Page 1 of 8 Ha

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON D.C., 20460

OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION

March 18, 2011

MEMORANDUM

SUBJECT: Materials for Review by the Human Studies Review Board for its

April 13

‐ 14, 2011 Meeting

TO: Jim Downing

Designated Federal Official

Human Studies Review Board

Office of Science Advisor (8105R)

FROM: William L. Jordan

Senior Policy Adviser

Office of Pesticide Programs (7501P)

This memorandum describes the materials that the Environmental Protection Agency’s

(EPA’s) Office of Pesticide Programs is providing for review by the Human Studies Review Board

(HSRB or Board) at the meeting scheduled for April 13

‐ 14, 2011. At this meeting, EPA will ask

the Board to address scientific and ethical issues surrounding these three topics, each of which

is discussed further below:

1. A report from the Agricultural Handler Exposure Task Force (AHETF) of completed

research monitoring the exposure of workers applying pesticide sprays to orchard and

trellis crops with open

‐ cab airblast equipment.

2. A report from the Antimicrobial Exposure Assessment Task Force II (AEATF) of

completed research monitoring the exposure of professional janitorial workers when

wiping indoor surfaces with liquid antimicrobial pesticide.

3. A published report (Gulson et al. 2010) of an intentional exposure human study

measuring dermal absorption of zinc oxides contained in sunscreens.Page 2 of 8 1. Completed AHETF research on exposure of workers applying pesticide sprays using

open

‐ cab airblast equipment.

In October 2008, the HSRB reviewed three protocols for research to measure the levels

of dermal and inhalation exposure received by pesticide applicators who spray pesticides with

open cab airblast equipment. Following favorable HSRB reviews and after revisions to address

EPA, HSRB, and California Department of Pesticide Regulation (CDPR) comments, this research

was conducted in summer 2009. The completed reports and monograph were submitted to

EPA in November 2010.

If the data for the Open Cab Airblast Applicator Scenario are accepted by EPA, the

resulting data will be added to the Agricultural Handler Exposure Database (AHED ® ). EPA

intends to use these data generically to estimate daily dermal and inhalation exposures of

workers who treat agricultural crops with conventional pesticides using open

‐ cab airblast

equipment. If considered appropriate, data from this scenario addressing exposures from open

cab airblast pesticide applications will be combined with data from an appropriate

mixing/loading scenario to estimate exposures of workers who both mix/load and apply.

Because this research involved scripted exposure, it meets the regulatory definition of

“research involving intentional exposure of a human subject” and thus is covered by subparts K

and L of EPA’s amended rule for the protection of human subjects of research. The rule at 40

CFR §26.1303 requires the submitter of reports of completed human research to document its

ethical conduct. The rule at 40 CFR §26.1602(a) requires EPA to “review the material submitted

under §26.1303 and other available, relevant information, and [to] document its conclusions

regarding the scientific and ethical conduct of the research.” The rule at 40 CFR §26.1602(b)

further requires EPA to submit the data and EPA’s review to the HSRB if it decides to rely on the

data.

EPA has reviewed the AHETF completed study reports, IIRB correspondence reports, and

monograph, and has concluded that the research provides scientifically sound, useful

information, and was conducted in substantial compliance with the ethics requirements at 40

CFR part 26, subparts A through L.

Charge Questions :

a. Was the research reported in the Agricultural Handler Exposure Task Force (AHETF)

completed monograph report and associated field study reports faithful to the

design and objectives of the protocol, SOPs, and governing documents?

b. Has EPA adequately characterized, from a scientific perspective, the limitations on

these data that should be considered when using the data in estimating exposure of

those who apply pesticides with open cab airblast equipment?

c. Does available information support a determination that the studies were

conducted in substantial compliance with subparts K and L of 40 CFR Part 26?Page 3 of 8 EPA is providing for HSRB review the following documents concerning the AHETF OCAB

completed studies and monograph:

a. EPA Reviews

1. EPA Science Review of OCAB Completed Studies

2. EPA Science Review of OCAB Monograph

3. EPA Ethics Review of OCAB Completed Studies

b. Background Documents

1. AHE62

a. AHE62 Final Cluster Report

b. AHE62 IIRB Correspondence Report

c. AHE62 Excel Files

2. AHE63

a. AHE63 Final Cluster Report

b. AHE63 IIRB Correspondence Report

c. AHE63 Excel File

3. AHE64

a. AHE63 Final Cluster Report

b. AHE63 IIRB Correspondence Report

c. AHE63 Excel File

4. AHE07 (Pre

‐ rule Study)

a. AHE07 Amended Summary Report FINAL

b. AHE07 Field Rpt Open

‐ Cab Airblast

c. AHE07 Analytical Phase Report

d. AHE07 Excel File

5. Monograph

a. OCAB Final Monograph Report (MRID 48326701)

b. Final MU Selection Plan OCAB 7

‐ 21

‐ 08

c. OCAB Monograph Excel Files

1. OCAB Data with MEA

‐ QAd FINAL 9

‐ 15

‐ 10

‐ to EPA 11

‐ 18

‐ 10

2. OCAB

‐ before MEA

‐ QAd

‐ FINAL 9

‐ 14

‐ 10 & 10

‐ 4

‐ 10

‐ to EPA 11

‐ 18

‐

10

d. OCAB Monograph SAS Files

1. Eval_OCAB.sas

2. Macro_GetEmpStats.sas

3. Macro_NormScores.sas

4. Macro_ObjEval_OCAB.sas

5. Macro_TestVCs_OCAB.sas

6. MakeSet_OCAB.sas

7. OCAB Derm Inh

‐ no Hats

‐ no MEA

8. OCAB Derm only

‐ wi Hats

‐ no MEA

9. OCAB Derm only

‐ wi Hats

‐ wi MEAPage 4 of 8 6. Reference Files

a. AHETF SOP Manual for AHE62

‐ AHE63

‐ AHE64 effective February 2009

b. AHETF Governing Document Version 2

‐ August 2010

c. EPA Science & Ethics Review Protocol AHE62 (9

‐ 23

‐ 08)

d. EPA Science & Ethics Review Protocol AHE63 (9

‐ 23

‐ 08)

e. EPA Science & Ethics Review Protocol AHE64 (9

‐ 23

‐ 08)

f. HSRB Report of Oct 2008 Meeting

‐ Protocols AHE62, AHE63, AHE64

g. IIRB, Inc. Human Research Protection Plan 11

‐ 3

‐ 10

h. IIRB, Inc. Current Membership Roster 11

‐ 3

‐ 10

2. Completed AEATF research on exposure of professional janitorial workers when

wiping indoor surfaces with an antimicrobial pesticide.

In April 2008, the HSRB reviewed a protocol for research to measure the dermal and

inhalation exposure of professional janitorial workers as they wiped indoor surfaces with a

liquid antimicrobial pesticide product. Following favorable HSRB review and after revisions to

address EPA, HSRB, and CDPR comments, this research was conducted in summer 2009. The

completed report was submitted to EPA in January 2011.

If the data for this scenario are accepted by EPA, the resulting data will be posted to the

Biocide Handlers Exposure Database (BHED®). EPA intends to use these data generically to

estimate daily dermal and inhalation exposures of those who clean indoor surfaces with

antimicrobial pesticides using a trigger

‐ spray bottle and wipes or ready

‐ to

‐ use wipes.

Because this research involved scripted exposure, it meets the regulatory definition of

“research involving intentional exposure of a human subject” and thus was covered by subparts

K and L of EPA’s amended rule for the protection of human subjects of research. The rule at 40

CFR §26.1303 requires the submitter of reports of completed human research to document its

ethical conduct. The rule at 40 CFR §26.1602(a) requires EPA to “review the material submitted

under §26.1303 and other available, relevant information, and [to] document its conclusions

regarding the scientific and ethical conduct of the research.” The rule at 40 CFR §26.1602(b)

further requires EPA to submit the data and EPA’s review to the HSRB if it decides to rely on the

data.

EPA has reviewed the AEATF Mop Scenario report and supplements and has concluded

that it provides scientifically sound, useful information, and was conducted in substantial

compliance with 40 CFR part 26, subparts A through L.

Charge Questions :

a. Was the research reported in the Antimicrobial Exposure Assessment Task Force II

(AEATF) completed wipe study report faithful to the design and objectives of the

protocol and governing documents of AEATF?Page 5 of 8 b. Has EPA adequately characterized, from a scientific perspective, the limitations on these

data that should be considered when using the data in estimating exposure of those

who clean indoor surfaces with antimicrobial pesticides using a trigger

‐ spray bottle and

wipes or ready

‐ to

‐ use wipes?

c. Does available information support a determination that the study was conducted in

substantial compliance with subparts K and L of 40 CFR Part 26?

EPA is providing for HSRB review the following documents concerning the AEATF wipe

completed study and monograph:

a. EPA Reviews

1. EPA Science Review of AEATF Wipe Completed Study

2. Appendix A

– Statistical Review of AEATF Wipe Study Using Trigger Spray and

Wipe

3. Appendix B

– Statistical Review of AEATF Wipe Study Using Ready

‐ to

‐ Use Wipes

4. EPA Ethics Review of AEATF Wipe Completed Study

b. Background Documents

1. Final Report AEATF Wipe Study 070264

‐ 1

‐ 21

‐ 2011 signed

2. EPA Science and Ethics Review of Wipe Study Proposal

3. HSRB Report of April 2008 meeting

– reviewing Mop and Wipe Study Proposals

4. AEATF II SOPs (7

‐ 15

‐ 09)

a. SOP Table of Contents_Effective 071509

1A.1 Organizational Structure

1B.1 Personnel Responsibilities

1C.1 Study Director Selection

1D.1 Inspection of AEATF II Facilities Data

1E.0 Communication Directives

1F.0 Adverse Effects Reporting

2A.1 Study Authorization and Approval

2B.1 Study Number Assignment

2C.1 Protocol Design and Preparation

3A.1 SOP Preparation, Approval, Maintenance, and Distribution

3B.1 Use of AEATF II and Contractor SOPs

4A.1 Study Report Preparation

5A.1 QA Personnel Administration.pdf

5B.1 AEATF II QAU Responsibilities

5C.1 QAU Records

5E.1 Protocol and Amendment Review

5F.1 Inspection Audit types and Frequency

5G.1 Study Inspections

5H.1 Data Audits

5I.1 Facility Inspections

5J.1 Report AuditsPage 6 of 8 5K.1 Inspection Report Distribution

6A.1 Storage of Raw Data

6B.1 Access to Archived Data

6C.1 Specimen and Retention Sample Storag

7A.1Test, Control, and Reference Substances Receipt and Shipment

7B.1 Test, Control, and Reference Substances Labeling

7C.1 Disposal of Test, Control, and Reference Substances

7D.1 Test, Control, and Reference Substances Chain of Custod

7E.1 Test and Reference Substance Analysis

8A.2 Whole Body Sampling

‐ Inner, Outer and Socks Dosimeters

8B.3 Hand Wash Samples

8C.2 Dermal Face Neck Wipe Samples

8D.1 Collection of Air Samples using OVS Tubes

8E.1 Fortification of Matrix Samples

8F.1 Sample Identification

8H.0 Pre

‐ Washing Dosimeter Garments

9A.1Body Surface Areas

9B.3 Field Fortification Adjustment Factors

9C.1 Numerical Formatting and Handling

9D.1 Analytical Method Number Assignment

9E.1 Raw Data Collection

9F.1 Data Corrections

9G.1 Raw Data Handling

9H.1 Preparation of True Copies

9I.1 Analytical Method Development and Validation

9J.1 Storage Stability

10A.1 Rotameter Calibration

10B.1 Packing, Handling and Shipping of Samples

10C.1 Worker and Study Observations

10D.1 Application Equipment Operation Verification

10E.1 Worker Sample Collection Sequence

10F.1 GPI Electronic Digital Flow Meter

10G.1 Personal Air Sampling Pump Calibration

11A.1 Pregnancy Testing and Nursing Status

11B.1 Heat Stress

11C.1 Emergency Procedures

11E.0 Heat Stress Management for Observational Worker Expos

11F.0 Adverse Events Reporting to IRB

5. IIRB, Inc. Human Research Protection Plan 11

‐ 3

‐ 10

6. IIRB, Inc. Current Membership Roster 11

‐ 3

‐ 10Page 7 of 8 3. A published report (Gulson et al. 2010) of an intentional exposure human study

measuring dermal absorption of zinc oxides contained in sunscreens.

EPA is interested in many aspects of nanotechnology, which presents opportunities to

create new and better products and improve assessment, management, and prevention of

environmental risks. There are, however, unanswered questions about the impacts of

nanomaterials on human health and the environment. One of the uncertainties concerns

dermal absorption of nanoparticles across intact skin. There is debate in the scientific

community as to whether nanoparticles are likely to penetrate the skin barrier upon dermal

contact. The results of in vitro studies using animal and human skin in the literature indicate

that small amounts of different kinds of nanoparticles may penetrate skin in some cases.

However

, in vitro dermal penetration data alone is of limited utility to the Agency in the

absence of evidence that the in vitro studies are predictive of in vivo results. The Gulson et al.

(2010) study investigates dermal exposure of human volunteers to ZnO nanoparticles in

sunscreen formulations. This study indicates that small amounts of Zn from sunscreens

containing nanoscale ZnO particles are absorbed into the bloodstream and eliminated in the

urine. It quantifies this amount as approximately 0.001%. This result in humans in the Gulson

study in vivo is similar to in vitro studies with human skin that have been published in the

literature. Although the Agency is aware that nanoparticle physicochemical properties, skin

treatment conditions, and formulations may differently influence dermal penetration, this

corroboration of in vitro and in vivo dermal penetration results increases the Agency's

confidence in the in vitro data indicating penetration of small amounts of other kinds of

nanoparticles and/or ions from nanoparticles. More importantly, it indicates to the Agency that

dermal risk assessments for occupational and residential dermal exposures to nanoparticles

should be considered, given evidence of penetration of small amounts of particles and/or ions

from nanoparticles both in vitro and in vivo.

Charge Questions :

a. Is the Gulson et al. (2010) study scientifically sound, providing reliable data?

b. If so, is the Gulson et al. (2010) study relevant for qualitative use in support of an

assessment of the absorption of metal oxide nanoparticles through the skin?

c. Is there adequate information to determine that the Gulson et al. (2010) study was

conducted in substantial compliance with procedures at least as protective as those in

subparts A

‐ L of EPA’s regulation at 40 CFR part 26?

EPA is providing for HSRB review the following documents concerning Gulson et al.

(2010):

a. EPA Reviews

1. EPA Science Review of Gulson et al 2010

2. EPA Ethics Review of Gulson et al 2010Page 8 of 8 b. Background Documents

1. Gulson et al 2010 (MRID 48387301)

2. Supplement 1

– Excerpt from Australian National Statement on Ethical Conduct

in Human Research 2007