National Toxicology Program

March 1996

NTP UPDATE FROM THE NTP LIAISON OFFICE

We are pleased to provide the following information highlighting 1996 activities of the National Toxicology Program and updating information provided earlier.

1) NTP Board of Scientific Counselor's Meeting Schedule

2) Chronic Studies Scheduled to Start in FY96

3) Request for Chemical Nominations

4) NTP Adds New Databases to NTP Web Site

5) Recently Published NTP Reports

6) Update: Biennial Report on Carcinogens (BRC)

7) NTP Board of Scientific Counselors' Technical Reports Review Subcommittee Minutes and Summary of Technical Reports-- December 5, 1995

8) NTP Workshop Report on Validation and Regulatory Acceptance of Alternative Toxicological Test Methods

9) NTP Mailing List Survey Responses

 

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	NTP Board of Scientific Counselors' Meeting Schedule

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Scientific peer review of the NTP programs is provided by reviewers outside the NTP who serve on the NTP Board of Scientific Counselors'. All meetings of the Board and the Board Subcommittees are open to the public:

The Board is scheduled to meet April 17, and October 22, 1996. A preliminary agenda for the April meeting includes: discussion of research partnerships in transgenic models, new research initiatives on environmental hormones and 'dioxin-like' chemicals, activities in alternative methods to animal research, report on the review of the criteria for the Biennial Report on Carcinogens (BRC), status reports on interagency collaborative studies with NIOSH and NCTR, and concept proposals in the areas of chemical disposition and reproductive toxicity. Information regarding the October 22nd meeting will be provided in a future UPDATE.

The recently established Biennial Report on Carcinogens (BRC) Subcommittee will have its first meeting May 7-8, 1996. The preliminary agenda for the meeting will include a discussion of the recent review of the criteria for listing substances in the BRC; the revised process for preparing the Report and the review responsibilities of the subcommittee, and a presentation of information on select chemicals previously identified for listing in the Eighth or Ninth BRCs to define data requirements for making recommendations regarding listing (see BRC Update).

The Technical Reports Review Subcommittee will be held December 11-12, 1996. Technical reports tentatively scheduled for this review are: 3'-azido-3'-deoxythymidine (AZT)/interferon (IFN), chloroprene, cobalt sulfate, ethylbenzene, isobutyraldehyde, oxazepam, polyvinyl alcohol, primaclone, tetrahydrofuran theophylline. All meetings will be held in the Conference Center, Building 101, South Campus, NIEHS. For information please contact Dr. Larry Hart (919) 541-3971.

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	Chronic Studies Scheduled to Start in Fiscal Year 1996

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Two-year toxicology and carcinogenesis studies on the following chemicals are scheduled to start in FY 1996:

Acrylonitrile	o-Nitrotoluene
Citral	p-Nitrotoluene
p,p'-Dichlorodiphenyl Sulfone	Riddelliine
Indium Phosphide	Urethane + Ethanol (Combination)(3 studies) (NCTR)
Methacrylonitrile	Vanadium Pentoxide
Naphthalene

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	Request for Chemical Nominations

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Selecting the highest priority chemicals from the broadest base of nominations is the main objective of efforts to strengthen NTP's nomination and selection process. Identifying potential hazards for human health, be they occupational, environmental, natural products, food additives, pharmaceuticals, etc. and increasing the understanding of the magnitude of the hazard are key to NTP's public health efforts.

NTP is soliciting recommendations for chemicals and chemical classes to be tested for toxicity. Chemicals are tested for any or all of the following health-related effects, including reproductive and developmental toxicity, carcinogenicity, genetic toxicity, immunotoxicity, neurotoxicity, general toxicity, chemical metabolism and disposition, mechanistic studies and clarification of structure activity relationships. The results of the NTP studies are used by other Federal and State agencies and private sector organizations. The results also are available to the public, and are published in the open scientific literature.

Nominating sources are asked to indicate the chemical or agent of interest, particular toxicity studies suggested, and the rationale for nomination. Nominators are also asked to provide available background data on production, use, exposure, environmental occurrence; and extent of existing toxicological data in a supporting summary document. However, we do not wish to discourage anyone from nominating a chemical or agent that could pose a health hazard. The Program will obtain literature and other background data when such support is not available to the nominator.

We encourage anyone who is aware of a chemical or agent that could pose a health hazard to nominate that chemical or agent for studies by the NTP. NTP staff will consider each nomination as it is received and assess the need for studies relative to other nominations. The nominator will be informed of the status of each nomination as decisions are reached.

Please send nominations and relevant information to: Dr. E. Zeiger, Chemical Selection Office, P.O. Box 12233, Research Triangle Park, NC 27709 (919)541-4482.

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	NTP Adds New Databases to NTP Web Site

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The "NTP Health and Safety Chemical Information" page has been added to the NTP homepage. This page provides access to chemical information and structures. Chemical health and safety, formulas, synonyms, physical chemical data and toxicity information are available on over 2000 chemicals. Structures for chemicals studied in the NTP carcinogenesis and toxicity studies are also available.

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	Recently Published NTP Reports

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Abstracts of the following most recently published NTP reports are now available on the Internet at WWW (World Wide Web). Full copies of these reports are also available free of charge from Central Data Management while supplies last.

NTP Technical Report on the Toxicology and Carcinogenesis Studies of Diethylphthalate (CAS No. 84-66-2) in F344/N Rats and B6C3F1 Mice (Dermal Studies) with Dermal Initiation/Promotion Study of Diethylphthalate and Dimethylphthalate (CAS No. 131-11-3) in Male Swiss (CD-1®) Mice. (TR-429) - May 1995

NTP Technical Report on the Toxicology and Carcinogenesis Studies of t-Butyl Alcohol (CAS No. 75-65-0) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies). (TR-436) - May 1995

NTP Technical Report on the Toxicology and Carcinogenesis Studies of Benzethonium Chloride (CAS No. 121-54-0) in F344/N Rats and B6C3F1 Mice (Dermal Studies). (TR-438) - July 1995

NTP Technical Report on the Toxicology and Carcinogenesis Studies of Methylphenidate Hydrochloride (CAS No. 298-59-9) in F344/N Rats and B6C3F1 Mice (Feed Studies). (TR-439) - July 1995

NTP Technical Report on Initiation/Promotion Study of o-Benzyl-p-Chlorophenol (CAS No.120-32-1) in Swiss (CD-1®:) Mice (Mouse Skin Study). (TR-444) - May 1995

NTP Technical Report on the Toxicity Studies of Dibutyl Phthalate (CAS No. 84-74-2) Administered in Feed to F344/N Rats and B6C3F1 Mice. (TOX-30) - May 1995

NTP Technical Report on the Toxicity Studies of Methylene bis(thiocyanate), (CAS No. 6317-18-6) Administered by Gavage to F344/N Rats and B6C3F1 Mice. (TOX-32) - January 1995

NTP Technical Report on the Toxicity Studies of Cadmium Oxide (CAS No. 1306-19-0) Administered by Inhalation to F344/N Rats and B6C3F1 Mice. (TOX-39) - May 1995

NTP Technical Report on the Toxicity Studies of 1,3-Diphenylguanidine (CAS No. 102-06-7) Administered in Feed to F344/N Rats and B6C3F1 Mice. (TOX-42) - September 1995

To request NTP documents contact:

Central Data Management
National Institute of Environmental Health Sciences
P.O. Box 12233
Mail Drop E1-02
Research Triangle Park, NC 27709
FAX number: (919) 541-3687 (new FAX number)
Telephone number: (919) 541-3419
Internet Email Address CDM@NIEHS.NIH.GOV

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	Update: Biennial Report on Carcinogens (BRC)

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The Biennial Report on Carcinogens (BRC) is prepared in response to section 301 (b) (4) of the Public Health Service Act which stipulates that the Secretary of the Department of Health and Human Services shall publish a report which contains a list of all substances (i) which either are known to be human carcinogens or may reasonably be anticipated to be human carcinogens; and (ii) to which a significant number of persons residing in the United States are exposed. This responsibility has been delegated by the Secretary to the Director, of the National Toxicology Program (NTP). Dr. Kenneth Olden, Director, NTP, initiated a review of the BRC in 1995 to broaden input into its preparation, broaden the scope of scientific review associated with the Report, and provide review of the criteria used for inclusion of substances in the BRC. The process for the review was open, public and included participation of, or input from, a broad base of interested parties including Academia, Industry, Labor, Federal, State and Local Agencies and Private Organizations. During 1995 the review included two open, public meetings, by the NTP Board of Scientific Counselors, several reviews by the NTP Executive Committee, and a review by the Public Health Services' Environmental Health Policy Committee (EHPC). At each step of the review there was concurrence with the following points: 1) the current criteria should be revised; 2) mechanistic information should be used as part of the listing criteria; 3) the categories (known to be human carcinogens and reasonably anticipated the be human carcinogens) should remain the same as described in the original legislation; and 4) there should be a formal mechanism which allows for the removal of substances from the BRC.

The criteria are being revised based on these recommendations, and it is expected that the revised criteria will be provided to the NTP Board Subcommittee when they have their first meeting on May 7-8, 1996.

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	NTP Board of Scientific Counselors' Technical Reports Review Subcommittee Meeting and Summary of Technical Reports -- December 5, 1995

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NTP Board of Scientific Counselors' Technical Reports Review Subcommittee met in public session at the National Institute of Environmental Health Sciences on December 5, 1995.

The Subcommittee, predominantly composed of scientists from outside the Federal government, provides peer review of the draft technical reports of NTP long-term (usually two-year) toxicology and carcinogenesis studies and short-term toxicity studies. The Subcommittee reviewed and accepted the conclusions for carcinogenic activity as written for six two-year study reports: D & C Yellow No. 11; molybdenum trioxide; nitromethane; phenolphthalein; sodium xylenesulfonate; and tetrafluoroethylene. A review summary, primary uses, and other information about the six studies are given in the table that follows. Copies of the draft reports, summary minutes of the Report Reviews, and final reports (when available) may be obtained from:
Central Data Management,
MD: E1-02,
P.O. Box 12233,
Research Triangle Park, NC 27709

CHEMICAL CAS NUMBER	TECHNICAL REPORT NUMBER	PRIMARY USES	ROUTE/ EXPOSURE LEVELS	REVIEW SUMMARY
D & C YELLOW NO. 11 8003-22-3	TR-463	Color additive used in cosmetics and externally applied to drugs. Contaminant of D&C Yellow 10, a compound which FDA is currently considering for approval for contact lenses.	Dosed-Feed (NIH-07): Rats: 0, 0.05, 0.17, OR 0.5%; 60/GROUP	The Subcommittee accepted with one abstention the conclusions as written, some evidence of carcinogenic activity, for male and female F344 rats.
MOLYBDENUM TRIOXIDE 1313-27-5	TR-462	In manufacture of molybdenum metals; corrosion inhibitor; catalyst; chemical analysis reagent; alloying agent in steel; agricultural chemical; component of ceramics, enamel & pigments.	Inhalation (AIR): Rats &Mice: 10, 30, OR 100 MG/M3; 50/SEX/SPECIES/GROUP	The Subcommittee accepted unanimously the conclusions as written, equivocal evidence of carcinogenic activity, for male rats, no evidence of carcinogenic activity, for female rats, and some evidence of carcinogenic activity, for male and female B6C3F1 mice.
NITROMETHANE 75-52-5	TR-461	Fuel additive and propellant. Cellulosic compound solvent. Intermediate for nitro and amino alcohols.	Inhalation (AIR): Rats: 0, 94, 188, OR 375 PPM; 50/GROUP. Mice: 0, 188, 375, OR 750PPM; 50/GROUP	The Subcommittee accepted unanimously the conclusions as written, no evidence of carcinogenic activity, for male rats, and clear evidence of carcinogenic activity, for female rats and male and female mice.
PHENOLPHTHALEIN 77-09-8	TR-465	Laboratory reagent. Dyes. Cathartic drug in laxatives.	Dosed-Feed (NIH-07): Rats: 0, 1.2, 2.5, OR 5%. Mice 0, 0.3, 0.6, OR 1.2% (50/SEX/SPECIES/GROUP)	The Subcommittee accepted with one abstention the conclusions as written, clear evidence of carcinogenic activity, for male rats and male and female mice, and some evidence of carcinogenic activity, for female rats.
SODIUM XYLENE SULFONATE 1300-72-7	TR-464	Hydrotrope in liquid detergents, shampoos, degreasing compounds. Used in textile, paper, and leather industries.	Topical (ETHANOL): Rats: 0, 60, 120, OR 240 MG/KG. Mice: 0, 182, 364, OR 727 MG/KG (50/SEX/GROUP)	The Subcommittee accepted the conclusions as written, no evidence of carcinogenic activity, for male and female rats and male and female mice.
TETRAFLUOROETHYLENE 116-14-3	TR-450	Monomer for polytetrafluoroethylene polymers. Preparation of propellants for food product aerosols. Chemical intermediate.	Inhalation (AIR): Mice & Female Rats: 0, 312, 625, OR 1250. Male Rats: 0, 156, 312,OR 625 PPM; 50/GROUP	The Subcommittee accepted unanimously the conclusions as written, clear evidence of carcinogenic activity, for male and female rats and male and female mice.

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	NTP Workshop Report on Validation and Regulatory Acceptance of Alternative Toxicological Test Methods

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An NTP Workshop on Validation and Regulatory Acceptance of Alternative Toxicological Test Methods was held in Arlington, Virginia, on December 11-12, 1995. The Workshop was sponsored by the National Institute of Environmental Health Sciences and the National Toxicology Program, and was organized by the ad hoc Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM). The purpose of the workshop was to receive comments and recommendations from the public and invited experts on the draft ICCVAM Report: Validation and Regulatory Acceptance of Toxicological Test Methods, which was developed by representatives from fifteen Federal regulatory and research agencies. The draft Report described proposed criteria and processes for the validation and regulatory acceptance of new and revised toxicological testing methods. The draft Report was developed in response to directives in the NIH Revitalization Act of 1993 (Public Law No. 103-43), which also directed NIEHS to develop and validate improved alternative toxicological testing methods.

The goals of the ICCVAM Report are to:

• Communicate the criteria and processes that Federal agencies should employ in considering new test methods;
• Encourage the development of new methods and improvement of existing test methods;
• Provide effective guidance for scientists and regulatory staff for validation and evaluation of new test methods;
• Contribute to the increased likelihood of regulatory acceptance of scientifically valid test methods;
• Encourage, when scientifically feasible, the reduction, replacement, and refinement of animal use in testing;
• Encourage the use of validated and accepted new and revised test methods.

Three breakout groups reviewed the report. The Validation Breakout Group reviewed the proposed chapter on validation criteria that discussed scientific assessment of the reliability and relevance of new and revised toxicological testing methods. The Regulatory Acceptance Criteria and Processes Breakout Group discussed the proposed process for determining the acceptability of test methods for regulatory use, and assessed the adequacy of the criteria for regulatory acceptance. The role of groups inside and outside of government in evaluating the status of validated methods was also discussed. The Proposals for Future Directions Breakout Group developed implementation strategies for the processes of validation and regulatory acceptance of test methods, and addressed how industry, government, academe, and public interest groups can work together both nationally and internationally to more efficiently develop, validate, and adopt new improved testing methods for regulatory use.

The Groups generally agreed that the criteria and guidance for validation and regulatory acceptance of new testing methods provided in the draft report would be useful to both government and non-government scientists, including regulatory scientists. Suggestions were provided to improve the clarity and format of the document. Other selected workshop recommendations included:

1. Involvement and communication between all stakeholders (developers, users, regulators, and the public) are essential at all stages of the process leading to regulatory acceptance of alternative methods, including development, validation, and review.
2. The current ad hoc Interagency Coordinating Committee on Validation of Alternative Methods (ICCVAM) or its equivalent should be sustained by establishment of a standing permanent committee that would facilitate communication and provide administrative guidance to the validation and acceptance process. Proposed functions included:
   • Provide an interagency clearinghouse to coordinate review of new methods and their data submissions with appropriate agencies.
   • Provide a critical communication link to government and non-government stakeholders at various stages of the process.
   • Foster interagency as well as international harmonization.
   • Determine regulatory need and relevance of proposed new methods at all stages of development and validation.
   • Provide guidance on validation criteria and processes, and maintain a link between method developers and regulators.
   • Facilitate domestic and international communication, coordination, and sharing of information during development, validation, review, and acceptance of new methods.
   • Promote awareness of accepted methods.
   It was recommended: a) that the committee include official representation, technical competence, and animal welfare advocacy from Federal research and regulatory agencies; b) that the committee be established and empowered through NIEHS/NTP within two months after ICCVAM Final Report issuance; and c) that financial resources be provided to support the committee.
3. Alternative methods should be considered for acceptance if they are adequate in terms of biological relevance and regulatory utility, and generate data at least equivalent for hazard identification and/or dose-response assessment purposes as the established method.
4. Consideration of reduction, refinement, and replacement of animal use must be formally included as regulatory acceptance criteria for proposed new test methods.
5. Existing and proposed testing regulations, test methods, and alternatives should be readily available on the Internet at a single location.
6. Periodic regulatory review and revision of test methods should be established.
7. International harmonization of test methods should be sought.

Recommendations from the Workshop will be considered by the ICCVAM in revising the draft ICCVAM Report. A Workshop Report will be available later this month and will be incorporated as an appendix in the final ICCVAM Report. The final ICCVAM Report is anticipated to be completed in mid-1996, with availability to be announced in the Federal Register and a later NTP Liaison Office Update.

Following the NTP Workshop, the Organization for Economic Cooperation and Development (OECD) conducted a Workshop on Harmonization of Validation and Acceptance Criteria for Alternative Toxicological Test Methods in Solna, Sweden, on January 22-24, 1996. The draft ICCVAM Report and the draft NTP Workshop Report served as background working documents. An OECD Workshop Report will be available in late spring and it is anticipated that an OECD Guidance Document will be developed to serve as an international reference on this subject.

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	Mailing List Survey

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"Thank you" to those who responded to the recent NTP mailing list survey. Approximately 7,000 queries were sent out in late 1995 to persons on the NTP list to receive one or more of the following items:

• The NTP Annual Plan
• The Annual Review of Current DHHS, DOE, and EPA Research Related to Toxicology,
• The Biennial Report on Carcinogens.
• The NTP Management Status Report.

Approximately 3,600 people responded and of this number, 102 asked to be removed from the list most often because they decided to access the NTP Web site to obtain the information. In addition, 172 new people registered on the Web site to begin receiving NTP information.