[Federal Register Volume 65, Number 184 (Thursday, September 21, 2000)]
[Notices]
[Pages 57203-57205]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-24244]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service


National Institute of Environmental Health Sciences (NIEHS), 
National Institutes of Health (NIH), National Toxicology Program (NTP); 
Notice of an International Workshop on In Vitro Methods for Assessing 
Acute Systemic Toxicity, co-sponsored by NIEHS, NTP and the U.S. 
Environmental Protection Agency (EPA): Workshop Agenda and Registration 
Information

SUMMARY: Pursuant to Public Law 103-43, notice is hereby given of a 
public meeting sponsored by NIEHS, the NTP, and the EPA, and 
coordinated by the Interagency Coordinating Committee on the Validation 
of Alternative Methods (ICCVAM) and the NTP Interagency Center for the 
Evaluation of Alternative Toxicological Methods (NICEATM). The agenda 
topic is a scientific workshop to assess the current status of in vitro 
test methods for evaluating the acute systemic toxicity potential of 
chemicals and to develop recommendations for future research, 
development, and validation studies. The workshop will take place on 
October 17-20, 2000, at the Hyatt Regency Crystal City Hotel, 2799 
Jefferson Davis Highway, Arlington, VA, 22202. The meeting will be open 
to the public.
    In a previous Federal Register notice (Vol. 65, No. 115, pp. 37400-
37403), ICCVAM requested information and data that should be considered 
at the Workshop and nominations of expert scientists to participate in 
the Workshop. A preliminary list of relevant studies to be considered 
for the Workshop was also provided. As a result of this request, an 
ICCVAM interagency Workshop Organizing Committee has selected an 
international group of scientific experts to participate in this 
Workshop. NICEATM, in collaboration with ICCVAM, has developed a 
background summary of data and performance characteristics for 
available in vitro methods. This summary will be made available to 
invited expert scientists and the public before the Workshop. Requests 
for the summary can be made to the address given below. This notice 
provides an agenda, registration information, and updated details about 
the Workshop.

Workshop Background and Scope

A. Background

    Acute toxicity testing is conducted to determine the hazards of 
various chemicals and products. This information is used to properly 
classify and label materials as to their lethality in accordance with 
an internationally harmonized system (OECD, 1998). Non-lethal endpoints 
may also be evaluated to identify potential target organ toxicity, 
toxicokinetic parameters, and dose-response relationships. While 
animals are currently used to evaluate acute toxicity, recent studies 
suggest that in vitro methods may also be helpful in predicting acute 
toxicity.
    Studies by Spielmann et al. (1999) suggest that in vitro 
cytotoxicity methods may be useful in predicting a starting dose for in 
vivo studies, and thus may potentially reduce the number of animals 
necessary for such determinations. Other studies (e.g., Ekwall et al., 
2000) have indicated an association between chemical concentrations 
leading to in vitro cytotoxicity and human lethal blood concentrations. 
A program to assess toxicokinetics and target organ toxicity utilizing 
in vitro methods has been proposed that may provide enhanced 
predictions of toxicity and potentially reduce or replace animal use 
for some tests (Ekwall et al., 1999). However, many of the necessary in 
vitro methods for this program have not yet been developed. Other 
methods have not been evaluated in validation studies to determine 
their usefulness and limitations for generating information to meet 
regulatory requirements for acute toxicity testing. Development and 
validation of in vitro methods which can establish accurate dose-
response relationships will be necessary before such methods can be 
considered for the reduction or replacement of animal use for acute 
toxicity determinations.
    This workshop will examine the status of available in vitro methods 
for assessing acute toxicity. This includes screening methods for acute 
toxicity, such as methods that may be used to predict the starting dose 
for in vivo animal studies, and methods for generating information on 
toxicokinetics, target organ toxicity, and mechanisms of toxicity. The 
workshop will develop recommendations for validation efforts necessary 
to characterize the usefulness and limitations of these methods. 
Recommendations will also be developed for future mechanism-based 
research and development efforts that might further improve in vitro 
assessments of acute systemic lethal and non-lethal toxicity.

B. Objectives of the Workshop

    Four major topics will be addressed:
     In Vitro Screening Methods for Assessing Acute Toxicity;

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     In Vitro Methods for Toxicokinetic Determinations;
     In Vitro Methods for Predicting Organ Specific Toxicity; 
and
     Chemical Data Sets for Validation of In Vitro Acute 
Toxicity Test Methods.
    The objectives of the meeting are to:
    1. Review the status of in vitro methods for assessing acute 
systemic toxicity:
    a. Review the validation status of available in vitro screening 
methods for their usefulness in estimating in vivo acute toxicity,
    b. Review in vitro methods for predicting toxicokinetic parameters 
important to acute toxicity (i.e., absorption, distribution, 
metabolism, elimination), and
    c. Review in vitro methods for predicting specific target organ 
toxicity;
    2. Recommend candidate methods for further evaluation in 
prevalidation and validation studies;
    3. Recommend validation study designs that can be used to 
characterize adequately the usefulness and limitations of proposed in 
vitro methods;
    4. Identify reference chemicals that can be used for development 
and validation of in vitro methods for assessing in vivo acute 
toxicity; and
    5. Identify priority research efforts necessary to support the 
development of mechanism-based in vitro methods to assess acute 
systemic toxicity. Such efforts might include incorporation and 
evaluation of new technologies, such as gene microarrays, and 
development of methods necessary to generate dose response information.

Workshop Information

A. Workshop Agenda

Tuesday, October 17, 2000
    8:30 a.m.--Opening Plenary Session
     Workshop Introduction
     Welcome from the National Toxicology Program (NTP)
     Overview of ICCVAM and NICEATM
     Acute Toxicity: Historical and Current Regulatory 
Perspectives
     Acute Toxicity Data: A Clinical Perspective
    10:30 a.m.--In Vitro Approaches to Estimate the Acute Toxicity 
Potential of Chemicals
     Estimating Starting Doses for In Vivo Studies using In 
Vitro Data
     An Integrated Approach for Predicting Systemic Toxicity
     Opportunities for Future Progress
    Public Comment
    Breakout Groups' Charges
    12:30 p.m.--Lunch Break
    1:45 p.m.--Breakout Groups: Identifying What Is Needed from In 
Vitro Methods
     Screening Methods;
     Toxicokinetic Determinations;
     Predicting Organ Specific Toxicity and Mechanisms; and
     Chemical Data Sets for Validation
    5:30 p.m.--Adjourn for the Day
Wednesday, October 18, 2000
    8:00 a.m.--Plenary Session--Status Reports by Breakout Group Co-
Chairs
    9:00 a.m.--Breakout Groups: Current Status of In Vitro Methods for 
Acute Toxicity
     Screening Methods;
     Toxicokinetic Determinations;
     Predicting Organ Specific Toxicity and Mechanisms; and
     Chemical Data Sets for Validation
    12:00 p.m.--Lunch Break
    1:30 p.m.--Breakout Groups: Current Status of In Vitro Methods for 
Acute Toxicity (Cont'd)
    5:30 p.m.--Adjourn for the Day
Thursday, October 19, 2000
    8:00 a.m.--Plenary Session--Status Reports by Breakout Group Co-
Chairs
    9:00 a.m.--Breakout Groups: Future Directions for In Vitro Methods 
for Acute Toxicity
     Screening Methods;
     Toxicokinetic Determinations;
     Predicting Organ Specific Toxicity and Mechanisms; and
     Chemical Data Sets for Validation
    12:00 p.m.--Lunch Break
    1:30 p.m.--Breakout Groups: Future Directions for In Vitro Methods 
for Acute Toxicity (Cont'd)
    5:30 p.m.--Adjourn for the Day
Friday, October 20, 2000
    8:00 a.m.--Closing Plenary Session--Reports by Breakout Group Co-
Chairs
     Screening Methods;
     Toxicokinetic Determinations;
     Predicting Organ Specific Toxicity and Mechanisms; and
     Chemical Data Sets for Validation
    Public Comment
    Closing Comments
    12:15 p.m.--Adjourn

B. Workshop Registration

    The Workshop meeting will be open to the public, limited only by 
the space available. Due to space limitations, advance registration is 
requested by October 13, 2000. Registration forms can be obtained by 
contacting NICEATM at the address given below or by accessing the on-
line registration form at: http://iccvam.niehs.nih.gov/invi_reg.htm. 
Other relevant Workshop information (i.e., accommodations, 
transportation, etc.) is also provided at this website.

C. Public Comment

    The Public is invited to attend the Workshop and the number of 
observers will be limited only by the space available. Two formal 
public comment sessions on Tuesday, October 17th and Friday, October 
20th will provide an opportunity for interested persons or groups to 
present their views and comments to the Workshop participants (please 
limit to one speaker per group). Additionally, time will be allotted 
during each of the Breakout Group sessions for general discussion and 
comments from observers and other participants. The Public is invited 
to present oral comments or to submit comments in writing for 
distribution to the Breakout Groups to NICEATM at the address given 
below by October 13, 2000. Oral presentations will be limited to seven 
minutes per speaker to allow for a maximum number of presentations. 
Individuals presenting oral comments are asked to provide a hard copy 
of their statement at registration. For planning purposes, persons 
wishing to give oral comments are asked to check the box provided on 
the Registration Form, although requests for oral presentations will 
also be accepted on-site (subject to availability of time). Persons 
registering for oral comments or submitting written remarks are asked 
to include their contact information (name, address, affiliation, 
telephone, fax, and e-mail).

Guidelines for Requesting Registration Form and Submission of 
Public Comment

    Requests for registration information and submission of public 
comments should be directed to the NTP Interagency Center for the 
Evaluation of Alternative Toxicological Methods, Environmental 
Toxicology Program, NIEHS/NTP, MD EC-17, PO Box 12233, Research 
Triangle Park, NC 27709; 919-541-3398 (phone); 919-541-0947 (fax); 
[email protected] (e-mail). Public comments should be accompanied by 
complete contact information including name, (affiliation, if 
applicable), address, telephone number, and e-mail address.

References

     OECD (Organisation for Economic Cooperation and 
Development). (1998). Harmonized integrated hazard classification 
system for human health and environmental effects of chemical 
substances. OECD, Paris. (website: http://www.oecd.org//ehs/Class/HCL6.HTM)
     Spielmann, H., Genschow, E., Leibsch, M., and Halle, W. 
(1999) Determination of the starting dose for

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acute oral toxicity (LD50) testing in the up and down procedure (UDP) 
from cytotoxicity data. ATLA, 27(6), 957-966.
     Ekwall, B., Ekwall, B., and Sjorstrom, M. (2000) MEIC 
evaluation of acute systemic toxicity: Part VIII. Multivariate partial 
least squares evaluation, including the selection of a battery of cell 
line tests with a good prediction of human acute lethal peak blood 
concentrations for 50 chemicals. ATLA, 28, Suppl. 1, 201-234.
     Ekwall, B., Clemedson, C., Ekwall, B., Ring, P., and 
Romert, L. (1999) EDIT: A new international multicentre programme to 
develop and evaluate batteries of in vitro tests for acute and chronic 
systemic toxicity. ATLA 27, 339-349.

    Dated: September 12, 2000.
Samuel H. Wilson,
Deputy Director, National Institute of Environmental Health Sciences.
[FR Doc. 00-24244 Filed 9-20-00; 8:45 am]
BILLING CODE 4140-01-P