Press Center
February 1995 Liaison Mailout
February 15, 1995
THE NTP LIAISON OFFICE IS PLEASED TO PROVIDE THE FOLLOWING:
1) Announcement of Society of Toxicology (SOT) Workshop: NTP Studies: Principles of Dose Selection and Applications to Mechanistic Based Risk Assessment, Tuesday, March 7th, Baltimore Convention Center, 8:30 - 11:30 am 2) 1995 Peer Review Meetings for NTP Toxicology and Carcinogenesis Technical Reports or Chemical Nominations (June 20-21 and December 5-6 3) Request for Chemical Nominations 4) Request for Public Comment on Identifying "High Production" Chemicals
for possible consideration by the NTP 5) Update: Review of the Criteria Used for Inclusion of Substances in the Biennial Report on Carcinogens (Upcoming reviews April 24-25 and June 29-30) 6) NTP Workshop: "Mechanism-Based Toxicology in Cancer Risk Assessment: Implications for Research, Regulation, and Legislation" January 11-13, 1995 7) NIEHS and NTP information in electronic format world-wideSOCIETY OF TOXICOLOGY - NTP WORKSHOP
The NTP has characterized the toxicity of hundreds of chemicals in rodents, under relatively standardized test conditions. The doses selected for use in these studies have generally been set sufficiently high to maximize the ability of the various assays to detect an adverse health effect. The use of animal data collected in this manner in the derivation of quantitative risk assessments for both cancer and non cancer endpoints has created discomfort with the assays, and stimulated attempts to restructure the tests to produce data more appropriate for this new purpose. Aside from the need to better define the lower end of the dose response relationship, the criteria for selection of the top most dose are also continually questioned. The merits of making basic changes in the toxicology study paradigm to accommodate the increasing use of these data for risk assessment are worthy of further debate, and other approaches to these problems need to be considered. The purpose of the workshop is to provide an overview of factors currently consideredimportant in selection of doses for NTP studies, to describe some of the confounding factors that can result from the indiscriminate use of bioassay data in quantitative risk assessment, and to suggest ways in which information from mechanistic studies or studies of biomarkers of exposure or effect might be used to better advantage in risk assessment. The Workshop speakers and their topics are: Dr. George Lucier, NIEHS : Introduction to the Workshop Dr. John Bucher, NIEHS: Overview of NTP Dose Selection Principles Dr. Chris Portier, NIEHS : Confounding Factors and Potential Improvements in the use of Typical Bioassay Data for Quantitative Risk Assessment Dr. Jay Goodman, Michigan State University: Biological Processes Relevant to Dose Selection for Cancer Risk Assessment Dr. Elaine Faustman, University of Washington: Biological Processes and Non-Cancer Risk Assessment: Meeting the Challenge of Mechanistic Inquiry Following the talks there will be a panel discussion led by Drs. Roger McClellan, Michael Gallo, Bernard Schwetz, Mary Jane Selgrade and Ellen Silbergeld, with audience participation.1995 PEER REVIEW SCHEDULE FOR NTP TOXICOLOGY AND
CARCINOGENESIS TECHNICAL REPORTS AND SHORT TERM
TOXICITY REPORTS
Two meetings of the Board of Scientific Counselors Technical Reports Review Subcommittee are scheduled for 1995. For the June 20 and 21 meeting, reports on toxicity and carcinogenicity studies of codeine, butyl benzyl phthalate, t-butylhydroquinone, salicylazosulfapyridine, scopolamine, hydrobromide trihydrate, and 1,2-dihydro-2,2,4-trimethylquinoline will be reviewed. The reports on butyl benzyl phthalate, t-butylhydroquinone, salicylazosulfapyridine, and scopolamine will in addition to the traditional two year study results, report findings with groups run under mild dietary restrictions. A separate report will deal with the effects of dietary restriction on the results of these collected studies and draw some conclusions about the usefulness of this approach to performing toxicity and carcinogenicity studies. Also to be reviewed at this meeting is a short-term toxicity report on 1,4-butanediol. Presentations are planned concerning the toxicological findings of a series of prechronic inhalation studies on carbon disulfide. At the December 5 and 6 meeting, reports on the toxicity and carcinogenicity studies of nitromethane, tetrafluoroethylene, molybdenum trioxide, D&C Yellow No. 11, sodium xylene sulfonate and phenolphthalein will be reviewed. Short-term toxicity studies that will be reviewed by ad hoc reviewers by mail during 1995 include studies of urethane/ethanol, comparative toxicity and carcinogenicity studies of o-nitrotoluene and o-toluidine, toxicity studies of t-butanol, cyclohexanone oxime, methyl ethyl ketoxime, o-chloroaniline and a series of halogenated ethanes. Meetings of the NTP Board of Scientific Counselors Reports Subcommittee are held at
the NIEHS in Research Triangle Park, NC and are open to the public. For information
contact: Dr. L.G. Hart, P.O. Box 12233, Research Triangle Park, NC 27709;
telephone: (919) 541-3971; Fax: (919) 541-0719REQUEST FOR CHEMICAL NOMINATIONS
NTP continues to solicit recommendations for chemicals and chemical classes to be tested for toxicity. Chemicals are selected for testing on the basis of the data and information needs of NTP member agencies and other Government agencies, and in response to public concerns regarding the safety and health effects of specific chemicals or chemical classes. 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, and chemical metabolism and disposition, as well as other efffects that may be considered relevant to human health concerns. The results of the NTP testing are used by other Federal and State agencies and private sector organizations. The results also are available to the public, and published in the open scientific literature. There is no time limit for nominating chemicals and health effects to be tested. The NTP will consider each nomination as it is received, but the available resources will limit the numbers of chemicals that can be tested, or the types of test that can be performed. Please send all chemical nominations and relevant information about the
nominated chemicals to: Dr. E. Zeiger, Chemical Selection Office, P.O. Box 12233,
Research Triangle Park, NC 27709 telephone: (919) 541-4482.REQUEST FOR PUBLIC COMMENT ON CHEMICALS IDENTIFIED
BECAUSE OF HIGH PRODUCTION LEVELS FOR POSSIBLE
CONSIDERATION FOR STUDY BY THE NTP
Efforts have been accelerated to increase the nomination of high priority chemicals for evaluation by the NTP. One area to receive attention is the identification and selection of high production chemicals to which significant segments of the population are exposed and for which chronic studies have not been conducted. The following list describes chemicals which are produced in excess of 100 million lbs/yr and have not been studied. Emphasis is being placed on these chemicals because even if the use of a chemical is 99% contained, production of 100 million lbs/yr results in release of 1 million lbs/yr. Emphasis will be placed on selecting high exposure chemicals and/or those that offer the greatest opportunities to identify and confirm structure/activity relationships which account for chemical toxicity/ carcinogenicity. Public comment is requested to identify those chemicals described which represent the greatest risks and offer the greatest opportunities to study structure/activity relationships.
PRODUCTION DATA AND COMMENTS FOR NTP STUDY CANDIDATES
High Production Volume Chemicals CAS # Chemical* 106-98-9 1-BUTENE 592-41-6 1-HEXENE 111-66-0 1-OCTENE 872-05-9 1-DECENE 108-10-1 2-PENTANONE, 4-METHYL 111-69-3 ADIPONITRILE 25155-30-0 BENZENESULFONIC ACID, DODECYL-, SODIUM SALT 71-36-3 BUTYL ALCOHOL 98-82-8 CUMENE 75-86-5 LACTONITRILE, 2-METHYL- 115-77-5 PENTAERYTHRITOL 109-66-0 PENTANE 1120-21-4 UNDECANE 106-42-3 p-XYLENE *These chemicals have not been selected for study. Some may be studied,
others will not be studied. Comments regarding their suitability for study
follow. Additional comment is invited and can assist in the nomination/
selection process. Comments: 1-Butene 1-Butene has not been the subject of a previous chronic study, but its primary reactive metabolite, butene oxide, has been studied. 1-HEXENE 1-OCTENE 1-DECENE Each of these linear alpha olefins is a major production chemical which has not
been studied previously. However, they do not have structural alerts, have low
acute toxicity and probably will not be metabolized to toxic intermediates. Thus,
it might be desirable to select a single representative from the group.
2-PENTANONE, 4-METHYL- (also known as methyl-isobutylketone) Methyl-isobutylketone is produced in large quantities and has not been evaluated for evidence of human carcinogenic potential. It is not highly toxic, but has considerable potential for human exposure by inhalation. ADIPONITRILE Adiptonitrile has appreciable toxicity probably as a result of metabolism to cyanide.
It should not be persistent in the environment, but should have appreciable
potential or exposure by virtue of its very large production.
BENZENESULFONIC ACID, DODECYL-, SODIUM SALT This moderately toxic detergent is produced in large quantities and is widely used in
numerous industries. Human exposure to this chemical is estimated to be in the
hundreds of thousands.
BUTYL ALCOHOL Butyl alcohol is produced in very large quantities and its wide use results in a
large exposure population. However, butyl alcohol has low acute toxicity and
would be expected to be metabolized to the respective short chain fatty acid which,
unless consumed in excessive amounts, would be readily cleared by intermediary
metabolism without the involvement of reactive intermediates.
CUMENE Cumene has only moderate acute toxicity, but has a very high level of production,
significant release into the environment and a large exposure population.
LACTONITRILE, 2-METHYL- This highly toxic chemical intermediate is used primarily in the synthesis of
insecticides and another important chemical intermediate, methyl. The toxicity of
this compound can be accounted for by its metabolism to cyanide.
PENTAERYTHRITOL Pentaerythritol finds its primary use in surface-coating compositions, especially in
the manufacture of alkyd resins. It is only moderately toxic, has no obvious
structural alerts and is not thought to be metabolized to reactive intermediates.
PENTANE Because of its low toxicity and reactivity, pentane is used primarily as a component
of aerosol propellants. Pentane is readily cleared by exhalation as the parent
compound and by metabolism to the respective short-chain fatty acid without the
involvement of reactive intermediates.
UNDECANE Undecane is a representative member of the n-paraffins, a class of chemicals which
are produced in high volume. Undecane is used as a chemical intermediate and
component of gasoline. It has only moderate toxicity, is not known to be
metabolized to toxic intermediates and has no apparent structural alerts.
p-XYLENE p-Xylene is a major chemical intermediate; however, mixed xylenes (0-, m-, and
p-xylenes) have been studied previously and found to be negative.
For information contact: Dr. E. Zieger, Chemical Selection Office,
NIEHS/NTP, P.O. Box 12233, Research Triangle Park, NC 27709;
telephone: (919) 541-4482UPDATE: REVIEW OF THE CRITERIA USED FOR INCLUSION OF
SUBSTANCES IN THE BIENNIAL REPORT ON CARCINOGENS
Background:: 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.
- broaden the input at all stages throughout the process;
- broaden the scope of scientific review, and
- provide a review of the criteria used for inclusion of substances in the BRC.
Scientific Counselors established to:
- (1) receive public comments on criteria, and
- (2) review and make recommendations on the criteria for listing substances in the
Biennial Report on Carcinogens (BRC).
- 1) The adequacy of existing criteria for listing substances in future Reports;
- 2) The incorporation of mechanistic data as part of the criteria for listing
substances in future Reports which may include the consideration of sensitive
sub-populations as well as procedures to upgrade or downgrade the evaluation of
the results of animal bioassay or epidemiology studies;
- (1) receive and review the report of the ad hoc working group,
- (2) receive public comment on the report, and
- (3) develop the Board's recommendations concerning the selection criteria.
for review and comment by the public is available upon request. Copies of the
document can be obtained by contacting Dr. C. W. Jameson at the address below.
The report of the ad hoc working group April 24-25 deliberations will be available for
public review as soon after the meeting as possible.
Action -- Request for Public Input: Public input concerning the criteria for listing a substance in the BRC is important to the review process and is encouraged. Written comments can be submitted to Dr. Jameson. To be considered by the ad hoc w orking group in their April 24-25 deliberations, written comments must be received by April 12, 1995. To be considered by the NTP Board of Scientific Counselors in their June 29-30 meeting, written comments must be received by June 16, 1995. Oral comments during the public session of both the April 24-25 and June 29-30 meetings will be limited to five minutes to permit maximum participation. Written comments accompanying oral statements are encouraged. Contact: Dr. C.W. Jameson, NIEHS, MD: WC-04, P.O. Box 12233,
Research Triangle Park, NC 27709; phone (919) 541-4096 or fax: (919) 541-2242 Registration for the Public Meetings: April 24-25 Meeting of the ad hoc working group of the NTP Board of Scientific
Counselors. Washington, DC:
To register to attend, make oral comments, or to receive information on the agenda
and site of the meeting.
Please contact: Dr. C. W. Jameson. June 29-30 Meeting of the NTP Board of Scientific Counselors.
Research Triangle Park, NC 27709
To register to attend, make oral comments, or receive information on the agenda.
Please contact: Dr. L.G. Hart, P.O. Box 12233, Research Triangle Park, NC 27709;
telephone: (919) 541-3971; Fax: (919) 541-0719
UPDATE: NTP WORKSHOP ON "MECHANISM-BASED TOXICOLOGY IN
CANCER RISK ASSESSMENT: IMPLICATIONS FOR RESEARCH,
REGULATION, AND LEGISLATION"JANUARY 11-13, 1995
A diverse group of over 200 participated in the workshop designed to bring regulators, researchers, and legislators together to address the following goals:
- To assess the scientific foundation for using mechanism-based toxicology to
address critical issues in risk assessment. - To identify and propose solutions to the regulatory problems which may emerge
by the use of mechanistic toxicology in conducting risk assessments. - To determine the applicability of mechanism-based toxicology and risk
assessment to current legislative issues.
- Screening chemicals and priority setting
- Hazard Identification
- Dose-response relationships
- Species extrapolation
- Distribution of risk
- Presentation to the NTP Board of Scientific Counselors as critical input to
further development of NTP research and testing strategies; tentatively
scheduled for the June 29-30 Board meeting.
- Presentation to the NTP Executive Committee for review of the recommendations
and their impact on implementing strategies for dealing with regulatory
issues.
- Presentation and/or submission to the appropriate Congressional committees and
legislative staff for consideration of the impact on legislation.
by contacting Sandy Lange, NTP Liaison Office, P.O. Box 12233, MD: B3-01,
Research Triangle Park, NC 27709, Phone: (919) 541-0530, Fax: (919) 541-0295.
NIEHS AND NTP INFORMATION: IN ELECTRONIC FORMAT WORLD-WIDE
In addition to contacting the NIEHS and NTP directly, selected information in electronic format is made available world-wide. For example, The 1994 NTP Annual
Plan, The 7th Annual Report on Carcinogens (Summary), Abstracts of the NTP
Reports, and The Status of All NTP Studies are all available on the Internet.
To view this information requires access to the Internet and internet client software.
The server is located at the National Institute of Environmental Health Sciences. To
access this server using the Gopher client the address is ntp.niehs.nih.gov and
the URL is http://ntp.niehs.nih.gov when using one of the world wide web
browsers e.g. Mosaic or Netscape.
For information contact: Dr. W. Eastin, NIEHS, P.O. Box 12233, Research Triangle Park,
NC 27709 : telephone: (919) 541-7941
