scenario

 One of 17 AEATF II exposure scenarios

 Includes pouring liquids indoors using

 Conventional pour (CP) containers

 Reduced-splash (RS) or “no glug” containers 

 Various size product & receiving containers

 Excludes applying treatment solution

4
Liquid Pour Study: Basics

 Monitoring was conducted in 2 rooms in a laboratory in 

Concord, Ohio – each subject only monitored once for 

conventional and the same subject once for reducedsplash (two distinct monitoring sets)

 To ensure diversity of individual exposures, one 

enrolled subject was assigned to each of six 

“Monitoring Events” (ME) in a group, defined by the 

size of the product container (3 groups x 6 ME/group 

= 18 ME)

 Also varied: receiving container type, height, use of 

measuring cup

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Liquid Pour Study: Basics (continued)

 Monitored dermal and inhalation exposure of 6 subjects 

in each of 3 groups (total of 18 subjects)

 Conventional containers used DDAC

 Reduced-splash containers used ADBAC

 Same subject poured both DDAC and ADBAC 

 Subjects wore outer/inner dermal exposure dosimeters:

 Long pants, long-sleeved shirt, and no gloves

 Whole body dosimeters (WBD) underneath clothing

 Subjects also wore OSHA Versatile Sampler (OVS) tubes

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7

Group Container Type Product 

Container Size

Number of 

Product 

Containers Poured 

per ME

Receiving 

Container

1a

Conventional (CP) [n=3] 24, 32, 64 oz 10 32 oz spray 

bottles

Reduced-splash (RS) [n=3] 64 oz 15

1b

Conventional (CP) [n=3] 24, 32, 64 oz 10 2 gallon 

buckets

Reduced-splash (RS) [n=3] 64 oz 15

2

Conventional (CP) [n=6] 128, 202, 256 oz 10 2 or 4 gallon 

buckets, or 

50 gallon 

troughs

Reduced-splash (RS) [n=6] 96, 128, 180 oz 15

3

Conventional (CP) [n=6] 5 gallons 4 50 gallon 

troughs

Reduced-splash (RS) [n=6] 6

To view more details on who poured what, see EPA science review (Table 2) and the AEATF II study report 

(Tables 7 & 8, pages 85 & 86 list the specific containers assigned to each of the individual 18 MEs).
Using a measuring cup

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Pouring into spray bottle

9
Pouring into 4 gallon bucket

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Pouring directly into trough

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Pouring from conventional 5 gal bucket

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Pouring from reduced splash 5 gal bucket

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Study Objective

Liquid pour protocol’s stated objective:

“...sample estimates of the arithmetic mean 

and 95

th percentile of normalized exposure 

are accurate to within 3-fold 95% of the 

time.”

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Responsiveness to EPA & HSRB Comments

 Many recommendations were provided by EPA & 

HSRB to improve clarity and design such as 

random procedures, design limitations, etc (too 

many to list – see EPA review Section 1.3.1) 

 AEATF II added clarifications and modifications to 

EPA’s satisfaction (detailed AEATF II responses 

and changes to protocol in EPA review Section 

1.3.1)

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Protocol Deviations

 9 reported protocol/SOP deviations, including

 Bathroom scale not calibrated (SOP)

 Hand wash 400 ml instead of 500 ml, etc.

 The deviations in the study do not affect the 

scientific validity of the use of the exposure 

results

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Sectioning of WBD (inner & outer)

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Rear Torso

Front Torso

Upper Leg

Lower leg

Upper Arm

Lower Arm
QA/QC Results

Sample LOQ

Air 10 ng

Neck/face 50 ng

Hands 0.8 ug

WBD sections 3 ug

 Controls

 All lab and field blanks were < LOQ

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 Laboratory Recoveries

 Individual recoveries ranged from 75 to 116%

 Field Recoveries

 Mean recovery for all samples ~90 to 100%

 Samples outside 70-120% were 64, 67, 174, 178

 Field recoveries were used to correct field samples (dosimeters)
Parameter Low High Mean

CP Pounds AI Handled 0.004 0.27 0.16

RS Pounds AI Handled 0.004 0.26 0.14

CP Duration (min) 3 14 8

RS Duration (min) 8 22 13

CP Gallons Poured ~0.3 20 NA

RS Gallons Poured ~0.5 30 NA

Summary of Liquid Pour Study Parameters

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Statistical Analysis–Unit Exposures (UE)

 3 methods were used to estimate UEs

 Empirical estimates

 Simple random sample (SRS)

 Mixed model

 Mixed model selected to best represent the 

UE results

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Three Data Issues to Highlight

(1) EPA identified 3 rather than 2 distinct 

exposure scenarios

(2) Results are atypical for clothing 

configurations

(3) Negative slope for dermal exposure

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Issue #1: Three Exposure Scenarios

 AEATF II designed the liquid pour scenario for 2 distinct 

exposure scenarios:

 Conventional pour (CP)

 Reduced splash (RS)

 EPA separated the results into 3 distinct exposure scenarios:

 Bottle (spray bottle used as receiving container)

 Conventional pour (CP) into non spray bottles

 Reduced splash (RS) into non spray bottles

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3 Exposure Scenarios (Issue #1 continued)

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Group Conventional Reduced-splash

1a

(bottle)

√

N=3

√

N=3

1b √

N=3

√

N=3

2 √

N=6

√

N=6

3 √

N=6

√

N=6
Justification for 3 Exposure Scenarios (Issue #1 continued)

 Pouring into “bottles” is a logical and 

statistically justified unit exposure

 Logical – spray bottles are commonly used 

for label disinfectant claims

 Statistical – 1aCP and 1aRS were not 

significantly different; bottle and other 

receiving containers were significantly 

different for CP & RS

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Issue #2: Results Are Atypical for Clothing Configurations

 3 clothing configurations

 Long sleeves, long pants, no gloves (Long-Long)

 Short sleeves, long pants, no gloves (Long-Short)

 Short sleeves, short pants, no gloves (Short-Short)

 UE for mixed model mean is greatest for Long-Long

 CP: Long-Long = 10, Long-Short = 9.9, Short-Short = 9

 Illogical; statistical “Quirk” of mixed model

 Hand exposure accounts for majority of dermal exposure

 EPA will use only the results of Long-Long

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Issue #3: Negative Slope for Dermal Exposure

 Log-Log-Linear Regression Model: 

Log(exposure) = group intercept + slope × log(AaiH) + error

 If slope = 1, arithmetic mean exposure is proportional to AaiH

 If slope = 0, exposure does not vary with AaiH (physically unrealistic)

 If slope < 0, exposure decreases with AaiH (physically unrealistic)

 Slope for Long Dermal: -0.3 (-1.1, 0.5)

 95% confidence that if log-log-linear model is true, slope < 1

 Although the estimated slope is negative, this is physically unrealistic. The 

statistical analysis does not “prove” that the actual slope is negative.

 Although the statistical test rejects a slope of 1 in favor of a slope of 0 

(independence), independence is physically unrealistic. The statistical analysis 

does not “prove” that the actual slope is zero. We can only say that with 95% 

confidence the slope is less than 1.

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Issue #3: Negative Slope for Dermal Exposure (cont)

 Assume same slope, different intercepts:

 For Bottle, uses all 36 MEs instead of 6 MEs

 Long Dermal slope: -0.3 (-1.1, 0.5)

 Assume different slopes, different intercepts, and 

different variances (Appendix A Table 24):

 Long Dermal Bottle slope: -3.5 (-13.5, 6.6)

 Long Dermal CP slope: -0.1 (-1.1, 1.0)

 Long Dermal RS slope: -0.6 (-1.9, 0.8) 

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Application of unit exposures

 EPA will still normalize the liquid pour data by AaiH

 Logically each drip and/or spill on the hands is a given volume 

of liquid and the exposure is dependent upon the concentration 

of AaiH in that drip and/or spill

 AaiH = volume poured x concentration

 This approach is health-protective: Threshold of AaiH that 

under-/over-predicts exposure can be used for characterization 

of the limitations in the data

 The study could not be designed to vary the concentration of AaiH

to further investigate this assumption because higher 

concentrations of AaiH would require the use of chemical resistant 

gloves

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Unit Exposures (UE) for Liquid Pour Scenario

Exposure Route Subgroups

Results of Mixed Model

Arithmetic Mean 95th Percentile

Dermal 

(mg/lb ai)

Bottle 299 1110

Conventional Pour 10 36.9

Reduced Splash 3.1 12

Inhalation 

Bottle

0.00022 mg/lb ai 0.00063 mg/lb ai

0.0011 mg/m3/lb ai 0.0031 mg/m3/lb ai

0.000046 8-hr TWA mg/m3/lb ai 0.00013 8-hr TWA mg/m3/lb ai

Conventional Pour

0.00188 mg/lb ai 0.00531 mg/lb ai

0.0174 mg/m3/lb ai 0.0508 mg/m3/lb ai

0.000235 8-hr TWA mg/m3/lb ai 0.000664 8-hr TWA mg/m3/lb ai

Reduced Splash

0.00093 mg/lb ai 0.00262 mg/lb ai

0.0049 mg/m3/lb ai 0.0143 mg/m3/lb ai

0.000116 8-hr TWA mg/m3/lb ai 0.000328 8-hr TWA mg/m3/lb ai
Was the Sample Large Enough?

 The results of the 3-fold relative accuracy goal (K ≤ 3) for 

the mixed-model results are as follows:

 For inhalation K < 3 for Bottle, CP, and RS

 For dermal K < 3 for CP and RS

 For dermal K = 3.1 to 3.6 for Bottle

 EPA will use all of the results from this study now

 If Bottle were to be combined with CP & RS, disinfectant uses would be 

under-estimated and all other uses would be over-estimated

 Once AEATF II planned studies are completed, there may be a need to 

refine the Bottle unit exposure with additional monitoring

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Study Design Limitations 

 Indoor versus outdoor

 The impact on the exposures are unknown; most AM uses indoors

 Janitors versus consumers

 The impact on the exposures are unknown; janitors are not expected to be 

more adapt at pouring (not a highly skilled task)

 Bottle sample size

 Relative accuracy goal between 3 and 4

 Normalizing dermal exposure by AaiH

 Threshold of AaiH characterizes when exposures are over- under-estimated

 Long-Long clothing configuration only

 Minimal impact; hand exposure is driving dermal exposure

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EPA Plan for Use of Liquid Pour Study Data

 Use unit exposure data generically to estimate 

potential exposure to low- or moderate-volatility 

pesticides packaged as liquids for open pouring

 Assess disinfectant & sanitizer uses that include spray 

bottle-type of applications using the Bottle UEs

 Assess most liquids using conventional pour UEs

 Provide EPA risk managers with options for 

engineering controls (i.e., reduced splash containers)

 Use chemical-specific hazard and dermal absorption 

data to estimate internal dose and risk

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Conclusions

 Study results are sufficiently sound to support estimates 

of dermal and inhalation unit exposures

 An adequate number of samples were collected for CP & 

RS; and therefore, no additional MEs are required 

 Additional monitoring of the Bottle may be warranted to 

refine the estimates

 Recalculate the inhalation unit exposures using the 

multiple imputation method for non detected samples

 Data limitations must be acknowledged in assessments

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Science Presentation– Extra Slides

34
Compare Groups

Comparison P-value for Long 

Dermal

P-value for 

Inhalation Conc

1aCP vs. 1aRS 0.88 0.73

All four group means 

equal for CP (1aCP = 

1bCP = 2CP = 3CP)

< 0.01 0.19

1bCP = 2CP = 3CP 0.02 0.89

All four group means 

equal for RS (1aRS = 

1bRS = 2RS = 3RS

< 0.01 0.01

1bRS = 2RS = 3RS < 0.01 0.45

1aCP = OtherCP < 0.01 0.03

1aRS = OtherRS < 0.01 < 0.01

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Unit Exposure Calculations

 Normalized Exposure Mixed Model: Assume slope = 1 

for the log-log-linear model

 ln (Exposure) = μ(group) + 1 × ln (AaiH) + Error

 Exposure = eμ(group) + Error × AaiH

 Exposure / AaiH = eμ(group) + Error 

 Unit Exposure = Arith Mean [Exposure / AaiH] = K

 Exposure = K × AaiH (Green Line)

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Linear Mixed Model

 Linear Mixed Model: General case means slope ≠ 1 

for the log-log-linear model

 ln (Exposure) = μ(group) + slope × ln (AaiH) + 

Error

 Exposure = eμ(group) + Error × AaiHslope

 Exposure / AaiHslope = eμ(group) + Error 

 Arith Mean [Exposure / AaiHslope ]= L

 Exposure = L × AaiHslope (Brown Curve)

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Threshold Calculation

 Assume linear mixed model & slope < 1

 Unit Exposure Formula overestimates if

 K × AaiH > L × AaiHslope Or

 AaiH > {L / K)}1/(Slope – 1)

 Threshold = {L / K)}1/(Slope – 1)

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Threshold for Bottle

39
Threshold for Conventional

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Threshold for Reduced Splash

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Ethics Assessment

AEATF II Liquid Pour Study

Kelly Sherman

Office of Pesticide Programs

January 17, 2013

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Timeline

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 Protocol reviewed by the HSRB in October 2011

 Recruiting and subject enrollment began in January 

2012

 Monitoring took place in February 2012

 Submitted to EPA in August 2012
Recruiting

 Subjects were recruited through newspaper 

advertisements in 3 newspapers

 Interested callers were phone-interviewed to determine 

if they met the inclusion criteria, and if so, they were 

scheduled for an informed consent meeting

 Recruiting was consistent with the protocol

 The process was equitable, and free of coercion or 

undue influence

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Consent Process

 Initial consent meetings were held with small 

groups of potential subjects

 Study procedures explained; inclusion/exclusion criteria 

described; consent form read; questions answered

 If a subject met the inclusion/exclusion criteria 

and was still interested in enrolling, he/she met 

one-on-one with the study director and then was 

asked to sign the ICF

 Followed protocol; no deviations related to 

consent

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Subject Demographics

 18 subjects monitored

 15 male, 3 female

 All subjects preferred to speak in English

 Mean age: 48 years (range: 19-65)

 Mean years of experience: 12 

(range 1-35 years)

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Preparation for Monitoring

 Hands/face examined

 Female subjects self-administered a 

pregnancy test

 Researchers helped each subject put on 

dosimeter and air-sampling pump

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Monitoring

 Conducted without noteworthy incident

 No instances of subjects reporting that 

they felt sick or injured

 Procedures in protocol and SOPs were 

followed

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Responsiveness to EPA & HSRB

Protocol Reviews

 Edits to improve the clarity of the Informed Consent 

Form

 Advertisements should be placed in newspapers 

targeting different demographic groups

 Add statement to the consent form that explains to 

subjects that if they experience a skin or eye 

reaction, they should contact the study director

 Develop procedures for handling such a call

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IRB Oversight

 Initial protocol approved by IIRB in August 2011

 Revised protocol approved by IIRB in January 

2012

 Investigators complied with IIRB procedures and 

requirements

 5 amendments approved by IIRB

 5 deviation reports reviewed and acknowledged 

by IIRB

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Amendments and Deviations

 None of the reported amendments or 

deviations were ethically significant

 No unreported deviations were noted

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Completeness of Documentation

 IIRB correspondence records are 

complete and well-indexed

 Requirements of §26.1303 are satisfied

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Substantive Acceptance Standards

 40 CFR §26.1703

 Prohibits reliance on data involving intentional exposure of 

pregnant or nursing women or of children

 40 CFR §26.1705

 Prohibits reliance on data unless EPA has adequate 

information to determine substantial compliance with 

subparts A through L for 40 CFR 26

 FIFRA §12(a)(2)(P)

 Makes it unlawful to use a pesticide in human tests without 

fully informed, fully voluntary consent

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Findings

 All subjects were at least 18; pregnant or nursing 

women were excluded; all females were tested for 

pregnancy

 No noteworthy deficiencies in the ethical conduct of 

the research

 Protocol was faithfully executed, and amended when 

needed; minor deviations did not compromise safety 

or consent of subjects

 Subjects were fully informed and their consent was 

fully voluntary, without coercion or undue influence

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Conclusion

 Available information indicates that the 

AEATF II Liquid Pour Study was 

conducted in substantial compliance 

with subparts K and L of 40 CFR part 26

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AEATF II Liquid Pour Study: Charge Questions

1. Was the research reported in the Antimicrobial Exposure 

Assessment Task Force II (AEATF) completed liquid pour 

study report faithful to the design and objectives of the 

protocol and governing documents of AEATF? 

2. Has EPA adequately characterized, from a scientific 

perspective, the limitations on these data that should be 

considered when using the data in estimating the exposure 

of people who pour liquid antimicrobial pesticide products?

3. Does available information support a determination that 

the study was conducted in substantial compliance with 

subparts K and L of 40 CFR Part 26?

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