A small county in Arizona is plagued by unusually high rates of lupus erythematosus and cancer, and residents are looking at air and water pollution from neighboring Mexico as the culprits.
A study released last December confirmed that the population of Santa Cruz county, located along the Mexican border, suffers from 2.4 times the National Cancer Institute's expected rate of multiple myeloma, a form of bone marrow cancer, and almost twice the expected number of lupus cases. The study, conducted by the University of Arizona Cancer Center, found that there were 12 cases of multiple myeloma from 1989 to 1993 in the county of about 30,000, while the expected rate is 5 cases per 100,000 people.
The study also found 94 cases of lupus per 100,000 people, whereas 50.8 cases per 100,000 are expected. According to Brad Christensen, a spokesperson for the Arizona Department of Health Services (ADHS), this is the highest incidence of lupus cases in one area on record in the world.
The study was undertaken at the urging of residents of Nogales, the town most affected by the illnesses, to investigate the health problems. In 1992, a group of cancer victims and their family members who were concerned about the high rates of disease formed a grassroots organization, Living Is for Everyone (LIFE), to lobby state officials and draw attention to the problem.
Noxious neighbors? Residents of Nogales, Arizona, believe their health problems may stem from pollution from a Mexican landfill across the border.
"The group grew out of the need to address what we thought at the time were only health issues," said Ana Acuna, a 54-year-old lupus patient who helped form the organization. "We had a suspicion that environmental factors were involved, and from there grew the tie to the environment."
In December 1993, the governor, university officials, and ADHS officials responded to LIFE's requests and visited Nogales. "We visited Carillo Street, which is a small neighborhood, and it seemed like every other household was touched by cancer," Christensen said.
The ADHS then committed $100,000 and contracted the university to conduct a study. Although the study did confirm that the disease incidences are unusually high, the researchers did not find an obvious link to environmental problems. However, epidemiologist Larry Clark, who headed the study, said environmental substances were probably a trigger for the lupus increase.
The residents believe the source of their health problems lies across the border in a landfill that catches on fire weekly. Burning in dumps is illegal in the United States because the practice causes air pollution and poses a health threat. The residents also blame their poor health on sewage and toxic chemicals that are carried north in a wash that runs through Nogales.
Following the release of the study, the director of the ADHS, Jack Dillenberg, took several copies to the Center for Disease Control in Atlanta to draw federal attention to the problem.
Dillenberg told Healthlink, a publication of the ADHS, that he felt the meetings were positive. "I want the CDC to recognize we've got some valuable data now, and I want them to get involved," he said. "Clearly this is a problem that requires solutions beyond what the city, the county, and the state can offer."
According to Christensen, the Santa Cruz community has been very pleased with the response of federal officials to date. On March 22, medical epidemiologist Rossanne Philen, of the CDC, visited Nogales and made a commitment to help further the study of the illnesses, possibly by placing a researcher on the border to look for the causes.
In addition, the Interagency Coordinating Council, which is made up of members of the EPA and the CDC, held a meeting May 2-3 in Rio Rico, which is just north of Nogales, to discuss border issues.
Mexican health officials indicated they would attend the meeting. According to Christensen, Mexican officials have responded well to the issue. Since the study was released, officials closed the dump in question and opened a new dump eight miles away that does not burn waste.
Now there's another reason to eat your fruits and vegetables. New research conducted at the Harvard University School of Public Health shows that poor diet combined with a high intake of alcohol increases the risk of colon cancer.
Edward Giovannucci co-authored the study which appeared in the 15 February 1995 issue of the Journal of the National Cancer Institute. Giovannucci and his colleagues examined the diets of 47,931 male health professionals 40-75 years old. In 1986, the subjects, free of diagnosed cancer, filled out questionnaires about their diets. The researchers followed up on the subjects for six years, and during that time they documented 205 new cases of colon cancer.
Bellyache up to the bar. A new study shows alcohol and a poor diet may increase risk of colon cancer.
The researchers were testing the hypothesis that diet plays an important role in the methylation of DNA, which they thought to be important in gene expression and the normal regulation of DNA, Giovannucci said. Diet controls methyl groups, which in turn control the methylation of DNA, he said. Past research has shown that methyl-deficient diets cause various cancers in animals.
The proposed mechanism by which methyl-deficient diets contribute to cancer is best understood from studies of rat hepatocarcinogenesis, the researchers reported in JNCI. It has been shown that a methyl-deficient diet in rats is followed by DNA hypomethylation, the overexpression of various genes including several proto-oncogenes, and elevated DNA methyltransferase activity in the liver. Rats eating a methyl-deficient diet for long periods develop liver tumors, and alcohol seems to accentuate this effect. The researchers also cited that abnormal DNA methylation patterns may contribute to carcinogenesis, possibly by influencing both the activation of oncogenes and the inactivation of tumor-suppressor genes.
The key factor in maintaining methyl groups is methionine, an amino acid found in poultry, fish, and low-fat dairy products such as skim milk, Giovannucci said. Folate, which is found in green leafy vegetables, is also important to methyl groups, in that it assists in the production of methionine. Other dietary components such as vitamin B12 and choline may relate to methyl-group availability, the researchers said.
Giovannucci and his colleagues looked at the diets to see how much methionine and folate they contained. They also looked at alcohol intake because alcohol has been shown to have suppressive effects on the metabolism of methyl groups.
The results seem to support the researchers' hypothesis. Those who had high alcohol intake combined with low intakes of folate and methionine had a relative risk of 234%, which is over twice the risk of men with low alcohol, high folate, and methionine intakes. High alcohol is defined in the study as 20 or more grams per day, which is about two drinks. Low folate intake is defined as 364 µg per day, and low methionine is 1.75 g per day.
Those who drink, but also have well-balanced diets, have about the same colon cancer risk as nondrinkers, Giovannucci said. All types of alcoholic beverages were related to the risk of colon cancer, and past, presumably heavy, drinkers were also at higher risk of developing colon cancer, the researchers said.
The associations observed for alcohol and methionine were not due to confounding by other dietary factors, smoking, physical activity, body mass, aspirin use, differential surveillance for disease, or family history of colorectal cancer, the researchers said.
The study did suggest that aspirin use modified the risk of colon cancer even with high alcohol and low folate intake, but the researchers said this modification of risk requires confirmation in other populations. Men who took vitamin supplements also appeared to have a lower risk of cancer, but Giovannucci warned that pills are no substitute for nutrient-rich food.
"We think overall that the results support the recommendation to eat lots of fruits and vegetables. Obviously, there are other reasons, but if someone follows these guidelines, he or she will also be benefiting regarding colon cancer," Giovannucci said.
Colon cancer afflicts about 150,000 men and women every year in about equal numbers and kills 60,000 per year, making it the second leading cause of cancer deaths. Giovannucci added that after the age of 65, a woman is just as likely to die from colon cancer as from breast cancer.
Giovannucci and his colleagues are currently conducting the same study in women, and Giovannucci says the effects appear to be similar so far. In the future, he says, the researchers hope to better understand the mechanism of DNA methylation.
With support from federal agencies and pharmaceutical companies, scientists are trying to tap nature's medicine cabinet while preserving the plants that stock it. How best to do this was the subject of a two-day conference on Biodiversity and Human Health, held in April in Washington, DC.
Western physicians and traditional healers alike rely on compounds found in plants to treat a wide variety of ills. Pharmaceutical companies now regularly test and develop the ingredients of plants for use in drugs. But plant species are going extinct at an increasingly rapid pace, which threatens this supply of healing ingredients, researchers warned at the conference, sponsored by the National Institutes of Health, the National Science Foundation, the Smithsonian Institution, the National Association of Physicians for the Environment, and the Pan American Health Organization.
People and plants. A recent conference on biodiversity and human health stressed protection of indigenous people and plants.
For the past 40 years, the National Cancer Institute has screened plants for their chemotherapeutic activity, said Thomas D. Mays of NCI's Office of Technology Development. Contractors working for NCI have collected 35,000 plant samples, representing 9,000 to 10,000 species, from Africa and Madagascar, Central and South America, and Southeast Asia. NCI now also looks for plant-based compounds that thwart the AIDS virus, Mays said. The institute is supporting preclinical investigations of three possible anti-HIV agents derived from plants. One, michellamine B, comes from a woody vine called a liana, found in Cameroon. Liana extracts may work against malaria as well, Mays added. Another possible anti-HIV agent is conocurvone, from the Australian smokeweed bush. Two related compounds from a Malaysian rainforest tree, calanolide A and costatolide, may also thwart HIV.
Researchers are also investigating the antiviral potential of prostratin, a molecule in the bark of a Samoan tree, said Paul Alan Cox, a professor of botany at Brigham Young University in Provo, Utah. Samoan healers use prostratin for treating patients with yellow fever. It appears to interfere with viral replication and protect cells from HIV, Cox said. Recently, Cox and his colleagues learned of a compound in the bark of the Samoan tree that appears to stimulate the immune system and double the life span of certain immune cells.
The unique behavior of certain animals may also offer clues for how to prevent or treat diseases, said Eric Chivian of Physicians for Social Responsibility in Washington, DC. For example, understanding why black bears, an endangered species in many parts of the world, can hibernate without losing bone mass may help scientists find ways to prevent bone loss suffered by the elderly, bedridden patients, and astronauts.
Collecting plants, insects, and other natural materials for research or for retail can threaten endangered species, speakers warned. It's a myth that harvesting nontimber products, such as nuts, doesn't harm the ecosystems of rainforests, where many medicinal plants grow, warned Charles Peters, curator of botany at the Institute of Economic Botany of the New York Botanical Garden in Bronx, New York. Local people may reap the benefits of a forest for centuries without causing problems, but increasing that harvest even slightly can prove disruptive, Peters said. For one, although there are many different species in the rainforest, no one species is very abundant. Also, tropical plants have difficulty establishing seedlings. Moreover, species are dependent on one another for survival.
People in the countries where valuable medicinal plants or other species exist, including the indigenous people knowledgeable about the plants, need protecting as well, speakers pointed out. The traditional healers of the world, experts on the medicinal power of plants, are dying off and no one is taking their places, conference speakers warned. One indigenous culture goes extinct every year in the Amazon alone, according to Katy Moran, executive director of the Healing Forest Conservancy in Washington, DC.
Current law fails to ensure that indigenous people receive any benefits when companies develop products that use the fruits of their forests, Mays said. At the same time, countries need incentives to preserve and to provide access to their plants for possible drug discovery. To address these problems, NCI has developed legal agreements that guarantee that countries receive financial rewards and scientific assistance for their contributions to new drugs.
Throughout the meeting, speakers emphasized the importance of taking a holistic approach to preserving biodiversity: saving not just the individual species, but entire ecosystems and cultures. Speakers also warned that medical, scientific, and environmental organizations working on biodiversity issues must strengthen and better coordinate their efforts, particularly in light of new congressional efforts to lift protections for endangered species.
From 1949 until 1956, workers at the Soviet Union's first nuclear weapons facility in the southern Ural mountains dumped nearly 80 million cubic meters of liquid radioactive waste into the Techa River, a regional waterway shared by 30 villages that dot its shores. Unaware that the river had been contaminated by plutonium, the 64,000 villagers drank its water, washed their clothes in it, and bathed in it for decades. Among other nuclear accidents at the plant, 217 villages of 272,000 inhabitants were also exposed to 2 million curies of radiation released when a liquid-waste storage tank blew up in 1957. Unlike any other region in the world, at least 400,000 people have been continuously exposed to both external radiation, the gamma rays deposited throughout the area, and internal radiation, the strontium-90 and cesium-137 absorbed from drinking water and contaminated vegetables, according to a February article in
Science.
Downriver risk. A family in Muslyumovo grows vegetables on the banks of the contaminated Techa river, 50 miles from Chelyabinsk-65.
Soviet scientists carefully studied the villagers for three decades. Soviet secrecy, however, prevented any results from becoming public; even the villagers were never told why they were being examined. But in early January, a team of radiation biologists from the United States, Europe, and Japan traveled to the city of Chelyabinsk, home of the long-secret nuclear facility Chelyabinsk-65 and its Mayak plutonium production plant, to meet their Russian counterparts and take a look at the research for the first time. Such data represent the only known studies in the world on long-term, low-dose radiation exposure; studies in Hiroshima and Nagasaki, in contrast, were based on short-term, high-dose exposure.
"The Russian scientists have carried out some unique studies, including the only reliable research on the long-term effects of plutonium exposure," writes Michael Balter in his article in Science. One epidemiological study of 28,000 Techa River villagers "found a statistically significant increase in leukemia incidence, as well as an overall increase in cancer mortality, compared to control populations that did not live in the contaminated zone. Still, the leukemia risk per unit of radiation dose was at least two times smaller than that of the atomic bomb survivors," he says.
Over the years, several local physicians had tried to gain access to the data being collected on their patients by the Institute of Biophysics Branch Number Four. According to Diahanna Lynch, coordinator of the Russian Environment and Energy Project at the Natural Resources Defense Council, Russian doctor Gulfarida Galimova threatened to prevent the institute's researchers from continuing to examine her patients if they did not provide more information on their condition. In 1993, the researchers gave her a list of 285 patients diagnosed with chronic radiation sickness in her village of Muslyumova, 50 miles downstream on the Techa River from Chelyabinsk-65.
"In 1993, Dr. Galimova determined that of the more than 4,000 residents in the village, about 3,000 were examined by the institute," says Lynch. "Of these, she says, 92% had some kind of chronic illness, ranging from circulatory problems to birth defects such as missing kidneys. Dr. Galimova has also been a local activist in the Chelyabinsk Movement for Nuclear Safety, encouraging people to lobby the government to resettle the village in a cleaner area, and to demand compensation for the damage to the villagers," said Lynch.
Traces of plutonium have been found in the organs and tissues of the villagers and local animals, according to a recent article in Surviving Together, published by the environmental organization ISAR (formerly the Institute for Soviet-American Relations), in Washington, DC. In addition, an article distributed by the Japanese Kyodo News Service after the January 1995 meeting in Chelyabinsk reported that villagers along the Techa River have more lymphatic genetic mutations than people who suffered radiation from the atomic bombing of Hiroshima. Scientists also discovered a buildup of strontium-90 and other radioactive isotopes in the livers and in other organs of the local residents, as well as an increasing incidence of mutations of the gene responsible for T-cell antigen receptors in lymphocytes in peripheral blood, according to the article.
In January, President Boris Yeltsin's former environment adviser, Alexei Yablokov, now in charge of environmental matters for the country's top policy-making body, the Security Council, warned that radiation from the Chelyabinsk site could ultimately spread to the North Pole. He said that radioactive groundwater was now contaminating the Tobol River, which feeds into the Ob River system. The Ob system empties into the Barents Sea, which flows toward the North Pole. He also said that total radiation around Chelyabinsk-65 is 22 times the radiation released in the 1986 explosion at the Chernobyl nuclear reactor in Ukraine. Although the Mayak facility's five industrial uranium-graphite reactors have been shut down, the plant is still used for reprocessing spent fuel.
Scientists have known for decades that exposure to certain environmental agents can lead to cancer, and many have suspected that this occurs through the alteration of cell cycle controls. Until recently, however, not enough was known about the molecular basis of cell growth and division to understand the specific pathways by which such agents could alter cell growth in a way that leads to cancer. In the last few years, a large number of specific control points in the cell cycle have been identified, as have the individual genes and proteins that regulate these checkpoints. Researchers have observed that alteration of such controls can disrupt normal cell cycle regulation, but the mechanisms by which chemical treatment or exposure affects these critical functions are largely unknown. Recent research in this area, however, has shed some light on how environmental agents and external cell signals affect cell cycle regulation.
The Cell Cycle
All eukaryotes, from yeast to humans, share many features in the process of cell division. Cells that are actively growing and dividing pass through four stages: G1 (gap), followed by the S-phase in which the chromosomal DNA replicates, G2, and finally M (mitosis), in which the chromosomes move to opposite ends of the cell and the cell then divides. Research has recently indicated that the transitions between cell cycle states are regulated at checkpoints by a family of protein kinases, the cyclin-dependent kinases (CDKs), and their activating partners, the cyclins.
One of the most important checkpoints is START in late G1, at which the cell commits itself to another round of DNA replication and at which both positive and negative signals are integrated into the cell cycle. Many checkpoints are deregulated in oncogenesis, and this is often due to changes in cyclin-CDK comp lexes. In particular, the deregulation of START may allow cell growth and division to become insensitive to external cues. Research has shown that this insensitivity can be a consequence of either the aberrant expression of positive regulators, such as the cyclins, or the loss of negative regulators, such as the cyclin-dependent inhibitor proteins (CDIs). Another consequence of abnormal START checkpoint control is that cells can bypass the normal restriction on entry into the S-phase that is normally imposed by damaged DNA, and this may allow the cells to replicate unrepaired mutations and thus accumulate genetic changes that contribute to carcinogenesis.
Much current research is focused on identifying factors internal to the cell nucleus that regulate cell growth, and how the over- or underexpression of those factors perturbs the cell cycle. At the NIEHS, Richard Paules heads a growth control and cancer group that is conducting in vitro studies on mouse and human cells. By overexpressing an oncoprotein, called mos, that can affect the ras/raf/MAP (mitogen activated protein) kinase pathway in mouse fibroblasts, Paules's group has observed that cells cannot exit G1 and go into resting mode. Rather, the cells are pushed by abnormally high levels of cyclin A and the cell division cycle gene, CDC2, and become unstable and thus vulnerable to further genomic alteration that can lead to uncontrolled growth. Similar studies are underway with the MAP kinase (MEK1) and v-Ha-ras transformed mouse fibroblasts.
Paules's team, in collaboration with William K. Kaufmann of the University of North Carolina-Chapel Hill School of Medicine, is also investigating checkpoint responses to the kind of damage that may result from exposure to environmental toxicants. Previous research has shown that a lack of the p53 tumor-suppressor gene can lead to genomic instability. Paules's team has shown that one consequence of this may be the loss of the G2 checkpoint function. G2 provides a protective delay, preventing entry into mitosis when there is DNA damage. Without this checkpoint, cells are vulnerable to the chromosomal aberrations frequently seen in cancers.
"We are very excited about the possibility of understanding the molecular consequences of exposure to a variety of environmental agents that impact normal cell cycle control," Paules said. "The hope for the future would be to develop intelligent approaches for early detection and better chemotherapeutic strategies exploiting these pathways."
Other researchers are examining chemical interactions with the cell cycle. Thomas Goldsworthy and his colleagues at the Chemical Industry Institute of Toxicology have teamed up with NIEHS researchers George Lucier and Robert Maronpot to examine pathways by which certain environmental agents affect the cell cycle. Goldsworthy's team is particularly interested in how nongenotoxic, carcinogenic agents affect the cell cycle.
"We know that genotoxic agents can cause direct mutation of some of the key cell cycle regulators, but we also believe that nongenotoxic agents can indirectly lead to these changes," said Goldsworthy. "Our hypothesis is that exposure to certain chemicals can cause aberrant expression of certain genes, such as the p53 tumor suppressor, which in turn prompts certain cell cycle events. Once you have an altered response to the growth signals, that can lead to cell cycle dysregulation. This can allow the cell to proceed to DNA synthesis and replication without repairing any DNA damage, and that in turn leads to altered growth, genomic instability, and the accumulation of DNA mutations--the hallmarks of cancer."
Goldsworthy has investigated unleaded gasoline and its mechanism of carcinogenesis in mouse liver and observed that precancerous cells exposed to gasoline lose their response to inhibitory growth factors and exhibit aberrant growth. The challenge now is to understand the dose and species susceptibility to these processes. "Although specific cell cycle genes may not be identical between mice and humans, we can say that the processes for controlling cell growth are similar, and certain chemicals, such as gasoline, do appear to affect these processes," Goldsworthy says. "Are these the critical changes that result in cancer? We don't know."
Goldsworthy's work with Maronpot is focusing on identifying the growth factors and oncogenes that are involved in chemically induced mouse liver neoplasms and relating those changes to cell proliferation and cell death. Chemicals being studied are mainly agents shown not to directly interact with DNA, including chlorinated hydrocarbons, furan, and phenobarbital. The team has identified a number of novel genes that have the potential to affect the regulation of the cell cycle and appear to be involved in mouse hepatocarcinogenesis.
Goldsworthy and Lucier have teamed up to study receptor-mediated carcinogenesis, particularly in response to dioxin exposure. The team has been examining dose-response effects, hormonal effects on receptor binding, gene expression, cell growth, and the induction of liver cancers.
"I believe this is the future of toxicology," says Goldsworthy of research examining the interaction of environmental agents and cell cycle controls. "We've been characterizing the cancer process with respect to altered cell growth, but we don't really understand the exact interaction between the chemical and the growth process and its role in inducing the cancer. The tools are now available to really understand the interactions of chemicals with the critical cellular and molecular components of the cell cycle, which will lead to better species extrapolations and, ultimately, improved risk assessment."
The summer solstice is a time when people's attention focuses on the sun. A World Wide Web site with the same name shares that focus. Created by the Center for Renewable Energy and Sustainable Technology (CREST), the Solstice site (http://solstice.crest.org) offers a fairly comprehensive introduction to the topics of renewable energy, energy efficiency, the environment, and sustainable development.
One of CREST's primary functions is to explore and demonstrate the use of advanced information and communication technologies. Solstice provides information arranged by subject and type in the categories of energy efficiency, the environment, renewables and alternatives; legislation, policy, and economics; education and social issues, planning, and computers and networking in the context of alternative energy resources.
Solstice also provides two interactive energy education modules that use text and images to teach the theoretical and practical basis of passive solar and renewable energy at an introductory level. The passive solar module provides an overview and information on design, benefits, and resources. Technology areas covered by the renewable energy module are labeled solar, wind power, small hydro, geothermal, and biomass. This module provides a basic overview of the history and theory of each technology, case studies and applications, and economics and global impact. Internet addresses are available for users to direct questions or comments about the modules to experts at Solstice. The Solstice site also offers hyperlinks to related sites including the U.S. Department of Energy's Energy Efficiency and Renewable Energy Network.
Once you have soaked up enough information about renewable resources, it might be time to soak up some sun (with sunscreen, of course). One way to do this is by throwing a frisbee. Users who would like to join pick-up games of ultimate frisbee should take a glance at The Frisbee Page (http://www.sccs.swarthmore.edu/ ~dalewis/frisbee.html). Everything you ever wanted to know about frisbee is in there and if you don't own a frisbee yet, you can order one through the Internet Disc Shoppe. Pick-up games are listed by state.
Last Update: July 16, 1997