[Federal Register Volume 65, Number 115 (Wednesday, June 14, 2000)]
[Notices]
[Pages 37400-37403]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-14968]


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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): Request for Data and Suggested 
Expert Scientists

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 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 preparing for this Workshop, ICCVAM is requesting: (1) 
Information and data that should be considered at the Workshop, 
including relevant data on currently available in vitro methods for 
assessing acute systemic toxicity; and (2) nominations of expert 
scientists to participate in the Workshop. An agenda, registration 
information, and other details will be provided in a subsequent Federal 
Register notice.

[[Page 37401]]

Background

    ICCVAM, with participation by 14 Federal regulatory and research 
agencies and programs, was established in 1997 to coordinate issues 
relating to the development, validation, acceptance, and national/
international harmonization of toxicological test methods. ICCVAM seeks 
to promote the scientific validation and regulatory acceptance of new 
and improved test methods applicable to Federal agencies, including 
methods that may reduce or replace animal use, or that refine protocols 
to lessen animal pain and distress. The Committee's functions include 
the coordination of interagency reviews of toxicological test methods 
and communication with stakeholders throughout the process of test 
method development and validation. The following Federal regulatory and 
research agencies participate:

Consumer Product Safety Commission
Department of Defense
Department of Energy
Department of Health and Human Services
    Agency for Toxic Substances and Disease Registry
    Food and Drug Administration
    National Institute for Occupational Safety and Health/CDC
    National Institutes of Health
    National Cancer Institute
    National Institute of Environmental Health Sciences
    National Library of Medicine
Department of the Interior
Department of Labor
    Occupational Safety and Health Administration
    Department of Transportation
    Research and Special Programs Administration
    Environmental Protection Agency

    NICEATM was established in 1998 and provides operational support 
for the ICCVAM. NICEATM and ICCVAM collaborate to carry out activities 
associated with the development, validation, and regulatory acceptance 
of proposed new and improved test methods. These activities may 
include:
     Test Method Workshops, which are convened as needed to 
evaluate the adequacy of current methods for assessing specific 
toxicities, to identify areas in need of improved or new testing 
methods, to identify research efforts that may be needed to develop new 
test methods, and to identify appropriate development and validation 
activities for proposed new methods.
     Expert Panel Meetings, which are typically convened to 
evaluate the validation status of a method following the completion of 
initial development and pre-validation studies. Expert Panels are asked 
to recommend additional validation studies that might be helpful in 
further characterizing the usefulness of a method, and to identify any 
additional research and development efforts that might enhance the 
effectiveness of a method.
     Independent Peer Review Panel Meetings, which are 
typically convened following the completion of comprehensive 
validations studies on a test method. Peer Review Panels are asked to 
develop scientific consensus on the usefulness and limitations of test 
methods to generate information for specific human health and/or 
ecological risk assessment purposes. Following the independent peer 
review of a test method, ICCVAM forwards recommendations on its 
usefulness to agencies for their consideration. Federal agencies then 
determine the regulatory acceptability of a method according to their 
mandates.
    Additional information about ICCVAM and NICEATM can be found at the 
website: http://iccvam.niehs.nih.gov.

Workshop Background and Scope

A. Background

    Federal regulatory agencies require toxicity testing to determine 
the safety or hazard of various chemicals and products prior to human 
exposure. Agencies use this information to properly classify and label 
products as to their hazard potential. Acute oral toxicity 
determinations are currently made using animals. However, recent 
studies (e.g., 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 in vitro cytotoxicity and human lethal blood 
concentrations. However, these in vitro methods have not yet been 
evaluated in validation studies to determine their usefulness and 
limitations for generating acute toxicity testing information necessary 
to meet regulatory testing requirements. Additionally, other in vitro 
methods would likely be necessary to establish accurate dose-response 
relationships before such methods could substantially reduce or replace 
animal use for acute toxicity determinations.
    This workshop will examine the status of available in vitro methods 
and develop recommendations for validation efforts necessary to 
characterize the usefulness and limitations of existing methods. 
Recommendations for future research and development efforts that might 
further enhance the usefulness of in vitro assessments of acute 
systemic lethal toxicity will also be developed.

B. Objectives of the Workshop

    Four major topics will be addressed:
    1. General cytotoxicity methods predictive of acute lethal 
toxicity;
    2. Toxicokinetic and organ specific toxicity methods;
    3. Reference chemicals for validation of the above methods; and
    4. The use of quantitative structure activity relationships (QSAR) 
and chemical/physical properties for predicting acute lethal toxicity.
    The objectives of the meeting are to:
    1 a. Identify and review the status of in vitro general 
cytotoxicity screening methods that may reduce animal use for assessing 
acute systemic toxicity;
    b. Identify information from in vitro methods necessary to predict 
acute systemic toxicity and review the status of relevant methods 
(e.g., in vitro methods to assess gut absorption, metabolism, blood-
brain barrier penetration, volume distribution to critical target 
organs, and specific target organ toxicity);
    2. Identify candidate methods for further evaluation in 
prevalidation and validation studies;
    3. Identify reference chemicals useful for development and 
validation of in vitro methods for assessing acute systemic toxicity;
    4. Identify validation study designs needed to adequately 
characterize the proposed methods in 2.; and
    5. Identify priority research efforts necessary to support the 
development of in vitro methods to adequately 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.

C. Methods for Consideration

    Given the breadth of the workshop topics, many methods are likely 
to be considered relevant to the discussion. Methods will include but 
are not limited to those proposed in the Multicentre Evaluation of In 
Vitro Cytotoxicity (MEIC) battery (http://www.ctlu.se). A background 
document summarizing the data and performance characteristics for 
available methods is being prepared by NICEATM in collaboration with 
the ICCVAM interagency organizing committee. Information received as a 
result of this Federal Register notice will be

[[Page 37402]]

considered for inclusion in the background document. In formulating its 
recommendations, the Workshop participants will evaluate information in 
the background document and relevant information from other sources.

D. Test Method Data and Information Sought

    Data are sought from completed, ongoing, or planned studies that 
provide comparative performance data for in vitro methods compared to 
currently accepted in vivo methods for determining acute lethal 
toxicity and hazard classification. Data from test methods that provide 
toxicokinetic and specific target organ toxicity information are also 
sought. Submissions should describe the extent to which established 
criteria for validation and regulatory acceptance have been addressed. 
These criteria are provided in ``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 97-3981 (http://ntp-server.niehs.nih.gov/htdocs/ICCVAM/iccvam.html). Where possible, submitted data and information should 
adhere to the guidance provided in the document, ``Evaluation of the 
Validation Status of Toxicological Methods: General Guidelines for 
Submissions to ICCVAM,'' NIH Publication 99-4496, (http://iccvam.niehs.nih.gov/doc1.htm). Both publications are also available on 
request from NICEATM at the address provided below. Relevant 
information submitted in response to this request will be incorporated 
into the background material provided to Workshop participants. A 
preliminary list of relevant studies is provided at the end of this 
announcement, and public comment and suggestions for additions are 
invited.
    NICEATM and the ICCVAM interagency workshop organizing committee 
will compile information on the studies to be considered at the 
Workshop. All data should be submitted by July 15, 2000 in order to 
ensure full consideration.

E. Request for Nomination of Expert Scientists for the Test Method 
Workshop

    NICEATM is soliciting nominations for expert scientists to 
participate in the Workshop. (See Guidelines for Submission of Comments 
below). Types of expertise likely to be relevant include acute toxicity 
testing in animals, evaluation and treatment of acute toxicity in 
humans, development and use of in vitro methodologies, statistical data 
analysis, knowledge of chemical data sets useful for validation of 
acute toxicity studies, and hazard classification of chemicals and 
products. Expertise need not be limited to these areas, nor will these 
areas necessarily be included on the Panel. An appropriate breadth of 
expertise will be sought. If other areas of scientific expertise are 
recommended, the rationale should be provided.
    Nominations should be accompanied by complete contact information 
including name, address, institutional affiliation, telephone number, 
and e-mail address. The rationale for nomination should be provided. If 
possible, a biosketch or a 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.
    Workshop experts will be selected by an ICCVAM interagency workshop 
organizing committee after 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. Candidates will be required to 
disclose potential conflicts of interest.

Schedule for the Workshop

    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 Workshop meeting will be open to the public, limited only by 
space available.
    Submitted methods and supporting data will be reviewed during the 
July to August 2000 timeframe and a background review document will be 
prepared by NICEATM in collaboration with the ICCVAM interagency 
organizing committee. The background information will be made available 
to Workshop experts for discussion at the meeting and will be available 
to the Public in advance of the Workshop.

Public Input Invited

    As described above, ICCVAM invites comments on the scope and 
process for the review; comments on the ICCVAM preliminary list of 
studies for consideration; the submission of other test methods for 
consideration; and the nomination of experts to participate in the 
Workshop. Nominations must be submitted within 30 days of the 
publication date of this notice, and other information should be 
submitted by July 15, 2000.

Guidelines for Submission of Public Comment

    Correspondence should be directed to Dr. William S. Stokes, 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.

Preliminary List of Studies to be Considered for the Workshop on In 
Vitro Methods for Assessing Acute Systemic Toxicity

    ICCVAM has compiled a preliminary list of relevant studies. The 
public is invited to comment on this list, and suggestions for 
additions may be submitted. (See Section of this Federal Register 
announcement on Guidelines for Submission of Public Comments).
    Studies that may be completed but not published are not included 
here. This list provides examples of studies and information that may 
be appropriate for consideration by the Workshop experts.

    Balls, M., Blaauboer, B.J., Fentem, J.H., Bruner, L., Combes, 
R.D., Ekwall, B., Fielder, R.J., Guillouzo, A., Lewis, R.W., Lovell, 
D.P., Reinhardt, C.A., Repetto, G., Sladowski, D., Spielmann, H., 
and Zucco, F. (1995) Practical aspects of the validation of toxicity 
test procedures--The report and recommendations of ECVAM Workshop 5. 
ATLA 23, 129-147.
    Bernson, V., Bondesson, I., Ekwall, B., Stenberg, K., and Walum, 
E. (1987) A multicenter evaluation study of in vitro cytotoxicity. 
ATLA, 14, 144-145.
    Bondesson, I., Ekwall, B., Stenberg, K., Romert, L., and Walum, 
E. (1988) Instruction for participants in the multicenter evaluation 
study of in vitro cytotoxicity (MEIC). ATLA, 15, 191-193.
    Bondesson, I., Ekwall, B., Hellberg, S., Romert, L., Stenberg, 
K., and Walum, E. (1989) MEIC--A new international multicenter 
project to evaluate the relevance to human toxicity of in vitro 
cytotoxicity tests. Cell Biol. Toxicol., 5, 331-347.
    Clemedson, C., and Ekwall, B. (1999) Overview of the final MEIC 
results: I. The in vitro-in vivo evaluation. Toxicology In vitro, 
13, 657-663.
    Clemedson, C., McFarlane-Abdulla, E., Andersson, M., Barile, 
F.A., Calleja, M.C., Chesnea, C., Clothier, R., Cottin, M., Curren, 
R., Daniel-Szolgay, E., Dierickx, P., Ferro, M., Fiskesj'', G., 
Garza-Ocanas, L., Goamez-Lechoan, M.J., Gualden, M., Isomaa, B., 
Janus, J., Judge, P., Kahru, A., Kemp, R.B., Kerszman, G., Kristen, 
U., Kunimoto, M., Karenlampi, S., Lavrijsen, K., Lewan L., Lilius, 
H., Ohno, T., Persoone, G., Roguet, R.,

[[Page 37403]]

Romert, L., Sawyer, T., Seibert, H., Shrivastava, R., Stammati, A., 
Tanaka, N., Torres Alanis, O., Voss, J-U., Wakuri, S., Walum, E., 
Wang, X., Zucco, F., and Ekwall, B. (1996) MEIC evaluation of acute 
systemic toxicity. Part I. Methodology of 68 in vitro toxicity 
assays used to test the first 30 reference chemicals. ATLA, 24, 
Suppl. 1, 249-272.
    Clemedson, C., McFarlane-Abdulla, E., Andersson, M., Barile, 
F.A., Calleja, M.C., Chesne, C., Clothier, R., Cottin, M., Curren, 
R., Dierickx, P., Ferro, M., Fiskesja, G., Garza-Ocanas, L., Gomez-
Lechon, M.J., Gulden, M., Isomaa, B., Janus, J., Judge, P., Kahru, 
A., Kemp, R.B., Kerszman, G., Kristen, U., Kunimoto, M., Karenlampi, 
S., Lavrijsen, K., Lewan L., Lilius, H., Malmsten, A., Ohno, T., 
Persoone, G., Pettersson, R., Roguet, R., Romert, L., Sandberg, M., 
Sawyer, T., Seibert, H., Shrivastava, R., Sjostrom, M., Stammati, 
A., Tanaka, N., Torres Alanis, O., Voss, J-U., Wakuri, S., Walum, 
E., Wang, X., Zucco, F. and, Ekwall, B. (1996) MEIC evaluation of 
acute systemic toxicity. Part II. In vitro results from 68 toxicity 
assays used to test the first 30 reference chemicals and a 
comparative cytotoxicity analysis. ATLA, 24, Suppl. 1, 273-311.
    Clemedson, C., Barile, F.A., Ekwall, B., Gomez-Lechon, M.J., 
Hall, T., Imai, K., Kahru, A., Logemann, P., Monaco, F., Ohno, T., 
Segner, H., Sjostrom, M., Valentino, M., Walum, E., Wang, X., and 
Ekwall, B. (1998). MEIC evaluation of acute systemic toxicity: Part 
III. In vitro results from 16 additional methods used to test the 
first 30 reference chemicals and a comparative cytotoxicity 
analysis. ATLA 26, Suppl. 1, 91-129.
    Clemedson, C., Aoki, Y., Andersson, M., Barile, F.A., Bassi, 
A.M., Calleja, M.C., Castano, A., Clothier, R.H., Dierickx, P., 
Ekwall, B., Ferro, M., Fiskeso, G., Garza-Ocanas, L. Gomez-Lechoan, 
M.J., Gulden, M., Hall, T., Imai, K., Isomaa, B., Kahru, A., 
Kerszman, G., Kjellstrand, P., Kristen, U., Kunimoto, M., 
Karenlampi, S., Lewan, L., Lilius, H., Loukianov, A., Monaco, F., 
Ohno, T., Persoone, G., Romert, L., Sawyer, T.W., Shrivastava, R., 
Segner, H., Seibert, H., Sjostrom, M., Stammati, A., Tanaka, N., 
Thuvander, A., Torres-Alanis, O., Valentino, M., Wakuri, S., Walum, 
E., Wieslander, A., Wang, X., Zucco, F., and Ekwall, B. (1998). MEIC 
evaluation of acute systemic toxicity. Part IV. In vitro results 
from 67 toxicity assays used to test reference chemicals 31-50 and a 
comparative cytotoxicity analysis. ATLA 26, Suppl. 1, 131-183.
    Clemedson, C., Barile, F.A., Chesne, C., Cottin, M., Curren, R., 
Ekwall, B., Ferro, M., Gomez-Lechon, M.J., Imai, K., Janus, J., 
Kemp, R.B., Kerszman, G., Kjellstrand, P., Lavrijsen, K., Logemann, 
P., McFarlane-Abdulla, E., Roguet, R., Segner, H., Seibert, H., 
Thuvander, A., Walum, E., and Ekwall, Bj. (2000) MEIC evaluation of 
acute systemic toxicity: Part VII. Prediction of human toxicity by 
results from testing of the first 30 reference chemicals with 27 
further in vitro assays. ATLA 28, Suppl. 1, 161-200.
    Ekwall, B. (1995) The basal cytotoxicity concept, pp 721-725. In 
Proceedings of the World Congress on Alternatives and Animal Use in 
the Life Sciences: Education, Research, Testing. Alternative Methods 
in Toxicology and the Life Sciences, Vol. 11. Mary Ann Liebert, New 
York, 1995.
    Ekwall, B. (1999) Overview of the Final MEIC Results: II. The In 
vitro/in vivo evaluation, including the selection of a practical 
battery of cell tests for prediction of acute lethal blood 
concentrations in humans. Toxicol. In vitro, 13, 665-673.
    Ekwall, B., Gomez-Lechon, M.J., Hellberg, S., Bondsson, I., 
Castell, J.V., Jover, R., Hogberg, J., Ponsoda, X., Stenberg, K., 
and Walum, E. (1990) Preliminary results from the Scandinavian 
multicentre evaluation of in vitro cytotoxicity (MEIC). Toxicol. In 
vitro, 4, 688-691.
    Ekwall, B., Clemedson, C., Crafoord, B., Ekwall, Ba., Hallander, 
S., Walum E., and Bondesson, I. (1998) MEIC evaluation of acute 
systemic toxicity. Part V. Rodent and human toxicity data for the 50 
reference chemicals. ATLA 26, Suppl. 2, 569-615.
    Ekwall, B., Barile., F.A., Castano, A., Clemedson, C., Clothier, 
R.H., Dierickx, P., Ekwall, B., Ferro, M., Fiskesjo;, G., Garza-
Ocanas, L., Gomez-Lechon, M-J., Gulden, M., Hall, T., Isomaa, B., 
Kahru, A, Kerszman, G., Kristen, U., Kunimoto, M., Karenlampi, S., 
Lewan, L, Loukianov, A., Ohno, T., Persoone, G., Romert, L., Sawyer, 
T.W., Segner, H., Shrivastava, R., Stammati, A., Tanaka, N., 
Valentino, M., Walum, E., and Zucco, F. (1998) MEIC evaluation of 
acute systemic toxicity. Part VI. Prediction of human toxicity by 
rodent LD50 values and results from 61 in vitro tests. ATLA 26, 
Suppl. 2, 617-658.
    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.
    Ekwall, B., Ekwall, B., and Sjostrom, M. (2000) MEIC evaluation 
of acute systemic toxicity: Part VIII. Multivariate partial least 
squares evaluation, including the selection of a battery cell line 
tests with a good prediction of human acute lethal peak blood 
concentrations for 50 chemicals. ATLA 28, Suppl. 1, 201-234.
    Hellberg, S., Bondesson, I., Ekwall, B., Gomez-Lechon, M.J., 
Jover, R., Hogberg, J., Ponsoda, X., Romert, L., Stenberg, K., and 
Walum, E. (1990) Multivariate validation of cell toxicity data: The 
first ten MEIC chemicals. ATLA, 17, 237-238.
    Hellberg, S., Eriksson, L., Jonsson, J., Lindgren, F., Sjostrom, 
M., Wold, S., Ekwall, B., Gomez-Lechon, J.M., Clothier, R., 
Accomando, N.J., Gimes, G., Barile, F.A., Nordin, M., Tyson, C.A., 
Dierickx, P., Shrivastava, R.S., Tingsleff-Skaanild, M., Garza-
Ocanas, L., and Fiskesjo;, G. (1990) Analogy models for prediction 
of human toxicity. ATLA, 18, 103-116.
    Shrivastava, R., Delomenie, C., Chevalier, A., John, G., Ekwall, 
B., Walum, E., and Massingham, R. (1992) Comparison of in vivo acute 
lethal potency and in vitro cytotoxicity of 48 chemicals. Cell Biol. 
Toxicol., 8(2), 157-170.
    Spielmann, H., Genschow, E., Liebsch, M., and Halle, W. (1999) 
Determination of the starting dose for acute oral toxicity (LD50) 
testing in the up and down procedure (UDP) from cytotoxicity data. 
ATLA, 27(6), 957-966.
    Walum, E, Nilsson, M, Clemedson, C. and Ekwall, B. (1995) The 
MEIC program and its implications for the prediction of acute human 
systemic toxicity, pp 275-282 In Proceedings of the World Congress 
on Alternatives and Animal Use in the Life Sciences: Education, 
Research, Testing. Alternative Methods in Toxicology and the Life 
Sciences, Vol. 11. Mary Ann Liebert, New York, 1995.

    Dated: June 6, 2000.
Samuel H. Wilson,
Deputy Director, National Institute of Environmental Health Sciences.
[FR Doc. 00-14968 Filed 6-13-00; 8:45 am]
BILLING CODE 4140-01-P