Mr. David R. Schwoegler
Public Affairs Office
7000 East Avenue, L-797
Livermore, CA 94551
Phone: 925-422-6900
Fax: 925-424-2780
E-mail: newsguy@llnl.gov
Number of Human Subjects projects reported: 50
| LLNL-94-105 | "Investigation of the Relationship between Numerical Chromosomal Aneuploidy in Sperm and Offspring." |
| LLNL-95-126 | "Influence of Heterocyclic Amine Metabolic Polymorphisms on Bioactivation of PhIP in the Human Colon." |
| LLNL-96-109 | "Age Effects on the Incidence of Genetic and Physiological Defects in Human Sperm." |
| LLNL-98-106 | "Melanoma and Other Mortality Rates in LLNL Employees." |
| LLNL-99-121 | "Improved Measurement of Cholinesterase Inhibition" |
| LLNL-00-103 | "Quantifying the Effects of Preventive Foods on the Metabolism of a Prostate Carcinogen in Humans and in Prostate Cells Grown in Culture." |
| LLNL-00-106 | "Prostate Cancer Screening and Dietary HA Exposure in African Americans." |
| LLNL-00-113 | "Use of Chelating Agents in Radiation Accidents." |
| LLNL-00-116 | "PhIP Metabolites in Human Urine After Consumption of Cooked Meats. " |
| LLNL-01-101 | "Background Uranium in Urine at LLNL." |
| LLNL-01-116 | "Biomechanics of Human Dentin." |
| LLNL-01-119 | "Changes in Diffraction-limited Spatial Vision Associated with Aging and Retinal Disease." |
| LLNL-01-124 | "Retrospective Plutonium Biodosimetry by Modeling Urinary 239-Pu from Archived Occupational Samples Analyzed by Accelerator Mass Spectrometry." |
| LLNL-01-128 | "A Study of Markers of Cosmic Radiation Exposure and Effect Among Flight Crews." |
| LLNL-02-101 | "Determining the Carcinogenic Significance of Heterocyclic Amines." |
| LLNL-02-106 | "The effect of daily soft-drink consumption on human bone resorption." |
| LLNL-02-110 | "Gene Expression Studies of Human Immature Oocytes." |
| LLNL-02-114 | "Study of the association of DNA damage with cancer risk." |
| LLNL-02-119 | "Vitamin B12 absorption and metabolism in humans." |
| LLNL-02-120 | "Measuring and correcting the eye's optical defects to temporarily improve vision and to improve images of the retina." |
| LLNL-02-123 | "Tracer Studies of RRR and All-Racemic Alpha-Tocopherol in Humans Under Steady State Conditions." |
| LLNL-02-124 | "Identification of markers of human exposure to biological agents, LLNL volunteers." |
| LLNL-02-126 | "Identification of markers of human exposure to biological agents. Hemodialysis patients." |
| LLNL-02-127 | "Effects of Low Dose Ionizing Radiation on Gene Expression in Human Subjects Undergoing Radiotherapy." |
| LLNL-03-103 | "Identification and Development of Biological Markers of Human Exposure to the Insecticide Permethrin." |
| LLNL-03-104 | "Biomarkers for Ductal Carcinoma In Situ by Fourier Transform Ion Cyclotron Resonance Mass Spectrometer (FTMA)." |
| LLNL-03-105 | "Acquisition and amplification of DNA contained in cells isolated from fingerprint ridges." |
| LLNL-03-106 | "Identification of markers of human exposure to biolgoical agents: Vaccinia study." |
| LLNL-03-107 | "In Vivo Dynamics of Beta Carotene Metabolism in Humans." |
| LLNL-03-109 | "Does Tamoxifen Cause DNA Damage in Human Colon?" |
| LLNL-03-110 | "Evaluation of an improved method for measuring plutonium and uranium." |
| LLNL-03-111 | "Non-Invasive Pneumothorax Detector." |
| LLNL-03-113 | "Host Pathogen Interactions: Biomarkers for Early Detection." |
| LLNL-03-114 | "Monitoring Bone Resorption Using 41Ca and Accelerator Mass Spectrometry." |
| LLNL-03-115 | "The effect of dietary protein on calcium metabolism." |
| LLNL-03-118 | "Quantifying the impact of diet on carcinogen exposure." |
| LLNL-03-121 | "The Dynamic and Kinetic Behavior of Folate Metabolism." |
| LLNL-03-126 | "Molecular modulation of calcium crystallization." |
| LLNL-04-104 | "Detection of Pathogen, Tumor and Damaged DNA in Cancer Patient Plasma." |
| LLNL-04-105 | "Character and Effective Leadership of the Knowledge Worker." |
| LLNL-04-113 | "Genetic Effects of Benzene Exposure in Human Sperm: A Study of Chinese Factory Workers." |
| LLNL-04-115 | "Monitoring Bone Resorption with Sweat Patches." |
| LLNL-04-116 | "Detecting Chemotherapeutics in Buccal Cells using Time-of-Flight Secondary Ion Mass Spectrometry." |
| LLNL-04-117 | "Determining the Effect of Green Tea on Gene Expression in Buccal, Bladder, and Blood Cells." |
| LLNL-04-118 | "Gene Expression Studies in Human Blood and Saliva." |
| LLNL-04-119 | "Anonymous Semen Donor Program." |
| LLNL-04-120 | "Determination of Long-Term Amino Acid Metabolism." |
| LLNL-04-121 | "Environmental Epidemiology of Essential Tremor." |
| LLNL-04-123 | "Evaluation and Validation of 41Ca as a Novel Isotopic Technique in Bone Research." |
| LLNL-04-126 | "Ultrawide Band Radar Camera Detection and Imaging of Human Presence." |
"Investigation of the Relationship between Numerical Chromosomal Aneuploidy in Sperm and Offspring."
Principal Investigator: Dr. Andrew J. Wyrobek, Lawrence Livermore National Laboratory
Project started in: 1994
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 105
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 08/06/04
IRB approval number: 94-105
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Fiscal Year 2004
Type(s) of Human Subjects Involvement:
Scientific context.
The specific aim of this study has been to determine whether fathers of children with Klinefelter Syndrome (KS; 47,XXY) who are known to have contributed the extra X chromosome have elevated frequencies of sperm bearing abnormal number of chromosomes (aneuploidy) compared to fathers of KS children where the extra X chromosome is known to be of maternal origin. The study population included index cases and the mothers and fathers of the index cases. In this study, the index cases consisted of boys with Klinefelter Syndrome who were six years old or younger at the time of recruitment.
Animal and human evidence indicates that: a) sperm can carry gene mutations or chromosomal abnormalities; b) genetically defective sperm can fertilize eggs; and c) an embryo's ability to survive through development to birth and beyond, depends on the specific chromosomal defect it carries.
Hypotheses.
Fathers of children with KS when the extra X chromosome was paternally-derived have higher levels of sperm with chromosomal abnormalities than fathers of children with KS where the extra X chromosome was maternally derived.
Experimental Design.
The laboratory research conducted at LLNL included (a) determination of the parent of origin of the extra X chromosome and (b) determination of the level of sperm aneuploidy in the father of affected children. At this time no additional laboratory research is being conducted. All samples have been collected, and only data analysis and manuscript preparation are ongoing.
A total of 38 families with a Klinefelter syndrome (XXY) child were recruited. The blood samples from father, mother, and child plus father's semen were collected and shipped to LLNL. We determined the parental origin of the extra X chromosome of each boy for all the families by polymerase chain reaction (PCR) and sequencing using a polymorphic X-linked microsatellite DNA marker. Inheritance was paternal in 10 families and maternal in 26. Two families were not informative. The frequencies of aneuploid sperm of each father for all the families were determined by fluorescence in situ hybridization (FISH) using DNA probes specific for chromosomes X, Y, and 21.
For the multiple aneuploidy study, we evaluated the fourth family recruited in the main study. This family had three aneuploid pregnancies prior to the index case. We established that the extra X chromosome of the index child was inherited from the father and that the father produces more aneuploid sperm than we have ever seen in any man including heavy smokers and men who have received cancer chemotherapy. Previously, we obtained tissue blocks from the aneuploid pregnancies that died before birth (trisomy 15 and 22) and determined that the extra chromosomes were also paternal in origin. Using an aliquot of semen we also determined that the aneuploidy frequency was also elevated for these chromosomes. In addition, we obtained a second semen sample from the father and determined that the aneuploid sperm were elevated persistently over a two-year period. The protocol and reporting procedures for these families was the same as for those in the main study.
Human Subjects Involvement.
According to our protocol, we requested blood samples from the mother, father, and index child. We requested a semen specimen from the father and arranged for telephone interviews. The findings of the family's blood and semen analysis are shared with the family if they are interested and request this in writing. A genetic counselor discussed with each of the parents whether they wanted both individual and study results or just the latter. Findings were conveyed by the study's genetic counselor. If requested in writing by the family, specific findings will be given via mail or telephone to the family's physician. Potential risks to privacy have been addressed.
Anticipated Results.
Children with Klinefelter syndrome (XXY) and their fathers provide a unique opportunity to characterize the relationship between sperm aneuploidy and aneuploidy at birth. We determined that fathers of children with paternally derived Klinefelter syndrome produced inherently elevated levels of aneuploid sperm. Data analyses and publication of results are expected to be completed during the next year.
The project has found an age-effect on the frequency of sperm carrying a wrong number of chromosomes (aneuploidy), specifically of the X-Y type.
"Influence of Heterocyclic Amine Metabolic Polymorphisms on Bioactivation of PhIP in the Human Colon."
Principal Investigator: Dr. Karen H. Dingley, Lawrence Livermore National Laboratory
Project started in: 1995
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 126
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 10/11/04
IRB approval number: 95-126
Explanation of IRB approval:
Protocol was due to expire on 10/15/04. The protcol was submited for renewal and was approved via the expedited review process on October 11, 2004.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 10
Reporting period for number of human subjects:
Fiscal Year 2004
Type(s) of Human Subjects Involvement:
Background :
Colon cancer is the second leading cancer killer in the United States. Although the causes remain largely unknown, dietary factors have been strongly implicated as a cause of this disease and some evidence suggests an increased risk associated with the consumption of well-done cooked meat. The identification of mutagenic and carcinogenic heterocyclic amines (HCAs) in cooked meat has raised the possibility that these compounds may play a role in the development of cancer in humans. Of all the HCAs, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is considered to be a significant colon cancer risk factor because it is usually the most mass-abundant in cooked meat and causes colon tumors in rats. Consequently, the cancer risk associated with exposure to PhIP is a major public health issue.
Objectives:
The development of colon tumors in rats administered PhIP has been associated with the formation of large numbers of DNA adducts in this organ. DNA adducts, which are a type of DNA damage, are the product of reactions between DNA and chemical carcinogens. If these adducts are not repaired they may lead to changes in DNA, and may ultimately result in tumor formation. Therefore, the presence of DNA adducts can give an indication of the carcinogenic potential of a compound. Since adducts are usually formed at very low levels, sensitive techniques must be employed for their detection. So far, the traditional methods have not proven sensitive enough to accurately determine if PhIP forms DNA adducts in the colon of people and the extent of interindividual variation. Our objectives are to: 1) Use PhIP that is labeled with carbon-14 and the sensitive technique of accelerator mass spectrometry (AMS) to measure adducts in human tissue samples and then to compare this with adduct levels detected in rats. This may give an indication of any potential risk of developing PhIP induced tumors in humans. 2) Identify the routes of PhIP metabolism (breakdown) in humans. 3) Determine if interindividual variation in the metabolism of PhIP in the body can influence the amount of PhIP that forms DNA adducts in the colon, which may help find a predictor of individual colon cancer risk.
Methodology:
This study is a collaboration between LLNL and the University of Arkansas for Medical Sciences (UAMS), the J. L. McClellan Memorial Veterans Administration Medical Center (VAMC) and The Arkansas Cancer Research Center. In this study, volunteers undergoing colorectal surgery will be administered a single dose of PhIP that is labeled with carbon-14. Tissue samples removed during surgery will then be collected and analyzed by AMS. In addition, blood, urine, and feces will be collected and analyzed to determine how the individuals metabolise PhIP. Approximately six weeks after surgery, a simple urine test will be conducted in which the volunteers will be administered caffeine and their urine analyzed for caffeine breakdown products. Caffeine is used because it is broken down by the enzymes considered to be important in PhIP metabolism.
Involvement of Human Subjects:
Briefly, human subjects who have been previously diagnosed with colon cancer and who are scheduled for surgery at the UAMS University Hospital or the J. L. McClellan Memorial VAMC in Little Rock, Arkansas will be fully informed as to the nature of the study. Subjects will be asked to participate and those willing to take part will provide written informed consent. Volunteers will then be administered [14C]PhIP in a capsule. The dose will not represent a chemical risk to volunteers beyond that presented by a normal diet, since it is roughly equivalent to the exposure resulting from the consumption of up to 2.3 kg of chicken, beef or bacon, depending upon the cooking time and temperature. Furthermore, the radiation exposure represents less than one percent of an individual's annual radiation exposure from natural sources. Blood will be drawn (30 mls by vein puncture) at several time points up until surgery to determine the circulating levels of the compound and its metabolites. Additionally, urine and feces will be collected from approximately 12 hours prior to PhIP administration and for up to 96 hours after administration of the PhIP. Approximately six weeks after surgery, patients who participate in this study will be given 200 mg of caffeine and a urine sample collected. In order to protect the confidentiality of volunteers in the study, records will be maintained at the UAMS and VAMC. LLNL will receive only coded samples for analysis.
Outcome:
This study will: (1) determine if adducts are formed by PhIP in humans at dietary-relevant doses; (2) identify the routes of PhIP metabolism (breakdown) in humans; and (3) determine if interindividual variation in the metabolism of PhIP in the body can influence the amount of PhIP that forms DNA adducts in the colon. This pilot study will be completed once we have collected and analyzed samples from 10 volunteers.
Conclusion:
The results of this study will help determine if PhIP is a human colon cancer risk factor at dietary levels of exposure and may establish a predictor of colon cancer risk.
Subject participation has been completed (or the study does not involve subject contact). There is no ongoing contact with any subjects. Follow-up, including review of private records or mailings, will continue.
"Age Effects on the Incidence of Genetic and Physiological Defects in Human Sperm."
Principal Investigator: Dr. Andrew J. Wyrobek, Lawrence Livermore National Laboratory
Project started in: 1996
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 109
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 07/04/04
IRB approval number: 96-109
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Fiscal Year 2004
Type(s) of Human Subjects Involvement:
Scientific Context:
Although it is well accepted that maternal age can result in adverse consequences to the fetus, it remains unclear whether paternal age also influences fetal viability and pregnancy outcome. Evidence for male-mediated developmental toxicity derives from strong animal data that premating paternal exposures can lead to adverse developmental effects. In addition, there is growing epidemiological evidence that exposures of fathers to environmental toxicants are associated with adverse consequences to the fetus. However, the underlying mechanism for the effects of paternal exposure remain unresolved and is likely to include genetic defects transmitted by sperm.
Hypotheses:
The hypotheses for this study are to: (1) determine whether there is an effect of a man's age on the types and proportions of genetic damage in sperm measured by various methods and semen quality, and (2) examine whether certain diets are associated with higher rates of genetic damage and decreased semen quality.
Experimental Design:
The sample collection phase is complete. The following laboratory analyses were performed: sperm concentration, visual motility, and CASA (computer-assisted sperm analysis) motility; nuclear morphometry assay; sperm chromatin assay, sperm chromosomal aneuploidy, and aberration assay. The following analyses are in progress or will be conducted next year: mutation frequency at various specific genes and micronutrient analyses.
Human Subjects:
There are no further procedures involving direct contact with human subjects. Further activity is limited to the analyses of archived samples. All information gathered is treated with respect and confidentiality to protect the privacy of each subject.
Anticipated Results:
This research will provide fundamental information on the effects of paternal age and diet on genetic damage to human sperm. These findings will also provide critical data needed for the design and interpretation of studies of paternal effects of exposure to environmental agents.
Status:
The recruitment phase is completed, the specimens are under laboratory analyses, and the resulting data are in statistical analyses. This research will provide fundamental information on the effects of paternal age and diet on genetic damage to human sperm. These findings will also provide critical data needed for the design and interpretation of studies of paternal effects of exposure to environmental agents.
"Melanoma and Other Mortality Rates in LLNL Employees."
Principal Investigator: Dr. Mortimer L. Mendelsohn, Lawrence Livermore National Laboratory
Project started in: 1998
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 106
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 03/25/04
IRB approval number: 98-106
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Fiscal Year 2004
Type(s) of Human Subjects Involvement:
Scientific context of the study and why are human subjects used in this research:
The primary purpose is to follow mortality rates in the LLNL population as an indicator of occupational and environmental exposure. Our concern began in the early 1980s when the laboratory experienced a highly significant cluster of melanoma cases. We responded in 1984 with a vigorous melanoma campaign including an aggressively active melanoma clinic, which in turn led to the detection of high levels of early melanomas and zero melanoma mortality from 1984 to 1996. General mortality at LLNL for this same time interval was 46 percent of U.S. levels, while cancer mortality was 73 percent and cardiovascular mortality was 42 percent. Such data can only be obtained with human studies.
Hypotheses:
Hypotheses concerned the reality and possible causes of the melanoma cluster and later its disappearance. With regard to mortality in general, we are evaluating what appears to be a very strong and increasing healthy worker effect, enhanced by low tobacco usage, and extending well into retirement.
Experimental design and how is the study being conducted:
We are using conventional methodology and standard U.S. statistics to evaluate our overall and specific causes of mortality. Census data are collected by laboratory administration, and primarily consists of name, social security number, birth date, and hiring and termination dates for all LLNL employees. Periodically (roughly in 10 to 20 year intervals) the data are assembled and submitted to the National Death Index (NDI). The NDI matches death certificates throughout the U.S. and provides diagnoses on the relevant matches.
Provide a brief description of the procedures involving human subjects; describe risks and benefits associated with the study, as well as any privacy/confidentiality issues:
The study is designed so that we have no interaction with the employee, their family, or their medical records. The NDI returns all the identifying information to us soon after it finds the relevant deaths. We maintain the identifiers in data files kept under lock and key. All our analyses and public data are given as rates, without any identifiers. By definition there is no risk to the dead and a miniscule risk of disclosure to the living due to possible mishandling of the data. On the other hand, the reassurance to the staff about the remarkably high level of their survival has been very beneficial, as would be any possible future detection of unexpected mortality.
Anticipated results, criteria for success or failure, and termination of the study:
We are about to send for publication a manuscript describing the significant reduction in melanoma mortality. This will be a first in the dermatological literature, and our poster presentation on it at the American Academy of Dermatology Meeting in Washington DC in February was awarded 3rd place among 600 competing posters. Our data suggest that the laboratory's melanoma problem has disappeared, but we should continue surveillance for a while longer to be certain of this and to protect the laboratory from claims to the contrary. Similarly, the remarkably low overall mortality at LLNL is worth following, partly because it has dropped significantly since a prior mortality study covering 1969 to 1980, partly because it is interesting in its own right, and finally as a precaution against an unexpected reversal related to some new laboratory activity. Several months ago we requested and received an amendment that was precipitated by laboratory management wanting an updated mortality study in conjunction with an environmental review about to be published. Within days of the amendment's approval, management changed its mind and cancelled the study. Ideally the mortality study should be repeated only after roughly 10 years have passed, i.e., after 2006.
Summary:
To the best of our knowledge, the literature is silent about the risks of well-done epidemiologic studies such as ours. We know of no comparable reports on proven reductions in melanoma mortality by intensive surveillance and educational campaigns. The benefits have become clearer and are partly published. The risks remain negligible.
The Melanoma Clinic will remain in operation. The final editorial details will be completed on a manuscript describing the Clinic and the reduction in melanoma mortality from 1984 to 1996. We have just begun a subsequent analysis of the cost-benefit aspects of the Melanoma Clinic and the zero melanoma mortality, and this should continue through this coming year. The next round of mortality analyses will be postponed for several years.
"Improved Measurement of Cholinesterase Inhibition"
Principal Investigator: Dr. Garrett Keating, Lawrence Livermore National Laboratory
Project started in: 1999
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 121
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 06/11/04
IRB approval number: 99-121
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 1
Reporting period for number of human subjects:
Fiscal Year 2004
Type(s) of Human Subjects Involvement:
Scientific Context:
Cholinesterase (ChE) inhibition is a consequence of exposure to certain chemical warfare agents and organophosphate (OP) pesticides. Current assessment of ChE inhibition involves the measurement of ChE activity in blood with a colorimetric assay. The percent of ChE inhibition is calculated by subtracting the measured activity from the background or normal level of activity which is usually based on a population average. Interindividual variability in normal ChE levels of 30 percent has been observed in the population so inhibition calculations based on a population average can misrepresent the degree of inhibition in the individual. The purpose of this study is to develop a method to determine the normal level of ChE activity from an inhibited blood sample. Due to differences in the levels and types of ChE between laboratory animals and humans, blood from human subjects is required so that methods developed by this study can be applicable to clinical ChE determinations.
Hypotheses:
The study is testing whether the ChE activity of an OP-inhibited blood sample can be reactivated so that the normal ChE level can be determined. This involves comparison of ChE activity in the reactivated blood samples with that from normal, untreated blood samples.
Experimental Design:
Whole blood samples will be serially inhibited with an OP pesticide and inhibition measured with a standard colorimetric assay. Free enzyme will then be inhibited with a radioactive probe and the sample subjected to chemical treatment to reactivate the OP-inhibited enzyme. This activity will then be assayed colorimetrically and with the radioactive probe. The objective of the research is to validate the reactivation methodology so that it can be performed without radioactive probes.
Procedures Involving Human Subjects:
Human blood must be used to perfect the methodology for use with existing clinical protocols for measuring cholinesterase inhibition in patients. Subjects will be solicited by a memo describing the research and involvement of subjects distributed to their mail box. Subjects who agree to participate will meet with the principal investigator and will be provided with a description of the study and the IRB Bill of Rights. Subjects will be asked to schedule an appointment with Health Services to provide the blood sample. Subjects will undergo a standard blood draw to provide 5 ml of blood.
Anticipated Results:
Reactivation of OP-inhibited ChE has been shown after prolonged chemical treatment (several hours) although the level of reactivation has not been complete. This study will combine several reactivation chemistries in an attempt to improve the level of reactivation. Reactivation of enzyme to a level of 90 percent of normal will be required for the new assay to be applicable given the level of variability in the clinical ChE assay. Also, reproducibility of the reactivation assay must exceed 90 percent so that it can be confidently applied to blood samples from different individuals where normal ChE levels can vary by as much as 30 percent. The variability and reproducibility of the activation assay will be tested with normal, untreated blood from the subjects so that accurate estimates of these two parameters can be obtained. Blood from one subject was obtained and stored to test the cholinesterase assay being modified for the reactivation protocol. Results using human blood have been comparable to those obtained with pure cholinesterase and mouse blood. Human subjects will be enrolled and the reactivation protocol performed on human blood samples.
"Quantifying the Effects of Preventive Foods on the Metabolism of a Prostate Carcinogen in Humans and in Prostate Cells Grown in Culture."
Principal Investigator: Dr. James S. Felton, Lawrence Livermore National Laboratory
Project started in: 2000
This project ended in fiscal year 2004.
Funding for Human Subjects Research:
This project involves the use of multiple protocols/subprojects.
Number of protocols/subprojects associated with this project: 1
Identifier or number: 103
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 12/11/03
IRB approval number: 00-103
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Fiscal Year 2004
Type(s) of Human Subjects Involvement:
Data Analysis Only.
Scientific Context:
Cooked meat has been linked to increased prostate cancer risk in human epidemiology studies. One potential carcinogen found in cooked well-done meat is 2-amino-1-methyl-6-phenylimidazo[4,5-b ]pyridine (PhIP). PhIP has been shown to cause prostate tumor formation in rats. We are interested in understanding how prostate cancer risk from PhIP exposure can be lowered by other components in the diet. Human subjects are used in this study because there is a growing body of evidence that suggests that humans metabolize PhIP differently from animals.
Hypotheses:
We are investigating primary interventions that may affect the impact of PhIP exposure. We are testing the effect of foods thought to be preventative, like tomatoes, soy products, and broccoli on the metabolic activation of PhIP.
Experimental Design:
The study population will be recruited from the local workforce and may include up to a total of 50 healthy males. The study will be conducted in two parts: a metabolism stability study that will profile the same three individuals every three months for two years (a total of 8 to 10 measurements), and a preventive intervention study that will measure the effects of three different dietary modifications in five individuals (each individual will be asked to eat chicken and collect urine up to six times). In both studies, PhIP metabolites are measured by having the volunteers consume approximately 200 grams of cooked meat. A representative sample of the meat is analyzed to determine the precise amount of PhIP formed naturally in the meat during cooking. Urine samples will be collected prior to eating the meat and for 24 hours after eating the cooked chicken. Volunteers will be asked to refrain from eating cooked meat for 24 hours before eating the cooked chicken and during the urine collection period. In the metabolism stability study we will perform this basic protocol at least seven (but no more than nine) times during the first two years. In the preventive intervention phase, we will measure the effects of tomato sauce, soy milk, or broccoli on PhIP urinary metabolites. After establishing a baseline metabolite profile (using the basic protocol described above), the subjects will consume just one of the food supplements daily for up to seven days. At the end of the intervention period, they will again eat cooked chicken and collect urine for 24 hours.
Procedures:
The involvement of human subjects will be limited to consuming chicken and food supplements and providing urine. This study involves only the minimal risks present in eating cooked chicken and food supplements and the discomfort of collecting urine for 24 hours. The amount of chicken provided will be the minimum amount necessary to provide enough PhIP to be able to detect metabolites. To minimize risk of embarrassment during the urine collections, opaque containers will be provided in paper bags. The identity of the subjects will remain entirely confidential. Subjects will be identified by a code, the code will be associated with the subject's name on the consent form, and the consent forms will be stored in a locked box.
Anticipated Results:
The collected urine will be analyzed for PhIP metabolites and any changes in the metabolite profile will be measured. A successful experiment will demonstrate less metabolic activation of PhIP after consuming the preventative foods. The study will be terminated when all of the samples are analyzed (1/31/05).
To date we have tested 13 individuals in the broccoli, soy, and tomato intervention trials. Preliminary results indicate that broccoli may affect the excretion of PhIP metabolites, both the rate of excretion and the relative amount. Six individuals participated in the broccoli intervention and in five of the volunteers the rate of total PhIP metabolite excretion was increased after eating broccoli for three days. In addition, the amount of the PhIP glucuronide metabolites excreted was increased in the majority of the volunteers after eating broccoli. Glucuronidation is a major detoxification pathway in humans, so increasing the amount of glucuronide metabolites may possibly indicate less metabolic activation of PhIP. A recent study by Murray et al. also demonstrated that broccoli affects the metabolism of PhIP in humans.
Preliminary analysis of the samples collected during the soy intervention trials is ongoing. It appears that soy may affect the N- hydroxylation of PhIP, which is the first step in the PhIP metabolism pathway. Data analysis of the samples collected during the tomato sauce intervention trials is ongoing. No conclusions about the effect of cooked tomatoes on PhIP metabolism can be made at this time. Data analysis of the samples collected for the metabolism stability phase of the study is ongoing. Subject participation in this phase of the study has been completed. Preliminary results from this study indicate that PhIP metabolism may be affected by diet and lifestyle factors.
"Prostate Cancer Screening and Dietary HA Exposure in African Americans."
Principal Investigator: Dr. Kenneth T. Bogen, Lawrence Livermore National Laboratory
Project started in: 2000
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 106
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 05/05/04
IRB approval number: 00-106
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 151
Reporting period for number of human subjects:
Fiscal Year 2004
Type(s) of Human Subjects Involvement:
Studies have shown African-American males, who have the highest prostate cancer (PC) rate worldwide, also have relatively higher Prostate-Specific Antigen (PSA) levels and more Digital Rectal Exam (DRE) abnormalities that correlate with current or eventual PC. This may be related to exposure to environmental carcinogens such as dietary heterocyclic amines (HAs). The major HAs, formed mostly in well-done meats, cause colon and mammary cancer and PC in rats. Increased tumor risks for these sites have been weakly or clearly associated with eating well-done meat in case-control studies. However, no study has focused on HA exposure in African-Americans, despite observations that African-American males ingest meat more often and more well done than do white males.
Hypotheses:
This five-year, clinic-based study will investigate the hypothesis that there is a positive association between dietary mutagen exposure and prediagnostic screening indicators of prostate cancer risk in African-Americans. The proposed study aims specifically to: (1) estimate dietary HA exposure in African-Americans who use HA-forming meats and cooking methods by means of questionnaires, and (2) collect PSA and DRE screening results for these African-Americans and use these data to test hypotheses relating higher HA exposures to increased abnormality in PC screening results.
Experimental design:
The study will include approximately 140 cases (with abnormal PSA and/or DRE screening results) and up to 430 controls, and use targeted solicitation of participants from churches and clinics serving primarily African-Americans in or near Oakland, California to gather data from potentially HA-exposed African-Americans who otherwise would not be likely to obtain early PC screening. To accommodate potential ambiguity in racial-ethnic identity for up to ~5% of participants enrolled, the study will involve a total of up to 1.05 x (140 + 430) = 600 participants.
Brief description of the procedures involving human subjects:
Questionnaires will all be collected prior to prostate screening. Available follow-up clinical diagnostic data subsequently obtained for abnormal PC-screen cases also will be analyzed separately, and together with corresponding prediagnostic PC-screening and available follow-up diagnostic data for HA-related associations. Data analyses will involve multivariate logistic regression, general additive and linear models, and analysis of variance using packaged computer programs.
Anticipated results:
By clarifying how HA exposure may be associated with prediagnostic PC-risk indicators, this study will help to define the potential for early diet/cooking interventions to reduce a possible source of PC risk in the population at greatest risk for this disease. Study success will entail completion of the study protocol, epidemiological analysis of the data gathered, and preparation of manuscripts describing study results for publication in peer-reviewed scientific journals. The study will terminate five years after it began in January of 2006.
"Use of Chelating Agents in Radiation Accidents."
Principal Investigator: Dr. Richard B. Watts, Lawrence Livermore National Laboratory
Project started in: 2000
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 113
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 06/10/04
IRB approval number: 00-113
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Fiscal Year 2004
Type(s) of Human Subjects Involvement:
Scientific Context:
Ca-DTPA and Zn-DTPA are calcium salts of diethylenetriaminepentaacetate (DTPA) and are used as chelating agents for plutonium and other transuranic elements such as americium, californium, and curium. These chelating agents have been in clinical use in major radiation accidents since 1958. They are regulated by the FDA and remain on investigational new drug (IND) status to help ensure accurate reporting of possible contamination accidents and to record any side effects. It has not been possible to conduct extensive clinical trials of DTPA at the dose levels known to be effective in removing radioactive forms of heavy metals from the body because of the infrequency of accidents involving this type of contamination in humans. Therefore, the agents will remain on IND status indefinitely.
Hypothesis:
There is no hypothesis being tested as this is not a research activity in the strictest sense. Rather, the chelating agents are being maintained on IND status to ensure accurate reporting of possible contamination accidents and to continue to record any side effects. These chelating agents have been used for over 30 years in radiation accidents in the U.S. and worldwide, and it is well documented that the drugs are effective against transuranic contamination.
Experimental Design:
There is no experimental design associated with the administration of these chelating agents. Rather, the drug would be administered during a significant transuranic exposure if there was a significant potential for internal contamination based on evaluation of the patient, the wound counts available, and the elements involved.
Human Subjects:
In the event of potential internal contamination, exposed workers would be taken to Health Services. If it was determined that a significant transuranic exposure had occurred, the risks and benefits of DTPA treatment would be explained to the worker(s). Workers are given the right to refuse treatment although, based on decades of clinical experience, chelation therapy has become a part of widely accepted medical practice in removing heavy metal contamination from humans. If workers agree to being treated with the DTPA, they are asked to review and sign the consent form. A baseline medical history, blood and urinalysis are performed prior to treatment. The drug may be injected or inhaled. Depending on the level of contamination, treatment may require repeated doses over a period of up to several weeks or months.
The risks involved in chelation therapy are those inherent in starting intravenous access and drawing blood. Privacy and confidentiality will be maintained to the extent possible. The medical records will be made available to the FDA and to Dr. Robert C. Ricks, Ph.D., of the Oak Ridge Institute for Science and Education. Dr. Ricks is responsible for reporting all uses of these agents to the FDA. General information relating to a worker's case may be used in professional medical literature, but the individual worker will not be identified in any way.
Anticipated Results:
We expect to continue to monitor the efficacy and safety of these drugs on an as-needed basis.
"PhIP Metabolites in Human Urine After Consumption of Cooked Meats."
Principal Investigator: Mr. Mark G. Knize, Lawrence Livermore National Laboratory
Project started in: 2000
This project ended in fiscal year 2004.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 116
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 05/08/03
IRB approval number: 00-116
Explanation of IRB approval:
Project was closed in March 2004.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Fiscal Year 2004
Type(s) of Human Subjects Involvement:
Project is closed.
Scientific Context:
Recent studies have estimated that many human cancers are caused by modifiable lifestyle factors, including diet. Cooking meat produces compounds that have been shown to cause DNA mutations and to cause cancer in rats. Although we know that humans are exposed to these compounds, the human health implications of this exposure have not been fully defined. This study is part of an investigation conducted by the National Cancer Institute (NCI).The purpose of the original study was to develop methods to assess the relationship between cooked meat intake and biomarkers of exposure. In the NCI study, 66 humans were fed a defined diet for two weeks. Blood, feces, and urine were collected from the subjects at prescribed intervals during the dietary period. For our part of the study, we are analyzing previously collected urine for metabolites and will provide these data to the primary investigators at NCI. Human subjects were used in this study because investigations have shown that the biological fate of these compounds in humans differs from their fate in animals.
Hypotheses:
This study was designed to develop analytical methods to measure dietary exposure to heterocyclic aromatic amines (HAs) which are carcinogens formed when meat is cooked at high temperatures. These methods are being used to examine the role of these compounds in human cancer etiology. One way to assess exposure to these compounds is to examine the relationship between the consumed HAs and biochemical measures of exposures, such as the presence of metabolites in the urine. We have developed a method to identify and quantify the metabolites of PhIP, a commonly occurring HA, in human urine. The objective of our study will be to analyze urine collected in the original study for PhIP metabolites.
Experimental Design:
In the original study, 66 healthy subjects, both males and females, aged 25 to 65, were fed a defined diet low in HAs (lightly cooked ground beef) for seven days, followed by seven days of a diet that is high in HAs (well-done beef). All foods in the diet were normal, commonly consumed foods. Blood, urine, and feces were collected at intervals during the feeding period. At the beginning and end of each seven-day controlled diet phase, the subjects had their metabolic enzymes phenotyped. Metabolic enzyme phenotyping involved consuming a drink containing caffeine (coffee or a cola drink) and collecting a urine sample four to five hours later. In addition, prior to the start of the main study, a subset of 20 subjects collected duplicate plate samples of their normal diet for one week, kept a detailed food diary, and collected urine during this period. The subject participation in the study was completed in 1993. We will be provided with frozen aliquots of previously collected urine, which we will thaw and analyze.
Human Subjects:
No subjects are recruited at the LLNL site. Participation of the human subjects included eating a defined diet for two weeks and donating urine, blood, and feces during the diet period. At the beginning and end of each seven-day controlled diet phase, the subjects provided blood and feces and had their metabolic enzymes phenotyped. The study involved the minimal risks present in eating a typical diet and the discomfort of collecting urine and feces. The blood collection was done by a physician, registered nurse or a registered medical technologist under the physician's supervision under strict antiseptic conditions. The entire study was conducted under a physician's supervision. The identity of the subjects will remain entirely confidential; subjects are identified by code numbers. Urine samples analyzed by LLNL are identified only by code numbers.
Anticipated Results:
The urine samples provided to us will be analyzed for PhIP metabolites. These data will then be given to the NCI investigators. The NCI investigators will correlate our data with other data gathered about the subjects, such as food intake levels and metabolic enzyme phenotypes. The LLNL study will be terminated when all of the urine samples have been analyzed.
"Background Uranium in Urine at LLNL."
Principal Investigator: Dr. Lori Johnson, Lawrence Livermore National Laboratory
Project started in: 2001
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 101
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 08/27/04
IRB approval number: 01-101
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 33
Reporting period for number of human subjects:
Fiscal Year 2004
Type(s) of Human Subjects Involvement:
Scientific context of the study:
Everyone has some level of naturally occurring uranium in their urine. The amount of uranium present in the urine varies greatly depending on diet, water consumption, where an individual lives, and on many other complex factors. The amount of uranium in an individual's urine can vary significantly over time, as eating habits and environmental uranium levels fluctuate. The Hazards Control Bioassay Laboratory analyzes hundreds of urine samples from LLNL employees that work with uranium on a routine basis for uranium each year. This is performed in conjunction with the LLNL Internal Dosimetry Program and is a part of the routine occupational safety surveillance program. The goal of this study is to obtain a representative range of the LLNL population uranium in urine level over time to be used as a control when evaluating the occupational safety surveillance results of LLNL employees that work with uranium on a routine basis. Based on recent demographic information, LLNL uranium workers who participate in the occupational safety surveillance program are mostly male (greater than 85 percent) and more than half of them live in the Central Valley. This study will focus on (but not be restricted to) males who are not occupationally exposed to uranium, with an additional specific request for individuals who reside in the Central Valley.
Human Subjects Involvement:
It is not possible to construct a simulation model or animal study that incorporates all of the different variables involved in variation of uranium concentration in human urine. Uranium concentration can vary greatly between individuals; diet, age, gender, metabolism, medication, water and beverage consumption (type and amount), smoking, organic food consumption, vitamin supplements, home and work locations, and many other factors can affect uranium concentration in urine. In particular, several foods and consumer products, such as beets and other root vegetables, shrimp and bottom feeding fish, cigarettes, etc., are known to contain more uranium than meat, poultry, eggs or fruit. Consumption/use of such items may impact the level of uranium in urine.
Hypotheses:
We are not testing a specific hypothesis. The primary objective of this study is to establish a representative range of uranium in urine for non-occupationally exposed LLNL workers. This range will be used as a control for evaluating the occupational surveillance results (i.e., discriminating between "background" and potentially occupationally enhanced levels of uranium). "Urine Blank" control samples (urine from individuals who do not work with uranium) are routinely collected and analyzed for uranium as part of the Hazards Control Bioassay Laboratory's quality control program. This study will analyze urine and drinking water from a larger population than that provided by the routine "Urine Blank" control samples. Corollary objectives include characterizing how uranium concentration in an individual's urine may vary over time and determining if there is a statistically significant correlation between uranium in urine and uranium in drinking water for the population at LLNL.
Experimental design:
Human subjects will provide one urine sample and one drinking water sample (of about 100 ml) every quarter for this study. All subjects will be volunteers. Subjects will be encouraged to participate in the study for at least one year and preferably longer. Samples will be assigned a Bioassay Laboratory sample number and processed in the same manner as routine occupational safety surveillance samples. All samples will be analyzed for uranium using Inductively Coupled Plasma Mass Spectrometry analysis. Some samples may be analyzed for the uranium-236 isotope by Accelerator Mass Spectrometry (see attached amendment). Specific gravity, pH, gross alpha, and gross beta may also be measured periodically to support the uranium measurements. No other constituents will be analyzed.
Anticipated Results:
Based on results from the routine occupational safety surveillance samples and this study, we anticipate a wide variety of uranium concentrations in the samples from our study subjects. The study will be successful if we can analyze all urine and drinking water samples from study subjects for uranium and establish a representative background uranium in urine range for the LLNL uranium worker population. The study will be terminated when routine occupational monitoring for uranium in urine is no longer required at LLNL. Excess urine will be disposed of in an appropriate manner. Study sample urine is processed, stored, and disposed of in the same manner as all urine from routine bioassay samples. Fully trained laboratory technicians and associates perform these functions in accordance with Hazards Control Department Radiation Safety Section Bioassay Laboratory procedures and protocols. The urine will not be used for further tests or studies.
"Biomechanics of Human Dentin."
Principal Investigator: Dr. John H. Kinney, Lawrence Livermore National Laboratory
Project started in: 2001
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 116
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 04/15/04
IRB approval number: 01-116
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 12
Reporting period for number of human subjects:
Fiscal Year 2004
Type(s) of Human Subjects Involvement:
Scientific context:
The project is designed to study the mechanical properties of human dentin. These properties include, but are not limited to, the elastic constants, fracture toughness, and cyclic fatigue behavior. Human subjects are required because we need to perform the mechanical tests on the actual human dentin.
Procedures involving human subjects:
The teeth are to be extracted for clinical reasons. If the clinician decides a tooth should be removed, the patient is asked if they would like to participate in our study by donating the extracted tooth. They are provided with a consent form, a description of the study, and the location of the laboratories where the tooth might be examined. All medical records or identifiers are kept in strictest confidence and are not available to the research team.
Hypotheses:
Specific Aim 1: Biomechanical Properties of Normal Dentin
These studies are designed to measure the elastic and fracture properties of normal human dentin. Specifically, it is hypothesized that the elastic properties, such as Young's modulus, are isotropic (the same in each direction). Other hypotheses consider the fracture properties of dentin: for example, can one measure a fracture toughness and is the fracture toughness isotropic or does it depend on the orientation of the mineralized collagen fibrils?
Specific Aim 2: Biomechanical Properties of Altered Forms of Dentin
In this specific aim, we examine the elastic and fracture properties of altered forms of dentin. Specifically, we will study carious and transparent dentin, as well as what is called reparative dentin (the dentin formed at the pulpal wall in response to trauma).
Specific Aim 3: Biomechanical Properties Affecting Tooth Lifetime
The studies in aim 3 are intended to explore the nature of failure of the human tooth, and the role that environmental factors might play on tooth strength. In particular, we will explore the fatigue (cyclic stress) behavior of dentin and attempt to determine if there is a limiting stress below which tooth failure cannot occur. Questions that will be addressed include whether there is a critical flaw size in dentin.
Experimental Design:
The above specific aims will be accomplished by augmenting the nanomechanical techniques developed in prior years with resonant ultrasound spectroscopy (RUS), fracture mechanics testing, and finite element modeling.
Anticipated Results:
We anticipate that the elastic properties will be controlled by the mineralized collagen fibrils. In addition, we believe that failure in the tissue will be dominated by preexisting or induced defects in the microstructure. The study will be terminated in five years at the end of the program.
"Changes in Diffraction-limited Spatial Vision Associated with Aging and Retinal Disease."
Principal Investigator: Dr. Scot S. Olivier, Lawrence Livermore National Laboratory
Project started in: 2001
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 119
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 05/05/04
IRB approval number: 01-119
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 20
Reporting period for number of human subjects:
Fiscal Year 2004
Type(s) of Human Subjects Involvement:
Scientific Context:
The human eye suffers from significant high-frequency optical aberrations that cannot be corrected by standard corrective eyewear and thus, limit visual acuity. Adaptive optics (AO), a mature technology used in astronomy to correct for the blurring effect of the atmosphere on astronomical images, can also be used to compensate for ocular aberrations, thereby providing normal eyes with supernormal vision. LLNL is developing an adaptive optics system for vision correction based on unique LLNL expertise in high-resolution optical control systems to demonstrate, for the first time, diffraction-limited human vision; i.e., vision that is essentially aberration-free. This adaptive optics instrument is an extension of a prototype system developed and in use at the University of Rochester. Using this instrumentation, we will seek to determine both the ultimate resolution and the ideal optical correction for the human eye based on both optical aberrations and neurological factors.
This project represents a collaborative effort between the Adaptive Optics Group in the Physics and Advanced Technology Directorate at LLNL, led by Dr. Scot Olivier, and the Visual Psychophysics Laboratory in the Department of Ophthalmology at the University of California-Davis Medical Center (UCDMC), led by Prof. John Werner. The researchers at LLNL will provide the adaptive optics instrumentation and will collaborate with researchers at UC Davis, who will use the instrument in a clinical setting at the UCDMC.
Hypotheses:
The broad purpose of our research program is to understand the limits of human visual acuity and the changes in vision associated with aging and retinal disease. The specific purpose of this study is to apply adaptive optics technology to the study of the human eye for two purposes: (1) to measure the visual performance of the eye when virtually all the aberrations of the eye are corrected and (2) to obtain high-resolution images of the retina, thereby allowing correlation of retinal structure with visual performance. Our collaborator's research programs at the University of California-Davis Medical Center (UCDMC) have been concerned with the optical and neural factors responsible for the normal aging of the human visual system, and cellular mechanisms of age-related macular degeneration(AMD), the leading cause of blindness in the United States. This project brings those two research programs together by allowing correlation of high-resolution images of cells in the retina with visual performance assessed using aberration-free stimuli. The human visual system changes continuously throughout the life span and may result in changes in the quality of life for healthy elderly people that do not come to the attention of health care providers. In one survey, 40 percent of individuals over age 65 years reported that visual changes impair daily life activities. Our collaborator's research has identified some of the optical and neural factors responsible for the degradation of human vision due to aging. However, there are still fundamental questions that have not been addressed about normal aging of the visual pathways that can now be investigated using aberration-free stimulus imaging afforded by adaptive optics. For example, what are the consequences for vision resulting from the losses in photoreceptor numbers beginning in early adulthood? Also, what changes occur in visual resolution as a result of the one-third loss in retinal nerve cells between the ages of 34 and 72 years? By using an adaptive optics instrument, it will be possible to address these questions systematically using established psychophysical (vision science) procedures. With better understanding of normal aging and adaptive optics instrumentation, it will also be possible to study abnormal aging of the human retina, for instance in the presence of retinal disease such as AMD.
Experimental Design:
The formal experimental tests will involve presentation of patterns on a computer screen that change over space and time, called sinusoidal gratings (fuzzy bars). We will vary the spatial frequency of the patterns from very coarse (fat bars) to very fine (skinny bars). The gratings will be greenish and the overall size will be varied. The computer screen will be viewed through an imaging system containing a combination of optical components (mirrors, lenses, windows) of similar complexity to a high-end amateur telescope. Tests will be conducted following up to 30 minutes of dark adaptation. Subjects will be asked to press a button to record whether the stimulus was more likely to have been detected in the first or the second interval denoted by beeps. A second set of measurements will present the letter C on a computer screen. The subject will be asked to press one of four buttons to denote the orientation of the gap in the letter so that visual acuity can be measured. Images of the subjects' retina may also be recorded using flash photography.
Human Subjects:
All involvement of human subjects in this project will be under the direction of our collaborators at UC Davis, following the protocol already approved and subsequently renewed by the IRB at UC Davis. Prior to any tests or examinations, each subject will be provided and asked to sign the Consent To Participate Form provided by UC-Davis Medical Center. Each subject will then have a standard ophthalmic eye exam prior to joining the study. They will then make about one to three visits to UC Davis Medical Center, where all of the testing for this project will be conducted. Each visit will be about one to two hours in length, and the subjects will be asked if they would like to take breaks frequently throughout the testing period. During the testing period, the subjects will be seated, have their eyes dilated, and bite down on a molded plastic "bite bar" to stabilize the motion of their head. The dilation requires the use of eye drops. The use of eye drops is standard medical practice and are routinely administered by eye doctors to improve the sharpness of the pictures we take. This plastic bite bar is attached to a steel bar that can be adjusted to a comfortable position for the patient. To measure the aberrations of the eye, it is imperative that the head be still, so once in place the steel bar is tightened down, and the motion of the patient's head is minimized. Every vision group doing similar research has empirically determined that the bite bar set-up is the best method for achieving the desired stability of the eye, as well as providing the most comfort for the patient. Once they are comfortably settled, and looking into the device, the subject will be asked to look at green and black patterns on a computer screen and press specified buttons depending on what they see. These tasks may seem tedious to the subjects, but do not pose a serious risk.
A potential risk to the subjects, which is explicitly mentioned in the Consent form, is dilation of the pupil of the eye. Subjects are warned about all potential hazards related to pupil dilation before their testing period, and the methods used to mitigate these risks are described. In addition to the computer screen, the subjects will be looking into an infra-red light source (currently an SLD) used for the aberration measurement by the adaptive optics instrumentation. The intensity of this light source was measured by the LLNL Safety Officer, David Taylor, and found that it is far below all applicable thresholds for damage or discomfort. LLNL Safety Officer, David Taylor, has calculated that the amount of laser light the subject will be exposed to is about 10 times lower that any ocular damage limits found in the ANSI Z136.1-2000 Safety Handbook. When the subject's retina is photographed, a flash lamp is used for illumination. The light flashes are similar to those routinely experienced by patients in ophthalmic examinations, and are well below all applicable damage thresholds, but may cause temporary discomfort, and the subjects are notified of this in the Consent form. All information obtained in connection with this study will be used in a manner that does not publicly disclose the subject's identity and will be kept confidential. Confidentially is assured by keeping data on each subject on a password-protected computer. Drs. Jack Werner and Thomas Barnes will keep any other records in a locked cabinet, behind locked doors. They will view this data for vision research purposes only. A detailed consent form, outlining all potential risks involved in the study, must be reviewed and signed before screening and subsequent testing can begin.
Anticipated Results:
We expect to discover the limits of normal human visual acuity when optical aberrations in the eye are rendered negligible. The limitations to visual performance will then be due to the physical structure of the retina and to the signal and image processing that takes place in the nerve systems within the eye and in the brain. Precise correction of the aberrations of the eye using the adaptive optics instrumentation is required for success of this project. The quality of this correction will be determined by a series of tests that will include the assessment of retinal images recorded using this instrumentation. We also expect to elucidate the effects of aging and retinal disease on visual performance. This particular study will be complete when the specified subject group has been tested and the results have been interpreted. Subsequent studies may then be initiated to further investigate visual performance issues related to age or disease. The criteria for a successful experiment will be that the data can be interpreted to show a statistically significant relationship between ocular aberrations and visual performance.
"Retrospective Plutonium Biodosimetry by Modeling Urinary 239-Pu from Archived Occupational Samples Analyzed by Accelerator Mass Spectrometry."
Principal Investigator: Dr. Kenneth T. Bogen, Lawrence Livermore National Laboratory
Project started in: 2001
This project ended in fiscal year 2004.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 124
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 08/04/03
IRB approval number: 01-124
Explanation of IRB approval:
Project was closed in July 2004.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Fiscal Year 2004
Type(s) of Human Subjects Involvement:
Project was closed in July 2004.
Scientific Context:
Plutonium (Pu) excretion kinetics in humans is now understood primarily from data involving about a dozen human volunteers, and few of these data clarify very poorly understood long-term (>five-year) Pu-excretion patterns. This data gap imposes major uncertainty on retrospective Pu dosimetry and prevents important applications of emerging ultrasensitive Pu-detection technology to achieve required occupational safety and needed nuclear security goals.
Hypothesis:
Data obtained from this study will be used to test the hypothesis that Pu-239 is excreted only negligibly from workers previously exposed to Pu-239. This hypothesis is contrary to currently used models of human Pu excretion.
Experimental Design:
Over the last quarter century, a routine bioassay program at LLNL has analyzed samples of urine and feces collected periodically from LLNL Pu workers, as a condition of employment and as part of federal requirements. Historically, these samples have been analyzed by the method of alpha spectrometry, which typically has detected no above-background levels of Pu in most samples analyzed. In this monitoring program, Pu was routinely extracted from each biosample obtained, and this Pu was electroplated onto steel plates (i.e., discs, planchettes) that were analyzed by alpha spectrometry. At LLNL (unlike any other Pu facility in the U.S.), most of the steel plates analyzed in the routine monitoring program were archived. The study utilizing Protocol 01-124 (the present protocol) has demonstrated that residual Pu present on such archived plates can be recovered by standard chemical procedures, and this (heretofore undetectable) residual Pu can then be analyzed using a new technology, namely, accelerator mass spectrometry (AMS), which is about 100 times more sensitive than alpha spectrometry. In this way for the first time, historical patterns of Pu-excretion by humans can be recovered, examined, and used, e.g., to test important hypotheses (see above) that heretofore could not be tested directly.
Procedures:
Describe risks and benefits associated with the study, as well as any privacy/confidentiality issues. AMS will be used to reanalyze Pu from archived occupational samples collected originally as a part of the routine LLNL Hazards Control bioassay/dosimetry program. The archived discs were obtained from radiochemical analysis of samples obtained from workers who were (and in some cases still are) required to participate in this monitoring program as a condition of employment. Under the present protocol, Health and Environmental Assessment (HEA) Program staff will be provided with a copy of corresponding coded plates to be prepared for AMS analysis, from which all individual identifying information has been removed. Thus, before providing archived plates to HEA, the Hazards Control Department will remove any identifiers that could be used to determine the name of the individual who originally provided any sample. There is no direct involvement of participants outside of their consent to have their archived biosamples used for the research purpose described. Direct risks to the individual are minimal. The risks that may result from this research are considered unlikely but include: accidental disclosure of name, association of the data with the subject name, and accidental use of subject name and data by people who are not involved in performing the research or loss of confidentiality.
Anticipated Results:
Results obtained will substantially increase the body of data now directly applicable to characterizing long-term urinary excretion biokinetics for Pu in humans. As a result, alternative urinary Pu-excretion models can be tested directly and, if needed, improved which in turn will improve the accuracy of doses and risks predicted to be associated with exposure to Pu.
"A Study of Markers of Cosmic Radiation Exposure and Effect Among Flight Crews."
Principal Investigator: Ms. Marilyn J. Ramsey, Lawrence Livermore National Laboratory
Project started in: 2001
This project ended in fiscal year 2004.
Funding for Human Subjects Research: No Funding Sources Reported
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 128
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 08/28/03
IRB approval number: 01-128
Explanation of IRB approval:
Project was closed in August 2004.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Fiscal Year 2004
Type(s) of Human Subjects Involvement:
Background. This application to use humans as experimental subjects is the latest in a series of work activities that involve LLNL and another Federal agency. In this case, the National Institute for Occupational Safety and Health (NIOSH) via the Battelle Memorial Institute has approached the laboratory about performing molecular cytogenetic analyses on blood samples from airline flight crews. Air travel is associated with increased exposure to ionizing radiation because of diminished atmospheric protection from space radiation. Pilots and flight attendants receive occupational radiation exposure which some believe may be significant enough to detect using biological assays. The purpose of this study is to quantify and evaluate that exposure.
As with other studies of this type, no one at LLNL will have any direct contact with the subjects. We will simply be a laboratory that is performing a service in exchange for a fee. Our scientific input has been solicited, but only in a very limited sense. We did not design the study, and we are not involved in any of the epidemiological aspects of the work. In the past we have performed a number of similar studies with NIOSH and they went flawlessly.
Objective. The purpose of this work is to test the hypothesis that occupational exposure to ionizing radiation by airline flight crews results in quantifiable levels of cytogenetic damage.
Methodology. In this study, 140 subjects, including approximately 60 controls, will be enrolled by NIOSH / Battelle. Peripheral blood will be obtained and shipped overnight to LLNL where it will be cultured and harvested for chromosome analyses using fluorescence in situ hybridization (FISH, whole chromosome painting). We will score 1,800 metaphase cells (1,000 cell equivalents) from each subject. In addition to the blood used for FISH, LLNL will receive enough blood from each subject to freeze approximately ten 2 mL aliquots at -80 degree C for eventual genotyping. These aliquots will be shipped frozen to Battelle / NIOSH at a later date; there are no plans for LLNL to perform the genotyping.
Involvement of Human Subjects. All human subjects will be recruited by NIOSH / Battelle. None will have any contact with LLNL personnel. Issues of informed consent, risk, privacy, and confidentiality will be handled entirely by NIOSH / Battelle.
Outcome. We will obtain chromosome aberration data from the equivalent of 1,000 cells from each of the 140 subjects and provide results of the FISH analyses to Battelle in monthly reports and in a final written report. A publication in a peer-reviewed journal is also anticipated and will include one or more LLNL personnel as authors. This is a one-year study.
Conclusion. We will learn the extent to which extensive commercial air travel results in the accumulation of chromosome damage. The results may be useful for analyses of the long term health effects, including cancer risks, of flight personnel.
"Determining the Carcinogenic Significance of Heterocyclic Amines."
Principal Investigator: Dr. James A. Felton, Lawrence Livermore National Laboratory
Project started in: 2002
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 101
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 09/14/04
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 13
Reporting period for number of human subjects:
Fiscal Year 2004
Type(s) of Human Subjects Involvement:
Scientific context of the study:
Recent studies have estimated that many human cancers are caused by modifiable lifestyle factors, including diet. Cooking meat produces compounds that have been shown to cause DNA mutations in animals and humans and to cause cancer in rats. Although we know that humans are exposed to these compounds, the human health implications of this exposure have not been fully defined. One potential carcinogen found in cooked well-done meat is 2-amino-1-methyl-6-phenylimidazo[4,5-b ]pyridine (PhIP).
There are two objectives in this study: (1) to relate individual differences in PhIP urinary metabolite profiles with metabolic phenotypes to predict risk associated with PhIP exposure; and (2) to determine if food items such as wheat bran, green tea, and parsley can affect the absorption and/or metabolism of PhIP, thereby decreasing cancer risk.
Experimental design:
Overall requirements of the study population: The volunteers for this study will be recruited from the local workforce and will include no more than 75 healthy individuals. The study will be conducted in two parts: (1) a metabolism study that will provide a metabolic profile of the individuals every six months for 12 months (a total of three measurements) by completing a 24-hour food diary, collecting urine and saliva, and (2) a preventive intervention study that will measure the effects of one of three different dietary modifications. Participation in the intervention part of the study will entail collecting urine an additional time (a total of four urine collections for each subject). No saliva will be collected for the intervention study. Blood will be collected one time during the study for a phenotyping assay. Participants will be compensated $25 for each completed urine collection and $10 for the blood donation- a total of $110 for completing all aspects of the study.
In both parts of the study, PhIP metabolites are measured by having the volunteers consume approximately 150 grams of cooked chicken (approximately two chicken breasts) that has been cooked to contain a known amount of PhIP. Prior to eating the chicken meal the volunteers will be asked to keep a 24-hour food diary that records a description of the food eaten, how much was consumed, and at what time. Urine samples will be collected before eating the meat and for 24 hours after, in six-hour increments. Volunteers will be asked to refrain from eating grilled meats, including pan-fried or flame-grilled hamburgers, steaks, fish, chicken, and bacon for 24 hours before eating the cooked chicken and again during the urine collection period.
In the metabolism stability study we will perform this basic protocol three times during a 12-month period. Within seven days of completing the urine collection, the individuals will also be asked to provide saliva samples for a caffeine phenotyping assay. Subjects will be asked to abstain from caffeine containing foods for 12 hours prior to the caffeine test dose and during the testing period. Approximately one teaspoon of saliva will be collected prior to being given caffeine in the form of one NoDoz tablet (equivalent to one cup of coffee). Additional saliva samples will be collected 4, 6, and 8 hours after the caffeine dose. Saliva samples will be assayed for caffeine metabolites. Caffeine metabolite ratios correlate with the activity of certain metabolizing enzymes that are important for PhIP metabolism. We will correlate the activity of these enzymes (measured by the caffeine assay) with the amount and type of metabolites excreted in the urine. Blood (no more than 30 ml or two tablespoons) will be collected only one time during the entire study from each subject for sulfotransferase phenotyping. Sulfotransferase is another metabolizing enzyme that is important for the metabolism of PhIP. We will correlate the activity of this enzyme with the amount and type of PhIP metabolites excreted. Trained personnel will collect the blood samples in the LLNL Health Services Department under strict antiseptic conditions.
In the second part of the study, the preventive intervention phase, we will measure the effects of parsley (4 ounces or 1/2 cup daily), bran (10 grams or two bran muffins daily), or green tea (24 ounces or three cups daily) on PhIP urinary metabolites. The subjects will be given their choice of intervention food. Immediately following one of the collection periods for the metabolic phase of the study, the subjects will consume just one of the food supplements daily for at least three, but no more than seven days. At the end of the intervention period, they will again eat cooked chicken and collect urine for 24 hours.
A subject who completes all aspects of the study will provide four 24-hour urine collections, three 24- hour food diaries, three sets of saliva samples, and a blood sample.
This study involves only the minimal risks present in eating cooked chicken and the intervention foods, donating a blood sample, and the discomfort and embarrassment of collecting urine and saliva. The amount of chicken provided will be the minimum amount necessary to provide enough PhIP to be able to detect metabolites. The identity of the subjects will remain entirely confidential. Subjects will be identified by a code, the code will be associated with the subject's name only on the consent form, and the consent forms will be stored in a locked cabinet. Individuals will be allowed to participate in the study only after they feel comfortable with an explanation of the study and have signed the consent form.
This work will increase our understanding of the risks of being exposed to potential carcinogens in cooked meats. The metabolism study will allow us to determine if there are individuals that may be more or less susceptible, based upon their metabolizing enzyme activity. The results from the intervention phase will provide insight into dietary interactions that may reduce risk from exposure.
"The effect of daily soft-drink consumption on human bone resorption."
Principal Investigator: Dr. Darren J. Hillegonds, Lawrence Livermore National Laboratory
Project started in: 2002
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 106
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 11/10/04
IRB approval number: 02-106
Explanation of IRB approval:
Most recent approval on record occurred AFTER FY2004 and is noted accordingly.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Fiscal Year 2004
Type(s) of Human Subjects Involvement:
Scientific context:
Osteoporosis is a debilitating, increasingly widespread disease characterized by compromised bone strength and predisposition to fracture; it can occur at any age, but often follows menopause in women and occurs later in life in men. In general consistent whole-body calcium equilibrium as well as peak bone strength are maintained between the ages of 30 and 50 in healthy individuals, after which bone mass is consistently lost; rapid postmenopausal bone loss leads to an earlier fracture risk for women versus men. Among the many interrelated factors affecting skeletal health are calcium and vitamin intake, hormone levels, exercise, and many nutritional factors. The interactions of nutrition and the skeletal health are exceedingly complex, requiring the use of human volunteers to assess the pertinent effects and reach conclusions relevant to human biology.
Hypotheses:
We will quantify the effect of phosphorous-containing food (e.g., phosphoric acid added to cola drinks for the purpose of maintaining carbonation) on rate of bone loss, variously reported to be benign and detrimental.
Experimental design:
The following outlines the currently approved protocol:
Up to fifteen postmenopausal volunteers will ingest 10 nCi (80 ng) of 41Ca as CaCO3, a chemical form found in many calcium supplements. Throughout the course of the study, subjects will maintain usual activities and consume their usual diets. To maintain caloric and caffeine intake, diet caffeine-free soft drinks will be used in the study. A day prior to the dose administration (day 1), one blood sample (10 ml, fasted sample), one 24-hour cumulative urine sample, and ten 5 ml saliva samples (fasted) will be collected. Starting from day 14 and continuing to day 90, on the second day of each week, one blood sample (10 ml, fasted) and one 24-hour cumulative urine sample will be collected. One blood sample (10 ml, fasted) and one 24-hour urine sample will be collected on days 120 and 160. Saliva samples (one 5 ml fasted sample for each time point) will be collected on days 4, 8, 15, 22, 29, and 36 of the study. Later in the study, additional fasted saliva samples will be collected on days where a blood sample is being taken (5 ml each).
Description of the procedures involving human subjects:
There are no major risks from participation in this study. The blood drawing is painful only for a few moments and may result in bruising at the puncture site (hematoma), or rarely, an infection. We will be using a licensed nurse and sterile techniques to reduce risk and discomfort, bruising, and infection.
This study involves a small radiation exposure that is less than that commonly experienced through airline travel or medical tests.
Anticipated Results:
We anticipate the results will allow quantification of the effect phosphorous-containing soft drinks have on bone resorption. The study is specifically designed to reflect common American diets and soft drink consumption so as to allow utilization of the resulting data for an accurate gauge of whether soft drink consumption has a quantifiable effect. Since the results for our first subject are positive (i.e., we see a quantifiable effect), we plan on recruiting two new subjects for this study, in order to reproduce the results from the first subject.
"Gene Expression Studies of Human Immature Oocytes."
Principal Investigator: Dr. Francesco Marchetti, Lawrence Livermore National Laboratory
Project started in: 2002
This project ended in fiscal year 2004.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 110
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 01/21/03
IRB approval number: 02-110
Explanation of IRB approval:
Project was reviewed in January 2003.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Fiscal Year 2004
Type(s) of Human Subjects Involvement:
Scientific Context:
New microarray and hystocytochemical technologies provide means for characterizing the gene expression profiles of human oocytes in order to examine the contribution of oocyte maturation failure as a cause of human infertility. Microarray technology uses microscope slides with thousands of spots each representing a specific gene to determine which genes are being expressed in a particular cell. Hystochemistry technology uses antibodies specific for single proteins to detect the presence and cellular localization of that specific protein. Approximately 20 percent of the eggs retrieved from subjects who are attempting in vitro fertilization (IVF) are immature oocytes which cannot be successfully fertilized and are generally discarded. An immature oocyte is defined as one that has not yet reached the metaphase stage of the second meiotic division. These oocytes are either in the germinal vescicle or metaphase I stage of development.
Objectives:
The goal of this research is to characterize the gene expression patterns of discarded immature oocytes to determine (1) What genes are expressed in immature oocytes? and (2) Does the expression pattern vary with the stage of oocyte development?
Experimental Design:
Patients undergoing IVF treatment at the In Vitro Fertilization Laboratory, Yale University School of Medicine, will be asked to donate immature oocytes collected during routine IVF procedures. Oocytes will be placed into lysis buffer to break the cells and preserve the RNA and sent to LLNL where the mRNA gene transcripts will be extracted and quantified using microarray technology. Alternatively, oocytes will be fixed and sent in suspension to LLNL where they will processed with antibodies against DNA repair-related protein to investigate the expression and cellular localization of these proteins.
Human Subjects:
Immature oocytes will be obtained from subjects following normal IVF procedure for the treatment of infertility. Informed written consent to use donated immature oocytes for research will be obtained from each couple before beginning the IVF procedure. The IVF procedure is undertaken by the subjects as part of their infertility treatment and its outcome is not affected by this research.
Anticipated Results:
This study will evaluate gene expression and protein localization in immature oocytes at various stages of development and characterize the expressional changes associated with the early oocyte maturation process.
Conclusion:
The use of the microarray technology and immunocytochemistry provides an opportunity to obtain a global view of gene expression in human oocytes at different stages of development. This research will broaden our knowledge of oocyte biology and may help in understanding and treating certain causes of infertility.
"Study of the association of DNA damage with cancer risk."
Principal Investigator: Dr. Irene M. Jones, Lawrence Livermore National Laboratory
Project started in: 2002
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 114
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 02/04/04
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 39
Reporting period for number of human subjects:
Fiscal Year 2004
Type(s) of Human Subjects Involvement:
Scientific context of the study and why are human subjects used in this research:
The purpose of this study is to determine whether ability to repair damaged DNA is related to risk of cancer in radiologic technologists who may have been exposed to radiation during their work. The National Institute of Cancer (NCI) has been following this group for many years, with particular focus on assessing radiation exposure many years ago and occurrence of cancer. Our study is a small part of a much larger study. Human subjects provide the only way to obtain information on actual occupational exposures to carcinogens such as radiation.
Hypotheses:
The primary hypothesis being tested is that reduced ability to repair damage in DNA is associated with increased risk of cancer in a group of people with occupational exposures to radiation. Reduced repair could lead to increased formation of mutations that contribute to cancer progression. It is also possible that, to the extent that the subjects studied are found to represent a special subset of long-term survivors of treatment, it might be found that poor repair is associated with improved survival from cancer due to greater impact of anti-cancer therapies.
Experimental design and how the study is being conducted:
The Livermore studies assess ability to repair DNA damage by measuring the level of DNA damage in cell lines developed from blood samples by NCI. In this study, we measure the DNA damage (specifically single strand breaks and altered DNA bases) present in cells that have not been treated with radiation. Much of this damage is similar to damage produced by radiation. The level of damage is used to represent the ability of the cells to repair this damage. Higher levels of damage reflect poorer repair when all other factors are kept constant, as we can do in laboratory studies of cells. To address the main question, measurements of DNA damage are made in cells from two groups of people, those who developed cancer and others of the same age and other characteristics who did not. The samples we receive have been assigned a code by our NCI collaborators. We do not know which samples come from people with cancer or which from cancer-free subjects.
Description of the procedures involving human subjects:
NCI scientists have in years past obtained information from the subjects about their work history and medical history. The subjects in this study were, in addition, asked to provide a blood sample so that cell lines could be prepared that would represent them in future studies such as ours. The risks of obtaining the blood sample are minimal. As confidentiality of all information and materials from subjects is protected, providing the information and blood samples carries little risk. The benefits of the study accrue to the general public rather than to individuals in the study. There is potential that studies such as this will contribute to the ability to identify people who are at increased risk of cancer from radiation exposure. This ability could influence policies and practices that relate to both occupational and therapeutic exposures to radiation and to better protection against unwanted effects of radiation on human health.
Anticipated Results:
We will obtain a measure of the ability to repair DNA damage for each subject. The experimental phase of the study will end when data on all the identified subjects are obtained. Our collaborators will then decode the data and relate our findings to the key attributes of the subjects, cancer status, age, history of radiation exposure, and such. Other studies have found that reduced ability to repair DNA damage increases risk of cancer. Those studies addressed other types of DNA damage and were not studies of populations with occupational exposures to radiation. So the outcome of this study will be very interesting and could lead to larger studies in the future.
The preliminary results of the data collected to date based on one measure of DNA damage suggest that there is increased risk of multiple cancers of which one is breast cancer, early onset breast cancer and thyroid cancer in members of this cohort with elevated level of DNA damage in normal cells. Other measures of DNA damage find elevated risk only in those with multiple cancers of which one is breast cancer. Detailed analysis of the results, incorporating repeat