[Federal Register Volume 66, Number 189 (Friday, September 28, 2001)]
[Notices]
[Pages 49686-49687]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-24370]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service


National Institute of Environmental Health Sciences (NIEHS); 
National Toxicology Program (NTP)

    Report of the International Workshop on In Vitro Methods for 
Assessing Acute Systemic Toxicity; Guidance Document on Using In Vitro 
Data to Estimate In Vivo Starting Doses for Acute Toxicity: Notice of 
Availability and Request for Public Comment.

Summary

    Notice is hereby given of the availability of the reports entitled, 
``Report of the International Workshop on In Vitro Methods for 
Assessing Acute Systemic Toxicity'' NIH Publication 01-4499 and 
``Guidance Document on Using In Vitro Data to Estimate In Vivo Starting 
Doses for Acute Toxicity'' NIH Publication 01-4500. The Report provides 
conclusions and recommendations from expert scientists based on their 
review of current in vitro methods for assessing acute toxicity at an 
October 17-20, 2000 workshop. The workshop was organized by the 
National Toxicology Program Interagency Center for the Evaluation of 
Alternative Toxicological Methods (NICEATM) and the Interagency 
Coordinating Committee on the Validation of Alternative Methods 
(ICCVAM). The Guidance Document

[[Page 49687]]

provides Standard Operating Procedures (SOPs) for performing two in 
vitro basal cytotoxicity assays and describes how to use this in vitro 
data to predict starting doses for in vivo acute oral toxicity studies.

Availability of the Documents

    To receive a copy of either report, please contact NICEATM at P.O. 
Box 12233, MD EC-17, Research Triangle Park, NC 27709 (mail), 919-541-
3398 (phone), 919-541-0947 (fax), or [email protected] (email). The 
reports are also available on the ICCVAM/NICEATM website at http://iccvam.niehs.nih.gov.

Request for Public Comments

    NICEATM invites written public comments on the Workshop Report and 
the Guidance Document. Comments should be sent to NICEATM by November 
13, 2001. Comments submitted via e-mail are preferred; the acceptable 
file formats are MS Word (Office 98 or older), plain text, or PDF. 
Comments should be sent to Dr. William S. Stokes, Director, NICEATM, 
NIEHS, MD EC-17, PO Box 12233, Research Triangle Park, NC, 27709; 
telephone 919-541-2384; fax 919-541-0947; e-mail [email protected]. 
Persons submitting written comments should include their contact 
information (name, affiliation, address, telephone and fax numbers, and 
e-mail) and sponsoring organization, if any. Public comments received 
in response to this Federal Register notice will be posted on the 
NICEATM/ICCVAM web site (http://iccvam.niehs.nih.gov).

Background

    The International Workshop on In Vitro Methods for Assessing Acute 
Systemic Toxicity was held October 17-20, 2000, at the Hyatt Regency 
Crystal City Hotel, 2799 Jefferson Davis Highway, Arlington, VA 22202. 
The workshop was organized by the NICEATM and ICCVAM, and sponsored by 
the NIEHS, the NTP, and U.S. EPA. The objectives of the workshop were 
(1) to assess the current validation status of in vitro test methods 
that might be useful for assessing the acute systemic toxicity 
potential of chemicals and (2) to develop recommendations for future 
research, development, and validation studies that might further 
enhance the use of in vitro methods for this purpose.
    A Federal Register notice (Vol. 65, No. 115, pp. 37400-37403, June 
14, 2000) requested information and data that should be considered at 
the workshop, and nominations of expert scientists to participate in 
the workshop. A second Federal Register notice (Vol. 65, No. 184, pp. 
57203-57205, September 21, 2000) announced availability of the workshop 
agenda, registration information, and a background summary of available 
in vitro methods.
    At the workshop, the invited expert scientists were divided into 
four breakout groups as follows:

Breakout Group 1: In Vitro Screening Methods for Assessing Acute 
Toxicity
Breakout Group 2: In Vitro Methods for Toxicokinetic Determinations
Breakout Group 3: In Vitro Methods for Predicting Organ-Specific 
Toxicity
Breakout Group 4: Chemical Data Sets for Validation of In Vitro Acute 
Toxicity Test Methods

    Each breakout group subsequently prepared a written report that 
represented the consensus of the invited scientists assigned to that 
group and these reports are included in the Workshop Report. It also 
includes as appendices: A detailed workshop agenda; summary minutes of 
plenary sessions and public comments; the background document for 
workshop participants; a NICEATM summary of the Multicenter Evaluation 
of In Vitro Cytotoxicity (MEIC); a summary of Federal regulations on 
acute toxicity; related Federal Register notices; and ICCVAM test 
method recommendations. The ICCVAM test recommendations were developed 
following the workshop to forward to Federal agencies in accordance 
with Pub. L. 106-545.
    The Breakout Group on In Vitro Screening Methods recommended 
preparation of a document that would provide guidance on how to use in 
vitro data to estimate starting doses for in vivo acute toxicity 
studies. Three scientists subsequently collaborated with the NICEATM to 
develop a ``Guidance Document on Using In Vitro Data to Estimate In 
Vivo Starting Doses for Acute Toxicity''. The Guidance Document 
provides SOPs for conducting two in vitro cytotoxicity tests (the BALB/
c 3T3 Neutral Red Uptake (NRU) and the Normal Human Keratinocyte (NHK) 
NRU assays) and instruction for using these assays to estimate starting 
doses for in vivo testing. The Guidance Document also includes the 
ZEBET (German National Centre for the Documentation and Evaluation of 
Alternatives to Animal Experimentation) Registry of Cytotoxicity (RC) 
Regression Analysis that provides a mathematical relationship between 
acute oral systemic rodent toxicity and in vitro basal cytotoxicity 
using data for 347 chemicals (Halle, 1998; Spielmann et al., 1999). The 
Guidance Document expands on an approach suggested by Spielmann and 
colleagues that--as an initial step--the relationship found with the RC 
data be used to predict starting doses for subsequent in vivo acute 
lethality assays.

Additional Information About ICCVAM and NICEATM

    ICCVAM, with 15 participating Federal agencies, was established in 
1997 to coordinate interagency issues on toxicological test method 
development, validation, regulatory acceptance, and national and 
international harmonization. The ICCVAM Authorization Act of 2000 (Pub. 
L. 106-545) formally authorized and designated ICCVAM as a permanent 
committee administered by the NIEHS with specific duties that include 
the technical evaluation of new and alternative testing methods. ICCVAM 
is charged with developing test recommendations based on those 
technical evaluations, and forwarding these to Federal agencies for 
their consideration. The NICEATM was established in 1998 to coordinate 
and facilitate ICCVAM activities, to provide peer review for validation 
activities and to promote communication with stakeholders. The NICEATM 
is located at the NIEHS, Research Triangle Park, NC. Additional 
information concerning ICCVAM and NICEATM can be found on the ICCVAM/
NICEATM web site at http://iccvam.niehs.nih.gov. In accordance with 
Public Law 106-545, the Workshop Report and the Guidance Document will 
be forwarded with ICCVAM test recommendations to Federal agencies for 
their consideration.

References

    Halle, W. 1998. Toxizitatsprufungen in Zellkulturen fur eine 
Vorhersage der akuten Toxizitat (LD50) zur Einsparung von 
Tierversuchen. Life Sciences/Lebenswissenschaften, Volume 1, 94 pp., 
Julich: Forschungszentrum Julich.
    Spielmann, H., E. Genschow, M. Liebsch, and W. Halle. 1999. 
Determination of the starting dose for acute oral toxicity 
(LD50) testing in the up and down procedure (UDP) from 
cytotoxicity data. ATLA 27: 957-966.

    Dated: September 18, 2001.
Samuel H. Wilson,
Deputy Director, National Institute of Environmental Health Sciences.
[FR Doc. 01-24370 Filed 9-27-01; 8:45 am]
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