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: 40
"Radiation Genotoxicity from Chernobyl Accident"
Principal Investigator: Dr. Irene M. Jones, Lawrence Livermore National Laboratory
Project started in: 1988
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: Full Board
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 05/19/00
IRB approval number: 88-105
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 2000 (10/1/99-9/30/2000)
Type(s) of Human Subjects Involvement:
In the event of accidental exposure to radiation, methods are needed to determine the dose an individual has received, so that they can receive appropriate care and follow-up. Use of biological assays to assess low doses of radiation exposure, biodosimetry, is especially challenging. A number of assays have been developed that might be useful for this purpose. In this study, three biodosimetric assays are compared for their ability to detect and assess the magnitude of radiation exposure in individuals assigned to work after April 1986 on the containment and cleanup of the nuclear power plant accident in Chernobyl, Ukraine. Each person’s work was planned to limit their exposure to 25 cGy, a relatively low dose.
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. 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 are collected by our Russian collaborators at St. Petersburg and Tula. All of the contact with the subjects is provided by our 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 are bruising at the site of venipuncture and minor infection. Any adverse effects will be treated by the appropriate Russian health service. The volume of blood drawn is 25-45 ml for adults, and 10 ml for children. Informed consent is 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 is required by a parent or legal guardian. The inclusion of children is necessary for the identification of germinal mutations.
In addition, each control and cleanup-worker completes 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 is coded so that individual identities cannot be associated with results.
"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: 11/02/99
IRB approval number: 88-111
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 2000 (10/1/99-9/30/2000)
Type(s) of Human Subjects Involvement:
Subject involvement in this study will be to provide peripheral blood for cytogenetic and DNA analyses, which will include calibration, validation, and quality control for laboratory purposes. In addition, metaphase chromosomes will be utilized for mapping or verifying DNA probes, and developing or evaluating potential new methods.
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.
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.
No chemical or radiation exposures will be administered to the subjects.
During FY00 we obtained blood from 3 subjects. This year we are requesting permission for 15 subjects. This is the same number we requested last year, and hopefully is more than we will need. 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.
"Protective Breathing Equipment (Respirators) Testing"
Principal Investigator: Dr. Art Biermann, Lawrence Livermore National Laboratory
Project started in: 1989
This project ended in fiscal year 2000.
Funding for Human Subjects Research: No Funding Sources Reported
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: 04/20/99
IRB approval number: 89-106
Explanation of IRB approval:
Protocol was closed at its expiration date.
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 2000 (10/1/99-9/30/2000)
Type(s) of Human Subjects Involvement:
The performance of respirators will be evaluated under simulated workplace conditions. The ability of the respirator to prevent leakage of outside contaminants into the breathing air will be determined by placing human subjects in a test chamber and measuring aerosol penetration into the respirator. All subjects will be LLNL employee volunteers and qualified according to the physical qualifications of subjects listed later in this section. Volunteers will be solicited primarily from the LLNL Hazards Control (HC) Special Projects Division, the LLNL HC Fire Department, and LLNL Protective Services.
The ability of the respirator to prevent leakage of outside contaminants into the breathing air will be measured by placing the subject in a test chamber. The subject will perform certain exercise protocols designed to simulate the use of respirators in the workplace. To evaluate the performance of the respirator, an atmosphere of air with one or more of the challenge agents listed in the table below will be used in the testing. The threshold limit value (TLV) concentrations, excursion levels, and maximum challenge concentrations are provided in the table. Concentrations of the challenge agents in the chamber are limited to the maximum challenge concentration listed.
Challenge agent--Threshold Limit Value(a)--80% of Max Excursion Level(b)--Max Challenge Conc(c)
Polyethylene glycol--5 mg/m3--20 mg/m3--80 mg/m3
Calcium carbonate--10 mg/m3--40 mg/m3--40 mg/m3
Aluminum oxide--10 mg/m3--40 mg/m3--40 mg/m3
Freon-12--1000 ppm--4000 ppm--4000 ppm
Polystyrene--3 mg/m3--12 mg/m3--12 mg/m3
(a) Threshold Limit Value (TLV), or that permitted for an 8-hr workday (American Conference of Government Industrial Hygiene). The TLV for polyethylene glycol and polystyrene are the TLVs for a nuisance oil mist and for particulates not otherwise classified, respectively.
(b) The established MEL is five times the TLV. Levels listed are 80% of the MEL.
(c) Maximum challenge concentration (in the chamber)
The subject may be in the test chamber for up to 45 minutes while they perform the various exercise protocols. Total exposure (in the respirator) to the challenge agent will be less than that permitted for an 8-hr workday under existing workplace exposure guidelines. The testing of a subject shall be terminated if the concentration within the face piece exceeds the 80% of maximum excursion level (MEL) in the table. Depending upon the challenge agent and detection device, two minutes may lapse before the excursion concentration is detected. Therefore, 80% of the MEL is listed for the excursion levels in the table below. Because of the detection capabilities of instrumentation, challenge concentrations of polyethylene glycol of up to 80 mg/m3 may be used to adequately assess respirators that are expected to offer protection factors of greater than 1000. Subjects shall be instructed not to remove their respirators while in the test chamber so as not to be exposed to concentrations at or above the MEL.
Test data and photographs and/or videos of subjects will be encoded to protect the confidentiality of the subject.
All subjects will be LLNL employee volunteers and certified respirator users. Subjects will required to complete and sign the respirator testing preliminary screening questionnaire and only those qualified by the clinical judgment of the reviewing MD will be allowed to participate in the study.
"LLNL Human Genome Center"
Principal Investigator: Dr. Anthony V. Carrano, Lawrence Livermore National Laboratory
Project started in: 1990
This project ended in fiscal year 2000.
Funding for Human Subjects Research: No Funding Sources Reported
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: 01/20/99
IRB approval number: 90-105
Explanation of IRB approval:
Project is 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:
Year prior to last IRB approval date
Type(s) of Human Subjects Involvement:
As part of the research carried out by members of the Human Genome Center, we occasionally need metaphase preparations of human chromosomes to localize probes (small segments of DNA) back on the chromosomes. Our current need for these chromosomes preparations is quite small, so we are obtaining samples only 1 - 3 times per year.
To generate the metaphase chromosomes preparations, a small aliquot of human peripheral blood is obtained from a donor, drawn by a qualified phlebotomist at the LLNL Health Services facility. White blood cells contained therein are cultured for 2-3 days. Chromosomes are harvested from the white blood cells and placed on microscope slides for the analyses. No long term cultured cells are preserved, nor is any personal data collected from the individual providing the blood sample. The donors are not exposed to any hazardous materials as part of this protocol. A human consent form is signed prior to sample collection.
There is minimal risk or discomfort to the individual donating the blood sample, but may including temporary pain, bruising, localized infection, and/or fainting. This activity does not involve medical treatment.
We have used this technique to continue to refine the physical map of human chromosome 19, and to identify the chromosomal location of some of the DNA repair genes that will be sequenced by other Genome Center staff. Additional details showing mapping results are viewable at http://www-bio.llnl.gov/genome/html/chrom_map.html.
"Glycophorin A-based Somatic Cell Mutation Measurements in Blood Samples from Normal Individuals"
Principal Investigator: Dr. Richard G. Langlois, Lawrence Livermore National Laboratory
Project started in: 1991
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: 03/09/00
IRB approval number: 91-102
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 2000 (10/1/99-9/30/2000)
Type(s) of Human Subjects Involvement:
The GPA human mutation assay was developed at LLNL, and this assay is now being extensively used for studies of genetic damage in human populations with exposure to potentially mutagenic agents and populations that are potentially unusually susceptible to mutational damage. Blood samples from normal donors are required for both quality control, and for defining the distribution of GPA variant frequencies in unexposed individuals for comparison with individuals with potential mutagen exposure.
Blood samples (5-30 ml) from volunteers at LLNL will be obtained by standard venipuncture done by members of the LLNL Medical Department. No more than four blood donations will be requested from each volunteer per year. All samples will first be M,N typed to identify which samples are of blood type MN, as the assay can only be performed on samples of this blood type. Blood samples will be fixed, labeled with monoclonal antibodies and propidium iodide, and analyzed by flow cytometry. The flow cytometer data will be used to calculate the frequency of variant phenotype erythrocytes in each sample.
Blood samples will be obtained from normal donors in the LLNL employee population for use in the glycophorin A (GPA) assay for somatic cell mutations in humans. Samples from normal donors will be used for instrument calibration, quality control tests on assay performance, and as test samples for modifications of the GPA assay method. Assay data from normal donors will also be combined with data from other normal donors to provide information on the distribution of variant cell frequencies in unexposed individuals.
Each donor will be assigned a code number by the principal investigator, Dr. Richard G. Langlois. Subject names will be known only to him and appropriate laboratory personnel. Data obtained from individual subjects will be referred to only by the code number so that the identity of donors will be protected.
Blood samples are obtained by standard venipuncture procedures, and it is expected that the subject will be able to function normally immediately. Possible risks and discomforts that may result from the procedure are considered unlikely but include:
a. Temporary pain
b. Bruising and/or soreness of the affected tissue or surrounding tissue
c. Formation of scar tissue
d. Infection
e. Fainting
"The Effects of Ergonomically Designed Computer Keyboards on the Incidence of Cumulative Trauma Disorders among VDT Workers"
Principal Investigator: Dr. Pat Tittiranonda, Lawrence Livermore National Laboratory
Project started in: 1992
This project ended in fiscal year 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: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 07/29/99
IRB approval number: 92-105
Explanation of IRB approval:
Protocol was closed on 7/11/00
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 2000 (10/1/99-9/30/2000)
Type(s) of Human Subjects Involvement:
This protocol has been used to study the effects of computer input devices on comfort, posture, productivity and muscle activity. Our study population has been computer users who volunteered to use a variety of input devices both in laboratory settings and in their own workplace. Over the years, our study has expanded to include clinical and biomechanical evaluations of not only computer keyboards, but also other input devices such as mice, trackballs, joysticks, touchpads, etc. Clinical evaluations requires the use of standardized criteria to diagnose ergonomic-related injuries and subjective ratings of discomfort, while biomechanical evaluations require the use of bi- and triaxial goniometers to measure joint positions and motion, 3 dimensional motion and video analysis systems to measure joint dynamic motion, velocity and acceleration, video analysis to measure workstyles and habits, and surface electromyography to measure muscle activity and fatigue.
Intensive computer users are asked to participate in a joint movement analysis during operation of various input device prototypes. Their wrist, hand and arm and upper extremity movement and muscle activities are measured during use of a variety of input devices. This activity does not involve medical treatment and involves no health effects as these measures and procedures are commonly used by physical therapists for recommendations in maintaining appropriate working postures. Subjects are also asked to use these products in their own work environment for 4-6 weeks.
There are no risks and discomforts associated with the laboratory experiments and field trials are considered unlikely as these alternative products have undergone a series of ergonomic reviews by numerous researchers.
Any publication arising from this study will be made without specific reference to participant's name. The researchers will encode the joint motion and muscle activity results to protect subject's identity and will not disclose his/her name to the individuals performing the research, or to anyone else.
"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.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 09/13/00
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:
Year prior to last IRB approval date
Type(s) of Human Subjects Involvement:
The specific aim of this study 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 consist 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.
The laboratory research conducted at LLNL includes (a) determination of the parent of origin of the extra X chromosome, (b) determination of the level of sperm aneuploidy in the father of affected children.
A total of 38 families with a Klinefelter syndrome(XXY) child have been recruited. The blood samples from father, mother and child plus father’s semen were collected and shipped to LLNL. We have 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 aneuplody 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 received cancer chemotherapy. During past year, we obtained tissue blocks from the aneuploid pregnancies that died before birth (trisomy 15 and 22) so that we can determine whether the extra chromosomes arose 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 will be the same as for those in the main study.
We proposed to recruit up to five families with multiple aneuploid pregnancies, obtaining the tissue blocks of aborted fetuses, blood samples from parents, and semen samples from father.
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. Families were compensated $150.00 for their time and participation upon completion of this study ($100 after providing the blood and semen samples and $50 for participating in the 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 are conveyed by the study's genetic counselor. The study physician will also be available to answer genetics and medical questions. 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.
"Influence of Heterocyclic Amine Metabolic Polymorphisms on Bioactivation of PhIP in the Human Colon"
Principal Investigator: Dr. Kenneth W. Turteltaub, 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: 11/16/99
IRB approval number: 95-126
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 2000 (10/1/99-9/30/2000)
Type(s) of Human Subjects Involvement:
It has been estimated that there will be 94,700 new cases of colon cancer in the United States in 1999. 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.
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: 1) To 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) To determine if interindividual variation in the breakdown 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.
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 breakdown PhIP. Approximately 6 - 8 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 breakdown. These results will be used to determine if adduct levels and PhIP breakdown are related to an individual's metabolic capacity.
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, since it is roughly equivalent to the exposure resulting from the consumption of 0.175-2.3 kg of chicken, beef or bacon, depending upon the cooking time and temperature. Furthermore, the exposure will not be a radiological risk, as it 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 - 8 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.
"Does Tamoxifen cause DNA Damage in Human Tissues"
Principal Investigator: Dr. Kenneth W. Turteltaub, 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: 07/19/00
IRB approval number: 96-103
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 4
Reporting period for number of human subjects:
Fiscal Year 2000 (10/1/99-9/30/2000)
Type(s) of Human Subjects Involvement:
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. 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. Our objective is to use [14C]tamoxifen 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 tamoxifen induced tumors in humans.
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.
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.
"Chernobyl Dosimetry"
Principal Investigator: Dr. Joe N. Lucas, Lawrence Livermore National Laboratory
Project started in: 1996
This project ended in fiscal year 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: 04/19/00
IRB approval number: 96-106
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 2000 (10/1/99-9/30/2000)
Type(s) of Human Subjects Involvement:
The purpose of this research was to validate the human lens micronucleus (MN) assay using derived radiation doses received by Chernobyl liquidators, that is, provide biological dose estimates to evaluate the relative magnitude of response of the results of the MN assay. Cytogenetics (both stable and unstable chromosome aberrations) has long been considered to be the most precise endpoint for quantifying radiation damage in people. We have demonstrated both the stability and accuracy of translocations as a predictor of genetic damage by radiation. Using the stable aberration data as the reference standard for the MN assay is viewed as an important part of evaluating the ability of the MN assay to quantify and characterize radiation-induced damage.
This study was undertaken to apply our expertise in chromosome painting and dose reconstruction to validate the MN assay for liquidators and populations exposed to Chernobyl radiation in the Ukraine. The objective was to develop a faster, cheaper and simpler biodosimeter, to estimate dose to Chernobyl victims.
The strategy that we proposed was is to evaluate a representative subset of the total number of individuals evaluated for MN assay (about 20 liquatators and 10 controls). We will score a sufficient number of cells to obtain unequivocal results (relative error of about 20%). The effort (funds) of this project is the limiting factor to the number of individuals that can be evaluated. This means scoring enough translocations per individual as to distinguish that particular individual from controls, provided that individual's translocation frequency is elevated compared to a control group. Scoring such a large number of translocations per individual is a major distinction of this proposal. It will allow us to determine for each individual (within confidence limits), whether that particular person’s translocation frequency is elevated compared to a control group (unirradiated age-matched Ukrainians).
My collaborator at Columbia University, Dr. Worgul, received cataract tissue samples from patients in the Ukraine. These patients were liquidators exposed to Chernobyl radiation, and were being seen for routine cataract surgery. Dr. Worgul arranged to have blood samples that were drawn during routine pro-op procedures cultured and fixed on slides prior to having them sent to LLNL. All samples were stripped of personal identifiers prior to being sent from the Ukraine. LLNL was not able to identify any individual, and will not report information back to the Ukraine directly. All sample collection and processing of samples are complete. Only data analysis remains to be done. The projected completion date is 9/1/00.
"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.
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 08/07/00
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 2000 (10/1/99-9/30/2000)
Type(s) of Human Subjects Involvement:
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.
This study uses biomarkers of physiological and genetic damage in human sperm, many of which have been developed at LLNL. The specific aims 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 sperm aneuploidy and semen quality ; and (2) examine whether certain diets are associated with higher rates of aneuploidy.
For all laboratory analyses, laboratory technicians were blinded to the identity and the age of the man. 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.
Study populations were comprised of healthy male volunteers employed or retired from the Lawrence Livermore National Laboratory (LLNL) having no known problems with fertility or subfertility. We recruited a total of 97 non-smoking men. These subjects were between 20 to 80+ years of age. Recruiting steps included: screening for eligibility; obtaining a self-administered questionnaire about dietary habits; obtaining a self-administered questionnaire about medical history and sociodemographic characteristics; obtaining consent for their dosimetry record; and collecting one or two semen specimens.
"The Dynamics of Folate Metabloism in Adults"
Principal Investigator: Dr. John S. Vogel, 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: 07/19/00
IRB approval number: 96-113
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 2000 (10/1/99-9/30/2000)
Type(s) of Human Subjects Involvement:
Folate compounds, including folic acid, are important nutritional chemicals found in many foods. We 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). 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 would 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 us to study folates in humans at relevant intake levels.
Our long range goal 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. This knowledge will be used to suggest more healthful nutritional balances in the American diet or a more beneficial use of vitaminic supplements.
No changes from the protocol used in our preliminary study will be made. The continuation of the protocol allows us to extend our methodology to a wider number and variety of volunteers. 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 very low levels of radiocarbon in the samples due to the labeled folate (0.05 to 1 times the natural levels of radiocarbon found in all people) will be quantified using a sensitive instrument (AMS) available at LLNL.
All recruiting, testing, dosing, sampling, and subsequent interactions with the volunteers takes place through UC at Davis, either in the Sacramento Medical Center or at the Nutrition Department on the main campus. A total of 30 volunteers will be recruited in two groups over the next 3 years: 10 men and 10 women who are not suspected of having unusual folate metabolism; and 10 people (preferably 5 men and 5 women) who have altered folate metabolism as indicated by the presence of unusual methionine levels in their blood. This variation will be determined by a methionine load test (MLT), and a hematocrit will identify volunteers who might suffer anemia during the initial blood draws. The effects of the methionine variation can be overcome with dietary changes and vitamin supplementation. Volunteers will fill out questionnaires about their dietary habits and will spend the first full day of the protocol at the University of California Medical Center (Sacramento) during which they will take the dose of traceable folate and will have a number of blood samples drawn from them over 14 hours through an implanted catheter. If the volunteer desires, they may stay overnight at the Medical Center’s outpatient housing facility at no charge. Subsequent blood draws will be made on a "walk-in" basis at the Medical Center over the next 7 months. Volunteers will make stool and urine collections at home during the early phase of the experiment in provided containers. The volunteers will learn 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. Confidentiality of records will be maintained to the fullest extent possible. However, records may be made available to the sponsor of the research (NIH) and to the FDA.
"Optical Diagnosis of Periodontal Tissues"
Principal Investigator: Dr. Bill W. Colston, Lawrence Livermore National Laboratory
Project started in: 1996
This project ended in fiscal year 2000.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 96-114
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 10/04/99
IRB approval number: 96-114
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 2000 (10/1/99-9/30/2000)
Type(s) of Human Subjects Involvement:
This protocol was instituted to evaluate performance of a new, noninvasive optical imaging system called optical coherence tomography (OCT). Lab volunteers sit in a chair and have their teeth and gums exposed to low energy near-infrared light. The new protocol will be:
The volunteer will sit in a chair in a lab in building 132 at Lawrence Livermore National Laboratory. A sterile cheek retractor will be used to pull back his lips to expose his teeth and gums. Focused near infra-red light from a super luminescent diode coupled through a single mode fiber will be scanned across his teeth and gums using a hand-held scanning device. Light scattered by the gums and teeth will be collected by the same device and used to produce a tomographic image of the gums and tissue. Standard infection control guidelines for dental procedures will be followed. Any material placed inside the subject’s mouth will have been disinfected or sterilized. The subject will be able to stop the procedure at any time if he or she feels any discomfort or does not wish to continue with the procedure for any reason. The procedure will take no more than 1.5 hours. It may be done repeatedly on the same volunteer, but no more than twice in a given day.
To make certain that no damage or discomfort occurs to the subject the light incident upon the subject's mouth will always be kept at a power level below the maximum permissible exposures (MPE's) limits for skin or eye exposure to a laser beam as given by the ANSI Z-136.1 Standard, Safe Use of Lasers 1993. Although the typical exposure of light will only be a few seconds to any location on the gums or teeth, the limit used will assume a continuous (up to eight hours) exposure to further safeguard the subject. No goggles or eye protection will be needed as the optical power level will be eye safe.
The wavelength of light which will be used in this diagnostic is 1.3 µm. The maximum permissible exposure limit (MPE) for up to eight hours of continuous exposure at this wavelength is 96.2 milliwatts on any region of skin of less than 3.5 mm diameter and 4.9 milliwatts on the eye. We have chosen a cautious approach in using the limit for the eye and assuming an 8 hour exposure time. Light from the superluminescent diode will never purposely be aimed at the eye and typically will only be focused on any one location for a few seconds. In addition the whole procedure will last no more than an hour and a half. As the scanner is eye-safe, no goggles or other eye protection will be necessary.
Records are coded and kept in locked files so that only the study investigators have access to them. No individual identities will be used in any reports or publications resulting from this study
"Generation of Contiguous Sequence-Ready DNA Clones in Human and Mouse"
Principal Investigator: Dr. Lisa Stubbs, Lawrence Livermore National Laboratory
Project started in: 1997
This project ended in fiscal year 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: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 09/16/99
IRB approval number: 97-110
Explanation of IRB approval:
Protocol was closed at its expiration date.
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 2000 (10/1/99-9/30/2000)
Type(s) of Human Subjects Involvement:
Abstract:
This project is a subcontract to LLNL on an NIH grant to the University of Wisconsin (Lloyd Smith, PI). The grant is for sequencing 2 Mb of DNA (1 Mb each of human and mouse DNA) in two years in conjunction with development of an improved sequencing system. Maps of human and mouse clones will be constructed at LLNL; sequencing of the mapped clones will be done at the University of Wisconsin; and annotation and submission of the completed sequence to the public database will be done at LLNL. The cloned fragments of human DNA that will be mapped and sequenced are from two sources: a human chromosome 19 cosmid library previously constructed at LLNL and human total genomic BAC libraries constructed at Caltech (commercially available from Research Genetics). Maps of overlapping clones spanning a 1 Mb region of human chromosome 19 will be constructed at LLNL, and a subset of minimally overlapping clones spanning the region will be selected for sequencing at the University of Wisconsin. The completed sequence will be annotated (analyzed for content of genes or other features of interest) and submitted to the public database by LLNL. This project will determine the sequence of 1 million bases of human DNA (out of a total of 3 billion bases in the human genome). A knowledge of the sequence of human DNA will contribute to our understanding of the genetic basis of human biology and the role of various genes in health and disease. This will ultimately lead to prevention strategies and improved therapies for a number of diseases.
"Evaluation of Chromosome Damage to Uranium Workers in Namibia for Assessment of Health Risk."
Principal Investigator: Dr. Joe N. Lucas, Lawrence Livermore National Laboratory
Project started in: 1998
This project ended in fiscal year 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: 07/21/99
IRB approval number: 98-102
Explanation of IRB approval:
All work on protocol was completed prior to 7/20/00 expiration date. Protocol has been 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 2000 (10/1/99-9/30/2000)
Type(s) of Human Subjects Involvement:
The purpose of this work was to measure stable chromosomal aberrations in uranium miners at Rossing Uranium, Ltd. compared to controls. The results of this study were compared to the findings of a study on chromosomal aberrations performed by Reinhard Zaire et al. (Rad. Res. 1996) on Rossing employees and controls.
This work, requested by Rossing Uranium, Ltd., Namibia (RTZ, UK), was accomplished by measuring chromosome translocation frequencies in a small group of miners, and comparing the data with the frequencies measured in a small control group of unexposed individuals with similar lifestyles. The endpoint of the work was to test whether the researchers saw an excess of translocations in the miners compared to controls. Because the control group was well selected for factors such as smoking, age, social class, etc., it was reasonable to conclude that if a statistically significant excess in translocations was observed in the miners, it was due to occupational radiation. The researchers could then make an estimate of the average dose.
The translocation frequencies were measured in blood lymphocytes of unexposed individuals. Peripheral blood samples (~20 ml) were drawn by sterile venipuncture from volunteer employees of Rossing Uranium, Ltd. at the medical department of the Rossing plant, cultured and spread on glass slides. A physician was available for consultation. All volunteer donors were informed of the purpose of the blood work and of the (minimal) risk involved. They were asked to sign an informed consent form prior to blood drawing. The consent form will be kept on file by the principal investigator or by the medical department at Rossing. The samples were coded, and the codes were kept confidential so that only the chief medical personnel knew the donor identity.
"Elucidating Dynamics of Beta-Carotene Metabolism in Adults"
Principal Investigator: Dr. John S. Vogel, Lawrence Livermore National Laboratory
Project started in: 1998
Funding for Human Subjects Research: No Funding Sources Reported
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: 07/19/00
IRB approval number: 98-104
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 2000 (10/1/99-9/30/2000)
Type(s) of Human Subjects Involvement:
Deficiencies in vitamin A are correlated with ill health and disease. For example, low vitamin A levels in the eyes leads to poor night vision or lack of color vision. Vitamin A is needed for normal growth of epithelial tissues that protect us from infections in our eyes, mouth, nasal passages, gut, and urinary tracts, as well as being needed for the production of lubricating fluids at body orifices. Vitamin A plays other essential roles in reproduction, cell differentiation, and bone development. High circulating levels of compounds, such as b-carotene that break down to vitamin A, correlate strongly with low chronic disease conditions.
Since vitamin A is harmful to tissues at high concentration and since it is not stored within the body to be called upon when needed, compounds like b-carotene that break down to vitamin A may be the body’s primary store of this vitamin. However, the ability to absorb b-Carotene from digested foods and to convert it to vitamin A was recently shown to vary widely from person to person. The reasons for this variability is not yet known. A person who does not absorb b-Carotene and subsequently convert it to vitamin A my need a modified diet or supplements to reduce chronic disease and other health risks, including cancers. However, an understanding of the distribution and conversion of dietary b-Carotene will be needed before such diets and supplements are designed.
We will determine the uptake of dietary b-Carotene, its conversion to retinoids, and quantify its eventual excretion. We hope to determine the source in the variation among people that leads to different levels of nutrient absorption and utilization.
A normal daily dose of b-Carotene (1 milligram) containing a very low level of radiocarbon (200 nCi) will be ingested by up to 30 volunteers. Blood samples are drawn over a 200-day period after dosing to monitor the uptake and conversion of the labeled carotene to vitamins. Urine and fecal collections are made for the first 7 days after dosing to find the elimination route of the ingested b-Carotene. Outermost cellular layers of skin are removed by "tape stripping" to assess the uptake of vitamin A derived from the ingested b-carotene. The chemical identity of the labeled compounds in retrieved plasma is quantified by AMS.
The LLNL principal investigator has no contact with human volunteers at any time. All recruiting, testing, dosing, sampling, and subsequent interactions with the volunteers takes place through UC at Davis, either in the Sacramento Medical Center or at the Nutrition Department on the main campus. A total of 30 healthy subjects, 15 men and 15 women, will receive b-Carotene containing radiocarbon. Samples of blood, urine, and feces will be collected from them for up to 7 months. A single volunteer took part in our study so far, providing sufficient data to pursue funding for the broader survey. The exposure received from participation in this research project is equivalent to the radiation exposure of a ~4 hour plane trip. Confidentiality of records will be maintained to the fullest extent possible. However, records may be made available to the sponsor of the research (NIH) and to the FDA.
"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.
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 04/14/00
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 2000 (10/1/99-9/30/2000)
Type(s) of Human Subjects Involvement:
This study will use the National Death Index (NDI) of the Centers of Disease Control to determine the death rate from melanoma and all other major causes of death in employees who worked at LLNL any time during the period from January 1984 to December 1996. The primary purpose is to assess the effectiveness of the Laboratory's melanoma prevention efforts; the secondary purpose is to provide an alert for any unusual mortality events that bear on health and safety at the Laboratory. The study involves assembly and analysis of approximately 16,000 records of identifying information, including such things as name(s), date of birth and social security number of each employee. The NDI will identify those who have died and will assign the cause of death. The Laboratory will make no approach to families or medical records. We will carefully safeguard the identifying information and the causes of death, keeping such material under lock and key. The overall results will be made available through LLNL publications and the scientific literature, but only in the form of blanket information on death rates. Likewise, NDI has careful safeguards in place to protect the information. They themselves will not use the data, and they will destroy their files shortly after the study is completed.
"Chromosome Aberration Persistence Study"
Principal Investigator: Dr. James D. Tucker, Lawrence Livermore National Laboratory
Project started in: 1998
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: 05/05/00
IRB approval number: 98-111
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 2000 (10/1/99-9/30/2000)
Type(s) of Human Subjects Involvement:
The objective of this study is to determine whether chromosome translocations in human cells exposed to low levels of ionizing radiation decline with time.
The study involves phlebotomy of normal, healthy subjects, followed by in vitro exposure to ionizing radiation and analysis of structural chromosome aberrations. Cells are grown under commonly-used conditions to promote growth for subsequent analysis by molecular cytogenetic methods.
No human subjects receive radiation or chemical exposure. Risks to the subjects are those associated with routine phlebotomy. All samples are processed encoded, and identifying information is kept in a locked file cabinet in the Principal Investigator's office; no identifier is published. All subjects provide fully informed consent.
"LLNL/AHS Study of Home-Cooked Foods"
Principal Investigator: Dr. David Layton, Lawrence Livermore National Laboratory
Project started in: 1998
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: 11/18/98
IRB approval number: 97-116
Explanation of IRB approval:
protocol was closed by PI at its expiration date
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 2000 (10/1/99-9/30/2000)
Type(s) of Human Subjects Involvement:
The objective of the study is to assess the intake of heterocyclic amines (HAs, carcinogenic by-products formed during the cooking of meat) in the U.S. diet. Acquiring data on the level of HAs in food prepared in the homes of human subjects will provide a better estimate of these carcinogenic by-products in the U.S. diet.
Human subjects in Iowa will provide samples of cooked meat prepared in their residences for analysis of HA content at LLNL. Anonymous (to LLNL) individuals will be asked by random telephone survey what their preferences are for the cooking method and level of doneness for beef steak and hamburger. Those indicating a preference for medium, well-done and very well done pan-fried steak and hamburger will be asked to provide samples of these meats from meals cooked in their residence. Enrolled subjects will be sent sampling kits, instructions, and a questionnaire. The instructions will inform the subject that he/she should prepare the meat as they indicated in the telephone survey, photograph the meat before during and after it is cooked with a disposable camera, complete the questionnaire and place the sample and sampling kit materials in the freezer. The questionnaire will ask how the meat was acquired, how it was prepared before cooking, how and to what degree of done-ness it was cooked and whether or not the subject cooked the meat. Staff members will go to the subject's residence, acquire the sample and provide the reimbursement.
Human subjects personal information is being held confidentially by the University of Iowa collaborator as part of a larger NCI study and will not be divulged to LLNL or any other investigators. No consent form was required for this use of human subjects on the basis that providing the subjects with a verbal and written statement of the research and allowing subjects to decide whether or not to participate in the study constitutes implied consent from the human subjects.
The subjects are not required to perform any procedures other than normal food preparation activities and will incur no additional risk from their involvement in the study.
"Molecular Genetic Analysis of Infertility in Men"
Principal Investigator: Dr. Andrew J. Wyrobek, Lawrence Livermore National Laboratory
Project started in: 1999
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: 11/16/99
IRB approval number: 99-104
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 2000 (10/1/99-9/30/2000)
Type(s) of Human Subjects Involvement:
Infertility affects 20% of couples in the US who are in in their reproductive age. In 40% of these cases, the problem can be identified in the male partner. A significant portion of male factor causes of infertility are due to defects in spermatogenesis. It is unfortunate that even with the significant advances in the field of assisted reproduction, we know very little about sperm and egg production in human beings. Recent studies have shown that loss of function of genes located on the Y chromosome can cause spermatogenic defects in men. It is our endeavor in this project to further characterize the molecular basis of infertility in several well-defined populations of infertile men. We hope to do such a characterization by studying quantitative defects in gene expression of genes located on X and Y chromosoems, as well as autosomes.
The specific objectives of this project are to: 1) identify genes that map to autosomes or sex chromosomes that are necessary for men to make sperm, 2) explore the function of each gene by using cDNA microarrays, a powerful tool of modern human genetics, to identify alterations in the expression of specific genes in infertile men with low or no sperm counts, and 3) determine the order of function of each gene and identifying mutations which disrupt their function.
mRNA is isolated from the tissue or blood samples obtained from these men. The mRNA will be labeled and hybridized on microarrays to study differences in gene expression.
Men with various types of infertility are selected for this study including men with decreased sperm density, men with no sperm in the semen and no sperm due to obstructive condition. In addition, normal fertile men and men who are the biological parents and/or siblings of men with various problems as mentioned above will also be selected for this study. A letter will be sent to each potential participant asking for their consent to join this study. Blood samples and semen samples will be collected from all men. Fine-needle aspirates or test is biopsy will be done on certain infertility phenotypes.
"Long-term Bioindicator for Radiation Exposure"
Principal Investigator: Dr. Joe Lucas, Lawrence Livermore National Laboratory
Project started in: 1999
This project ended in fiscal year 2000.
Funding for Human Subjects Research: No Funding Sources Reported
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: 02/19/99
IRB approval number: 99-106
Explanation of IRB approval:
This protocol has been closed due to lack of funding
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 2000 (10/1/99-9/30/2000)
Type(s) of Human Subjects Involvement:
The overall goal of this project is to identify cytogenetic biomarkers that strongly correlate with the quality (ability to break chromosomes) of radiation, are independent of radiation dose, and can indicate recent and distant past high quality radiation. The quality of radiation is referred to as the linear energy transfer (LET) of the radiation. To accomplish this, five cytogenetic biomarkers for high LET radiation will be tested in the same study.
My collaborator at AECL in Canada, Dr. Morrison, collects blood samples from volunteers who are participating in the Canadian National Dose Reconstruction Program for Tritium exposure. The subjects’ only involvement in this protocol will be the blood draw. At random, 1 to 2 samples will be neutron irradiated, cultured and spread on glass slides. Slides will be sent to LLNL for chromosome painting analysis. Dr. Morrison is a long time collaborator, and his lab is equipped to conduct the specific type of irradiation required for this project, neutrons. As the exposures will take place in his lab, the experiments are better facilitated if the samples are also collected locally by him.
We hope to obtain 1 to 2 neutron-irradiated samples from Dr. Morrison. We are obtaining these samples because of Dr. Morrison’s ability to neutron irradiate them. The samples will come from individuals who are controls and are being seen for routine medical exams. The samples are stripped of personal identifiers prior to being sent to LLNL. We will not be able to identify any individual.
"Absorbed Beta-Carotene: A Retinoid Source in Humans"
Principal Investigator: Dr. John Vogel, Lawrence Livermore National Laboratory
Project started in: 1999
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: 06/21/00
IRB approval number: 99-109
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 2000 (10/1/99-9/30/2000)
Type(s) of Human Subjects Involvement:
Localized tissue deficiencies in vitamin A are correlated with ill health and disease. For example, low Vitamin A levels in the eyes leads to poor night vision or lack of color vision. Vitamin A is needed for normal growth of epithelial tissues that protect us from infections in our eyes, mouth, nasal passages, gut, and urinary tracts, as well as being needed for the production of lubricating fluids at body orifices. Vitamin A plays other essential roles in reproduction, cell differentiation, and bone development. High circulating levels of compounds, such as beta-carotene that break down to vitamin A, correlate strongly with low chronic disease conditions.
Since pure vitamin A is harmful to tissues at high concentration and since it is not stored within the body to be called upon when needed, compounds like beta-carotene that break down to vitamin A may be the body's primary store of this vitamin. However, the ability to absorb beta-Carotene from digested foods and to convert it to vitamin A was recently shown to vary widely from person to person. Someone who depends on primary absorption or digestive production of vitamin A from beta-Carotene requires a diet or supplements to reduce chronic disease and other health risks, including cancers, that is different from people whose bodies respond to localized vitamin deficiencies by making the vitamin as needed from available compounds circulating in the bloodstream. The level of vitamin A production from circulating beta-Carotene, and its variability among people, is not known.
We will determine the rate and form of conversion of circulating beta-Carotene to retinoids and quantify its excretion. We 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. We will put the beta-Carotene directly into the blood stream and look for conversion to active vitamins.
Serial blood samples are drawn over a 60-day period after dosing to monitor the conversion of the labeled carotene to vitamins. Urine and fecal collections are made for the first 7 days after dosing to find the elimination route of the injected beta-Carotene. The chemical identity of the labeled vitamins in retrieved plasma is quantified by AMS.
Twenty healthy subjects, 10 men and 10 women, will receive isotope-labeled beta-Carotene. Samples of blood, urine, and feces will be collected from them periodically. The radio-labeled isotope in this protocol is 14C beta-carotene. Because the beta-carotene is radio-labeled, investigators can easily track its conversion to active vitamin A in retrieved plasma and its elimination route through fecal and urine collections.
There are minimal health risks from participation in this study. A person licensed to draw blood or a registered nurse will perform all blood draws using sterile techniques to minimize discomfort, bruising, and infection. A physician will administer the injection of the dose. Any infection could cause a mild fever and soreness at the injection site. Subjects with anemia, heart disease, or undiagnosed disorders might suffer light dizziness from the blood draws during the first day. They will be diagnosed and advised by the participating physician at the UCD Medical Center of any condition discovered during this study.
The b-carotene dose is faintly radioactive, and will expose the volunteer to a small amount of radiation, about the same amount received during an hour airplane flight at 30,000 ft. altitude or less than 10% of the radiation exposure in a chest x-ray. The total effective dose is much less than the levels that are thought to result in significant risk of harmful effects.
The results of this study will be published in a biomedical journal. The identity of the participants will not be published. The confidentiality of the records will be maintained to the fullest extent possible, but absolute confidentiality cannot be guaranteed, since research documents are not protected from subpoena. Investigators at LLNL will have no knowledge that can link any samples to a particular volunteer or even the group of volunteers who participate.
"Characterization of Dentin"
Principal Investigator: Dr. John H. Kinney, Lawrence Livermore National Laboratory
Project started in: 1999
This project ended in fiscal year 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: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 05/03/99
IRB approval number: 99-115
Explanation of IRB approval:
Protocol was closed in February, 2000 when the PI left LLNL
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 67
Reporting period for number of human subjects:
Fiscal Year 2000 (10/1/99-9/30/2000)
Type(s) of Human Subjects Involvement:
Before we can significantly improve upon dental restorative materials, it is essential that the structure and properties of dentin be fully understood. We have developed new characterization tools aimed at understanding mineralized tissues, and are applying these tools to improve upon our understanding of dentin's structure and properties.
Our objective is to determine the mechanical properties of dentin within the context of bonding restorative materials. In particular, we aim to develop a micromechanics model of dentin that describes its properties in terms of a limited set of measureable parameters such as mineral density.
We will use the atomic force microscope indenter, a specially developed shear punch, and x–ray microtomography to develop a model of dentin's elastic properties in terms of mineral density and tubule density and organization.
Teeth to be used in this study will be selected from those planned for extraction in the University of California, San Francisco (UCSF) dental and oral surgery clinics. The teeth must be non–carious and unrestored or have the types of lesions desired in the grant. After collection, the teeth will again be screened for potential environmental or dental influences, such as tetracycline treatment during development, which is evident in the enamel. Participation will be voluntary and no specific subject population will be sought. Minors will be included in the study. Parent/guardian permission will be necessary. Patients who appear in the oral surgery clinics will be asked if they wish to participate. Patients will be paid $15.00 for participation. As of 1998, 284 subjects have donated 893 teeth. It is anticipated that 500 more teeth will be needed during the current project period which will last for three more years. UCSF requested, and received a modification to the earlier protocol that will allow us to collect more teeth.
"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.
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 05/11/00
IRB approval number: 99-117
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 64
Reporting period for number of human subjects:
Fiscal Year 2000 (10/1/99-9/30/2000)
Type(s) of Human Subjects Involvement:
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.
This research evaluates alternate procedures to measure the amount of genetic damage in cells and the ability of cells to repair damage in their genetic material, DNA. In the future, if these tests are reliable, they will be used to determine if people whose cells repair damage to their DNA more efficiently have lower health risk.
The tests use cells obtained from a blood sample. In the laboratory, the cells will be exposed either to radiation or to chemicals that damage the genetic material. The amount of damage produced and how quickly this damage is repaired will be studied. Alternatively, extracts will be made of the cells and the ability of the extract to repair damage in a synthetic DNA will be studied.
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.
"Naturally Occuring Uranium in Urine"
Principal Investigator: Ms. Lori Johnson, Lawrence Livermore National Laboratory
Project started in: 1999
This project ended in fiscal year 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: Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 05/12/99
IRB approval number: 99-118
Explanation of IRB approval:
Protocol was closed at its expiration date of 5/11/00.
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 2000 (10/1/99-9/30/2000)
Type(s) of Human Subjects Involvement:
Everyone has some level of naturally occurring uranium in their urine. The amount of uranium present in the urine can vary greatly depending on diet, water consumption, where an individual lives, and on many other complex factors. The Hazards Control Bioassay Lab analyzes hundreds of urine samples (from LLNL employees that work with uranium on a routine basis) for uranium each year. This is done in conjunction with the LLNL Internal Dosimetry Program and is a part of a routine occupational safety surveillance program. In the past, urine samples were analyzed for uranium using a Kinetic Phosphorescence Analyzer. They are currently being analyzed using the Elan 6000 Inductively Coupled Plasma Mass Spectrometer (ICP/MS).
"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 Lab's quality control program. This study will analyze urine from a larger population than that provided by the routine "urine blank" control samples.
The overall objective of this study is to establish an average range of uranium in urine for the population at LLNL using ICP/MS analysis.
Human subjects will provide one 100 ml urine sample for this study. 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, only, using ICP/MS analysis.
Human subjects will provide a urine sample for this study. All subjects will be LLNL employees; they will differ in age, ethnicity, race, diet, water consumption, and residence. All subjects will be informed of the nature of the study before they are handed a sample bottle. Risks to humans in this study are minimal. 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 Lab. Only the investigator and other individuals in the LLNL internal dosimetry program with a need to know will have access to sample and subject data. The study will be terminated after all urine samples from study subjects have been analyzed for uranium using ICP/MS. We will only collect one sample per subject. Excess urine will be disposed of in an appropriate manner; it will not be used for further tests or studies.