Children of Chernobyl
Little people, big effects. The children of Belarus may bear the biggest brunt of adverse health effects from the accident at Chernobyl. Operation Belarus
In the aftermath of the April 1986 explosion of the Chernobyl nuclear power plant in the Ukraine, incidence rates of childhood cancers, especially of the thyroid, have been dramatically increasing. The United States agreed this past May to join with the Ukraine to study the effects of radiation exposure on childhood thyroid cancer.
The accident at Chernobyl is the only full-scale meltdown of a graphite core in a nuclear energy station that has ever occurred. It released radioactive material over parts of the former Soviet Union, Eastern Europe, Scandinavia, and later, Western Europe, killing 31 and hospitalizing 300. Scientists predicted that it would lead to an undetermined number of future cancer deaths over a large area.
In particular, the independent nation of Belarus, northwest of Ukraine, where more than two million people were exposed to radiation from Chernobyl, has recorded steadily increasing numbers of cancer incidences and congenital malformations and illnesses. "At first people did not want to link these medical problems with Chernobyl, and many accused us of radiation phobia," Yevgeny Konoplya, director of the Radiobiology Institute of Belarus's Academy of Sciences and an expert on post-Chernobyl effects, told the Washington Post. "But now they know. All the problems they faced in Nagasaki we face here. There was no place as hard hit by Chernobyl as Belarus.
In 1986, there were 2 cases of thyroid cancer in children under 14 in Belarus, but by 1994 there were 82 registered cases. According to the Washington Post article, at the Borovlyani cancer institute outside Minsk, more than 50 children are now being treated for brain tumors, bone tumors, kidney tumors, and other cancers.
Since the collapse of the Soviet Union, independent nations have lacked funding to support such widespread public health problems. Therefore, the United States has agreed to step in and help. The U.S. Department of Energy announced this past spring that it will work with the government of Ukraine to establish an international nuclear safety and environmental research center at Slavutich near Chernobyl.
Efforts to establish the center are a result of a collaboration between the State Department, the DOE, the Nuclear Regulatory Commission, and Ukrainian nuclear and environmental agencies and organizations. "This action is a significant step toward establishing a Center of Excellence to improve the safety of nuclear energy generation in Ukraine, and reduce the risks posed by Chernobyl reactor operation, Secretary of Energy Hazel R. O'Leary said in a press release. "The center will also serve as a focal point for international environmental research in the areas of environmental contamination and site restoration." The DOE will spend about $3 million over the next two years to establish the center. These funds are part of a $38 million international effort to clean up Chernobyl.
In addition to establishing the center, the DOE and the NRC plan to provide funding for the National Cancer Institute to lead studies on the effects of radiation exposure on childhood thyroid cancer. Over the next 15 years, the DOE and the NRC will provide $1 million annually for researchers to regularly test about 70,000 children exposed to radiation from the accident. The researchers will compare their findings to data gathered from children in the weeks following the accident. They hope to determine the extent to which radioiodine, especially iodine-131, causes thyroid cancer and the role of possible cofactors such as iodine deficiency, according to the DOE.
In one of those serendipitous events that sometimes lead to scientific breakthroughs, researchers attending a lecture late last year by University of Florida biologist Louis Guilette on developmental problems in male alligators realized they were seeing similar effects in laboratory rats recently exposed to a fungicide. The ensuing discussion spurred research that may illuminate how environmental agents act like hormones to disrupt development and possibly cause cancers.
Guilette reported that the alligators had been exposed to DDT, a hazardous pesticide that he said acts as an environmental estrogen. Too much estrogen, Guilette stated, resulted in an imbalance of androgen in the alligators, causing developmental defects. William Kelce and L. Earl Gray, biologists at the EPA's Health Effects Research Laboratory, guessed, however, that DDT was really acting as an anti-androgen.
Kelce and Gray had just published a paper in the June 1994 issue of Toxicology and Applied Pharmacology detailing how the fungicide vinclozolin demasculinized rat pups by altering the action of the male hormone testosterone. Vinclozolin blocked normal hormonal function by binding to the androgen receptor. The fungicide bound loosely enough that the receptor was not activated, however, and therefore could not signal transcription of androgen-dependent genes, which disrupted sexual development. Vinclozolin was the first chemical reported to have an anti-androgenic effect.
The EPA investigators and molecular biologists from the University of North Carolina at Chapel Hill began to compare their data with Guilette's and months later invited Guilette to the EPA to examine the results. The team found that DDE, the primary metabolite of DDT, shrunk sex organs in male rats by up to 20% in four days. And pregnant rats exposed to DDE gave birth to male rats with female sexual characteristics.
Guilette and the rest of the scientific world were surprised by the results, published in Nature on June 15. "There was quite significant binding that helps explain what we saw in the alligators," says Guilette. "I'm rethinking the whole concept of hormone receptor specificity. It's much more complex than we realized." Guilette noted that because some minor isomers of DDT are clearly estrogenic, DDT and its metabolites are now known to affect both estrogenic and androgenic hormone action.
DDE's anti-androgenic effects may help explain recent adverse changes in male reproductive health, such as decreasing sperm counts in various parts of the world, and increases in testicular cancer and cases of abnormal development of the penis and testis. The work also raises the question of how chemicals can act simultaneously as agonists and antagonists for both estrogen and androgen, says Kenneth Korach, an NIEHS researcher who was involved in creating an estrogen knock-out mouse. Elizabeth Wilson, a University of North Carolina at Chapel Hill investigator working with Kelce, is researching whether the androgen receptor forms a heterodimer, binding both DDE and androgen. The dose response of DDE would be critical in this case, she says.
Although DDT was banned in the United States in 1973, DDT and its metabolites persist in the environment (it has a half-life of up to 100 years), and it is still used to control malaria in some countries such as Mexico and Brazil, and in some areas of Africa.
The EPA/UNC team reported that the concentration of DDE needed to inhibit androgen receptor transcriptional activity in cell culture or to affect newborn rat pups is analogous to levels found in other instances of DDT contamination including Guilette's Florida alligator eggs and in kidneys of stillborn babies in the United States in the mid-1960s, when DDT was still being used.
Scientifically, the study offers more questions than answers. It raises the issue of the adequacy of testing manufactured chemicals for hormonally active compounds. "Past regulatory testing was insensitive to these kinds of problems," says Kelce. "We are only now beginning to appreciate what tests need to be conducted."
Guilette also wonders about the effect of an anti-androgen on females: "If it modifies the estrogen-androgen ratio in women, increasing their estrogen, it could result in increased breast cancer and like diseases." Kelce says he has identified 20 other chemicals that have anti-androgenic effects. Although he says he can't release the list yet, he indicated that none of them is currently banned.
Telomerase, an enzyme that gives some cells a permanent stay of execution, appears to play a role in lung cancer progression, according to a study in the June 25 issue of the Journal of the National Cancer Institute. Jerry Shay and his colleagues at the University of Texas Southwestern Medical Center at Dallas and at the Hiroshima University School of Medicine found telomerase activity in approximately 80% of the 136 primary lung cancer tissues they tested, versus only about 4% of 68 adjacent normal tissue samples. Of the 136 primary lung cancer samples, all 11 of the small cell lung cancers (SCLC) showed telomerase activity, while telomerase activity varied in non-small cell lung cancers (NSCLC).
Normally, telomerase is inactive in somatic cells, which die naturally after a number of cell divisions. Each time a chromosome is reproduced, the telomere, a small part at the end of the chromosome, is lost. In order to counter these losses, each of the chromosome's telomeres carries repeating nucleotide sequences. However, once those sequences are used up, the cell stops dividing and dies. Cells that need to continue to reproduce, such as germ line reproductive cells, carry telomerase, a DNA polymerase which adds repeating nucleotide sequences to the shortened telomeres. Previous studies have also found telomerase activity in malignant tumors of numerous cell types including breast, prostate, colon, skin, and brain, suggesting that the enzyme allows cancer cells to continue to divide.
The reactivation of telomerase may occur at either of two stages of cell death, mortality stage 1 (M1) or mortality stage 2 (M2). During M1, cells lose their ability to divide, a state known as senescence. The malfunction of a tumor-suppressor gene or the mutation of an oncogene might transform a cell, allowing it to avoid senescence. However, although such defects extend the cell's life span, it will eventually die. During M2, cells reach a point known as crisis, in which most cells die; however, the survivors are immortal and capable of unlimited proliferation.
The presence of NSCLC tumors containing both mortal and immortal cells suggests that the immortalization of an existing tumor cell is rare, requiring two separate events and occurring after many cell divisions. In SCLCs, cells show signs of having already undergone the number of divisions and chromosomal changes necessary for the reactivation of telomerase before becoming cancerous.
Shay and his colleagues observed variations in telomerase activity that may reflect characteristics of the cells or the ratio of mortal to immortal cells within the tumors. However, although levels of telomerase activity varied dramatically among some of the samples tested, immortalized lung cancer cell lines all showed similar activity, whether SCLC or NSCLC. The study's authors cautiously suggest that once a lung cell is immortalized, it achieves a set level of telomerase activity no matter what its type.
The absence of telomerase activity in some tumors may indicate that they consist entirely of mortal cells. A previous study, published in Science, found that benign fibroid tumors did not have telomerase activity. According to Shay's study, "If cancers that have mortal cells exist, their growth might be self-limiting in contrast to those that consist of immortal cells," a possible reason why SCLCs are the most difficult lung cancers to treat. This distinction between cell populations with telomerase activity and those without it may serve as the basis for tests to predict the cells' capacity for continued proliferation and, therefore, the disease's severity. Telomerase activity might even be found in cells obtained from a patient's lung wash, a procedure Shay used in his study and one which is already commonly used for other types of lung cancer diagnostic tests.
Researchers are already searching for a drug that inhibits telomerase, in hopes of cutting short the lives of the most proliferative lung cancer cells. In the August 31 issue of Science, researcher Calvin B. Harley of Geron Corporation and his colleagues at Cold Spring Harbor Laboratory reported that they were able to produce reverse RNA that blocked the action of telomerase and caused HeLa cells, an experimental cancer cell line, to begin dying after 23-26 cell divisions. While Harley emphasizes that a drug able to mimic this effect may take years to find and develop, such a drug could prevent the spread of cancer without harming normal cells. In an interview with the Associated Press, Shay said, "This is the first laboratory proof that inhibiting of telomerase RNA will result in limiting cell division. . . . This is the most important next step in telomerase research."
In an earlier AP interview Shay pointed out that the existence of metastatic tumors lacking telomerase activity implies that there are other immortalization mechanisms. According to molecular epidemiologist Curtis Harris of the National Cancer Institute, a mechanism that enabled cells to escape senescence would be one that bypasses the problem of shrinking telomeres, such as DNA recombination, probably a very inefficient mechanism. If drugs were developed to target telomerase, these alternate mechanisms of immortalization might come into play to allow tumor cells to escape senescence, says Harris. Even in those cells where telomerase inhibitors successfully prevented immortalization, any remaining supply of telomeric repeats would allow the cell to continue to divide for a finite period of time, with possible adverse consequences to the patient. In addition, other cells in the body, such as stem cells and stomach cells, might be sensitive to telomerase inhibitors, leading to serious side effects.
It may seem unusual for U.S. scientists and medical researchers to lobby strongly against a government program to clean up the contaminated Fernald nuclear plant in Ohio, but that's exactly what's happening. The Fernald plant, which processed uranium for nuclear weapons from 1951 to 1989, now has about 10,000 tons of radioactive waste contained in two special silos. Within this waste, however, is a medically priceless stockpile of radium as well as millions of dollars worth of gold and other precious metals. Scientists are arguing that this radium, which is scheduled to be disposed of starting in early 1996, may be critical to saving the lives of cancer patients if a clinical trial that attempts to cure cancer with a radium-based monoclonal antibody is successful.
David Scheinberg, a medical oncologist at the Memorial Sloan Kettering Cancer Center, is enrolling patients in a clinical trial to test a new methodology that links a radium-based isotope, bismuth-213, to a monoclonal antibody to target cancer cells. The treatment is being tested on 10-20 patients who have acute myeloid leukemia (AML) or chronic myeloid leukemia (CML). In a preliminary experiment using a leukemia mouse model, the bismuth-213 antibody treatment led to remission of the diseases and longer survival rates. If the phase I trial scheduled for November is successful, it will be followed by a slightly larger study within a year of the phase I results. If further clinical trials show positive results and the treatment is approved by the FDA, it could potentially be used to treat approximately 30,000 people in the United States who have CML and AML. Experiments are also underway to test this isotope therapy in other types of cancers.
Radium is a very rare element. The stockpile of radium-containing waste at the Fernald plant is the largest cache in the world. The 4,500 grams of radium present at the site could provide thousands of doses of the new cancer treatment and has been estimated to be worth about $68 million. The cost of extracting the radium has not been estimated, and it has not been determined who would pay for it.
The waste has been scheduled to be melted into a glasslike substance through a process called vitrification in a joint cleanup effort by the Department of Energy and the EPA. The DOE has contracted with the Fernald Environmental Restoration Management Company (FERMCO) to manage the cleanup. "A pilot vitrification run is scheduled to begin in November" said Perry Richardson, spokesperson for FERMCO. "Depending on the pilot run, a full-scale cleanup could begin in mid-1996 and may last two to three years."
Both the DOE and FERMCO oppose delaying the cleanup to remove the radium. Mike Jacobs, a public affairs officer at the DOE in Cincinnati, explains one reason why: "The DOE gets a certain budget for each site per year. If the radium extraction process is costly, it may deplete a majority of the cleanup funds." Jacobs asserts that the DOE "is open to any suggestions from the medical community" but says they have not received any formal requests to temporarily halt the cleanup to extract the radium.
The residents of the towns surrounding the Fernald plant are excited that the cleanup is about to begin. "They, along with the DOE, EPA, and other groups, have wanted the site cleaned up for years," said Jacobs. Although residents understand the potential good that the waste can contribute, they wonder why this issue did not surface earlier. Residents also have many questions regarding the logistics and the implications of radium extraction, few of which can be answered satisfactorily, as no group has prepared an extraction plan.
Manoranjan Misra, a professor of chemical engineering at the University of Nevada, Reno, is an expert in separation processes. He estimates that radium extraction at Fernald may cost $5 to $6 million, not including additional costs to refine and purify the radium to be used as a medical therapy. Misra explained a possible radium recovery process which uses physical separation and other techniques: "Special chemicals are added to the vast waste pile to dissolve barium and uranium and float them to the top. This top layer will contain most of the radium [attached to the barium] and will weigh in at about five to ten tons. It can be removed and subsequently processed into pure radium without slowing the waste cleanup." The DOE and FERMCO want the scientists to extract the radium from the vitrified material, although, according to Misra, there is no known process for doing this.
All parties involved in the Fernald cleanup have stated they would like to save the radium if it is economically and logistically possible. If Scheinberg and other scientists obtain positive clinical trial results with medical isotopes, the loss of the Fernald radium to the cleanup process will really be a waste.
A gene that when mutated causes a rare and fatal hereditary disorder has been isolated by a team led by Yosef Shiloh, a geneticist at Tel Aviv University in Israel. "This is a turning point in our understanding of AT [ataxia telangiecstasia], but also in our understanding of cell growth and cancer," said Shiloh at a news conference announcing the discovery of the gene. The research suggests that the gene may also be a major contributor to hereditary forms of breast cancer.
Researchers hope the gene will aid in deciphering how cells work, as well as provide new understanding of how cancers develop. "It's a biologically complex area [that we have] very little way of unraveling. By having the gene, we've broken the logjam," said Richard Gatti, a member of the team at the University of California at Los Angeles. "This is a Rosetta stone gene," he said.
Scientists believe the gene encodes a protein that recognizes DNA damage and halts cell growth and division until the damage is repaired. In patients with AT, damaged cells continue to replicate and divide without being repaired. "The molecule transmits the message [to halt cell division] to the cell, and somewhere the telephone lines were down," said Gatti.
The gene was located as the result of a hunt by four laboratories--Shiloh's, Gatti's, one led by Malcolm Taylor at the University of Birmingham, U.K., and one led by Pat Concannon at the Virginia Mason Research Center in Seattle, Washington--using positional cloning. "First we do linkage analysis, and then go in and pluck out the gene. It is done purely mathematically," Gatti said.
AT affects children, who inherit two defective copies of this gene (one from each parent), at an early age, causing the deterioration of muscle coordination and defects in the immune system. AT also causes extreme sensitivity to radiation, sometimes to the point of fatality. Patients with AT frequently develop cancers, usually leukemia and lymphomas, and most patients succumb to the disease by their 20s due to infection or cancer. The disease affects about 1 in every 40,000 people worldwide. About 500 American children have AT, and an estimated 2.5 million Americans are carriers of one copy of the AT mutation.
Researchers are now studying the possibility that carriers have increased risks of cancer. It has been estimated that carriers are four times more likely to develop cancer and that female carriers have a fivefold increased risk of developing breast cancer.
A possibility is that the very procedures used to detect breast cancer in women may be increasing the risk of developing cancer in female carriers because of its link to radiation sensitivity. In 1991, Michael Swift of New York Medical College in Valhalla proposed that diagnostic X-rays might cause breast cancer in certain women. He showed that women from AT families who have breast cancer were more likely to have been exposed to high-dose diagnostic or therapeutic X-rays than family members without breast cancer. This finding was consistent with data indicating that cultured cells containing the mutated gene suffer more DNA damage and have a higher death rate than do normal cells when exposed to X-rays.
Swift's theory is controversial because the amounts of radiation used in current diagnostic X-rays are lower than an individual's normal annual exposure to natural radiation and lower than the doses given to the cultured cells. Now that the gene has been cloned, theories such as Swift's can be tested. The National Center for Human Genome Research, the National Cancer Institute, and the Danish Cancer Registry in Copenhagen are initiating studies to research this possibility. Meanwhile, the NCI has said that women should continue to follow the recommended mammography screening for breast cancer. "We hope to find [the gene's] role in radiation sensitivity, so that we can find out how to protect and who to protect," said Gatti. "We can now do the experiments that without the gene we had no handle on."
Richard Paules, head of the Growth Control and Cancer Group in the Laboratory of Environmental Carcinogenesis and Mutagenesis at the NIEHS says, "a better understanding of this important pathway contolling cell proliferation holds the promise of developing new diagnostic procedures and offers hope that scientists may be able to design better therapies for cancers."
EHPnet
In war and football, it's often said that the best defense is a good offense. This same philosophy is the basis for a World Wide Web site aimed at improving the environment through pollution prevention.
Enviro$en$e (http://wastenot.inel.gov:80/envirosense/), which is maintained at the Idaho National Engineering Laboratory, is funded by the EPA and the Strategic Environmental Research and Development Program (SERDP), a joint effort of the Department of Defense, the Department of Energy, and the EPA that supports environmental quality research, development, demonstration, and applications programs.
Eight hyperlinks on the Enviro$en$e homepage offer a vast array of information in categories such as news and resources, pollution prevention programs from the local to the federal level, international programs, technical research and development, compliance and enforcement, and more.
For example, the news hyperlink connects users to information such as a Pollution Prevention Directory, several hotlines and clearinghouses, the National Consortium for Environmental Education and Training's Environmental Education Link (a gopher site that offers access to teaching resources including instructional materials, articles, databases, and grant information), and the National Pollution Prevention Center for Higher Education.
Federal laws, regulations, environmental activities, and presidential executive orders, and both state and local pollution prevention servers may be accessed through another hyperlink. The international resources hyperlink provides information on pollution prevention programs around the world by connecting to organizations such as the U.S. Agency for International Development's Environmental Prevention Protection Project, the Montreal Protocol (protection of ozone layer), the North American Free Trade Agreement, the Organization for Economic Cooperation and Development, and the United Nations Environment Program.
The technical research and development hyperlink provides access to case studies and fact sheets on EPA studies of commercial companies, as well as environmental research briefs, project summaries, and pollution prevention assessments. This link also connects to the EPA Office of Research and Development and a pollution prevention publications bibliography.
Perhaps the most innovative element of the site is an interactive search function that allows users to query the Solvent Alternatives Guide (SAGE), the Hazardous Solvent Substitution Data System (HSSDS), and the Department of Defense Pollution Prevention Technical Library. SAGE is a logic-tree system that evaluates a manufacturer's current operating scenario and then identifies possible alternative surface-cleaning solvent chemistries and processes that best suit the operating and material requirements. HSSDS is an on-line system of information on alternatives to hazardous solvents that contains product information, material safety data sheets, and other related information. Also available on this site is access to the Department of Defense Ozone Depleting Chemical/ Substance Information.
The pursuit of excellence in environmental health and science continues.
Several organizations have recently acknowledged the success of individuals and
organizations in improving the environment.
General Motors Cancer Research Foundation Awards
In a ceremony June 20 at the National Institutes of Health at Bethesda, Maryland, three $100,000 prizes were awarded to scientists "who have made outstanding contributions in the fight against cancer."
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1995 Charles F. Kettering Prize for Outstanding Contributions to the Treatment of Cancer-Norbert Brock, former chief of the Department of Cancer Research ASTA-Werke in Bielefeld, Germany. Brock made a breakthrough discovery of the synthesis and delivery of the chemotherapeutic agents cyclophosphamide and ifosfamide and continues research on making these agents safer and more effective.
- 1995 Alfred P. Sloan, Jr., Prize for Outstanding Basic Science Contributions to Cancer Research-Edward E. Harlow, American Cancer Society Research Professor, Massachusetts General Hospital Cancer Center, Harvard Medical School. Harlow followed E1A, an oncoprotein produced by an adenovirus, to its cellular target, the retinoblastoma susceptibility protein, and found that other viral oncoproteins disrupt cell cycle regulation.
- 1995 Charles S. Mott Prize for Outstanding Research in Cancer Causation and Prevention-Frederick P. Li, chief of the Division of Cancer Epidemiology and Control, Dana-Farber Cancer Institutes, and Joseph F. Fraumeni, Jr., director of the Epidemiology and Biostatistics Program, National Cancer Institute. Li and Fraumeni discovered an inherited cancer syndrome predisposing family members to several cancers including soft-tissue sarcomas, early breast cancer, osteosarcoma, acute leukemia, adrenocortical carcinoma, brain tumors, and tumors induced by radiation therapy. After connecting the newly named Li-Fraumeni syndrome with an inherited p53 gene alteration, the researchers formulated recommendations for genetic testing.
Blue Planet Prizes
- Academic Award-Bert Bolin, professor emeritus at Stockholm University. Bolin was awarded for his groundbreaking research on the carbon cycle and generating a model of the influences of oceans, atmosphere, and the biosphere on global warming. Bolin has led numerous international scientific committees dedicated to the study of climate change and since 1988 has been head of the Intergovernmental Panel on Climate Change, an international group of experts who suggest policies to halt global warming.
- Development and Implementation Award- Maurice Strong. Strong brought conservation and environmental issues to the attention of political and business leaders as secretary-general of the 1972 UN Conference on the Human Environment and as the first head of the UN Environment Program. Strong also served as secretary general to 1992 UN Conference on Environment and Development (the Earth Summit) in Rio de Janeiro, the largest environmental conference in history.
Global 500 Roll of Honour
In a June 5 ceremony in Pretoria, South Africa, the United Nations Environment Program named 27 individuals and organizations, in youth and adult categories, Gobal 500 laureates for "outstanding achievements in the protection and improvement of the environment." The following summaries represent the types of activities for which the laureates were awarded.
- George Monbiot, an investigative journalist from the United Kingdom. Monbiot has worked to expose perpetrators of environmental destruction and abuses of the rights of indigenous peoples. Monbiot wrote of his investigation of rainforest destruction and wetland habitats and the dispossession of indigenous people in Irain Jaya (formerly part of New Guinea) in his book, Poisoned Arrows.
- Father Balemans, a priest from The Netherlands. Balemans founded the Association pour le Developpement de la Region de Kaya to teach rural communities natural resource management and sound agricultural practices to avoid desertification. Twenty-five villages in Burkina Faso have successfully implemented Baleman's model.
- Safina Z. Siddiqi of Pakistan. Siddigi founded the Karachi Administration Women's Welfare Society as part of a campaign to improve local living conditions. The women established a garbage collection system and eight parks, planted saplings, and pressured the local authorities to help them make road and sewer repairs.
- Yokkaichi City, Japan and Mayor Kanshi Kato. Notorious for its smog in the 1970s, the Yokkaichi Pollution Control Board instituted a successful pollution control project integrating environment and development that resulted in cleaner air. They also pioneered public medical care programs to help patients with pollution-related respiratory diseases.
- The Green Machine Nature Conservation Club of Sunridge Primary School. This student group, in one of the most underprivileged sections of South Africa, ran soup kitchens, organized workshops for narcotic addicts, cleaned up a squatter settlement, created a park, instituted a program to exchange recyclables for food packets, and initiated an environmental awareness campaign.
Last update: November 17, 1995