Mr. David R. Schwoegler
Public Affairs Office
7000 East Avenue, L-404
Livermore, CA 94551
Phone: 510-422-6900
Fax: 510-424-2780
Email: newsguy@llnl.gov
Projects are approved by an IRB located at: Lawrence Livermore National Laboratory.
The approving IRB operates under a Multiple Project Assurance (MPA) recognized by DOE or by the Department of Health and Human Services (HHS).
MPA number of the IRB: M-1415-01-XB
Number of Human Subjects Projects reported: 43
Project Identifier: LLNL-84-P-101-03
Project Title:
Human Sperm Chromatin and Chromosomes
Principal Investigator:
Ms. Laurie A. Gordon
Project started in: 1984
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
This project is a core function of the Human Genome Center and is funded under A.V. Carrano's Grant. Estimate is based on amount of funding directed for use of this protocol only.
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: May 15, 1996
IRB Approval Number: 84P-101-03
Number of Human Subjects who participated in this project/protocol during
FY 1996 (10/1/95 - 9/30/96): 5
Type of Human Subjects Involvement:
A sperm donor will be asked at least 5 days in advance to provide a semen sample on a specified day. He will be provided with a sterile container and will collect a fresh sample and deliver it to the lab or an appropriate intermediate contact person. Once the semen sample arrives in the lab it will be given time to liquefy, then placed in a special buffer for overnight storage in a refrigerator. The following day the sample will be washed 3x in another buffer and sperm will be isolated by centrifugation. Small aliquots of washed sperm cells are distributed into culture dishes. Specially prepared hamster eggs are added to achieve gamete fusion. After 2 to 3 hours of co-incubation, eggs are washed free of sperm and cultured overnight. Early the next morning, the eggs are fixed on microscope slides for analysis of pronuclei formed from the sperm heads which penetrated the eggs. Such sperm pronuclei have very extended chromatin which are used for fluorescence in situ hybridization (FISH) mapping to support the Human Genome Project's chromosome mapping efforts. Any remaining sperm cells or seminal constituents are discarded under regulations pertaining to biohazards.
The benefit of this project to society is derived from its contribution to the Human Genome project. The sperm cells (after fusion with hamster eggs) provide a very extended DNA/chromatin target compared to other nuclear targets. This advantage allows us to identify the location of genes and other markers of interest within the human genetic complement with a much greater resolution than with conventional molecular biology techniques. Using fluorescence in situ hybridization (FISH) mapping techniques we can order and estimate distances between markers along the chromosome, taking advantage of the unique, very extended chromatin produced from human sperm using this system. The maps created by using sperm pronuclei support a broader effort to locate, identify and sequence genes, including genes responsible for genetic diseases. A long-term goal of the Human Genome Project is to devise new diagnostic and therapeutic interventions, and improve those currently available.
Donors are NOT subjected to any treatment, chemicals or radiation.
Our donor pool consists of two to five men. We use only one sperm sample per experiment, performing 10-15 experiments per year. Donors are generally asked to donate a sperm sample at intervals of no more than once a month. Only sperm cells will be used for experimental purposes; all other seminal constituents are discarded.
We do not administer a questionnaire in connection with this study. There are no known risks to donating a semen sample.
Project Identifier: LLNL-88-105
Project Title:
Radiation Genotoxicity from Chernobyl Accident
Principal Investigator:
Ms. Irene Jones
Principal Investigator's Institution: LLNL
Project started in: 1988
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: March 20, 1996
IRB Approval Number: 88-105
Number of Human Subjects who participated in this project/protocol during
03/20/96 - 09/30/96: 150
Type of Human Subjects Involvement:
Clean up workers for the Chernobyl accident which occurred in 1986 were exposed to moderate amounts of ionizing radiation. To detect early biological effects of radiation exposure on these individuals, peripheral blood samples are obtained and analyzed for cytogenetic and somatic mutations in lymphocytes and erythrocytes. In addition, peripheral blood samples are obtained from spouses and children of such workers to determine whether germinal mutations are induced by radiation exposure by detection of such mutations in DNA from children with detailed comparison to parents.
The present or actual benefit to society in doing this project is the development of early somatic biomarkers as indicators of ionizing radiation exposure would provide a useful monitoring tool for populations that are at high risk of exposure. This study is designed to provide the first multiple end point, persistence study on a population exposed to moderate levels of radiation. In addition, long term health effects are being monitored on this population, and correlation between biomarkers and health effects should allow early health risk analysis to be performed with these tests. The goal of this program project is to determine whether several newly developed molecular and cellular analytical procedures can be used to measure effects of ionizing radiation on humans. We also will test whether a combination of these measurements made on each individual can provide a set of data that can be used to estimate:
(1) the radiation dose received by that individual
(2) his susceptibility to radiation-induced genotoxicity.
(3) the relative risk of induced health effects (e.g., cancer) in the exposed
individual and/or birth defects in his progeny.
Our method for accomplishing these goals is to simultaneously obtain genotoxicity measurements using four different analytical techniques on blood samples from approximately 1,000 individuals including people who were exposed to ionizing radiation as a result of the accident at the nuclear power plant in Chernobyl, Ukraine in April-May 1986 and their progeny.
Data from the four areas of research will be used in two ways. For each individual assay of somatic cells, a dose-response from ionizing radiation will be generated by comparing the analytical results with physical dosimetry and with immediate biological dosimetry that was performed by the Soviet medical scientists in 1986 shortly after the Chernobyl accident. This should provide a means for interpreting each of the bioassays for its capabilities as a monitoring biodosimeter for similar radiation exposures (both sensitivity and precision will be determined). In addition, the combination of measurements from the four different research areas will allow an overall effect of exposure of each individual to be determined. A weighted sum of these effect will be derived, and in the future this may serve as an individual dosimeter for dose, and indicator for higher susceptibility to damage, and an estimator for that individual's risk to develop cancer.
We will obtain samples from workers who were exposed during clean up of the site and sarcophagus construction for the reactor and their progeny. 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 allowed to receive no more than 0.25 Gy. We have since obtained information that some of the liquidators received greater than the 0.25 Gy limitation.
Each year, samples from 150 children, born to exposed individuals more than 12 months following exposure, will be obtained. An additional 100 samples will be obtained each year from an appropriately matched control group. An ideal control would be older siblings of the target children, that is, children who were born shortly before the parental exposure. However, we are uncertain that our Russian collaborators can identify sufficient families with this ideal structure. Thus we anticipate that other families will need to be identified as controls. These parents will need to be matched with the "liquidators" for lifestyle and other potentially mutagenic exposures. It will also be important to have the control cohort match the exposed cohort for parental age. This is most important for mothers as the age effect on mutation rate is more pronounced in mothers than fathers. Samples from both parents must be obtained for all Children. Although having more samples in the exposed group than in the control group is not a good statistical design it is felt that it is important to maximize the data from the exposed group during the pilot study.
A unique aspect of this project is the opportunity to obtain the data necessary for generating an estimate of the de novo germinal mutation rate in a cohort of individuals where extensive physical and biodosimetry data are (or will be) available. The key individual for identifying in the triad to be included in the germinal mutation screen will be the exposed parent and in the initial 200 triads, this individual will be the father. Approximately 50% of the exposed individuals included in their germinal mutation screen will be studied for the frequency of mutations at the glycophorin A locus. The number of individuals in the germinal cell screen that are screened for mutations at this locus is limited by the necessity for the individual to be heterozygous at this locus. The lymphocytes of a subset of these same individuals will be screened for the frequency of chromosomal anomalies and mutations at the HPRT locus. Thus, within the cohort studied for germinal mutations, it will be possible to relate the level of radiation exposure as obtained by physical dosimetry to three different somatic cell endpoints. The biodosimetry data can be related to the estimate of the increase in heritable or transmitted genetic damage. In addition to obtaining the first estimate of the radiation induced germinal mutation rate using molecular techniques, the projects of the program will provide the first opportunity to relate somatic indicators of genetic damage, in their capacity as biodosimeters, transmitted genetic alterations.
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 untoward 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.
Project Identifier: LLNL-88-111
Project Title:
Cytogenetic Studies
Principal Investigator:
Dr. James D. Tucker
Project started in: 1988
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: November 15, 1995
IRB Approval Number: 88-111
Number of Human Subjects who participated in this project/protocol during
FY 1996 (10/1/95 - 9/30/96): 15
Type of Human Subjects Involvement:
Subject involvement in this study will be to provide peripheral blood for cytogenetic analyses, which will include calibration, validation, and quality control for laboratory purposes. In addition, metaphase chromosomes will be utilized for mapping DNA probes, and developing or evaluating potential new cytogenetic 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
We obtained blood from 5 subjects since November, 1995. One donor gave 4 times, one gave twice, and the other three people each donated once. The samples were used to provide metaphase cells for hybridization, for evaluating DNA isolation methods, for fluorescence in situ hybridization probe calibration and testing, and media testing. Each of these activities constitutes an essential activity in my laboratory, without which we could not perform our other work.
Society will benefit in several ways. First, samples obtained will be used to verify that our various molecular probes continue to perform at the expected standard. This will directly benefit all of our projects by providing assurance that our procedures are performing appropriately. Normal control samples, like those requested here, are the most appropriate method for accomplishing this task Second, cross-validation of various techniques continues to play an important role in our evaluation of various molecular methods. Finally, these blood samples provide raw material for testing new procedures on a limited basis. When or if such new procedures become used on a large scale, a separate Human Subjects approval will be sought.
This use of normal human blood is a vital part of our cytogenetic work. Without this supply the rest of our work would be impossible to conduct. We require human metaphase chromosomes and nuclei on microscope slides for a very large portion of our work. While these slides are needed on a regular basis, the actual number used in any one week or month varies significantly. Thus, our need for fresh peripheral blood can be irregular and sometimes unpredictable. Accordingly, we cannot anticipate with any degree of accuracy how much will be required in any one year. However, the amount requested in previous years has proven to be adequate for our work. Our current request is unchanged, i.e. no more than 8 separate individuals (mostly from BBRP) will provide blood, with no more than 10 venipunctures per individual per year, and no more than 250 mL per person per year. Venipunctures will be performed by the LLNL Health Services Department using normal procedures.
Project Identifier: LLNL-89-104
Project Title:
Characterization of Dentin
Principal Investigator:
Dr. John H. Kinney
Project started in: 1989
This project ended in Fiscal Year 1996.
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: March 22, 1995
IRB Approval Number: 89-104
Number of Human Subjects who participated in this project/protocol during
03/22/95 - 04/15/96: 62
Type of Human Subjects Involvement:
Protocol expired and closed as of the renewal date 4/15/96.
a) objectives
This is a research effort aimed at measuring the mechanical properties, chemical and composite structure, and resistance to demineralization in dentin, the mineralized hard tissue beneath the enamel in teeth. Characterization of Dentin will lead to improved adhesion and bonding of restorations and improved clinical treatment of caries.
b) Methodology
We have developed several new technologies to explore the mechanical behavior of dentin in its fully hydrated state. Chief among these is the development of a nanoprobe scanning force microscope that allows measurements of hardness and modulus of the constituent materials of dentin with nanometer spatial resolution. In addition, three-dimensional x-ray microscopy/x-ray diffraction is giving us information on how the measured properties are controlled by the structure and chemistry of the dentin, and in how these properties are altered due to age and disease.
c) Ionizing radiation: none
d) Involvement of human subjects
Teeth to be used in this study will be selected from those planned for extraction in the UCSF dental and oral surgery clinics. The teeth must be noncarious and unrestored. 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. Patients who appear in the oral surgery clinics will be asked if they wish to participate. Patients will be paid $15.00 for participation.
There is no risk to human subjects as a result of this study.
Project Identifier: LLNL-89-106
Project Title:
Protective Breathing Equipment (Respirators) Testing
Principal Investigator:
Mr. Art Biermann
Project started in: 1989
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: March 22, 1996
IRB Approval Number: 89-106
Number of Human Subjects who participated in this project/protocol during
FY 1996 (10/1/95 - 9/30/96): 20
Type of Human Subjects Involvement:
For Respirator protection testing
The ability of the respirator to prevent leakage of outside contaminants into the breathing air will be measured by placing the human subject wearing a respirator in a test chamber containing a challenge atmosphere of air with one or more of the following added: 2000 ppm of sulfur hexafluoride gas, 2000 ppm of Freon 12 gas, 20 mg/m3 polyethylene glycol 400 (PEG 400) aerosol, 20 mg/m3 of calcium carbonate aerosol, 20 mg/m3 of aluminum oxide, or 20 mg/m3 of polystyrene latex. These chemicals have been determined to be safe for respirator testing. The subject may be in the test chamber for up to 45 minutes while they perform a variety of exercises and movements. Occasionally, subjects are asked to walk/run on treadmills.
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 faceseal leakage. The sufficiency of breathing air will be determined by measuring the differential pressure between inside the facepiece and the atmosphere. The quality of the air will be determined by measuring the oxygen and carbon dioxide concentrations inside the facepiece when applicable. Oxygen and carbon dioxide concentrations as well as the subject's heart rate will be made measured continuously and monitored by the experimenter to ensure the safety of the human subject. The subject's respiration rate will also be recorded. Conditions for terminating the tests will be: 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.
The these tests will provide a better understanding of existing respirators. It will also assist in the development of new and improved respirators and will provide workers with a greater selection of respiratory protection devices and hopefully with greater protection from hazardous atmospheres.
Project Identifier: LLNL-89-112
Project Title:
Glycophorin A-based Somatic Mutation Analysis of Blood Samples from Grain Agricultural Workers that Apply Pesticides or Herbicides
Principal Investigator:
Dr. Richard G. Langlois
Project started in: 1989
This project ended in Fiscal Year 1996.
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project did not use human subjects in Fiscal Year 1996.
Explanation:
The human studies covered in this protocol were completed and PI closed the protocol 11/17/95 when it was up for renewal.
Funding Sources:
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: March 22, 1995
IRB Approval Number: 89-112
Number of Human Subjects who participated in this project/protocol during
FY 1996 (10/1/95 - 9/30/96): 0
Type of Human Subjects Involvement:
Blood samples from agricultural workers exposed to pesticides or herbicides and matched unexposed control individuals will be used to determine if the exposed workers have an elevated frequency of glycophorin A (GPA)-based somatic mutations in red blood cells.
The benefit to society is to determine if occupational exposure to pesticides or herbicides produces an elevated frequency of mutant-phenotype red cells in exposed individuals, and to determine the utility of the GPA-based somatic mutation analysis method for detecting occupational exposure to genotoxic agents.
Coded blood samples from a total of approximately 100 individuals (total includes both exposed workers and matched controls) will be provided by Dr. Vincent Garry, Laboratory of Environmental Medicine and Pathology, University of Minnesota. Samples will be collected and coded aliquots will be sent by express mail to LLNL. The blood samples will be serotyped for the MN blood group. Samples from individual with MN photype will be tested at LLNL using the glycophorin A mutation assay to determine if exposed workers have elevated frequencies of variant red blood cells compared with matched controls.
Project Identifier: LLNL-90-103
Project Title:
Somatic Cell Mutations Detected in Human Reticulocytes
Principal Investigator:
Dr. Richard G. Langlois
Project started in: 1990
This project ended in Fiscal Year 1996.
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project did not use human subjects in Fiscal Year 1996.
Explanation:
Protocol was closed on 2/96 due to completion of project. Samples had already been collected prior to the start of FY96.
Funding Sources:
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: January 18, 1995
IRB Approval Number: 90-103
Number of Human Subjects who participated in this project/protocol during
01/18/95 - 02/18/96: 0
Type of Human Subjects Involvement:
A. Objectives
Blood samples will be used for the development and application of a new assay for somatic cell mutations at the glycophorin A (GPA) locus detected in human reticulocytes. A reticulocyte-based mutagenesis assay has a number of potential advantages over our current erythrocyte-based GPA assay. These include a rapid response and increased sensitivity to acute exposures to genotoxic agents, and the potential for molecular characterization of the mutations responsible for the variant phenotype reticulocytes detected by the assay. Thus, the reticulocyte project should provide important new capabilities for studying the human risk from exposure to genotoxic agents and for studying the molecular nature of fetal mutations.
B. Methodology
Blood samples (5-15 ml) from volunteers at LLNL will be obtained by standard venipuncture done by members of the LLNL Medical Department. Similar samples of cord blood collected by outside collaborators will be refrigerated and sent to LLNL within one week of collection. 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. Centrifugation or immunomagnetic selection procedures will then be used to obtain samples enriched in reticulocytes. The enriched 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 reticulocytes in each sample. For some samples, flow sorting will be used to purify variant reticulocytes for molecular analysis of messenger RNA in these cells.
C. Ionizing Radiation, Radioactive Substances, or Chemical Substances
None
D. Involvement of Human Subjects
Blood samples will be used for the development and application of a new assay for somatic cell mutations at the glycophorin A (GPA) locus detected in human reticulocytes. Blood samples from LLNL volunteers and cord blood samples will be used for the development of this new assay system. After the assay is developed, it will be applied to samples from unexposed individuals and individuals that have been exposed to ionizing radiation or mutagenic chemicals. These samples will be provided by outside collaborators that have access to populations of exposed individuals.
Samples will be obtained from two sources. Samples from unexposed volunteers at LLNL are currently being collected for the erythrocyte-based GPA assay (IRB# 91-102, R. Langlois, P.I.). Samples of cord blood will be obtained from The Children's Hospital, Denver CO.
Samples from outside collaborations will be encoded by the collaborator, so the names of the participants will not be known by anyone at LLNL. Samples from LLNL volunteers will be encoded by the Principal Investigator, Dr. Richard Langlois, and all data and records will use code numbers only.
Blood samples are obtained by standard venipuncture procedures, and that 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-90-105
Project Title:
Center for Genome Research
Principal Investigator:
Dr. Anthony V. Carrano
Project started in: 1990
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: January 17, 1996
IRB Approval Number: 90-105
Number of Human Subjects who participated in this project/protocol during
FY 1996 (10/1/95 - 9/30/96): 4
Type of Human Subjects Involvement:
Genome mapping is a nationally funded project with strong links to the medical community. Livermore's Human Genome Center mapping work is recognized worldwide. Many researchers working on specific diseases have established collaborations with the Center. Some examples of disease whose genes are localized to chromosome 19 include myotonic dystrophy, familial hypercholesterolemia, dominant autosomal stroke, and a form of diabetes.
As a part of this project, human blood samples are obtained specifically to culture lymphocytes and produce chromosomes on microscope slides for physical mapping. Prior to obtaining samples, all donor sign informed consent and have received "The Experimental Subject's Bill of Rights". A small sample (5-10 ml) of venous blood is drawn at the LLNL medical facility from volunteers. Risk to the donor is minimal, but may include local bruising or fainting. Blood donors are not subjected to any in vivo procedures, nor any procedures associated with in vitro fertilization, long term cell culture or genetic engineering. Blood samples are coded before culturing, and all data linked to sample codes. Blood is cultured for two days, and lymphocyte chromosomes harvested. Chromosomes are used as a "target" templates for determining order of fluorescently labeled markers used as probes. Data is scored directly from coded microscope slides.
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
Project started in: 1990
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
This is one third of a $210,000 project.
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: March 20, 1996
IRB Approval Number: 90-108
Number of Human Subjects who participated in this project/protocol during
FY 1996 (10/1/95 - 9/30/96): 10
Type of Human Subjects Involvement:
Medical Therapy
a. Objectives:
The objectives of this research are to develop new methods for detecting aneuploidy in human sperm using multi-probe FISH and image analyses for automation.
b. Methodology:
A small amount of human semen is smeared onto glass slides and is analyzed for sperm aneuploidy by fluorescence in situ hybridization (FISH) using chromosome specific DNA probes.
c. Ionizing Radiation, Radioactive Substances, or Chemical Substances.
No persons is exposed to these substances for the purpose of our study. Most of the men used in this study are healthy normal men. For validation of our assays, we also utilize a small number of archived semen samples provided by cancer patients before, during and after they have been treated with drug and/or radiation therapies.
d. Involvement of Human Subjects.
1. Men are invited to be volunteers for providing semen samples and some choose to participate in our studies. Samples are delivered to the laboratory and 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.
2. There is no know risk to the semen donors.
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
Project started in: 1991
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: March 20, 1996
IRB Approval Number: 91-102
Number of Human Subjects who participated in this project/protocol during
FY 1996 (10/1/95 - 9/30/96): 35
Type of Human Subjects Involvement:
A) Objectives
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. 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 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 that 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-91-109
Project Title:
Ultratrace Hair Analysis
Principal Investigator:
Dr. Brian D. Andresen
Project started in: 1991
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: March 20, 1996
IRB Approval Number: 91-109
Number of Human Subjects who participated in this project/protocol during
FY 1996 (10/1/95 - 9/30/96): 15
Type of Human Subjects Involvement:
Objective
Hair can possibly be a biological sample that will reveal chemical exposures in humans. Incidental inhalation and ingestion of particles over extended periods of time may result in the formation of a diagnostic chemical fingerprint in hair samples. Methods will be explored to ascertain if routine chemical exposures in the work environment can be revealed through ultratrace analysis of human hair samples.
Methodologies
Human hair from individuals known to have been exposed to chemicals in the workplace will be analyzed. New analytical methods will be developed to assay for ultralow levels of and certain organics (e.g., high explosives) and specific elements (e.g., actinides).
The focus of the hair analysis program centers first on reviewing the literature concerning the extraction of target analytes in laboratory-fortified hair samples. Several approaches will be reviewed in detail. For example, enzymatic digestion, organic solvent extractions, and mild acidic extractions. Depending on the harshness of the extraction, solid phase extraction (SPE) may be proposed as a partial method to clean up the extracts. Every extraction technique will be evaluated on its efficiency and ease of use.
The work also includes the development of a laboratory protocol for organic extracts of hair that will either pre-concentrate the sample prior to analysis, or evaporate the sample to dryness and then derivatize the isolated compounds and elements. It will be proposed to analyze each sample utilizing gas chromatography-mass spectrometry (GC-MS) and inductively coupled plasma mass spectrometry (ICP-MS). We will recommend equipment that is readily available to most all analytical chemistry laboratories.
The use of matrix assisted laser desorption and ionization (MALDI) mass spectrometry will be evaluated for sectional hair analysis. Because hair grows at approximately 1 cm/month it may be used to detect a history of chemical exposures. We plan to review the application of MALDI-MS for hair analysis of HE and actinide incorporation. MALDI-MS will enable us to precisely focus laser power on a selected portion of a hair strand utilizing a miniaturized video camera with newly designed laser optics to monitor the ionization points on the hair shaft. The ions created should allow an ion trap mass spectrometer (with MS/MS option) to detect target species. We will consider in our studies the level of concentration of chemicals in the hair and if at what level the target species must be present in order to be seen with MALDI-MS. Most all of the preliminary work will be performed with laboratory fortified hair samples.
Ionizing Radiation
No radiation experiments are anticipated in these studies. Only hair samples from individuals who work with radioactive materials will be utilized in these studies. No human experiments are anticipated.
Involvement of Human Subjects
1. Hair samples from selected volunteers will be obtained for these studies. Typically hair is obtained during routine hair cuts at the local barber shops. The hair samples are placed in suitable containers and collected for analysis.
2. There is very little risk of injury in obtaining hair samples. The information obtained following the analysis is maintained confidential to all and only available to selected researchers as coded data. No names are associated with the analytical chemistry findings.
Project Identifier: LLNL-91-114
Project Title:
Food Mutagen Metabolism
Principal Investigator:
Dr. James S. Felton
Project started in: 1991
This project ended in Fiscal Year 1996.
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project did not use human subjects in Fiscal Year 1996.
Explanation:
No human subjects during this period. Project used old, archived samples.
Funding Sources:
Used for metabolism of food mutagens. Human liver extracts.
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: January 18, 1995
IRB Approval Number: 91-114
Number of Human Subjects who participated in this project/protocol during
FY 1996 (10/1/95 - 9/30/96): 0
Type of Human Subjects Involvement:
The objectives of this work are to understand the metabolic products of heterocyclic amines produced from human liver extracts in a test tube. Samples are acquired in Australia and shipped here as frozen extracts. Samples are primarily normal tissues from cancer dissections taken under normal surgical procedures for removal of cancerous tissues. Researchers at LLNL never know the identification of the individual, but do know the samples are HIV and Hep B negative and whether the donor is a smoker or nonsmoker. The extracts are incubated with carcinogens in a test tube and the metabolites are identified by HPLC and LC/MS. There are no risks imposed by these experiments beyond the required surgery for the cancer.
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. Stephen R. Burastero
Project started in: 1992
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
Total Funding: $254,000
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: May 15, 1996
IRB Approval Number: 92-105
Number of Human Subjects who participated in this project/protocol during
FY 1996 (10/1/95 - 9/30/96): 80
Type of Human Subjects Involvement:
Recruited heavy keyboard users (>4 hours per day) involved with data entry and word processing will be eligible for the keyboard trials. Ergonomic keyboard evaluation will be administered to identify various causes of Carpal Tunnel Syndrome (CTS) and/or tendinitis. CTS subjects will be randomized into 3 different groups where they will be assigned to use different keyboards for a 12 week trial period. Selected subjects will also be asked to participate in a laboratory based experiment to measure their wrist deviation patterns using a video analysis system. Subjects will be asked to type from a pangrammic text as their hand and arm movements are monitored using a camera system that relays positional information to a computer for motion analysis.
Standard clinical care will be given regardless of selection into the study.
Project Identifier: LLNL-94-101
Project Title:
Immunological Treatment of Metastatic Melanoma
Principal Investigator:
Dr. Max W. Biggs
Project started in: 1994
This project ended in Fiscal Year 1996.
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: March 20, 1996
IRB Approval Number: 94-101
Number of Human Subjects who participated in this project/protocol during
FY 1996 (10/1/95 - 9/30/96): 6
Type of Human Subjects Involvement:
The purpose of this study is to see whether the "soluble" antigens of an enteroviral autologous melanoma lysate, when injected into metastatic melanoma and followed by cyclophosphamide, will produce a remission in the treated metastatic lesions.
BACKGROUND:
There is extensive evidence in immunology that a normal suppressor branch of the system exists to limit the magnitude and duration of immune responses. It is postulated that "melanoma vaccines" fail because the host is tolerized to melanoma antigens.
In the past we have studied the effects of injection of a murine tumor lysate prepared in tissue culture by infection with a murine enterovirus. This was followed by the administration of cyclophosphamide. Both allogeneic and autologous mammary tumors in mice were studied. Ninety percent of the transplanted tumors were cured and significant remissions were obtained in 50% of the spontaneous tumors. Since the 'vaccine" was filtered through a 50 nm Millipore filter and contained "soluble antigens" without aggregates and the cyclophosphamide was given AFTER the antigen, the mechanism of action is thought to be reversal of immune suppression. We believe that the cells involved with in vivo immune suppression were stimulated to divide and were then destroyed with cyclophosphamide.
In FY'95 we have studied 6 patients with metastatic melanoma to evaluate whether or not the murine experiments can be repeated in man. Melanoma tissue cultures have been established from these patients. We have demonstrated that human melanoma cells in tissue culture can be infected and lysed with the enterovirus, poliovirus 1 (Sabin).
In 2 of the studied patients it has been possible to generate in vitro a cytotoxic T-cell lymphocyte response against their autologous melanoma cells using peripheral blood lymphocytes. Cr51 microcytotoxicity assays were used to make these determinations. We have demonstrated in these 2 patients that a melanoma lysate prepared with poliovirus 1 (Sabin) and filtered through a 50 nm Millipore filter is immunosuppressive and prevents the in vitro generation of a cytotoxic response. Thus we are now ready to repeat the animal experiments in man.
PATIENT ELIGIBILITY: The patients must have multiple cutaneous or subcutaneous melanoma metastases. The patient must be immunologically competent.
TREATMENT PLAN: Several of the multiple metastatic lesions will be removed surgically. The pathology and character of the tumor infiltrating lymphocytes will be described. Melanoma cell tissue cultures will be established and the poliovirus lysate will be generated.
Several of the patient's remaining metastases will be injected with the autologous poliovirus lysate followed in 24 hours with a single dose of cyclophosphamide, 300 mg/M2. Changes in the treated tumors will be followed clinically. Any evidence of tumor regression will be recorded.
In addition some of the treated lesions will be removed surgically for evaluation and for comparison with pre-treatment biopsy data. The number and nature of the tumor infiltrating lymphocytes will be evaluated. The secretion of Interleukin-10 will be measured using RT-PCR methodologies.
If any evidence of a cytotoxic T-cell response in the treated tumors can be demonstrated, it is anticipated such reversal of immune suppression will aid in the immunotherapy of metastatic melanoma with various tumor vaccines.
Project Identifier: LLNL-94-103
Project Title:
Percutaneous Absorption of Radiolabeled Chemicals in Humans
Principal Investigator:
Dr. John S. Vogel
Project started in: 1994
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: March 20, 1996
IRB Approval Number: 94-103
Number of Human Subjects who participated in this project/protocol during
FY 1996 (10/1/95 - 9/30/96): 10
Type of Human Subjects Involvement:
dermal exposure
Basic research. CS used as tracer.
Objectives: The ultimate objective of this research is to develop and experimentally validate algorithms which predict the absorbed dose following topical application or dermal exposure to chemical substances of therapeutic and toxicological interest. The initial objectives of the experiments are: (a) To measure, in vivo in man, the cutaneous uptake of a series of substituted phenols following exposure to the skin. (b) To quantify uptake by application of the chemical 'spiked' with a very small amount of 14C (~nCi) and assessing the mass entering the stratum corneum via repeated adhesive tape-stripping and analysis of the strips for 14C. (c) To alternatively quantify uptake by selecting phenol derivatives of unique infrared (IR) spectroscopic characteristics and using attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) to again determine the quantity of chemical taken up into the stratum corneum (once more, using the adhesive tape-stripping routine). (d) To correlate the results from the two methods, and to demonstrate that they may be used interchangeably. (e) To compare the experimentally determined levels of chemical within the stratum corneum at the end of the exposure period with those amounts predicted by dermal uptake models.
Methodology: Radiochemical Methodology: Aqueous solutions of the penetrants, 'spiked' with a very low level of 14C-radiolabel (~10 nCi) will be applied, under occlusion, to the ventral forearms of the human volunteers. Administration will involve saturation of a gauze pad (area = 20 cm2) with approximately 1 mL of solution. After application, the delivery system will be covered with an adhesive, occlusive dressing and left in place for a defined period of time, not to exceed 3-hours. At the end of the exposure time, the gauze is removed and the skin surface is carefully dried with cotton Q-tips. Delivery system and Q-tips will be reserved for analysis. After a period of 10 minutes, sequential layers of stratum corneum at the application site will be removed using preweighed pieces of adhesive tape in the standard way. Up to a maximum of 20 tape-strips will be removed (this is sufficient to excise the entire stratum corneum in most individuals). The tape-strips will then be extracted in methanol and taken to the Center for Accelerator Mass Spectrometry (CAMS) for analysis of 14C. Background levels will be assessed from tape-strips removed from the contralateral, untreated forearm skin. In this way, the concentration profile of chemical across the stratum corneum, and the absolute amount taken up into the membrane during the exposure period will be evaluated.
ATR-FTIR Technique: ATR-FTIR is used to obtain spectral measurements of the phenols in the skin of the human volunteers. Prior to administration, a pretreatment spectrum of each subject's stratum corneum will be recorded with ATR-FTIR. After exposure, sequential tape-stripping and spectroscopy will be performed, providing an alternative assay, thereby, of the distribution of chemical as a function of depth into the stratum corneum (weight of the tape-strips again being used as a marker for position within the membrane). Therefore, the 14C and IR determinations will be performed at the same time; that is, the applied solution of chemical will be both 'spiked' with radioactivity and with a spectroscopic marker. Assay of uptake by CAMS can be utilized, then, as a further calibration of the spectroscopic measurements.
Radioactive and Chemical Substances: The chemicals chosen for the study are a series of phenol derivatives, which are commercially available both 14C-radiolabelled and (separately) with significant deuteration [with the exception of cyanophenol, which possesses an inherently unique IR absorbance via the -CºN functionality]. Chemical doses are from 10-50 mg/mL. Radioactive doses are 10 nCi/mL.
Involvement of Human Subjects: Human subjects have an occlusive patch (2 X 9 cm) moistened with a 1-ml chemical solution (10-50 mg/ml) applied to their forearm for periods up to 3 h. The application site is then serially tape-stripped and analyzed for chemical penetration with ATR-FTIR. Approximately 10 mg of outer skin tissue is removed from each human subject. Little if no physical risk is posed to the human subject by this procedure. Dose estimates for the application site and whole body are 0.134 rad/cm2 and 0.0075 mr.
Project Identifier: LLNL-94-105
Project Title:
Investigation of the Relationship between Numerical Chromosomal Aneuploidy in Sperm and Offspring: A Feasibility Study
Principal Investigator:
Dr. Andrew J. Wyrobek
Project started in: 1994
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: March 20, 1996
IRB Approval Number: 94-105
Number of Human Subjects who participated in this project/protocol during
FY 1996 (10/1/95 - 9/30/96): 40
Type of Human Subjects Involvement:
a. 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).
b. Methodology:
Blood from the parents and child is used to determine the parental origin of the abnormal chromosome and sperm from the father is used to determine the frequency of aneuploidy in the sperm.
c. Ionizing Radiation, Radioactive Substances, or Chemical Substances.
None
d. Involvement of Human Subjects.
1. Families are identified who have a child with Klinefelter syndrome. A genetic counselor will approach the family to request participation in our study and will obtain the questionnaire information and arrange for the visit by the nurse. A nurse will go to the family residence to draw the blood and to pick-up the semen sample which was provided by the father. All samples will 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 will perform this procedure. There are no known risks for the semen donor.
Project Identifier: LLNL-94-111
Project Title:
Do Food Mutagens Cause Damage in Human Colon?
Principal Investigator:
Dr. Kenneth W. Turteltaub
Project started in: 1994
This project ended in Fiscal Year 1996.
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
Some of this funding supported collaborators in the United Kingdom for handling samples and patient interactions.
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: September 20, 1995
IRB Approval Number: 94-111
Number of Human Subjects who participated in this project/protocol during
09/20/95 - 08/26/96: 3
Type of Human Subjects Involvement:
The aim of this study is to determine if two well-characterized mutagens that are present in the human diet are metabolized similarly in humans and rodents. 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. 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 animals models. This study is a collaboration between LLNL, Dr. S Leveson (York District Hospital, UK) and Dr. C. Garner (University of York, UK). Human subjects will given low amounts of 14C-MeIQx and PhIP ((2-amino-3,4-dimethylimidazo[4,5-f]quinoxaline) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, respectively; 0.592 MBq/person) that are naturally present in food. The human subjects (a total of 10 individuals ages 40 - 70) will be patients at the York District Hospital (Wigginton Road, York UK) with previously established colorectal cancer and who are to undergo surgery to remove the tumors. The samples we will use are colon tissue samples removed during surgery and blood drawn prior to surgery. Administration of the compounds, blood collection and surgery's will be supervised and carried out at the York District Hospital by Dr. S Leveson. DNA will be isolated in the laboratory of Dr. C Garner University of York (Heslington, York). Only the purified DNA will be handled and analyzed at LLNL. Briefly, Human subjects who are colon cancer patients at the York District Hospital, first after being fully informed as to the nature of the study and after being asked and giving consent to participate, will be administered either [14C]-PhIP or [14C]-MeIQx in a gelatin capsule, per os, (2 - 6 µg/kg; maximum activity 0.592 MBq/person) 6 hr prior to surgery. 1 hr prior to surgery, blood will be drawn (50 mls by vein puncture) to determine the circulating levels of PhIP or MeIQx. Colon tissue removed during surgery will be placed on dry ice and immediately frozen. The location and amount of tissue removed will be determined by the surgeon but will principally be tumor tissue. The frozen tissue will be homogenized and the DNA will be extracted using phenol:chloroform followed by anion exchange chromatography at the University of York. The purified DNA will be sent to LLNL and analyzed for 14C-content by Accelerator mass spectrometry. Likewise, blood removed 1 hr prior to surgery will be dried and sent to LLNL for analysis of 14C content by AMS. The levels of 14C will then be used to calculate the amount of PhIP or MeIQx covalently bound to the DNA of the colon or present in the blood. The activity of 14C given to the participants will be 3 x 10-3 mSv, approx. 20-times lower than a chest x-ray. Further, the chemical dose will be approx. equivalent to what a human receives from consumption of 1 - 10 hamburgers (2 - 6 µg/kg body weight). The human subjects will be undergoing the surgery whether or not they participate in this study.
Project Identifier: LLNL-94-112
Project Title:
Micropower Impulse Radar Human Organ Motion Studies
Principal Investigator:
Mr. Thomas E. McEwan
Project started in: 1994
This project ended in Fiscal Year 1996.
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
Total Funding: $250,000
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: July 19, 1995
IRB Approval Number: 94-112
Number of Human Subjects who participated in this project/protocol during
07/19/95 - 07/20/96: 4
Type of Human Subjects Involvement:
Micropower radar pulses will be directed into various parts of the body and echoes will be recorded. Initial work is aimed at detection of organ motion. These samples include radar echoes detected externally from the:
1. Heart
2. Lungs
3. Arterial system
4. Skull and skeleton
5. Larynx (also with external acoustic excitation)
6. Tongue and throat region
7. Ear drum (with external acoustic excitation)
In the case of vocal tract organs, the subjects will be asked to speak while radar motion data is being recorded and will have a loudspeaker direct ordinary listening levels of sound into the mouth or into the ear for radar detection of vocal chord and ear drum response. It will provide substantially enhanced and, in some cases, enabling capabilities to existing commercial (non-medical) technologies
This project will launch new medical diagnostic tools that will have a broad impact on professional medicine, sports medicine, and home health care. An initial benefit will be the development of a non-contact cardiopulmonary motion for wireless patient monitoring and SIDs detection.
All tests are non-invasive. Subjects will not be asked to exercise or in any way elevate their heart or respiration rates, except for an occasional deep breath. In some cases, skin contact with the plastic micropower radar housing will be required, and male subjects may (rarely) have to remove their shirts. The plastic micropower radar housing may be strapped or taped to the subject, or may be held by hand to the subject.
Project Identifier: LLNL-94-113
Project Title:
Molecular Cytogenetic Studies of Human Lymphocytes
Principal Investigator:
Dr. James D. Tucker
Project started in: 1994
This project ended in Fiscal Year 1996.
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: July 19, 1995
IRB Approval Number: 94-113
Number of Human Subjects who participated in this project/protocol during
07/19/95 - 07/20/96: 28
Type of Human Subjects Involvement:
The objectives of this work are to quantify the frequency of cytogenetic damage in healthy, unexposed, people of various ages, and to relate this damage to different genetic polymorphisms and lifestyle factors obtained by a questionnaire. The subjects' involvement is limited to phlebotomy (< 30 ml total volume), followed by routine tissue culture of the blood to obtain metaphase chromosomes and binucleated cells from the peripheral lymphocytes. In addition, a portion of each blood sample will be used to obtain DNA for analysis of genetic polymorphisms. Subjects also complete a questionnaire inquiring about lifestyle factors that may be useful for interpreting the results of our validation and quality control analyses. No ionizing radiation or chemicals are administered to these people as part of this project. The risks to the subjects are those associated with venipuncture, and include temporary pain, bruising and/or soreness of the affected tissue or surrounding tissue, formation of scar tissue, infection, and fainting.
Project Identifier: LLNL-94-94-116
Project Title:
Personnel Detection and Imaging with Micropower Impulse Radar
Principal Investigator:
Dr. Stephen G. Azevedo
Project started in: 1994
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
The LDRD work included other efforts besides the human subjects work.
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: November 15, 1995
IRB Approval Number: 94-116
Number of Human Subjects who participated in this project/protocol during
FY 1996 (10/1/95 - 9/30/96): 1
Type of Human Subjects Involvement:
a. Objective:
Micropower radar pulses will be directed at human subjects from behind walls and other structures for the purpose of detecting and imaging the subjects and their motion. This type of radar imaging will provide the information necessary for law enforcement or military personnel to ascertain the location and movement of people in houses or buildings. Safety of law enforcement personnel may depend upon knowledge of a situation behind walls before surreptitious entry or hostage rescue. Such a device could be useful in these types of situations. Initial tests need to be performed to assess its capabilities.
b. Methodology:
1. Define experiment and review with subject, and ascertain the exposure
levels. These levels will depend on distance from the radar (no less than 10
cm). Location of the experiments will vary in order to test different wall
types and thicknesses, but will be in areas where the radar complies with FCC
regulations.
2. Explain that there is no direct benefit to the subject.
3. Explain long term benefit of experiment to subject: development of an
imaging array for military and law enforcement.
4. Brief subject on proposed exposure levels, known safety standards and risks,
and source of expert information on exposure.
5. Inform subject of maximum possible exposure in the event of a worst case
equipment fault, and inform subject should a fault occur. The worst-case fault
is described in the consent form.
6. Inform subject that no special exertion is needed and that no discomfort
should occur.
7. Obtain signed and dated consent form.
8. Assign code to patient for data logging ID.
9. Conduct experiment. Generally, the experiment will involve placing the
subject on the opposite side of a wall from the radar, and using the detection
equipment to image his/her location and movement.
c. Ionizing Radiation, Radioactive Substances, or Chemical Substances: None.
d. Involvement of human subjects:
Only the external dimensions of large objects (people) and their motion will be scanned; imaging of internal body structure will not be performed in this experiment. Detection of cardio-pulmonary function will be attempted by measurement of small external body motions. In all cases, the radar transmitter and receiver will not come in contact with the subject. Tests will take place at various locations/buildings on-site at LLNL.
Project Identifier: LLNL-94-94-117
Project Title:
Direct Measurement of Uptake of Toxic Chemicals from Water, Soil & Dust into Human Skin In Vivo, Phase I: Aqueous Expos
Principal Investigator:
Dr. Kenneth T. Bogen
Project started in: 1994
Project Funding Information:
Project did not receive funding in Fiscal Year 1996.
Project did not use human subjects in Fiscal Year 1996.
Explanation:
As of 7/96, funding agency said funding was coming.
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: January 17, 1996
IRB Approval Number: 94-117
Number of Human Subjects who participated in this project/protocol during
FY 1996 (10/1/95 - 9/30/96): 0
Type of Human Subjects Involvement:
See abstract.
See Abstract.
In three experiments to be conducted under this protocol, a single (1) human subject will receive an extremely low total dose (<250 nCi and <1µg) involving two (2) 14C-radiolabeled chemicals (chloroform and trichloroethylene) via dermal exposure to the forearm. In each experiment, each of four application sites will be sampled by a superficial shave biopsy that removes 1 to 5 mg (~2 mm2) of tissue from the outer skin layers. The samples will be analyzed for 14C-radiolabel uptake by accelerator mass spectrometry (AMS), a highly sensitive technique allowing measurements of extremely small uptakes that present a negligible health risk to the research subject.
The project will provide critical human in vivo validation for a much larger series of parallel data on dermal uptake of key environmental contaminants (namely, certain chlorinated solvents and pesticides) to be obtained using an in vitro method involving human cadaver skin. These data are needed to accurately assess human exposures to environmental chemicals through the dermal exposure route. The data obtained will be used to establish more detailed procedures to be included in a future protocol applicable to nine additional subjects in a second phase of AMS-based research on human dermal uptake of several environmental pesticides via two additional dermal exposure media (soil and household dust), which media are of critical concern to the funding agency. Chloroform and trichloroethylene were selected for use in Phase I because results from these studies will be directly comparable to previous results we have obtained using similar AMS and other procedures applied to skin in vitro and hairless guinea pig skin in vivo. In parallel with the experiments involving a human subject under this protocol, we will be conducting similar experiments using human cadaver skin in vitro (LLNL Protocol 94-118 [Certification of Exemption], Approved 19 Nov. 1994). The present experiments will allow the first direct comparisons of dermal uptake and its kinetics in vivo using AMS methods applied to human skin tissue, thereby providing a firm basis for extrapolating more easily obtained in vitro AMS results applied to human cadaver skin in setting safety standards for drinking water and hazardous waste sites. Such data cannot be obtained using only experimental animals, due to (1) substantial interspecies variation in dermal permeability for chemicals and (2) very limited data currently available upon which to base valid animal-to-human extrapolations of in vivo dermal uptake of chemicals specifically from soil, dust or water (the media of interest to the sponsoring agency).
Potential Hazards
Each experiment will expose the volunteer to a total of 80 nCi plus <1 µg of 14C-radiolabeled test compound. The subject will not be used for more than three experiments, each separated by at least two weeks, and applications will not be repeated at the same location on the subject. The whole-body-equivalent dose corresponding to the 3-experiment maximum 240-nCi exposure is estimated to be approximately 0.5 mrem, or <0.01% of the ~300-mrem U.S. average annual exposure to ionizing radiation from natural background sources (National Council on Radiation Protection and Measurements, 1987, Ionizing Radiation Exposure of the Population of the United States, NCRP No. 93, NCRP, Washington, DC). The corresponding local dose to (a total of ~12 cm2 of) skin is estimated to be <500 mrem. These experimental maximum doses correspond to upper-bound estimates for total increased lifetime risks of 0.1 and 0.01 per million respectively for cancer and for transmitting inherited disease. Acute toxic effects from the chemicals and doses to be used are not expected, and any related cancer risk is considered to be negligible (all chemical doses to be administered are below the corresponding acceptable daily intakes defined by current, applicable California and U.S. Environmental Protection Agency regulations (maximum applied doses = 0.35 micrograms/day for either compound, for a total of 3 days separated by at least 2 wk, which is <10% of the corresponding acceptable levels for daily intake over a lifetime). In no case will a particular application site on a subject be used if it exhibits any sign of cut, abrasion, discoloration, or abnormality of any kind.
Project Identifier: LLNL-95-101
Project Title:
Sperm Aneuploidy in Men Carrying Mutations in the Cystic Fibrosis Gene and Who Have Congenital Absence of Vas Deferens
Principal Investigator:
Dr. Andrew J. Wyrobek
Project started in: 1995
This project ended in Fiscal Year 1996.
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project did not use human subjects in Fiscal Year 1996.
Explanation:
Archived frozen epidiymal sperm samples from men with congenital absence of the vas deferens were used for this project. These samples were considered 'discarded pathological speciments by UC Irvine IRB.
Funding Sources:
This is one third of a $210,000 project.
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: January 18, 1995
IRB Approval Number: 95-101
Number of Human Subjects who participated in this project/protocol during
01/18/95 - 01/18/96: 0
Type of Human Subjects Involvement:
a. Objectives:
The objective of this study is to determine whether men with cystic fibrosis mutations have more chromosomally abnormal sperm than men who do not have the mutation.
b. Methodology:
A small amount of sperm is smeared onto glass slides and is analyzed for sperm aneuploidy by fluorescence in situ hybridization (FISH) using chromosome specific DNA probes.
c. Ionizing Radiation, Radioactive Substances, or Chemical Substances.
None
d. Involvement of Human Subjects.
1. Men who carry a cystic fibrosis mutation affecting the development of the vas deferens are identified by a physician in a collaborating medical genetics clinic and the physician arranges for a sperm sample. Samples are frozen. All samples are coded to protect the confidentiality of the donors.
2. There is no know risk to semen donors associated with this sperm analyses.
Project Identifier: LLNL-95-102
Project Title:
Cytogenetic Analyses of X-Ray Technologists
Principal Investigator:
Dr. James D. Tucker
Project started in: 1995
This project ended in Fiscal Year 1996.
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Expedited
Most Recent Approval: January 17, 1996
IRB Approval Number: 95-102
Number of Human Subjects who participated in this project/protocol during
01/17/96 - 03/20/96: 40
Type of Human Subjects Involvement:
Subjects received occupational or accidental radiation exposure only. No radiation was deliberately administered.
The objectives of this work are to: (1) validate the measured radiation doses experienced by radiologic technologists; (2) provide an evaluation of the possible range of exposures experienced by this well-characterized cohort of 143,000 radiological technologists; and (3) provide guidance on estimating radiation doses for pioneering technologists in the 1920s through 1940s for whom dosimeter measurements are not available. Each subject provides a sample of peripheral blood (~3 ml) which is cultured to obtain metaphase cells for cytogenetic analysis. The subjects received occupational exposure to X-rays, but do not receive any radiation or chemical exposure as part of this study. The risks to the subjects are those associated with venipuncture, and include temporary pain, bruising and/or soreness of the affected tissue or surrounding tissue, formation of scar tissue, infection, and fainting.
Project Identifier: LLNL-95-109
Project Title:
An Investigation of Human Calcium Kinetics Using 41Ca and Stable Isotope Labeled Calcium
Principal Investigator:
Dr. Stewart P. Freeman
Project started in: 1995
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project did not use human subjects in Fiscal Year 1996.
Explanation:
This protocol has yet to be performed. The subject has not been used and no money has been spent. Funded by Laboratory Directed Research Development.
Funding Sources:
Unable to attain funding information
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: March 20, 1996
IRB Approval Number: 95-109
Number of Human Subjects who participated in this project/protocol during
03/20/96 - 03/22/97: 0
Type of Human Subjects Involvement:
Objectives
We seek to develop novel methodologies for measuring human calcium kinetics. The development at LLNL of technology capable of measuring the very long lived isotope of calcium, 41Ca (105 yr halflife), at environmental levels, enables this isotope to be added to the cannon of calcium isotopic tracers. 41Ca tracer might be employed where others are precluded for radiological, physiological and/or economical reasons, permitting unique long term studies of resorbing labeled bone and so-call continuous feeding studies. Here, having previously demonstrated the feasibility of the continuous feeding approach, we attempt to do so again with a second subject in order to obtain further data.
Methodology
The concentration of 41Ca in feces and urine obtained before, during and up to 6 months after 15 days of consumption of 41Ca labeled orange juice with each meal will be measured to permit the calculation of various parameters of calcium metabolism. In additional, supporting data and data for comparison will be obtained by performing a conventional stable isotope test beginning on the 10th day of 41Ca consumption. That day the test will involve the administration of stable calcium isotopes IV and PO and blood draws. Excreta samples obtained that day and subsequently will also be measured for the stable isotopic tracers. After appropriate preparation, the blood and excreta tracer isotope concentrations will be determined by mass spectrometry.
Radioactive and Chemical Substances
The single subject will ingest a total of 40 nCi 41Ca @ 10-6 of total calcium in the form of the carbonate dissolved in orange juice. 2 µg/kg 46Ca and 0.5 mg/kg 44Ca will be administered IV and PO respectively having first been tested for sterility and pyrogenicity.
Human Subject Involvement
The subject will provide urine, fecal and nine 3 mL blood samples. Excreta collections will be spot collections except for a 3 day complete urine collection and week long complete fecal collection beginning on the day of the stable isotope test.
The risks to the subject are those associated with the lifetime radiation dose from the subsequent decay of 41Ca absorbed by bone. 40 nCi 41Ca will be ingested of which roughly 10 nCi will be taken up. About 40% of this will be incorporated into the stable bone. The remainder of the radiocalcium will be quickly excreted from the body and is assumed to not contribute to the dose. The radiations as a consequence of decaying 41Ca have such short ranges that essentially only the target organs receive a radiation dose (ÂDf=0.0059 g·rad/mCi·hr). Assuming that the biological halflife of the stable bone component and therefore the effective radionuclide halflife is 50 years, and that the subject survival post administration is 30 years, the cumulated radioactivity will be 633 mCiáhr and the total average dose to the standard man 4 kg cortical bone mass will be 1 mrad or 0.03 mrem/yr. For comparison, background radiation is approximately a factor of 7000 greater. The essentially negligible dose can also be expressed in terms of cancer risk: the relative risk of a 1 mrad dose to bone is a 0.001% increase and the equivalent absolute risk is about 3 cancer cases per year per 10 billion subjects. (The subject has previously been made surgically menopausal and therefore there is no risk of a radiation dose to any fetus.)
Project Identifier: LLNL-95-110
Project Title:
Molecular Genetics of DNA Repair
Principal Investigator:
Dr. Christine A. Weber
Project started in: 1995
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: March 20, 1996
IRB Approval Number: 95-110
Number of Human Subjects who participated in this project/protocol during
FY 1996 (10/1/95 - 9/30/96): 8
Type of Human Subjects Involvement:
A. Objectives: Our primary objective is to gain an understanding of the genetic and biochemical bases of the genetic disorders resulting from defects in the DNA repair and transcription factor gene ERCC2 (trichothiodystrophy and xeroderma pigmentosum group D) and why one disorder is cancer-prone and the other is not. To achieve this objective, cells from trichothiodystrophy and xeroderma pigmentosum group D patients and family members are used for genetic analysis of the mutations in the ERCC2 gene and in studies of the DNA repair characteristics of the cells. The data generated provides information that is useful both to our research (greater numbers of patients increases our ability to identify commonly occurring mutations and to correlate specific alterations in the protein with the specific clinical presentation) and to the clinicians and families (confirmation of diagnosis, information on degree of photosensitivity of the cells, knowledge of specific mutations in that family useful for future prenatal diagnosis).
B. Methodology: We receive cultures of archived material established in other laboratories (either clinical or research) along with case histories. We request that no identifying information be provided to us. Patient confidentiality is ensured by blacking out any identifying information received and, whenever possible, duplicating the item and destroying the original. Once received in our laboratory, a code designation is assigned (disorder name, #, and 2 letter city abbreviation) and the samples grown for experimental use (e.g., survival curves, mutation analysis) as well as frozen for future studies. All experimental notes and materials use only the code designation. The code database (showing clinician names, their sample identification, and our corresponding code designations), patient photographs, and any original documents with blacked out identifying information that must be maintained are kept in a locked file. Experimental results are then provided to the clinician and are published. Publications will typically include case histories (sometimes referencing an already published case history) as well as experimental data. In some cases, recognizable photographs may be included. In such cases, the clinicians are co-authors and obtain consent for publication from the parents, legal guardian, or patient, as appropriate to each case (the patients are typically minors).
C. Human subjects are not exposed to any chemical or radioactive substances or ionizing radiation under this project.
D. Involvement of human subjects
1. Archived cell cultures from trichothiodystrophy and xeroderma pigmentosum group D patients and family members are used for UV-survival studies, DNA repair assays, and preparation of RNA and DNA samples for genetic analysis of the mutations in the ERCC2 gene. No cell samples are collected specifically for this project.
2. Since only archival materials are used, the only risks to which human subjects are exposed under this project involve loss of privacy. Steps for ensuring confidentiality are outlined in B above.
Project Identifier: LLNL-95-111
Project Title:
Detection of Chromosomal Abnormalities in Sperm from Men Carrying Specific Constitutive Chromosomal Genetic Factors
Principal Investigator:
Dr. Andrew J. Wyrobek
Project started in: 1995
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
This is one third of a $210,000 project.
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: March 20, 1996
IRB Approval Number: 95-111
Number of Human Subjects who participated in this project/protocol during
FY 1996 (10/1/95 - 9/30/96): 1
Type of Human Subjects Involvement:
a. Objectives:
The objective of this study is to determine whether men who carry chromosomal abnormalities produce hig