Shedding Light on Skin Cancer
A rare disease in which people develop skin cancers at the mildest exposure to sunlight may shed new light on how other environmental factors produce disease in humans.
Both ultraviolet radiation from the sun and pollutants produced from cigarettes and fossil fuels cause damage in human cells that may be repaired by the same set of crucial cellular enzymes, say researchers at the University of Texas Medical Branch in Galveston. At the university's Sealy Center for Molecular Science, scientists are focusing on a group of genes that is responsible for repairing damage that occurs in DNA. In its first year, the Sealy Center has brought together the largest group of DNA repair experts in the United States: 7 scientists, each with a research staff of up to 25 people.
An example of the kind of research fostered by the center is the recent finding published in Nature October 28. A team led by molecular biologist Satya Prakash uncovered the cause of one form of the genetic disorder xeroderma pigmentosum. Patients with the disease cannot tolerate ultraviolet radiation. Their skin burns severely at the slightest exposure to the sun, they have rashes, and they suffer from a variety of skin cancers, including melanoma and basal cell carcinoma. They generally die by age 20.
Researchers knew that people with xeroderma pigmentosum had a defective gene, called XPD, but they didn't know the role of the gene's protein. Now Prakash and his research team, who came to the Sealy Center from the University of Rochester, have purified the protein and discovered that it is a DNA helicase, whose role is to unwind the DNA double-helix.
Now the pathogenesis of the disease has become clear: ultraviolet radiation routinely causes base pairs in double-stranded DNA to fuse, producing a distorting bulge. This damage is normally detected by the XPD enzyme as it uncoils the DNA in preparation for other repair enzymes to snip out and repair the damage. "But when the enzyme is disabled, the damage remains, and cancer likely results due to mutations in genes that normally protect the cell against uncontrolled growth," said Prakash.
So far, seven genes have been identified that act in concert to repair DNA damage. Disease can result when mutations occur in any of these genes or when environmental insult damages the action of the enzymes. Identifying the disorders and their triggers are the goals of the Galveston researchers.
Research has shown that the same kind of pathway that helps to repair UV damage is potentially involved in removing chemicals that attach to DNA such as products of fossil fuel combustion, said center researcher Stephen Lloyd. In these cases, the chemicals, known as polycyclic aromatic hydrocarbon compounds, don't fuse DNA bases but attach directly onto base pairs, causing distortions in the DNA.
Lloyd, who came to Galveston from Vanderbilt University, plans to collaborate with Prakash to determine how the cellular repair system responds to each different compound. He will work with Thomas Harris, an expert in DNA synthesis, to attach different chemicals to synthesized DNA, after which Prakash will experimentally subject the DNA lesion to the full complement of seven repair enzymes to see if they can repair the damage. Researchers can then learn if cellular repair systems can clear specific environmental damage. Said Lloyd, "It will help us make predictions about the true impact chemicals found throughout our daily lives have on our health."
Gasoline, Asbestos, and Dioxin
New data on the health hazards of gasoline, chrysotile asbestos, and dioxin were presented at the annual conference of the Collegium Ramazzini, an international group of scientists dedicated to the study of issues of environmental and occupational health. The collegium, created in 1982 by the late Irving J. Selikoff of the Mount Sinai School of Medicine, was established in Carpi, Italy, to honor the birthplace of Bernardino Ramazzini, the founder of the science of occupational medicine.
At the conference, held October 29-31, data presented by Ronald Melnick of NIEHS highlighted inconsistencies and gaps in the hypothesis linking accumulation of 2u-globulin, a protein synthesized in livers of male rats, and gasoline-induced carcinogenicity in the male rat kidney. Although the 2u-globulin hypothesis explains some rat male kidney tumors caused by some chemicals, new data support the view that alternative mechanisms must be operating for gasoline. Cesare Maltoni and colleagues from the Institute of Oncology in Bologna reported that trimethylpentane produced testicular tumors but not kidney tumors in male rats after lifetime exposure. In long-term studies on the new gasoline additive methyl-tert-butyl ether (MTBE), significant increases in lymphomas and leukemias were observed in female rats, and testicular tumors were increased in male rats. Larry Andrews of ARCO chemical company also reported significant increases in kidney tumors and a borderline increase in testicular tumors in male rats and an increase in liver tumors in mice as a result of exposure to MTBE. The role of 2u-globulin in the induction of kidney tumors by MTBE was seriously questioned, however, because 2u-globulin was not detected in protein droplets present in the kidneys of male rats treated with MTBE.
The collegium reaffirmed its position that chrysotile asbestos is a cause of cancer, based on well-documented animal and human studies that have consistently demonstrated lung cancer and mesothelioma after exposure. No safe levels of exposure to any type of asbestos have been found. Yasunosuke Suzuki of the Mount Sinai School of Medicine pointed out that lung burden analyses are not satisfactory indicators of exposure or carcinogenic risk because chrysotile fibers can translocate from the lung to the mesothelium. To protect public health and prevent diseases caused by chrysotile, the collegium recommends that asbestos not be used in the future and be removed where appropriate.
In the session on pesticides and dioxin, Mary Wolff, also of the Mount Sinai School of Medicine, reported an association between blood levels of organochlorine residues and increased risk of breast cancer. Many of these environmental contaminants may cause adverse biological effects through estrogenlike activities. Ellen Silbergeld of the University of Maryland described the mechanistic link between receptor-mediated changes in gene expression and multiple toxic effects induced by dioxin. Pier Alberto Bertazzi of the University of Milan presented a 10-year follow-up of epidemiological data showing increases in several cancers resulting from the accidental release of dioxin in Seveso, Italy, in 1976.
The 1993 Ramazzini Award was presented to Suzuki for his contribution to the scientific knowledge on the pathology of mesotheliomas among asbestos-exposed workers. The proceedings of the conference will be published in a 1994 issue of the Ramazzini Annals.
Hexane and Carbon Disulfide
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Killing the messengers. Carbon disulfide and hexane damage nerves by causing swellings of neurofilaments and degeneration of nerve axons. |
The solvents
n-hexane and carbon disulfide are commonly used in industrial settings around the world. Although chemically different, both solvents can result in identical damage to the human nervous system characterized by the initial development of large swellings and subsequent degeneration of the distal axon, the part of the nerve that sends messages to other cells.
Under a grant from NIEHS, researchers Doyle Graham, Venkataraman Amaranth, and William Valentine of Duke University Medical Center, and Sally Pyke and Douglas Anthony of Harvard Medical School have detailed the mechanism by which these chemicals damage neurons. In the process, they have also identified a red blood cell protein that can serve as a biomarker for exposure.
n-Hexane is used primarily as a glue solvent in the furniture and shoe industries. Before widespread knowledge of the danger of this chemical, facilities were often poorly ventilated, and workers inhaled the vapors throughout the workday. The neurotoxicity of n-hexane was initially discovered in 1964 among Japanese workers, and later among workers in Italy, Morocco, France, and the United States. Neurotoxicity has also been observed in youths in various countries who intentionally sniff glue to get high.
Carbon disulfide has been used since the early nineteenth century as a solvent in the manufacture of sulfur matches and in the extraction of fats. More recently, it was used in the cold vulcanization of rubber, and today it is used in converting cellulose into rayon fiber and cellophane.
The symptoms of hexane and carbon disulfide neurotoxicity are numbness of the toes and fingers, followed by loss of sensation in the feet and hands, loss of distal reflexes, and weakness of the intrinsic muscles of the feet and hands. Studies of peripheral nerve biopsies typically reveal paranodal axonal swellings, retraction of myelin, the fatty substance that sheaths nerve fibers, from cerain nodes, and degeneration of the distal axon. The axonal swellings have been shown by electron microscopy to contain disordered masses of neurofilaments. After exposure ceases, sensory and motor functions continue to decline for one to four months, followed by recovery. The degree of recovery is inversely related to the severity of the neuropathy, and is complete in mild cases.
Over the past 20 years, studies in a number of laboratories have revealed the sequence of molecular events that result in damage from n-hexane and carbon disulfide exposure. For both animal and human subjects, it has been observed that long axons are more vulnerable than short ones, reflecting the greater number of axonal targets for injury with each increment of axonal length.
n-Hexane is metabolized in the liver to -diketone, 2,5-hexanedione (HD)--its ultimate toxic metabolite. Early studies by Valentine and colleagues demonstrated intramolecular and intermolecular cross-linking of proteins after incubation with -diketones. Given the stability of neurofilaments in the axon and their slow rate of transport to the site of hydrolysis of proteins at the synapse where simpler, more soluble products are formed, researchers hypothesized that neurofilament cross-linking was the central, underlying event leading to neurofilament-filled swellings.
Recently, Valentine and colleagues have shown that carbon disulfide also results in protein cross-linking, although by a different mechanism from n-hexane. The initial dithiocarbonate adduct formed on protein decomposes to isothiocyanate derivatives, which then react with protein nucleophiles (electron-donating reagents) to result in cross-linking.
During chronic intoxication with either hexane or carbon disulfide, covalent cross-linking of proteins in the axon is paralleled by cross-linking of spectrin, a red blood cell membrane protein. This finding suggests that exposed populations could be evaluated through periodic blood sampling, and the quantity of spectrin cross-linking could be used to identify people in danger of developing neurotoxicity.
In the United States and other industrialized nations, instances of damage from hexane and carbon disulfide exposure have almost disappeared thanks to protective measures in the workplace and substitution of other chemicals. Processes using either of these chemicals are typically sealed off and ventilated separately. Workers who occasionally work around these processes must wear respirators. Workers that have physical contact with products, such as rayon, that may contain small concentrations of hexane or carbon disulfide, wear protective clothing and gloves.
Both industry and labor groups have expressed interest in the recent findings. "We still have locals who use these chemicals, and any information as to how exposure leads to neuropathy can help us in training workers how to protect themselves," said Rich Uhlar, industrial hygienist with the International Chemical Workers Union. Uhlar said the ICWU is particularly interested in findings that might allow a simple blood test to be used as a biomarker of exposure.
John Stewart, president of Courtauld Fibers in Axis, Alabama, uses carbon disulfide in the manufacture of rayon in his plant. "Any information that would lead us to better understand how carbon disulfide is metabolized--particularly the reversibility of the condition--is of value to us," Stewart said.
Cleaner Air in Volgograd
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Scenic Volgograd. U.S. and Russian scientists are working to restore the air quality that industries along the Volga River destroyed. |
There was a time when the city of Volgograd was a mecca for Russian citizens suffering from respiratory problems such as asthma. There, along the banks of the river they fondly called Mother Volga, Russians could find an ideal dry climate and clean air. But in the last several decades, the Volga River's character has changed: today, it is a highly polluted receptacle for industrial, agricultural, petrochemical, and radioactive wastes dumped along its 2300-mile stretch from the north of Moscow to the Caspian Sea.
In mid-1993, Volgograd was chosen as the test site for the initial phase of a four-year Russia Air Management Program (RAMP), a joint U.S. Agency for International Development (USAID)-EPA project working with the Russian Ministry of Environment and Nature Protection. Before deciding on Volgograd, a team of American and Russian scientists evaluated several other Russian industrial centers, including Lipetsk, Samara, and Nizhny Novgorod, but only Volgograd had such a large number of different kinds of polluters.
Long and narrow, the city of Volgograd stretches for 70 miles along the river's west bank a few hundred miles north of its delta. Clusters of heavy industry follow the city in a checkerboard pattern from north to south, including a steel mill and iron foundries, aluminum reduction and carbon black manufacturing plants, a caustic soda manufacturer, several chemical factories, a petroleum refinery, and large-equipment manufacturing facilities.
"It was this variety of sources that made us choose Volgograd," says Tom Pace, the EPA's program manager for RAMP, managed by the EPA Office of Air Quality Planning and Standards. "This way the city can be used as basically a palette, allowing the Russians to look at how they can deal with many different air pollution problems. It can give us a lot of flexibility."
RAMP is one of the first federal projects funded under the 1993 U.S. Freedom Support Act (FSA) and administered by USAID. Initial FSA allocations for environmental projects totaled $35 million, of which EPA was granted approximately one-third, according to Ken Baum, a USAID senior environment policy advisor. Among its many tasks, the research team will look at ways to improve monitoring air pollution levels, the regulatory process, and the role of public participation, as well as make technical recommendations. Successful approaches will be applied to other Russian industrial centers where appropriate.
"We have a whole environmental health strategy that we're evolving," says Michelle Brown, USAID senior environment advisor in Moscow. "Our main objectives are to first reduce the health risks caused by pollution by helping to improve the air quality in Volgograd. Then we will apply that strategy to Russia as a whole."
Still in its genesis, the program included several U.S./Russian trips to factories in Volgograd during 1993 and early 1994. As part of its short-term recommendations, the team will stress low-cost/no-cost control measures that can be put into effect quickly. For example, during a visit to a farm equipment factory, the team suggested changing the nozzles used to spray paint tractor parts in order to reduce organic emissions. In another plant, they determined that a larger hood over an electric arc furnace would greatly improve the capture and conduction of fumes and smoke to an existing emissions control device. Both the new nozzles and hoods can be made in Russia.
"We're hopeful that a lot of short-term improvements can be made using Russian materials and Russian labor because they have the workers available but not the money to purchase equipment from abroad," says Pace. "In the long term, however, they may need to buy specific air pollution control equipment from vendors on the outside."
In October 1993, the team conducted its first air quality evaluation tests in Volgograd, using an American air quality sampler that can measure inhalable particulates at the PM10 level, a standard signifying particulate matter less than 10 millimeters in diameter. Until now, the Russians were unable to measure particulates this small. EPA researchers are currently analyzing the filters from those experiments to determine the precise nature and sources of the city's pollutants and to make further recommendations.
"The Russian monitoring systems and standards are currently configured much differently than ours," says Jon Schweiss, chief of the EPA air characterization section based in Seattle and member of the air quality evaluation team in Volgograd. "But now they are considering suspending their total particulate standard and replacing it with one similar to our own. Throughout this program, we've found the Russians to be very open to new ideas--just tremendously motivated and professional."
IARC on Risk
The International Agency for Research on Cancer of the World Health Organization held a five-day workshop in Lyon, France, to discuss quantitative estimation and prediction of carcinogenic risks (QEP). The purpose of the workshop was to provide IARC with some guidance concerning the role they may play in providing research support for QEP and on whether they should expand their current risk assessment activities to include QEP.
There has been increasing pressure on IARC in recent years to expand the monograph program, which evaluates the strength of the evidence for a carcinogenic effect from an agent and generally does not quantify the magnitude of that effect as a function of the level of exposure to the agent. In the standard paradigm for risk assessment, QEP involves adding dose- response evaluation and exposure assessment to IARC's current hazard identification role.
The workshop, held 18-22 October 1993, consisted of 40 researchers and regulatory officials from North America, Europe, Japan, and Australia. The first three days of the workshop focused on a review of the methodology used for QEP. The review consisted of a general discussion of the methods and the use of QEP performed for three example compounds: dioxin, radon, and methylene chloride. Following the review, the work group broke into four smaller groups to draft background summaries on QEP and to draft recommendations for IARC.
The main recommendations of the working group can be summarized as follows. First, the hazard indentification process currently used by IARC for determining if an agent is carcinogenic should be preserved in its present form. The working group felt that adding QEP to the current IARC monograph program would lead to a process that is unwieldly and difficult to manage. The working group also said that the addition of QEP to the current monograph series could detract from its scientific excellence. However, the group did say that IARC can and should play a key role in risk estimation.
The second recommendation concerned a variety of roles IARC could play with regard to improving the scientific validity of QEP. These include basic research on QEP, a symposium on research issues related to QEP, performance of QEP for selected compounds, and the publication of reports from these activities in their IARC Monograph Series.
New Directions for IARC
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Kleihues--New director seeks expansion of IARC. |
The cornerstones of epidemiology and laboratory research will remain vital aspects of the International Agency for Research on Cancer, according to Paul Kleihues, who assumed the IARC directorship in January. While the agency intends to keep the balance between epidemiology research and laboratory research, study will be expanded in the area of cancer genetics, which Kleihues called "traditionally underrepresented," in a new unit to be created this year.
According to Kleihues, the agency plans to decrease its efforts in the areas of mutagenesis and DNA adduct studies, programs IARC has strongly developed in the past, to allow for considerable expansion into new aspects of cancer research.
The first of these new areas will be a new agency unit devoted to studying the molecular aspects of cancer, specifically genetic susceptibility. Said Kleihues, "We want to identify genes which predispose people to developing cancer, whether it is spontaneous or induced by exposure to environmental carcinogens." For instance, he added, "Many people smoke, but only a small portion of those develop lung cancer. We want to know why 10 out of 11 do not get cancer." The new unit will also attempt to identify in certain populations whether there are genes that may protect people from developing cancer.
Although considerable progress has been made in the area of chemoprevention in the last three to four years, Kleihues says, it is not enough. "If on the one hand you can identify people at risk for cancer, then on the other hand you must offer these people some means to prevent it," he said. For this reason, said Kleihues, IARC will expand research into chemoprevention of cancer in a new unit that will investigate prevention strategies for individuals who are at high risk for developing cancer because they are genetically predisposed, have been exposed to high levels of environmental carcinogens, or have developed a single tumor in a site where multiple tumors usually occur.
Kleihues outlined plans for the IARC Monograph Series, which he called "one of the more important and visible aspects of the agency over the last 20 years." In a move which he calls "a first and modest step towards risk assessment," the series, which in the past has been devoted to classifying carcinogenic agents based primarily on animal and human data, will be expanded to include data on mechanisms of carcinogenesis. Understanding such mechanisms, said Kleihues, is key to determining what agents will produce cancer in humans. He stressed, however, that in the foreseeable future, the agency "will not engage in quantitative risk assessment."
Kleihues, who replaces Lorenzo Tomatis as director of IARC, obtained his medical degree in 1962 from the University of Münster in Westphalia, Germany. From 1964 to 1976 he worked as a research assistant at the Max-Planck Institute for Brain Research in Cologne. Kleihues served as a professor of neuropathology and head of the Division of Neuropathology in the Institute of Pathology at the University of Freiburg, in Germany, from 1976 to 1983. In 1983 he became a professor of neuropathology at the University of Zurich and in 1992 assumed the directorship of its newly created Institute of Neuropathology before leaving to take his position at IARC.
Kleihues called departing director Tomatis the "father of the monograph series" and says that the international standing of the series is due in great part to Tomatis's efforts. To his credit, Kleihues said, Tomatis kept IARC an independent institution, not subject to political or national influences, which he called "a remarkable achievement," and a goal he plans to continue.
Last Update: August 21, 1998