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###### Department of Health and Human Services

###### Public Health Service 

# 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.                               ( print 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                           ( print 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);                     *iccvam@niehs.nih.gov*                     (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., Chesneá, C., Clothier, R., Cottin, M., Curren, R., Daniel-Szolgay, E., Dierickx, P., Ferro, M., Fiskesj”, G., Garza-Ocanas, L., Goámez-Lechoán, M.J., Guälden, M., Isomaa, B., Janus, J., Judge, P., Kahru, A., Kemp, R.B., Kerszman, G., Kristen, U., Kunimoto, M., Kärenlampi, S., Lavrijsen, K., Lewan L., Lilius, H., Ohno, T., Persoone, G., Roguet, R.,                               ( print 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., Chesné, C., Clothier, R., Cottin, M., Curren, R., Dierickx, P., Ferro, M., Fiskesjä, G., Garza-Ocanas, L., Gómez-Lechón, M.J., Gülden, M., Isomaa, B., Janus, J., Judge, P., Kahru, A., Kemp, R.B., Kerszman, G., Kristen, U., Kunimoto, M., Kärenlampi, 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., Sjöström, 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., Gömez-Lechön, M.J., Hall, T., Imai, K., Kahru, A., Logemann, P., Monaco, F., Ohno, T., Segner, H., Sjöström, 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., Fiskesö, G., Garza-Ocanas, L. Gömez-Lechoán, M.J., Gülden, M., Hall, T., Imai, K., Isomaa, B., Kahru, A., Kerszman, G., Kjellstrand, P., Kristen, U., Kunimoto, M., Kärenlampi, S., Lewan, L., Lilius, H., Loukianov, A., Monaco, F., Ohno, T., Persoone, G., Romert, L., Sawyer, T.W., Shrivastava, R., Segner, H., Seibert, H., Sjöström, 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., Chesné, C., Cottin, M., Curren, R., Ekwall, B., Ferro, M., Gómez-Lechön, 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., Go                                                mez-Lecho                                                n, M.J., Hellberg, S., Bondsson, I., Castell, J.V., Jover, R., Ho                                                gberg, 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., Go                                                mez-Lecho                                                n, M-J., Gu                                                lden, M., Hall, T., Isomaa, B., Kahru, A, Kerszman, G., Kristen, U., Kunimoto, M., Ka                                                renlampi, 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., Go                                                mez-Lecho                                                n, M.J., Jover, R., Ho                                                gberg, 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., Sjo                                                stro                                                m, M., Wold, S., Ekwall, B., Go                                                mez-Lecho                                                n, 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