A Bayesian network model for biomarker-based dose response.

A Bayesian network model was developed to integrate diverse types of data to conduct an exposure-dose-response assessment for benzene-induced acute myeloid leukemia (AML). The network approach was used to evaluate and compare individual biomarkers and quantitatively link the biomarkers along the exposure-disease continuum. The network was used to perform the biomarker-based dose-response analysis, and various other approaches to the dose-response analysis were conducted for comparison. The network-derived benchmark concentration was approximately an order of magnitude lower than that from the usual exposure concentration versus response approach, which suggests that the presence of more information in the low-dose region (where changes in biomarkers are detectable but effects on AML mortality are not) helps inform the description of the AML response at lower exposures. This work provides a quantitative approach for linking changes in biomarkers of effect both to exposure information and to changes in disease response. Such linkage can provide a scientifically valid point of departure that incorporates precursor dose-response information without being dependent on the difficult issue of a definition of adversity for precursors.

Methods and measurements for estimating human dermal uptake of volatile organic compounds and for deriving dermal permeability coefficients.

ABSTRACT Water contamination of public drinking and recreational waters with volatile organic compounds (VOCs) is widespread, resulting in human exposure through multiple routes. Although dermal absorption is of considerable importance, there is great uncertainty in the dermal permeability coefficient (K(P)) for many VOCs due to the methods by which they are derived. We present a human in vivo experimental approach for the measurement of VOC dermal uptake from water contaminated at environmentally relevant concentrations and for determination of K(P). Dermal permeability was estimated from 11 adult subjects following immersion of their hand and forearm into a sealed 4.8-L Plexiglas cylinder containing 100 mug/L each of chloroform, 1,1,1-trichloroethane (111-TCA), and toluene and 400 mug/L of methyl tertiary butyl ether (MTBE) in water. Uptake was determined by measuring the decrease in VOC water concentration during the exposure. A control glass arm accounted for nondermal losses. The concentration of VOCs was determined by solid-phase microextraction (SPME) and analysis with gas chromatography/mass spectrometry. For the eight male and three female adult subjects, on average there was a dermal uptake-attributed 13.5%, 14.9%, 20.8%, and 7.3% decrease in the concentration after 1 h exposure for chloroform, 111-TCA, toluene, and MTBE, respectively. The resulting mean K(P) (standard deviation) was estimated to be 0.166 (0.108), 0.167 (0.107), 0.250 (0.064), and 0.109 (0.157) cm/h for the respective analytes. The experimental K(P) values presented here exceed the previously published model-estimated K(P) values by factors ranging from 6 to 57, suggesting that the published model-estimated K(P) values may underestimate actual VOC dermal absorption from water.

Two-dimensional electrophoretic protein profile analysis following exposure of human uroepithelial cells to occupational bladder carcinogens.

Protein biomarkers to occupational carcinogens were investigated using a transformable human uroepithelial cell system, SV-HUC.PC. SV-HUC.PC was treated with N-hydroxy-4,4'-methylene bis (2-chloroaniline) (N-OH-MOCA) or N-hydroxy-4 aminobiphenyl (N-OH-ABP). Two-dimensional gel electrophoresis of cell lysates compared protein changes across treatments. Increasing N-OH-MOCA resulted in a dose-related increase in protein spots altered. Comparing cell profiles treated with either carcinogen revealed alterations in the expression of nine proteins, identified using the TagIdent database. These demonstrated isoelectric point shift (1) or quantity change (8). Our investigation may be useful in identifying biomarkers of effects of exposure to bladder carcinogens.

Priorities for development of research methods in occupational cancer.

Occupational cancer research methods was identified in 1996 as 1 of 21 priority research areas in the National Occupational Research Agenda (NORA). To implement NORA, teams of experts from various sectors were formed and given the charge to further define research needs and develop strategies to enhance or augment research in each priority area. This article is a product of that process. Focus on occupational cancer research methods is important both because occupational factors play a significant role in a number of cancers, resulting in significant morbidity and mortality, and also because occupational cohorts (because of higher exposure levels) often provide unique opportunities to evaluate health effects of environmental toxicants and understand the carcinogenic process in humans. Despite an explosion of new methods for cancer research in general, these have not been widely applied to occupational cancer research. In this article we identify needs and gaps in occupational cancer research methods in four broad areas: identification of occupational carcinogens, design of epidemiologic studies, risk assessment, and primary and secondary prevention. Progress in occupational cancer will require interdisciplinary research involving epidemiologists, industrial hygienists, toxicologists, and molecular biologists.

Assessing biomarker use in risk assessment--a survey of practitioners.

Advances in molecular epidemiology and mechanistic toxicology have provided increased opportunities for incorporating biomarkers in the human health risk assessment process. For years, the published literature has lauded the concept of incorporating biomarkers into risk assessments as a means to reduce uncertainty in estimating health risk. For all the potential benefits, one would think that markers of effective dose, markers of early biological effects, and markers of human susceptibility are frequently selected as the basis for quantitative human health risk assessments. For this article, we sought to determine the degree to which this evolution in risk assessment has come to pass. The extent to which biomarkers are being used in current human health risk assessment was determined through an informal survey of leading risk assessment practitioners. Case studies highlighting the evolution of risk assessment methods to include biomarkers are also described. The goal of this review was to enhance the implementation of biomarker technology in risk assessment by (1) highlighting successes in biomarker implementation, (2) identifying key barriers to overcome, and (3) describing evolutions in risk assessment methods.