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: 46
| LLNL-88-105 | "Radiation Genotoxicity from Chernobyl Accident" |
| 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-96-113 | "The Dynamics of Folate Metabolism in Adults" |
| LLNL-98-106 | "Melanoma and other Mortality Rates in LLNL Employees" |
| LLNL-98-111 | "Chromosome Aberration Persistence Study" |
| LLNL-99-109 | "Absorbed Beta-Carotene: A Retinoid Source in Humans" |
| LLNL-99-117 | "Methods Development for Studies of Genetic Damage and DNA Repair Function" |
| LLNL-99-119 | "Endoscopic Sub-Surface Optical Imaging for Cancer Detection" |
| LLNL-99-121 | "Improved Measurement of Cholinesterase Inhibition" |
| LLNL-99-131 | "PEREGRINE 3-D Monte Carlo Dose Calculations" |
| LLNL-00-101 | "Cytogenetic Analyses of Spermatozoa from Testicular Cancer Patients Exposed to Radiotherapy" |
| LLNL-00-102 | "A Model for Genetic Susceptibility: Melanoma" |
| 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-00-114 | "Smoking During Pregnancy: Chromosome Damage in Mothers and Newborns " |
| LLNL-00-116 | "PhIP Metabolites in Human Urine After Consumption of Cooked Meats " |
| LLNL-01-101 | "Background Uranium in Urine at LLNL" |
| LLNL-01-107 | "Optical Quantification of Neurotransmitters in Human Blood" |
| LLNL-01-110 | "Elucidating Dynamics of Beta-Carotene Metabolism in Adults" |
| LLNL-01-113 | "BioLuminate Probe: The Characterization of Breast Tissue Using Photonic and Electrical Impedance Measurements" |
| 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 239Pu 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" |
"Radiation Genotoxicity from Chernobyl Accident"
Principal Investigator: Dr. Irene M. Jones, Lawrence Livermore National Laboratory
Project started in: 1988
This project ended in fiscal year 2002.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 88-105
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 04/19/01
IRB approval number: 88-105
Explanation of IRB approval:
Project was closed during the reporting period -- 4/19/02.
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 2002
Type(s) of Human Subjects Involvement:
This project applies three somatic mutation assays to a human population exposed to low-dose, whole-body, ionizing radiation to define the exposure and evaluate the dosimetric assays alone and in combination. In addition, the ability of low dose radiation exposure to induce inherited changes in mini-satellite DNA sequences is studied. This study is designed to provide guidance on the use of the biodoismetric assays in future studies of radiation exposed populations.
The project will study approximately 300 Russians exposed to doses in the range of ~5-25 cGy while working on the containment and cleanup of the Chernobyl nuclear power plant accident in Chernobyl, Ukraine after April 1986, and 300 controls for somatic effects. Fifty control and 25 liquidator families will be studied for heritable effects. The somatic cell assays are 1) stable chromosome aberrations in lymphocytes detected by fluorescence in situ hybridization; 2) glycophorin A mutation in red blood cells; and 3) hypoxanthine phosphoribosyltransferase (HPRT) mutation in lymphocytes (both frequency and deletion spectrum). The results of this study should determine the utility of these biological dosimeters in the study of low-dose human radiation exposure; and the advisability of subsequent pursuit of health effects in this population.
All laboratory analyses start with cells in blood samples. The cytogenetic and HPRT studies both require that white blood cells be cultured. Cytogenetic (chromosomal) changes are studied by microscope studies using fluorescent in situ hybridization methods. For HPRT studies, cultured cells are evaluated by microscopic inspection to determine how many cells are mutated; DNA of mutated cells is studied to define any deletions of the HPRT gene. The glycophorin A assay studies red blood cells by treating them first with a preservative, then with fluorescent label for glycophorin A markers; a flow cytometer determines the number of mutated cells. The germinal mutation studies process DNA from peripheral blood so that a large number of special, highly repeated DNA sequences called mini-satellites can be detected in each person. The patterns of these sequences are compared to determine if there are any sequences in a child that are not present in a parent’s somatic cells; such an alteration is the result of a genetic change, mutation, that occurred in a parent’s germ cell that was transmitted to the child.
Blood samples were collected by the PI's Russian collaborators at St. Petersburg and Tula and Moscow. All of the contact with the subjects was provided by the Russian collaborators in conjunction with the Russian Ministry of Health, the agency charged with providing health care to these individuals. The risks to the individual from the drawing of the blood sample were bruising at the site of venipuncture and minor infection. Any adverse effects were treated by the appropriate Russian health service. The volume of blood drawn was 25-45 ml for adults, and 10 ml for children. Informed consent was obtained from both the exposed and the control individual, and spouses, by standard means, using forms and explanations in their native language. Consent on behalf of minor children was required by a parent or legal guardian. The inclusion of children was necessary for the identification of germinal mutations.
In addition, each control and cleanup-worker was asked to complete a brief questionnaire that provides information on their date of birth, current health status, medications they take, medical treatments involving radiation exposure, their current occupation, the dates they were at Chernobyl and the work assignment they had when at Chernobyl. All subject information was coded so that individual identities cannot be associated with results.
The study has been successful in meeting its aims. Final data analyses are in progress but some key conclusions can be stated. Analysis of chromosome translocations in lymphocytes by FISH was the biomarker most sensitive to past, low dose radiation exposure in the Chernobyl clean up workers studied. HPRT mutant frequency in lymphocytes also detected an effect of radiation exposure, but was less sensitive. GPA mutant frequency did not detect an effect of radiation exposure. No increase in the frequency in inherited mutations of mini-satellite sequences were detected.
"Cytogenetic Studies"
Principal Investigator: Dr. James D. Tucker, Lawrence Livermore National Laboratory
Project started in: 1988
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 11/27/01
IRB approval number: 88-111
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 2002
Type(s) of Human Subjects Involvement:
Background –For many years our 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. The present request for access to human subjects is unchanged from prior years.
Objectives –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.
Methodology – The laboratory methods vary according to the needs at the time. The consistent factor is the involvement of human subjects, which is limited to phlebotomy and occasionally the use of a questionnaire as noted in the paragraph below.
Involvement of Human Subjects – Primarily phlebotomy, and always of LLNL employees who are not under the PI's line of supervision. Pregnant women will be excluded. We will continue our practice of limiting the phlebotomies to no more than 10 venepunctures per individual per year, and no more than 250 ml per person per year. Venepunctures will continue to be performed by the LLNL Health Services Department using normal procedures. In some cases we may elect to have donors complete a questionnaire inquiring about lifestyle factors. This is the same questionnaire that we have used for our other studies, and the data may be useful for interpreting the results of our analyses. No chemical or radiation exposures will be administered to the subjects. The risks to these subjects are those associated with routine phlebotomy. All identifying material is kept in a locked file cabinet in the PI's office to maintain full confidentiality. No identifying information will be published. All subjects are required to complete a consent form.
Outcome –Continued access to the human chromosomes and DNA that we need to do our work. This year we will also have a need to evaluate RNA as part of our anticipated effort for DTRA. Because our needs for validation, calibration, and testing will continue into the foreseeable future, there are no plans to terminate this work.
Conclusion – Since this protocol does not involve an experiment in the usual sense, there is no "conclusion" per se. However, without these samples we will not be able to conduct our other work in a scientifically valid manner.
"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: 08/22/02
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 2002
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 was 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.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 03/04/02
IRB approval number: 95-126
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 2002
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 6 wks 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 Veterans Administration Medical Center (VAMC) in Little Rock, AR. 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 1% 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 6 wks 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. 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. Consequently, this study will help determine if PhIP may be a cancer risk factor at dietary levels of exposure and may help find a predictor of individual colon cancer risk. 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 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
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
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
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 2002
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.
Hypotheses:
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 MRC 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: 07/22/02
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 2002
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.
"The Dynamics of Folate Metabolism in Adults"
Principal Investigator: Dr. John S. Vogel, Lawrence Livermore National Laboratory
Project started in: 1996
This project ended in fiscal year 2002.
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: Full Board
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 07/18/01
IRB approval number: 96-113
Explanation of IRB approval:
Project terminated 7/18/02
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 2
Reporting period for number of human subjects:
Fiscal Year 2002
Type(s) of Human Subjects Involvement:
Folate compounds, including folic acid, are important nutritional chemicals found in many foods. Humans require daily intake of small amounts of folates for proper health and development. Marginal to poor intake of folate in approximately 10% of the American public is associated with chronic and developmental diseases that include neural tube defects, cancer, and homocysteinemia (an independent risk factor for coronary heart disease). A recent study related incidence of Alzheimer’s disease to a low folate intake.
The long range goal of this study is to understand the metabolism and dynamics of folate chemicals in humans in terms of known hereditary and environmental factors that might affect the incidence and progression of diseases. The relationships of nutritional intake of folate to such diseases are not fully understood, and the natural processing of folates in healthy humans is not known in detail. Detailed knowledge of normal folate metabolism might illuminate paths to disease that result from modifications of this metabolism.
Studies of these chemicals at levels that are naturally consumed by healthy humans have not been possible because no analytical technique could follow the small daily amounts in easily obtained human samples, such as urine, feces, and blood. The development of accelerator mass spectrometry (AMS) at LLNL for tracing chemicals in small biological samples allows researchers to study folates in humans at relevant intake levels. Volunteers will ingest less than a normal daily dose of folic acid that is labeled at a very low level with radiocarbon. The digestion and distribution of this single dose within their bodies will be studied over a period of 7 months using small samples of their blood, urine, and feces.
The LLNL principal investigator has no contact with the human volunteers at any time. All recruiting, testing, dosing, sampling, and subsequent interactions with the volunteers takes place at the University of California, Davis, either in the Sacramento Medical Center or at the Nutrition Department on the main campus. Volunteers fill out questionnaires about their dietary habits and spend the first full day of the protocol at the University of California Medical Center (Sacramento) during which they take the dose of traceable folate and have a number of blood samples drawn from them over 14 hours through an implanted catheter. Subsequent blood draws are made on a "walk-in" basis at the Medical Center over the next 7 months. Volunteers take stool and urine collections at home during the early phase of the experiment in provided containers. Benefits to volunteers include learning about human nutrition, in general, about their own nutritional status, in particular, and about any important health implications of findings about their samples, if warranted.
Researchers expect to determine an average fate and behavior of nutritionally relevant folate within the adult American population, along with an estimate of the variability in this usual behavior. They expect to determine differences from these data in data obtained from a population that possesses a well known inherited modification of folate metabolism. All data, and any conclusions, will be reported in the open literature, will be provided to the research sponsor (National Institute of Digestive, Diabetic, and Kidney Diseases: grant number R01-DK-45939), and will be useful in establishing optimal guidelines for nutritional or supplemental ingestion of folate.
The results of this study may be published, but the identify of participants will not be released. The confidentiality of all research records will be maintained to the fullest extent possible, and may not be disclosed without the subject's written permission. However, the FDA and/or funding agencies or sponsors may inspect the research records. A signed consent form will be obtained from subjects prior to their participation in the research and in a manner compliant with federal regulations.
"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: 04/05/02
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 2002
Type(s) of Human Subjects Involvement:
Scientific Context:
The melanoma phase of the study is to search in the National Death Index for melanoma deaths among employees of the Lawrence Livermore National Laboratory who worked at least 6 months during the period July 1. 1984 to Dec 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 Jan 1 1984 but otherwise as above. Both studies can only be done in 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 population.
Experimental Design:
The design of both phases is that of a classical mortality study using US (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 US, 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 D. Tucker, Lawrence Livermore National Laboratory
Project started in: 1998
This project ended in fiscal year 2002.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 04/16/02
IRB approval number: 98-111
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 2002
Type(s) of Human Subjects Involvement:
Scientific Context:
This effort was a 1-year Supplement to our Chernobyl Program Project designed to quantify the persistence of chromosome translocations 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. Our purpose for performing this work is to improve the dosimetry for the Chernobyl clean-up workers by assessing the magnitude of the loss of translocations 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 data analyses remain.
Hypotheses:
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 analyses remain.
Human Subjects:
N/A. There will be no more contact with the human subjects under this protocol.
Anticipated Results:
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. I expect to complete these tasks in the coming year.
"Absorbed Beta-Carotene: A Retinoid Source in Humans"
Principal Investigator: Dr. John Vogel, Lawrence Livermore National Laboratory
Project started in: 1999
This project ended in fiscal year 2002.
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: Full Board
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 07/18/01
IRB approval number: 99-109
Explanation of IRB approval:
Project was terminated 6/6/02
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 2002
Type(s) of Human Subjects Involvement:
Localized tissue deficiencies in vitamin A are correlated with cancer development. The local generation of vitamin A, independent of alimentary absorption, may explain the apparent ability of the nutrient beta-carotene to reduce risks of cancer in these tissues. This ability to convert beta-carotene to vitamin A was recently shown to vary from person to person. A person who depends on primary absorption or digestive production of vitamin A from beta-carotene requires a different diet and supplements to reduce cancer risks than a person whose body responds to localized vitamin deficiencies by making the vitamin in situ.
The level of vitamin A production from circulating beta-carotene, and its variability among people, is not known for humans. Under this protocol, researchers hope to determine the rate and form of conversion of circulating beta-carotene to retinoids and quantify its excretion. They will determine the chemical form of the hydrophobic retinoids and the modes of their distribution.
Since any beta-carotene that is eaten passes through the intestine and liver to produce retinoids like vitamin A, the retinoids derived directly from circulating beta-carotene cannot be distinguished through experiments involving ingested beta-carotene. Therefore, researchers will inject the beta-carotene directly into the blood stream after mixing a small amount of [14C]-beta-carotene directly with blood withdrawn from the volunteer. Serial blood samples are drawn over a 60-day period after dosing. Urine and fecal collections are taken for the first 18 days after dosing to find the elimination route of the injected beta-carotene. The quantity of the isotope-labeled vitamin and pro-vitamin in retrieved plasma is quantified by AMS.
Because the administered beta-carotene is radiolabeled, the subject will be exposed to a very small amount of radiation (total effective dose equivalent * 0.5 mrem). By comparison, the total effective dose (TED) equivalent of a chest radiograph, lateral view is 8 mrem and the TED of a coast to coast airline flight is 3 mrem. Blood draws could cause momentary discomfort and/or bruising. A licensed phlebotomist, registered nurse, or physician will be responsible for the blood draws to minimize these risks.
The researchers anticipate highly quantitative conclusions about the value of beta-carotene circulating on lipoproteins as a source of vitamin A in humans. Success is defined as quantitating any such conversion of carotene to vitamin A. They have already succeeded under that criteria. The study will be done when they have enough data from several volunteers to determine the variability of this process in the general population.
The results of this study may be published, but the identify of participants will not be released. The confidentiality of all research records will be maintained to the fullest extent possible, and may not be disclosed without the subject's written permission. However, the FDA and/or funding agencies or sponsors may inspect the research records. A signed consent form will be obtained from subjects prior to their participation in the research and in a manner compliant with federal regulations.
"Methods Development for Studies of Genetic Damage and DNA Repair Function"
Principal Investigator: Dr. Irene Jones, 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: 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
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 2002
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.
Hypotheses:
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:
Last year (2000-2001) the goal was to recruit a small (10-15) 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 NIH. The majority of subjects are 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 (Jones and Thomas), or referred to us by other participants, who met the criteria outlined above. In the current 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, procedure, 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 by Fall 2002.
Results of these studies will included as preliminary data for grants to DOE April 16, 2002 and NIH 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.
"Endoscopic Sub-Surface Optical Imaging for Cancer Detection"
Principal Investigator: Dr. Stavros Demos, Lawrence Livermore National Laboratory
Project started in: 1999
This project ended in fiscal year 2002.
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: 08/13/01
IRB approval number: 99-119
Explanation of IRB approval:
Study was closed during the reporting period - 8/13/02.
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 2002
Type(s) of Human Subjects Involvement:
There would be tremendous advantages for the development of imaging techniques that could provide sensitive and accurate real time histo-pathologic diagnosis to guide therapy. If, for example, a physician could examine patient tissues with an optical device that could provide the same information as a tissue biopsy, then a biopsy may not need to be performed. Extending the application to a fibro-optic scope device such as a cystoscope to examine the bladder or colonoscope, any tissue sampling will be more directed and precise with the elimination of unnecessary biopsies. Currently, many benign tissue samples are submitted from these and other locations resulting in an enormous cost to the health care system and anxiety and uncertainty for patients. An in-vivo sensitive and accurate imaging system that can provide histo-pathologic information would be an enormous advancement in clinical medicine both for diagnosis and monitoring of on-going therapy. In the field of surgery and interventional radiology, such imaging systems could assist with more accurate and complete removal of cancerous tissue by determining whether extra tissue margins are necessary. Many internal benign lesions would no longer require surgical removal to confirm their benign nature.
The goal of this research effort is to develop an endoscopic subsurface optical imaging system that has the capability to image different tissue components located underneath the surface. The images obtained using this subsurface technique delineate the differences in depolarized backscattering light between normal and cancer tissues arising from differences in the cellular level. These differences include size and concentration of cells and light scattering centers within and between cells, and their absorption properties. In addition, tissue autofluorescence is explored as a secondary method for the detection of superficial cancer lesions. This second method aims in probing differences in the biochemical constituents of cancer tissues as a result of its different metabolism.
In this research effort, the PI is testing the optical imaging modality's ability to address a number of clinical situations associated with bladder, colon, prostate and kidney cancers. They first need to know if in a variety of tumors the system is able to: 1) identify the depth of penetration of the tumor (this would be especially applicable in bladder and colon cancers); 2) identify if the tumor was unifocal or multifocal (renal cancer would be such a situation since it may be either unifocal or multifocal); 3) whether it would act as an aid in identifying cancer from non-cancer tissue in order to aid research.
The research approach is the following: 1) Utilize a prototype imaging system to establish methodology and explore limits of detection using isolated animal (obtained from the local market) and human tissues; 2) Conduct studies in human tissues to establish methodology for its use in vivo and to demonstrate its applicability in the analysis of different types of lesions; 3) Design and build endoscopic subsurface imaging systems that can reach different parts of the human body; 4) Conduct pilot studies to explore its applicability in clinical research and clinical diagnostics; 5) Investigate the possibility of combining this technique with other optical imaging approaches which can serve as a verification method once a "suspicious" lesion is detected.
Human tissue samples obtained from the surgeon immediately after the operation will be used in this investigation. There are no risks for the patient from this study.
The outcome of this work is to provide the basic understanding as well as a proof of principle that will allow the researchers to move to a Phase II where the investigation will be performed in vivo. In the long term, the endoscopic imaging technology to be developed will utilize inexpensive technology and will be easy to operate once the imaging methodology is established. As a result, this technology may become an easily accessible screening and diagnostic tool to the medical community due to the anticipated low cost of acquisition and operation and the limited expertise and training required. This imaging technology may find application in the early detection/screening of cancer, in providing minimally invasive monitoring of the tumor’s response to various stages of treatments and in assisting during surgery by providing information on the depth of penetration of the tumor.
The results of this study may be published, but the identity of participants will not be released. The confidentiality of all research records will be maintained to the fullest extent possible, and may not be disclosed without the subject's written permission. However, the FDA and/or funding agencies or sponsors may inspect the research records. A signed consent form will be obtained from subjects prior to their participation in the research and in a manner compliant with federal regulations.
"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: 07/01/02
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 2002
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% 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% 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% so that it can be confidently applied to blood samples from different individuals where normal ChE levels can vary by as much as 30%. 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
"PEREGRINE 3-D Monte Carlo Dose Calculations"
Principal Investigator: Dr. Marie-Anne Descalle, Lawrence Livermore National Laboratory
Project started in: 1999
This project ended in fiscal year 2002.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 131
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 09/24/01
Explanation of IRB approval:
Study was terminated 8/15/02
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 15
Reporting period for number of human subjects:
Fiscal Year 2002
Type(s) of Human Subjects Involvement:
Background – External beam radiation therapy is one of the standard modalities in cancer treatment. It is non-invasive and takes advantage of the susceptibility of cancer tissue to ionizing radiation to destroy the tumor while leaving normal tissues intact. The success of radiation therapy depends on diagnosis and tumor localization, treatment planning, and dose delivery. Treatment planning is the determination of optimal treatment parameters for the management of a patient's disease with radiotherapy. Because it is not feasible to directly measure radiation dose in a patient, the dose distribution resulting from treatment planning usually serves as the best estimate of the dose delivered to the patient. Today, even the most sophisticated three-dimensional radiation treatment planning systems use a variety of simplifications for actual dose calculations. The PEREGRINE dose calculation system, developed at LLNL, provides highly accurate dose calculations, based on a 3D computer simulation of radiation transport in both the beam delivery system and the patient. Because PEREGRINE calculations are substantially more accurate than conventional dose calculations, it is believed that their implementation in the clinic will result in improvements in the safety and effectiveness of radiation therapy.
Objectives – The primary objective of this study is to evaluate the clinical utility of the PEREGRINE dose calculation system in radiation oncology treatment planning. Secondary objectives from the National Institutes of Health (NIH) point of view are to provide NIH trainees with experience in advanced dose calculation methodology, establish the Radiation Consultation Workstation (a data/video link between NIH and LLNL) as a feasible interactive facility for complex, online treatment planning, implement a technology transfer collaboration with LLNL, and establish an NIH presence at the forefront of radiotherapy treatment planning. Additional secondary objectives from the LLNL point of view are to develop an ongoing relationship with the NIH/National Cancer Institute with the goal of drawing on their substantial research and clinical expertise in the area of radiation therapy.
Methodology – Patients will be screened in the NIH Radiation Oncology Branch (ROB) Clinic. Patient suitability for treatment will be evaluated in light of the existing and anticipated research needs of the ROB. Treatment planning for each individual will follow the schema normally used in the development of a three dimensional conformal radiotherapy treatment plan. The plan actually used for the implementation of the patient's treatment will be generated by the NIH treatment planning system. After the patient has been treated, the treatment parameters used on the patients will serve as input to the PEREGRINE dose calculation system. PEREGRINE will not be used to develop a radiation treatment plan. It is used only to provide accurate dose calculations based on the beam and patient parameters established in the NIH treatment plan. Differences between the NIH- and PEREGRINE-generated dose distributions will be assessed by three experienced radiation oncologists for clinical acceptability. Three radiation oncologists will score each NIH treatment plan based on the more-accurate PEREGRINE dose calculation. A score of YES means that the NIH plan would have benefited from further optimization, and is less acceptable for patient treatment, based on PEREGRINE findings. A score of NO means that the Treatment Planning System (TPS) plan is still considered acceptable and needs no additional optimization.
Involvement of Human Subjects – Subjects are not recruited at LLNL site. The medical risks from this study are those normally expected risks associated with CT scans and standard radiotherapy. Each patient will be treated using the best standard therapy for his or her disease. Experimental treatments will not be applied to patients on this protocol. All patients who meet the inclusion criteria are eligible for this protocol. A patient's rights representative is available to patients on this protocol. Patients may ask any questions about the study, and may withdraw their consent at any time without compromising their ability to receive protocol related medical care from the NIH. LLNL’s role in this study is to provide 3D Monte Carlo dose calculation of dose delivered to each subject. In support of this, a patient’s treatment plan may be provided to LLNL. In discussions with NCI staff on results of calculations, complications or tumor recurrence may also be discussed for individual patients. However, patient identification is protected from LLNL researchers providing PEREGRINE calculations. This is accomplished through a patient coding scheme, in which each patient case is assigned a number, and his/her identity is never shared with LLNL personnel. No research results will be returned to the patient.
Outcome – By comparing dose distributions calculated by the NIH treatment planning system with more accurate dose calculations provided by the PEREGRINE system, we will be able to better establish the role and importance of accurate, 3D Monte Carlo calculations in radiation therapy.
"Cytogenetic Analyses of Spermatozoa from Testicular Cancer Patients Exposed to Radiotherapy"
Principal Investigator: Dr. Andrew Wyrobek, Lawrence Livermore National Laboratory
Project started in: 2000
This project ended in fiscal year 2002.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 11/15/01
IRB approval number: 00-101
Explanation of IRB approval:
Protocol was terminated during the reporting period.
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 2002
Type(s) of Human Subjects Involvement:
Some environmental agents have been shown to cause mutations in somatic cells, but for many agents, as well as ionizing radiation, little information is available on the effects on human gametes and thus on the genetic risk to future generations. Fluorescence In Situ Hybridization (FISH) represents a valuable methodology to detect chromosomal abnormalities in germ cells which are known to be major contributors to infertility, pregnancy loss, mental retardation, infant death and behavioral abnormalities.
The goal of this research is to investigate the effects of ionizing radiation on semen quality and genetic damage in sperm of Stage I Seminoma patients (testicular cancer) who are treated with radiotherapy. The research questions include: (1) What are the effects of radiotherapy on genetic quality of human male germ cells? (2) Do the effects persist with time after the end of treatment?
Stage I Seminoma patients are invited to participate in our study by providing semen samples before, during and after radiotherapy treatment. All samples are coded to protect the confidentiality of the patients. Fresh and frozen samples are used as dictated by the requirements of the specific laboratory methods. There is no known risk to the semen donors. The samples are collected and conventional semen parameters are analyzed. A small proportion of human semen is smeared onto glass slides and is analyzed for sperm aneuploidy and structural aberrations by Fluorescence In Situ hybridization (FISH) using specific-DNA probes.
This study will evaluate and characterize effects of exposure to ionizing radiation on the production of various categories of chromosomally abnormal sperm.
Several newly developed sperm FISH methods provide an efficient approach to study structural and numerical chromosomal abnormalities produced by environmental mutagenic and cytotoxic agents and thus to evaluate the potential genetic risk to future generations.
"A Model for Genetic Susceptibility: Melanoma"
Principal Investigator: Dr. Harvey Mohrenweiser, 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: 102
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 01/24/02
IRB approval number: 00-102
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 2002
Type(s) of Human Subjects Involvement:
Scientific Context:
Melanoma is a paradigm for gene-environment interactions in the development of cancer. Sun exposure, the major environmental risk factor, although responsible for 65-90 percent of melanoma, has a small relative risk for the development of melanoma when genetic factors are measured: phenotype (skin color, hair color, eye color), nevus number, and possibly DNA repair. No other cancer has both such a well-identified genetic component and a well-substantiated environmental factor. We hypothesize that there are wide variations among individuals in terms of susceptibility to melanoma. This variation is probably influenced in a heterogeneous manner by multiple susceptibility genes, and sun exposure, the major known exogenous factor, may exert its influence interacting with these genes.
Hypotheses:
The objective of this large, international population-based case control study is determination of the relative risk for developing melanoma due to polymorphisms in the nucleotide excision repair genes, the pathway for repair of DNA damage induced by sunlight. The LLNL component of the proposal will be the resequencing of DNA repair genes to identify common genetic variation in a population of individuals with melanoma.
Experimental Design:
To identify the common (polymorphic) varaints, we will resequence 18 genes in 50 individuals with multiple primary melanomas.
Procedures:
The DNA samples being screened for DNA sequence variation were randomly selected by Dr. Marianne Berwick from the repository of more than 400 samples obtained from patients with multiple primary melanomas being collected for this study at Memorial Sloan Kettering Cancer Institute. The 50 DNA samples sent to LLNL for the resequencing were randomly assigned numbers 1-50 and thus the specific donors will be anonymous.
Anticipated Results:
The results from the LLNL effort will only identify variants and will not address questions related to functional relevance. The results of the complete study will provide quantitative data on the contribution of variation in a specific group of DNA repair genes in melanoma risk, data that will form the basis for credible public health recommendations regarding solar exposure and screening.
"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: 01/10/02
IRB approval number: 00-103
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 3
Reporting period for number of human subjects:
Fiscal Year 2002
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 2 parts: a metabolism stability study that will profile the same three individuals every 3 months for two years (a total of 8-10 measurements), and a preventive intervention study that will measure the effects of 3 different dietary modifications in five individuals (each individual will be asked to eat chicken and collect urine up to 6 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 7 (but no more than 9) times during the first 2 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 7 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: 06/04/02
IRB approval number: 00-106
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 29
Reporting period for number of human subjects:
Fiscal Year 2002
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 5-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% 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 5 years after it begins.
"Intracranial Hematoma Detection Using Impulse Radar"
Principal Investigator: Dr. John Chang, 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: 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
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 2002
Type(s) of Human Subjects Involvement:
Scientific Context:
In the United States alone, 2 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 John Chang 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.
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 John Chang at the conclusion of the project.
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.
Informed consent will be obtained from either the patient, the legal representative, or responsible family member by UCDMC IRB approved care providers listed in the UCDMC IRB protocol. These care providers will verify that the individual giving consent fit’s one of these categories. This is because new trauma patients requiring a head CT scan often have a decreased level of consciousness and/or are sedated and paralyzed. The use of this device and procedure under this study protocol poses a non-significant risk and is not a life safety device. While the projected use of this device in the future will be diagnostic in nature, this study is focused on the efficacy and not diagnostic.
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
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
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
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 7
Reporting period for number of human subjects:
Fiscal Year 2002
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 s