MEMORANDUM

FROM:	William L. Jordan

		Senior Policy Adviser

		Office of Pesticide Programs (7501P)

TO:		Paul I. Lewis

		Designated Federal Official for the Human Studies Review Board

		Office of the Science Adviser		

SUBJECT:  	OPP Comments on the Draft Report of the June 27-30, 2006,
Meeting of the Human Studies Review Board

	We appreciate the opportunity to offer comments on the draft report on
the first meeting of the Human Studies Review Board (HSRB), held June
27-30, 2006.  In general, the report reflects the oral comments made
during the meeting and provides useful additional clarification.  We
also thank the Board members for the extraordinary efforts they made to
prepare for the meeting, to provide such useful commentary, and to
produce their completed report.

	Members of the Office of Pesticide Programs (OPP) staff have carefully
reviewed the draft to identify any portions that are either unclear or
inconsistent with our notes from the meeting.  In addition, OPP has
identified places in the text of the draft report that appear to contain
typographical or other minor editorial errors.  

Major comments

	OPP has the following major comments on the sections of the draft
report dealing with the proposed insect repellent efficacy protocols and
agricultural handler exposure protocols.

1.  Conclusions regarding the use of the Chloropicrin Study 

	The Board concluded that the human study conducted with chloropicrin
“was scientifically sound for estimating a safe level of inhalation
exposure” and that a “LOAEL of 100 ppb was a scientifically
justified point of departure (POD).” (p 1, lines27- 29 and p. 19,
lines 8-10.)  EPA agrees that the data from the study should be used in
our assessment of the risk from inhalation exposure to chloropicrin. 
EPA performed a Benchmark Concentration (BMC) analysis of the results
from phase III of the chloropicrin study to derive an estimate of the
concentration at which 10% of an exposed population would experience
irritation effects.  EPA requests clarification of whether the Board’s
comment regarding the use of the LOAEL signifies a scientific
disagreement with EPA’s use of the data to derive a BMC10.

2.  Characterization of Repellent Efficacy Studies as of “more than
minimal risk”.

In the context of discussing elements required for informed consent to
participate in a test of repellent efficacy, it is mentioned in passing,
without discussion or explanation, that “insect repellent studies
should be classified as research involving more than minimal risk, . .
.” (p. 37, lines 30-31)  Is this the conclusion of the Board?  Is it
therefore never permissible for an IRB to approve a new protocol for
repellent efficacy testing using expedited review procedures?  Please
clarify.

3.  Criteria for Judging Ethical Acceptability of Proposed Research

	In discussing “Scientific Validity and Social Value,” the HSRB
states “Further, the Human Studies Review Board is not limited by
Subpart K in evaluating the ethical acceptability of a proposed human
research study.” (p. 40, lines 34-35).  The Agency finds this
statement unclear in light of the provisions in its Human Studies
regulation that require covered research to comply with the requirements
contained in subparts K and L and that prohibit EPA from relying on
research initiated after the effective date of the rule unless the
research substantially complies with the requirements of part 26.  (See
40 CFR §26.1705).  The Agency requests clarification of the Board’s
statement, particularly identification of what different criteria the
Board would use to evaluate the ethical acceptability of proposed
research.

4.  Proposed Insect Repellent Efficacy Protocols.

	The HSRB concluded that one of the two proposed protocols did not
comply with the requirements in EPA’s Human Studies regulation, 40 CFR
part 26, subparts K and L.  The Board further concluded that the
documentation of one of the proposed protocols did not comply with the
requirements of 40 CFR part 26, subpart M.  (Page 4, lines 29-32; p. 45,
lines 24-28; p. 47, lines 5-8).  EPA disagrees in part.

	EPA believes both proposed protocols comply with the substantive
requirements of subpart L by specifically excluding potential subjects
who are under 18 or pregnant.  EPA agrees that the documentation of the
tick protocol was deficient, but notes that the applicable standard of
documentation is in 40 CFR §26.1125, which as part of subpart K applies
to proposals for new research, not subpart M, which applies only to
reports of completed research.  

	The Board suggests that a negative “vehicle” control (formulation
matrix minus the repellent) would be useful for the mosquito efficacy
field research.  (p. 48, lines 19-20; p. 49, lines 16-17).  In light of
the discussion in the guidelines section concerning negative controls,
(p. 27, line 15 to p.28, line 12) EPA requests clarification of the
purpose such a negative vehicle control might serve. 

	EPA further notes that the Board’s comments on the two proposed
repellent efficacy studies were very differently organized and, despite
the similarities of the two protocols, differed substantively as well.  
For example, the review of the tick protocol expresses concern about
recruitment of subjects who may potentially be vulnerable to coercion
(p. 46, lines 4-12), while the review of the mosquito protocol notes
only that the “sample was not a vulnerable group” (p. 48, line 28),
even though the two protocols both relied on the same description of the
investigator’s recruitment strategy.  For another example, the Board
recommends a separate informed consent document for female subjects in
the tick study (p. 46, lines 30-33) but not for female subjects in the
mosquito study (p. 51, lines 23-27.)

5.  Proposed Agricultural Handler Exposure Protocols

The HSRB concluded that the proposed protocols did not comply with the
requirements in EPA’s Human Studies regulation, 40 CFR part 26,
subparts K, L, and M.  (Page 6, lines 23-24; p. 63, lines 20-24; p. 66,
lines 26-28.)  EPA disagrees in part.

	EPA believes the proposed protocols did comply with the substantive
requirements of subpart L by specifically excluding potential subjects
who are under 18 or pregnant.  EPA agrees that the documentation of the
AHETF protocols was deficient, but notes that the applicable standard of
documentation is in 40 CFR §26.1125, which as part of subpart K applies
to proposals for new research, not subpart M, which applies only to
submitted reports of completed research.

	OPP requests further consideration of one aspect of the Board’s
discussion regarding “Alternatives to Participation” in the AHETF
protocols.  The draft HSRB report states that agricultural handlers must
have a real option of not participating in the proposed research–a
point with which we agree.  The report further states that the growers,
who have agreed to allow the research to occur on their property and who
would normally pay the wages of the handlers, must offer any handler who
declines to participate in the research a normal day’s work and pay. 
OPP also agrees with this conclusion.  Inclusion of such a provision as
part of the recruitment process and IC materials would help to avoid a
situation in which handlers were unduly influenced to participate.  The
report further states: 

One option is that [any handlers who chose not to participate] could be
offered the choice of applying that pesticide that day, but not needing
to participate in any other study procedures (such as wearing the long
underwear).  Some members of the Board believed that if that is the only
alternative to participation, then this aspect of the study would not
comply with 40 CFR Part 26, subpart K.  A primary purpose of the EPA
rule is to prevent a person from being intentionally exposed to a
pesticide without their voluntary informed consent.

In OPP’s view, the text quoted above seems to rest on the incorrect
premise that EPA’s Human Studies rule would apply to the employment
relationship between a grower and a handler who chooses not to become a
subject in an AHETF protocol.  While it is correct that an important
purpose of the Agency’s Human Studies rule is to prevent subjects of
third-party human research for pesticides from being intentionally
exposed without their fully informed, fully voluntary consent, OPP
questions whether the regulation applies to a grower who directs a
handler to apply a pesticide when the handler is not a subject
participating in human research.  The fact that a handler may be mixing,
loading or applying a pesticide at the same time other handlers are
mixing, loading or applying the same pesticide as part of a research
study does not make the first handler a “human subject” within the
meaning of 40 CFR 26.1102(e).

6.  Mischaracterization of EPA’s Preliminary Ethics Reviews

In its comments on one of the repellent efficacy protocols (EMD-003, at
p. 4, line 26, and p. 47, line 2) and on the AHETF protocols (p. 6, line
20, and p. 66, line 24) the Board “concurred with the initial
assessment of the Agency that the studies submitted for review failed to
meet the ethical requirements established in the 40CFR26.”  (Emphasis
added.)  The conclusions of EPA’s reviews in these cases were that
there were “several deficiencies . . . relative to the standards of 40
CFR part 26 and FIFRA §12(a)(2)(P).  These deficiencies should be
corrected before research begins.”

EPA’s preliminary reviews found these proposals to have fallen short
of the standards in the new rule, many of which concern documentation,
and could be corrected by provision of further documentation.  EPA did
not find these proposals to be unethical.  This distinction is
important, and could be clarified by deleting the word “ethical” in
the four passages cited above.

Minor comments

	The Agency recommends that the draft report identify the individuals
hired to provide expert consultation to the Board on insect repellent
efficacy research, either when it lists members of the Board or in the
same section as it identifies public commenters.

EPA has made a number of editorial corrections and suggestions with
respect to the draft report.  They appear in a separate file entitled
“OPP edits to june2006finaldraftreport.doc”

