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: 41
Project Identifier:
LLNL-88-105
Project Title:
"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 involves the use of multiple protocols/subprojects.
Number of protocols/subprojects associated with this project: 2
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Most recent IRB approval: 05/21/99
IRB approval number: 88-105
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 192
Reporting period for number of human subjects:
Year prior to last IRB approval date
Type(s) of Human Subjects Involvement:
This project, about to enter its eighth year, is applying a suite of somatic mutation assays to a human population exposed to low-dose, whole-body, ionizing radiation for the dual purpose of defining the exposure and evaluating the dosimetric assays alone and in combination. 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 will be studied over 4 years (start date August 1, 1996). We will study cells from peripheral blood samples from workers who were exposed during clean up of the site and sarcophagus construction for the reactor. These workers (who are termed "liquidators" by the Soviets) were recruited from throughout the Soviet Union because of their particular skills (e.g., helicopter pilots, construction engineers, drivers of large earth movers, steel workers). It is estimated that approximately 300,000-400,000 such workers were used in this task. Although documentation on the exposures of these individuals is difficult to obtain, our Russian collaborators have stated that physical radiometers were used to monitor radiation and that each person was assigned work tasks with the goal that he/she would receive no more than 25 cGy.
Three measures of genetic damage in somatic cells are being performed. In white blood cells, the frequency of cells with aberrant chromosomes and the frequency and type of genetic alterations of a specific gene are being studied. In red blood cells, the frequency of cells with genetic alterations of a second gene are being studied.
The results of this study should determine:
* the magnitude and nature of the radiobiological injury sustained by the population;
* the relative merit and optimal deployment of the biological dosimetric assays employed in this and other populations;
* the utility of these biological dosimeters in the study of low-dose human radiation biology;
* the advisability of subsequent pursuit of health effects in this population.
The fourth study is determining the frequency of differences in specific DNA sequences between parents and children, to learn about the frequency with which radiation induces changes in these sequences in parents reproductive cells that are passed on to their children.
For all studies, peripheral blood samples provide the biological materials needed to complete the studies planned. Blood samples of up to 50 ml from adults, and 15 ml from family members, are collected by Russian physicians at clinics in Moscow, Tula and St. Petersburg, where the person receives routine health care. In the case of families, members of the family may attend the clinic on different days, or be asked to make special plans to all attend on a given date. All of the contact with the subjects including obtaining informed consent and collection of blood samples will be provided by our Russian collaborators in conjunction with the Russian Ministry of Health, the agency charged with providing health care to this group of individuals. Informed consent will be obtained from both the exposed and the control individuals by standard means, using forms and explanations in their native language. A parent or legal guardian is required to provide informed consent for Minor Children. The risks to the individual from the drawing of the blood sample are bruising at the site of venipuncture and minor infection. These are unlikely events. Any adverse effects will be treated by the appropriate Russian health service. This population provides a unique opportunity to obtain an estimate of the level of genetic damage caused by exposure to radiation. Surveillance of this population for health effects is an ongoing concern. Thus, the risks involved in obtaining the blood samples for the studies outlined in this proposal are recognized, but minimal, and would seem to be acceptable as a compliment of the effort to monitor the long-term health status of this population.
No radiation exposure or chemical exposure occurs as a consequence of participation in this study.
For the coming year, it is our objective to receive ~200 samples from individuals, half from exposed individuals, half from unexposed controls. In addition, our collaborators may send up to 20 samples from other radiation exposed people, that could increase our understanding of radiation genotoxicity. Few, if any, samples from families will be collected. Sample collection for that part of the study has been ended.
In addition to the blood samples, each participant is asked to complete a questionnaire that provides information about age, smoking, diet, health, marital status, exposures to radiation or chemicals that occurred independent of Chernobyl and, if the person went to Chernobyl, the dates, places of work and type of work performed. For families, only the father completes a questionnaire.
Russian participants in this study are compensated for their participation. Each is paid approximately one US dollar. Additionally, the liquidators receive a second medical checkup each year beyond the one that they routinely receive. On rare occasions, they have in the past received other materials, such as vitamin pills on the occasion of the 10th anniversary of the Chernobyl reactor accident. It is our understanding that the primary motivator for subjects is participation in a joint Russian-US study that may contribute to better understanding of the health risks of exposure to radiation.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Most recent IRB approval: 05/20/98
IRB approval number: 98-110
Explanation of IRB approval:
This protocol was closed by the PI on 5/19/99.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 10
Reporting period for number of human subjects:
Year prior to last IRB approval date
Type(s) of Human Subjects Involvement:
a. Objectives
To provide quality control, this project tests reagents and develops methods for studies of genetic alterations of the hypoxanthine phosphoribosyltransferase (HPRT) gene in lymphocytes collected in Protocol #1.
b. Methodology
All laboratory analyses start with cells in blood samples. The HPRT studies require that white blood cells be cultured. For HPRT studies, 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.
c. List any agents to which subjects are exposed.
The people studied are local, LLNL controls, and are not exposed to any agent as a consequence of this study. They provide blood samples that are used only to test reagents and develop methods in support of Protocol #1.
d. Involvement of Human Subjects.
Blood samples are collected by the Medical Department of LLNL. 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 Medical Department of LLNL. The volume of blood drawn is 25-45 ml. Informed consent is obtained from all individuals.
Project Identifier:
LLNL-88-111
Project Title:
"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: Full Board
Most recent IRB approval: 11/18/98
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:
Year prior to last IRB approval date
Type(s) of Human Subjects Involvement:
A. Objectives. To provide human peripheral blood and DNA for cytogenetic and DNA analyses for use in calibration, validation, and quality control for laboratory purposes. Metaphase chromosomes will be utilized for mapping or verifying DNA probes, and developing or evaluating potential new methods.
B. Methodology. Phlebotomy of normal, healthy subjects. In some cases we may elect to have donors complete a questionnaire inquiring about lifestyle factors which may affect the results.
C. Radiation or chemical exposures. None.
D. Involvement of human subjects. Phlebotomy, followed by DNA isolation and/or cell culture to provide material to be used as described in "A" above. Cells are grown under commonly-used conditions to promote growth for subsequent analysis by a variety of molecular and genetic methods. 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.
Project Identifier:
LLNL-89-106
Project Title:
"Protective Breathing Equipment (Respirators) Testing"
Principal Investigator: Dr. Art Biermann, Lawrence Livermore National Laboratory
Project started in: 1989
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
Most recent IRB approval: 04/20/99
IRB approval number: 89-106
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 3
Reporting period for number of human subjects:
Year prior to last IRB approval date
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.
The subject may be in the test chamber for up to 45 minutes while they perform the exercise protocols outlined below. 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.
Challenge agent : Threshold : 80% of Maximum : Maximum Challenge
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
Limit Value (a) : Excursion Level (b) : Concentration (c)
(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 majority of the test protocols call for testing with polyethylene glycol (PEG 400) challenge aerosol.
Our respirator challenge agents were chosen initially because they were the least toxic materials with the properties necessary for our experimental protocols. They have low toxicity regarding inhalation exposure. They have been gathered from many years of past experience and we have existing instrumentation that is adequately sensitive to measure their leakage into respirators. Further, we have made a considerable effort to characterize the aerosol properties of the PEG 400 challenge agent that is the primary challenge agent used in our studies.
In our experiments, the ability of a respirator to provide sufficient breathing air of an adequate quality to its wearer will be determined in addition to its ability to prevent face seal leakage. The sufficiency of breathing air will be determined by measuring the differential pressure between inside the face piece and the atmosphere. Leakage of challenge agent into the respirator will be measured using an aerosol detector, usually a photometer.
In the protocols involving high stress levels, the subject's heart rate will be measured continuously and monitored by the experimenter to ensure the safety of the human subject. The subject's respiration rate will also be recorded. The quality of the air will be determined by measuring the oxygen and carbon dioxide concentrations inside the face piece when applicable. Conditions for terminating the tests will be: concentrations of challenge agent that exceed the excursion levels for over 2 minutes, oxygen concentration below 16%, carbon dioxide concentration above 5%, heart rate above 90% of cardiac reserve at any time, heart rate above 80% of cardiac reserve for more than one minute, or at the request of the subject for any reason.
An operating safety procedure (OSP) describing the hazards and prescribing safety procedures will be in effect and a copy of the OSP will be made available to the test subjects before the test. MSDSs of the challenge agents to be used will be available to the test subject.
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.
Project Identifier:
LLNL-90-105
Project Title:
"LLNL Human Genome Center"
Principal Investigator: Dr. Anthony V. Carrano, Lawrence Livermore National Laboratory
Project started in: 1990
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
Most recent IRB approval: 01/20/99
IRB approval number: 90-105
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 3
Reporting period for number of human subjects:
Other: 01/20/99 to 01/10/00
Explanation:
anticipated subject population during the current protocol approval period
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.
Project Identifier:
LLNL-90-108
Project Title:
"Detection of Aneuploid Human Sperm by In-Situ Hybridization and Image Analysis"
Principal Investigator: Dr. Andrew J. Wyrobek, Lawrence Livermore National Laboratory
Project started in: 1990
This project ended in fiscal year 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
Most recent IRB approval: 04/14/98
IRB approval number: 90-108
Explanation of IRB approval:
This protocol has been closed
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 3
Reporting period for number of human subjects:
Other: 04/14/98 to 04/14/99
Explanation:
Protocol did not receive continuing approval and has been closed.
Type(s) of Human Subjects Involvement:
a. Background Chromosomal abnormalities transmitted via germ cells are major contributors to infertility, pregnancy loss, infant death, congenital malformation, mental retardation and behavioral abnormalities. The development and application of fluorescence in-situ hybridization (FISH) has opened the way for comprehensive studies on both structural and numerical chromosome abnormalities in human spermatozoa.
b. Objectives The goal of the research is to investigate the risk factors of paternally transmitted genetic damage. The specific questions being asked during the next year include: (1) what is the baseline variation in the frequency of structural and numerical chromosome aberrations in sperm, (2) what are the effects of paternal age, (3) do men exposed to toxic agents show elevated levels of genetically defective sperm?
c. Methodology A small amount of human semen is smeared onto glass slides and is analyzed for sperm aneuploidy and structural aberrations by fluorescence in situ hybridization (FISH) using chromosome specific DNA probes.
d. Involvement of Human Subjects Men are invited to be volunteers for providing semen samples and some choose to participate in our studies. All samples are coded to protect the confidentiality of the donors. Either frozen or fresh samples are used as dictated by the requirements of the specific laboratory methods. There is no known risk to the semen donors.
e. Outcome We expect to be able to assess and characterize effects of exposure to chemical mutagens and to evaluate host factors which may predispose individuals to produce chromosomally defective sperm.
f. Conclusion A broad variety of detrimental health effects observed in the embryo and offspring are attributable to paternally derived chromosomal and gene mutations. The purpose of this research is to identify and understand the factors that influence the paternally transmitted genetic abnormalities.
Project Identifier:
LLNL-91-102
Project Title:
"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
Most recent IRB approval: 03/10/99
IRB approval number: 91-102
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 12
Reporting period for number of human subjects:
Fiscal Year 1999 (10/1/98-9/30/99)
Type(s) of Human Subjects Involvement:
A) Objectives
The glycophorin A (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. Thus, the GPA assay provides an important approach for studying the human risk from exposure to genotoxic agents. 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.
B) Methodology
Blood samples (5-30 ml) from volunteers at LLNL will be obtained by standard venipuncture done by members of the LLNL Medical Department. 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.
C) Ionizing Radiation, Radioactive Substances, or Chemical Substances
None
D) Involvement of Human Subjects
Blood samples will be obtained from normal donors in the LLNL employee population for use in the 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
Project Identifier:
LLNL-92-105
Project Title:
"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
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
Most recent IRB approval: 07/29/99
IRB approval number: 92-105
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 50
Reporting period for number of human subjects:
Fiscal Year 1999 (10/1/98-9/30/99)
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.
Project Identifier:
LLNL-94-105
Project Title:
"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
Most recent IRB approval: 09/15/99
IRB approval number: 94-105
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 12
Reporting period for number of human subjects:
Year prior to last IRB approval date
Type(s) of Human Subjects Involvement:
Objectives:
The objective of this study is to study the relationship between numerical chromosomal abnormalities in semen and the chance of fathering a child with a chromosomal defect (e.g., Klinefelter syndrome, 47,XXY).
Methodology:
Blood from the parents and child was used to determine the parental origin of the abnormal chromosome and sperm from the father was used to determine the frequency of aneuploidy in the sperm.
Ionizing Radiation, Radioactive Substances, or Chemical Substances.
None
Involvement of Human Subjects.
1. Families were identified who have a child with Klinefelter syndrome. A genetic counselor approached the family to request participation in our study and obtained the questionnaire information and arranged for the visit by the nurse. A nurse went to the family residence to draw the blood and to pick-up the semen sample which were provided by the father. All samples were be coded to protect the identity of the family.
2. There is a small risk to the puncture area associated with drawing blood and a certified nurse performed this procedure. There are no known risks for the semen donor.
Project Identifier:
LLNL-95-115
Project Title:
"Linking a Dietary Carcinogen to Cancer Suspectibility (formally called Determining Metabolism Differences by Urine Analysis)"
Principal Investigator: Dr. James S. Felton, Lawrence Livermore National Laboratory
Project started in: 1995
This project ended in fiscal year 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
Most recent IRB approval: 08/10/99
IRB approval number: 95-115
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 8
Reporting period for number of human subjects:
Year prior to last IRB approval date
Type(s) of Human Subjects Involvement:
This study investigates the human metabolism of a chemical, PhIP, known to be a animal carcinogen that is found naturally in well-cooked meat. Individuals are asked to refrain from eating meat for 24 hours prior to eating a meal of grilled chicken breast meat. Urine is collected prior to eating the meat and for 24 hours after the meal. This work examines the role of phenotypic differences among individuals in the metabolism of PhIP and may lead to a better understanding of the role of individual metabolism in human cancer etiology.
In 12/98, we amended the protocol to include determination of the individual's metabolism of caffeine. This was done using a known procedure from the literature: volunteers ingested 100 mg caffeine in the form of one commercially available caffeine tablet (equivalent to 1 cup of coffee) and collected 1-2ml of saliva 6 hours later. The saliva was analyzed by HPLC to determine the ratio of 2 caffeine metabolites. Caffeine metabolism is an indicator of metabolic phenotype for cytochrome P450 which we need to interpret our data on PhIP metabolism.
We would like to determine the stability of individual PhIP metabolism by recruiting 3 men to participate in this study over a 2 year period. These subjects will agree to eat well-cooked chicken and collect urine once every three months (for a total of 8 times). All of the details will be the same as described in our standard protocol. The caffeine metabolism assay will also be repeated at 3 month intervals, to determine the changes in an individual's cyctochrome P450 status. This modification will not significantly impact the risks of the study.
Individuals are given chicken breast to eat, urine is collected for 24 hrs, and prior to meat consumption. At a separate time individuals are given a caffeine tablet and 1-2 ml of saliva is collected 6 hrs later.
There are no apparent risks from the meat or caffeine consumption.
We use standard consent forms and privacy is maintained by coding the samples. Only the PI will have access to the code and names both and it will be under lock and key.
Project Identifier:
LLNL-95-119
Project Title:
"Background Translocation Frequencies in Humans"
Principal Investigator: Dr. Joe N. Lucas, Lawrence Livermore National Laboratory
Project started in: 1995
This project ended in fiscal year 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
Most recent IRB approval: 09/16/98
IRB approval number: 95-119
Explanation of IRB approval:
Protocol has been closed.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 2
Reporting period for number of human subjects:
Other: 09/16/98 to 07/19/99
Explanation:
Project closed this year.
Type(s) of Human Subjects Involvement:
The present study to measure background translocation frequencies in humans evolved from early studies that began in the mid 80's, soon after we developed chromosome painting and began to measure chromosome translocations with that technique. Most of the early donors were from Bio Med, however, we expanded to lab wide in the late 80's and early 90's. The translocation frequencies are measured in blood lymphocytes of donors who are unexposed to ionizing radiation or chemotherapy.
Peripheral blood samples will be drawn by sterile venipuncture from human volunteers at the LLNL medical Department. The samples are taken from LLNL employees, retirees, and their relatives. All donors will be unexposed, and range in ages from 18 to healthy elderly relatives of LLNL employees.
Peripheral blood samples (~5ml) will be taken from volunteers or during routine medical examination for analysis of chromosome aberration frequencies. Blood samples from volunteers will be taken at LLNL. Blood samples will be drawn from LLNL donors, cultured, and cells stored on glass slides for analysis. All volunteer donors will be informed of the purpose of the blood work and of the (minimal) risk involved. They will be asked to sign an informed consent form prior to blood drawing. The consent form will be kept on file by the principal investigator. The samples will be coded, and the codes will be kept confidential so that only the chief medical personnel knows the donor identity.
Project Identifier:
LLNL-95-126
Project Title:
"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
Most recent IRB approval: 11/18/98
IRB approval number: 95-126
Explanation of IRB approval:
NA
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 5
Reporting period for number of human subjects:
Fiscal Year 1999 (10/1/98-9/30/99)
Type(s) of Human Subjects Involvement:
The aim of this study is to determine if a well-characterized mutagen that is present in the human diet, primarily from cooked meat consumption, binds to DNA in human tissue and how this binding differs among humans. Additionally it is a goal of this work to establish the minimal amount of isotope-labeled compound that can be administered and still measured quantitatively by accelerator mass spectrometry (AMS). It has been established that prolonged dietary intake of well-cooked meats increases the risk for colorectal cancer. Well-cooked meats contain significant quantities of heterocyclic aromatic amines (HAAs), which have been established as mutagens. The compound present in the highest concentrations (30-50 ng/g) is 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP). In fact, PhIP-DNA adducts have been detected by us in animal experiments using AMS.
The primary benefit from this study is determining if PhIP binding can be detected in humans and how the binding compares to what has been seen in animal studies. This comparison is very important for determining if these compounds contribute to the incidence of colon cancer in the western world since rodents have been used to assess the potential carcinogenicity of these compounds. Importantly, these compounds are carcinogenic in rodents and produce tumors at multiple sites in both rats and mice. This comparison will help establish how the rodents used in cancer studies compare to the human response and will thus increase the confidence in the human risk assessments made using animal models. Further, this study will demonstrate for the first time that DNA adducts are formed in human tissues with these compounds. DNA adducts are believed to be a critical early step in the process of tumorigenesis. Finally, it will help establish if there are individuals with a genetic predispostion (based on phenotype and genotype) for sensitivity to this compound and will lead to studies to attempt to reduce risk by chemical or dietary intervention.
The study is a collaboration between LLNL, and Dr. N. Lang (University of Arkansas, Medical Center). Administration of the compound, blood collection, urine collection and surgeries will be supervised and carried out by Dr. Lang at the UAMS University Hospital and the J.L. McClellan Memorial Veterans Administration Medical Center (VAMC) in Little Rock. Samples of tissue sections removed during the course of colon surgery will be sent to LLNL for analysis. DNA will be isolated at LLNL and analyzed for DNA adducts. Only the tissue and purified DNA will be handled and analyzed at LLNL. Briefly, VAMC patients who have been previously diagnosed with colon cancer and who are scheduled for colon resection at the UAMS University Hospital and the VAMC will be informed as to the nature of the study and then asked to participate. A total of 10 human subjects will be enrolled into this study. They will be asked to read and sign the consent form. Patients may be of either sex and must be >= 18 yrs old. Twenty-four (24) hours prior to surgery patients who consent to participate will be administered 14C-PhIP in a gelatin capsule, per os, (0.07 - 1 micro g/kg; maximum activity 15.6 micro Ci/person). Lactose powder will be used as a bulking agent in the capsule. Blood will be drawn (50 mls by vein puncture) 12 hr after PhIP administration, 24 hr after PhIP administration, and 36 hr after PhIP administration 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 containing capsule to determine clearance rates and metabolic profiles. Approximately 24 hrs after the capsule is given the patients will undergo colon surgery and the tissue removed during surgery will be placed on dry ice. Specimens will then be divided into four portions, labeled, quick frozen in liquid nitrogen, and then stored at -70 degrees C until sufficient quantities are collected for overnight shipment to LLNL.
Approximately 6 - 8 wks after surgery, patients who participate in this study will be phenotyped and genotyped for enzymes potentially involved in the metabolism of the heterocyclic amines. These polymorphic genes include the cytochrome P450s (cyp1A1 and cyp1A2), N-acetyl-transferase (NAT-1 and NAT-2), sulfotransferase and glutathione-S-transferase genes (GSTM1 and GSTP1). In the case of the cyp and NAT genes, caffeine metabolism will be examined. Caffeine is used because it is an indicator of cyp phenotype and N-acetyltransferase phenotype which are significant enzymes involved in PhIP metabolism. Results from this test will be used to assess human variation in metabolism capability. At this time, the participants will be asked to take 200 mg caffeine (2 No-Doz tablets). The patients will be asked to empty his/her bladder 4 hours later. This specimen will be discarded. The bladder will again be emptied one hour later (a total of 5 hrs after taking the caffeine) and this urine will be treated with HCl to preserve metabolites and frozen at -20 degrees C until extraction and analysis can be performed. High performance liquid chromatography (HPLC) will be used to quantitatively measure caffeine urinary metabolites. In the case of sulfotransferase, a platelet based activity test will be used to determine phenotype. Finally, the glutathione-S-transferase genotype will be determined by PCR using lymphocyte DNA obtained from the pre-dose blood draw.
Project Identifier:
LLNL-96-103
Project Title:
"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
Most recent IRB approval: 07/29/99
IRB approval number: 96-103
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 6
Reporting period for number of human subjects:
Year prior to last IRB approval date
Type(s) of Human Subjects Involvement:
a. Background: 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. However, tamoxifen causes liver tumors in rats and 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.
b. Objectives: 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. 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.
c. Methodology: 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.
d. Involvement of 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 micro curies [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 micro sieverts 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.
Outcome: Since 1996, we have recruited 17 volunteers on this protocol. The first 11 volunteers received a radioactive dose of 10 micro curies of [14C]tamoxifen. Although tamoxifen itself was measurable in the tissue, DNA adducts were not detected because the amount of radioactivity administered was too low. Consequently, within the last year a further 6 volunteers were administered a higher dose, 50 micro curies of [14C]tamoxifen. Tamoxifen and/or its metabolites were detected in the uterine tissue at levels of approximately 100ng tamoxifen equivalents /g tissue, demonstrating that the drug actually reaches the uterus. Low numbers of DNA adducts were detected in DNA from both the myometrium (muscle layer) and endometrium (lining) of the uterus. Tamoxifen was also found to covalently bind to myometrial and endometrial protein (7000pg tamoxifen/g tissue) at levels 30 fold higher than to DNA.We have also determined that women have approximately 8 fold greater numbers of DNA adducts in their uterus than similarly dosed 6 weeks old rats. However, this level in women is still very low, about 10 fold lower than the number of adducts seen in the livers of rats. Over the next year, we will complete this study by administering the last 4 capsules to volunteers.
Conclusion: The results of this study will provide better information on the risk-benefit ratio for tamoxifen as a chemopreventive drug.
Project Identifier:
LLNL-96-106
Project Title:
"Chernobyl Dosimetry"
Principal Investigator: Dr. Joe N. Lucas, 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
Most recent IRB approval: 05/17/99
IRB approval number: 96-106
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 30
Reporting period for number of human subjects:
Other: 05/17/99 to 09/30/99
Explanation:
samples obtained since approval of protocol
Type(s) of Human Subjects Involvement:
The overall goal of this project is to apply our expertise in chromosome painting doses reconstruction to validate the micronucleus (MN) technology used by my collaborator at Columbia University for validating radiation doses received by liquidators and populations exposed to Chernobyl radiation in the Ukraine.
The purpose of this research is to validate the MN assay derived radiation doses received by the 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.
Preliminary data previously obtained under this protocol, using chromosome painting, have shown that doses for 23 subjects were elevated based on chromosome translocations compared to unexposed controls. In the current protocol, LLNL will perform chromosome painting biodosimetry on a subset of the total number of people evaluated by MN to validate the micronucleus assay.
Dr. Worgul will arrange to have blood samples that have been cultured and fixed on glass slides sent to LLNL. These samples will come from pre-op work-ups done on patients that are undergoing routine cataract surgery. All samples will have been stripped of identity prior to being sent to LLNL. Dr. Worgul will arrange for LLNL to receive subsamples from two liquidator groups of 10 individual each, and from 10 controls. The selected doses for the two groups will be for ~ 0.3 Sieverts and ~ 1.00 Sieverts. LLNL will compare the translocation frequency derived doses for each individual in the two groups with that derived by the MN assay. The central question is whether the MN assay gives the same dose estimate for these two groups of individuals as does chromosome painting assay. We will derive a calibration curve to cross calibrate the two assays. We are supplying only dosimetry information to my collaborator to compare with his measurements for validation of the MN method.
Project Identifier:
LLNL-96-108
Project Title:
"Genetic and Molecular Analysis of a Normal Human Population"
Principal Investigator: Dr. James D. Tucker, Lawrence Livermore National Laboratory
Project started in: 1996
This project ended in fiscal year 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
Most recent IRB approval: 05/19/99
IRB approval number: 96-108
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 232
Reporting period for number of human subjects:
Year prior to last IRB approval date
Type(s) of Human Subjects Involvement:
The central focus of this investigation is to determine whether maternal environments induce detectable levels of chromosome damage in human newborns. This study is designed to address the hypothesis that maternal environmental exposures, specifically to active and passive tobacco smoke, impose a significant genotoxic burden on the developing fetus that can be quantitated by measuring chromosome damage in placental blood lymphocytes. This study also seeks to identify the relationship between sensitivity to environmental exposures, chromosome damage and exposure to maternal tobacco smoke and other maternal lifestyle factors.
This project builds upon work completed in the past which looked at the complex association between an individual's (both adult and fetal) environmental exposures, genetic makeup and relationship to chromosome damage. It will also confirm preliminary work completed several years ago which showed maternal exposure to tobacco smoke increased the frequency of chromosome damage in utero.
This effort involves a close collaboration with an ongoing study in the laboratory of Dr. William L. Bigbee, which is funded by the National Institute of Child Health and Human Development (NICHD). This work incorporates the study design of Dr. Bigbee's grant and will use aliquots of the placental and maternal blood samples currently being acquired by Dr. Bigbee's staff. Samples received from Dr. Bigbee's laboratory are being cultured for cytogenetics and the microscope slides prepared are being stored until the necessary additional funds are received to analyze this material. The IRB at the University of Pittsburgh has approved Dr. Bigbee's work and all proper procedures with regards to human subjects privacy, confidentiality and consent are being followed.
Project Identifier:
LLNL-96-109
Project Title:
"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
Most recent IRB approval: 08/13/99
IRB approval number: 96-109
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 10
Reporting period for number of human subjects:
Year prior to last IRB approval date
Type(s) of Human Subjects Involvement:
Objective: The specific aim for this study was to 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 using semen chromatin structure assay, CASA (computer assisted sperm analyses) motility, and nuclear morphometry.
This research will provide fundamental information on the effects of paternal age on genetic damage to human sperm. These findings will also provide the critical data needed for the design and interpretation of studies of paternal effects of exposure to environmental agents.
Methodology: The following laboratory analyses are being performed: sperm concentration, visual motility, and CASA (computer-assisted sperm analysis) motility; nuclear morphometry assay; sperm chromatin assay, sperm chromosomal aneuploidy and aberration assay.
Ionizing Radiation, Radioactive Substances or Chemical Substances: None
Involvement of Human Subjects: 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 semen sample for assessment of sperm and semen quality (any additional samples will be collected only in the event of damage to the original). We recruited 97 non-smoking men in the following age groups: 21 men 20-29 years old; 19 men 30-39 years old; 16 men 40-49 years old; 16 men 50-59 years old; and 25 men 60+ years old.
The subjects received $25 in compensation for their time and effort, the results of the dietary questionnaire, and the results of the conventional semen parameters (volume, count, and motility). Possible risks and discomforts that may have resulted from the procedure were considered unlikely.
Project Identifier:
LLNL-96-111
Project Title:
"MIR Speech Science Experiments on the Human Vocal Tract"
Principal Investigator: Dr. Greg Burnett, Lawrence Livermore National Laboratory
Project started in: 1996
This project ended in fiscal year 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
Most recent IRB approval: 07/08/99
IRB approval number: 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:
Year prior to last IRB approval date
Type(s) of Human Subjects Involvement:
Background MIR stands for Micropower Impulse Radar, a technology invented by Tom McEwan at LLNL in 1993. We use a homodyne variant of the MIR that can reliably detect very small motions of reflective objects in its field of view. The tissue motions of humans may be detected as well.
Objectives We will be using MIR sensors to detect (during both voiced and unvoiced speech) the motion of the trachea, jaw, tongue, velum, and other associated human articulators. We will use this information to demonstrate how human-computer interfaces may be improved using the MIR sensor.
Methodology The involvement of most of the subjects will be limited to the utilization of homodyne MIR sensors to observe the movements of the tissues surrounding the glottis (Adams Apple) and the jaw/tongue structures as they speak several different sentences and words. The plastic case of the radar will be in light contact with the skin on the neck as they speak into a microphone. A second sensor may be used in conjunction with the glottal sensor that will attempt to detect jaw and tongue movement. This secondary sensor will be placed under the jaw and may or may not be in contact with the skin. No biological specimens will be collected.
Involvement of Human Subjects The number of subjects involved at LLNL will be 15-20, mostly adult males but with some females and possibly a few children.
Outcome We will gather and record several volumes of data from these experiments and use the data ourselves to demonstrate improvements in speech recognition, synthesis, and communication. We will also share the data with qualified researchers in order that they might also demonstrate substantial improvements over current technology. The identity of the subjects will be kept confidential, and no information will be solicited from the subjects except for their name, gender, and age.
Conclusion The data gathered from these experiments has the potential to revolutionize the speech industry and make ubiquitous hands-free computing possible.
Project Identifier:
LLNL-96-113
Project Title:
"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
Most recent IRB approval: 09/29/99
IRB approval number: 96-113
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Year prior to last IRB approval date
Type(s) of Human Subjects Involvement:
a) Background: 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.
b) Objectives: 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.
c) Methodology: 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 injest 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.
d) Involvement of human subjects: 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 through UC at Davis, either in the Sacramento Medical Center or at the Nutrition Department on the main campus. A single volunteer took part in our study so far, providing sufficient data to obtain funding for this broader survey. 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 an easily detected variant in plasma methionine concentrations. The effects of this 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 15 hours. Subsequent blood draws will be made occasionally 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.
e) Outcome: We 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. We 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.
f) Conclusion: We are exploring the relationship between diet and disease initiation and progression. Improved dietary and supplement recommendations arising from this study could minimize the human and economic cost of cancer and other diseases.
Project Identifier:
LLNL-96-114
Project Title:
"Optical Diagnosis of Periodontal Disease"
Principal Investigator: Dr. Bill W. Colston, Lawrence Livermore National Laboratory
Project started in: 1996
Funding for Human Subjects Research:
This project involves the use of multiple protocols/subprojects.
Number of protocols/subprojects associated with this project: 1
Identifier or number: 96-114
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Most recent IRB approval: 09/16/98
IRB approval number: 96-114
Explanation of IRB approval:
Protocol was reviewed at a full-board meeting on 9/15/99. Action items were identified and have not yet been resolved. No human subjects contact will occur until action items have been resolved and protocol has been approved.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 3
Reporting period for number of human subjects:
Other: 09/16/98 to 08/13/99
Explanation:
This information was provided by the PI at the 9/15/99 full-board review.
Type(s) of Human Subjects Involvement:
The volunteer will sit in a chair. A sterile cheek retractor will be used to pull back the subject's lips to expose her/his teeth and gums. Focused near infra-red light from a super luminescent diode coupled through a single mode fiber will be scanned across her/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.
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 (MPEs) 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 to any location will only be a few seconds, the limit used will assume a continuous (up to eight hours) exposure to further safeguard the subject.
The wavelength of light which will be used in this diagnostic is 1310 nm. The MPEs limits for up to eight hours of continuous exposure at this wavelength is 96.2 milliwatts for the skin and 4.9 milliwatts for the eye. We have chosen a highly cautious approach in using the 8 hour limit for exposure to the eye as light from the superluminescent diode will not purposely be directed at the eye and the whole procedure will last under an hour.
Outcome/Scientific Benefit: Information about usefulness of OCT for imaging/diagnosis of periodontal disease and improvement of OCT imaging device
Project Identifier:
LLNL-97-102
Project Title:
"Assessment of Dermal Exposure to Metals and Metal Compounds"
Principal Investigator: Dr. Graham Bench, Lawrence Livermore National Laboratory
Project started in: 1997
This project ended in fiscal year 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
Most recent IRB approval: 09/16/98
IRB approval number: 102
Explanation of IRB approval:
Protocol was not renewed and has been closed by the PI
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 14
Reporting period for number of human subjects:
Fiscal Year 1999 (10/1/98-9/30/99)
Type(s) of Human Subjects Involvement:
The growing accumulation of metals and metal-based compounds in occupational or environmental settings raises concerns about their potential effects on human health. Several metals are known or suspected carcinogens, and a large number of metals and metal compounds can induce dermal allergic and/or hypersensitivity reactions. Xenobiotic metal ions can also affect the balance of trace elements critical for maintenance of normal function and injury repair. Skin contact represents an important route of exposure for some hazardous metals/metal compounds, since: (a) they are absorbed through it, (b) skin can act as a reservoir for metals, (c) skin surface deposition can be an important source of secondary contamination, and (d) impairment/loss of skin barrier function can occur as the result of exposure. Proton induced X-ray emission (PIXE) is a well-characterized analytical technique based on X-ray spectrometry that can be used to localize metals with micron resolution and quantitate them with ppm sensitivity. It is ideal for detecting and identifying metals on the outer layers of the skin and can be used as a valuable tool for risk assessment, in the assay of exposure following dermal contact, and as an aid in the diagnosis of metal-induced allergic or contact hypersensitivity.
In this study, our goal is to characterize the average metal background in the stratum corneum (the outer, dead layer of the skin) of healthy volunteers. Stratum corneum samples will be obtained by tape-stripping with a special adhesive tape and the analysis of these tape samples will be performed by PIXE.
The selected skin site (appx. 10x3 cm; volare forearm, or abdomen, or back only one site will be selected per volunteer) will be cleaned with distilled water, and wiped dry with a tissue. A 10x1 cm piece of a low-metal, hypoallergenic tape will be adhered to one selected skin site and then be peeled off. This procedure will be repeated for up to a maximum of 20 times from the one selected skin site. The time required for this procedure will be 15 minutes.
There are no anticipated risks associated with the procedures described above. If unusual discomfort other than local skin reddening or itching is experienced, the experiment will be discontinued immediately.
Subjects will be identified, through coding of data sheets by alphanumeric strings.
Project Identifier:
LLNL-97-110
Project Title:
"Generation of Contiguous Sequence-Ready DNA Clones in Human and Mouse"
Principal Investigator: Dr. Lisa Stubbs, Lawrence Livermore National Laboratory
Project started in: 1997
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
Most recent IRB approval: 09/16/99
IRB approval number: 97-110
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: 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.
Project Identifier:
LLNL-98-102
Project Title:
"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
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
Most recent IRB approval: 07/21/99
IRB approval number: 98-102
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 20
Reporting period for number of human subjects:
Year prior to last IRB approval date
Type(s) of Human Subjects Involvement:
The purpose of this work is to measure stable chromosomal aberrations in uranium miners at Rossing Uranium, Ltd. compared to controls. The results of this study will be compared to the findings of a study on chromosomal aberrations performed by Reinhard Zaire et al. (Rad. Res. 1996) on Rossing employees and controls.
Summary of work: This work, requested by Rossing Uranium, Ltd., Namibia (RTZ, UK), will be 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 our work is to test whether we see an excess of translocations in the miners compared to controls. Because the control group will be well selected for factors such as smoking, age, social class, etc., it will then be reasonable to conclude that if a statistically significant excess in translocations is observed in the miners, it is due to occupational radiation. We can then make an estimate of the average dose.
The translocation frequencies are measured in blood lymphocytes of unexposed individuals. Peripheral blood samples (~20 ml) will be 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 will be available for consultation. All volunteer donors will be informed of the purpose of the blood work and of the (minimal) risk involved. They will be 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 will be coded, and the codes will be kept confidential so that only the chief medical personnel knows the donor identity.
Project Identifier:
LLNL-98-104
Project Title:
"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:
This project does not involve the use of multiple protocols/subprojects.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Most recent IRB approval: 09/28/99
IRB approval number: 98-104
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 1
Reporting period for number of human subjects:
Year prior to last IRB approval date
Type(s) of Human Subjects Involvement:
Beta carotene produces Vitamin A, needed for development, growth and health. Isotopic labeling was not possible in healthy humans because the radioactivity to produce a signal would produce unsatisfactory risk to volunteers. This study uses sensitive detection of 14C by accelerator mass spectrometry to trace labeled carotene metabolities in a healthy volunteer to establish the fate and distribution of a single, sub-Recommended Daily Allowance (RDA) dose of folic acid. Nutritional studies, in general, provide data for better estimation of daily requirements of specific nutrients.
Beta carotene (300 micro g) is labeled with 14C (200 nCi) and is consumed in a single dose with food by a human volunteer. Blood, urine and fecal samples are collected at frequent convenient time points, starting 10 minutes after the dose to 200 days. Blood and urine samples are fractionated to give metabolite identities. 14C levels in the measured components are fit to distribution models in order to deduce the chemical carotene levels in unavailable tissues.
Human metabolism of beta carotene is unlike that of any common animal host. No tissue culture can faithfully replicate this cycle. The labeled compound is a nutrient and is supplied at a fraction of the normal daily dose, no chemical toxicity endangers the volunteer. A volunteer receives a total radiation dose of approximately 2 micro Sievert, equivalent to the normal exposure to cosmic radiation at mid-latitudes on the earth's surface for two days. The added risk of illness is so small that it cannot be calculated.
Volunteers are from the Davis, CA community and are provided with a description of the research and risks. They sign an approved consent form. All human contact is through the Nutrition Department at University of California - Davis. The samples measured at LLNL contain no label revealing the volunteer's identity.
Project Identifier:
LLNL-98-105
Project Title:
"Optical Diagnosis through Blood"
Principal Investigator: Dr. Matthew J. Everett, Lawrence Livermore National Laboratory
Project started in: 1998
This project ended in fiscal year 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
Most recent IRB approval: 03/01/99
IRB approval number: 98-105
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 2
Reporting period for number of human subjects:
Year prior to last IRB approval date
Type(s) of Human Subjects Involvement:
We required fresh normal blood to measure in vitro the effects of optical scattering of blood on an optical coherence tomography (OCT) imaging system. This information was necessary for determining whether imaging systems based on optical coherence tomography are feasible as an alternative/improvement to intervascular ultrasound (IVUS) systems for in vivo diagnosis of the human arterial system. To make this determination, we took fresh human blood and placed it in excised pig arteries. We then generated cross-sectional images of the pig artery by imaging through the human blood with the OCT system. We used small amounts of fresh peripheral human blood for this study. When blood was required an appointment was made by one of the volunteers to have blood drawn at LLNL Health Services. The venipunctures were performed by the LLNL Health Services Department using normal procedures and thus not incurring any unusual risks. To retain confidentiality, names were not recorded with the blood samples taken.
Project Identifier:
LLNL-98-106
Project Title:
"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: Full Board
Most recent IRB approval: 04/14/99
IRB approval number: 98-106
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 7757
Reporting period for number of human subjects:
Year prior to last IRB approval date
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 8500 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.
"Development of Improved Methods for the Detection of Individual Sensitivity to Beryllium and Identification of Immunologic and Genetic Factors (DUPLICATE PROJECT LANL-99-02; ALSO SEE LANL-96-05)"
This project is a duplicate of project LANL-99-02.
Project Identifier:
LLNL-98-111
Project Title:
"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
Most recent IRB approval: 05/06/99
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 1999 (10/1/98-9/30/99)
Type(s) of Human Subjects Involvement:
A. Objectives. To determine whether chromosome translocations in human cells exposed to low levels of ionizing radiation decline with time.
B. Methodology. Phlebotomy of normal, healthy subjects, followed by in vitro exposure to ionizing radiation and analysis of structural chromosome aberrations.
C. Radiation or chemical exposures. None.
D. Involvement of human subjects. Phlebotomy, followed by cell culture. Cells are grown under commonly-used conditions to promote growth for subsequent analysis by molecular cytogenetic methods. 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.
Project Identifier:
LLNL-98-112
Project Title:
"Perchloroethylene Exposure Study"
Principal Investigator: Dr. James D. Tucker, Lawrence Livermore National Laboratory
Project started in: 1998
This project ended in fiscal year 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
Most recent IRB approval: 05/20/98
IRB approval number: 98-112
Explanation of IRB approval:
Protocol was closed at expiration date by PI
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 1999 (10/1/98-9/30/99)
Type(s) of Human Subjects Involvement:
A. Objectives. To determine whether humans exposed to perchloroethylene (PCE) in an occupational setting experience adverse health effects.
B. Methodology. Phlebotomy of normal, healthy subjects, followed by cell culture and analysis of structural chromosome aberrations.
C. Radiation or chemical exposures. None.
D. Involvement of human subjects. Phlebotomy, followed by cell culture. Cells are grown under commonly-used conditions to promote growth for subsequent analysis by molecular cytogenetic methods. 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.