2004-2005 CROET Highlights
Surveillance, Applications and Outreach
CROET conducts workplace surveillance so that prevention and research needs can be identified, and applications research to bring the benefits of science to the workplace floor. It also reaches out to provide education and information to the Oregon workforce and beyond.
Oregon Fatality Assessment and Control Evaluation (OR-FACE) ProgramDr. Gary Rischitelli leads the Oregon Fatality Assessment and Control Evaluation (OR-FACE) program that tracks, investigates, and reports on occupational fatalities in Oregon. Each incident is investigated, entered in a database, and codes are added for industry, occupation, and event. During 2004 and 2005, OR-FACE recorded 62 and 67 fatalities, respectively. OR-FACE investigates incidents in specific national and local target areas of concern, and each year produces about 12 investigation reports with safety recommendations. During 2004-05, OR-FACE also published two hazard alerts — one on electrocution from high-voltage power lines during highway work and another on the unexpected finding that parked vehicles are a common cause of fatal injury. In 2005, OR-FACE published its first annual report, summarizing data from the program’s first full year of operation in 2003. The report charted frequencies by age, gender, race/ethnicity, day, time, month, county, industry, occupation, and event and included an abstract of each incident. Principal areas of concern were highlighted in relation to logging, mobile machinery, and transportation. In the 2004 annual report, an additional area of concern was observed in an elevated fatality rate among workers aged 65 and over, including a high incidence of falls and suicide. OR-FACE investigation reports and other publications are available on the program’s website (www.ohsu.edu/croet/face). Investigation reports from Oregon and other FACE states are also available in the electronic library maintained by the National Institute for Occupational Safety and Health (www.cdc.gov/niosh/face), which funds the program.
Computer-based Training Effective for Shop Floor Workers (food services)In collaboration with an urban hospital in Portland, Dr. Kent Anger provided interactive computer-based safety training to workers in a food services department that supplies food to hospital patients, visitors, and staff. The food services workers evaluated the training very positively. Based on tests given before and after the training, knowledge improved significantly. Generalization of the knowledge to the workplace was confirmed by increased accuracy in answering on-the-job questions that required application of knowledge to the work setting. Observations were also made of work practices and workplace conditions before and after the training. Problematic kitchen conditions, such as puddles, decreased after-training and after-adjustment for increasing production/workload. Work practice improvement was seen in three-fourths of the workers. These findings demonstrate that the benefits of computer-based safety instruction extend to blue collar workers who do not usually receive computer-based training, which is only rarely studied. It is even more rare for research to study and report changes in reaction (did they like the training?), knowledge, and behavior or work practice change, which adds confidence to the findings. This and other studies demonstrate, in an experimentally rigorous way, that computer-based training can be used with workers on the shop floor, not just in offices where it is most typically used. This work was published in the Journal of Safety Research.
Evidence of Increased Pesticide Metabolic By-Products in Agricultural AreasDr. William Lambert and others at CROET have been investigating the possibility that children of migrant farm workers are at increased risk of exposure to organophosphate (OP) pesticides due to “carry-home” transport processes and residential location. Although this at-risk status is generally recognized, few available reports describe the extent of this exposure among agricultural communities. It is very difficult to measure the very low levels of pesticide exposures, so Dr. Lambert and others at CROET quantified the metabolic products of organophosphate pesticides in samples of urine from 176 children, 2-6 years of age. The children were from three Oregon communities hosting differing agricultural industries: pears, cherries, and fruit berries. Up to three spot samples of urine were collected from children at the beginning, mid-point, and end of their parents’ work seasons. The median levels of dimethylthiophosphate (DMTP), the most commonly detected metabolite of OP pesticides, was 2.5 to 4 times higher in urine samples from children in the agricultural communities when compared to a reference group of children who lived in an urban community and whose parents did not work in agriculture. After controlling for confounders, the median level of DMTP in children in the pear community was 1.92 times higher than the level in children of the berry community and 1.75 times higher than the level in children of the cherry community. DMTP levels increased across the work season only within the berry community. Levels decreased in the cherry community and remained constant in the pear community. This variation across time in pesticide levels within the children who were followed demonstrates the need for multiple urine samples to accurately characterize longer term and/or cumulative exposure. This variability could be attributed to the types and amounts of organophosphate pesticides used, the timing of applications and degradation of residues in the environment, work operations and hygiene practices, the proximity of housing to orchards and fields, or the movement of these working families.
Improved Training for Beginning Flight StudentsFlight students have the highest risk of landing accidents when flying solo during their first 30 hours of training. Since training innovations may help prevent these potentially fatal crashes, Dr. Ryan Olson investigated the potential benefits of one type of interactive training for new flight students. Personal Computer-Based Aviation Training Devices (PCATDs) are increasingly sophisticated and affordable, but are currently approved only for limited instrument training with experienced students. Dr. Olson hypothesized that PCATDs could be used strategically to prevent landing crashes among novice pilots. In 2005, Dr. Olson published evidence in the Journal of Aviation/Aerospace Education and Research that experimental PCATD training during the first 30 flight hours may improve multiple performance measures. Since no measurable harm was found, early PCATD training should be tested more aggressively as a risk-management intervention.
CROET Outreach Expansion ContinuesCROETweb.com is the Center’s occupational safety and health resource directory that provides information 24 hours a day, seven days a week.
• CROETweb topics expanded from 46 different English topics in 2004 to 72 topics
• Spanish-language topic pages expanded from 37 in 2004 to 60 topic pages
• More than 1,250 links are posted on the CROETweb page
more than 19,000 downloads in 2004-2005.
• When Employees’ Personal Lives Interact with Occupational Safety and Health
• The Multidimensional Causes of Accidents and Injuries
Exhibits• Central OR-OSHA; Southern OR-OSHA; Cascade Western Pulp & Paper (OR-OSHA)
• Northwest Occupational Health Conferences
• Governor’s Occupational Safety and Health (GOSH) Conference
• NexCon Construction Summit
• Oregon Governor’s Fire Service Summit
• Healthcare Ergonomics
• Oregon Worker Compensation Educational Conference
CROET Advisory Committee
Injury and Recovery of the nervous System and Muscles
CROET scientists conduct basic research that examines the causes of injury to nerves and muscles in order to identify protective, preventive, and recovery methodologies for such injuries.
Organophosphate but not Pyrethroid Pesticides Associated with Airway Muscle Spasm
Important Mechanisms of Neuronal Protein Transport Revealed
Dominant Schwann Cell Role in Nerve Function and Recovery from Injury
area than almost any cell in the body. How Schwann cells form myelin was described at the level of cell behavior many years ago. But little is known about what tells Schwann cells to form myelin in the manner required for normal function. Dr. Bruce Patton’s research on a family of proteins called laminins has led to the discovery that they control Schwann cell proliferation and the decision to form myelin in the manner required for normal function. The laminin proteins form a covering sheet on the outer surface of the myelin, like the cellophane on a new roll of wrapping paper. Mice engineered to be missing the laminins had a normal set of nerves, but none of the nerve fibers were myelinated. The mutant Schwann cells were stuck in an immature state, unable to respond to signals to either proliferate or myelinate nerve fibers. Further studies revealed that laminins serve as a sort
of molecular switch, which not only determines the ability of the cells to change after birth, but also ensures that cells proliferate in exactly the proportion needed for the size of the nerve. Dr. Patton is now deciphering molecular networks inside the cells that respond to this laminin switch, in hopes that clinical workers in the future can not only increase functional recovery during nerve regeneration after injury, but possibly reduce the extent of injury in the first place. Dr. Patton’s original report can be found at www.jcb.org/cgi/content/abstract/168/4/655.
Chronic Disease and Working Safely
Chronic disease takes a significant toll on our workforce just as it does in the broader community. CROET research seeks to discover causes of chronic diseases that are produced or exacerbated by workplace factors and identifies processes or procedures that can prevent or ameliorate those diseases and improve workplace safety.
Model of Metabolic Syndrome in Obesity
The growing epidemic of human obesity is estimated to affect more than 60 million adult Americans, with secondary consequences including, but not limited to, decreased job performance, increased medical costs, decreased life span, non-alcohol-induced fatty liver disease, increased cardiovascular disease, and an increased incidence of stroke and type 2 diabetes. A majority of the obese population (more than 45 million Americans) has a combination of at least four of these diseases, collectively known as the Metabolic Syndrome. The underlying cause of these diseases is believed to be a combination of genetic susceptibility and chemical stressors, including exposure to pro-oxidant chemicals. Recently, Dr. Stephen Lloyd and his group have created genetically modified mice that are unable to repair certain types of oxidative DNA damage, and discovered that these mice develop symptoms consistent with all the defining hallmarks of the Metabolic Syndrome: severe obesity, disruptions in blood lipids, insulin resistance, and hyperleptinemia. Oxidative damage is believed to underlie some occupational disorders as well as diseases affecting broad segments of our population. The outcome of these investigations will be to provide a working model of the Metabolic Syndrome with which to design and test effective human therapies. By reducing the incidence or severity of disease associated with obesity, a healthier and more productive workforce can be realized.
Neurodegeneration: Drosophila, a Model Test System
Dr. Doris Kretzschmar uses the fruit fly, Drosophila melanogaster, to study basic mechanisms of neurodegeneration that are known to occur in occupational (e.g., chronic solvent exposure) and other diseases, including Alzheimer’s disease. A key factor in Alzheimer’s disease is the production, within the central nervous system, of small protein fragments called Aß, which are the major component of the amyloid plaques found in the brains of Alzheimer’s patients. Aß is known to be produced by enzymatic cleavage of a larger protein called Amyloid Precursor Protein; therefore, if a drug can be developed to inhibit the enzymes involved in this processing step, it may be possible to treat Alzheimer’s disease. However, besides Aß, three more protein fragments are produced by these enzymatic cleavage events. The Kretzschmar laboratory is using Drosophila as an easily manipulated experimental animal model to study these fragments because they have shown that the pathogenic functions of Aß, including plaque formation and neuronal cell death, are the same as in human disease. An understanding of the function of the other Amyloid Precursor Protein fragments might aid the design of therapeutic drugs that have fewer adverse side effects than currently used drugs. Moreover, changes in the cleavage pattern as occurs in Alzheimer’s disease might disrupt functions mediated by these other fragments, an effect that may also contribute to the disease. Although most cases of Alzheimer’s disease are thought to be sporadic, several environmental and occupational agents have been described as risk factors. The Drosophila model can now be used to study the effects of such factors. By gaining a more complete understanding of the mechanisms of neurodegeneration in the fruit fly, it will be possible to transfer that knowledge from insects to vertebrates, to develop a fuller understanding of processes involved in a variety of human neurodegenerative diseases, including occupational diseases. More information about Dr. Kretzschmar’s work with fruit flies can be found in the CROET Newsletter, Volume 14, No. 2 (2006), located at www.ohsu.edu/croet/about/pubs.cfm.
Mechanisms Underlying Chronic Health Effects of Organic Solvents are Illuminated
Organic solvents are valuable chemicals with a multitude of uses in a variety of industry sectors. While many are considered safe, a few solvents have the potential to cause neurological disease. Identifying the bad actors, and the reasons for their neurotoxicity, continues to be an important area of investigation in the laboratories of Dr. Peter Spencer and Dr. Mohammad Sabri. Previously reported studies revealed that both straight chain (aliphatic) and ring-structure (aromatic) solvents have neurotoxic potential if their metabolites possess chemical side chains with a particular (gamma-diketone) structure. Advanced methods of protein and gene analysis (toxicogenomics, see below), in combination with mass spectrometry, are being applied to understand why these chemicals are problematic and how they attack the nervous system. Drs. Spencer and Sabri demonstrated that the neurotoxicity of these solvents is directly related to a variety of specific chemical and physical characteristics of proteins, such that proteins in the nervous system are differentially susceptible to damage from the solvent metabolites. They also found that the loss of neuroproteins is accompanied by changes in gene expression that precede the onset of pathological changes in nerve fibers that underlie the appearance of neurological disease. This is hoped to lead to an understanding of how to predict which organic solvents have the potential to cause neurotoxicity and which are safe to use in the workplace.
Publication in Nature Methods Sets Standards for the Practice of Toxicogenomics, a Leading-edge Research Method to Assess Impacts of Stressors on Gene Expression and Its Relationship with Health and Disease
Toxicogenomics is a powerful method to analyze the response of biological systems to changes induced by chemicals, drugs, trauma, and other agents that cause disease and injury. Tens of thousands of genes are simultaneously interrogated to determine whether and how gene expression has been changed from the normal state. The resulting mass of data is interpreted with software that reveals alterations in molecular networks that correlate with abnormal function or a disease state. The reproducibility of this new technique was examined by a CROET investigative team, part of a prestigious Toxicogenomics Research Consortium (TRC) funded by the National Institutes of Environmental Health Sciences (NIEHS). CROET at OHSU
carried out experiments conjointly with TRC members at NIEHS, MIT, Fred Hutchinson Cancer Research Center, University of Washington, Duke University and University of North Carolina. The collaborative research effort revealed critical elements, including the quality and stability of the microarray platform, the precision of the experimental procedures, anchoring gene expression data to established biological landmarks, and the power of innovative biostatistical methods to extract information from the mountain of data that results from toxicogenomics experiments. In sum, these studies show the challenges as well as the strengths of toxicogenomics as a tool to probe and increase understanding of health and disease.(Bammler, et al., Nature Methods, 2005; 2: 351-356).
Reducing the Risk of Prostate Cancer
Prostate cancer is the second leading cause of cancer deaths among U.S. men, and there are currently few options for prevention. Prostate cancer is most likely to be diagnosed in men over the age of 50, and many men are diagnosed with this potentially debilitating disease while still an active part of the workforce. While treatable if caught early, surgery is highly invasive, and five-year survival rates for recurrent disease remain quite low. Dr. Jackilen Shannon has found that men who have been prescribed statins to treat high cholesterol have a 65 percent lower risk of developing prostate cancer than men who have taken no statins at all. When the men were analyzed separately according to the severity of their cancer at diagnosis, the
association between statin use and prostate cancer prevention was found to be strongest for the more severe cases. One hundred prostate cancer patients were recruited into the study. They had been referred for prostate biopsies at the Portland Veterans Affairs Medical Center (PVAMC) because of elevated prostate-specific antigen (PSA) levels, or abnormal prostate exams. Statin use among these men was recorded and compared to the use of statins among a control group of 202 PVMAC patients whose PSA levels had remained unchanged for a year. Statin use was grouped by duration and intensity of use: those who had used statins for the longest period (more than 2.8 years) and at higher doses (average daily dose of more than
40mg/day) reduced their risk the most. (Shannon et al., American Journal of Epidemiology, 2005; 162: 318-325)
Integrity of DNA (DNA damage, genetic alterations, and disease)
Human health and risk for disease ultimately depend on the integrity of our DNA, the genetic material that provides the body’s blueprint for manufacturing proteins that carry out the function of cells and organs. Aberrant forms of DNA can produce inherited diseases, and changes in DNA during life are believed to trigger cancer and many other chronic diseases. Such changes can result from exposure to certain chemicals found in the workplace and others in the diet and medications. Two broad types of DNA changes are recognized: DNA damage and DNA silencing.
Persistence of DNA Damage After a Single Exposure to Ionizing Radiation
DNA damage represents one of the earliest steps in the development of cancer because such damage can lead to mutations in genes that function to prevent cancer. Mutation is defined as changes in DNA structure that alter the ability of a gene to make a protein. Because proteins constitute the basic functional machinery of cells, the resultant change in the amount or activity of a protein (after DNA mutation) can fundamentally alter cellular behavior. Ionizing radiation, such as the common X-ray or ultraviolet radiation from sunlight, causes two types of DNA damage: (1) breaks in the DNA strand and (2) damage to nucleotides, the building blocks of DNA. Cells have a variety of mechanisms to repair DNA damage and hence avoid the
induction of a harmful mutation. Dr. Mitchell Turker’s laboratory is asking whether DNA damage caused by exposure to ionizing radiation persists in tissues or whether the damage is fixed by DNA repair mechanisms. Some mouse tissues are exposed to ionizing radiation while others are shielded from exposure. DNA damage is assessed in tissues of the irradiated mice by examining chromosome structure (chromosomes contain the DNA strands) long after treatment. The results demonstrated that specific types of chromosome abnormalities caused by ionizing radiation persist for two years and at levels that were essentially the same as those observed one to four weeks after exposure. Although the ionizing radiation dosages used for this experiment were far higher than those employed in diagnostic procedures, these results support the concept that such procedures should be limited only to those necessary for medical evaluations. While we have learned a great deal about acute exposures, the effects of long-term exposure to low doses of ionizing radiation is still an open question.
Mutations Increase with Age in Mouse Tissues
The greatest risk factor for cancer is age, and cancer is more common in older than in younger persons. This is believed to reflect basic changes in cell structure and function as people get older, but the exact nature of these changes remains to be determined. One type of cellular change that is important in cancer is gene mutation, which occurs when the DNA sequence is altered and expression of genes required to prevent cancer is lost. Dr. Turker examined the frequency of mutations most commonly found in cancer cells of two cell types from mice ranging in age from 6 months to 36 months (laboratory mice rarely live past 40 months of age). The cell types examined were those found in connective tissue and kidney epithelial cells. Most tumors that increase with age arise from epithelial cells. The results of Dr. Turker’s experiments demonstrated a steady increase in the frequency of mutations for the kidney cells as a function of age, which was higher at all ages in the female mice. Interestingly, female mice do not live as long as male mice in the strain that was used for this study. For the connective tissue cells, an age-related increase in mutations was only observed for female mice and only in the oldest females. These results demonstrate that mutations with relevance for cancer increase with age mostly in epithelial cell types and suggest that this cell-type-specific increase plays an important role in cancers that arise in older individuals.
The federal government, the State of Oregon, and OHSU encourage the translation of research findings into immediate real-world benefits to society. Often that is in the form of commercial products that generate income for OHSU, part of which returns directly to the laboratory where the idea for the product was generated. This is a natural outgrowth of CROET’s legislative mandate since many of its research activities are aimed at solving workplace probems, either through prevention or treatment. Two corporate spinoffs and one for-fee service operating within CROET have achieved significant milestones in 2004-2005. They are described below.
Restoration Genetics, Inc.
The occurrence of skin cancer is rapidly increasing, affecting more than 1 million people in the United States annually. Sunlight exposure produces DNA damage or lesions, and they in turn can produce cancer. Human cells have only one mechanism to repair these DNA lesions, whereas lower organisms possess multiple pathways for protection against the adverse effects of sunlight exposure. In order to implement proactive strategies to prevent skin cancer, Dr. Amanda McCullough and Dr. Stephen Lloyd have discovered, characterized and patented multiple DNA-repair enzymes that possess activities that can initiate a second DNA-repair pathway in human cells. Cell-based studies have demonstrated that repair of sunlightinduced DNA damage can be improved 100 fold over that of non-treated cells. Based on these patented technologies, Drs. McCullough and Lloyd
co-founded a start-up biotechnology research and development company, Restoration Genetics, Inc., in August 2004. In 2005, the McCullough and Lloyd laboratories were awarded a Springboard Grant from OHSU to facilitate start-up operations for the company. Additionally, a BioScience Innovation Fund Grant from OHSU was awarded to provide funds to demonstrate the feasibility of incorporating these enzymes in an active form in skin-specific vesicles that, upon topical application to skin, will enhance repair of sunlight-induced DNA damage. What this promises is a postsunburn application that can reverse the damage done to the DNA in the skin. These technologies have the potential to repair the most harmful damage caused by sunlight exposure. By restoring the cellular DNA to its original state, mutations that could lead to cancer are prevented and the skin’s immune responses are restored. It is envisioned that this technology could be used either pre- or post-sunlight exposure, resulting in improved skin health.
Northwest Education Training and Assessment, LLC (NwETA)
Computer-based training is efficient but developed largely by and for well-educated segments of the working population. In 1999-2001, Dr. Kent Anger and Dr. Diane Rohlman developed cTRAIN, a computer-based training software aimed at training populations that had limited or no experience with computers. In 2005, the cTRAIN software was licensed by OHSU to Northwest Education Training and Assessment (www.nweta.com), an OHSU spin-off company formed by Dr. Anger, Dr. Rohlman and other colleagues. The goal of the company is to commercialize cTRAIN and use the proceeds from sales to evolve the software in order to maintain and enhance its utility and competitiveness with other training software. The
software presents training created in Dr. Anger’s laboratory, but it also has an editing tool in which new content topics can be created. The cTRAIN computer-based training program received seed funding from an OR-OSHA grant to the Painter’s District Council. Through this grant, Dr. Anger and Mr. Kirkpatrick developed training content on respiratory protection that is still in use at the Painter’s District Council Training Center today. Federal grants further supported the development of content on slip-and-fall safety in food service operations, ladder safety in agriculture, ergonomic issues in dry wall finishing, hazard communication, Worker Protection Standard for agricultural workers, and a variety of training content programs for vineyards. This led to a small business grant to NwETA from the National Institute of Environmental Health Sciences and a cooperative agreement from the National Institute for Occupational Safety and Health (NIOSH) to develop training content programs for vineyards in collaboration with Leda Garside, RN, BSD, of Tuality Healthcare ¡Salud! Services. NwETA’s goal is to bring the efficiencies and advantages of computer-based training to every working person, including those in the workforce with limited or no education.
Chemical Risk Information Service
OSHA regulations require employers to maintain Material Safety Data Sheets (MSDS) for hazardous chemicals used in their workplace. This often proves to be a difficult record-keeping task, and it can be burdensome to ensure that employees have quick access to health and safety information in the workplace when they need it. Since 1998, CROET’s Chemical Risk Information Service, directed by Dr. Gregory Higgins, has helped a growing number of local and international industries manage and distribute chemical safety information through its computer-based MSDS management system. CROET’s working relationship with the Oregon Poison Center also ensures that employees covered by the program have ready access to medical information in the event of exposure. During 2004-2005, the Chemical Risk Information Service provided MSDS management
services to more than 35 municipal, construction, and service companies, most of which are Oregon-based. CROET is currently focused on upgrading the database system and improving client websites for MSDS management. All database files and websites were relocated from CROET’s local server to OHSU’s main server bank, which improved the security and reliability of the service. We also began development of improved search codes for clients to retrieve MSDSs, so that they can begin to search not only by product name, but also by key location parameters at their facilities. This change allows clients to use CROET’s system as an inventory control mechanism, as well as a source for MSDSs. CROET continues to provide expert MSDS management service at a reasonable cost which is attractive to both small and large organizations.