Endocrine Disruptor Screening Program
[Federal Register: August 11, 1998 (Volume 63, Number 154)]
[Notices]
[Page 42852-42855]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr11au98-101]
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ENVIRONMENTAL PROTECTION AGENCY
[OPPTS-42206; FRL-6021-3]
Endocrine Disruptor Screening Program
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: As mandated by the Federal Food, Drug, and Cosmetic Act, as
amended by the Food Quality Protection Act of 1996, EPA is setting
forth its screening program for determining which pesticide chemicals
and other substances may have an effect in humans that is similar to an
effect produced by a naturally occurring estrogen or other endocrine
effects. In developing the screening program, EPA considered
recommendations of the Endocrine Disruptor Screening and Testing
Advisory Committee, a panel chartered pursuant to the Federal Advisory
Committee Act. EPA refers to this program as the ``Endocrine Disruptor
Screening Program'' or the ``Screening Program.'' This document
describes the major elements of EPA's Endocrine Disruptor Screening
Program. EPA will provide operational details regarding the Screening
Program, its regulatory implementation, and provide an opportunity for
public comment in a later Federal Register document. After public
comment and before implementation, EPA will submit the Screening
Program for review to a joint panel of the Federal Insecticide,
Fungicide, and Rodenticide Act Scientific Advisory Panel and the EPA
Science Advisory Board.
ADDRESSES: The official record for this document, including a public
version, has been established for this document under docket control
number OPPTS-42206. The public version of this record is available for
inspection from noon to 4 p.m., Monday through Friday, excluding legal
holidays. The public record is located at the TSCA Nonconfidential
Information Center, Rm. NE-B607, 401 M St., SW., Washington, DC 20460.
FOR FURTHER INFORMATION CONTACT: For general information or copies of
the EDSTAC report: Environmental Assistance Division (7408), Office of
Pollution Prevention and Toxics, Environmental Protection Agency, 401 M
St. SW., Washington DC, 20460; telephone 202-554-1404; TDD 202-554-
0551; e-mail: TSCA-Hotline@epa.gov.
For technical information: Anthony Maciorowski, Ph.D., Senior
Technical Advisor, Office of Prevention, Pesticides and Toxic
Substances; telephone: 202-260-3048; e-mail:
maciorowski.anthony@epa.gov or Gary Timm, Senior Technical Advisor,
Chemical Control Division, Office of Pollution Prevention and Toxics;
telephone: 202-260-1859; e-mail: timm.gary@epa.gov).
SUPPLEMENTARY INFORMATION:
[[Page 42853]]
I. General Information
A. Does this document apply to me?
This document describes the major elements of EPA's Endocrine
Disruptor Screening Program, and does not require any action by any
potentially affected entity. EPA will provide operational details
regarding the Endocrine Disruptor Screening Program and its regulatory
implementation in a later Federal Register document. EPA will provide
an opportunity for public comment on the Screening Program in this
later document. You may be interested in the program set forth in this
document if you produce, manufacture or import pesticide chemicals,
substances that may have an effect cumulative to an effect of a
pesticide, or substances found in sources of drinking water. To
determine whether you or your business may have an interest in this
document you should carefully examine section 408(p) of the Federal
Food, Drug, and Cosmetic Act (FFDCA), as amended by the Food Quality
Protection Act (FQPA) of 1996 (Pub. L. 104-170), 21 U.S.C. 346a(p) and
amendments to the Safe Drinking Water Act (Pub. L. 104-182), 42 U.S.C.
300j-17. If you have any questions regarding the applicability of this
action to a particular entity, consult the technical person listed in
the ``FOR FURTHER INFORMATION CONTACT'' section at the beginning of
this document.
B. How can I get additional information or copies of this document.
1. Electronically. You may obtain electronic copies of this
document from the EPA internet Home Page at http://www.epa.gov/. On the
Home Page select ``Laws and Regulations'' and then look up the entry
for this document under the ``Federal Register - Environmental
Documents.'' You can also go directly to the ``Federal Register''
listings at http://www.epa.gov/homepage/fedrgstr/.
2. In person or by phone. If you have any questions or need
additional information about this action, contact the technical person
identified in the ``FOR FURTHER INFORMATION CONTACT'' section at the
beginning of this document. A public version of this record, including
printed, paper versions which does not include any information claimed
as CBI, is available for inspection at the address in the ``ADDRESSES''
section at the beginning of this document. The Document Control Office
telephone number is 202-260-7093.
II. Background
Section 408(p) of the Federal Food, Drug, and Cosmetic Act, as
amended by the Food Quality Protection Act of 1996 (Pub. L. 104-170),
21 U.S.C. 46a(p), requires EPA, not later than August 3, 1998, to:
* * *develop a screening program using, appropriate validated
test systems and other scientifically relevant information, to
determine whether certain substances may have an effect in humans
that is similar to an effect produced by a naturally occurring
estrogen, or such other endocrine effect as the Administrator may
designate.
When carrying out the Screening Program, EPA ``shall provide for
the testing of all pesticide chemicals'' and ``may provide for the
testing of any other substance that may have an effect that is
cumulative to an effect of a pesticide chemical if the Administrator
determines that a substantial population may be exposed to such a
substance.'' 21 U.S.C. 346a(p)(3).
In addition, Congress amended the Safe Drinking Water Act and gave
EPA authority to provide for the testing, under the FQPA Screening
Program, ``of any other substance that may be found in sources of
drinking water if the Administrator determines that a substantial
population may be exposed to such substance.'' 42 U.S.C. 300j-17.
This document sets forth the Screening Program that EPA has
developed to comply with requirements of section 408(p) of the FFDCA as
amended by FQPA. In a later Federal Register document, EPA will provide
additional information about the Screening Program and its
implementation and an opportunity for the public to comment on it.
After public comment and before implementation, EPA will submit the
Screening Program to a joint panel of the Federal Insecticide,
Fungicide, and Rodenticide Act Scientific Advisory Panel and the EPA
Science Advisory Board for review.
III. Endocrine Disruptor Screening Program
EPA has considered recommendations of the Endocrine Disruptor
Screening and Testing Advisory Committee (EDSTAC) in developing its
Screening Program. The full text of the EDSTAC Draft Final Report is
available on EPA's worldwide web site at: www.epa.gov/opptintr/
opptendo. Paper copies can be obtained upon request from the TSCA
Hotline at the address listed in ``FOR FURTHER INFORMATION CONTACT'' at
the beginning of this document.
Initially, the Endocrine Disruptor Screening Program will focus on
estrogenic, androgenic, and thyroid hormone effects. These three
hormone systems are presently the most studied of the approximately 50
known vertebrate hormones. In vitro and in vivo test systems to examine
estrogen, androgen, and thyroid effects exist, and are currently the
most amenable for regulatory use. Further, inclusion of estrogen,
androgen, and thyroid effects will cover aspects of reproduction,
development, and growth.
EPA recognizes that there is a great deal of ongoing research
related to other hormones and test systems. As more scientific
information becomes available, EPA will consider expanding the scope of
the Endocrine Disruptor Screening Program to other hormones. For now,
however, the estrogen, androgen, and thyroid hormone effects and test
systems represent a scientifically reasonable focus for the Agency's
Endocrine Disruptor Screening Program.
EPA's Endocrine Disruptor Screening Program uses a tiered approach
for determining whether a substance may have an effect in humans that
is similar to an effect produced by naturally occurring estrogen,
androgen, or thyroid hormones. The core elements of the tiered approach
include initial sorting, priority setting, Tier 1 analysis, and Tier 2
analysis.
A. Initial Sorting
Chemicals under consideration for estrogen, androgen, and thyroid
screening will undergo initial sorting based on existing,
scientifically relevant information. EPA will use the existing
information to place a chemical into one of the following four
categories.
1. Category 1--Hold. Chemicals with sufficient, scientifically
relevant information to determine that they are not likely to interact
with the estrogen, androgen, and thyroid hormone systems. If EPA is
able to determine, based on scientifically relevant information, that a
specific chemical is not likely to interact with the estrogen,
androgen, or thyroid hormone systems, it will place that chemical in a
hold category. Chemicals in this hold category will have the lowest
priority for further analysis and may not undergo further analysis
unless new and compelling information suggests that the chemical may
interact with the endocrine system. Although EPA will place chemicals
in the hold category during the initial sorting phase of the Screening
Program, it may add chemicals to this category if, during a later phase
of the Screening Program (priority setting, Tier 1 analysis, or Tier 2
analysis), the Agency determines that a particular chemical is not
likely to interact with the endocrine system.
2. Category 2--Priority Setting/Tier 1 Analysis. Chemicals for
which there is
[[Page 42854]]
insufficient, scientifically relevant information to determine whether
or not they are likely to interact with the estrogen, androgen, and
thyroid systems. If EPA is not able to determine, based on
scientifically relevant information, whether or not a chemical is
likely to interact with the estrogen, androgen, and thyroid hormone
systems, it will place that chemical into a ``priority setting''
category. Category 2 chemicals are those for which there is
insufficient scientifically relevant information to be placed on hold
(Category 1), or assigned to Tier 2 analysis (Category 3) or hazard
assessment (Category 4). EPA anticipates that it will likely place the
majority of chemicals into this category. Category 2 chemicals will be
subjected to formal priority setting, Tier 1 analysis, and as
appropriate, Tier 2 analysis.
3. Category 3--Tier 2 Analysis. Chemicals with sufficient,
scientifically relevant information comparable to that provided by the
Tier 1 analysis. Recognizing the need for flexibility, EPA has included
Tier 1 analysis bypass possibilities. For example, if sufficient,
scientifically relevant information exists regarding a specific
chemical, EPA may move that chemical directly into Tier 2 analysis. In
addition, EPA may allow a chemical to bypass Tier 1 analysis if the
chemical's producer or registrant chooses to conduct Tier analysis
without performing Tier 1.
4. Category 4--Hazard Assessment. Chemicals with sufficient,
scientifically relevant information to bypass Tier 1 and Tier 2
analysis. For certain chemicals, there already may be sufficient,
scientifically relevant information regarding their interaction with
the estrogen, androgen, thyroid hormone systems--information comparable
to that derived from Tier 1 and Tier 2 analysis--to move them directly
into hazard assessment for endocrine disruption. These chemicals, thus,
will bypass Tier 1 and Tier 2 analysis. It is anticipated that this
will be a relatively small number (less than 100) of chemicals.
B. Priority Setting
During priority setting, EPA will determine in what order the
chemicals placed in Category 2 during ``initial sorting'' will enter
Tier 1 analysis. EPA will set priorities using existing exposure and
effects data and statutory criteria. The exposure and effects data will
consist of empirical data where available and may also employ models to
estimate exposure or effects characteristics. EPA recognizes that
existing endocrine specific effects data are incomplete or lacking for
most chemicals. To address this inadequacy, EPA, in partnership with
others, will conduct selected in vitro assays in a high-speed,
automated fashion. This step is called ``high throughput pre-
screening'' (HTPS). EPA will use the data that it generates from HTPS
for priority setting. HTPS data alone is insufficient to ascertain
whether or not a chemical may be an endocrine disruptor. Priority
setting will result in a phased approach to screening with the highest
priority chemicals evaluated first, followed by medium priority
chemicals, and then low priority chemicals. EPA has adopted a priority
setting approach because the available resources and laboratory
capacity necessary for the Endocrine Disruptor Screening Program will
not allow simultaneous entry of hundreds to thousands of chemicals into
the process.
C. Tier 1 Analysis
Tier 1 analysis is designed to identify those chemicals that are
not likely to interact with the estrogen, androgen, and thyroid hormone
systems. During Tier 1 analysis, the Agency hopes to eliminate those
chemicals that are unlikely to interact with the estrogen, androgen,
and thyroid hormone systems. EPA does not believe that Tier 1 analysis
will be adequate to determine whether a chemical may have an endocrine
effect. Completion of Tier 1 analysis will result in either a decision
to move the chemical into Tier 2 analysis, or an initial decision that
no further analysis is needed, in which case EPA will place the
chemical on hold (Category 1).
Under EPA's Screening Program, Tier 1 analysis involves both in
vitro and in vivo test systems. The Tier I assays were designed and
selected as a battery. EPA believes that data from the entire battery
are necessary to make the necessary decisions about the chemicals. The
individual assays and the battery were selected on the basis of
scientific relevance and state of scientific development. All of the
assays will be validated prior to the Screening Program's
implementation. Validation will be addressed by EPA in the future
Federal Register document. EPA will also include several alternative
assays in its validation activities. The Tier 1 in vivo and in vitro
assays are listed below.
1. In Vitro assays include an estrogen receptor binding or reporter
gene assay, an androgen receptor binding or reporter gene assay, and a
steroidogenesis assay with minced testis.
2. In Vivo assays include a rodent 3-day uterotrophic assay, a
rodent 20-day pubertal female assay with enhanced thyroid endpoints, a
rodent 5 to 7-day Hershberger assay, a frog metamorphosis assay, and a
fish gonadal recrudescence assay.
D. Tier 2 Analysis
Tier 2 analysis is designed to determine whether a chemical may
have an effect in humans similar to that of naturally occurring
hormones and to identify, characterize, and quantify those effects for
estrogen, androgen, and thyroid hormones. Like the Tier 1 battery, the
Tier 2 analysis scheme is designed as a battery. A negative outcome in
Tier 2 analysis will supersede a positive outcome in Tier 1 analysis.
Furthermore, each Tier 2 assay includes endpoints that will permit a
decision regarding whether or not a tested chemical may be an endocrine
disruptor for estrogen, androgen, or thyroid effects. Conducting all
five assays in the Tier 2 battery will provide the type of information
necessary for endocrine disruptor hazard assessment. A decision to
require less testing may be made by EPA based on scientifically
relevant information showing that exposure is limited or that effects
can be adequately characterized in a one generation assay.
1. Tier 2 assays. Tier 2 assays include a two-generation mammalian
reproductive toxicity study or a less comprehensive alternative
mammalian reproductive toxicity assay, an avian reproduction toxicity
assay, a fish life cycle toxicity assay, an opossum shrimp (Mysidacea)
or other invertebrate life cycle toxicity assay, and an amphibian
development and reproduction assay.
2. Assay selection. EPA will provide guidance on the selection of
Tier 2 assays, focusing upon:
a. The determination of which of the five taxonomic groups should
be included in the Tier 2 analysis of a specific chemical.
b. The circumstances under which it may be appropriate to perform
an alternative assay, with a particular focus on the selection of
alternative mammalian assays.
c. The selection of endpoints.
d. The special case of chemicals that bypass Tier 1 analysis and go
directly to Tier 2 analysis.
e. The potential need for supplemental information to complete Tier
2 analysis.
E. Evaluation of Results
A weight-of-evidence approach will be used to evaluate Tier 1 and
Tier 2 analysis results. The weight-of-evidence approach will include:
[[Page 42855]]
1. The balance of positive and negative responses observed in both
the in vitro and in vivo assays.
2. The nature and range of the biological effects observed.
3. The shape of the dose-response curves when available.
4. The severity and magnitude of the effects induced.
5. The presence or absence of responses in multiple taxa.
The evaluation of Tier 1 data, and other scientifically relevant
information (e.g., HTPS or literature data), will result in a decision
that either the chemical needs no further analysis and can be moved to
the hold category or a decision that the chemical needs to undergo Tier
2 analysis to determine whether it may have an effect in humans that is
similar to the effect produced by a naturally occurring hormone.
Similarly, an evaluation of Tier 2 data will result in a decision
either to move the chemical into the hold category or to move it into
hazard assessment.
IV. Development of EPA Policies
EPA currently is developing policies to implement the Endocrine
Disruptor Screening Program. EPA will set forth these policies in
another Federal Register document later this year. This document will
provide interpretive and operational details, and address such issues
as standardization and validation of the assays, statutory and
regulatory mechanisms for requiring the development of data, data
reporting requirements, data compensation, confidential business
information, and the process for granting waivers from screening
requirements.
List of Subjects
Environmental protection.
Dated: July 31, 1998
Approved by:
J. Charles Fox,
Assistant Administrator for Water.
Lynn R. Goldman,
Assistant Administrator for Prevention, Pesticides, and Toxic
Substances.
[FR Doc. 98-21522 Filed 8-10-98; 8:45 am]
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