Page 1 of 4 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF PREVENTION, PESTICIDES AND

TOXIC SUBSTANCES

December 5, 2008

MEMORANDUM

SUBJECT : Ethics Review of Zinc Pyrithione Worker Exposure Study

TO: Timothy Leighton

Antimicrobial Division

FROM: Kelly Sherman

Human Research Ethics Reviewer Office of Pesticide Programs

REF: Wu, M. (2005) Assessment of Potential Inhalation and Dermal Exposure to Zinc Pyrithione During Outdoor Painting of Ship Hulls with Commercial Antifouling Paint Containing ZINC OMADINE ® . Unpublished study prepared by Arch Chemicals Inc. under Study Identification No. BWE03001. 630 p. (MRID 46707001)

I have reviewed the referenced document and determined that all applicable requirements of EPA’s Rule for the Protection of Human Subj ects of Research (40 CFR Part 26) have been

satisfied.

Summary Characteristics of the Research

In this research, 31 dry dock workers were monitored as they performed tasks associated with the commercial application of antifouling paint to the hulls of commercial cargo and passenger ships. The research was conducted between November 2004 and April 2005 in Boston, Massachusetts and Freeport, Grand Bahama Island. Subjects wore whole-body dosimeters under fresh work clothes and Tyvek® hooded coveralls, dosimeter gloves under work gloves, dosimeter patches on the back of their work shirts and on the front of their coveralls, and personal air sampling pumps for monitoring dermal and inhalation exposure.Page 2 of 4 Some of the 31 workers were monitored more than once, for a total of 49 “replicates.” All of the subjects were professional dry dock wo rkers who normally performed tasks associated with the commercial application of antifouling pain t to ship hulls. No information is provided about how the subjects were recruited, or what they were told of the purposes, procedures, risks, benefits, costs, and other aspects of the research. The report does not indicate whether the subjects consented to participate, or what form their consent took. The research was not reported to have been overseen by an IRB or any comparable independent ethics review entity.

1. Value of the Research to Society: The purpose of this study was to monitor and quantify the exposure levels of zinc pyrithione to dry dock workers as they perform tasks associated with applying antifouling paint to the hulls of commercial cargo or passenger ships. The study was funded by Arch Chemicals Inc. It contributes to the assessment of worker exposure while mixing, loading, and a pplying zinc pyrithione and possibly other types of antifouling paint to commercial cargo and passenger ships.

2. Subject Selection : Although participating shipyards were reportedly selected to represent a typical range of circumstances and practices, no information is given about how the subjects were recruited or selected. Their gender, age, and pregnancy or nursing status is not reported. There is no indication that any subjects came from an especially vulnerable group.

3. Risk-Benefit Ratio : Neither risks to the subjects nor actions taken to minimize those risks are discussed. Since subjects were performing their usual jobs and wearing both PPE and whole-body dosimeters, the risks associated with their participation in the research were low. The report does not identif y societal benefits of the research or how they would be distributed, or how the inve stigators weighed likely benefits of the research against the risks to individual subjects.

4. Independent Ethics Review : The study does not report any independent ethics oversight or review of the protocol or of the conduct of the research.

5. Informed Consent : The report is silent about whether informed consent was obtained from the subjects. Because subjects wore extensive dosimetry, it is implausible that their participation was not consensual. What is less clear is whether it was adequately

informed.

6. Respect for Potential and Enrolled Subjects : The report does not contain identifying information about any of the subjects. It is not reported whether s ubjects were free to

withdraw from the research.Page 3 of 4 Applicable Standards

This research was initiated in December 2003, well before April 7, 2006, the effective

date of EPA’s amended Rule for the Protection of Human Subjects of Research. The report was submitted to EPA on December 5, 2005, before the effective date of EPA’s Amended Rule, and thus it was not subject to the requirement of 40 CFR §26.1303 to document the ethical conduct

of the research.

The amount of active ingredient handled was not manipulated by the investigators, nor was subject behavior or the equipment they used influenced by the investigators. Therefore, the research may not constitute “research involving intentional exposure of a human subject” as that phrase is defined in the rule at 40 CFR §26.1102(i). However, documentation of how cooperating employees and employers were recruited is inadequate to support a definitive finding.

The Agency’s rule defines standards that EPA must apply in deciding whether to rely on research—like this study—which may have involved intentional exposure of human subjects. (See 40 CFR §26 subpart Q.) Because this study was initiated before the effective date of the rule, the applicable acceptance standards from 40 CFR §26 are these:

§26.1703. Prohibition of reliance on research involving intentional exposure of human subjects who are pregnant women (and therefore their fetuses), nursing women, or children. Except as provided in §26.1706, in actions within the scope of §26.1701 EPA shall not rely on data from any research involving intentional exposure of any human subject who is a pregnant woman (and therefore her fetus), a nursing woman,

or a child.

§26.1704. Prohibition of reliance on unethical human research with nonpregnant adults conducted before April 7, 2006. Except as provided in §26.1706, in actions within the scope of §26.1701, EPA shall not rely on data from any research initiated before April 7, 2006, if there is clear and convincing evidence that the conduct of the research was fundamentally unethical ( e.g. , the research was intended to seriously harm participants or failed to obtain informed consent), or was significantly deficient relative to the ethical standards prevailing at the time the research was conducted. This prohibition is in addition to the prohibition in §26.1703.

FIFRA §12(a)(2)(P) also applied to this research. This provision reads:

In general, [i]t shall be unlawful for any person . . . to use any pesticide in tests on human beings unless such human beings (i) are fully informed of the nature and purposes of the test and of any physical and mental health consequences which are reasonably foreseeable therefrom, and (ii) freely volunteer to participate in the test.Page 4 of 4 Compliance with Applicable Standards

All subjects were adults. The study is silent with respect to the age, sex, and pregnancy or nursing status of the subjects, but there is no indication that any of the subjects were pregnant or nursing women. In the absence of any info rmation suggesting that pregnant or nursing women were among the subjects, the Agency’s view is that reliance on the study is not prohibited by 40 CFR 26.1703.

40 CFR §26.1704 forbids EPA to rely on data from pre-rule research—such as this study—if there is “clear and convincing evidence that the conduct of the research was fundamentally unethical (e.g., the research was intended to seriously harm participants or failed to obtain informed consent), or was significantly deficient relative to the ethical standards prevailing at the time the research was conducted.” This study had a clear research purpose and was not designed with the intent to seriously harm the subjects. There is no direct evidence that the subjects provided consent, but it is unlikely that the workers could have been compelled to wear the dosimeters and air sampling equipment without their consent. Although there are significant gaps in the documentation of the ethical conduct of this research, these gaps do not in themselves amount to “clear and convincing evidence.” I found no evidence that this research was fundamentally unethical, or that its conduct was significantly deficient relative to standards prevailing at the time it was conducted. 40 CFR §26.1704 does not prohibit EPA reliance on this

research.

FIFRA §12(a)(2)(P) requires that human subjects of research with pesticides be “fully informed of . . . any physical and mental health consequences which are reasonably foreseeable” from their participation in the research. The study does not report what the subjects were told about the potential health effects of participating in this research, or whether they consented to participate. The lack of documentation regarding informed consent is a significant deficiency, but this deficiency does not, in my judgment, necessarily indicate that the subjects were not properly informed or that their participati on was non-consensual, in violation of FIFRA §12(a)(2)(P). Uncertainty in this respect could be removed if further information were obtained about the process and content of informed consent in this study.

Conclusion

Although there are many significant gaps in the documentation of the ethical conduct of this study, there is no clear evidence that the research was intended to harm participants, or that it was fundamentally unethical in other ways. Deficient documentation does not itself constitute evidence that the ethical conduct of this study was deficient relative to standards prevailing when

it was conducted.

I therefore conclude that, whether or not the reported research met the regulatory definition of “research involving intentional exposur e of a human subject,” there is no barrier in law or regulation to EPA’s relying on this research in its actions taken under FIFRA or §408 of

FFDCA. I defer to others for a full review of th e scientific validity of this study. If it were determined not to have scientific validity, it would also not be ethically acceptable.