[Federal Register Volume 68, Number 88 (Wednesday, May 7, 2003)]
[Proposed Rules]
[Pages 24410-24416]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-11002]


=======================================================================
-----------------------------------------------------------------------

ENVIRONMENTAL PROTECTION AGENCY

40 CFR Chapter I

[OPP-2003-0132; FRL-7302-8]
RIN: 2070-AD57


Human Testing; Advance Notice of Proposed Rulemaking

AGENCY: Environmental Protection Agency (EPA).

ACTION: Advance notice of proposed rulemaking.

-----------------------------------------------------------------------

SUMMARY: This advance notice of proposed rulemaking announces EPA's 
plan to conduct rulemaking about criteria and standards EPA would apply 
in deciding the extent to which it will consider or rely on various 
types of research with human subjects to support its actions. This 
notice also initiates the rulemaking process by requesting public 
comments and suggestions on a broad range of issues relating to this 
subject.

[[Page 24411]]


DATES: Comments must be received on or before August 5, 2003.

ADDRESSES: Submit your comments, identified by docket ID number OPP-
2003-0132, online at http://www.epa.gov/edocket (EPA's preferred 
method) or mailed to the Public Information and Records Integrity 
Branch (PIRIB), (7502C), Office of Pesticide Programs (OPP), 
Environmental Protection Agency, 1200 Pennsylvania Ave., NW., 
Washington, DC 20460-0001. For additional submission methods and 
detailed instructions, go to Unit I.C. of the SUPPLEMENTARY 
INFORMATION.

FOR FURTHER INFORMATION CONTACT: William L. Jordan, Mail code 7501C, 
Office of Pesticide Programs, Environmental Protection Agency, 1200 
Pennsylvania Ave., NW., Washington, DC 20460; telephone number: (703) 
305-1049, fax number: (703) 308-4776; e-mail address: 
[email protected].

SUPPLEMENTARY INFORMATION: This Advance Notice of Proposed Rulemaking 
(ANPR) is organized into four Units. Unit I. contains ``General 
Information'' about the applicability of this ANPR, how to obtain 
additional information, how to submit comments in response to the 
request for comments, and certain other related matters. Unit II. 
provides background and historic information pertaining to human 
subject research. Unit III. describes the rulemaking process, 
identifies relevant statutory provisions, and requests public comments 
and suggestions on a broad range of issues related to the Agency's 
consideration of or reliance on research with human subjects. Unit IV. 
describes procedures followed in the development of this ANPR and 
certain statutes and Executive Orders that the public may wish to 
consider in preparing comments.

I. General Information

A. Does this Action Apply to Me?

    This action is directed to the public in general. This action may, 
however, be of particular interest to those who conduct testing of 
substances regulated by EPA. Since other entities may also be 
interested, the Agency has not attempted to describe all the specific 
entities that may be affected by this action. If you have any questions 
regarding the applicability of this action to a particular entity, 
consult the person listed under FOR FURTHER INFORMATION CONTACT.

B. How Can I Get Copies of this Document and Other Related Information?

    1. Docket. EPA has established an official public docket for this 
action under docket identification (ID) number OPP-2003-0132. The 
official public docket consists of the documents specifically 
referenced in this action, any public comments received, and other 
information related to this action. Although a part of the official 
docket, the public docket does not include Confidential Business 
Information (CBI) or other information whose disclosure is restricted 
by statute. The official public docket is the collection of materials 
that is available for public viewing at the Public Information and 
Records Integrity Branch (PIRIB), Rm. 119, Crystal Mall 2, 
1921 Jefferson Davis Hwy., Arlington, VA. This docket facility is open 
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal 
holidays. The docket telephone number is (703) 305-5805.
    2. Electronic access. You may access this Federal Register document 
electronically through the EPA Internet under the ``Federal Register'' 
listings at http://www.epa.gov/fedrgstr/.
    An electronic version of the public docket is available through 
EPA's electronic public docket and comment system, EPA Dockets. You may 
use EPA Dockets at http://www.epa.gov/edocket to submit or view public 
comments, access the index listing of the contents of the official 
public docket, and to access those documents in the public docket that 
are available electronically. Once in the system, select ``search,'' 
then key in the appropriate docket ID number.
    Certain types of information will not be placed in the EPA Dockets. 
Information claimed as CBI and other information whose disclosure is 
restricted by statute, which is not included in the official public 
docket, will not be available for public viewing in EPA's electronic 
public docket. EPA's policy is that copyrighted material will not be 
placed in EPA's electronic public docket but will be available only in 
printed, paper form in the official public docket. To the extent 
feasible, publicly available docket materials will be made available in 
EPA's electronic public docket. When a document is selected from the 
index list in EPA Dockets, the system will identify whether the 
document is available for viewing in EPA's electronic public docket. 
Although not all docket materials may be available electronically, you 
may still access any of the publicly available docket materials through 
the docket facility identified in Unit I.B.1. EPA intends to work 
towards providing electronic access to all of the publicly available 
docket materials through EPA's electronic public docket.
    For public commenters, it is important to note that EPA's policy is 
that public comments, whether submitted electronically or on paper, 
will be made available for public viewing in EPA's electronic public 
docket as EPA receives them and without change, unless the comment 
contains copyrighted material, CBI, or other information whose 
disclosure is restricted by statute. When EPA identifies a comment 
containing copyrighted material, EPA will provide a reference to that 
material in the version of the comment that is placed in EPA's 
electronic public docket. The entire printed comment, including the 
copyrighted material, will be available in the public docket. Public 
comments submitted on computer disks that are mailed or delivered to 
the docket will be transferred to EPA's electronic public docket. 
Public comments that are mailed or delivered to the docket will be 
scanned and placed in EPA's electronic public docket. Where practical, 
physical objects will be photographed, and the photograph will be 
placed in EPA's electronic public docket along with a brief description 
written by the docket staff.

C. How and to Whom Do I Submit Comments?

    You may submit comments electronically, by mail, or through hand 
delivery/courier. To ensure proper receipt by EPA, identify the 
appropriate docket ID number in the subject line on the first page of 
your comment. Please ensure that your comments are submitted within the 
specified comment period. Comments received after the close of the 
comment period will be marked ``late.'' EPA is not required to consider 
these late comments. If you wish to submit CBI or information that is 
otherwise protected by statute, please follow the instructions in Unit 
I.D. Do not use EPA Dockets or e-mail to submit CBI or information 
protected by statute.
    1. Electronically. If you submit an electronic comment as 
prescribed in this unit, EPA recommends that you include your name, 
mailing address, and an e-mail address or other contact information in 
the body of your comment. Also include this contact information on the 
outside of any disk or CD ROM you submit, and in any cover letter 
accompanying the disk or CD ROM. This ensures that you can be 
identified as the submitter of the comment and allows EPA to contact 
you

[[Page 24412]]

in case EPA cannot read your comment due to technical difficulties or 
needs further information on the substance of your comment. EPA's 
policy is that EPA will not edit your comment, and any identifying or 
contact information provided in the body of a comment will be included 
as part of the comment that is placed in the official public docket, 
and made available in EPA's electronic public docket. If EPA cannot 
read your comment due to technical difficulties and cannot contact you 
for clarification, EPA may not be able to consider your comment.
    i. EPA Dockets. Your use of EPA's electronic public docket to 
submit comments to EPA electronically is EPA's preferred method for 
receiving comments. Go directly to EPA Dockets at http://www.epa.gov/edocket, and follow the online instructions for submitting comments. 
Once in the system, select ``search,'' and then key in docket ID number 
OPP-2003-0132. The system is an ``anonymous access'' system, which 
means EPA will not know your identity, e-mail address, or other contact 
information unless you provide it in the body of your comment.
    ii. E-mail. Comments may be sent by e-mail to [email protected], 
Attention: Docket ID Number OPP-2003-0132. In contrast to EPA's 
electronic public docket, EPA's e-mail system is not an ``anonymous 
access'' system. If you send an e-mail comment directly to the docket 
without going through EPA's electronic public docket, EPA's e-mail 
system automatically captures your e-mail address. E-mail addresses 
that are automatically captured by EPA's e-mail system are included as 
part of the comment that is placed in the official public docket, and 
made available in EPA's electronic public docket.
    iii. Disk or CD ROM. You may submit comments on a disk or CD ROM 
that you mail to the mailing address identified in Unit I.C.2. These 
electronic submissions will be accepted in WordPerfect or ASCII file 
format. Avoid the use of special characters and any form of encryption.
    2. By mail. Send your comments to: Public Information and Records 
Integrity Branch (PIRIB), Office of Pesticide Programs (OPP), 
Environmental Protection Agency (7502C), 1200 Pennsylvania Ave., NW., 
Washington, DC 20460-0001, Attention: Docket ID Number OPP-2003-0132.
    3. By hand delivery or courier. Deliver your comments to: Public 
Information and Records Integrity Branch (PIRIB), Office of Pesticide 
Programs (OPP), Environmental Protection Agency, Rm. 119, Crystal Mall 
2, 1921 Jefferson Davis Hwy., Arlington, VA, Attention: Docket 
ID Number OPP-2003-0132. Such deliveries are only accepted during the 
docket's normal hours of operation as identified in Unit I.B.1.

D. How Should I Submit CBI to the Agency?

    Do not submit information that you consider to be CBI 
electronically through EPA's electronic public docket or by e-mail. You 
may claim information that you submit to EPA as CBI by marking any part 
or all of that information as CBI (if you submit CBI on disk or CD ROM, 
mark the outside of the disk or CD ROM as CBI and then identify 
electronically within the disk or CD ROM the specific information that 
is CBI). Information so marked will not be disclosed except in 
accordance with procedures set forth in 40 CFR part 2.
    In addition to one complete version of the comment that includes 
any information claimed as CBI, a copy of the comment that does not 
contain the information claimed as CBI must be submitted for inclusion 
in the public docket and EPA's electronic public docket. If you submit 
the copy that does not contain CBI on disk or CD ROM, mark the outside 
of the disk or CD ROM clearly that it does not contain CBI. Information 
not marked as CBI will be included in the public docket and EPA's 
electronic public docket without prior notice. If you have any 
questions about CBI or the procedures for claiming CBI, please consult 
the person listed under FOR FURTHER INFORMATION CONTACT.

E. What Should I Consider as I Prepare My Comments for EPA?

    You may find the following suggestions helpful for preparing your 
comments:
    1. Explain your views as clearly as possible.
    2. Describe any assumptions that you used.
    3. Provide copies of any technical information and/or data you used 
that support your views.
    4. If you estimate potential burden or costs, explain how you 
arrived at the estimate that you provide.
    5. Provide specific examples to illustrate your concerns.
    6. Make sure to submit your comments by the deadline in this ANPR.
    7. To ensure proper receipt by EPA, be sure to identify the docket 
control number assigned to this action in the subject line on the first 
page of your response. You may also provide the name, date, and Federal 
Register citation.

II. Introduction

A. Background on Federal Standards for Conducting Human Research

    Over the years, scientific research with human subjects has 
provided much valuable information to help characterize and control 
risks to public health, but its use has also raised particular ethical 
concerns for the welfare of the human participants in such research as 
well as scientific issues related to the role of such research in 
assessing risks. Society has responded to these concerns by defining 
general standards for conducting human research. In the United States, 
the National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research issued in 1979 ``The Belmont Report: 
Ethical Principles and Guidelines for the Protection of Human Subjects 
of Research.'' This document can be found on the web at http://ohrp.osophs.dhhs.gov/humansubjects/guidance/belmont.htm.
    For most federal agencies in the United States, the principles of 
the Belmont Report are implemented through the Common Rule, which was 
developed cooperatively by some 17 departments and agencies, including 
EPA, and which guides all research with human subjects conducted or 
supported by these departments and agencies of the federal government. 
The Common Rule as promulgated by EPA (40 CFR part 26) has guided human 
research conducted or supported by EPA since it was put in place in 
1991.
    More broadly, the international medical research community has 
developed and maintains ethical standards documented in the Declaration 
of Helsinki, first issued by the World Medical Association in 1964 and 
revised several times since then. These standards apply to research on 
matters relating to the diagnosis and treatment of human disease, and 
to research that adds to understanding of the causes of disease and the 
biological mechanisms that explain the relationships between human 
exposures to environmental agents and disease.
    In addition, many public and private research and academic 
institutions and private companies, both in the United States and in 
other countries, including non-federal U.S. and non-U.S. governmental 
organizations, have their own specific policies related to the 
protection of human participants in research.
    Much of the scientific research supporting EPA's actions, including 
a significant portion of the research with human subjects submitted to 
the Agency or retrieved by the Agency from

[[Page 24413]]

published sources, is conducted by this broader research community, 
without direct participation or support by the U.S. government. Such 
research, referred to here as ``third party'' research, while it may be 
governed by specific institutional policies intended to protect 
research participants or may fall within the scope of the Declaration 
of Helsinki, is not subject to the Common Rule. In general, EPA cannot 
readily determine whether such policies are consistent with or as 
protective of human subjects as the Common Rule, nor the extent to 
which such policies or standards have been followed in the conduct of 
any particular study. Thus, even well-conducted third-party human 
studies may raise difficult questions for the Agency when it seeks to 
determine their acceptability for consideration.

B. Human Research Issues in EPA's Pesticide Program

    Questions about the Agency's consideration of and reliance on 
third-party human research studies have arisen most notably, but not 
exclusively, in EPA's pesticides program. Under the Federal 
Insecticide, Fungicide, and Rodenticide Act (FIFRA), EPA may require 
pesticide companies to conduct studies with human subjects, for 
example, to measure potential exposure to pesticide users or to workers 
and others who re-enter areas treated with pesticides, and to evaluate 
the effectiveness of pesticide products intended to repel insects and 
other pests from human skin. In addition, EPA sometimes encourages 
other research with human subjects, including tests of the potential 
for some pesticides--generally those designed for prolonged contact 
with human skin--to irritate or sensitize human skin, and tests of the 
metabolic fate of pesticides in the human system. These latter studies 
typically precede monitoring studies of agricultural workers and others 
to protect them from exposure to potentially dangerous levels of 
pesticide residues.
    In addition to these kinds of research which have been required or 
encouraged by EPA, other kinds of studies involving human subjects 
intentionally exposed to pesticides have occasionally been submitted to 
the agency voluntarily. Among these voluntarily submitted studies have 
been tests involving intentional dosing of human subjects to establish 
a No Observed Adverse Effect Level (NOAEL) or No Observed Effect Level 
(NOEL) for systemic toxicity of certain pesticides to humans. Before 
passage of the Food Quality Protection Act (FQPA) in 1996, submission 
of such studies was rare. EPA considered and relied on human NOAEL/NOEL 
studies in a few regulatory decisions on pesticides made prior to 1996. 
Since the passage of FQPA, submission of these types of studies to the 
Office of Pesticide Programs has increased; the Agency has received 
some 20 studies of this kind since 1996.
    In response to concerns about human testing expressed in a report 
of a non-governmental advocacy organization, the Environmental Working 
Group, in July 1998, the Agency began a systematic review of its policy 
and practice. In a press statement on July 28, 1998, EPA noted that it 
had not relied on any such studies in any final decisions made under 
FQPA; this remains true today.
    In further response to growing public concern over pesticide 
research with human subjects, EPA convened an advisory committee under 
the joint auspices of the EPA Science Advisory Board (SAB) and the 
FIFRA Scientific Advisory Panel (SAP) to address issues of the 
scientific and ethical acceptability of such research. This advisory 
committee, known as the Data from Testing of Human Subjects 
Subcommittee (DTHSS), met in December 1998 and November 1999, and 
completed its report in September 2000. Their report is available in 
the Docket cited above in this ANPR, and on the web at: http://www.epa.gov/science1/pdf/ec0017.pdf
    The DTHSS advisory committee heard many comments at their two 
public meetings, and further comments have been submitted in response 
to their published report. No clear consensus emerged from the advisory 
committee process on the acceptability of NOAEL or NOEL studies of 
systemic toxicity of pesticides to human subjects, and significant 
differences of opinion remain on both their scientific merit and 
ethical acceptability. A vigorous public debate continues about the 
extent to which EPA should accept, consider, or rely on third-party 
intentional dosing human toxicity studies with pesticides.

C. EPA's Current Agency-wide Focus on Human Research Issues

    EPA is now interested in addressing these issues more broadly, and 
in all Agency programs. In December 2001, EPA asked the advice of the 
National Academy of Sciences (NAS) on the many difficult scientific and 
ethical issues raised by this debate, and also stated the Agency's 
interim approach on third-party intentional dosing human subjects 
studies. The Agency's press release on this subject is on the web at 
http://yosemite.epa.gov/opa/ admpress.nsf/b1ab9f485b098972 
852562e7004dc686/c232a45f5473 717085256b2200740ad4? OpenDocument. At 
that time the Agency committed that when it receives the NAS report, 
``EPA will engage in an open and participatory process involving 
federal partners, interested parties and the public during its policy 
development and/or rulemaking regarding future acceptance, 
consideration or regulatory reliance on such human studies.'' Since 
making that commitment, EPA has decided to initiate a rulemaking 
process by issuing this ANPR.
    In early 2002, various parties from the pesticide industry filed a 
petition with the U.S. Court of Appeals for the District of Columbia 
for review of EPA's December 2001 press release. These parties argued 
that the Agency's interim approach constituted a ``rule'' promulgated 
in violation of the procedural requirements of the Administrative 
Procedure Act and the Federal Food, Drug, and Cosmetic Act. The court 
has denied motions concerning emergency relief and other matters, 
briefs have been filed, and oral argument of the merits of the case 
occurred on March 17, 2003.
    Under a contract with EPA, the NAS has convened a committee to 
provide the requested advice. The committee met in December 2002, and 
again in January and March 2003. The membership, meeting schedule, and 
other information about the work of this committee can be found on the 
NAS website at: http://www4.nas.edu/webcr.nsf/ 
5c50571a75df494485256a95007 a091e/ 9303f725c15902f685256c44005d8931? 
OpenDocument&Highlight=0,EPA. The committee's final report is due in 
December 2003.
    Notwithstanding these many recent developments concerning human 
studies, some things have not changed. EPA remains committed to full 
compliance with the Common Rule for all research with human subjects 
conducted or supported by the Agency. This body of research has 
provided many important insights and has contributed significantly to 
the protection of human health. The Agency will continue to conduct and 
support such research, and to consider and rely on its results in 
Agency actions. EPA also remains committed to scientifically sound 
assessments of the hazards of environmental agents, taking into 
consideration available, relevant, and appropriate scientific research.

[[Page 24414]]

III. EPA's Rulemaking Process and Request for Public Comment

    EPA intends to undertake notice-and-comment rulemaking on the 
subject of its consideration of or reliance on research involving human 
subjects. The Agency will particularly focus on third-party intentional 
dosing human studies, but recognizes that the principles applicable to 
third-party studies may also be relevant to studies conducted or 
supported by the federal government. The first step in this process is 
this ANPR which calls for comments and suggestions from all interested 
parties. The next step the Agency would expect to undertake would be to 
issue a proposed rule for public comment. In developing any proposed 
rule, EPA will consider the advice in the National Academy of Sciences 
committee report, along with comments received in response to this 
ANPR. Comments received on any proposed rule would then be taken into 
consideration in developing a final rule or policy.
    In general, the Agency expects that any rule or policy coming out 
of this process may do one or more of the following:
    [sbull] Specify, if and to the extent determined by EPA to be 
appropriate, whether EPA would accept, consider, or rely on results 
from particular types of studies involving intentional dosing of human 
subjects or from human studies with particular characteristics.
    [sbull] Establish minimum standards relating to the protection of 
human subjects which would be required to be met in the design and 
conduct of a study with human subjects, in order for EPA to accept, 
consider, or rely on the results of the study.
    [sbull] Establish procedures for ensuring that any minimum 
standards for the conduct of third-party research with human subjects 
had been adhered to in the conduct of any such study that EPA intended 
to accept, consider, or rely on.

A. Legal Authority

    Section 25(a) of FIFRA gives the Administrator authority to 
``prescribe regulations to carry out the purposes of [FIFRA].'' Such a 
rule would implement EPA's authority to require data in support of 
registration of pesticides (see, for example, FIFRA sections 3(c)(1)(F) 
and 3(c)(2)(B)) and to interpret the provision making it 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.'' (FIFRA section 12(a)(2)(P)). In addition, 
section 408(e)(1)(C) of the FFDCA authorizes the Administrator to issue 
a regulation establishing ``general procedures and requirements to 
implement this section.''
    The Clean Air Act gives EPA general rulemaking authority in 42 
U.S.C. 7601(a). The Clean Water Act, 33 U.S.C. 1361, authorizes the 
Administrator to promulgate regulations necessary to carry out the 
Agency's functions under that Act. Section 42 U.S.C. 9615 in the 
Comprehensive Environmental Response, Compensation, and Liability Act 
authorizes the President to establish regulations to implement the 
statute; this authority has been delegated to EPA by Executive Order 
12580. The Emergency Planning and Community Right-to-Know Act also 
contains a general rulemaking provision, 42 U.S.C. 11048, authorizing 
the Administrator to promulgate rules necessary to carry out the Act. 
The Resource Conservation and Recovery Act specifically authorizes the 
Administrator to prescribe regulations necessary to carry out EPA's 
functions under the Act, 42 U.S.C. 6912. The Safe Drinking Water Act 
contains similar language, authorizing the Administrator to prescribe 
such regulations ``as are necessary and appropriate'' to carry out 
EPA's functions under the Act, 42 U.S.C. 300j-9. In addition, EPA has 
authority under 5 U.S.C. 301 and 42 U.S.C. 300v-1(b).

B. Request for Comments

    Neither this ANPR nor the specific questions presented below for 
public comment are intended to indicate that EPA now favors any 
particular policy approaches regarding the Agency's consideration of or 
reliance on third-party intentional dosing human studies. Similarly, 
neither this ANPR nor the specific questions presented below for public 
comment are intended to indicate that EPA has decided on a particular 
scope for any potential future rulemaking. Nor is this ANPR intended to 
impede or otherwise delay any Agency assessments or actions. Rather, 
this ANPR is designed to encourage public input from all interested 
parties on a broad range of issues that could help inform any rule or 
policy that EPA eventually promulgates or issues, respectively.
    The Agency fully appreciates the number, the range, and the 
interconnectedness of the scientific and ethical concerns raised 
especially by intentional dosing human studies of the wide range of 
environmental agents addressed by EPA's programs. Reflecting the 
breadth of issues that have been raised, the Agency has identified 
specific questions on which it particularly invites comment. These 
questions are intended to help organize and focus the discussion, but 
not to constrain it. Commenters should feel free to address any other 
relevant topics as well.
    1. Applicability of existing standards--a. Is it appropriate to use 
a standard intended to guide the conduct of research (e.g., the Common 
Rule, Declaration of Helsinki, or the Nuremberg Code) to assess the 
acceptability for review of completed research?
    b. Is it appropriate to use a standard intended to guide the 
conduct of therapeutic or diagnostic medical research or to clarify 
causes of disease, such as the Declaration of Helsinki, to assess the 
acceptability for review of other kinds of research without diagnostic 
or therapeutic intent, conducted with healthy subjects?
    c. Should the Agency apply the same standard of acceptability 
independent of the type of substance tested (e.g., pharmaceutical, 
pesticide, pathogen, or environmental contaminant)? If not, how might 
differing standards be applied when a single substance has multiple 
uses, e.g., as both a pesticide and a drug?
    d. Does it matter who maintains a standard, or by what process it 
is maintained? For example, would it be appropriate for EPA to accept 
and apply a standard maintained by a private, non-governmental 
organization, as is the Declaration of Helsinki?
    e. Should the Agency extend the requirements of the Common Rule to 
the conduct of third-party research with human subjects intended for 
submission to EPA? What are the advantages and disadvantages of 
conducting a rulemaking or undertaking other Agency action for this 
purpose alone?
    2. Should the standard of acceptability vary depending on the 
research design?--a. Should the Agency apply the same standard of 
acceptability independent of whether the research design involves 
intentional exposure? For example, should the same standard apply to 
research involving intentional exposures to human subjects, to research 
designed to follow-up accidental exposure, and to studies of 
individuals occupationally or incidentally exposed?
    b. Should the Agency apply the same standard of acceptability 
independent of the level of exposure of the human subjects? For 
example, does it matter if the level of exposure to a chemical is below 
the Reference Dose or other established health standard designed to

[[Page 24415]]

protect the general public? Should the same standard apply if 
intentional exposure to an environmental pollutant occurs at ambient 
levels, or at elevated levels? If research involves intentional 
exposure to a pesticide, does it matter if exposure results from use of 
the pesticide in conformity with approved label directions?
    c. Should the Agency apply the same standard of acceptability 
independent of the pathway of exposure? For example, should the same 
standard apply when exposure is oral, or dermal, or by inhalation?
    d. Should the Agency apply the same standard of acceptability 
independent of the effects being evaluated? For example, should the 
same standard apply to a study measuring transitory changes in blood 
chemistry or levels of a substance in urine that applies to studies 
measuring longer-lasting changes? Should the same standard apply to a 
study of localized skin irritation that applies to a study of systemic 
dermal toxicity? Should the same standard apply to studies measuring 
organoleptic effects, such as taste or smell, that applies to studies 
of toxic effects? Should the same standard apply to measurements of 
toxic effects and to measurements through genomic or proteomic 
assessments?
    e. Should conduct of research in compliance with the provisions of 
the Common Rule or another standard for the protection of human 
subjects be accepted as evidence of its ethical acceptability?
    f. Should the Agency consider whether research has been performed 
consistent with an EPA guideline for data development in determining 
its acceptability? For example, EPA has published guidelines for 
certain kinds of human studies required for pesticide registration; 
should conduct of a required study in compliance with an EPA guideline 
be accepted as evidence of its acceptability?
    g. Should the Agency apply the same standard of acceptability 
independent of a study's statistical power?
    h. Should the Agency apply the same standard of acceptability 
whether or not a human study design is able to measure the same 
endpoints in humans that have been observed in animal testing of the 
same substance? For example, if the most sensitive adverse effects 
shown in animal studies have been detected through histopathological 
evaluation of brain tissue, is subsequent research involving 
intentional exposure of human subjects acceptable?
    i. Should the Agency apply the same standard of acceptability to 
intentional dosing studies independent of whether there are alternative 
methods of obtaining data of comparable scientific merit that would not 
require deliberate exposure of humans? If not, to what extent, if any, 
should the cost of the alternate method be a factor?
    j. What special considerations, if any, should the Agency apply in 
judging the acceptability of studies when some or all of the subjects 
are from populations likely to be vulnerable to coercion or undue 
influence, such as children, prisoners, pregnant women, mentally 
disabled persons, or economically or educationally disadvantaged 
persons?
    3. Should the standard of acceptability vary depending on the 
provenance of the research?--a. Should the Agency apply the same 
standard of acceptability without regard to who or what organization 
sponsors or supports the research? Since 1991, human research conducted 
or supported by the U.S. government has been subject to the Common 
Rule. Should the same standard apply to research conducted or supported 
by others? Should a single standard apply independent of whether the 
sponsor is a commercial enterprise, a non-profit organization, another 
government in the United States (such as state, tribal, or local), or 
the government in another country? Should the same standard apply 
without regard to the test sponsor's interest in a regulatory matter 
that could be affected by EPA's consideration of the data?
    b. Should the Agency apply the same standard of acceptability 
independent of who or what organization conducts the research? For 
example, a research organization--public or private--holding a 
``Federal-Wide Assurance'' from the Department of Health and Human 
Services's Office of Human Research Protections usually promises to 
comply with the Common Rule in all its human research. Should third-
party work conducted by a research organization holding a Federal-Wide 
Assurance be assessed by the same standard that applies to other third-
party human research?
    c. Should the Agency apply the same standard of acceptability 
without regard to where the research was conducted? For example, does 
it matter whether research is conducted entirely in the United States 
or partially in the United States? If it is conducted outside the 
United States, does it matter in what country it is conducted? What are 
the advantages and disadvantages of judging the acceptability of human 
studies based on a single uniform standard versus prevailing local 
standards (e.g., in different countries)?
    d. Should the Agency apply the same standard of acceptability 
without regard to the reasons the research was conducted? If not, how 
might the Agency determine intent?
    e. Should the Agency apply the same standard of acceptability to 
submitted research without regard to who submitted it? For example, 
should the same standard apply to submissions from regulated industry, 
from public interest groups, from the public, or from other 
governments? Should the Agency apply the same standard of acceptability 
independent of whether the study was submitted voluntarily, or in 
response to a particular regulatory requirement of EPA?
    f. Should the Agency apply the same standard of acceptability to 
human research which is not submitted, but which the Agency obtains at 
its own initiative from the scientific literature or other sources, 
independent of how or where EPA obtains it?
    4. Should the standard of acceptability vary depending on EPA's 
potential use of the data?--a. Should the Agency apply the same 
standard of acceptability independent of whether the results of the 
study would support a more or less stringent regulatory position? For 
example, should the same standard apply whether the data indicate that 
the substance tested is more risky or less risky than is indicated by 
other available data?
    b. Should the Agency apply the same standard of acceptability 
without regard to how EPA intends to use the results, e.g., to reduce 
or remove the traditional tenfold interspecies uncertainty factor, to 
provide an endpoint for use in calculating a Reference Dose or 
Reference Concentration for the test substance, to provide a dose-
response function for use in quantitative risk assessment, or for some 
other purpose?
    5. Should the standard of acceptability vary depending on EPA's 
assessment of the risks and benefits of the research to the subjects or 
to society?--a. Should the Agency apply a standard of acceptability 
based on a comparison of the anticipated benefits of the research in 
relation to the risks to human subjects, provided the risks are 
minimized and informed consent is obtained?
    b. Should the Agency independently assess the risks of the research 
to the subjects and the benefits of the research to the research 
subjects or to society, or should it defer to the judgment of 
Institutional Review Boards or similar oversight panels?
    c. If EPA were to assess independently the risks and benefits of 
human research, on what range of information should it base its 
assessment? How might EPA obtain

[[Page 24416]]

information relevant to such an assessment?
    6. How should the Agency implement standards of acceptability?--a. 
To what extent and how should the submitter of research with human 
subjects to EPA be required to document or otherwise demonstrate 
compliance with appropriate standards for the protection of human 
research subjects, e.g., fully informed and fully voluntary 
participation, and independent oversight of research design and conduct 
by an Institutional Review Board or comparable entity?
    b. How should the Agency determine compliance with an appropriate 
standard for human research data which is not submitted, but which it 
obtains from the scientific literature or other sources?
    c. To what extent should new standards be applied to research which 
has already been conducted, or is underway? Should a different standard 
be applied to such research? Does fairness require a period of 
transition to any new rule or standards of acceptability, or do other 
considerations override that factor?
    d. Should the Agency apply the same standard of acceptability to 
research already submitted to or obtained by EPA and to research newly 
submitted to or obtained by EPA? Does it matter if the submitted 
research was conducted for the specific regulatory purpose at hand or 
for other purposes (even though the study was conducted after EPA 
issued a policy on human testing)? Does fairness require a period of 
transition to any new rule or standards of acceptability, or do other 
considerations override that factor?
    e. Is rulemaking needed at all? Would it be better to address the 
issues surrounding acceptance of human research, or some of them, by 
other means, such as policy statements or internal guidelines?

IV. Statutory and Executive Order Reviews

    Under Executive Order 12866, entitled Regulatory Planning and 
Review (58 FR 51735, October 4, 1993), it has been determined that this 
ANPR is a ``significant regulatory action'' under section 3(f) of the 
Executive Order. The Agency therefore submitted this document to OMB 
for the 10-day review period afforded under this Executive Order. Any 
changes made in response to OMB comments during that review have been 
documented in the public docket as required by the Executive Order.
    Since this ANPR does not impose any requirements, and instead seeks 
comments and suggestions for the Agency to consider in developing a 
subsequent notice of proposed rulemaking, the various other review 
requirements that apply when an agency imposes requirements do not 
apply to this action.
    As part of your comments on this ANPR you may include any comments 
or information that you have regarding these requirements. In 
particular, any comments or information that would help the Agency to 
assess the potential impact of a rule on small entities pursuant to the 
Regulatory Flexibility Act (RFA) (5 U.S.C. 601 et seq.); to consider 
voluntary consensus standards pursuant to section 12(d) of the National 
Technology Transfer and Advancement Act of 1995 (NTTAA), Public Law 
104-113, section 12(d) (15 U.S.C. 272 note); or to consider 
environmental health or safety effects on children pursuant to 
Executive Order 13045, entitled Protection of Children from 
Environmental Health Risks and Safety Risks (62 FR 19885, April 23, 
1997). The Agency will consider such comments during the development of 
any subsequent notice of proposed rulemaking as it takes appropriate 
steps to address any applicable requirements.

List of Subjects

    Environmental protection, Protection of human research subjects.


    Dated: April 29, 2003.
Christine T. Whitman,
Administrator.

[FR Doc. 03-11002 Filed 5-6-03; 8:45 am]
BILLING CODE 6560-50-S