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NTP Update Aloe Ext
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 email@example.com ♦ 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 firstname.lastname@example.org 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 email@example.com 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, firstname.lastname@example.org. 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 email@example.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, firstname.lastname@example.org 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 email@example.com (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: firstname.lastname@example.org. 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 email@example.com 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 firstname.lastname@example.org 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 email@example.com 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 firstname.lastname@example.org 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: email@example.com 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 firstname.lastname@example.org 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 The Environmental Health Information ♦ Subscribe online at Service (EHIS) adds new technical http://ehis.niehs.nih.gov (secure online reports to the NTP’s online library. To order forms) access these reports, follow the NTP ♦ Send encrypted email orders to email@example.com Reports link at http://ehis.niehs.nih.gov. ♦ Mail orders with payment to: OCR A full listing of NTP reports is now Services, Inc.; Attn: Order Processing, online, showing availability of reports, P.O. Box 12510, Research Triangle with links to abstracts and full text of Park, NC 27709 reports. Subscribers obtain unlimited access to Subscribe Now to the EHIS all areas of the EHIS as well as printed Make sure you do not miss any copies of the journals they select, developments in the ever-expanding including EHP, EHP Supplements, NTP field of environmental health, subscribe Technical Reports, Toxicity Reports, and now to the EHIS using one of five easy the Report on Carcinogens. Many NTP options: documents are available only through ♦ Call 1-800-315-3010 or 919-541-3841 the EHIS. ♦ Fax orders to 919-541-0763 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: firstname.lastname@example.org 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: email@example.com 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 firstname.lastname@example.org 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: email@example.com 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: firstname.lastname@example.org 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: email@example.com *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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