Biomedical subjects

Elaine M Faustman

Publications and source records attributed to Elaine M Faustman.

At least 19 recordsLinked to original sources

PubMed2007

Computational models of neocortical neuronogenesis and programmed cell death in the developing mouse, monkey, and human.

This paper presents a computational model allowing quantitative simulations of acquisition of neocortical neuronal number across mammalian species. When extrapolating scientific findings from rodents to humans, it is particularly pertinent to acknowledge the importance of the accelerated enlargement of the neocortex during human evolution. Neocortex development is marked by discrete stages of neural progenitor cell proliferation and death, neuronal differentiation, and neuronal programmed cell death. We have developed computational models of human and rhesus monkey neocortical neuronal cell acquisition based on experimentally derived parameters of cell cycle length, commitment to cell cycle exit, and cell death. Our model results agree with independent stereological studies estimating neocortical neuron number in adult and developing rhesus monkey and human. Comparisons of our primate models with previously developed rodent models suggest correlations between the lengthening of the duration of the neuronogenesis period and a lengthening of the cellular processes of cell cycle progression and death can account for the vast increase in size of the primate neocortex. Furthermore, when compared with rodents, we predict that cell death may play a larger role in shaping the primate neocortex. Our mathematical models of the development and evolution of the neocortex provide a quantitative, biologically based construct for extrapolation between rodent and humans. These models can assist in focusing future experimental research on the differing mechanisms of rodent versus human neocortical development.

Aging↗

PubMed2006

A system-based approach to interpret dose- and time-dependent microarray data: quantitative integration of gene ontology analysis for risk assessment.

Although microarray technology has emerged as a powerful tool to explore expression levels of thousands of genes or even complete genomes after exposure to toxicants, the functional interpretation of microarray data sets still represents a time-consuming and challenging task. Gene ontology (GO) and pathway mapping have both been shown to be powerful approaches to generate a global view of biological processes and cellular components impacted by toxicants. However, current methods only allow for comparisons across two experimental settings at one particular time point. In addition, the resulting annotations are presented in extensive gene lists with minimal or limited quantitative information, data that are crucial in the application of toxicogenomic data for risk assessment. To facilitate quantitative interpretation of dose- or time-dependent genomic data, we propose to use combined average raw gene expression values (e.g., intensity or ratio) of genes associated with specific functional categories derived from the GO database. We developed an extended program (GO-Quant) to extract quantitative gene expression values and to calculate the average intensity or ratio for those significantly altered by functional gene category based on MAPPFinder results. To demonstrate its application, we applied this approach to a previously published dose- and time-dependent toxicogenomic data set (J. F. Dillman et al., 2005, Chem. Res. Toxicol. 18, 28-34). Our results indicate that the above systems approach can describe quantitatively the degree to which functional gene systems change across dose or time. Additionally, this approach provides a robust measurement to illustrate results compared to single-gene assessments and enables the user to calculate the corresponding ED(50) for each specific functional GO term, important for risk assessment.

Animals↗

PubMed2006

Policy implications of genetic information on regulation under the Clean Air Act: the case of particulate matter and asthmatics.

The U.S. Clean Air Act (CAA) explicitly guarantees the protection of sensitive human subpopulations from adverse health effects associated with air pollution exposure. Identified subpopulations, such as asthmatics, may carry multiple genetic susceptibilities to disease onset and progression and thus qualify for special protection under the CAA. Scientific advances accelerated as a result of the groundbreaking Human Genome Project enable the quantification of genetic information that underlies such human variability in susceptibility and the cellular mechanisms of disease. In epidemiology and regulatory toxicology, genetic information can more clearly elucidate human susceptibility essential to risk assessment, such as in support of air quality regulation. In an effort to encourage the incorporation of genomic information in regulation, the U.S. Environmental Protection Agency (EPA) has issued an Interim Policy on Genomics. Additional research strategy and policy documents from the National Academy of Science, the U.S. EPA, and the U.S. Department of Health and Human Services further promote the expansion of asthma genetics research for human health risk assessment. Through a review of these government documents, we find opportunities for the inclusion of genetic information in the regulation of air pollutants. In addition, we identify sources of information in recent scientific research on asthma genetics relevant to regulatory standard setting. We conclude with recommendations on how to integrate these approaches for the improvement of regulatory health science and the prerequisites for inclusion of genetic information in decision making.

Air Pollutants↗

PubMed2006

Organophosphate pesticide exposure and work in pome fruit: evidence for the take-home pesticide pathway.

Organophosphate (OP) pesticides are commonly used in the United States, and farmworkers are at risk for chronic exposure. Using a sample of 218 farmworkers in 24 communities and labor camps in eastern Washington State, we examined the association between agricultural crop and OP pesticide metabolite concentrations in urine samples of adult farmworkers and their children and OP pesticide residues in house and vehicle dust samples. Commonly reported crops were apples (71.6%), cherries (59.6%), pears (37.2%), grapes (27.1%), hops (22.9%), and peaches (12.4%). Crops were grouped into two main categories: pome fruits (apples and pears) and non-pome fruits. Farmworkers who worked in the pome fruits had significantly higher concentrations of dimethyl pesticide metabolites in their urine and elevated azinphos-methyl concentrations in their homes and vehicles than workers who did not work in these crops. Among pome-fruit workers, those who worked in both apples and pears had higher urinary metabolites concentrations and pesticide residue concentrations in dust than did those who worked in a single pome fruit. Children living in households with pome-fruit workers were found to have higher concentrations of urinary dimethyl metabolites than did children of non-pome-fruit workers. Adult urinary concentrations showed significant correlations with both the vehicle and house-dust azinphos-methyl concentrations, and child urinary concentrations were correlated significantly with adult urinary concentrations and with the house-dust azinphos-methyl concentration. The results provide support for the take-home pathway of pesticide exposure and show an association between measures of pesticide exposure and the number of pome-fruit crops worked by farmworkers.

Adolescent↗

PubMed2005

Cell cycle inhibition by sodium arsenite in primary embryonic rat midbrain neuroepithelial cells.

Arsenite (As3+) exposure during development has been associated with neural tube defects and other structural malformations, and with behavioral alterations including altered locomotor activity and operant learning. The molecular mechanisms underlying these effects are uncertain. Because arsenic can cross the placenta and accumulate in the developing neuroepithelium, we examined cell cycling effects of sodium arsenite (As3+ 0, 0.5, 1, 2, and 4 microM) on embryonic primary rat midbrain (gestational day [GD] 12) neuroepithelial cells over 48 h. There was a concentration- and time-dependent As3+-induced reduction in cell viability assessed by neutral red dye uptake assay but minimal apoptosis at concentrations below 4 microM. Morphologically, apoptosis was not apparent until 4 microM at 24 h, which was demonstrated by a marginal but statistically significant increase in cleaved caspase-3/7 activity. Cell cycling effects over several rounds of replication were determined by continuous 5-bromo-2'-deoxyuridine (BrdU) labeling and bivariate flow cytometric Hoechst-Propidium Iodide analysis. We observed a time- and concentration-dependent inhibition of cell cycle progression as early as 12 h after exposure (> or =0.5 microM). In addition, data demonstrated a concentration-dependent increase in cytostasis within all cell cycle phases, a decreased proportion of cells able to reach the second cell cycle, and a reduced cell cycle entry from gap 1 phase (G1). The proportion of affected cells and the severity of the cell cycle perturbation, which ranged from a decreased transition probability to complete cytostasis in all cell cycle phases, were also found to be concentration-dependent. Together, these data support a role for perturbed cell cycle progression in As3+ mediated neurodevelopmental toxicity.

Animals↗

PubMed2005

Essential role of extracellular matrix (ECM) overlay in establishing the functional integrity of primary neonatal rat Sertoli cell/gonocyte co-cultures: an improved in vitro model for assessment of male reproductive toxicity.

The development of in vitro models for testicular toxicity may provide important tools for investigating specific mechanisms of toxicity in the testis. Although various systems have been reported, their application in toxicological studies has been limited by the poor ability to replicate the complex biochemical, molecular, and functional interactions observed in the testis. In the present study, we evaluated a significantly improved Sertoli cell/gonocyte co-culture (SGC) system that employs a 3-dimensional extracellular matrix Matrigel (ECM) applied as an overlay instead of a substratum. We explored the dose- and time-dependent effects of the addition of such an ECM overlay on cytoskeletal and morphological changes in the SGC system, and the resulting effects on cellular integrity. Furthermore, we correlated the latter effects with the ECM-dependent modulation of stress and survival signaling pathways and, most critically, the expression levels of the spermatogonia-specific protein, c-Kit. Finally, we applied this co-culture system to investigate the dose- and time-dependent effects on the morphology and induction of apoptosis of cadmium. We observed that the dose-dependent addition of an ECM overlay led to an enhanced attachment of Sertoli cells and facilitated the establishment of SGC communication and cytoskeletal structure, with a dramatic improvement in cell viability. The latter was consistent with the observed dose- and time-dependent modulation of both stress signaling pathways (SAPK/JNK) and survival signaling pathways (ERK and AKT) in the presence of the ECM overlay. Furthermore, the dose-dependent stabilization of c-Kit protein expression confirmed the functional integrity of this co-culture system. We conclude that this modified SGC system will provide investigators with a simple, efficient, and highly reproducible alternative in the screen for testicular cell-specific cytotoxicity and the assessment of molecular mechanisms associated with both normal development and reproductive toxicity induced by environmental toxicants.

Actins↗

PubMed2005

The magnitude of methylmercury-induced cytotoxicity and cell cycle arrest is p53-dependent.

BACKGROUND: Methylmercury (MeHg), a ubiquitous environmental contaminant, is a known potent teratogen selectively affecting the developing central nervous system. While a definitive mechanism for MeHg-induced developmental neurotoxicity remains elusive, in utero exposure has been associated with reduced brain weight and reduction in cell number. This suggests early toxicant interference with critical molecular signaling events controlling cell behavior, i.e., proliferation. METHODS: To examine the role of p53, a major regulator of the G(1)/S and G(2)/M cell cycle checkpoints, in MeHg toxicity, we isolated GD 14 primary embryonal fibroblasts from homozygous wild-type p53 (p53+/+) and homozygous null p53 (p53-/-) mice. Cells were treated at passages 4-7 for 24 or 48 hr with 0, 1.0, or 2.5 microM MeHg and analyzed for effects on viability, cell cycle progression (using BrdU-Hoechst flow cytometric analysis), and apoptosis via annexin V-FITC and propidium iodide (PI) staining. RESULTS: The p53+/+ cells are more sensitive than p53-/- cells to MeHg-induced cytotoxicity, cell cycle inhibition, and induction of apoptosis: at 24 hr, 2.5 microM MeHg reduced p53+/+ cell viability to 72.6% +/- 3.2%, while p53-/- viability was 94.6% +/- 0.4%. The p53-/- cells underwent less necrosis and less apoptosis following MeHg treatment. MeHg (2.5 microM) also halted all cycling in the p53+/+ cells, while 42.6% +/- 7.2% of p53-/- cells were able to reach a new G(0)/G(1) in 48 hr. Time- and dose-dependent accumulation of cells in G(2)/M phase (1.0 and 2.5 microM MeHg) was observed independent of the p53 genotype; however, the magnitude of change was p53-dependent. CONCLUSIONS: These studies suggest that MeHg-induced cell cycle arrest occurs via both p53-dependent and -independent pathways in our model system; however, cell death resulting from MeHg exposure is highly dependent on p53.

Animals↗

PubMed2005

Improving predictive modeling in pediatric drug development: pharmacokinetics, pharmacodynamics, and mechanistic modeling.

A workshop was conducted on November 18-19, 2004, to address the issue of improving predictive models for drug delivery to developing humans. Although considerable progress has been made for adult humans, large gaps remain for predicting pharmacokinetic/pharmacodynamic (PK/PD) outcome in children because most adult models have not been tested during development. The goals of the meeting included a description of when, during development, infants/children become adult-like in handling drugs. The issue of incorporating the most recent advances into the predictive models was also addressed: both the use of imaging approaches and genomic information were considered. Disease state, as exemplified by obesity, was addressed as a modifier of drug pharmacokinetics and pharmacodynamics during development. Issues addressed in this workshop should be considered in the development of new predictive and mechanistic models of drug kinetics and dynamics in the developing human.

Adult↗

PubMed2005

Framing scientific analyses for risk management of environmental hazards by communities: case studies with seafood safety issues.

Risk management provides a context for addressing environmental health hazards. Critical to this approach is the identification of key opportunities for participation. We applied a framework based on the National Research Council's (NRC) analytic-deliberative risk management dialogue model that illustrates two main iterative processes: informing and framing. The informing process involves conveying information from analyses of risk issues, often scientific, to all parties so they can participate in deliberation. In the framing process, ideas and concerns from stakeholder deliberations help determine what and how scientific analyses will be carried out. There are few activities through which affected parties can convey their ideas from deliberative processes for framing scientific analyses. The absence of participation results in one-way communication. The analytic-deliberative dialogue, as envisioned by the NRC and promoted by the National Institute of Environmental Health Sciences (NIEHS), underscores the importance of two-way communication. In this article we present case studies of three groups--an Asian and Pacific Islander community coalition and two Native American Tribes--active in framing scientific analyses of health risks related to contaminated seafood. Contacts with these organizations were established or enhanced through a regional NIEHS town meeting. The reasons for concern, participation, approaches, and funding sources were different for each group. Benefits from their activities include increased community involvement and ownership, better focusing of analytical processes, and improved accuracy and appropriateness of risk management. These examples present a spectrum of options for increasing community involvement in framing analyses and highlight the need for increased support of such activities.

Asian↗

PubMed2005

Methodologic and logistic issues in conducting longitudinal birth cohort studies: lessons learned from the Centers for Children's Environmental Health and Disease Prevention Research.

In anticipation of the National Children's Study, lessons can be learned from the smaller birth cohort studies conducted by five Centers for Children's Environmental Health and Disease Prevention Research funded by the National Institute of Environmental Health Sciences and the U.S. Environmental Protection Agency. The populations studied are diverse in ethnicity and social class and reside in urban and rural environments. Although almost all of the centers chose to enroll participants through medical care facilities, they had to develop independent staffs and structures because of the overburdened medical care system. Some of the lessons learned by the centers include the importance of continuous funding, building community partnerships to conduct culturally appropriate research, hiring bilingual and bicultural staff from the community, prioritizing research goals, developing biorepositories to ensure future utility of samples, instituting quality control procedures for all aspects of specimen and data collection, maintaining frequent contact with study participants, ensuring ethical conduct of the research in a changing medical-legal climate, and communicating results in a timely and appropriate manner to participants and the wider community. All centers underestimated the necessary start-up time, staff, and costs in conducting these birth cohort studies. Despite the logistical complexity and added expenses, all centers emphasize the importance of studying the impact of environmental exposures on those children most at risk, those living in minority and low-income communities. These centers present barriers encountered, solutions found, and considerations for future research, with the hope that the lessons learned can help inform the planning and conduct of the National Children's Study.

Adolescent↗

PubMed2004

The role of cell death during neocortical neurogenesis and synaptogenesis: implications from a computational model for the rat and mouse.

We are quantitatively evaluating the acquisition of neocortical neurons through key stages of development including neurogenesis, migration, and synaptogenesis. Here we expand upon a previous computational model describing neocortical neurogenesis in the rat and mouse [Dev. Neurosci. 24 (2002) 467], to include the period of synaptogenesis (P0-P14) when programmed cell death (PCD) is known to play a major role in shaping the neocortex. We also quantitatively evaluate differing hypotheses on the role of cell death during neurogenesis. This new model construct allows prediction of acquisition of adult neuronal number in the rat and mouse neocortex from the beginning of neurogenesis through synaptogenesis. The mathematical model output is validated by independently derived stereologically determined neuron number estimates in the adult rat and mouse. Simulations suggest cell death during synaptogenesis reduces the neocortical neuronal population by 20-30%, while cell death of progenitor cells and newly formed neurons during neurogenesis may reduce output by as much as 24%. However, higher death rates during neurogenesis as suggested by some research would deplete the progenitor population, not allowing for the vast expansion that is the hallmark of the mammalian neocortex. Furthermore, our simulations suggest the clearance time of dying neurons labeled by TUNEL or pyknosis is relatively short, between 1 and 4 h, corroborating experimental research. This novel mathematical model for adult neocortical neuronal acquisition allows for in silico analysis of normal and perturbed states of neocortical development as well as interspecies and evolutionary analyses of neocortical development.

Animals↗

PubMed2004

Effects of occupational solvent exposure on reproductive hormone concentrations and fecundability in men.

BACKGROUND: Little is known about the effects of organic solvents on male reproductive health. To assess fertility and reproductive endocrine function in solvent-exposed men, we investigated time-to-pregnancy using a retrospective cohort design and cross-sectionally measured reproductive hormone concentrations in painters and millwrights compared to a reference group of carpenters. METHODS: Detailed occupational, exposure, medical, and time-to-pregnancy histories were obtained by telephone interview. Plasma luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone concentrations were determined by immunoassay. Exposure indices, which summarized working life exposure to total solvents, chlorinated solvents, aromatic solvents, and thinners, degreasers, varnishes, and adhesives as a category were calculated from exposure histories. RESULTS: FSH concentrations increased significantly with increasing exposure indices for all solvents and for chlorinated solvents. There were no significant associations of solvent exposure indices with LH or testosterone levels. LH, FSH, and testosterone concentrations also did not differ by job title. Using Cox regression, time-to-pregnancy was non-significantly longer in the painters and millwrights than the carpenters. There was no significant association between time-to-pregnancy and any of the solvent exposure indices; however, it should be noted that some of the pregnancies occurred more than 20 years previously, potentially reducing the reliability of the retrospectively collected pregnancy and exposure data. CONCLUSIONS: The significant associations between FSH levels and solvent exposure indices suggest the potential for adverse effects of solvent exposures on reproductive function in men.

Adult↗

PubMed2004

Contribution of PCB exposure from fish consumption to total dioxin-like dietary exposure.

Polychlorinated biphenyls (PCB) are the second greatest cause of fish advisories, and are often the greatest contributors to dioxin-like toxic equivalency (TEQ) in fish and seafood. Because fish consumption is associated with both contaminant risks and health benefits, incremental health risks from PCBs in fish should be considered within the context of overall TEQ associated dietary risk to enable consumers to make informed decisions about choosing to eat fish or alternate foodstuffs. In this paper, potential TEQ exposure from PCBs in fish for adults with a variety of consumption patterns and consuming fish from a variety of sources are calculated using recent consumption and fish contaminant data from the literature and compared to total TEQ exposure from all sources. For high-level consumers and individuals eating fish from relatively contaminated sites, PCB TEQ exposure from fish consumption alone may exceed the 1 pg TEQ/kg/day average adult daily intake estimated by EPA, which itself carries an upper bound cancer risk of 1 in 1000. PCB TEQ risk for average consumers of commercial fish is expected to be far less, but is highly uncertain, since there is a dearth of congener specific PCB data for commercial fish and seafood.

Administration, Oral↗

PubMed2004

Temporal error in biomarker-based mean exposure estimates for individuals.

Biomarker measurements from single time points are often used to make inferences about longer periods of toxicant intake. However, toxicant exposures rarely, if ever, occur under steady-state conditions, and biomarkers are typically most sensitive to recent toxicant exposures. Moreover, toxicant exposures are typically episodic and vary in magnitude over time. While it is often believed that the error introduced by the steady-state assumption is minimal and can safely be ignored, no rationale is typically presented to support this belief. Moreover, no guidelines have been established for determining a de minimus error level or for estimating the degree of error potentially introduced by a fallacious steady-state assumption in biomarker interpretation. We present a statistical framework for evaluating the potential magnitude of the error introduced by the steady-state fallacy and demonstrate applications of the framework to blood mercury and hair mercury exposure biomarkers in human adults. The magnitude of error clearly depends on many factors, including the exposure frequency, exposure magnitude, exposure duration, and exposure inference duration. Graphical presentation of the error as a function of those factors provides insight into the interpretation of mercury exposure biomarkers. We describe a general approach for determining the mean and variance of temporal error, present explicit solutions for several special cases, and demonstrate an example using the framework to evaluate the error resulting from the use of a steady-state model to estimate time-varying exposure from mercury biomarkers.

Biomarkers↗

PubMed2004

Assessing the health benefits of air pollution reduction for children.

Benefit-cost analyses of environmental regulations are increasingly mandated in the United States. Evaluations of criteria air pollutants have focused on benefits and costs associated with adverse health effects. Children are significantly affected by the health benefits of improved air quality, yet key environmental health policy analyses have not previously focused specifically on children's effects. In this article we present a "meta-analysis" approach to child-specific health impacts derived from the U.S. Clean Air Act (CAA). On the basis of data from existing studies, reductions in criteria air pollutants predicted to occur by 2010 because of CAA regulations are estimated to produce the following impacts: 200 fewer expected cases of postneonatal mortality; 10,000 fewer asthma hospitalizations in children 1-16 years old, with estimated benefits ranging from 20 million U.S. dollars to 46 million U.S. dollars (1990 U.S. dollars); 40,000 fewer emergency department visits in children 1-16 years old, with estimated benefits ranging from 1.3 million U.S. dollars to 5.8 million U.S. dollars; 20 million school absences avoided by children 6-11 years old, with estimated benefits of 0.7-1.8 billion U.S. dollars; and 10,000 fewer infants of low birth weight, with estimated benefits of 230 million U.S. dollars. Inclusion of limited child-specific data on hospitalizations, emergency department visits, school absences, and low birth weight could be expected to add 1-2 billion U.S. dollars (1990 U.S. dollars) to the 8 billion U.S. dollars in health benefits currently estimated to result from decreased morbidity, and 600 million U.S. dollars to the 100 billion U.S. dollars estimated to result from decreased mortality. These estimates highlight the need for increased consideration of children's health effects. Key needs for environmental health policy analyses include improved information for children's health effects, additional life-stage-specific information, and improved health economics information specific for children.

Air Pollution↗

PubMed2003

Changes in cell cycle parameters and cell number in the rat midbrain during organogenesis.

We employed 5-bromo-2'-deoxyuridine (BrdU) labeling to identify in vivo changes in the cell cycle patterns of the rat midbrain during the major period of midbrain organogenesis, gestational days (gd) 11 to 16. We also used quantitative stereology to determine changes in absolute cell numbers during these gestational time points. Between gd 12 and 16, the length of S-phase did not change significantly while the fraction of cycling cells decreased from 73 to 11%. The average cell cycle length was determined to be 15 h on gd 12 and 17 h on gd 16, the difference not being statistically significant. The cell number in the midbrain increased from 1.3E5 cells on gd 11 to 1.7E7 cells on gd 16. On gd 12 and gd 13, there was a significant negative correlation between litter position and midbrain cell number, the effect diminishing on later days of gestation. The combined use of quantitative stereology and flow cytometry to study brain development represents a novel application that allows for simultaneous evaluation of changes in cell proliferation kinetics and the resulting effect of those kinetic changes on embryonic midbrain development.

Animals↗

PubMed2003

Localization of glutamate cysteine ligase subunit mRNA within the rat ovary and relationship to follicular apoptosis.

Ovarian levels of the antioxidant tripeptide glutathione (GSH) increase following gonadotropin administration, suggesting that GSH synthesis in the ovary may be associated with follicular growth. In situ hybridization with (35)S-labeled riboprobes was used to localize ovarian mRNA expression of the catalytic and modulatory subunits of glutamate cysteine ligase (Gclc and Gclm), the rate-limiting enzyme in GSH synthesis, during each stage of the rat estrous cycle. Gclm was highly expressed in the granulosa cells and oocytes of healthy, growing follicles, not in atretic follicles. Gclc was also highly expressed in follicles; however, unlike Gclm, Gclc was also expressed in corpora lutea and interstitial cells. In a subsequent experiment, the hypothesis that GSH synthesis occurs in healthy, but not in apoptotic, follicles was tested. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) was used to detect apoptotic cells in the ovaries, and in situ hybridization for Gclm and Gclc was performed in adjacent sections of the same ovaries. TUNEL staining was found to be significantly associated with absence of Gclm hybridization in granulosa cells and oocytes and with lack of strong Gclc hybridization in granulosa cells. These results suggest that follicular apoptosis may be associated with down-regulation of Gclm and Gclc transcription in granulosa cells and oocytes.

Animals↗

PubMed2003

A model for optimization of biomarker testing frequency to minimize disease and cost: example of beryllium sensitization testing.

A common problem with medical surveillance programs using biomarkers is determining the optimal frequency of testing to minimize adverse health effects and cost. In the case of beryllium-exposed workers, frequency of testing for beryllium sensitization may be especially important. Recent studies indicate a lack of dose response for beryllium sensitization, but do support a dose response for the development of chronic beryllium disease (CBD). Though unproven, this implies that early identification of sensitization and immediate removal from exposure may reduce development of CBD. A model is proposed to project the optimal frequency of sensitization testing using the current beryllium lymphocyte proliferation test (BeLPT) to minimize disease-related costs, assuming that a positive BeLPT will precede CBD. Conversion rates for cumulative exposure to disease development were adapted from the literature and used with testing costs and cost of disease estimates in the model. The model was run assuming several test frequency regimes. Results support the use of periodic testing in line with the annual schedule proposed in the Final Chronic Beryllium Disease Prevention Program Rule (1999) following initial testing within three months of first beryllium exposure. The financial and health benefits of reducing the time from exposure to detection of early disease was also explored with the model and demonstrated as a highly desirable characteristic for an alternative test or improved BeLPT. Limitations of the approach are discussed as well as options for adapting this biomarker optimization methodology to consider biomarkers of other exposure-associated diseases.

Berylliosis↗