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: 49
| LLNL-88-111 | "Cytogenetic Studies" |
| 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-96-103 | "Does Tamoxifen Cause DNA Damage in Human Tissues" |
| 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-98-111 | "Chromosome Aberration Persistence Study" |
| LLNL-99-117 | "Methods Development for Studies of Genetic Damage and DNA Repair Function" |
| 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-00-107 | "Intracranial Hematoma Detection Using Impulse Radar " |
| LLNL-00-108 | "Study to Assess the Safety of Toremifene in the Uterus of Women: Comparison with Tamoxifen" |
| LLNL-00-112 | "Former Beryllium Workers Medical Surveillance Program (Component of ORAU-99-87a Protocol)" |
| 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-01-117 | "Multi-Modality Transurethral and Transvestical Prostate Imaging for Diagnostics, Treatment Planning and Therapy Monitoring" |
| LLNL-01-119 | "Changes in Diffraction-limited Spatial Vision Associated with Aging and Retinal Disease" |
| LLNL-01-122 | "Evaluation of a sweeping range finder micropower impulse radar (MIR) for heart rate and motion detection" |
| 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-02-103 | "Comparison of micropower impulse radar (MIR) and electrocardiogram (EKG) for assessment of the cardiac cycle" |
| LLNL-02-105 | "Elucidating Dynamics of Lutein Metabolism in Humans" |
| LLNL-02-106 | "The effect of daily soft-drink consumption on human bone resorption" |
| LLNL-02-108 | "Optical spectroscopic detection and imaging of breast cancer" |
| LLNL-02-110 | "Gene Expression Studies of Human Immature Oocytes" |
| LLNL-02-111 | "The detection of genetic damage in oligozoospermic infertility patients" |
| LLNL-02-114 | "Study of the association of DNA damage with cancer risk" |
| LLNL-02-116 | "Personnel Security Improvement Opportunity" |
| LLNL-02-119 | "Vitamin B12 absorption and metabolism in humans" |
| 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-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" |
"Cytogenetic Studies"
Principal Investigator: Dr. James Tucker, Lawrence Livermore National Laboratory
Project started in: 1988
This project ended in fiscal year 2003.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 111
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 11/20/01
IRB approval number: 88-111
Explanation of IRB approval:
Study was open in FY03 from 10/1/02 until 11/20/02 when approval ran out for FY02 and study was closed.
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 2003
Type(s) of Human Subjects Involvement:
Backgound:
For many years the laboratory has relied on fresh samples of human blood for a variety of purposes, including chromosome and DNA analyses. This continues to be an essential aspect of our laboratory's needs. Approval of this protocol continues to be essential for many aspects of the work in our laboratory, not all of which can be predicted in advance. There is no "experiment" being conducted under this protocol.
Objective:
To obtain peripheral blood for cytogenetic, DNA, and RNA analyses, which will include calibration, validation, and quality control for laboratory purposes. Cytogenetic analyses are needed to support our Tobacco project. RNA expression will be evaluated as part of our anticipated project supported by the Defense Threat Reduction Agency (DTRA). Metaphase chromosomes will be utilized for mapping or verifying DNA probes, and developing or evaluating potential new methods.
Involvement of Human Subjects:
Primarily phlebotomy: Subjects will not be under the PI's line of supervision.
Outcome: Continued access to chromosomes and DNA that is needed to do the work.
Protocol terminated because the investigator left the laboratory.
"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: 08/22/03
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 2003
Type(s) of Human Subjects Involvement:
Scientific Context:
This is an ongoing study. The specific aim has been to determine whether fathers of children with 47,XXY who are known to have contributed the extra chromosome have elevated frequencies of sperm bearing abnormal number of chromosomes (aneuploidy) compared to fathers of children with 47,XXY where the extra 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 (47,XXY) who are six years old or younger.
Animal and human evidence indicates that: a) both human sperm and animal sperm can carry gene mutations or chromosomal abnormalities; b) genetically defective sperm can fertilize; and c) an embryo’s ability to survive through development to birth and beyond, depends on the specific chromosomal defect it carries. There is no animal model.
Hypotheses:
The laboratory research conducted at LLNL includes (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.
Experimental Design:
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 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 probe 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) to determine whether the extra chromosomes were also paternal in origin. We used an aliquot of semen to determine whether the aneuploidy frequency was also elevated for these chromosomes. In addition, we obtained a second semen sample from the father to determine whether the aneuploid sperm are elevated persistently (two semen samples are two years apart). The protocol and reporting procedures for these families were the same as for those in the main study.
Human Subjects:
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 want 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.
"Influence of Heterocyclic Amine Metabolic Polymorphisms on Bioactivation of PhIP in the Human Colon"
Principal Investigator: Dr. Karen 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: Full Board
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 03/04/03
IRB approval number: 95-126
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 2003
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 hr 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.
"Does Tamoxifen Cause DNA Damage in Human Tissues"
Principal Investigator: Dr. Karen Dingley, Lawrence Livermore National Laboratory
Project started in: 1996
This project ended in fiscal year 2003.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 103
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 05/08/02
IRB approval number: 96-103
Explanation of IRB approval:
Study was open between 10/1/02 until 5/8/03 when approval for FY02 was over and study was closed.
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 2003
Type(s) of Human Subjects Involvement:
Scientific Context:
Tamoxifen is a drug used in the treatment of breast cancer and is currently being evaluated for its use as a chemopreventive agent in women at high risk of developing this disease. Tamoxifen is well-tolerated and causes relatively few well-documented side effects. However, tamoxifen causes liver tumors in rats which is associated with DNA damage. Furthermore, epidemiological evidence suggests that long-term administration of tamoxifen to women leads to an increase in the incidence of endometrial and possibly gastro-intestinal tumors. Consequently, the cancer risk associated with taking tamoxifen as a chemotherapeutic agent is a major public health issue.
The development of liver tumors in rats administered tamoxifen is 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. In women, it is not yet clear if endometrial cancer occurs with tamoxifen as a result of a genotoxic (DNA damaging) or hormonal (estrogenic) mechanism.
Human subjects are required for the study because our objective is to measure adducts in human tissue samples and then to compare this with adduct levels detected in rats. No suitable in vitro test system or computer models exists for this work, as the absorption, tissue distribution, and excretion of tamoxifen can only be determined in whole human subjects.
Hypothesis:
The hypothesis is that tamoxifen causes DNA damage in human endometrial tissues. By comparing these adduct levels to data obtained in rats, we will obtain an indication of any potential risk of developing tamoxifen induced tumors in humans.
Experimental Design:
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 tamoxifen forms DNA adducts in tissues of women. For a different approach we will use [14C]tamoxifen and the sensitive technique of accelerator mass spectrometry (AMS) to measure adducts in human tissue.
This study is a collaboration between LLNL, Leicester Royal Infirmary, UK and the Medical Research Council Toxicology Unit, Leicester, UK. In this study, women volunteers undergoing hysterectomy will be administered a single therapeutic dose of [14C]tamoxifen. Tissue samples removed during surgery, blood, and urine will then be analyzed by AMS and results compared to data obtained in female rats.
Human Subjects:
Briefly, human subjects at Leicester Royal Infirmary, UK 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. Patients will be asked to fill in a simple questionnaire, which will center particularly on which drugs they are currently taking. They will then be orally administered 50 µCi [1.85 MBq] of [14C]tamoxifen diluted in unlabeled tamoxifen to provide a dose of 20 mg/person, which is the normal daily therapeutic dose. The radiation dose will be 170.9 µSv and is less than the natural background radiation to which people are exposed in daily life during the course of a month. Surgical specimens and a blood sample will be taken at the time of surgery and urine will be collected for 24 hours following [14C]-tamoxifen administration. Samples will be taken to the MRC Toxicology Unit for further processing. DNA, protein and metabolites will be extracted from the tissue, urine, and blood and sent to LLNL for analysis by AMS. In order to protect the confidentiality of volunteers in the study, records will be maintained at the MRC Toxicology Unit and LLNL will receive only coded samples for analysis.
Anticipated Results:
We anticipate that we will determine the level of adduct formation in human tissues analyzed. The study will be completed after the determination of the amount of tamoxifen which is covalently bound to DNA bases and attempt to identify the DNA adducts formed in human uterine tissue by comparison to adducts of known structure formed in rat liver DNA.
"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: 07/22/03
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 2003
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 method 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.
"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: 04/05/03
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 2003
Type(s) of Human Subjects Involvement:
Scientific Context:
The melanoma phase of the study is to search in the National Death Index (NDI) for melanoma deaths among employees of the Lawrence Livermore National Laboratory who worked at least 6 months during the period July 1, 1984 to December 31, 1996. These dates coincide with the operation of the Melanoma Clinic at LLNL, and we wish to ascertain the effectiveness of the clinic in preventing melanoma mortality. The general mortality phase of the study is to use the same search to review all sources of death beginning January 1, 1984 but otherwise as above. Both studies can only be done using data from the relevant human subjects.
Hypotheses:
For melanoma we are testing the hypothesis that operation of the melanoma clinic reduced LLNL mortality in relation to national, state, and local county rates. For general mortality, the hypothesis is that LLNL employees are healthy compared to the overall US and California populations.
Experimental Design:
The design of both phases is that of a classical mortality study using U.S. (or California, or county) rates as a basis for comparison. The NDI will provide coded causes of death based on name, birth-date, social security number, race, and sex, with the requirement that we not explore mortality status further with families, local institutions, or medical records.
Procedures:
There will be no direct contact of families or employees regarding health status. The results will be shared widely with employees and the public, but only in the form of overall rates and with no divulgence of private information. We will address the significance of the results as fairly and honestly as we can. The files are being carefully protected.
Anticipated Results:
The melanoma-specific outcome will be the updated melanoma mortality rates for men and women, and their comparison to U.S., California, and county rates. The overall outcome will be updated disease-specific standardized mortality ratios for all coded diseases. We anticipate that in both cases the rates and confidence limits will reflect favorably on the laboratory’s health status. The final polishing and dissemination of results should be completed within the next year.
"Chromosome Aberration Persistence Study"
Principal Investigator: Dr. James Tucker, Lawrence Livermore National Laboratory
Project started in: 1998
This project ended in fiscal year 2003.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 111
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 04/05/02
IRB approval number: 98-111
Explanation of IRB approval:
Study was open between 10/1/02 until 4/5/03 when continuing review was not sought and the study was closed.
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 2003
Type(s) of Human Subjects Involvement:
Scientific Context:
This past year was a one-year supplement to our Chernobyl Program Project designed to quantify the persistence of chromosome translocation induced by ionizing radiation. The major emphasis was upon doses of 0.2 to 0.5 Gy, which are similar to those received by most of the Chernobyl clean-up workers. Most exposures to ionizing radiation are below 0.5 Gy, which are lower than those used in our previous in vitro and in vivo experiments. One possible mechanism for translocation loss is cell lethality due to partly coincidental and partly correlated types of radiation damage other than translocations. This suggests that the magnitude of loss will decrease as dose decreases, and that it may become vanishingly small at doses such as those encountered by the clean–up workers by assessing the magnitude of the loss of translocation in vitro after low-dose exposure. All contact with the human subjects has been completed, and the laboratory phase of the work is also done. Only the final analysis remains.
Hypothesis:
Our aim was to evaluate the persistence of chromosome aberrations induced in vitro in human peripheral blood lymphocytes by acute exposure to ionizing radiation. This work was needed to refine the biological dose estimates of the Chernobyl clean up workers. No further contact with human subjects is being requested. Furthermore, all the laboratory phases of this work have been completed and only the statistical analysis remains.
Results:
Only statistical analysis remains. The study has been successful in that we have documented the decline of translocation frequencies following acute in vitro exposure to ionizing radiation in peripheral blood lymphocytes. The study will be completed as soon as the final data analyses have been performed and the papers have been published.
"Methods Development for Studies of Genetic Damage and DNA Repair Function"
Principal Investigator: Dr. Irene Jones, Lawrence Livermore National Laboratory
Project started in: 1999
This project ended in fiscal year 2003.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 117
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 04/15/02
IRB approval number: 99-117
Explanation of IRB approval:
Study was open from 10/1/02 until 4/15/03 when continuing review was not sought and study was closed.
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 2003
Type(s) of Human Subjects Involvement:
Scientific Context:
The goal of this work is to increase understanding of the factors that determine the amount of genetic damage in cells, both as a result of exposure to radiation or chemicals and as a result of normal life processes. It is believed that increased genetic damage in cells of the body is associated with increased risk of cancer. People differ in the health consequences of exposure to chemicals and radiation, but the biological reason for these differences is not known. One reason that individuals may differ in their response to exposures is that they may differ in their ability to repair damage in their cells. This project is developing sensitive tests to measure the ability of cells to remove DNA damage by DNA repair functions. To be applicable to studies of human populations, the methods use cells from peripheral blood.
Hypothesis:
The long-term goal is to test the hypothesis that the risk of cancer, or other health outcomes, following radiation exposure is increased in people with reduced DNA repair function. Underlying this hypothesis is the expectation that there is variation in DNA repair function in healthy people, that this variation is largely determined by the forms of DNA repair genes that they inherited from their parents, and that this genetic endowment defines a susceptibility that is only revealed after exposure to radiation. This project works to develop sensitive measures of DNA repair function using cells in human peripheral blood. The methods developed will ultimately be employed to study the relationship between repair function, genetic determinants of DNA repair, and risk of radiation exposure.
Experimental Design:
The tests use cells obtained from a blood sample. In the laboratory, the cells are exposed either to radiation or to chemicals that damage the genetic material. The amount of damage produced and how quickly this damage is repaired are studied. Alternatively, extracts may be made of the cells and the ability of the extracts to repair damage in a synthetic DNA studied.
Procedures:
In years 2000-2001 the goal was to recruit a small (10 to 15 member) multi-ethnic group of individuals whose age range was ~40 to 60 years, to match subjects in a case control study to be submitted to the National Institutes of Health (NIH). The majority of subjects are Biology and Biotechnology Research Program (BBRP) staff who had participated in earlier studies, whom we approached for potential participation in the DNA repair capacity studies. This group was supplemented by a few LLNL employees from other directorates known to us, or referred to us by other participants, who met the criteria outlined above. In the year (2001-2002) previously cryopreserved samples were assayed for reproducibility of results. There was no new contact with subjects.
Prior to participation in the study, each potential subject must review and sign a consent form that presents the purpose, procedures, alternatives, risks and benefits of participation. Each subject will provide one or more blood sample and is paid $10 for each sample. Each sample is given a code and only that code is used in experimental work, data analysis, and data presentation. A subject when first contacted may be asked to complete a questionnaire to obtain information needed to interpret the experimental results: their age, smoking history, diet, and exposure to radiation and chemicals. The questionnaire is given a code and only coded information is communicated to others. For evaluating the reliability and reproducibility of methods, it may be desirable to request that some donors provide samples at multiple times, as much as weekly. To avoid the implication of requesting a long-term commitment, each subject will be asked to complete the informed consent form each time he/she agrees to provide a sample. For most people this will be once or twice, but for a few others this might be as many as four times in a month. Pregnant women will not be excluded from the study, but there will be a preference to not ask for repeat samples from them.
Anticipated Results:
The next set of results will include the development of statistical methods for analysis for data from the rate of repair of single strand break and base damage assay we are developing. These analyses will define the sensitivity of the assay to detect differences between groups, such as in case control studies. In addition, reproducibility of results from cryopreserved samples will be determined. Funding permitting, the statistical analyses will be completed this summer and results submitted for publication.
Results of these studies were included as preliminary data in grants from DOE on April 16, 2002 and NIH on October 1, 2002 and perhaps in a proposal pending revision for resubmission at NIH should the external PI proceed with resubmission. The first stage of success will be funding to conduct studies of radiation exposed populations. The second stage of success will be finding an association between reduced DNA repair function and increased risk of cancer after radiation exposure.
As long as studies continue using non-anonymous blood samples for repair function assays, this protocol will be kept active. It provides the basis for method development and quality control.
"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: 07/01/03
IRB approval number: 99-121
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 2003
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. The research will be completed within the following year of this renewal application.
"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 Felton, 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: 103
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 01/10/03
IRB approval number: 00-103
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 5
Reporting period for number of human subjects:
Fiscal Year 2003
Type(s) of Human Subjects Involvement:
Scientific Context:
Red 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 will prevent PhIP from causing prostate cancer. 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 the 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 in three years.
"Prostate Cancer Screening and Dietary HA Exposure in African Americans"
Principal Investigator: Dr. Kenneth 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: 06/04/03
IRB approval number: 00-106
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 155
Reporting period for number of human subjects:
Fiscal Year 2003
Type(s) of Human Subjects Involvement:
Scientific Context:
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 HA-analyses of home-cooked meat and of urine; 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 140 cases (with abnormal PSA and/or DRE screening results) and 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 percent of participants enrolled, the study will involve a total of 1.05 x (140 + 430) = 600 participants.
Procedures:
Questionnaires and samples of home-cooked meat and 12-hour urine 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 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 begins.
"Intracranial Hematoma Detection Using Impulse Radar"
Principal Investigator: Dr. John Chang, Lawrence Livermore National Laboratory
Project started in: 2000
This project ended in fiscal year 2003.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 107
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 05/08/02
IRB approval number: 00-107
Explanation of IRB approval:
Study was open from 10/1/02 through 5/8/03 when continuing review was not sought and study was closed.
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 2003
Type(s) of Human Subjects Involvement:
Scientific Context:
In the United States alone, two million people are treated for head injuries each year. Positive identification of intracranial hemorrhage is achieved through in-hospital computed tomography (CT) scans. This scenario predisposes the injured to potentially deadly delays in delivering definitive treatment. A recently developed enabling technology suggests the potential of providing in-field diagnosis of intracranial hematoma as well as providing a novel neural scanning modality. The device is based upon the technology known as the impulse radar. The device emits electromagnetic pulses with extremely short duration and low power toward objects such as the head. The device also receives electromagnetic pulses reflected by these objects. The need to involve human subjects for this study is critical in obtaining the necessary information on efficacy, specificity, and sensitivity of this novel neural scanning device and technique.
Hypotheses:
The objective for this human subject study in a projected four-year project is to evaluate the prototype micropower impulse radar for the ability to detect the presence of large intracranial hematomas. We will be collecting data from up to 20 enrolled subjects. These data will subsequently be compared to the CT data. These data will provide design guidelines for the next generation prototypes and the experience necessary for the investigators in a controlled human subject environment.
Experimental Design:
Patients found on CT scanning to have an intracranial hematoma will undergo scanning with the hand-held micropower impulse radar detector in the Emergency Department, Operating Room, or Intensive Care Unit. A random sample of patients without intracranial hematomas will also be studied. The scanning will be done by neurosurgery residents or faculty. The scanning time will last 5-10 minutes and will be done at a time when no other diagnostic or therapeutic interventions are being done. The data from the scanning will be stored in a laptop computer for subsequent analysis. The scans will be randomly coded named by the PI for subsequent comparison with the patient’s CT scans which will be similarly coded.
Procedures:
The device will be held by one of the investigators with the signal emitting aperture touching the subject’s head. The scanning process involves simply moving the detection device over the subject’s head in a systematic fashion. The detection device will be protected with a sterile, disposable cover. The head will not need to be shaved and no other preparation of the scalp will be necessary. The head and the body will not be moved or repositioned for these measurements. The investigator(s) will record signals collected from the device onto a portable computer. The time it will take to collect one signal trace will be about 15 seconds. The investigator(s) will collect no more than 15 signal traces on the head per subject. The scanned locations on the head will be recorded in a notebook and used later for comparison with the CT scans. The emitted electromagnetic radiation has both peak and average power levels that are orders of magnitude lower than that of a hand-held cellular phone and well below the level of existing safety standards for non-ionizing radiation, and is thus believed to be of no health threat.
Any confidential data with individually identifiable records will be de-identified by John Chang or stored with the investigators under lock and key. All individually identifiable records will be destroyed by the PI at the conclusion of the project. Informed consent will be obtained from either the patient, the legal representative, or responsible family member by the University of California-Davis Medical Center (UCDMC) IRB approved care providers listed in the UCDMC IRB protocol. These care providers will verify that the individual giving consent fits one of these categories. This is required because new trauma patients requiring a head CT scan often have a decreased level of consciousness and/or are sedated or paralyzed. The use of this device and procedure under this study protocol poses a non-significant risk and is not a life threatening device. While the projected use of this device in the future will be diagnostic in nature, this study is focused on its efficacy and not its diagnostic capabilities.
Anticipated Results:
The data collected will provide information regarding the potential value of the device as an intracranial hematoma detector given CT as the standard of comparison. The data collected will further facilitate statistical evaluations of person-to-person variations, variation at different locations on the head per person, false positive and false negative indications. Success or failure will be dependent on critical evaluation of these comparisons and subsequent indication of clinical relevance. The study will be terminated according to technical relevance and funding status. The project is currently projected to continue through September 2004.
"Study to Assess the Safety of Toremifene in the Uterus of Women: Comparison with Tamoxifen"
Principal Investigator: Dr. Karen Dingley, Lawrence Livermore National Laboratory
Project started in: 2000
This project ended in fiscal year 2003.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 108
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 03/13/02
IRB approval number: 00-108
Explanation of IRB approval:
Study was open between 10/1/02 and 3/13/03 when continuing review was not sought and study was closed.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 21
Reporting period for number of human subjects:
Fiscal Year 2003
Type(s) of Human Subjects Involvement:
Scientific Context:
Tamoxifen is a drug used in the treatment of breast cancer and is currently being evaluated for its use as a chemopreventive agent in women at high risk of developing this disease. Toremifene is a closely related analogue which is undergoing clinical trials for the treatment of breast cancer. Both drugs are well-tolerated and cause relatively few well-documented side effects. However, tamoxifen causes liver tumors in rats which is associated with DNA damage. Furthermore, epidemiological evidence suggests that long-term administration of tamoxifen to women leads to an increase in the incidence of endometrial and possibly gastro-intestinal tumors. In contrast, long-term treatment of rats with toremifene does not lead to the development of liver tumors and there is very little or no detectable DNA damage. The cancer risk associated with taking tamoxifen as a chemotherapeutic agent is a public health issue.
The development of liver tumors in rats administered tamoxifen is 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. In women it is not yet clear if endometrial cancer occurs with tamoxifen as a result of a genotoxic (DNA damaging) or hormonal (estrogenic) mechanism. We are presently involved in a study designed to determine the mechanisms of tamoxifen induced endometrial cancer, the results from which will be compared to those obtained from this study. Toremifene has similar estrogenic activity to tamoxifen but it causes little or no DNA adduct formation in rat liver. By analyzing human samples for the presence of toremifene-DNA adducts this may give an indication of any potential risk of developing toremifene-induced tumors. If the mechanism of tamoxifen induced endometrial cancer is found to be genotoxic, then toremifene therapy may be a safer alternative.
Our objective is to use [14C]toremifene and the sensitive technique of accelerator mass spectrometry (AMS) to measure adducts in human tissue samples and then to compare this data with results obtained from a similarly designed study in which women were administered [14C]tamoxifen. This may give an indication of any potential risk of developing toremifene induced tumors in humans.
Hypothesis:
The hypothesis being tested is whether toremifene forms DNA adducts in the human uterus and, therefore, gives an indication of the risk of developing endometrial tumors as a result of treatment with this drug.
Experimental Design:
This study is a collaboration between LLNL, Leicester Royal Infirmary, UK, the Medical Research Council (MRC) Toxicology Unit, Leicester, UK and Orion Pharma, Finland. In this study, 10 women volunteers undergoing hysterectomy were administered a single therapeutic dose of [14C]toremifene. Blood samples and uterine tissue removed during surgery are then analyzed by accelerator mass spectrometry (AMS) and results compared to data obtained from a similar ongoing study in which patients were administered tamoxifen. Results from both these studies will also be compared to data obtained in female rats.
Human Subjects:
Human subjects at Leicester Royal Infirmary, UK were fully informed as to the nature of the study. Subjects were asked to participate and those willing to take part were provided written informed consent. Patients were asked to fill in a simple questionnaire to obtain relevant information such as age, weight, height, health status and which drugs they were taking. They were then orally administered 50 µCi [1.85 MBq] of [14C]toremifene diluted in unlabeled toremifene to provide a dose of 40 mg/person, which is the normal daily therapeutic dose. The radiation dose was 284 µSv, or 330 µSv for elderly patients, and is less than the natural background radiation to which people are exposed in daily life during the course of a year. Blood samples (20 ml) were taken pre-dose and at the time of surgery. Uterine tissue removed during surgery and not required for diagnosis or staging was separated into myometrium and endometrium. Tissue was frozen (-80°C) and transported to the MRC Toxicology Unit for further processing. DNA and protein were extracted from the tissue and blood and sent to LLNL for analysis by AMS. This is the only role of LLNL, we had no involvement with human subjects. In order to protect the confidentiality of volunteers in the study, records have been maintained at the MRC Toxicology Unit. LLNL received only coded samples for analysis.
Anticipated Results:
Results obtained will provide information on whether toremifene forms DNA adducts in the human uterus and, therefore, gives an indication of the risk of developing endometrial tumors as a result of treatment with this drug. Success will be achieved by showing that AMS sensitivity allows the measurement of DNA adducts in human tissue. The study will be terminated after all 10 patients samples are measured by AMS and the data returned to the collaborators.
"Former Beryllium Workers Medical Surveillance Program (Component of ORAU-99-87a Protocol)"
Principal Investigator: Dr. Stephen Burastero, Lawrence Livermore National Laboratory
Project started in: 2000
Funding for Human Subjects Research: No Funding Sources Reported
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 112
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 06/06/03
IRB approval number: 00-112
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 450
Reporting period for number of human subjects:
Fiscal Year 2003
Type(s) of Human Subjects Involvement:
Scientific Context:
The Beryllium Worker Medical Surveillance Program (BMSP) provides initial and follow-up screening for chronic beryllium disease (CBD) to former LLNL workers who worked with or think they may have worked with beryllium. Without the surveillance program, former workers would have difficulty gaining access to the specialized medical tests required to diagnose CBD. Two databases are being developed by this program, and both will be made available for research in the future.
Hypotheses:
At the present time, no hypotheses are being tested using these databases. The test results are DOE-owned, confidential medical records and are placed in a database that is used by the surveillance team to notify participants of results, to keep track of the participants’ progress in the surveillance process, and to contact participants about future testing. It is possible that, at some time in the future, this database may be requested by other researchers who are studying CBD and beryllium exposure. The information would not be given to these researchers unless their proposed use of the information had been reviewed and approved by an IRB. Participants may request that their identifiable information is NOT made available to future researchers without losing the benefit of being tested. The hard copy records for participants choosing this option are maintained in separate locked files clearly demarcated as NOT TO BE RELEASED FOR RESEARCH. No copies are stored in any other location. Only the information necessary to contact the individual and the date for retesting by the Beryllium Medical Surveillance Program is maintained in the identifiable database.
A second de-identified database is being developed to meet the specifications of the DOE-mandated beryllium registry (10 CFR 850, "Chronic Beryllium Disease Prevention Program."). This database is to contain information on all current and former workers who are known or suspected to have been exposed to beryllium. Information in the database includes basic facts such as year of birth, gender, employment dates, dates and types of exposure to beryllium, beryllium-related jobs, dates and results of medical tests such as the Be-LPT or other studies recommended by physicians, and causes of death. The Registry will not contain any personally identifiable information such as names, addresses, phone numbers, or SSNs. A unique identifier will be assigned to each worker’s records by the ORISE Beryllium Registry staff. The unique identifier will be used on all records sent to the Beryllium Registry. Only the ORISE physician and the Registry database administrator will be able to link the unique identifier to the worker.
Experimental Design:
This is a surveillance program. All former LLNL workers will be contacted by mail and offered the opportunity to be screened for beryllium sensitivity. As part of this effort, their personal and medical information will be entered into the two databases described above.
Procedures:
Those who wish to be screened are scheduled for an appointment on-site at LLNL (if they live within driving distance) or off-site at a clinic within driving distance of their residence. The initial examination consists of a questionnaire and a blood test to detect beryllium sensitivity (beryllium lymphocyte proliferation test, Be-LPT). Some participants may be offered a chest x-ray. There is little physical risk in drawing blood. In a few people, slight pain and bruising may take place. Rarely, an infection from the needle puncture is possible.
Referrals for CBD medical evaluations are made for any of the following reasons: beryllium sensitized (two positive Be-LPTs), chest x-ray with small opacity profusion of 1/0 or greater, or clinical symptoms consistent with CBD without other explanations.
The CBD medical evaluation may involve physical examination, blood work, chest x-ray, chest CT, pulmonary function tests, exercise tolerance tests, or bronchoscopy with lavage and/or biopsy. The plan for the medical evaluation is decided by the physician who examines the participant after reviewing the preliminary test results, medical history, and after discussing options with the participant. The extent of the evaluation is determined by the physician and the patient and there is no standard protocol. All of the CBD medical evaluations are conducted in hospitals and medical centers.
Addresses are usually obtained by matching lists of former workers against files maintained by Trans Union, a large credit agency. The agency provides last known address, but does not provide any credit information. Additional assistance will be needed from LLNL for approximately 1,200 former workers whose addresses could not be found using this methodology. For these individuals, LLNL will provide last known address to ORISE.
Privacy and confidentiality are discussed in the informed consent for the project, and specifically, how these issues apply to the data that will be contained in the two databases.
Anticipated Results:
We anticipate identifying a group of former workers who are sensitized to beryllium who need further medical evaluation for diagnosis of CBD. The program will be deemed successful if we are able to identify a group of former workers who wish to be tested and if we are able to provide testing to that group. Workers who have normal tests should be re-tested at three- to four-year intervals for an indefinite period of time. The program will continue to test and re-test participants until the participant loses interest, dies, or demonstrates a sensitivity to beryllium or until funding is terminated by DOE. The databases will be made available for future research that has been approved by the appropriate IRB.
"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: 06/19/03
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 2003
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 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: Dr. Mark Knize, 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: 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
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 40
Reporting period for number of human subjects:
Fiscal Year 2003
Type(s) of Human Subjects Involvement:
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: 09/21/03
IRB approval number: 01-101
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 50
Reporting period for number of human subjects:
Fiscal Year 2003
Type(s) of Human Subjects Involvement:
Scientific Context:
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.
Human Subjects:
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, beet and 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 other 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 potential 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. The samples will be analyzed for uranium using Inductively Coupled Plasma Mass Spectrometry analysis. Specific gravity, pH, alkalinity, gross alpha, and gross beta may also be measured periodically, to support the uranium measurements. No other constituents will be analyzed.
Procedures Involving Human Subjects:
Human subjects will provide a quarterly urine sample and a quarterly drinking water sample for this study. There will be negligible risks to subjects involved with this study. The probability and magnitude of direct physical harm or discomfort anticipated in the research are not greater in and of themselves than that ordinarily encountered in daily urination. However, there is the potential for "indirect risk" as a result of participating in this study: Although not likely, uranium in urine results higher than the typical U.S. range and/or uranium in water levels approaching the EPA limit (30 ug/L) may be discovered. This could be perceived as a risk "greater than ordinarily encountered in daily life." We expect a broad range of uranium-in-urine and uranium-in-water levels based on past background /non-occupational sample results (0 to 1.5 micrograms uranium per liter of urine, and 0 to 12 micrograms uranium per liter of water are typical ranges). Per the original protocol, results would be provided to the subject by an internal dosimetrist, upon request by the subject. The subject will be contacted if his/her urine sample implies a whole body and/or kidney uranium burden that approaches the chemical toxicity threshold, or if his/her water sample exceeds the EPA uranium in drinking water standard. If either of these conditions occur, the Internal Dosimetry Health Physicist will contact the individual to discuss any potential consequence associated with the elevated uranium results and possible follow-up actions. Note: To date, we have not observed any results that remotely approach these levels.
All data generated from this study will be held "in strict confidence" and treated as private and confidential. Data, including name and sample result, will be stored and treated in the same manner as routine occupational safety surveillance data generated by the Hazards Control Bioassay Laboratory. Only the investigator and a limited number of individuals in the LLNL internal dosimetry program with a need-to-know will have access to sample and subject data.
Anticipated Results:
Based on results from the routine occupational safety surveillance samples, we anticipate a wide variation in uranium concentration 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 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 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: 05/08/03
IRB approval number: 01-116
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 6
Reporting period for number of human subjects:
Fiscal Year 2003
Type(s) of Human Subjects Involvement:
Scientific Context:
The goal of our research is to understand the mechanical properties of dentin, and in particular, to derive this understanding from knowledge of its microstructure. This will require an understanding of dentin properties at all relevant length scales. The research requires microstructural characterization and mechanical properties measurements of human dentin tissue.
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.
Human Subjects:
This project will involve subjects who are patients that have teeth scheduled for extraction for clinical reasons at the University of California, San Francisco, clinics. Prior to extraction of teeth, the patient will be asked by the supervising dentist if they would like to participate in a research study at the UCSF School of Dentistry and Lawrence Livermore National Laboratory by donating the extracted tooth to a project to characterize dentin. Each patient who agrees to participate will be paid $15 for his or her cooperation. Each subject will sign a consent form that has been approved by the UCSF Committee on Human Research and by the Human Subjects Committee at Lawrence Livermore Laboratory. By agreeing to participate in this project, each subject is agreeing to release his or her extracted tooth to the principal investigator, to complete questionnaires concerning fluoride history, and to release the principal investigator from any liability related to procedures for collecting the teeth or any subsequent changes in their dental status. Participation in the study will take an additional ten minutes in order to complete a history form. There is no additional time required for the actual clinical procedure as a result of agreeing to be in this study. There will be no patient contact with researchers from Lawrence Livermore National Laboratory.
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.
"Multi-Modality Transurethral and Transvestical Prostate Imaging for Diagnostics, Treatment Planning and Therapy Monitoring"
Principal Investigator: Dr. Elaine Ashby, Lawrence Livermore National Laboratory
Project started in: 2001
This project ended in fiscal year 2003.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 117
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 06/05/02
Explanation of IRB approval:
Study was open between 10/1/02 and 6/5/03 when continuing review was not sought and study was closed.
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 2003
Type(s) of Human Subjects Involvement:
Background:
This project will develop a method of early detection of prostate cancer. It will collect images using a number of different techniques. Because the sensors are all on one device, the images can be overlaid for viewing. In addition to providing a low-cost diagnostic tool, this device will fill the need for visualization during biopsy and therapy.
Objectives:
Measurements on pathology specimens were made to determine properties of the tissues for use in computer modeling. The model will help us to optimize the design of the imaging system. It is necessary to use human material, as there is no adequate animal model.
Hypothesis:
The hypothesis is that use of these multiple imaging techniques will provide registered images of the prostate with higher diagnostic accuracy than any of the current prostate imaging methods.
Methodology:
As previously mentioned, we will be performing measurements of material properties of normal, benign, and malignant prostate tissue from surgical specimens. These properties are key to assuring a valid model for design purposes. The postoperative material will be available through the University of California San Francisco (UCSF), and facilities for the measurements are available at LLNL. No additional surgery or additional tissue removal will occur as a result of this research. We will be examining prostates that are removed in the normal course of treatment for prostate cancer.
Measurements were done on very small amounts of tissue to determine small-scale material properties. These properties are essential to the development of an accurate model. Most measurements will be made on post-operative pathology specimens. If there is not adequate normal tissue in the specimens, we will make some of the measurements on fresh cadaveric specimens. We plan to make measurements on tissue from a variety of age ranges and disease states (as is available), so that the equipment design can be optimized to differentiate benign from malignant states.
Involvement of Human Subjects:
The tissue measurements were made on pathology (post-operative) specimens and/or cadaver specime