1 Tim Leighton Ke lly S herman 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 containers2 

# 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 reduced splash (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 5

# 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 67

Group Container T ype Product

Container Size Num ber 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 v** **iew more details on w**  **ho poured w hat, see EP**  **A science**  **review (** **Ta ble 2) and the**  **AE AT**  **F II**  **study r** **eport (T**  **ables 7 & 8, pages 85 & 86 list the specific containers assigned to each of the individual 18 MEs).** 

# Using a measuring cup

8

# Pouring into spray bottle

9

# Pouring into 4 gallon bucket

10

# Pouring directly into trough

11

# Pouring from conventional 5 gal bucket

12

# Pouring from reduced splash 5 gal bucket

1314



# 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.”

14

# 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)

15

# 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

16

# Sectioning of WBD (inner & outer)

17 

### Rear T **orso Front T**  **orso Upper Leg**  **Low er**  **leg Upper**  **Arm Low** **er Arm** 

# QA/QC Results **Sa mp**  **le LOQ** 

Ai r 10 ng Nec k/f ac e 50 ng Hands 0. 8 ug WB D secti ons 3 ug  

### Controls 

###  All lab and field blanks were < LOQ

18  

### 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)

### Pa **ra me**  **te r**  **Low Hi**  **gh Me**  **an** CPPo undsAIH andl ed 0. 004 0. 27 0. 16 RSPo undsAIH andl ed 0. 004 0. 26 0. 14 CPD urat io n (m in ) 3 14 8 RSD urat io n (m in ) 8 22 13 CPG al lo nsPo ured ~0 .3 20 NA RSG al lo nsPo ured ~0 .5 30 NA 

## Sum **ma ry** **o f**  **Li qui**  **d Pour**  **S tu**  **dy P**  **ar am**  **et er** 

**s**

19

# 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

20

# 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

21

# 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 22

# 3 Exposure Scenarios (Issue #1 continued)

23

**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 24

### 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 25

## 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. 26

### 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) 27

# 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 2829

**Unit Exposures (UE) for Liquid Pour Scenario Exposure Route**  **Subgroups Results**  **of Mixed Model Ar** **ithmetic Mean**  **95th Percentile** Dermal ( mg/lb ai ) Bottle 299 111 0

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/m 3/lb ai 0.0031 mg/m 3/lb ai 0.000046 8- hr TWA mg/m 3/lb ai 0.00013 8- hr TWA mg/m 3/lb ai Conventional Pour 0.00188 mg/lb ai 0.00531 mg/lb ai 0.0174 mg/m 3/lb ai 0.0508 mg/m 3/lb ai 0.000235 8- hr TWA mg/m 3/lb ai 0.000664 8- hr TWA mg/m 3/lb ai Reduced Splash 0.00093 mg/lb ai 0.00262 mg/lb ai 0.0049 mg/m 3/lb ai 0.0143 mg/m 3/lb ai 0.000116 8- hr TWA mg/m 3/lb ai 0.000328 8- hr TWA mg/m 3/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 30

# 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 31

# 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 32

# 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 33

# 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 35

# 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 = e μ (group) + Error 

### × AaiH 

##  Exposure / AaiH = e μ (group) + Error 

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

##  Exposure = K × AaiH (Green Line) 36

# 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 = e μ (group) + Error 

### × AaiH slope 

##  Exposure / AaiH slope 

### = e μ (group) + Error 

##  Arith Mean [Exposure / AaiH slope 

### ]= L 

##  Exposure = L × AaiH slope 

### (Brown Curve) 37

# Threshold Calculation  

# Assume linear mixed model & slope < 1  

# Unit Exposure Formula overestimates if  

# K × AaiH > L × AaiH slope 

# Or  

# AaiH > {L / K)} 1/(Slope – 1) 

###  

# Threshold = {L / K)} 1/(Slope – 1) 38

# Threshold for Bottle

39

# Threshold for Conventional

40

# Threshold for Reduced Splash

41

# Ethics Assessment AEATF II Liquid Pour Study

**Kelly Sherman Office of Pesticide Programs**  **January 17, 2013** 

42

# Timeline

43  

### 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

44

# 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 45

# 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) 46

# Preparation for Monitoring  

# Hands/face examined  

# Female subjects self-administered a pregnancy test  

# Researchers helped each subject put on dosimeter and air-sampling pump

47

# Monitoring  

## Conducted without noteworthy incident  

## No instances of subjects reporting that they felt sick or injured  

## Procedures in protocol and SOPs were followed

48

# 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 49

# 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 50

# Amendments and Deviations  

# None of the reported amendments or deviations were ethically significant  

# No unreported deviations were noted

51

# Completeness of Documentation  

# IIRB correspondence records are complete and well - indexed  

# Requirements of § 26.1303 are satisfied

52

# 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 53

# 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 54

# 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

55

# 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? 56