Serving Science and Society Into the New Millenium (1998) / Chapter Skim
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Health Effects Research at the Crossroads
Health Effects Research at the Crossroads
Pages 56-82
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From page 56... ...
For example, a collection of 70-80% of all human genes is laid out before us now in the form of recombinant-DNA clones. With the unique technologies of molecular biology, bioinformatics, and bioinstrumentation, we can identify the genes responsible for susceptibility or resistance to radiation and chemical exposure and potentially use those genes as individual-specific biologic sentinels.
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From page 57... ...
The human-genome project will play a key role in identifying genes and providing technologies to address those issues. We are very good at determining the shape of the dose-response curve at moderate to high doses, but we do poorly at low doses.
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From page 58... ...
Because these libraries represent material from over 30 human tissues and in many cases are highly redundant for specific genes or gene segments, one can begin to put together entire genes directly on the computer. Given that resource, it is possible to start with sequences known in other species to be involved in DNA repair or chemical detoxification and use them to see whether there are corresponding human genes.
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From page 59... ...
BUILDING THE BRIDGES The human-genome project has produced and will continue to produce excellent and extensive resources and technologies relevant to health-effects research. These take the form of genom~c clones, cDNAs, DNA sequences, bioinformatics tools, automation, and instrumentation.
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From page 60... ...
Proc Natl Acad Sci USA 1990;87:5288-5292.
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From page 61... ...
Leukemia was first studied in pioneering radiologists4 and is now studied in nuclear-industry workers;5 osteosarcomas in radium-dial painters6 and now in retinoblastoma patients;7 cancers after radiotherapy for ankylosing spondylitis8 and cervical cancer9 and now after radiotherapy for childhood cancer;~° childhood cancers after prenatal X-raysii and now adult cancers after in utero irradiation; i3 thyroid cancer after thymic irradiationi4 and now after Chernobyl releases;~5 breast cancer after tuberculosis fluoroscopyi6 and now after Hodgkin's disease radiotherapy;~7 lung cancer among underground miners and now among above-ground residents;~9 and cancer among atomic-bomb survivors20 and still among atomic-bomb survivors.2i DOE and the national laboratories have supported key studies over the years, such as those of radiumdial painters, radiation workers, Chernobyl and other Russian workers, and atomic-bomb survivors. DOE has also been in the forefront of biodosimetry research, including classical cytogenetics, FISH technology, and GPA.
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From page 62... ...
Thyroid screening of 2,400 Estonian cleanup workers with ultrasonography and needle biopsy of nodules revealed no radiation-related increase in thyroid disease.34 No excess incidence of leukemia or other cancers was found among nearly 5,000 workers from Estonia, and only death due to suicide was statistically significantly increased.35 Much larger studies will be required to provide information on the effects of protracted exposures,36 although a recent study of 155,000 Russian cleanup workers also failed to reveal a relationship between leukemia and recorded dose.37 Continuing collaborative research in the Ukraine and elsewhere has been supported by DOE and other agencies. Radiologic Technologists Radiologic technologists who likely received much-lower total doses than did radiologists38 have not been reported to be at increased risk for leukemia39 or breast cancer.40 A survey of 145,000 radiologic technologists in the United Stated should provide new information on radiation risks well into the next millennium, accounting for genetic susceptibility4i and other cancer risk factors.42 Airline Crews Airline crews are exposed to higher levels of cosmic rays than are earth-bound workers, in addition to a variety of physical and chemical carcinogens.
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From page 63... ...
Fractionation appears to have little effect on reducing the risk of radiogenic breast cancer in tuberculosis patients repeatedly exposed to fluoroscope, but it appears to reduce dramatically the risk of radiogenic lung cancer with a dose-rate effectiveness factor closer to 10 than to 2.53 STUDIES OF IODINE-131 It has been known since the 1950s that X-rays in childhood result in high rates of thyroid cancer. Exposure of the thyroid gland in adult life results in little if any cancer risk, whether from external photons54 or internal I- 131.55 Thyroid cancer has not been linked to diagnostic uses of I-13 1, but results of a recent study suggest an association between thyroid nodular disease and I-13 1 administration.56 The reactor accident at Chernobyl was followed by remarkable excesses of thyroid cancers after childhood exposure, which have been attributed to radionuclides of iodine, including I-13 1.~5 57-59 Other shorter lived isotopes of iodine possibly contributed to thyroid-cancer risk, as they did after the weapons-testing accident in the Marshall Islands in 1954.6°6i The studies of Marshall Islanders have been supported over the years by the Brookhaven National Laboratory.
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From page 64... ...
Estimates based on underground-miner exposures suggest that perhaps 10-14% of all lung cancers in the general population are related to breathing of residential radon. The possibility that radiation causes characteristic mutational features in lung-tumor cells has been investigated in several laboratories.
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From page 65... ...
Lung cancer in radon-exposed miners and estimation of risk from indoor exposure. J Natl Cancer Inst 1995;87:817-27.
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From page 66... ...
Breast cancer mortality between 1950 and 1987 after exposure to fractionated moderate-dose-rate ionizing radiation in the Canadian fluoroscopy cohort study and a comparison with breast cancer mortality in the atomic bomb survivors study. Radiat Res 1996;145:694-707.
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From page 67... ...
Indoor radon exposure and risk of lung cancer: a nested case-control study in Finland. J Natl Cancer Inst 1996;88:966-72.
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From page 68... ...
In doing so, perhaps we have pushed aside concern for other risk factors. We need to adopt a systems orientation as we look at human health risks, and our range of concern must extend from sources to human health responses.
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From page 69... ...
We need to keep in mind that despite our attention to single risk factors, the real concern is not the small individual relative risks, but all the risk factors. A big cofactor in risk for many diseases is cigarette-smoking.
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From page 70... ...
To that end, NIEHS recently announced plans for a new Environmental Genome Project. It will be a multiyear, multicenter endeavor that will sequence the 200 or more genes that we think predispose people to environmentally associated disease.
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From page 71... ...
We need to define the biologically effective dose for individual toxicants. We will probably discover that the biologically effective dose is different for different people; this is another aspect of individual susceptibility.
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From page 72... ...
Basically, the project will involve sequencing the allelic variants of genes known to control venous processes. The technologies developed by the Human Genome Project will enable the Environmental Genome Project to proceed more rapidly than previously has been possible.
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From page 73... ...
Neutron diffraction complements X-ray diffraction because of its ability to locate hydrogen easily and provide the orientation of water molecules and the direction of hydroxyl groups, data that are important for understanding the catalytic and other functions of proteins and nucleic acids. In elucidating the lowresolution solution structures of large multisubunit protein and protein-nucleic-acid complexes, neutron scatter is the technique of choice because the scattering length of hydrogen has the opposite sign to that of the other atoms found in biologic macromolecules and also to that of deuterium.
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From page 74... ...
In comparison with the neutron-beam situation, synchrotron radiation beams are becoming widely available. Synchrotron beams extend our capabilities beyond those of conventional X-ray sources in 3 ways: Regular crystal structures can be solved more rapidly; the structures of biologic macromolecules and their complexes that give small or irregular crystals can be solved; and the structures of complex biologic assemblies, such as viruses and multisubunit complexes, can be solved in a reasonable period.
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From page 75... ...
The problem of understanding the functions of such a large number of unknown proteins is formidable and will be the task of the functional-genomics component of the Human Genome Project and of molecular and cellular biology. The initial phase of functional genomics is to devise strategies to provide information on the possible functions of unknown proteins; for example, an antibody to an unknown protein would allow its subcellular location to be determined.
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From page 76... ...
This approach is ideally suited to functional genomics and the selection of antibodies against toxins. In addition to the large number of unknown genes that will be found by the Human Genome Project, unusual noncoding DNA sequences will be identified.
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From page 77... ...
There is little doubt that the future of structural biology in this country lies in the unique facilities provided by DOE. A broad structural-biology initiative would link the capabilities of these facilities with the human-genome and microbial-genome projects through functional genomics and health-effects reasearch as outlined in figure 2.
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From page 78... ...
Others have discussed the details of gene targeting and provided examples of how mouse targeted mutations can be used to study human diseases. My focus is on other types and uses of "model mice." VARIABLE TRAITS, DISEASE SUSCEPTIBILITIES, AND INBRED STRAINS Gene targeting is best used to study genes that have already been linked to human disease, but targeting techniques are of limited utility in the discovery of new health-related genetic factors.
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From page 79... ...
Because the maps of related mouse and human regions are, in many senses, mirror images of each other, genetic data, DNA sequence data, and other information can be extrapolated from human regions into mouse. Similarly, genetic and physiologic data derived from the analysis of mouse mutations can be used to predict the existence and locations of human genes with specific biologic functions.
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From page 80... ...
Although it can be difficult to link such "randomly generated" mutations to defects in specific genetic loci, the process is becoming less and less difficult as the results of the Human Genome Project begin to unfold and as new information about genome structure, gene location, and gene function begins to flood the public databases. The genes that are found linked to the randomly generated mutations are often novel or are known genes that would not have been expected to be associated with the types of disorders seen in the mutant mice.
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From page 81... ...
As new mutants are created and the human and mouse genomes are further linked through gene mapping, gene sequencing, and basic gene-expression studies, the mouse is certain to become a major tool for linking mapped human genes to biologically relevant, in vivo functions. The combined power of targeted and induced mutagenesis methods, together with well-controlled methods for studying the influence of genetic background and environment on the expression of traits in normal and mutant animals, makes the mouse a unique and valuable resource for the dissection of complex human traits.
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From page 82... ...
Human and mouse T-cell receptor loci: the importance of comparative large-scale DNA sequence analysis. Cold Spring Harb Symp on Quantit Biol, 1993;58:339-348.
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