Kidney injury biomarkers and urinary creatinine variability in nominally healthy adults.

Environmental exposure diagnostics use creatinine concentrations in urine aliquots as the internal standard for dilution normalization of all other excreted metabolites when urinary excretion rate data are not available. This is a reasonable approach for healthy adults as creatinine is a human metabolite that is continually produced in skeletal muscles and presumably excreted in the urine at a stable rate. However, creatinine also serves as a biomarker for glomerular filtration rate (efficiency) of the kidneys, so undiagnosed kidney function impairment could affect this commonly applied dilution calculation. The United States Environmental Protection Agency (US EPA) has recently conducted a study that collected approximately 2600 urine samples from 50 healthy adults, aged 19-50 years old, in North Carolina in 2009-2011. Urinary ancillary data (creatinine concentration, total void volume, elapsed time between voids), and participant demographic data (race, gender, height, and body weight) were collected. A representative subset of 280 urine samples from 29 participants was assayed using a new kidney injury panel (KIP). In this article, we investigated the relationships of KIP biomarkers within and between subjects and also calculated their interactions with measured creatinine levels. The aims of this work were to document the analytical methods (procedures, sensitivity, stability, etc.), provide summary statistics for the KIP biomarkers in "healthy" adults without diagnosed disease (distribution, fold range, central tendency, variance), and to develop an understanding as to how urinary creatinine level varies with respect to the individual KIP proteins. Results show that new instrumentation and data reduction methods have sufficient sensitivity to measure KIP levels in nominally healthy urine samples, that linear regression between creatinine concentration and urinary excretion explains only about 68% of variability, that KIP markers are poorly correlated with creatinine (r(2) ∼ 0.34), and that statistical outliers of KIP markers are not random, but are clustered within certain subjects. In addition, we interpret these new adverse outcome pathways based in vivo biomarkers for their potential use as intermediary chemicals that may be diagnostic of kidney adverse outcomes to environmental exposure.

Post-operative elimination of sevoflurane anesthetic and hexafluoroisopropanol metabolite in exhaled breath: pharmacokinetic models for assessing liver function.

Sevoflurane (SEV), a commonly used anesthetic agent for invasive surgery, is directly eliminated via exhaled breath and indirectly by metabolic conversion to inorganic fluoride and hexafluoroisopropanol (HFIP), which is also eliminated in the breath. We studied the post-operative elimination of SEV and HFIP of six patients that had undergone a variety of surgeries lasting between 2.5 to 8.5 h using exhaled breath analysis. A classical three compartments pharmacokinetic model developed for the study of environmental contaminants was fitted to the breath data. We found that SEV kinetic behavior following surgery (for up to six days) is consistent across all subjects whereas the production and elimination of HFIP varies to some extent. We developed subject specific parameters for HFIP metabolism and interpreted the differences in the context of timing and dose of anesthesia, type of surgery, and specific host factors. We propose methods for assessing individual patient liver function using SEV as a probe molecule for assessing efficiency of liver metabolism to HFIP. This work is valuable not only for the clinical study of metabolism recovery, but potentially also for the study of the interaction of other manufactured and environmental compounds with human systems biology in controlled exposure and observational studies.

Cumulative exposure assessment for trace-level polycyclic aromatic hydrocarbons (PAHs) using human blood and plasma analysis.

Humans experience chronic cumulative trace-level exposure to mixtures of volatile, semi-volatile, and non-volatile polycyclic aromatic hydrocarbons (PAHs) present in the environment as by-products of combustion processes. Certain PAHs are known or suspected human carcinogens and so we have developed methodology for measuring their circulating (blood borne) concentrations as a tool to assess internal dose and health risk. We use liquid/liquid extraction and gas chromatography-mass spectrometry and present analytical parameters including dynamic range (0-250 ng/ml), linearity (>0.99 for all compounds), and instrument sensitivity (range 2-22 pg/ml) for a series of 22 PAHs representing 2-6-rings. The method is shown to be sufficiently sensitive for estimating PAHs baseline levels (typical median range from 1 to 1000 pg/ml) in groups of normal control subjects using 1-ml aliquots of human plasma but we note that some individuals have very low background concentrations for 5- and 6-ring compounds that fall below robust quantitation levels.