Succimer Gets TLC
Kenneth Olden, director of NIEHS, and John Ruffin, director of NIH's Office of Minority Health Research, have announced the signing of five contracts for a 5-year clinical trial of succimer, a drug that reduces blood lead levels in children. The purpose of the trial is to determine whether treating children with relatively low blood-lead levels prevents or reduces associated developmental delay and whether the drug is safe. Walter J. Rogan is the project officer for the trial, and the coordinating center will be at Harvard University, with James Ware as principal investigator. The other principal investigators and clinical centers are 1) Frances M. Gill of Joseph Stokes, Jr. Research Institute, Children's Hospital of Philadelphia, 2) Julian Chisolm of Kennedy-Krieger Research Institute, Inc., in consortium with Johns Hopkins University and University of Maryland at Baltimore, 3) Richard P. Wedeen of the University of Medicine and Dentistry of New Jersey, and 4) Robert L. Bornschein of the University of Cincinnati.
Walter J. Rogan,
project officer for the TLC Trial
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J. Julian Chisolm,
Kennedy-Kreiger Research Institute
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James H. Ware,
Harvard University
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Each of the centers will treat about 250 children 18-24 months of age and follow them for up to 4 years. All children will have the lead dust and paint in their homes cleaned up and will receive vitamin and mineral supplements so they meet current recommended daily allowances, especially for zinc and calcium. The Toxicity of Lead in Children (TLC) clinical trial will cost approximately $30 million over the next 5 years.
Recent studies of lead-exposed children show that blood-lead levels once thought to be harmless cause significant delays in motor control and intellectual development. These developmental delays may impede social development and readiness for school. The TLC trial will determine if succimer reduces or eliminates such developmental delays.
Succimer is a relatively new drug that has not been adequately tested clinically. It is the first available drug of its type (a chelating agent) since 1950, and it can be orally administered at home. Succimer appears to be relatively safe and may not cause as much loss of elements needed by the body, such as zinc and iron, as do other drugs.
The TLC trial is made possible through an agreement between NIEHS and the Office of Research on Minority Health, which allocates $5 million per year for five years to address minority health concerns related to the environment. The agreement was signed in March by Olden and Ruffin.
"This clinical trial could have tremendous impact on the health of minority children. Lead poisoning is just one health concern that disproportionately affects minorities. By joining forces on this issue and others, the ORMH and the NIEHS are working to reduce the burden of illness shouldered by minority Americans," said Ruffin.
In a recent article in
Preventive Medicine
, Olden noted "Children ingest their environment. When that environment is contaminated by lead, they ingest lead. They absorb and transport lead across their gastrointestinal tracts and into their bloodstreams about six times more efficiently than adults do. A major environmental health issue for children today is the extremely high prevalence of unacceptable exposure to lead, especially in inner cities, but occurring throughout the country. This clinical trial will address the terrible toll lead takes on our children's futures."
Predicting Carcinogenicity
In response to the publication of a set of predictions and a novel challenge by Raymond Tennant and colleagues at NIEHS and John Ashby at Zeneca, experts attempted to predict the outcomes of 44 rodent cancer bioassays conducted by the National Toxicology Program before the results were known. In May, about 200 scientists and other professionals from all over the the world met at NIEHS, home base of the NTP, to review 10 separate attempts to predict rodent bioassay results.
The purpose of the workshop, "Predicting Chemical Carcinogenesis in Rodents," was to assess prediction methods. If carcinogenicity could be predicted, chemicals could be prioritized for study and warnings issued for exposure to certain chemicals until cancer studies could be done. In the first part of the workshop, participants gave overviews of the methods they used to make predictions. In the second part of the workshop, organizations that use study results (regulatory agencies, research institutions, etc.) discussed the strengths and weaknesses of the various methods. In a summary of the workshop, Michael Shelby of NIEHS gave an overview, citing both the positive aspects of the prediction methods and the many hurdles yet to be overcome.
Shelby pointed out that there were at least three strengths evident in the prediction efforts. First, some of the systems described at the workshop were successful in predicting strongly carcinogenic chemicals and some clearly noncarcinogenic chemicals; second, the systems performed better with certain classes of chemicals; and finally, all the systems have the potential to be improved.
A major problem in optimizing the performance of the various prediction methods is the lack of detailed information on mechanisms of carcinogenicity. An understanding of the bioavailability of a given chemical, as well as possible changes in the metabolism of the chemical during aging, would be beneficial in predicting carcinogenicity. Likewise, improvements in the ability to monitor early events in the carcinogenic process such as genetic instability, changes in gene expression, and activation of oncogenes would help establish structure-activity relationships. Researchers at the workshop were optimistic about the continued evolution of methods to predict a variety of biological activities.
Other issues confronted in the workshop included changes in tumor rates of control animals over time, the unknown reproducibility of most rodent bioassays, and the fact that most models used in the prediction process do not account for the multitude of differences between rodents and humans. In addition, Shelby pointed out that some computer predictions were not subjected to review by human experts at the end of the analyses, and called for "one more loop through the human mind" before results are offered as predictions.
Two challenges presented at the workshop were how to deal with equivocal results in rodent cancer bioassays when assessing their predictions and the question of how carcinogenic potency can be predicted. Workshop participants noted that confirmation of their predictions depend on the rodent bioassay, which has some limitations. Because concordance between rat and mouse bioassays is only about 70%, this might represent an upper limit for extrapolating from rodent carcinogens to human carcinogens. In considering the limitations of the predictive process, Ashby said "Although we have had successes, there is a limit to how far such methods can be refined."
At the end of the workshop, Bernard Schwetz, acting director of the Environmental Toxicology Program at NIEHS, indicated that a variety of prediction methods were under consideration as aids for prioritizing chemicals for rodent carcinogenicity bioassays. A list of chemicals currently being tested in rodent bioassays was distributed, and participants were invited to use this list to further develop their prediction methods. Participants proposed that a similar workshop in about 3 years to evaluate results of new predictions and to review progress in the development of prediction methods.
NTP Announces Study Results for Six Chemicals
The National Toxicology Program presented six technical reports in its ongoing series of toxicology and carcinogenesis studies of selected chemicals at the semiannual public peer review meeting June 22 at NIEHS. Each report involves a series of studies in which male and female rats and mice are given a range of doses of the chemical for 14 days, 13 weeks, and then 2 years. In each study extensive histopathologic diagnoses are performed on all tissue systems, and growth patterns, blood chemistry, urinalysis, and genetic toxicity are evaluated.
"Predicting Chemical Carcinogenesis in Rodents" Scientific Program Committee (left to right) Joseph Wachsman, Stanley Stasiewicz, John Ashby, Raymond Tennant, Michael Shelby, Judson Spalding, and Douglas Bristol
Methylphenidate
is the active ingredient of Ritalin, a drug used in the treatment of narcolepsy and attention-deficient hyperactivity disorders. In both short-term and two-year studies in mice, the liver was the primary target of toxicity. The incidences of liver tumors were significantly elevated in male and female mice receiving the drug for two years in the feed at doses 5- to 50-fold greater than human doses (on a body weight basis). Similar studies in rats showed no evidence of carcinogenic activity.
T
ricresyl phosphate
is an organophosphate plasticizer widely used in vinyl plastics and as a flame retardant in hydraulic fluids. When given at concentrations in the feed of up to 300 parts per million (ppm) for rats or 250 ppm for mice, tricresyl phosphate showed no evidence of carcinogenic activity.
4,4'-Thiobis(6-t-butyl-m-cresol)
is used as an antioxidant in the rubber and plastics industry and as a stabilizer in polyethylene and polyolefin packaging materials for foods. The chemical did not induce tumors at any site when given at concentrations up to 2500 ppm in the feed for male and female rats or 1000 ppm for male and female mice.
Barium chloride
is used in the manufacture of pigments, glass, and ceramics, as a flux in the manufacture of magnesium metal, a lubricating oil additive, and in aluminum refining, leather tanning, photographic paper, and water softening. There was no evidence of carcinogenic activity in male or female rats or mice given feed containing up to 2500 ppm barium chloride for 2 years.
Hexachlorocyclopentadiene
(HCCP) is a chemical intermediate used in the manufacture of flame retardants, resins, and pesticides. All rats and mice exposed to atmospheres containing 1 ppm or more of HCCP died within 1 to 5 weeks. Rats exposed to 0.2 ppm HCCP for 2 years developed pigmentation of the epithelial lining of the airways, and mice similarly exposed developed suppurative inflammation of the nose and lungs. Tumors were not produced by exposure at these concentrations.
p-Nitrobenzoic acid
is used in organic synthesis, in the manufacture of pesticides, dyes, explosives, and solvents, and as a reagent for alkaloids and thorium. When given at doses up to 5000 ppm in the feed for two years,
p
-nitrobenzoic acid caused increases in clitoral gland tumors in female rats, but decreased incidences of leukemia in male and female rats. Mice were relatively unaffected by the chemical.
Copies of NTP reports are available from NTP Central Data Management, NIEHS, PO Box 12233, Research Triangle Park, NC 27709 USA.
Casida Receives International Wolf Prize
John E. Casida,
recipient of the Wolf Prize
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John E. Casida, who has been a grantee of the NIEHS since 1966, received the international Wolf Foundation Prize for Agriculture. The prize was presented in May by President Ezer Weizman of Israel at the Knesset (parliament) building in Jerusalem. Casida has been on the faculty of the University of California at Berkeley for almost 30 years, where he is a professor of entomology and director of the pesticide chemistry and toxicology laboratory, as well as principal investigator for an NIEHS program project.
Casida's research serves as the basis for evaluating the benefits and risks of established pesticides and for the rational design and use of safer and more effective replacements. Casida pioneered research on almost all the major insecticides and synergists and is responsible directly or indirectly for much of the basic knowledge on their mode of action and metabolism. Casida has published about 530 papers and obtained 26 patents; his discoveries span much of the history of organic pesticides and account for several of the fundamental breakthroughs in the fields of entomology, neurobiology, toxicology, and biochemistry. In addition to his extensive research accomplishments, Casida is recognized as an inspiring teacher, and many of his students and postdoctoral fellows have become leading figures in pesticide science.
"Since the beginnings of NIEHS, research involving pesticides and other agricultural chemicals has been an important part of the institute's mission and extramural portfolio. Dr. Casida's grant was among the original ones supported by NIEHS and has continued to yield significant new information that is important in designing pesticides that are effective on the target organism but are safe for humans," said Anne P. Sassaman, director of the NIEHS Division of Extramural Research and Training.
The Wolf Foundation was established by inventor, philanthropist, and diplomat Ricardo Wolf to promote science and art. The first prizes were awarded in 1978. To date, 145 laureates from 18 countries have been honored with the prize, which consists of a diploma and $100,000 in each category; Casida is this year's sole recipient for Agriculture.
Millar Steps Down, Henney Elected
J. Donald Milla
r,
former NTP Executive Committee Chair
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Jane E. Henney
,
new NTP Executive Committee Chair
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FDAJ. Donald Millar, former director of the National Institute for Occupational Safety and Health, stepped down in June after four years as the Chairman of the National Toxicology Program Executive Committee. The executive committee provides primary program oversight to the NTP and is composed of the heads of federal health research and regulatory agencies. The committee serves as the NTP's major advisory group on research and testing needs, selection and priority setting for specific chemicals to be studied, and as a forum for science policy issues and information exchange. The chairman is elected by the committee and serves a renewable one-year term.
Millar succeeded James Wyngaarden, then the NIH director, in May 1989. At the meeting in Washington, DC, on June 10, the committee elected Jane Henney, deputy commissioner for operations, FDA, as the new chair. Millar retired as NIOSH director in August.
Maternal Smoking Associated with Preterm Delivery and Infant Death
"Cigarette packages warn that smoking by pregnant women may result in low birth weight. What they should say is that smoking in pregnancy may cause preterm delivery and infant death," says Allen J. Wilcox, chief of the epidemiology branch at NIEHS. Wilcox is the author of a study on maternal smoking published in June in the
American Journal of Epidemiology
(vol. 137, no. 10).
Women who smoke are known to have higher rates of infant mortality. However, public health experts have usually emphasized the lower birth weight of infants born to smokers. Wilcox applied a new analytic method to data from nearly 260,000 births in Missouri and found that smokers are at higher risk of delivering small preterm infants, and these infants have higher death rates at every birth weight. It has not been generally recognized that the mortality risk of smokers' infants are independent of low birth weight.
Wilcox used data from Colorado to show that high altitude reduces fetal growth in a similar way, but without any apparent harm to the baby. Colorado babies tend to be lighter than babies born at lower altitudes, but their survival is just as good as those born at lower altitudes. "We keep focusing on the smaller birth weights of babies born to smokers. But the example of altitude suggests that smaller weights are not the issue," Wilcox says. "We should make sure that women know the real risk of smoking: they might lose their baby."
Indoor Allergens Endanger Health
NIEHS was among five federal agencies sponsoring a committee study and report from the National Academy of Sciences Institute of Medicine titled
Indoor Allergens: Assessing and Controlling Adverse Health Effects
. The report concludes that indoor allergens endanger health and can increase medical care costs to such an extent that comprehensive and systematic efforts are needed for better monitoring and control.
"Allergens play a key role in triggering some cases of asthma, and treatment for asthma-related illnesses costs more than $6 billion a year," said committee chair Roy Patterson, Ernest S. Bazley professor of medicine and chief of the division of allergy-immunology at Northwestern University Medical School. Most Americans spend more than 90% of their time inside. One in five Americans will experience allergy-related illness at some time during their lives.
Other sponsors of the report were U.S. EPA, National Institute of Allergy and Infectious Diseases, National Heart, Lung, and Blood Institute, and the Agency for Toxic Substances and Disease Registry. Copies of the report may be obtained from the National Academy Press, 2101 Constitution Avenue N.W., Washington, DC 20418 USA; the cost of the report is $39.95 (prepaid) plus $4 shipping for the first copy and $0.50 for each additional copy. A five-page press release summarizing the report is available from the NAS at no cost by calling (202) 334-2138.
NIEHS Requests Applications for Development of Educational Material
As the first component of a proposed comprehensive NIEHS environmental health sciences education program, the institute has requested grant applications for the development of educational materials related to environmental health sciences in grades K-12. The request for applications is an outgrowth of a national forum on environmental health sciences education held at NIEHS in December 1992. The forum brought together educators, scientists, and policymakers from around the country to lay a foundation for an environmental health sciences curriculum for the kindergarten through 12th-grade classroom and was coordinated by Marian Johnson-Thompson, NIEHS director of Institutional Development.
Organizations with a scientific or educational mission are eligible to apply, such as colleges and universities, state and local education agencies, professional societies, museums, and research laboratories. Letters of intent are requested by September 20, and application must be received by November 15. Copies of the announcement of the request for applications are available from Michael J. Galvin, Environmental Health Resources Branch, Division of Extramural Research and Training, NIEHS, MD 3-02, PO Box 12233, Research Triangle Park, NC 27709 USA. Leave your name, address, and phone number on voice mail at (919) 541-3319 or FAX this information with your request to (919) 541-2843.
NIEHS Awards Grants on Health Effects of Ozone
Under the Clean Air Act Amendments of 1990, the NIEHS was directed to conduct a program of basic research related to the health effects of exposure to air pollution, particularly ozone. In mid-1992, NIEHS and its sister institute, the National Heart, Lung and Blood Institute, issued a request for applications to study the mechanisms of the health effects and risks associated with prolonged and/or intermittent, recurrent ozone exposure.
Five applications were recommended for approval for funding: Duke University, Harvard School of Public Health, North Carolina State University, University of California-Davis, and University of Cincinnati. The NHLBI council recommended approval for funding of an additional three applications: Johns Hopkins University, University of Rochester, and Lovelace Biomedical and Environmental Research Institute.
Goldstein Receives Kehoe Award of Merit
Bernard D. Goldstein,
recipient of the Kehoe Award of Merit
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Bernard D. Goldstein, director of the Robert Wood Johnson/Rutgers Environmental Health Research Center, funded by NIEHS, received the 1993 Robert A. Kehoe Award of Merit from the American College of Occupational and Environmental Medicine at its annual meeting in April in Atlanta. Goldstein is the founding Director of the Environmental and Occupational Health Sciences Institute (EOHSI), jointly sponsored by Rutgers and the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, where he also chairs the Department of Environmental and Community Medicine. The award is in recognition of Goldstein's significant contributions to academic excellence and research in occupational and environmental medicine.
"I am very pleased that Dr. Goldstein, who has been associated and worked with NIEHS since its inception, has received this award. It is recognition of his skill, concern, and leadership in the field of environmental health sciences," said Kenneth Olden, director of NIEHS.
The American College of Occupational and Environmental Medicine is an organization of more than 6500 physicians who promote worker and environmental health through preventive medicine, clinical care, research, and education. The award honors the late Robert A. Kehoe, a pioneer in the field of environmental medicine.
Molecular Interventions for Environmentally Induced Disease Prevention
NIEHS awarded grants to support research efforts aimed at the development and ultimate clinical use of methods to prevent, modulate, or treat environmentally induced toxic diseases. The focus of this research is development and use of appropriate biomarkers to study the effectiveness of intervention methods.
Five research proposals have been funded. Three focus on respiratory diseases resulting from environmental and occupational exposures. David Schwartz of the University of Iowa was awarded a grant to study grain dust, endotoxins, and airflow obstruction and other inflammatory processes in the lung. Patricia Finn at Brigham and Women's Hospital in Boston, Massachusetts, will study molecular markers for environmentally induced asthma. Lee Newman at the National Jewish Center for Respiratory Diseases in Denver, Colorado, will explore the role of cytokine biomarkers of environmental lung disease in beryllium-exposed workers.
Two other studies were funded dealing with prevention and treatment of effects of two important toxins, dioxins and lead. James Olson of the Research Foundation at the State University of New York at Buffalo will study biomarkers for dioxinlike compounds in human populations and animals studies. James Keogh from the University of Maryland School of Medicine will study biomarkers of dose and effect in adult lead poisoning to determine if they are useful in monitoring lead intervention therapy. These grants will help further the understanding of some important molecular mechanisms of these diseases as well as develop tools to assist in clinical treatment and intervention strategies to reduce disease burden.
Biotechnology Transfer to Epidemiology Studies in Cancer
A request for applications was jointly sponsored with the National Cancer Institute to promote an interdisciplinary approach to studying cancer etiology combining traditional epidemiologic methods with approaches from the laboratory to measure biological dose and susceptibility. Its aim was to validate and apply existing biomarkers in cancer epidemiologic research. NIEHS has funded four applications. These projects include a study of biomarkers of benzene exposure and genotoxicity by Martyn Smith, University of California at Berkeley; a study which explores the mutational spectra of aflatoxin in humans and rodents by Neal Cariello at the University of North Carolina; investigations on the molecular epidemiology of bladder cancer by Zuo-Feng Zhang at Sloan Kettering Institute for Cancer Research; and a study of biomarkers of the effects of ambient air pollution on women and their developing fetuses by Fredrica Perera at Columbia University. Scientists receiving these grants will meet annually with the grantees funded by NCI to discuss study progress and important findings from their work.
Last Update: August 26, 1998