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					      July 2000                               NTP Update
                                 We are pleased to provide the following information to update our readers
                                       on programs and initiatives of the NTP, as well as to highlight
                                     upcoming meetings. We invite public input and participation in all
                                                           aspects of our programs.


                                 ♦ NTP Study Reports
                                   - Technical Reports Reviewed in May 2000
                                   - Technical Reports to be Reviewed in 2001

                                 ♦ Report on Carcinogens (RoC)
NATIONAL TOXICOLOGY
PROGRAM LIAISON                  ♦ NTP Centers
AND SCIENTIFIC
REVIEW OFFICE
                                   - NTP Center for the Evaluation of Risks to Human Reproduction
                                   - NTP Interagency Center for the Evaluation of Alternative
Sandra V. Lange,                     Toxicological Methods
Director

P.O. Box 12233
                                 ♦ NTP Testing Programs
MD: A3-01                          - Input and Nominations Requested for New Agents of Study
Research Triangle Park,            - Testing Initiatives
NC 27709-2233
                                 ♦ Upcoming Meetings
(919) 541-0530
Fax: (919) 541-0295
                                   - Endocrine Disruptors Low Dose Peer Review
E-mail:                            - Risk Assessment Workshop
liaison@starbase.niehs.nih.gov
                                 ♦ Environmental Health Information Service (EHIS)

NATIONAL INSTITUTE               ♦ Calendar of Events
OF ENVIRONMENTAL
HEALTH SCIENCES


NATIONAL                           The NTP Update is issued approximately four times each year. To
INSTITUTES                         subscribe to the “list-server” and receive these “Updates” and news
OF HEALTH                             announcements electronically, register online at http://ntp-
                                                           server.niehs.nih.gov or
                                     send email to ntpmail-request@list.niehs.nih.gov with the word
                                                 “subscribe” as the body of the message.
                                                        ♦ Naphthalene (TR-500)
                                                            Ingredient in moth repellants and toilet bowl
                                                            deodorants and used as an intermediate in a
                                                            variety of chemical synthesis processes.
A Subcommittee of the NTP Board met May                     Exposure by inhalation.
18, 2000 to review technical reports for the            Clear evidence of carcinogenic activity (nose) in
six long-term toxicology and carcinogenicity            male and female rats.
studies listed below. Five categories of
evidence of carcinogenic activity are used in           ♦ Sodium Nitrite (TR 495)
the NTP Technical Report (TR) series to                     Color fixative and preservative in meats and
summarize the strength of the evidence                      fish; also used in a variety of industrial
                                                            processes. Exposure in drinking water.
observed in each experiment: two categories
                                                        No evidence of carcinogenic activity in male rats
for positive results (clear evidence and some           and male mice, no evidence of carcinogenic
evidence); one category for uncertain                   activity in female rats, and equivocal evidence
findings (equivocal evidence); one category             of carcinogenic activity (forestomach) in female
for no observable effects (no evidence); and            mice.
one category for experiments that cannot be
evaluated because of major flaws                        ♦ p,p'-Dichlorodiphenyl Sulfone (TR 501)
(inadequate study). The level of evidence                  Starting product in production of
for carcinogenicity for each of the reports is             polysulfones and polyethersulfones; by-
also listed below.                                         product of pesticide production. Exposure
                                                           in feed.
♦ Chloral Hydrate (TR-502)                              No evidence of carcinogenic activity in male and
    The primary sedative used in children.              female rats and in male and female mice.
    Exposure by gavage.
Equivocal evidence of carcinogenic activity             Draft technical reports or summary of the
(pituitary gland) for female mice that were             minutes can be viewed on the NTP web site,
continuously treated for two years.                     http://ntp-server.niehs.nih.gov or can be
                                                        obtained by contacting Central Data
♦ Chloral Hydrate (TR-503)                              Management, NIEHS/NTP, P.O. Box 12233
   The primary sedative used in children.
                                                        MD E1-02, Research Triangle Park, NC
   Exposure by gavage: ad libitum and dietary
   controlled feeding.                                  27709; (919)-541-3419, fax (919)-541-3687
Some evidence of carcinogenic activity (liver) in       or e-mail: CDM@niehs.nih.gov.
male mice.
                                                        Completed NTP technical reports can be
♦ Indium Phosphide (TR499)                              procured through the Environmental Health
    Used in making semiconductors, lasers,              Information Service http://ehis.niehs.nih.gov
    solar cells, and photodiodes. Exposure by           or by calling (919) 541-3841 or Fax: (919)
    inhalation.                                         541-0763.
Clear evidence of carcinogenic activity (lung
and adrenal gland) in male and female rats and
clear evidence of carcinogenic activity in male
(lung and liver) and female (lung) mice.                The following are candidate Technical
                                                        Reports tentatively scheduled for review in
                                                        2001.

                                                    1
Spring 2001 Review:                                    Fall 2001 Review:
♦ Acrylonitrile and Methacrylonitrile                  ♦ Vanadium Pentoxide - Used in light filters
  Used in making polymers and plastics                   and in the semiconductor industry
♦ o-Nitrotoluene and p-Nitrotoluene                    ♦ Riddelliine - Plant alkaloid found as a
  Used in the manufacture of chemicals                   contaminant in some foods
  including dyes, toluidines, and nitrobenzoic         ♦ Urethane/Ethanol - By-product of
  acid                                                   fermentation found in alcoholic beverages
♦ Citral - Used in lemon flavors and                   ♦ Dipropylene Glycol - Component of
  fragrances                                             antifreezes and air fresheners




Prepared by the NTP, the Report on                     scientists, consumers and other interested
Carcinogens (RoC) identifies substances --             parties.
such as metals, pesticides, drugs, and natural
and synthetic chemicals -- and mixtures or             ♦ New to the 9th Report as “Known”:
                                                       •Alcoholic Beverage Consumption
exposure circumstances that are “known” or
                                                       •Dyes metabolized to benzidine (benzidine dyes
are “reasonably anticipated” to be human               as a class)
carcinogens, and to which a significant                •Environmental Tobacco Smoke
number of Americans are exposed.                       •Smokeless Tobacco
                                                       •Solar Radiation and Exposure to Sunlamps and
The “known” category is reserved for those             Sunbeds
substances for which there is sufficient               •Strong Inorganic Acid Mists Containing
evidence of carcinogenicity from studies in            Sulfuric Acid
humans that indicates a cause and effect               •Tamoxifen
relationship between the exposure and                  •Tobacco Smoking
human cancer. The “reasonably anticipated”
category includes those substances for                 ♦ New to the 9th Report as “Reasonably
which there is limited evidence of                         Anticipated”:
carcinogenicity in humans and/or sufficient            •Chloroprene
                                                       •Diesel Exhaust Particulates
evidence of carcinogenicity in experimental
                                                       •Isoprene
animals. Conclusions regarding                         •Phenolphthalein
carcinogenicity in humans or experimental              •Tetrafluoroethylene
animals are based on expert, scientific                •Trichloroethylene
judgment, with consideration given to all
relevant information.                                  ♦ Reclassified as a “Known” in the 9th
                                                         Report:
                                                       •1, 3-Butadiene
                                                       •Cadmium and Cadmium Compounds
The Department of Health and Human                     •Direct Black 38
Services released the 9th edition on May 15,           •Direct Blue 6
2000. The new and upgraded listings and                •Ethylene Oxide
the delistings in the 9th edition are identified       •Silica, Crystalline (respirable size)
below. The RoC’s findings are based on                 ♦ Removed from the 9th Report:
three years of study that included three               •Saccharin
scientific reviews and public comment from             •Ethyl Acrylate

                                                   2
♦ Review for the 9th Report also                        ♦ Beryllium and Beryllium Compounds
  Included:                                             Used in fiber optics and cellular network
•Employment in Boot and Shoe Industry                   communications systems, aerospace, defense
Remains in an appendix.                                 and other industry applications.
•Methyl-t-butyl ether
Not recommended for listing.                            ♦ Dyes Metabolized to 3,3
•Nickel and Nickel Compounds                            Dimethoxybenzidine (Dimethoxybenzidine
Deferred listing nickel compounds as a                  Dyes as a Class)
“Known” until completion of review of metallic          Dyes formerly widely used for leather, paper,
nickel and nickel alloys.                               plastics, rubber, and textile industries.
•2,3,7,8-Tetrachlorodibenzo-p-dioxin
Proposed for upgrade to the “Known” category.           ♦ Dyes Metabolized to 3,3
The proposed listing is currently in litigation.        Dimethylbenzidine (Dimethylbenzidine Dyes as
Depending on the outcome of the litigation an           a Class)
addendum may be published following the                 Dyes formerly widely used for leather, paper,
Court’s ruling.                                         plastics, rubber, and textile industries.

For more information on how to order a                  ♦ IQ (2-Amino-3-methylimidazo[4,5
hard copy of the Report or to access it on              f]quinoline)
                                                        Found in cooked meat and fish.
the Web, visit the NTP Homepage at
http://ntp-server.niehs.nih.gov or contact the          ♦ Styrene-7,8-oxide
National Toxicology Program, Report on                  Used mainly in the preparation of fragrances and
Carcinogens, MD EC-14, P.O. Box 12233,                  in some epoxy resin formulations.
Research Triangle Park, NC 27709.
                                                        ♦ Vinyl Bromide
                                                        Used commercially since 1968, primarily in the
                                                        manufacture of flame retardant synthetic fibers.
The 10th edition will be published in 2002.
                                                        ♦ Vinyl Fluoride
Nominations are being reviewed in two                   Used commercially since the 1960s, in the
groups.                                                 production of polyvinylfluoride that is used for
                                                        plastics.
Review of First Group of Nominations
Scientific reviews of the first group of                A list of the recommendations by the three
nominations being considered for inclusion              review groups for listing in or delisting from
in the 10th edition of the RoC have been                the 10th RoC can be obtained by accessing the
completed. This group of nominations                    NTP Home Page on the Web at: http://ntp-
includes the following:                                 server.niehs.nih.gov or by contacting Dr.
♦ 2,3-Dibromo-1-propanol                                C.W. Jameson at the address provided below.
Used as a flame retardant, as an intermediate in        Background documents provided to the
the preparation of the flame-retardant tris (2,3-       review committees and the public are
dibromopropyl) phosphate, and as an                     available on the web in PDF at the above
intermediate in the manufacture of pesticides           URL address. Hard copies of these
and pharmaceutical preparations.                        documents are also available upon request.
                                                        The NTP will review the recommendations
♦ 2,2-Bis-(bromomethyl) –1,3-propanediol                from each of the review committees and
Used in a fire retardant in unsaturated polyester       consider the public comments received
resins, in molded products, and in rigid
                                                        throughout the process in making decisions
polyurethane foam.
                                                        regarding the NTP recommendations to the
                                                        Secretary, DHHS for listing of the nominated

                                                    3
substances in the 10th RoC. The NTP has                  ♦ Talc (Containing Asbestiform Fibers)
already solicited public comment to                      Talc (containing asbestiform fibers) occurs in
supplement any previously submitted                      various geological settings around the world.
comments or to provide comments for the                  Occupational exposure occurs during mining,
                                                         milling and processing. To be reviewed for
first time on any substance identified above.
                                                         possible listing in the 10th Report.
Review of the Second Group of
Nominations                                              ♦ Trichloroethylene
                                                         Trichloroethylene is widely used as a solvent
Review of the second group of nominations
                                                         with 80-90% used worldwide for degreasing
for possible listing in the 10th Report is               metals. To be reviewed for possible upgrading
underway. These nominations include:                     to a known human carcinogen in the 10th Report.
♦ Chloramphenicol
Used widely as an antibiotic since the 1950s.            ♦ Broad Spectrum UV Radiation
Chloramphenicol is currently used in the United          Solar and artificial sources of ultraviolet
States only to combat serious infections where           radiation. To be reviewed for possible listing in
other antibiotics are either ineffective or              the 10th Report.
contraindicated. To be reviewed for possible             ♦ Wood Dust
listing in the 10th Report.                              It is estimated that at least two million people
♦ Lead and Lead Compounds                                are routinely exposed occupationally to wood
Used widely in pipes for water distribution,             dust worldwide. Non-occupational exposure also
lead-based paints, lead additives in gasoline, and       occurs. The highest exposures have generally
many other applications. To be reviewed for              been reported in wood furniture and cabinet
possible listing in the 10th Report.                     manufacture, especially during machine sanding
                                                         and similar operations. To be reviewed for
♦ Methyleugenol                                          possible listing in the 10th Report.
Flavoring agent used in jellies, baked goods,
nonalcoholic beverages, candy, and ice cream.            The NTP has solicited public input on these
Also used as a fragrance for many perfumes, and          nominations and asks for relevant
soaps. To be reviewed for possible listing in the        information anyone may have concerning
10th Report.                                             their carcinogenesis, as well as current
                                                         production data, use patterns, or human
♦ Nickel (metallic) & Nickel Alloys
                                                         exposure information. The NTP also invites
Widely used in commercial applications for over
100 years. Action required to complete review
                                                         interested parties to identify any scientific
of Nickel and Nickel Compounds for possible              issues related to the possible listing of a
listing in the RoC that began in 1998/99.                specific nomination in the RoC that they feel
                                                         should be addressed during the reviews.
♦ Estrogens, Steroidal                                   Comments or questions should be directed
Estrogens are widely used in oral contraceptives         to Dr. C. W. Jameson at the address listed
and in post-menopausal therapy for women. To             below.
be reviewed for possible upgrading to a known
human carcinogen in the 10th Report.                     December Board Meeting and
♦ Talc (Non-Asbestiform)                                 Opportunity for Public Review and
Talc (non-asbestiform) occurs in various                 Comment
geological settings around the world.                    The second group of nominations will be
Occupational exposure occurs during mining,              reviewed in public session by the NTP
milling and processing. Exposure to general              Board of Scientific Counselors Report on
population occurs through use of products such           Carcinogens Subcommittee December 13-
as cosmetics. To be reviewed for possible                15, 2000. This review will include an
listing in the 10th Report.

                                                     4
opportunity for public comment and will be
held in the Washington, DC area.
Background documents for these
nominations will be available for public           The NTP solicits and encourages the
review October 1, 2000 and will be                 broadest participation from interested
accessible from the NTP Home Page at               individuals or parties in nominating agents,
http://ntp-server.niehs.nih.gov.                   substances, mixtures or exposure
Hard copies can be obtained by contacting          circumstances for listing in or delisting from
Central Data Management, NIEHS/NTP,                the RoC. Nominations should contain a
P.O. Box 12233 MD E1-02, Research                  rationale for listing or delisting.
Triangle Park, NC 27709; (919)-541-3419,           Appropriate background information and
fax (919)-541-3687 or e-mail:                      relevant data (e.g., journal articles, NTP
CDM@niehs.nih.gov.                                 Technical Reports, IARC listings, exposure
                                                   surveys, release inventories, etc.) which
Additional information regarding the Board         support a nomination should be provided or
meeting will be announced in the near              referenced when possible. Anyone may
future. Questions regarding the Board              nominate a substance to be considered for
meeting can be addressed to the Board              listing in or delisting from the RoC.
Executive Secretary, Dr. Mary Wolfe, at
wolfe@niehs.nih.gov or 919-541-3491.               To submit nominations for listing or
                                                   delisting or for information about the Report
                                                   on Carcinogens, contact Dr. C. W. Jameson,
                                                   telephone: (919) 541-4096, fax, (919) 541-
                                                   0144, e-mail, jameson@niehs.nih.gov.



         NTP Center for the Evaluation of Risks to
                  Human Reproduction

The NTP and the NIEHS established the              following seven phthalate esters will be held
NTP Center for the Evaluation of Risks to          July 12-13, 2000 at the Sheraton National
Human Reproduction (CERHR) in June                 Hotel in Arlington, Virginia.
1998. The purpose of the Center is to
                                                      •butyl benzyl phthalate (85-68-7) BBP
provide timely and unbiased, scientifically
                                                      •di(2-ethylhexyl) phthalate (117-81-7)
sound evaluations of human and
                                                      DEHP
experimental evidence for adverse effects on          •di-isodecyl phthalate (26761-40-0, 68515-
reproduction, including development, which            49-1) DIDP
may be caused by agents to which humans               •di-isononyl phthalate (28553-12-0, 68515-
are exposed.                                          48-0) DINP
                                                      •di-n-butyl phthalate (84-74-2) DBP
                                                      •di-n-hexyl phthalate (84-75-3) DnHP
                                                      •di-n-octyl phthalate (117-84-0) DnOP
The third and final meeting of an Expert
Panel to complete the evaluation of the

                                               5
                                                    for further consideration by the NTP. An
                                                    evaluation of Methanol (67-56-1) is planned
Expert panel reports to be reviewed at the          for late 2000. Additional information will
July 12-13 meeting are available to the             be announced in the near future. Questions
public and can be obtained electronically on        regarding the review can be directed to Dr.
the NTP website: http://cerhr.niehs.nih.gov         Michael Shelby as indicated below.
or in hardcopy by contacting Ms. Peggy
Sheren at CERHR, 1800 Diagonal Road,
Suite 500, Alexandria, VA 22314-2808,
Phone 703 838 9440,                                 Nominations of chemicals for future
psheren@sciences.com.                               evaluations are also encouraged. Any
                                                    individual or organization may nominate.
Following the July 12-13 meeting and                Nominations should include the chemical
finalization of the Expert Panel Phthalate          name, Chemical Abstract Service registry
Reports, public review and comment of the           number (if known), reason for the
final Expert Panel reports will be solicited.       nomination, and references or articles on the
The NTP will then prepare an NTP Center             chemical, when possible. The nominator's
Report, that is based on the expert panel           name, address, telephone number and e-mail
reports, public comments, and any newly             address should be included with the
available information. The NTP Center               nomination. Nominations can be made
Report will include a lay summary of any            through the Center's web site or by mail to:
evidence that exposure may lead to harm             Dr. John Moore, CERHR, 1800 Diagonal
and identification of any research needs and        Road, Suite 500, Alexandria, VA 22314-
gaps. The NTP Center Report will then be            2808, Phone: (703) 838-9440.
transmitted to Federal and State agencies,
the scientific community and to the general         Further information about the NTP Center
public. Announcement of the availability of         for the Evaluation of Risks to Human
the final phthalate reports will be made as         Reproduction can be obtained through the
soon as the final reports are complete.             Center's web site: http://cerhr.niehs.nih.gov
                                                    or by contacting: Michael D. Shelby, Ph.D.,
                                                    NIEHS, shelby@niehs.nih.gov or
The CERHR Core Committee, composed of               P.O. Box 12233, Research Triangle Park,
representatives of NTP-participating                NC 27709. Telephone: 919-541-3455
agencies, reviews chemicals nominated for
further study and recommends candidates


        NTP Interagency Center for the Evaluation
           Of Alternative Toxicological Methods
The NTP Interagency Center for the                  Committee on the Validation of Alternative
Evaluation of Alternative Toxicological             Methods (ICCVAM). ICCVAM (14 Federal
Methods (NICEATM) provides                          regulatory and research agencies) was
administrative and technical support and            established in 1997 to facilitate cross-agency
serves as a communication and information           coordination and communication on issues
resource for the Interagency Coordinating           relating to the development, validation,

                                                6
acceptance, and national/international                Background Review Document that includes
harmonization of toxicological test methods.          the revised UDP protocol and documents
NICEATM and ICCVAM collaborate to                     supporting the basis and validity of the test
carry out related activities needed to                method. The Document is available for
develop, validate, and achieve regulatory             comment and can be obtained by contacting
acceptance of new and improved test                   NICEATM at the address listed below.
methods applicable to Federal agencies.
                                                      A Federal Register notice providing more
                                                      detail on the meeting is available at:
                                                      http://iccvam.niehs.nih.gov/udp.htm.



An international peer review panel of
experts will meet on July 25, 2000, from
8:30 a.m. to 5:30 p.m. at the Sheraton
Crystal City Hotel in Arlington, VA. The              NICEATM and ICCVAM are convening a
public is welcome to attend and provide               scientific workshop to assess the current
comment during designated public comment              status of in vitro test methods for evaluating
sessions. The agenda includes a brief                 the acute systemic toxicity potential of
orientation on ICCVAM and the UDP,                    chemicals and to form recommendations for
followed by a peer review of the UDP and              future development and validation studies.
supporting information. ICCVAM and                    The workshop will take place on October
NICEATM have organized this independent               17-20, 2000, at the Hyatt Regency Crystal
peer review evaluation of a revised UDP for           City Hotel in Arlington, VA. The meeting
assessing acute oral toxicity at the request of       will be open to the public.
U.S. EPA. This procedure is a revised                 An agenda, registration information, and
version of the Organization for Economic              other details will be distributed in the near
Cooperation and Development (OECD) Test               future. To receive this information directly,
Guideline 425, “Guideline for the Testing of          please contact Dr. Stokes as indicated
Chemicals, Acute Oral Toxicity: Up-and-               below.
Down Procedure,” and is proposed as a
substitute for the existing traditional OECD
Test Guideline 401 for Acute Oral Toxicity.
The UDP uses fewer animals to determine
acute oral toxicity potential of chemicals as
compared to Guideline 401. OECD has
proposed that Guideline 401 should be                 An Expert Panel Meeting was held on May
deleted since three alternative methods are           16 - 18, 2000, in Research Triangle Park,
now available. Prior to deletion of                   NC, to evaluate the Frog Embryo
Guideline 401, U.S. agencies have requested           Teratogenesis Assay -- Xenopus (FETAX), a
that ICCVAM conduct an independent peer               screening method proposed for evaluating
review of the revised UDP to determine the            the developmental toxicity potential of
validity of the method as a substitute for            chemicals. The objectives of this meeting
Guideline 401.                                        included developing consensus on the
                                                      current validation status of FETAX,
Background Document Now Available                     providing recommendations for FETAX
NICEATM, in conjunction with U.S. EPA                 protocol modifications and further validation
and other scientists, recently prepared a             studies, recommending current and potential
                                                  7
uses of FETAX, and recommending                     ICCVAM website:
additional research and further test method         http://iccvam.niehs.nih.gov for updates on
development.                                        when the report will be available, and to
                                                    access an electronic version. For hard
The international Expert Panel consisted of         copies of the report please contact Dr.
45 scientists in five breakout groups that          William Stokes at the address listed below.
evaluated the protocol, reliability,
performance, environmental applications             For further information on any aspects of
and future research and development needs.          NICEATM please contact:
Each working group developed                        Dr. William S. Stokes
recommendations for improving the test              NTP Interagency Center for the Evaluation
method’s intra- and inter-laboratory                of Alternative Toxicological Methods,
reproducibility and accuracy. Research and          Environmental Toxicology Program,
development efforts that might enhance the          NIEHS/NTP, MD EC-17, PO Box 12233,
future usefulness of the assay, including the       Research Triangle Park, NC 27709; 919-
integration of microarray technology, were          541-3398 (phone); 919-541-0947 (fax);
also recommended. The final meeting                 iccvam@niehs.nih.gov (e-mail).
report is currently being prepared. Visit the




                                                    designed to address specific data gaps for
                                                    priority substances such as biological fate,
                                                    mechanisms of toxicity and other adverse
                                                    effects that may be of human health concern.
The nomination and selection process is
                                                    Data developed by NTP are critical to
integral to the effective operation and
                                                    assessments of human health hazards
success of the NTP’s testing program with
                                                    associated with exposure to those chemicals
respect to the testing of chemicals of
                                                    and agents studied. NTP also supports an
greatest public health concern. The NTP is
                                                    active program to develop and to validate
soliciting nominations of new chemicals and
                                                    new and improved assays for chemical
agents for study from all sources including
                                                    toxicity and test methods and systems that
academia, industry, labor unions, Federal
                                                    eliminate or minimize the use of laboratory
and State agencies and the general public.
                                                    animals.
NTP studies include research and testing of
                                                    Significant time and resources are consumed
selected chemicals and agents in order to
                                                    by the selection and testing of a single agent,
characterize toxicity and determine possible
                                                    so each nomination is considered carefully
adverse effects that may be associated with
                                                    before final selection for NTP testing.
human and environmental exposure. Health-
                                                    Chemicals or other agents for which a
related effects addressed include subchronic
                                                    significant portion of the population is
toxicity, chronic toxicity and
                                                    known to be exposed and for which there is
carcinogenicity, as well as reproductive,
                                                    a lack of adequate toxicological information
developmental, genetic, immunological and
                                                    available are the best candidates for study.
neurological toxicity. Studies are also
                                                    All submitted nominations should be
                                                8
accompanied by a rationale for study, i.e.          strives to balance the selection of substances
populations exposed, source of exposure,            for study so that adverse effects from
any known adverse health effects, etc. When         occupational, environmental and consumer
possible, nominations should also be                exposures are all addressed. Over the history
accompanied by available information                of the NTP, this has resulted in a diverse
describing production and use, possible             research and testing program with emphasis
adverse effects associated with exposure as         on synthetic industrial chemicals,
well as a chemical name, structure and CAS          environmental pollutants, agricultural
number.                                             chemicals, pharmaceuticals, consumer
                                                    product chemicals, constituents of food,
The NTP will consider each nomination as it         food additives, and natural products. Some
is received. Information received supporting        major NTP testing initiatives already
each nomination will be supplemented with           underway and recently discussed with the
an additional literature search, and all            NTP Board of Scientific Counselors are
material will be carefully reviewed to              listed below. It should be realized that this
establish priority for further review and           information is presented to give a
study. The nominator will be informed of            perspective on the breadth of current NTP
the status of their nomination as it moves          research and testing activities and directions
through the selection and testing process.          and is not meant to limit the solicitation of
In addition to formal nominations for study,        additional nominations to these areas.
comments on testing directions and                  Safe Drinking Water Program
priorities are welcome. Current testing             Safe drinking water represents a balance
initiatives are presented below; however, it        between microbial and chemical risk and is
is important to emphasize that the NTP              of enormous public health concern, since it
seeks the broadest participation in the             is estimated that more than 200 million
nomination process and nominations need             Americans use treated drinking water.
not be limited to the areas listed.                 Chlorination of our water supply is a
Nominations and inquires regarding                  standard treatment technique that reduces
nominations on testing initiatives should           mortality and morbidity from infectious
be addressed to:                                    disease; however, despite advances in
Dr. Scott Masten, Office of Chemical                expertise to purify and disinfect our water,
Nomination and Selection (B3-10), NIEHS,            chemical contaminants may still be found in
P.O. Box 12233, Research Triangle Park,             finished water. These agents can be grouped
NC 27709                                            into two broad categories, those that occur
E-mail: masten@niehs.nih.gov.                       as a result of the disinfection process
Visit the NTP web page to find more                 (disinfection by-products: DBPs) and those
detailed information about the NTP                  that occur naturally or by contamination
chemical nomination and selection process           (candidate contaminants) in public water
as well as how to submit nominations                systems. One of the most complex issues
online: http://ntp-                                 facing water utilities and the EPA is
server.niehs.nih.gov/NomPage/noms.html.             minimizing the potential for DBP-related
                                                    health effects while still achieving effective
                                                    control of waterborne microbial pathogens.
                                                    The NTP is playing a critical role in
The NTP has a broad mandate to provide              providing data to assess the potential risks
toxicological characterizations for chemicals       from human exposure to the major DBPs
and agents of public health concern and
                                                9
through a collaborative effort with the EPA.        toxins). The NIEHS/NIH in collaboration
The research program includes a systematic,         with the EPA is selecting the major
mechanism-based, toxicological evaluation           contaminants for future study. Both
of DBPs that can help provide the EPA data          aluminum fluoride and aluminum citrate
for setting drinking water standards. The           have been nominated to the NTP for
study of DBPs is not easy, and their                consideration for long-term neurotoxicity
selection for study is based upon their             studies.
presence in drinking water, their occurrence
with different disinfection processes, their        Requests for additional information and
chemical structure, and their representation        questions about this initiative can be
from among the different DPB families:              directed to Dr. Gary Boorman, NIEHS:
trihalomethanes, haloacetic acids, and              boorman@niehs.nih.gov or P.O. Box 12233
haloacetonitriles. The DBPs currently under         MD B3-08, RTP, NC 27709.
study include: 3-Chloro-4-(Dichloromethyl)-         DNA-Based Products
5-Hydroxy-2(5H)-Furanone(MX),                       DNA-based therapies are currently being
Bromochloroacetic Acid,                             developed for the treatment of a wide range
Bromodichloroacetic Acid,                           of human diseases. Examples include
Bromodichloromethane, Chloramine,                   plasmid DNA encoding one or more
Chloroform, Dibromoacetic Acid,                     antigenic proteins for vaccines against viral
Dibromoacetonitrile, Dibromochloracetic             and bacterial pathogens, triplex forming
Acid, Dichloroacetic Acid, Sodium                   synthetic oligonucleotides to modulate gene
Bromate, Sodium Chlorite, Sodium                    expression, and viral vectors for gene
Chlorate. Research focuses on reproductive          therapy. Though DNA-based products show
toxicity, immunotoxicity, and neurotoxicity         significant promise, by their very nature
as well as carcinogenesis, and research             they all pose a risk of interacting with the
approaches include investigations using             host genome or disrupting normal cellular
transgenic mouse models, standard rodent            processes in unexpected and unpredictable
bioassays, and studies in fish. NTP research        ways and with potentially adverse
is being conducted through agreements with          consequences. Presently the FDA has only
the U.S Army, EPA, and industry. The NTP            limited authority to require evaluation of
is also involving the extramural research           non-acute, long-term safety risk associated
community through grant support of                  with these therapies. In addition, the
hypothesis-based mechanistic studies on             majority of the manufacturers of DNA-
DBPs and is working closely with the                based products are generally small
American Water Works Association                    biotechnology companies and academic
Research Foundation (AWWARF) sharing                sponsors that lack the resources to perform
protocols and research plans and making             long-term, large-scale studies on their
them aware of ongoing research activities.          products. The NTP and FDA are
Some of the AWWARF's own research                   collaborating on an initiative to study the
awards are being designed to complement             safety of DNA-based products that will
activities of the NTP and EPA.                      address three major safety issues:
Besides the DBPs, a complex array of                ♦ The intracellular persistence and
candidate contaminants can occur naturally              potential for integration into the host
(e.g., arsenic, aluminum), as a result of               genome. Since certain of these products
contamination [e.g., methyl-tertiary butyl              are intended for use in children (e.g.,
ether (MTBE), pesticides, organotins], or               DNA vaccines), there is concern about
with environmental changes (e.g., algae                 life-long risk posed by integration.
blooms resulting in micotoxins and other
                                               10
♦ Their distribution to the gonads and the             Act. Under this Act, proof of their safety is
    potential for integration and germ line            not required prior to herbal products being
    transmission. DNA-based products may               marketed. Approximately 1500 botanicals
    reach tissues in the body outside their            are sold as dietary supplements or ethnic
    presumably sequestered sites of                    traditional medicines. These herbal
    administration (intradermal or                     formulations are not subject to FDA pre-
    intramuscular); therefore, there is                market toxicity testing to assure their safety
    concern about the potential for                    or efficacy; package inserts are not required
    reproductive toxicity and/or transmission          to inform consumers of possible adverse
    of altered genetic material to subsequent          effects or possible herb/herb or herb/drug
    generations.                                       interactions; and there is minimal post-
♦ The potential for abnormal immune                    market surveillance for possible adverse or
    activation. Both viral vectors and DNA             allergic reactions. The 1997 Presidential
    vaccines carry genes that stimulate host           Commission on Dietary Supplements
    cells to secrete self and foreign proteins.        recommended additional research by Federal
    There is concern about the potential for           agencies on dietary supplements including
    DNA-based products to promote                      medicinal herbs.
    development of autoimmune disease and
    disrupt immune homeostasis.                        The NTP has received numerous
While initial efforts are focusing on DNA-             nominations for study of herbal medicines
based therapies, the NTP is aware of public            and other dietary supplements from both the
concern for other DNA-based products, such             public and Federal agencies. The NTP is
as bioengineered foods, and may consider               currently conducting or planning research on
future research in this area.                          several medicinal herbs (Table 1). These
                                                       studies focus on characterization of potential
Requests for additional information and                adverse health effects including reproductive
questions about this initiative can be                 toxicity, neurotoxicity, and immunotoxicity
directed to Dr. Richard Irwin, NIEHS:                  as well as those associated with acute high
irwin@niehs.nih.gov or P.O. Box 12233,                 dose exposure and chronic exposure to
MD B3-07, RTP, NC 27709.                               lower doses. In addition, special attention
                                                       will be given to potential herb/herb or
Medicinal Herbs (Botanicals)                           herb/drug interactions and the responses of
Medicinal herbs are some of our oldest                 sensitive subpopulations (e.g., pregnant
medicines and their increasing use in recent           women, the young, the developing fetus, the
years is evidence of a public interest in              elderly, etc).
having alternatives to conventional
medicine. It is estimated that approximately           Requests for additional information and
one-third of the U.S. population uses some             questions about this initiative can be
form of alternative medicine. The                      directed to Dr. Tom Burka, NIEHS:
regulation of botanicals in the United States          burka@niehs.nih.gov or P.O. Box 12233,
is restrained since passage of the 1994                MD B3-10, RTP, NC 27709.
Dietary Supplement Health and Education




                                                  11
            Table 1: Medicinal Herbs (Botanicals) under Consideration by the NTP
Herb or Ingredient         Information
Substances for which studies are ongoing or planned
Berberine                  An alkaloid, active constituent ingredient in Golden Seal.
Goldenseal                 Second or third most popular medicinal herb used in this country; traditionally used to treat
                           wounds, digestive problems, and infections. Current uses include as a laxative, tonic, and diuretic.
Comfrey                    Herb consumed in teas and as fresh leaves for salads; however, it contains pyrrolizidine alkaloids
                           (e.g., symphatine), which are known to be toxic. Used externally as an anti-inflammatory agent in
                           the treatment of bruises, sprains, and other external wounds.
Echinacea                  One of the most commonly used medicinal herb in the United States. Used as a stimulant of the
                           immune system to treat colds, sore throat, and flu.
Milk Thistle Extract       Used to treat depression and several liver conditions including cirrhosis and hepatitis and to
                           increase breast milk production.
Substances being considered for study
Aloe Vera Gel              Seventh most widely used herb; used as both a dietary supplement and component of cosmetics.
                           The gel has been used for centuries as a treatment for minor burns and is increasingly being used in
                           products for internal consumption (e.g., 'health' drinks).
Ginkgo Biloba Extract      Among the five or six most frequently used medicinal herbs. Ginkgo fruits and seeds have been
                           used medicinally for thousands for years. The extract of green-picked leaves has increasing
                           popularity in the United States. Ginkgo biloba extract promotes vasodilatation and improved blood
                           flow and appears beneficial, particularly for short-term memory loss, headache, and depression.
Ginseng and                Fourth most widely used medicinal herb; gensenosides are thought to be the active ingredients.
Gensenosides               Ginseng has been used as a treatment for a variety of conditions: hypertension, diabetes, and
                           depression, and intake has also been associated with various adverse health effects.
Kava Kava                  Reported to be the fifth most widely used medicinal herb, has psychoactive properties, and is sold
                           as a calmative and antidepressant.
Pulegone                   A major terpenoid constituent of the herb, Pennyroyal, and is found in lesser concentrations in
                           other mints. Pennyroyal has been used as a carminative insect repellent, emmenagogue, and
                           abortifacient. Pulegone has well-recognized toxicity to the liver, kidney, and central nervous
                           system.
Thujone                    Terpenoid found in a variety of herbs, including sage and tansy, and in high concentrations in
                           wormwood. Suspected as the causative toxic agent associated with drinking absinthe, a liqueur
                           flavored with wormwood extract


   Occupational Exposure and Mixtures                               addressing worker exposure to cellulose
   The NTP is coordinating an interagency                           inhalation and asphalt fumes including
   effort between NIEHS and NIOSH to                                worker practices and exposures and the
   better characterize worker exposures and                         physical and chemical characteristics of
   to use this information both for worker                          the substances. Future initiatives are
   education and to identify occupational                           proposed for 1-bromopropane, metal
   health research gaps. This project                               working fluids, and welding fumes.
   involves NIOSH-wide participation and                            NIOSH will work with the NTP in
   should impact the health agenda of both                          nominating agents for study and
   NIOSH and NTP by focusing NTP                                    designing laboratory studies and will
   resources on obtaining '”real world”                             undertake its own research projects
   information about worker practices,                              under this agreement.
   complex occupational exposures, and
   possibly related adverse health effects.                         NIOSH is currently planning to conduct
   Such information is needed to better                             a national, cross-sectional, on-site survey
   identify areas for research and to design                        of establishments and workers that
   better laboratory studies on the health                          should provide information for targeting
   effects of chemicals, complex mixtures,                          future research. The new survey will
   and exposure circumstances encountered                           include all industry sectors covered by
   in the workplace. Current efforts are                            the OSHA and Mine Safety and Health

                                                             12
Administration and will gather                      and should provide high quality data
nationally representative data on                   upon which to base public health
chemical, physical, and biological agents           decisions about the interactions of drugs
to which workers are potentially                    or other compounds with sunlight. Solar
exposed, as well as data on exposure                light is simulated in the animal facilities
controls and health and safety practices.           using 6.5 kWatt xenon-arc lights filtered
                                                    through Schott quartz glass. The
Requests for additional information and             transmitted light is attenuated to achieve
questions about either initiative can be            a spectrum that closely mimics terrestrial
directed to Dr. Mark Toraason, NIOSH:               solar light. The facility is also equipped
mht1@cdc.gov or C23, 4676 Columbia                  for fluorescent light exposures.
Parkway, Cincinnati, OH 45226.                      Photocarcinogenicity studies will use the
Phototoxicology Studies and the NTP                 SKH-1 hairless mouse as the primary
Center for Phototoxicology                          test animal, and as appropriate,
The exposure of U.S. citizens to UV                 additional test animals (e.g., transgenic
radiation is increasing through more                models) will be used.
frequent use of tanning booths to                   The α- and β-hydroxy acids are acidic
augment skin coloration and the trend               compounds included in many over-the-
toward spending leisure and pleasure                counter cosmetics as dermatological
times in sunlight-oriented activities (e.g.,        chemoexfoliants; their use is increasing
beach, swimming pools). The FDA has                 as the beauty-conscious public seeks
an ongoing interest in phototoxicity and            drugs or cosmetic preparations that will
photocarcinogenicity of therapeutics,               give a more youthful appearance. The
cosmetics, devices, and food                        most widely used α-hydroxy acid is
supplements/additives and recently                  glycolic acid, while the most widely
developed an inter-agency photobiology              used β- hydroxy acid is salicylic acid.
research program with the NIEHS. This
                                                    Two possible consequences of
agreement has resulted in establishment
                                                    chemoexfoliation are increased
of the FDA-NIEHS Phototoxicology
                                                    proliferation of the epidermal epithelial
Research and Testing Laboratory and the
                                                    cells and deeper penetration of
new NTP Center for Phototoxicology;
                                                    electromagnetic radiation into the skin.
both are housed at the National Center
                                                    In light of these changes, the impact of
for Toxicological Research of the FDA
                                                    continuous use of this type of treatment
in Jefferson, Arkansas. The Center's
                                                    on the incidence of skin cancer is not
primary purpose is to conduct
                                                    known. Studies are now underway to
mechanistic-based research and
                                                    allow quantitative determination of the
photocarcinogenesis studies on
                                                    effect of these compounds on the
compounds of regulatory importance to
                                                    induction of mouse skin cancer (SKH-1
the FDA. Mechanistic-based studies are
                                                    hairless mouse) by simulated solar light.
concurrently conducted, as needed, to
facilitate interpretation of the                    Requests for additional information and
photocarcinogenesis studies.                        questions about this initiative and the
                                                    NTP Center can be directed to Dr. Paul
The laboratory is designed to allow
                                                    Howard, NCTR: phoward@nctr.fda.gov
study of many types of compounds (e.g.,
                                                    or HFT-110, 3900 NCTR Road,
cosmetics, tanning enhances, drugs, etc.)
                                                    Jefferson, AR 72079.


                                               13
                         October 10-12
                 Endocrine Disruptors Low Dose
                          Peer Review
The U.S. Environmental Protection                 for humans. A main topic to be
Agency (EPA) has asked the NTP to                 addressed is defining the shape of the
establish an independent panel of                 dose/response curves for endocrine-
scientists to review the scientific               active substances in the low-dose region.
evidence related to low-dose effects of           This analysis and evaluation will be
endocrine disruptors and to consider              accomplished through the three-day
their implications for the development,           scientific peer review that includes
validation, and interpretation of test            plenary sessions and several breakout
protocols for reproductive and                    sessions.
developmental toxicity. If this panel
concludes that significant effects may            *The Selection/Organizing Committee
occur at low doses and that the standard          for the Low-Dose Peer Review decided
dose-setting paradigm is inadequate to            not to include dioxin and PCB issues in
detect such effects, then the EPA intends         the October Peer Review. It is likely
to pursue through a separate forum, the           that a separate Peer Review will be held
question of how to test for such effects          in the spring of 2001 to consider these
including endpoints to be measured,               chemicals and to integrate information
dose-setting protocols, and appropriate           from them with conclusions from the
test methods. If the Panel believes that          October Peer Review.
the current data are inconclusive, it will        Further information about this peer
be asked to describe specific research            review can be found in Federal Register
that would resolve the ambiguities. The           notices dated January 6, 2000 and April
meeting, which is open to the public,             17, 2000 located on the NTP website at:
will be held at the Sheraton Imperial             http://ntp-
Hotel and Convention Center in                    server.niehs.nih.gov/htdocs/liason/LowD
Research Triangle Park, North Carolina.           oseEndocrineFR.html and http://ntp-
Peer Review Goals*                                server.niehs.nih.gov/htdocs/liason/Endoc
Analyses will focus on interpretation of          rineMtgDelayFR.html.
selected major studies showing or                 For additional information about this
refuting effects at low doses for                 peer review as it becomes available
endocrine disruptors on reproductive and          please visit the NTP website at
developmental endpoints. The intent is            http://ntp-server.niehs.nih.gov or contact
to examine data supporting the presence           The NTP Office of Liaison and
or absence of low-dose effects in                 Scientific Review at:
specific studies and then evaluate the            liaison@starbase.niehs.nih.gov or fax
likelihood and significance of these              (919) 541-0295. To make reservations
and/or other potential low-dose effects           at the Sheraton please call (919) 941-
                                                  5050.


                                             14
         Of Mice, Humans and Models: Future
        Research Directions for Improving Risk
                     Assessment
As part of the NTP’s efforts to expand            assessment methods, identifying and
and improve risk assessment methods               overcoming problems with current
and their application, the NIEHS in               methods, and developing partnerships
cooperation with NIOSH, EPA, the                  for increasing stakeholder and
Chemical Manufacturers Association,               community input.
and the United Auto Workers is                    Inquiries about the workshop should be
sponsoring a workshop. The meeting is             directed to Estella Lazenby, KEVRIC
scheduled for August 16-18, 2000 at the           Company, 8401 Colesville Road, Suite
Silver Tree Hotel, Snowmass Village at            610, Silver Spring, Maryland 20910 (t:
Aspen, Colorado. The goals for this               301-588-6000 ext 239, f: 301-588-2106).
workshop include developing a national
agenda and support for research on risk




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                                             15
                                 Upcoming Events


      DATE                            EVENT                                    CONTACT
 July 12-13, 2000                 Meeting:                              Ms. Peggy Sheren, CERHR
                        NTP-CERHR Final Meeting of the                1800 Diagonal Road, Suite 500
                            Phthalate Expert Panel                      Alexandria, VA 22314-2808
                                Sheraton National Hotel                     Phone:703-838-9440
                                    Arlington, VA                     Email: psheren@sciences.com
   July 25, 2000                    Meeting:                               ICCVAM/NICETAM
                        ICCVAM/NICETAM Peer Review                      MD EC-17, PO Box 12233
                        Evaluation of the Revised Up-and-            Research Triangle Park, NC 27709
                         Down Procedure for Acute Oral                     Phone: 919-541-3398
                                     Toxicity                                Fax: 919-541-0947
                              Crystal City Sheraton Hotel              Email: iccvam@niehs.nih.gov
                                    Arlington, VA
August 16-18, 2000                Workshop:                            Estella Lazenby, KEVRIC Co.
                      Of Mice, Humans and Models: Future               Phone: 301-588-6000 ext. 239
                       Research Directions for Improving                     Fax: 301-588-2106
                           Risk Assessment Methods
                          Silver Tree Hotel, Snowmass Village
                                       Aspen, CO
October 10-12, 2000               Peer Review:                                     Email:
                       Endocrine Disruptors Low Dose Peer              liaison@starbase.niehs.nih.gov
                                     Review                                  Fax: 919-541-0295
                      Sheraton Imperial Hotel & Convention Center
                              Research Triangle Park, NC
October 17-20, 2000                Workshop:                               ICCVAM/NICEATM
                       ICCVAM/NICEATM Workshop on                       MD EC-17, PO Box 12233
                       In Vitro Methods for Acute Toxicity           Research Triangle Park, NC 27709
                           Crystal City Hyatt Regency Hotel                Phone: 919-541-3398
                                    Arlington, VA                           Fax: 919-541-0947
                                                                       Email: iccvam@niehs.nih.gov
November 28, 2000                    Meeting:                       NTP Office of Liaison and Scientific
                          NTP Advisory Committee on                               Review
                        Alternative Toxicological Methods               MD A3-07, PO Box 12233
                              Washington, DC Area: TBA               Research Triangle Park, NC 27709
                                                                           Phone: 919-541-3971
                                                                      Email: wilson9@niehs.nih.gov
 December 13-15,                   Meeting:                         NTP Office of Liaison and Scientific
      2000             NTP Board of Scientific Counselors                         Review
                      Report on Carcinogens Subcommittee                MD A3-07, PO Box 12233
                              Washington, DC Area: TBA               Research Triangle Park, NC 27709
                                                                           Phone: 919-541-3971
                                                                      Email: wilson9@niehs.nih.gov

                         *For further calendar details please visit the web:
              http://ntp-server.niehs.nih.gov/Main_Pages/NTP_EVENTS_PG.html




                                                   16

				
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