Ms. Ann-Marie
B.
Dake
Institutional Review Board
7000 East Avenue, L-350
Livermore, CA 94551
Phone: 925-422-0260
Fax: 925-422-8226
E-mail: dake1@llnl.gov
Number of Human Subjects projects reported: 62
| LLNL-98-106 | "Melanoma and Other Mortality Rates in LLNL Employees" |
| LLNL-00-113 | "Use of Chelating Agents in Radiation Accidents" |
| LLNL-01-101 | "Background Uranium in Urine at LLNL" |
| LLNL-01-116 | "Biomechanics of Human Dentin" |
| LLNL-01-119 | "Changes in Diffraction-limited Spatial Vision Associated with Aging and Retinal Disease" |
| LLNL-02-101 | "Determining the Carcinogenic Significance of Heterocyclic Amines" |
| LLNL-02-119 | "Vitamin B12 Absorption and Metabolism in Humans" |
| LLNL-03-103 | "Identification and Development of Biological Markers of Human Exposure to the Insecticide Permethrin" |
| LLNL-03-106 | "Identification of Markers of Human Exposure to Biolgoical Agents: Vaccinia Study" |
| LLNL-03-109 | "Does Tamoxifen Cause DNA Damage in Human Colon?" |
| LLNL-03-113 | "Host Pathogen Interactions: Biomarkers for Early Detection" |
| LLNL-03-114 | "Monitoring Bone Resorption Using 41Ca and Accelerator Mass Spectrometry" |
| LLNL-03-115 | "The Effect of Dietary Protein on Calcium Metabolism" |
| LLNL-03-126 | "Molecular Modulation of Calcium Crystallization" |
| LLNL-04-115 | "Monitoring Bone Resorption with Sweat Patches" |
| LLNL-04-117 | "Determining the Effect of Green Tea on Gene Expression in Buccal, Bladder, and Blood Cells" |
| LLNL-04-118 | "Gene Expression Studies in Human Blood and Saliva" |
| LLNL-04-121 | "Environmental Epidemiology of Essential Tremor" |
| LLNL-04-123 | "Evaluation and Validation of 41Ca as a Novel Isotopic Technique in Bone Research" |
| LLNL-05-104 | "Prostate Cancer Screening and Dietary HA Exposure in African-Americans: Phase II" |
| LLNL-05-109 | "Test Bed Deployment of SIRAD" |
| LLNL-05-113 | "ToF-SIMS Analysis of Cancer Tissue" |
| LLNL-05-115 | "Identifying Metastatic Breast Cells from Peripheral Blood" |
| LLNL-05-118 | "Buccal Mucosa Cell Sampling in Head and Neck Radiotherapy for Molecular Biodosimetry" |
| LLNL-05-121 | "Medical Surveillance for Former Department of Energy Workers" |
| LLNL-05-122 | "41Ca Absorption and Distribution in a Total Hip Replacement Patient" |
| LLNL-05-124 | "The Effects of Nickel (II) on Human Sperm DNA Integrity" |
| LLNL-05-UCM-05-001 | "Systems of Election, Latino Representation, and Student Outcomes in California Schools" |
| LLNL-05-UCM-05-002 | "Implementing Student Excellence - A Unique Opportunity" |
| LLNL-06-101 | "Chlorophylls as Trans-species Blocking Agents" |
| LLNL-06-102 | "Detecting and Monitoring Prostate Cancer Metastasis Using 41Ca AMS" |
| LLNL-06-105 | "A Multiplexed Diagnostic Platform for Point-of-Care Pathogen Detection" |
| LLNL-06-110 | "Metalloproteomics of the Human Blood Cell" |
| LLNL-06-113 | "The Effect of Surveillance on the Thickness of LLNL Melanoma" |
| LLNL-06-117 | "The Clinical Use of 41Ca as a Novel Isotopic Assay for High Precision Non-Invasive Assessment of Metastatic Bone Disease, Therapeutic Response and Disease Progression in Breast Cancer Patients" |
| LLNL-06-121 | "DNA Repair Phenotype and Testicular Cancer Type" |
| LLNL-06-123 | "Leading Innovation: A Case Study of Sustained Innovation" |
| LLNL-06-UCM-05-005 | "Effectiveness of Success Workshops on First-Year Student Academic Performance" |
| LLNL-06-UCM-05-006 | "Evaluation of Adipose Hormones, Serum Cytokine Levels, Serum Oxidative Stress Markers and Presence or Absence of NASH in Morbidly Obese Subjects Undergoing Bariatric Surgery" |
| LLNL-06-UCM-05-008 | "National Survey of Student Engagement (NSSE)" |
| LLNL-06-UCM-06-002 | "Creating a Community College Transfer Culture at UC-Merced" |
| LLNL-06-UCM-06-003 | "Engineering Innovation - Measuring the Impacts" |
| LLNL-06-UCM-06-006 | "Genetic Polymorphism of Glutamate Cysteine Ligase in Idiopathic Pulmonary Fibrosis " |
| LLNL-06-UCM-06-007 | "Children's Questions: Insight into Cognitive Development" |
| LLNL-06-UCM-06-008 | "Animals Are Like Humans: How Parents Help Children Understand Biology" |
| LLNL-06-UCM-06-110 | "Animals vs. Inanimate Objects: How Do Parent/Child Conversations Differ?" |
| LLNL-07-101 | "Assessment of Vitamin B12 Bioavailability from Beef" |
| LLNL-07-103 | "To Measure the Response of Bone Turnover Markers Following Short-Term Vitamin B-12 Supplementation" |
| LLNL-07-105 | "Characterization of Dental Materials" |
| LLNL-07-107 | "Detection of Normal Viral Background in the Human Upper Respiratory Tract" |
| LLNL-07-108 | "Modular Sampling and Spectrometry Techniques for Rapid Screening of Human Breath with a Miniaturized System" |
| LLNL-07-111 | "A New Model for Increasing the Number of Highly Qualified Science Teachers: A CSU and LLNL Collaboration. Assessment Phase I" |
| LLNL-07-UCM07-005 | "Development of Reasoning in Young Children" |
| LLNL-07-UCM07-006 | "Reimaging the Nation in Post-Civil War El Salvador" |
| LLNL-07-UCM07-009 | "Spatial Cognition and the Bilingual Brain" |
| LLNL-07-UCM07-110 | "Indigenous Immigration from Latin America to California: Ethnic Community Formation, Native American Collaborations, and Nation-state Engagements" |
| LLNL-07-UCM07-111 | "What Sorts of Addressees do Children Trust?" |
| LLNL-07-UCM07-112 | "Partnership for the Assessment of Communities" |
| LLNL-07-UCM07-113 | "Metacogitive Skill and Academic Performance in High School" |
| LLNL-07-UCM07-116 | "SOCS3 Study (Advanced Testing for Predicting Responsiveness to HCV Treatment)" |
| LLNL-07-UCM07-117 | "Knowledge Effects on Children's Diversity-Based Reasoning" |
| LLNL-07-UCM07-118 | "The Development of Implicit Social Cognition" |
"Melanoma and Other Mortality Rates in LLNL Employees"
Principal Investigator: Dr. Mortimer L. Mendelsohn, Lawrence Livermore National Laboratory
Project started in: 1998
Status of the Research this Fiscal Year:
Study protocol is inactive.
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 106
Institutional Review Board (IRB) Review:
Type of Review:
Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 03/13/06
IRB approval number: 98-106
Explanation of IRB approval:
Protocol is currently inactive/suspended.
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 2007
Type(s) of Human Subjects Involvement:
The primary purpose of this study is to follow mortality rates in the Lawrence Livermore National Laboratory (LLNL) population as an indicator of occupational and environmental exposure. Our concern began in the early 1980s when the laboratory experienced a highly significant cluster of melanoma cases. We responded in 1984 with a vigorous melanoma campaign including an aggressively active melanoma clinic, which in turn led to the detection of high levels of early melanomas and zero melanoma mortality from 1984 to 1996. General mortality (i.e., all causes of death) of LLNL employees for this same time interval was 46 percent of U.S. levels, while cancer mortality was 73 percent and cardiovascular mortality was 42 percent. Such data can only be obtained with human studies.
Hypotheses concerned the reality and possible causes of the melanoma cluster and later its disappearance. With regard to mortality in general, we are evaluating what appears to be a very strong and increasing healthy worker effect in association with low tobacco usage, extending well into retirement.
We are using conventional methodology and standard U.S. statistics to evaluate the overall and specific causes of mortality. The relevant census data are collected by laboratory administration and consist of name, social security number (SSN), birth date, and hire and termination dates for all LLNL employees. Periodically (roughly in 10 to 20 year intervals), the data are assembled and submitted to the National Death Index (NDI) where deaths are identified throughout the U.S., and diagnoses are provided to us.
The study is designed so that we have no interaction with the employee, their family, or their medical records. The NDI returns all the identifying information to us soon after relevant deaths are found. We maintain the identifiers in data files kept under lock and key. The identifying data are never transmitted electronically. All our analyses and public data are given as rates, without any identifiers. By definition there is no risk to the dead and a miniscule risk of disclosure to the living due to possible mishandling of the data. The reassurance to the staff about the remarkably high level of their survival has been very beneficial, as might be any possible future detection of unexpected mortality.
Further details on the data collected and its handling:
The research requires periodic mortality studies of the LLNL workforce using the NDI. The crux of this system is the use of sufficient personal identifiers to determine whether an individual is dead or alive. Typically this includes full name, SSN, birth date, state of residence, gender, and race. Death certificates with correspondence in all categories have a 97 percent chance of being correctly attributable to the given individual.
This information was in the past and will be in the future assembled by LLNL's Applied Information System. It covers all laboratory employees in each calendar year of the study (typically five years or more) and is provided on a compact disc (CD) handed to the pricipal investigator (PI). The data are entered into the PI's digital computer, and the CD is kept under lock and key. The computer resides in a locked single-occupant office and is password protected. When necessary, for checking and computational advancements, the data are shared with the collaborator, Dan Moore, who also keeps it on a password protected computer in an adjoining locked office. Periodically, when a mortality study is done, the subset of data representing ex-employees (deaths, transfers, retires, etc.) are digitally coded and sent by mail to the NDI, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics, Hyattsville, Maryland. The NDI searches its registries for matches and mails back positive results with details about the cause of death and the quality of the match. They take scrupulous care of the data and return the files by mail when the study is completed. They also require that we do not use local medical records or family contacts to elaborate or pursue causes of death. We in turn guard the data carefully, as described above, and use it only for general statements about causes of death, i.e., only for rates for a particular disease or category and never for individuals.
We keep the collected identifiers on employees and ex-employees, since the search for death of an employee continues indefinitely with each year of the study, that terminates only when the study ends or the individual dies. The first 13 years of the study have netted 460 deaths among 14,492 persons. If and when the study terminates, the computer files will be erased and the CDs will be destroyed.
We give our full assurance that we have not and will not disclose to the PI any of our subjects, except that required to determine death and cause of death through the NDI.
We have shown a striking absence of melanoma mortality at LLNL for the period from 1984 to 1996, corresponding to the operation of the melanoma clinic. This is associated with a dramatic reduction in invasive melanoma and a brisk increase in early, in situ melanoma. Meanwhile we are in a holding period, waiting for sufficient time to make yet another mortality study a reasonably efficient effort (i.e., until 2008 at the earliest). However, recent budget restrictions have led to the decision to close the melanoma clinic in April 2006. Employees will be encouraged to continue surveillance using their own traditional health caregivers. It is unclear at this time how termination of the clinic will affect either future mortality studies or future melanoma risk to our population. The laboratory has access to two endpoints to study the risk: mortality and cancer incidence. The latter would have more sensitivity but is administratively more difficult to do. In the interim, the prudent thing to do is to preserve the necessary databases. For mortality, this means to continue this IRB-approved project.
"Use of Chelating Agents in Radiation Accidents"
Principal Investigator: Dr. Richard B. Watts, Lawrence Livermore National Laboratory
Project started in: 2000
Status of the Research this Fiscal Year:
Protocol approved, but no funding and no human participants
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 113
Institutional Review Board (IRB) Review:
Type of Review:
Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 05/22/07
IRB approval number: 00-113
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Fiscal Year 2007
Type(s) of Human Subjects Involvement:
Ca-DTPA and Zn-DTPA are calcium and zinc salts of diethylenetriaminepentaacetate (DTPA) that are administered intravenously and are used as chelating agents for plutonium and other transuranic elements such as americium, californium, and curium. These chelating agents have been in clinical use in major radiation accidents since 1958. They are regulated by the Food and Drug Administration (FDA) and were classified as investigational new drugs (INDs) until recently, when a New Drug Application (NDA) was issued. However, the current stocks of these drugs managed by DOE/Oak Ridge Associated Universities (ORAU) will continue to be managed under IND procedures.There is effectively no alternate to these drugs for chelation of transuranics.
An oral chelating agent, Prussian Blue, is used to treat internal contamination with thallium and cesium-137. Like DTPA, Prussian Blue recently changed status from IND to NDA but current stocks managed by DOE/ORAU will continue to be managed under IND procedures.
There is no hypotheses being tested as this is not a research activity in the strictest sense. Rather, the chelating agents are being maintained on IND status to ensure accurate reporting of possible contamination accidents and to continue to record any side effects. These chelating agents have been used for over 30 years in radiation accidents in the U.S. and worldwide, and it is well documented that the drugs are effective against transuranic contamination.
There is no experimental design associated with the administration of these chelating agents. Rather, the drugs would be administered during significant transuranic, cesium-137, or thallium exposures if there was a significant potential for internal contamination based on evaluation of the patient, the wound counts available, and the elements involved.
In the event of potential internal contamination, exposed workers would be taken to Health Services. If it was determined that a significant transuranic exposure had occurred, the risks and benefits of DTPA treatment would be explained to the worker(s). If the exposure is to cesium-137 or thallium, the risks and benefits of Prussian Blue would be explained to the worker(s). Workers are given the right to refuse treatment although, based on decades of clinical experience, chelation therapy has become a part of widely accepted medical practice in removing heavy metal, cesium, and thallium contamination from humans. If workers agree to being treated with a chelating agent, they are asked to review and sign the appropriate consent form. A baseline medical history, blood and urinalysis are performed prior to treatment. DTPA may be injected intravenously or inhaled. Depending on the level of contamination, treatment may require repeated doses over a period of up to several weeks or months. Initial dose is typically 1 gram, but may be as much as 1 gram three times the first day. Prussian Blue is administered orally with dose ranges of 3 to 20 grams daily in divided doses, with the duration of treatment contingent on exposure dose estimates and excretion rates after initiation of treatment.
The risks involved in DTPA therapy are relatively few and include those inherent in starting intravenous access and drawing blood, electrolyte and blood component problems, and possible exacerbation of kidney or bone marrow disease. Prussian Blue is not absorbed from the gastrointestinal tract and has no known risks other than constipation. Privacy and confidentiality will be maintained to the extent possible. The medical records will be made available to the FDA and to Drs. Albert L. Wiley and Patrick C. Lowry, of the Oak Ridge Institute for Science and Education. Drs. Wiley and Lowry are responsible for reporting all uses of these agents to the FDA. General information relating to a worker's case may be used in professional medical literature, but the individual worker will not be identified in any way. Termination of treatment would be decided on a case by case basis after consultation with the Radiation Emergency Assistance Center/Training Site (REAC/TS) at ORAU and an internal radiation dosimetry expert at LLNL.
Internal dosimetrist:
Although DTPA is not approved by the FDA for uranium or neptunium, they may be used for this purpose on an off-label basis after consultation with ORAU.
We expect to continue to monitor the efficacy and safety of these drugs on an as-needed basis.
"Background Uranium in Urine at LLNL"
Principal Investigator: Dr. Lori Johnson, Lawrence Livermore National Laboratory
Project started in: 2001
Status of the Research this Fiscal Year:
Recruitment and/or enrollment of new participants or review of records/specimens continue.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 101
Institutional Review Board (IRB) Review:
Type of Review:
Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 08/17/07
IRB approval number: 01-101
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 2007
Type(s) of Human Subjects Involvement:
Everyone has some level of naturally occurring uranium in their urine. The amount of uranium present in the urine varies greatly depending on diet, water consumption, where an individual lives, and on many other complex factors. The amount of uranium in an individual's urine can vary significantly over time, as eating habits and environmental uranium levels fluctuate. The Hazards Control Bioassay Laboratory analyzes hundreds of urine samples for uranium from Lawrence Livermore National Laboratory (LLNL) employees that work with uranium on a routine basis each year. This is performed in conjunction with the LLNL Internal Dosimetry Program and is a part of the routine occupational safety surveillance program. The goal of this study is to obtain a representative range of the LLNL population uranium in urine level over time to be used as a control when evaluating the occupational safety surveillance results of LLNL employees that work with uranium on a routine basis. Based on recent demographic information, LLNL uranium workers who participate in the occupational safety surveillance program are mostly male (greater than 85 percent) and more than half of them live in the Central Valley. This study will focus on (but not be restricted to) males who are not occupationally exposed to uranium, with an additional specific request for individuals who reside in the Central Valley.
It is not possible to construct a simulation model or animal study that incorporates all of the different variables involved in variation of uranium concentration in human urine. Uranium concentrations can vary greatly between individuals; diet, age, gender, metabolism, medication, water and beverage consumption (type and amount), smoking, organic food consumption, vitamin supplements, home and work locations, and many other factors can affect uranium concentration in urine. In particular, several foods and consumer products, such as beets and other root vegetables, shrimp and bottom feeding fish, cigarettes, etc., are known to contain more uranium than meat, poultry, eggs, or fruit. Consumption/use of such items may impact the level of uranium in urine.
We are not testing a specific hypothesis. The primary objective of this study is to establish a representative range of uranium in urine for non-occupationally exposed LLNL workers. This range will be used as a control for evaluating the occupational surveillance results (i.e., discriminating between "background" and potentially occupationally enhanced levels of uranium). "Urine Blank" control samples (urine from individuals who do not work with uranium) are routinely collected and analyzed for uranium as part of the Hazards Control Bioassay Laboratory's quality control program. This study will analyze urine and drinking water from a larger population than that provided by the routine "Urine Blank" control samples. Corollary objectives include characterizing how uranium concentration in an individual's urine may vary over time and determining if there is a statistically significant correlation between uranium in urine and uranium in drinking water for the population at LLNL.
Human subjects will provide one urine sample and one drinking water sample (of about 100 ml) every quarter for this study. All subjects will be volunteers. Subjects will be encouraged to participate in the study for at least one year and preferably longer. Samples will be assigned a Bioassay Laboratory sample number and processed in the same manner as routine occupational safety surveillance samples. All samples will be analyzed for uranium using inductively coupled plasma-mass spectrometry analysis. Some samples may be analyzed for the uranium-236 isotope by accelerator mass spectrometry. Specific gravity, pH, gross alpha, and gross beta may also be measured periodically to support the uranium measurements. No other constituents will be analyzed.
Based on results from the routine occupational safety surveillance samples and this study, we anticipate a wide variety of uranium concentrations in the samples from our study subjects. The study will be successful if we can analyze all urine and drinking water samples from study subjects for uranium and establish a representative background uranium in urine range for the LLNL uranium worker population. The study will be terminated when routine occupational monitoring for uranium in urine is no longer required at LLNL. Excess urine will be disposed of in an appropriate manner. Study sample urine is processed, stored, and disposed of in the same manner as all urine from routine bioassay samples. Fully trained laboratory technicians and associates perform these functions in accordance with Hazards Control Department Radiation Safety Section Bioassay Laboratory procedures and protocols. The urine will not be used for further tests or studies.
"Biomechanics of Human Dentin"
Principal Investigator: Dr. John H. Kinney, Lawrence Livermore National Laboratory
Project started in: 2001
Status of the Research this Fiscal Year:
Study protocol is inactive.
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 116
Institutional Review Board (IRB) Review:
Type of Review:
Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 05/01/06
IRB approval number: 01-116
Explanation of IRB approval:
Protocol is currently inactive/suspended.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 27
Reporting period for number of human subjects:
Fiscal Year 2007
Type(s) of Human Subjects Involvement:
Scientific context:
The project is designed to study the mechanical properties of human dentin. These properties include, but are not limited to, elastic constants, fracture toughness, and cyclic fatigue behavior. Human subjects are required because we need to perform the mechanical tests on the actual human dentin.
Procedures involving human subjects:
The teeth are to be extracted for clinical reasons. If the clinician decides a tooth should be removed, the patient is asked if they would like to participate in our study by donating the extracted tooth. They are provided with a consent form, a description of the study, and the location of the laboratories where the tooth might be examined. All medical records or identifiers are kept in strictest confidence and are not available to the research team.
Hypotheses:
Specific Aim 1: Biomechanical Properties of Normal Dentin
These studies are designed to measure the elastic and fracture properties of normal human dentin. Specifically, it is hypothesized that the elastic properties, such as Young's modulus, are isotropic (the same in any direction). Other hypotheses consider the fracture properties of dentin: for example, can one measure fracture toughness, and is the fracture toughness isotropic or does it depend on the orientation of the mineralized collagen fibrils?
Specific Aim 2: Biomechanical Properties of Altered Forms of Dentin
In this specific aim, we examine the elastic and fracture properties of altered forms of dentin. Specifically, we will study carious and transparent dentin, as well as what is called reparative dentin (the dentin formed at the pulpal wall in response to trauma).
Specific Aim 3: Biomechanical Properties Affecting Tooth Lifetime
The studies in Aim 3 are intended to explore the nature of failure of the human tooth, and the role that environmental factors might play on tooth strength. In particular, we will explore the fatigue (cyclic stress) behavior of dentin and attempt to determine if there is a limiting stress below which tooth failure cannot occur. Questions that will be addressed include whether there is a critical flaw size in dentin.
Experimental design:
The above specific aims will be accomplished by augmenting the nanomechanical techniques developed in prior years with resonant ultrasound spectroscopy (RUS), fracture mechanics testing, and finite element modeling.
Anticipated results:
We anticipate that the elastic properties will be controlled by the mineralized collagen fibrils. In addition, we believe that failure in the tissue will be dominated by preexisting or induced defects in the microstructure. The study will be terminated in five years at the end of the program.
"Changes in Diffraction-limited Spatial Vision Associated with Aging and Retinal Disease"
Principal Investigator: Dr. Scot S. Olivier, Lawrence Livermore National Laboratory
Project started in: 2001
Status of the Research this Fiscal Year:
Recruitment and/or enrollment of new participants or review of records/specimens continue.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 119
Institutional Review Board (IRB) Review:
Type of Review:
Full Board
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 05/09/07
IRB approval number: 01-119
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 38
Reporting period for number of human subjects:
Fiscal Year 2007
Type(s) of Human Subjects Involvement:
The human eye suffers from significant high-frequency aberrations that can not be corrected by standard corrective eyewear and thus, limit visual acuity. Adaptive Optics (AO), a mature technology used in astronomy to correct for the blurring effect of the atmosphere on astronomical images, can also be used to compensate for ocular aberrations, thereby providing normal eyes with supernormal vision. Lawrence Livermore National Laboratory (LLNL) is developing an adaptive optics system for vision correction based on the LLNL expertise in high-resolution optical control systems to demonstrate, for the first time, diffraction-limited human vision; i.e., vision that is essentially aberration-free. This adaptive optics instrument is an extension of a prototype system developed and in use at the University of Rochester. Using this instrumentation, we will seek to determine both the ultimate resolution and the ideal optical correction for human eyes based on both the optical aberrations and neurological factors.
This project represents a collaborative effort between the Adaptive Optics Group in the Physics and Advanced Technology Directorate at LLNL, led by Dr. Scot Olivier, and the Visual Psychophysics Laboratory in the Department of Ophthalmology at the University of California-Davis Medical Center(UCDMC), led by Dr. John S. Werner. The researchers at LLNL will provide the adaptive optics instrumentation and will collaborate with researchers at UCDMC, who will use the instrument in a clinical setting at the UCDMC.
The broad purpose of our research program is to understand the limits of human visual acuity and the changes in vision associated with aging and retinal disease. The specific purpose of this study is to apply adaptive optics technology to the study of the human eye for two purposes: (1) to measure the visual performance of the eye when virtually all the aberrations of the eye are corrected and (2) to obtain high-resolution images of the retina, thereby allowing correlation of retinal structure with visual performance. Our collaborator's research programs at the UCDMC have been concerned with the optical and neural factors responsible for the normal aging of the human visual system, and cellular mechanisms of age-related macular degeneration(AMD), the leading cause of blindness in the United States. This project brings those two research programs together by allowing correlation of high-resolution images of cells in the retina with visual performance assessed using aberration-free stimuli.
The human visual system changes continuously throughout the life span and may result in changes in the quality of life for healthy elderly people that do not come to the attention of health care providers. In one survey, 40 percent of individuals over age 65 years reported that visual changes impair daily life activities. Our collaborator's research has identified some of the optical and neural factors responsible for the degradation of human vision due to aging. However, there are still fundamental questions that have not been addressed about normal aging of the visual pathways that can now be investigated using aberration-free stimulus imaging afforded by adaptive optics. For example, what are the consequences for vision resulting from the losses in photoreceptor numbers beginning in early adulthood? Also, what changes occur in visual resolution as a result of the one-third loss in retinal nerve cells between the ages of 34 and 72 years? By using an adaptive optics instrument, it will be possible to address these questions systematically using established psychophysical (vision science) procedures. With better understanding of normal aging and adaptive optics instrumentation, it will also be possible to study abnormal aging of the human retina, for instance in the presence of retinal disease such as AMD. Changes for year 2005 renewal included a request by the lead group in this study headed, by John S. Werner MD, to the UCDMC IRB board, to lower the study age to children to a minimum age of eight years. As stated in the UCDMC IRB request: "There are certain eye diseases that manifest at a very early age, and by including these young patients, this will allow us to conduct longitudinal studies that will enhance our understanding of disease processes."
The formal experimental tests will involve presentation of patterns on a computer screen that change over space and time, called sinusoidal gratings (fuzzy bars). We will vary the spatial frequency of the patterns from very coarse (fat bars) to very fine (skinny bars). The gratings will be greenish in color and the overall size will be varied. The computer screen will be viewed through an imaging system containing a combination of optical components (mirrors, lenses, and windows) of similar complexity to a high-end amateur telescope. Tests will be conducted following up to 30 minutes of dark adaptation. Subjects will be asked to press a button to record whether the stimulus was more likely to have been detected in the first or the second interval denoted by beeps. A second set of measurements will present the letter "C" on a computer screen. The subject will be asked to press one of four buttons to denote the orientation of the gap in the letter so that visual acuity can be measured. Images of the subjects' retina may also be recorded using flash photography.
All involvement of human subjects in this project will be under the direction of our collaborators at UC-Davis, following the protocol already approved and subsequently renewed by the IRB at UC-Davis. Prior to any tests or examinations, each subject will be provided and asked to sign the Consent To Participate Form provided by UCDMC. Each subject will then have a standard ophthalmic eye exam prior to joining the study. They will then make about one to three visits to UC-Davis Medical Center, where all of the testing for this project will be conducted. Each visit will be about one to two hours in length, and the subjects will be asked if they would like to take breaks frequently throughout the testing period. During the testing period, the subjects will be seated, have their eyes dilated, and bite down on a molded plastic "bite bar" to stabilize the motion of their head. The dilation requires the use of eye drops. The use of eye drops is standard medical practice and are routinely administered by eye doctors to improve the sharpness of the pictures we take. This plastic bite bar is attached to a steel bar that can be adjusted to a comfortable position for the patient. To measure the aberrations of the eye, it is imperative that the head be still, so once in place the steel bar is tightened down, and the motion of the patient's head is minimized. Every vision group doing similar research has empirically determined that the bite bar set-up is the best method for achieving the desired stability of the eye, as well as providing the most comfort for the patient.
Once comfortably settled and looking into the device, the subject will be asked to look at green and black patterns on a computer screen and press specified buttons depending on what they see. These tasks may seem tedious to the subjects but do not pose a serious risk. A potential risk to the subjects, which is explicitly mentioned in the consent form, is dilation of the pupil of the eye. Subjects are warned about all potential hazards related to pupil dilation before their testing period, and the methods used to mitigate these risks are described. In addition to the computer screen, the subjects will be looking into an infra-red light source [currently a superluminescent diode (SLD)] used for the aberration measurement by the adaptive optics instrumentation. The intensity of this light source was measured by the LLNL Safety Officer and found that it is far below all applicable thresholds for damage or discomfort. The LLNL Safety Officer has calculated that the amount of laser light the subject will be exposed to is about 10 times lower that any ocular damage limits found in the ANSI Z136.1-2000 Safety Handbook. When the subject's retina is photographed, a flash lamp is used for illumination. The light flashes are similar to those routinely experienced by patients in ophthalmic examinations and are well below all applicable damage thresholds but may cause temporary discomfort, and the subjects are notified of this in the consent form. All information obtained in connection with this study will be used in a manner that does not publicly disclose the subject's identity and will be kept confidential. Confidentially is assured by keeping data on each subject on a password-protected computer. Drs. Jack Werner and Thomas Barnes will keep any other records in a locked cabinet behind locked doors. They will view this data for vision research purposes only. A detailed consent form, outlining all potential risks involved in the study, must be reviewed and signed before screening and subsequent testing can begin.
LLNL's involvement in this protocol is the design and support of the hardware used for these tests. Although LLNL personnel may be in the room when the study is being run, they are not involved in subject preparation, application of eye drops, and not involved with subject data collection. These tasks are done by UCDMC personnel exclusively. The LLNL personnel, during alignment of the system, can and may make suggestions regarding placement of subjects, changes to enhance performance, etc., but UC-Davis Medical Center personnel make the final decisions regarding all subject changes.
We expect to discover the limits of normal human visual acuity when optical aberrations in the eye are rendered negligible. The limitations to visual performance will then be due to the physical structure of the retina and to the signal and image processing that takes place in the nerve systems within the eye and in the brain. Precise correction of the aberrations of the eye using the adaptive optics instrumentation is required for success of this project. The quality of this correction will be determined by a series of tests that will include the assessment of retinal images recorded using this instrumentation. We also expect to elucidate the effects of aging and retinal disease on visual performance. This particular study will be complete when the specified subject group has been tested and the results have been interpreted. Subsequent studies may then be initiated to further investigate visual performance issues related to age or disease. The criteria for a successful experiment will be that the data can be interpreted to show a statistically significant relationship between ocular aberrations and visual performance.
"Determining the Carcinogenic Significance of Heterocyclic Amines"
Principal Investigator: Dr. James A. Felton, Lawrence Livermore National Laboratory
Project started in: 2002
This project ended in fiscal year 2007.
Status of the Research this Fiscal Year:
Current study is completed.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 101
Institutional Review Board (IRB) Review:
Type of Review:
Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 08/31/07
IRB approval number: 02-101
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 2007
Type(s) of Human Subjects Involvement:
Recent studies have estimated that many human cancers are caused by modifiable lifestyle factors, including diet. Cooking meat produces compounds that have been shown to cause deoxyribonucleic acid (DNA) mutations in animals and humans and to cause cancer in rats. Although we know that humans are exposed to these compounds, the human health implications of this exposure have not been fully defined. One potential carcinogen found in cooked, well-done meat is 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP).
There are two objectives in this study: (1) to relate individual differences in PhIP urinary metabolite profiles with metabolic phenotypes to predict risk associated with PhIP exposure and (2) to determine if food items such as wheat bran, green tea, and parsley can affect the absorption and/or metabolism of PhIP, thereby decreasing cancer risk.
Experimental design:
Overall requirements of the study population: The volunteers for this study will be recruited from the local workforce and will include no more than 75 healthy individuals. The study will be conducted in two parts: (1) a metabolism study that will provide a metabolic profile of the individuals every six months for 12 months (a total of three measurements) by completing a 24-hour food diary, collecting urine and saliva, and (2) a preventive intervention study that will measure the effects of one of three different dietary modifications. Participation in the intervention part of the study will entail collecting urine an additional time (a total of four urine collections for each subject). No saliva will be collected for the intervention study. Blood will be collected one time during the study for a phenotyping assay. Participants will be compensated $25 for each completed urine collection and $10 for the blood donation; a total of $110 for completing all aspects of the study.
In both parts of the study, PhIP metabolites are measured by having the volunteers consume approximately 150 grams of cooked chicken (approximately two chicken breasts) that has been cooked to contain a known amount of PhIP. Prior to eating the chicken meal the volunteers will be asked to keep a 24-hour food diary that records a description of the food eaten, how much was consumed, and at what time. Urine samples will be collected before eating the meat and for 24 hours after, in six-hour increments. Volunteers will be asked to refrain from eating grilled meats, including pan-fried or flame-grilled hamburgers, steaks, fish, chicken, and bacon for 24 hours before eating the cooked chicken and again during the urine collection period.
In the metabolism stability study we will perform this basic protocol three times during a 12-month period. Within seven days of completing the urine collection, the individuals will also be asked to provide saliva samples for a caffeine phenotyping assay. Subjects will be asked to abstain from caffeine containing foods for 12 hours prior to the caffeine test dose and during the testing period. Approximately one teaspoon of saliva will be collected prior to being given caffeine in the form of one NoDoz tablet (equivalent to one cup of coffee). Additional saliva samples will be collected 4, 6, and 8 hours after the caffeine dose. Saliva samples will be assayed for caffeine metabolites. Caffeine metabolite ratios correlate with the activity of certain metabolizing enzymes that are important for PhIP metabolism. We will correlate the activity of these enzymes (measured by the caffeine assay) with the amount and type of metabolites excreted in the urine. Blood (no more than 30 ml or two tablespoons) will be collected only one time during the entire study from each subject for sulfotransferase phenotyping. Sulfotransferase is another metabolizing enzyme that is important for the metabolism of PhIP. We will correlate the activity of this enzyme with the amount and type of PhIP metabolites excreted. Trained personnel will collect the blood samples in the Lawrence Livermore National Laboratory (LLNL) Health Services Department under strict antiseptic conditions.
In the second part of the study, the preventive intervention phase, we will measure the effects of parsley (4 ounces or 1/2 cup daily), bran (10 grams or two bran muffins daily), or green tea (24 ounces or three cups daily) on PhIP urinary metabolites. The subjects will be given their choice of intervention food. Immediately following one of the collection periods for the metabolic phase of the study, the subjects will consume just one of the food supplements daily for at least three, but no more than seven days. At the end of the intervention period, they will again eat cooked chicken and collect urine for 24 hours.
A subject who completes all aspects of the study will provide four 24-hour urine collections, three 24- hour food diaries, three sets of saliva samples, and a blood sample.
This study involves only the minimal risks present in eating cooked chicken and the intervention foods, donating a blood sample, and the discomfort and embarrassment of collecting urine and saliva. The amount of chicken provided will be the minimum amount necessary to provide enough PhIP to be able to detect metabolites. The identity of the subjects will remain entirely confidential. Subjects will be identified by a code, the code will be associated with the subject's name only on the consent form, and the consent forms will be stored in a locked cabinet. Individuals will be allowed to participate in the study only after they feel comfortable with an explanation of the study and have signed the consent form.
This work will increase our understanding of the risks of being exposed to potential carcinogens in cooked meats. The metabolism study will allow us to determine if there are individuals that may be more or less susceptible, based upon their metabolizing enzyme activity. The results from the intervention phase will provide insight into dietary interactions that may reduce risk from exposure.
"Vitamin B12 Absorption and Metabolism in Humans"
Principal Investigator: Dr. Bruce A. Buchholz, Lawrence Livermore National Laboratory
Project started in: 2002
Status of the Research this Fiscal Year:
Recruitment and/or enrollment of new participants or review of records/specimens continue.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 119
Institutional Review Board (IRB) Review:
Type of Review:
Full Board
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 07/23/07
IRB approval number: 02-119
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 1
Reporting period for number of human subjects:
Fiscal Year 2007
Type(s) of Human Subjects Involvement:
Vitamin B12 (B12 or cobalamin) deficiency is caused primarily by malabsorption. Malabsorption of B12 is diagnosed as pernicious anemia. The gold standard for clinical assessment of B12 absorptive capacity is the Schilling test. Schilling tests are, however, rarely used currently to diagnose B12 malabsorption because the test is cumbersome, unreliable, and expensive, and the material required for its performance, 57Co-cyanocobalamin, is both difficult to procure and dispose. The ability of accelerator mass spectrometry (AMS) to precisely measure attomolar (10 to 18) fluctuations in carbon-14 (14C) in biological samples presents an opportunity to develop an improved and reliable test of B12 absorptive capacity.
Freshly absorbed B12 enters the circulation bound to the serum transport protein, transcobalamin. We have obtained preliminary evidence indicating that a recently characterized common polymorphism (G775C) in transcobalamin may significantly influence B12 absorption, as well as cellular delivery, metabolism, and turnover of the vitamin. AMS will be used to conduct in vivo mass-balance studies of B12 distribution, metabolism, and elimination. The relation between kinetics of B12 absorption and turnover and several genetic variations in enzymes related to B12 will be explored. Human subjects are required to accurately develop a suitable clinical tool for assessing B12 absorption and kinetics.
Objectives
The purpose of the study is to assess the absorption and turnover of a tracer dose of [14C]B12 in individuals with normal and impaired B12 absorptive capacity and to determine the influence of transcobalamin genotype on B12 absorption and turnover in humans.
Methodology
Individual subjects will be studied over a one-year period. On the day of dosing, they will be given a single, oral dose of [14C]B12 (100 nCi, 2.25 microgram, taken in water) followed by a light breakfast (a donut and a cup of coffee or apple juice). Blood will be drawn at baseline, and at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, and 24 hours; and at 2, 3, 4, 5, 6, 7, 10, 14, 21, 28, 35, 42, 49, 100, 150, 200, 250, 300, and 350 days postdosing (35 total blood draws). Blood collected over the first day of the study will be from an indwelling catheter. Subsequent blood draws will be made by needle stick. Mean volume of blood taken at each time point will be ~16 mL (3 teaspoons). Subjects will collect complete (cumulative) 24-hour urine samples and all stool samples on day 0 (starting 24 hours before taking the oral dose of labeled B12) and on each day for 10 days post-dosing (11 samples total). All samples will be processed for 14C measurement at the University of California (UC)-Davis and analyzed by AMS at LLNL. Bioavailabilty and pharmacokinetics will be determined using the data provided by AMS.
Involvement of Human Subjects
Dosing and sampling are described above. Potential risks to the study participants are minimal. Slight discomfort, bruising, and rarely infection may result from the blood draws. To minimize discomfort, bruising, and infection, a licensed phlebotomist using sterile techniques will perform all blood draws. An experienced physician or registered nurse will insert the in-dwelling catheter required for the first day blood collections. The subjects might become anemic due to the multiple blood draws. A 60-mg iron supplement will be given to each volunteer after the 24-hour blood draw to replace the iron removed by the blood draws performed during the first 24 hours. Individual hematocrits will be monitored throughout the study. At-risk individuals will be released from the study. The study will not affect the treatment regimen for the pernicious anemia patients. Although the administered B12 is radioactive, subjects will be exposed to a very small amount of radiation (total effective dose equivalent = 8.16 mrem). For contrast, one receives 3 mrem during a coast-to-coast airline flight. Subjects will complete a dietary questionnaire before beginning the study and be screened for genetic variations in enzymes related to the use of B12, and specifically the G775C genotype in transcobalamin. All subject information will be kept confidential in locked file cabinets by the UC-Davis principal investigator (PI). Subjects will only be identified by number (e.g., S1, S2) in all communication with LLNL. Informed consent agreements will be obtained from all participants and stored at UC-Davis by the PI.
Outcome
The study will provide new information on the absorption and dynamics of B12 in healthy and pernicious anemia subjects under treatment. The study will be terminated at the end of the sampling time.
Conclusion
The study results will constitute a major advance toward understanding the dynamics of B12 absorption and metabolism.
"Identification and Development of Biological Markers of Human Exposure to the Insecticide Permethrin"
Principal Investigator: Dr. Bruce A. Buchholz, Lawrence Livermore National Laboratory
Project started in: 2003
Status of the Research this Fiscal Year:
Recruitment and/or enrollment of new participants or review of records/specimens continue.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 103
Institutional Review Board (IRB) Review:
Type of Review:
Full Board
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 11/08/06
IRB approval number: 03-103
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 3
Reporting period for number of human subjects:
Fiscal Year 2007
Type(s) of Human Subjects Involvement:
Military personnel are exposed to the insecticide permethrin when using the DOD Insect Repellent System. A urinary metabolite of permethrin, that is in high abundance and is relatively stable, may be an ideal biomarker of exposure to this pesticide. Over-exposure to permethrin may result in adverse health effects, thus a rapid monitoring method is desirable. Rodent studies are often not adequate predictors of human metabolism. In addition, the ratio of one metabolite to another may vary, even in humans according to the route of administration. The results of this study would be used to identify candidates for the development of a rapid, sensitive immunochemical based analytical method that can be used to routinely monitor human exposure to permethrin.
The purpose of this study is to determine the human metabolite(s) of permethrin in urine following dermal exposure that are in greatest abundance and are the most stable. Accelerator mass spectrometry (AMS) is a method for measuring levels of carbon-14 (14C) several orders of magnitude more sensitive than liquid scintillation counting. With this ability to measure ultralow levels of 14C, much lower doses of radiolabeled test chemical can be used, making it possible to conduct human metabolism studies at biologically relevant doses.
We will utilize three leading edge analytical technologies in an integrated approach to identify and develop both laboratory-based and field portable methods for the detection and quantitation of human exposure to permethrin. High performance liquid chromatography coupled to a state-of-the-art tandem mass spectrometer (LC/MS) will be used to fractionate and identify urinary metabolites of permethrin. AMS is a method for measuring levels of 14C several orders of magnitude more sensitive than liquid scintillation counting. With this ultrasensitivity, doses of 14C-permethrin reflective of actual human exposure will be used to determine the metabolite profile with minimal radiation risk. The metabolites identified by LC/MS and AMS will be used to develop a rapid, sensitive immunoassay for routine monitoring of human exposure to permethrin.
Six human volunteers will be exposed to low dermal doses of 14C-permethrin for eight hours. Excess permethrin will be removed from the skin by washes with soap and water and tape stripping to remove the outer layer of dead skin at the completion of the experiment. Urine, blood, and saliva samples will be collected over a seven-day period with more frequent time points in the first 24 hours. A pilot study utilizing one subject will be conducted first to test the methods developed for separating anticipated metabolites. An exposure study utilizing five other subjects will provide confidence that the metabolite patterns observed can be a predictor for the general population. The amount of permethrin absorbed by the subjects will be much less than the Environmental Protection Agency (EPA) considers to be a hazard to health. The radiation exposure received in this study is less than that received in a cross-country plane flight and below the level that is thought to result in a significant risk of harmful effects. The results of this study will be published in a biomedical journal. The identity of the participants will not be published. Volunteers will be recruited from the Sacramento, CA area and sign informed consent agreements.
The urinary metabolites will be identified and quantified. Based on this information, the most abundant, stable metabolite or metabolite conjugate will be chosen for the target of the development of an immunoassay. Success will be include a clear quantitative relation between the exposure, absorbed dose, and measured metabolites of permethrin in the urine among the six subjects. If there is little correlation between exposure and absorbed dose, further study will be required to determine other variables that affect absorption. We expect the absorbed dose and metabolite profiles to follow trends among the subjects. The study will be terminated upon completion of exposure and sample collection of the sixth subject.
The results of this study will be used to identify candidates for the development of a rapid, sensitive immunochemical based analytical method that can be used to routinely monitor human exposure to permethrin. The ability to carefully monitor the presence of absorbed doses of permethrin will be a useful tool to prevent the possibility of human health effects due to permethrin exposure.
"Identification of Markers of Human Exposure to Biolgoical Agents: Vaccinia Study"
Principal Investigator: Dr. Kenneth W. Turteltaub, Lawrence Livermore National Laboratory
Project started in: 2003
This project ended in fiscal year 2007.
Status of the Research this Fiscal Year:
Current study is completed.
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 106
Institutional Review Board (IRB) Review:
Type of Review:
Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 01/13/06
IRB approval number: 03-106
Explanation of IRB approval:
Project ended.
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 2007
Type(s) of Human Subjects Involvement:
This study is one component of a broad, long-term Grand Challenge program to elucidate the components and mechanisms of host-pathogen interactions that occur in infectious diseases. Tools of genomics, proteomics, biochemistry, and computer modeling will be applied to study mechanisms of pathogen virulence, and host responses in animals and humans. The purpose of this study is to determine if human blood samples can be used to define the spectrum of molecular changes that occur in infection and the time course of these changes.
The long-term goals of this study are to address the following three hypotheses:
1) Determine if specific biochemical components in blood can be used to detect infection before clinical symptoms are present. These components could be used for pre-symptomatic detection of a naturally emerging epidemic or a biological attack.
2) Determine if the spectrum of host biological changes varies among infectious disease types. The spectra of host responses could be used for early diagnosis of infection type or initiation of therapy.
3) Determine if biological agents with similar virulence mechanisms produce similar patterns of host marker responses. This would allow classification of unknown genetically modified organisms or newly emerging diseases into virulence classes, suggesting likely candidates for therapeutic intervention.
The experimental design is to use the following analytical approaches to identify potential biochemical markers for human infection with vaccinia virus. Broad screens of many candidate markers will be used in this initial discovery phase. We propose studies of gene expression in blood cells, antigen profiles of serum, and protein profiles of serum. Blood samples will be collected into PAXgene tubes to lyse the cells and stabilize the messenger ribonucleic acid (mRNA). Purification of mRNA, reverse transcription, and quantitative polymerase chain reaction (PCR) are used for gene expression analysis. PCR analyses will be performed for 30 to 40 gene loci such as inflammatory cytokines, chemokines, proteinases, proteinase inhibitors, adhesion molecules, receptors, and intracellular signaling systems. Blood samples collected into a serum separation tube are aliquoted for use in protein and antigen studies. The technique of 2-D gel electrophoresis is being used to identify protein spots with differential expression between samples. Surface enhanced laser desorption/ionization-mass spectrometry (SELDI-MS) and liquid chromatography-mass spectrometry (LC-MS) will also be used to screen for protein differences. Multiplex immunoassays will be used to analyze 150 serum components including cytokines, signaling factors, autoimmune antigens, and infectious agent serum antibodies.
Human subjects will be recruited from among health care workers selected for smallpox vaccination at the participating institutions and research personnel selected for vaccination. The Clinical Coordinators will have the responsibility of describing the study, recruiting study subjects, and obtaining informed consent. Participation will involve providing a blood samples and limited questionnaire data. Blood samples not to exceed 10 ml each will be collected at a series of time points before and after vaccination. The medical procedure for obtaining this material is standard (not of an experimental nature) venipuncture, and it is expected that the subject will be able to function normally immediately afterwards. Possible risks and discomforts that may result from the blood draw are considered unlikely but include temporary pain, bruising and/or soreness of the affected tissue or surrounding tissue, formation of scar tissue, infection, and fainting. While there is always some risk from loss of confidentiality, the Principal Investigator and the Clinical Coordinators will take a number of steps to minimize this risk. Development of new detection methods for infectious diseases leading to early treatment and containment of epidemics would be of benefit to individuals in the future.
We anticipate that this study will yield a detailed characterization of gene expression, protein, and antigen profiles in vaccinated subjects. One measure of success would be the identification of early infection markers in blood. Even if specific markers are not identified, the study will be successful if its results assist in designing future studies of infectious diseases.
"Does Tamoxifen Cause DNA Damage in Human Colon?"
Principal Investigator: Dr. Paul T. Henderson, Lawrence Livermore National Laboratory
Project started in: 2003
This project ended in fiscal year 2007.
Status of the Research this Fiscal Year:
Current study is completed.
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 109
Institutional Review Board (IRB) Review:
Type of Review:
Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 02/08/06
IRB approval number: 03-109
Explanation of IRB approval:
Project ended.
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 2007
Type(s) of Human Subjects Involvement:
Scientific context of the study:
Tamoxifen is an antioestrogenic drug used in the treatment of breast cancer and currently being evaluated for use as a chemopreventive agent in women at high risk of developing this disease. It is well tolerated and causes relatively few well-documented side effects. However, tamoxifen causes liver tumors in rats, which is associated with deoxyribonucleic acid (DNA) damage. Furthermore, epidemiological evidence has demonstrated that long-term administration of tamoxifen to healthy women and breast cancer patients leads to an increase in the incidence of endometrial tumors. There is also some evidence that tamoxifen treatment increases the incidence of colon cancers in women. Consequently, the cancer risk associated with taking tamoxifen as a chemotherapeutic agent is a major public health issue.
Hypotheses:
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. Using accelerator mass spectrometry (AMS), we have previously demonstrated that tamoxifen binds to DNA and protein in the uterus of women. Our objective is to use [14C]tamoxifen and the sensitive technique of AMS to measure adducts in human colon tissue samples and then to compare this with our previous data on adduct levels in rats and human uterine tissues. This may give an indication of any potential risk of developing tamoxifen induced colon tumors in humans.
Experimental design:
This study is a collaboration between Lawrence Livermore National Laboratory (LLNL), Leicester Royal Infirmary, UK, and the University of Leicester, Leicester, UK. The design of this study and recruitment of human subjects was undertaken solely in Leicester without any contribution from LLNL. The extent of LLNL involvement will be in the measurement of high performance liquid chromatography (HPLC) fractions, DNA and protein samples by AMS, handling the raw data, and assisting in data interpretation.
In this study, ten female volunteers undergoing colorectal surgery for carcinoma of the colon were administered a single therapeutic dose of [14C]tamoxifen. The human subjects were fully informed as to the nature of the study. Those willing to participate were provided written informed consent. Patients recruited to the study were asked to fill in a simple questionnaire, which centered particularly on the drugs they were taking at the time of surgery. They were then orally administered 50 µCi [1.85 MBq] of [14C]tamoxifen diluted in unlabeled tamoxifen citrate, which provided a dose of 20 mg/person. This dose is equivalent to the normal daily therapeutic dose. The radiation dose was 170.9 µSv, which 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 were taken at the time of surgery. DNA was extracted from each tissue sample and shipped to LLNL for analysis by AMS. In order to protect the confidentiality of volunteers in the study, all patient information will be maintained at the University of Leicester and no information will be disclosed. LLNL will receive only coded samples for analysis.
Brief description of the procedures involving human subjects:
It was explained in the patient information leaflet that there were no direct benefits to the participants and that inclusion in the study would not alter the treatment they were receiving. The patients were informed that there were unlikely to be any side effects from a single dose of tamoxifen, but that the most commonly experienced side effects caused by this type of drug were hot flushes, increased sweating, nausea, leucorrhoea, and dizziness. The patient information leaflet also explained that the tamoxifen would be in a radioactive form but that the radiation dose they would be exposed to is small, less that the natural background radiation we are all exposed to in daily life during the course of two months. It was also stated that no patient information would be divulged to the U.S. collaborators (at LLNL). In order to protect the confidentiality of volunteers in the study, any information relating to the patients will be maintained at the University of Leicester, and LLNL will receive only coded samples for analysis. Analysis of the samples by LLNL will not be associated with any risks to the patients. No adverse effects were experienced by any of the subjects as a result of participation in this study. Participation in this study will not provide any direct benefit to the patient and this was stated in the patient information leaflet. However, the results of this study will provide important information relating to the risks associated with the use of tamoxifen and will therefore be of benefit to women receiving tamoxifen for the treatment of breast cancer and healthy women at a high risk of developing breast cancer.
Anticipated Results:
The results of this study will indicate whether tamoxifen is capable of binding to DNA and protein in the human colon and will, therefore, provide important information relating to the risks associated with the use of tamoxifen, particularly as a chemopreventive treatment in healthy women. The study will end once all patient samples have been analysed and studies have been conducted to determine what proportion of the [14C]-radiolabel measured in DNA samples is due to covalent DNA adduct formation.
"Host Pathogen Interactions: Biomarkers for Early Detection"
Principal Investigator: Dr. Brett Chromy, Lawrence Livermore National Laboratory
Project started in: 2003
Status of the Research this Fiscal Year:
Protocol approved, but no funding and no human participants
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 113
Institutional Review Board (IRB) Review:
Type of Review:
Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 06/11/07
IRB approval number: 03-113
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Fiscal Year 2007
Type(s) of Human Subjects Involvement:
Protein levels in human blood are characterized to identify potential biomarkers for early detection of infectious disease.
The hypothesis is that an infection results in a distinct host response that can be measured before symptoms occur.
Blood is drawn from healthy volunteers and exposed to human pathogens in the laboratory. After four hours, plasma and white blood cells are collected, and protein differences are measured by proteomic methods.
Blood will be drawn by venipuncture by staff at Lawrence Livermore National Laboaratory (LLNL) Health Services or in an office in the Chemistry, Materials and Life Sciences Directorate by a certified laboratory phlebotomist. Risks are low but include temporary pain, bruising and soreness of the affected tissue, formation of scar tissue, infection, and fainting. Benefits of the study include the ability to rapid and specific detection of human disease prior to onset of symptoms, which has the potential to save lives in the event of an outbreak or epidemic. At no time will health status be drawn from experimental results.
We expect to identify biomarkers that are distinct for exposure to different human pathogens. Success will be measured by validation of biomarkers via the ability to distinguish "blinded" samples.
"Monitoring Bone Resorption Using 41Ca and Accelerator Mass Spectrometry"
Principal Investigator: Dr. Darren J. Hillegonds, Lawrence Livermore National Laboratory
Project started in: 2003
Status of the Research this Fiscal Year:
Recruitment and/or enrollment of new participants or review of records/specimens continue.
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 114
Institutional Review Board (IRB) Review:
Type of Review:
Full Board
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 05/09/07
IRB approval number: 03-114
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 2007
Type(s) of Human Subjects Involvement:
Background:
Bone is a complex tissue that is in a continuous state of remodeling. The balance between bone synthesis and resorption is determined by many factors including diet, hormones, active vitamins, gastro-intestinal function, and renal status. Currently, most of the laboratory methods for determining the status of bone health are indirect. The ideal measure of bone health would be a direct measurement of the amount of calcium (Ca) that is being resorbed from the bone matrix. This can be accomplished using accelerator mass spectrometry (AMS).
Hypotheses:
Specific Aim #1 is to establish baseline pharmacokinetic data on the excretion of 41Ca in healthy adult volunteers. The primary parameter of interest is the terminal elimination halflife of 41Ca after equilibration with the stable bone pool of calcium.
Specific Aim #2 is to compare currently available techniques for assessing bone resorption, such as standard blood chemistries, hand x-rays, bone density scans, and parathyroid hormone (PTH) measurements with 41Ca excretion.
Specific Aim #3 is to use 41Ca to monitor bone turnover in chronic renal failure (CRF) patients on hemodialysis. In order that these results be clinically relevant, the subjects must be human.
Experimental design:
Up to 10 healthy male volunteers and 10 chronic renal failure patients on hemodialysis will be studied. These volunteers will be given a 10 mL intravenous injection of a saline solution containing 370 Bq 41Ca as calcium carbonate, and the kinetics of the 41Ca will be monitored over a two-year period.
The study protocol will include the following tests:
1. Standard Blood Chemistries - every month (calcium, phosphorus, alkaline phosphatase, blood urea nitrogen, creatinine, sodium, potassium, chloride, carbonate, and glucose)
2. Bone mineral densitometry - baseline and at 18 months
3. PTH blood measurements - every month
-PTH intact (Quest Diagnostics)
-PTH mid-molecule (Dr. Deftos' laboratory)
-PTH whole (Quest Diagnostics)
-Bone markers: N-telo peptides and bone alkaline phosphatase (Quest Diagnostics)
4. Accelerator mass spectrometry analysis of 41Ca in urine and serum. Baseline urine and serum samples will be drawn prior to beginning the study to ensure that 41Ca levels are zero. Twenty-four hour urine samples will be collected for the first day after dosing. Serum samples will be drawn at 2 hours, 24 hours, 48 hours, 72 hours, 7 days, 14 days, and 28 days after dosing and at monthly intervals thereafter. Urine samples will be collected on day 2, day 3, day 7, day 14, and day 28 at the time of the blood draws. After the first month, urine samples will be collected at monthly intervals at the time of the blood draws.
5. Other protocol tests - hand radiogrammetry (hand x-rays) - baseline and at 18 months.
All blood draws will be 10 mL. The total number of blood draws will be day 1 (three samples), day 2, day 3, day 7, day 14, day 28, and monthly draws (23 samples) for a total of 31 samples from each subject.
Brief description of the procedures involving human subjects:
There are very limited risks from participation in this study. All volunteers will receive a small dose of radiation as a result of the 41Ca tracer, equivalent to about three minutes of a commercial airline ride. An additional radiation dose for all study participants will result from two hand x-rays and two dual x-ray absorptiometry (DEXA) measurements of bone density; the x-ray dose is similar to that received during a typical medical x-ray procedure.
Anticipated results:
We anticipate that the 41Ca assay will be a useful measure for calcium homeostatic parameters including bone turnover. We hope that our results will result in improved clinical management of patients with renal problems including renal failure.
"The Effect of Dietary Protein on Calcium Metabolism"
Principal Investigator: Dr. Darren J. Hillegonds, Lawrence Livermore National Laboratory
Project started in: 2003
Status of the Research this Fiscal Year:
Recruitment and/or enrollment of new participants or review of records/specimens continue.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 115
Institutional Review Board (IRB) Review:
Type of Review:
Full Board
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 05/09/07
IRB approval number: 03-115
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 48
Reporting period for number of human subjects:
Fiscal Year 2007
Type(s) of Human Subjects Involvement:
Scientific context:
Osteoporosis is a major health concern worldwide. While there are drugs available for the treatment and prevention of osteoporosis, they are not practical for population-wide prevention efforts. Demonstrating the effectiveness of safe and widely available dietary interventions to prevent osteoporosis could have important public health ramifications.
Hypotheses:
Different food sources of dietary protein may have different effects on bone metabolism. Animal foods provide a dietary acid load that may lead to negative calcium balance and increased bone resorption. In contrast, vegetable sources of protein, while providing some acid due to their protein content, provide proportionally more base that counters the dietary acid load. The effect of dairy products, which are rich in animal protein but also contain potential base precursors not found in vegetable foods, has not been established. Finally, soy protein sources may have a dual benefit: soy foods provide base precursors as well as plant estrogens that may have a beneficial effect on bone.
Experimental design:
We propose to study randomized postmenopausal women using one of four diets equal in calories, protein, calcium, and sodium. The diets will differ by having 80 percent of the protein from one of the four sources: non-dairy animal, vegetable, dairy, or soy foods, resulting in significant differences among the diets in acid, base, and isoflavone content. All food will be prepared and provided by the General Clinical Research Center (GCRC). The subjects will consume the diets for six weeks with measurements of acid-base status, isoflavone excretion, and calcium metabolism (including urinary 41Ca/Ca).
Procedures involving human subjects:
Research participants will consume 185 Bq of 41Ca contained in 200 mg calcium carbonate. After an equilibration period of 100 days, subjects will begin their study diet and continue eating this diet for eight weeks. Volunteers will visit the GCRC a total of 20 times. During five of these visits, blood and urine will be collected. There will also be one intravenous infusion of a stable calcium isotope during the last week of the study period.
This project entails little physical risk. The intervention in this study consists of food items readily available in grocery stores. The 41Ca tracer is very benign and involves a radioactive dose equivalent to one minute of a commercial airline ride. One blood draw will involve gentle heating of the forearm and hand using a fixed-temperature heating pad after insertion of a butterfly needle into a superficial vein in the participant's hand. This so-called arterialized venous blood sample allows determination of blood pH, pCO2, pO2, and HCO3-values without the discomfort and risks associated with collecting a true arterial blood sample.
Anticipated results:
We anticipate that these study results will elucidate the specific differences between different types of food protein and how they affect factors associated with bone turnover.
"Molecular Modulation of Calcium Crystallization"
Principal Investigator: Dr. James De Yoreo, Lawrence Livermore National Laboratory
Project started in: 2003
Status of the Research this Fiscal Year:
Study protocol is inactive.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 126
Institutional Review Board (IRB) Review:
Type of Review:
Expedited
Approving Institution: Lawrence Livermore National Laboratory
Most recent approval: 07/31/06
IRB approval number: 03-126
Explanation of IRB approval:
Current protocol is not approved. Awaiting additional documentation from 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 2007
Type(s) of Human Subjects Involvement:
Understanding the molecular mechanisms of biological control over calcium oxalate (CaOx) crystallization is crucial for development of effective kidney stone disease therapies. Moreover, extension to other systems may suggest strategies for synthesis of biologically inspired materials as well as treatment of other hard tissue diseases. Calcium oxalate monohydrate (COM) which plays a functional role in plant physiology is a source of pathogenesis in humans, causing kidney and renal stone disease. Despite extensive research on COM modification by proteins and small molecules, the control mechanisms remain unknown.
The specific aims of this study are: determine the mechanisms of modulation of CaOx nucleation and growth by small urinary modulators, determine the mechanisms by which urinary modulators affect the sequence of events during phase transformations of CaOx, and understand the surface events underlying protein modulation of CaOx crystal aggregation.
The involvement of human subjects at Lawrence Livermore National Laboratory (LLNL) is limited to utilization of proteins purified from urine specimens obtained from subjects enrolled in a study previously conducted by Dr. John Hoyer (co-investigator on this project) and Dr. John Asplin at the University of Chicago. Dr. Hoyer at the Children's Hospital of Philadelphia obtained coded samples from Dr. John Asplin collected under grant (DK33501-12AI). He purifies the protein and sends the coded samples to Dr. De Yoreo for use in the current project (1R0DK61673-01).
For all of the urine samples obtained from normal individuals (not patients with stone disease) use of a consent form was waived by the LLNL IRB and the IRB at the University of Chicago. Only samples of proteins from normal individuals will be studied in the present LLNL grant from the National Institutes of Health (NIH). The urine samples from normal individuals were collected and used as the source for purification of proteins in the laboratory.
Some urine samp