[Federal Register: March 21, 2006 (Volume 71, Number 54)]
[Notices]
[Page 14229-14231]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr21mr06-102]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Toxicology Program (NTP), NTP Interagency Center for the
Evaluation of Alternative Toxicological Methods (NICEATM); Announcement
of an Independent Scientific Peer Review Meeting on the Use of In Vitro
Testing Methods for Estimating Starting Doses for Acute Oral Systemic
Toxicity Tests and Request for Comments
AGENCY: National Institute of Environmental Health Sciences (NIEHS),
National Institutes of Health (NIH).
ACTION: Meeting Announcement and Request for Comment.
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SUMMARY: NICEATM in collaboration with the Interagency Coordinating
Committee on the Validation of Alternative Methods (ICCVAM) announces a
public, independent, scientific peer review meeting to evaluate the
validation status of the in vitro 3T3 and normal human keratinocyte
(NHK) neutral red uptake (NRU) basal cytotoxicity test methods for
estimating starting doses for in vivo acute oral toxicity tests. These
two in vitro cytotoxicity test methods are proposed as adjuncts to the
in vivo acute oral toxicity tests to refine (i.e., to lessen or avoid
pain and distress) and/or reduce animal use. At this meeting, a
scientific peer review panel (``Panel'') will peer review the
background review document (BRD) on the 3T3 and NHK cytotoxicity test
methods, evaluate the extent that the BRD addresses established
validation and acceptance criteria, and provide comment on the draft
ICCVAM recommendations on the proposed use of these test methods, draft
test method protocols, and draft performance standards. NICEATM
requests public comments on the BRD, draft ICCVAM test method
recommendations, draft test method protocols, and draft performance
standards.
DATES: The meeting will be held on May 23, 2006, from 8:30 a.m. to 5
p.m. The meeting is open to the public with attendance limited only by
the space available. In order to facilitate planning for this meeting,
persons wishing to attend the meeting are asked to register via the
ICCVAM/NICEATM Web site (http://iccvam.niehs.nih.gov) by May 12, 2006.
ADDRESSES: The meeting will be held at the National Institutes of
Health (NIH), Natcher Conference Center, 45 Center Drive, Bethesda, MD
20892.
FOR FURTHER INFORMATION CONTACT: Correspondence should be sent by mail,
fax, or email to Dr. William S. Stokes, NICEATM Director, NIEHS, P.O.
Box 12233, MD EC-17, Research Triangle Park, NC 27709, (phone) 919-541-
2384, (fax) 919-541-0947, (e-mail) niceatm@niehs.nih.gov, Courier
address: NICEATM, 79 T.W. Alexander Drive, Building 4401, Room 3128,
Research Triangle Park, NC 27709.
SUPPLEMENTARY INFORMATION:
Background
In September 2001, ICCVAM recommended that in vitro basal
cytotoxicity test methods be considered as tools for estimating
starting doses for in vivo acute systemic toxicity studies (Federal
Register Vol. 66, No. 189, pp. 49686-7, September 28, 2001). The
recommendations were based on the Report of the International Workshop
on In Vitro Methods for Assessing Acute Systemic Toxicity (ICCVAM,
2001a). The Guidance Document on Using In Vitro Data to Estimate In
Vivo Starting Doses for Acute Toxicity (ICCVAM, 2001b) was also made
available at that time. The guidance document provided standard
procedures for two in vitro basal cytotoxicity test methods and
instructions for using these test methods to estimate starting doses
for in vivo testing.
[[Page 14230]]
U.S. Federal agencies' responses to the ICCVAM recommendations from
the International Workshop were announced in 2004 (Federal Register
Vol. 69, No. 47, pp. 11448-9, March 10, 2004). The U.S. Federal
agencies agreed to encourage, to the extent applicable, the use of in
vitro tests for determining starting doses for acute oral systemic
toxicity testing. Furthermore, the U.S. Environmental Protection Agency
(EPA) specifically encouraged those participating in the High
Production Volume Challenge Program to consider using the recommended
in vitro test methods as a supplemental component when conducting any
new in vivo acute oral toxicity studies for the program (http://www.epa.gov/chemrtk/toxprtow.htm
).
In 2002, NICEATM and the European Committee on the Validation of
Alternative Methods began a collaborative validation study to
independently evaluate the usefulness of two in vitro basal
cytotoxicity test methods proposed for estimating starting doses for in
vivo rodent acute oral toxicity tests. In vitro NRU cytotoxicity test
methods using either BALB/c 3T3 fibroblasts, a mouse cell line, or NHK
cells, primary human epidermal cells, were evaluated in a multi-
laboratory international validation study. During the pre-validation
phases of the study, the test method protocols were standardized
further and revised to improve their intra- and inter-laboratory
reproducibilities. NICEATM recommended using the revised test method
protocols (Federal Register, Vol. 69, No. 201, pp. 61504-5, October 19,
2004) rather than the standard procedures outlined in the guidance
document (ICCVAM, 2001b). During the validation study, 72 reference
chemicals were tested using the 3T3 and NHK NRU test methods. The in
vitro NRU cytotoxicity test results were used to estimate acute oral
LD50 values, which in turn were used to identify the
starting doses for simulated acute oral toxicity testing using the Up-
and-Down Procedure (UDP; EPA 2002; OECD 2001a) and the Acute Toxic
Class method (ATC; OECD 2001b). The in vivo test simulations were used
to compare the number of animals used and the number of deaths expected
to occur when starting with the default starting doses versus using a
starting dose based on in vitro cytotoxicity data.
To assist in an evaluation of the usefulness of these two in vitro
NRU basal cytotoxicity test methods for estimating starting doses for
in vivo. acute oral toxicity tests, NICEATM requested the submission of
existing in vivo and in vitro acute toxicity data (Federal Register,
Vol. 69, No. 201, pp. 61504-5, October 19, 2004 and Vol. 65, No. 115,
pp. 37400-3, June 14, 2000). In 2005, NICEATM announced a request for
nominations of scientists to serve on the Panel and again requested
existing in vivo and in vitro data (Federal Register Vol. 70, No. 54,
pp. 14473-4, March 22, 2005).
Expert Panel Meeting
The purpose of this meeting is the scientific peer review
evaluation of the validation status of the 3T3 and NHK NRU basal
cytotoxicity test methods to determine starting doses for the UDP and
ATC acute oral toxicity test methods in order to refine and reduce the
use of animals. The Panel will first peer review the BRD on the 3T3 and
NHK cytotoxicity test methods and then evaluate the extent that the
BRDs address established validation and acceptance criteria (Validation
and Regulatory Acceptance of Toxicological Test Methods: A Report of
the ad hoc Interagency Coordinating Committee on the Validation of
Alternative Methods, NIH Publication No. 97-3981, http://iccvam.niehs.nih.gov
). The Panel will also be asked to provide comment
on the draft ICCVAM test method recommendations, draft standardized
test method protocols, and draft performance standards. Information
about the Panel meeting, including a roster of the members of the Panel
and the agenda, will be made available two weeks prior to the meeting
on the ICCVAM/NICETATM Web site (http://iccvam.niehs.nih.gov) or can be
obtained after that date by contacting NICEATM (see FOR FURTHER
INFORMATION CONTACT above).
Attendance and Registration
The public Panel meeting will take place May 23, 2006, at the NIH
Campus, Natcher Conference Center, Bethesda, MD (a map of the NIH
Campus and other visitor information are available at http://www.nih.gov/about/visitor/index.htm
). The meeting will begin at 8:30
a.m. and conclude at approximately 5 p.m. Persons needing special
assistance, such as sign language interpretation or other reasonable
accommodation in order to attend, should contact 919-541-2475 voice,
919-541-4644 TTY (text telephone), through the Federal TTY Relay System
at 800-877-8339, or by e-mail to niehsoeeo@niehs.nih.gov. Requests
should be made at least seven business days in advance of the event.
Availability of the BRD and Draft ICCVAM Recommendations
NICEATM prepared a BRD on the 3T3 and NHK NRU basal cytotoxicity
test methods that contains comprehensive summaries of the data
generated in the validation study, an analysis of the accuracy and
reliability of the two test methods, a simulation analysis of the
refinement and reduction in animal use that would occur if these tests
were used as adjuncts to the UDP and ATC acute oral systemic toxicity
test methods, and related information characterizing the validation
status of these assays. The BRD, draft ICCVAM test method
recommendations, draft test method protocols, and draft test method
performance standards will be provided to the Panel and made available
to the public. Copies of these materials can be obtained from the
ICCVAM/NICEATM Web site (http://iccvam.niehs.nih.gov) or by contacting
NICEATM (see FOR FURTHER INFORMATION CONTACT above).
Request for Comments
NICEATM invites the submission of written comments on the BRD,
draft ICCVAM test method recommendations, draft test method protocols,
and draft test method performance standards. When submitting written
comments, it is important to refer to this Federal Register notice and
include appropriate contact information (name, affiliation, mailing
address, phone, fax, email and sponsoring organization, if applicable).
Written comments should be sent by mail, fax, or email to Dr. William
Stokes, Director of NICEATM, at the address listed above not later than
May 5, 2006. All comments received will be placed on the ICCVAM/NICEATM
website and made available to the Panel, ICCVAM agency representatives,
and attendees at the meeting.
This meeting is open to the public and time will be provided for
the presentation of public oral comments at designated times during the
peer review. Members of the public who wish to present oral statements
at the meeting (one speaker per organization) should contact NICEATM
(see FOR FURTHER INFORMATION CONTACT above) no later than May 12, 2006.
Speakers will be assigned on a consecutive basis and up to seven
minutes will be allotted per speaker. Persons registering to make
comments are asked to provide a written copy of their statement by May
12, 2006, so that copies can be distributed to the Panel prior to the
meeting or if this is not possible to bring 40 copies to the meeting.
Written statements can supplement and expand the oral presentation.
Each speaker is asked to
[[Page 14231]]
provide contact information (name, affiliation, mailing address, phone,
fax, email and sponsoring organization, if applicable) when registering
to make oral comments.
Summary minutes and a final report of the Panel will be available
following the meeting at the ICCVAM/NICEATM Web site (http://iccvam.niehs.nih.gov
). ICCVAM will consider the conclusions and
recommendations from the Panel and any public comments received in
finalizing test method recommendations and performance standards for
these test methods.
Background Information on ICCVAM and NICEATM
ICCVAM is an interagency committee composed of representatives from
15 U.S. Federal regulatory and research agencies that use or generate
toxicological information. ICCVAM conducts technical evaluations of
new, revised, and alternative methods with regulatory applicability and
promotes the scientific validation and regulatory acceptance of
toxicological test methods that more accurately assess the safety and
hazards of chemicals and products while refining (less pain and
distress), reducing, and replacing animal use. The ICCVAM Authorization
Act of 2000 (Pub. L. 106-545, available at http://iccvam.niehs.nih.gov/about/PL106545.htm
) establishes ICCVAM as a permanent interagency
committee of the NIEHS under the NICEATM. NICEATM administers the
ICCVAM and provides scientific and operational support for ICCVAM-
related activities. NICEATM and ICCVAM work collaboratively to evaluate
new and improved test methods applicable to the needs of U.S. Federal
agencies. Additional information about ICCVAM and NICEATM can be found
at the ICCVAM/NICEATM Web site: http://iccvam.niehs.nih.gov.
References
EPA. 2002a. Health Effects Test Guidelines OPPTS 870.1100 Acute Oral
Toxicity. EPA 712-C-02-190. Washington, DC: U.S. Environmental
Protection Agency.
ICCVAM. 2001a. Report of the international workshop on in vitro
methods for assessing acute systemic toxicity. NIH Publication 01-
4499. Research Triangle Park, NC: National Institute for
Environmental Health Sciences. Available at: http://iccvam.niehs.nih.gov/
.
ICCVAM. 2001b. Guidance document on using in vitro data to estimate
in vivo starting doses for acute toxicity. NIH Publication 01-4500.
Research Triangle Park, NC: National Institute for Environmental
Health Sciences. Available at: http://iccvam.niehs.nih.gov/. OECD.
2001a. Guideline for Testing of Chemicals, 425, Acute Oral
Toxicity--Up-and-Down Procedure. Paris France: OECD. Available at:
http://www.oecd.org [accessed June 2, 2004]. OECD. 2001b. Guideline
For Testing of Chemicals, 423, Acute Oral Toxicity--Acute Toxic
Class Method. Paris France: OECD.
Dated: March 9, 2006.
Samuel H. Wilson,
Deputy Director, National Institute of Environmental Health Sciences
and National Toxicology Program.
[FR Doc. E6-4075 Filed 3-20-06; 8:45 am]
BILLING CODE 4140-01-P