[Federal Register Volume 65, Number 4 (Thursday, January 6, 2000)]
[Notices]
[Pages 784-787]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-228]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health service


National Institute of Environmental Health Sciences, NIH; 
National Toxicology Program; Solicitation of Comments on Proposed Peer 
Review of Low-Dose Issues for Endocrine Disruptors

SUMMARY: NTP is soliciting comments on the planned scope and process 
for a proposed peer review of studies bearing on the question of 
whether endocrine disruptors may cause effects at doses lower than are 
tested using standard toxicological testing procedures. Nominations for 
peer reviewers, as well as nominations for studies to be reviewed, are 
also being solicited. Results from the peer review will help the U.S. 
Environmental Protection Agency (a member agency of the NTP) and, in 
particular the EPA's Endocrine Disruptor Screening Program, determine 
how to address low-dose questions in endocrine disruptor screening, 
testing, and hazard assessment.

Background

    The U.S. Environmental Protection Agency (EPA) is implementing an 
Endocrine Disruptor Screening Program as required by the Food Quality 
Protection Act of 1996 (See 63 FR 71542-71568, Dec. 28, 1998). The EPA 
is in the process of choosing appropriate assays to use in this 
screening program and is also developing standardized, validated 
protocols for these assays. A critical aspect of protocol development 
is dose-setting. In recent years, there have been suggestions that 
hormonally active agents may cause effects at doses lower than those 
normally selected for toxicological testing. A review of the issue can 
be found in the National Academy of Science's recently-released report 
Hormonally Active Agents in the Environment (NRC [National Research 
Council]. 1999. Washington, DC: National Academy Press, pp. 103-111).
    The EPA has asked the National Toxicology Program to establish an 
independent panel of scientists to review the evidence related to low-
dose effects and consider their implications for the development, 
validation, and interpretation of test protocols. If this Panel 
concludes that significant effects at low doses occur and that the 
standard dose-setting paradigm is inadequate to detect such effects, 
the EPA intends to pursue in a separate forum the question of how to 
test for such effects, including endpoints to be tested, dose-setting 
protocols and appropriate test methods. If the Panel believes the 
current data to be inconclusive, it will be asked to describe specific 
research that would resolve the ambiguities.

Proposed Scope and Process for the review

A. Scope of the Review

    Analysis will focus on interpretation of the major data sets 
showing or refuting effects at low doses. ``Low doses'' are defined for 
the purposes of discussion as ``doses below the currently accepted No 
Observed Adverse Effect Level for that substance''. The intent is to 
evaluate the presence or absence of low-dose effects in specific 
studies, then evaluate the likelihood and significance of these and/or 
other potential low-dose effects to humans.
    The main topic to be addressed is evidence for defining the shape 
of the dose/response curves for endocrine-active substances in the low-
dos region.
    The review is expected to examine all evidence, including such 
things as relevant pharmacokinetic and mechanistic information, which 
may have a bearing on the low-dose issue. In order to come to 
disclosure on the central issue of whether there are sufficient grounds 
to change the traditional dose-setting paradigm for endocrine-active 
substances, it will not be possible to go into the details of non-
central issues. Issues which may enter the discussion but which are not 
the central forcus and will not get exhaustive review include:

    --existence of inverted U-shaped dose/response curves as a general 
phenomenon in toxicology;
    --completeness of the list of endpoints examined in two-generation 
toxicity tests;
    --definition of ``adversity''.

B. Selection of Studies for Review

    Given the breadth of the scope, many studies are likely to be 
considered relevant to the discussion. NTP proposes to divide studies 
into two categories: those which provide background information and 
those which hare critical to the resolution of the issue. Hard copies 
of both the background information and critical studies will be 
provided to the Panel in advance of the Peer Review Meeting. For the 
critical studies, principal investigators will be invited for in-depth 
discussions with the Panel, and the data sets from these critical 
studies will be subjected to independent analyses by the panel. NTP 
anticipates that approximately 10 to 12 studies might be designated 
critical.

C. Criteria for Selection of Studies for Review

    Studies which provide direct evidence for the presence of effects 
related to the endocrine system at doses below the No Observed Adverse 
Effect Level will generally be considered critical. Studies which 
provide direct evidence against such effects at similar doses for the 
same chemical will also generally be considered critical. Studies which 
provide direct evidence for endocrine-related effects for chemicals for 
which NOAELs have not been established will generally be considered 
critical if there is reason to believe that normal procedures for 
establishing a NOAEL would set NOAELs at a higher level than those 
indicated by the study in question, as long as the difference in 
putative NOAELs would be due to dose/response considerations rather 
than to definitions of adversity or selection of endpoints for 
observation. Studies which provide direct evidence against effects at 
similar doses from chemicals for which such claims have been made will 
also generally be considered critical.
    Pharmacokinetic and mechanistic studies which provide insight into 
the plausibility or relevance of effects established in the direct 
studies may be either critical or background information depending on 
how closely they address low-dose issues.
    Studies of other endocrine effects caused by a substance for which 
a low-dose endocrine effect is established will be considered 
background information unless mechanistic information establishes a 
relevant relationship to the low-dose effect.
    In general, potency per se, is not a central issue. Studies which 
show effects at low doses but whose central issue in setting a NOAEL is 
either the definition of adversity or the completeness of the list of 
endpoints for which observations are made will not be considered 
relevant to the dose/response issues that this peer review will 
address.
    For background information, well-written reviews will be preferred 
over individual studies. Only studies or reviews which have been 
published in standard, peer-reviewed scientific journals or books will 
be considered.

[[Page 785]]

    Critical studies must be accepted for publication in a standard, 
peer-reviewed scientific journal or book by April 1, 2000. Studies 
presented at scientific meetings but not formally accepted for 
publication in a peer-reviewed journal will not be accepted.
    Raw data for critical studies must be available for the Panel to 
review and analyze. ``Raw data'' includes data on individual laboratory 
animals, prior to aggregation by statistical or other methods. Data 
reported under Good Laboratory Practices, for example, will generally 
be considered ``raw data''.

D. Selection Procedure

    An NTP interagency workshop organizing committee will choose the 
studies to be considered by the Panel.
    NTP recognizes that the date of acceptance for publication cannot 
be predicted with accuracy. Similarly, co-operation by principal 
investigators to include a study in this review cannot be guaranteed. 
For planning purposes, it may become necessary to designate certain 
studies as ``likely to be critical'' before April 1 and to treat them 
as if they will be examined at the Panel meeting. However, the criteria 
will be applied on April 1.

E. Preliminary List of Published Studies To Be Considered by the Low-
Dose Peer Review Panel

    The NTP has compiled the attached preliminary list of relevant 
studies and invites public comment on the list.

F. Peer Review Panel Members

    A panel of 16 to 20 members is anticipated. NTP is soliciting 
nominations for the Panel from the public. (See Guidelines for 
Submission of Comments below). Kinds of expertise that are likely to be 
relevant include reproductive biology (male and female, whole animal 
and cellular), endocrinology, pharmacology, statistical data analysis, 
and dose/response modeling. Expertise need not be limited to these 
areas, nor will these areas necessarily all be included on the Panel. 
NTP will try to ensure an appropriate breadth of expertise across the 
Panel. If there are particular kinds of expertise that you feel the 
Panel should include, please provide a justification in your comments, 
especially if the expertise is not covered in the list above.
    Nominations should be accompanied by complete contact information, 
including name, address, institutional affiliation, telephone number, 
and e-mail address. Where possible, a Web page address for research 
interests and/or curriculum vitae should be included. To avoid the 
potential for candidates being contacted by a large number of 
nominators, candidates need not be contacted prior to nomination. NTP 
will solicit curricula vitae and interest in participation at an 
appropriate time.

G. Criteria for Selection of Panel Members

    Expertise in a scientific field relevant to the low-dose issue is 
required.
    Investigators associated with critical studies will not be 
considered for the Panel. Principal investigators (or their designated 
co-authors) for critical studies will be asked to present their data 
and be available for discussion at the Peer Review Panel meeting, but 
will not be asked to be part of the Panel itself.

H. Selection Procedure

    Panelists will be chosen after critical studies have been selected. 
An NTP interagency organizing committee will select panel members 
considering all nominations received from the public as well as 
nominations developed internally. All nominees will be contacted for 
interest and availability, and curricula vitae will be solicited from 
the nominees. Selection will be based on the CVs and accompanying 
information such as statements of research interest. Official 
invitations to participate will be sent out in approximately April of 
2000. The final list of Peer Review panel members will be available to 
the public through the Endocrine Disruptor Screening Program's Interent 
Web site (http://www.epa.gov/scinpoly/oscpendo/index.htm). Panel 
members will be paid as consultants, and candidates will be required to 
disclose potential conflicts of interest.

I. Subcommittee Structure

    NTP proposes to have Subcommittees of the Peer Review Panel examine 
specific aspects of the low-dose issue. Subcommittee topics will be 
determined after studies for review have been selected. Topics that may 
be appropriate for Subcommittees include:
     Data Analysis and Statistics
     Pharmacokinetics, Receptor Binding, and Modeling
     Effects on Males
     Effects on Females
    Comments on the appropriateness of having Subcommittees, and of the 
specific topics suggested, are welcome.

Approximate Schedule for the Review

    A meeting of the Peer Review Panel is tentatively planned for late 
July 2000 in the Research Triangle Park, NC area. The entire peer 
review panel meeting will be open to the public, limited only by space 
available. Details of the meeting location, dates, and times will be 
announced at a later time.
    In order to meet this deadline, designation of critical studies 
will take place in March, with Panel selection to begin in the March/
April time frame.
    Between May and late June, the data analysis subcommittee will be 
asked to review the data on critical studies. Investigators may be 
asked to run analyses of their own data according to the specifications 
of the Data Analysis Subcommittee. Approximately four weeks before the 
Peer Review, this Subcommittee will have the opportunity to meet with 
the investigators by conference call (or, if necessary, at a central 
location) to ask questions and obtain additional data that might be 
needed in preparation for the Panel meeting. The findings of the Data 
Analysis Subcommittee will be made available to the full Peer Review 
Panel for discussion at the meeting.
    On the first day of the Peer Review Meeting, presentation from 
principal investigators for the critical studies will be heard by the 
entire Panel. Also, the Data Analysis and Statistics Subcommittee will 
present its analysis of the data to the remainder of the Low-Dose 
Panel. Principal investigators of the critical studies will be 
available for comment.
    On the second day, the remaining Subcommittee will meet separately 
for discussion. Members of the Data Analysis and Statistics 
Subcommittee will be asked to split up between the remaining 
subcommittees.
    On the third day, the entire Panel will reconvene as a group to 
discuss the deliberations of each of the Panels and to integrate the 
separate aspects into a report.
    Each of the Subcommittees, as well as the full Panel, will produce 
a written Report following the meeting, documenting the discussions and 
explaining reasons for the scientific judgments made. These reports 
will be submitted for publication in an appropriate peer-reviewed 
scientific journal. Reports will also be made on the NTP and EPA 
(Endocrine Disruptor Screening Program) Web sites.

Public Input Solicited

    As described above, the NTP solicits comments on the scope and 
process for the review; comments on the NTP preliminary list of studies 
for review; the nomination of studies to be considered for review; and 
the nomination of peer review panel members. Comments, identified by 
docket control number OPPTS-42208A,

[[Page 786]]

must be received on or before February 22, 2000.

Guidelines for Submission of Public Comments

    EPA will manage the record-keeping aspects of the Peer Review as 
part of the Endocrine Disruptor Screening Program.
    You man obtain electronic copies of this document, and certain 
other related documents that might be available electronically, from 
the EPA Internet Home Page at http://www.epa.gov/. To access this 
document, 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/fedrgstr/.
    For general information about the Endrocrine Disruptor Screening 
Program go to http://www.epa.gov/scipoly/oscpendo/index.htm.
    The EPA has established an official record for this action under 
docket control number OPPTS-42208A. The official record consists of the 
documents specifically referenced in this action, any public comments 
received during an applicable comment period, and other information 
related to this action. This official record includes the documents 
that are physically located in the docket, as well as the documents 
that are referenced in those documents. The public version of the 
official record does not include any information claimed as CBI. The 
public version of the official record, which includes printed, paper 
versions of any electronic comments submitted during an applicable 
comment period, is available for inspection in the TSCA Nonconfidential 
Information Center, North East Mall Rm. B-607, Waterside Mall, 401 M 
St., SW, Washington, DC. The Center is open from noon to 4 p.m., Monday 
through Friday, excluding legal holidays. The telephone number for the 
Center is (202) 260-7099.
    You may submit comments through the mail, in person, or 
electronically. To ensure proper receipt by EPA, it is imperative that 
you identify docket control number OPPTS-42208A in the subject line on 
the first page of your response.
    1. By mail. Submit your comments to: Document Control Office 
(7407), Office of Pollution Prevention and Toxics (OPPT), Environmental 
Protection Agency, 401 M St., SW, Washington, DC 20460.
    2. In person or by courier. Deliver your comments to: OPPT Document 
Control Office (DCO) in East Tower Rm. G-099, Waterside Mall, 401 M St. 
SW, Washington, DC. The DCO is open from 8 a.m. to 4 p.m., Monday 
through Friday, excluding legal holidays. The telephone number for the 
DCO is (202) 260-7093.
    3. Electronically. You may submit your comments electronically by 
e-mail to: ``[email protected],'' or mail your computer disk to the 
address identified above. Do not submit any information that you 
consider to be CBI. Electronic comments may be submitted in WordPerfect 
6.1/8.0 or as an ASCII file avoiding the use of special characters and 
any form of encryption. Comments and data will also be accepted on 
standard disks in WordPerfect 6.1/8.0 or ASCII file format. All 
comments in electronic form must be identified by docket control number 
OPPTS-42208A. Electronic comments may also be filed online at many 
Federal Depository Libraries.
    Do not submit any information that you consider to be Confidential 
Business Information. If you believe that relevant information will be 
overlooked because of this restriction, please consult the person 
identified under FOR FURTHER INFORMATION CONTACT.

FOR FURTHER INFORMATION CONTACT:
James P. Kariya, Office of Science Coordination and Policy (7203), 
Office of Prevention, Pesticides, and Toxic Substances, Environmental 
Protection Agency, 401 M St. SW, Washington, DC 20460; telephone 
number: (202) 260-2916; e-mail address: [email protected].

    Dated: December 28, 1999.
Kenneth Olden,
Director, National Toxicology Program, Department of Health and Human 
Services.

Attachment--Preliminary List of Published Studies to Be Considered 
by the Low-dose Peer Review Panel

    The NTP has compiled a preliminary list of relevant studies. The 
public is invited to comment on this list; suggestions for 
additions, deletions, and substitutions may be submitted. (See 
Section of this FR announcement on Guidelines for Submission of 
Public comments.) Submission of a complete copy of the journal 
article in which the study and its results are described is 
preferred, but a complete reference (authors' names, name of 
journal, volume, issue, pages, title, date) will be sufficient if 
the complete article cannot be submitted. Include a brief narrative 
explaining the reason for each addition, deletion, or substitution. 
Raw data need not be submitted at this stage.
    Studies which are as yet unpublished but which are expected to 
be accepted for publication before April 1, 2000 may be nominated. 
An abstract of the study describing highlights of the study 
(including species and strain, dosing regimen, duration of study, 
number of animals per dose, endpoints evaluated and, if available, 
results) must be submitted in order for the Selection Committee to 
be able to evaluate the likelihood that the study will be a critical 
study. As with published studies, a brief narrative explaining the 
significance of as yet unpublished studies should be included.
    Studies which are completed but not published are not included 
here. This list is being provided as an example of the kinds of 
studies that may be appropriate for the Panel to consider. Final 
selection of studies has not been made.
    Ashby J, Elliott BM. 1997. Reproducibility of endocrine 
disruption data. Reg Toxicol Pharmacol 26:94-95.
    Ashby J, Tinwell H, Lefevre PA et al. 1997. Normal sexual 
development of rats exposed to butyl benzyl phthalate from 
conception to weaning. Reg Toxicol Pharmacol 26:102-118.
    Boettger-Tong H, Murthy L, Chiapetta C, et al. 1998. A case of a 
laboratory animal feed with high estrogenic activity and its impact 
on in vivo responses to exogenously administered estrogens. Environ 
Health Perspect 106(7):369-373.
    Cagen SZ, Waechter JM Jr, Dimond SS, et al. 1999. Normal 
reproductive organ development in CF-1 mice following prenatal 
exposure to bisphenol A. Toxicol Sci 50:36-44.
    Colerangle JB, Roy D. 1997. Profound effects of the weak 
environmental estrogen-like chemical bisphenol A on the growth of 
the mammary gland of Noble rats. J Steroid Biochem Molec Biol 60(1-
2), 153-160.
    Makela SI, Pylkkanen LH, Santti RSS, Adlercreutz H. 1995. 
Dietary soybean may be antiestrogenic in male mice. J Nutr 125:437-
445.
    Nagel SC, vom Saal FS, Thayer KA, et al. 1997. Relative binding 
affinity-serum modified access (RBA-SMA) assay predicts the relative 
in vivo bioactivity of the xenoestrogens bisphenol A and 
octylphenol. Environ Health Perspect 105:70-76.
    Odum J. Pyrah ITG, Foster JR, et al. 1999. Comparative 
activities of p-nonylphenol and diethylstilbestrol in Noble rat 
mammary gland and uterotrophic assays. Reg Toxicol Pharmacol 29:184-
195.
    Portier C, Tritscher A, Kohl M. et al. 1993. Ligand/receptor 
binding for 2,3,7,8-TCDD: implications for risk assessment. 
Fundamental and Applied Toxicol 20:48-56.
    Sharpe RM, Fisher JS, Millar MM, et al. 1995. Gestational and 
lactational exposure of rats to xenoestrogens results in reduced 
testicular size and sperm production. Environ Health Perspect 
103(12): 1136-1143.
    Sharp R, Turner KJ, Sumpter JP. 1998. Endocrine disruptors and 
testis development [letter]. Environ Health Perspect 106(5): A220-
A221.
    Sheehan DM, Willingham E, Gaylor D, et al. 1999. No threshold 
dose for estradiol-induced sex reversal of turtle embryos: how 
little is too much? Environ Health Perspect 107:155-159.
    Spearow J, Doemeny P, Sera R, et al. 1999. Genetic variation is 
susceptibility to endocrine disruption by estrogen in mice. Science 
285:1259-1261.
    vom Saal FS, Quadagno DM, Even MD, et al. 1990. Biology of 
Reproduction 43:751-761.
    vom Saal FS, Timms BG, Montano MM, et al. 1997. Prostate 
enlargement in mice due to

[[Page 787]]

fetal exposure to low doses of estradiol or diethylstilbestrol and 
opposite effects at high doses. Proc Natl Acad Sci USA 94:2056-2061.
    vom Saal FS, Cooke PS, Buchanan DL, et al. 1998. A 
physiologically based approach to the study of bisphenol A and other 
estrogenic chemicals on the size of reproductive organs, daily sperm 
production, and behavior. Toxicol Indust Hlth 14(__):239-260.
    Welshons WV, Nagel SC, Thayer KA, et al. 1999. Low-dose 
bioactivity of xenoestrogens in animals: fetal exposure to low doses 
of methoxychlor and other xenoestrogens increases adult prostate 
size in mice. Toxicol Indust Health 15:12-25.

[FR Doc. 00-228 Filed 1-5-00; 8:45 am]
BILLING CODE 4140-01-M