Derivation of whole blood biomonitoring equivalents for titanium for the interpretation of biomonitoring data.

Biomonitoring equivalents (BEs) have been increasingly applied for biomonitoring purposes by regulatory bodies worldwide. The present report describes the development of a BE for titanium based on a 4-step process: (i) identification of a critical study/point of departure (PoD) supporting an established oral exposure guidance value (OEGV);, (ii) review the available oral PK data and application of a pharmacokinetic model for titanium; (iii) selection of the most appropriate biomarker of exposure in a specific tissue and calculation of steady-state tissue levels corresponding to the PoD in the critical study; and (iv) derivation of BE value adjusting for the uncertainties considered in the original OEGV assessment. Using the above 4-step approach, a blood BE value of 32.5 µg titanium/L was derived. Key components of the analysis included a pharmacokinetic model developed by investigators at the Netherlands National Institute of Public Health (RIVM) and a two-year rodent bioassay of titanium conducted by the US National Cancer Institute. The most sensitive pharmacokinetic parameter involved in the current BE derivation is the oral absorption factor of 0.02%. The provisional BE proposed in this article may be updated as new information on the pharmacokinetics of titanium becomes available.

Derivation of whole blood biomonitoring equivalents for lithium for the interpretation of biomonitoring data.

INTRODUCTION: Lithium salts have numerous industrial uses and are also used in the treatment of bipolar disorders. The main source of lithium exposure to the general population is drinking water and foods. Lithium is nephrotoxic at higher doses. Thus, oral exposure guidelines for lithium have been derived, including ICH's permitted daily exposure (PDE = 0.008 mg lithium/kg-bw/day) adopted by Health Canada and the United States Environmental Protection Agency's (U.S. EPA) provisional peer reviewed toxicity value (PPRTV = 0.002 mg lithium/kg-bw/day), both based on human data. OBJECTIVE: To derive whole blood biomonitoring equivalents (BEs) associated with PDE and PPRTV to interpret population-level biomonitoring data in health risk context. METHOD: A simple kinetic relationship based on plasma clearance value (0.5 L/kg-bw/day) and the oral absorption fraction (100%) was used to derive blood BEs for PDE and PPRTV. RESULTS: This analysis resulted in BE values in plasma and whole blood of 16 and 10 µg/L, respectively, based on the PDE values developed by the Health Canada and of 4.2 and 2.7 µg/L, respectively, based on the PPRTV developed by U.S. EPA. CONCLUSION: The derived BE values can be used to interpret population-level biomonitoring data.

Biomonitoring Equivalents for interpretation of urinary fluoride.

Exposure to fluoride is widespread due to its natural occurrence in the environment and addition to drinking water and dental products for the prevention of dental caries. The potential health risks of excess fluoride exposure include aesthetically unacceptable dental fluorosis (tooth mottling) and increased skeletal fragility. Numerous organizations have conducted risk assessments and set guidance values to represent maximum recommended exposure levels as well as recommended adequate intake levels based on potential public health benefits of fluoride exposure. Biomonitoring Equivalents (BEs) are estimates of the average biomarker concentrations corresponding to such exposure guidance values. The literature on daily urinary fluoride excretion rates as a function of daily fluoride exposure was reviewed and BE values corresponding to the available US and Canadian exposure guidance values were derived for fluoride in urine. The derived BE values range from 1.1 to 2.1mg/L (1.2-2.5µg/g creatinine). Concentrations of fluoride in single urinary spot samples from individuals, even under exposure conditions consistent with the exposure guidance values, may vary from the predicted average concentrations by several-fold due to within- and across-individual variation in urinary flow and creatinine excretion rates and due to the rapid elimination kinetics of fluoride. Thus, the BE values are most appropriately applied to screen population central tendency estimates for biomarker concentrations rather than interpretation of individual spot sample concentrations.

Modeling the Human Kinetic Adjustment Factor for Inhaled Volatile Organic Chemicals: Whole Population Approach versus Distinct Subpopulation Approach.

The objective of this study was to evaluate the impact of whole- and sub-population-related variabilities on the determination of the human kinetic adjustment factor (HKAF) used in risk assessment of inhaled volatile organic chemicals (VOCs). Monte Carlo simulations were applied to a steady-state algorithm to generate population distributions for blood concentrations (CAss) and rates of metabolism (RAMs) for inhalation exposures to benzene (BZ) and 1,4-dioxane (1,4-D). The simulated population consisted of various proportions of adults, elderly, children, neonates and pregnant women as per the Canadian demography. Subgroup-specific input parameters were obtained from the literature and P3M software. Under the "whole population" approach, the HKAF was computed as the ratio of the entire population's upper percentile value (99th, 95th) of dose metrics to the median value in either the entire population or the adult population. Under the "distinct subpopulation" approach, the upper percentile values in each subpopulation were considered, and the greatest resulting HKAF was retained. CAss-based HKAFs that considered the Canadian demography varied between 1.2 (BZ) and 2.8 (1,4-D). The "distinct subpopulation" CAss-based HKAF varied between 1.6 (BZ) and 8.5 (1,4-D). RAM-based HKAFs always remained below 1.6. Overall, this study evaluated for the first time the impact of underlying assumptions with respect to the interindividual variability considered (whole population or each subpopulation taken separately) when determining the HKAF.

Physiologically based modeling of the inhalation pharmacokinetics of ethylbenzene in B6C3F1 mice.

A physiologically based pharmacokinetic (PBPK) model was developed for inhaled ethylbenzene (EB) in B6C3F1 mice. The mouse physiological parameters were obtained from the literature, but the blood:air and tissue:air partition coefficients were determined by vial equilibration technique. The maximal velocity for hepatic metabolism (Vmax) obtained from a previously published rat study was increased by a factor of approximately 3 to account for enzyme induction during repeated exposures. The Michaelis affinity constant (Km) for hepatic metabolism of EB, obtained from a previously published rat PBPK modeling study, was kept unchanged during single and repeated exposure scenarios. Hepatic metabolism alone could not adequately describe the clearance of EB from mouse blood. Additional metabolism was assumed to be localized in the lung. The parameters for pulmonary metabolism were obtained by optimization of PBPK model fits to kinetic data collected following exposures to 75-1000 ppm. The PBPK model successfully predicted all available blood and tissue concentration data in mice exposed to 75 or 750 ppm EB. Overall, the results indicate that the rate of EB clearance is markedly higher in B6C3F1 mice than rats or humans and exceeds the hepatic metabolism capacity. Available biochemical evidence is consistent with a significant role for pulmonary metabolism; however, the extent to which the extrahepatic metabolism is localized in the lung is unclear. Overall, the PBPK model developed for the mouse adequately simulated the blood and tissue kinetics of EB by accounting for its high rate of clearance.

Modeling interchild differences in pharmacokinetics on the basis of subject-specific data on physiology and hepatic CYP2E1 levels: a case study with toluene.

The objective of the present study was to evaluate the magnitude of interindividual variability in the internal dose of toluene in children of various age groups, on the basis of subject-specific hepatic CYP2E1 content and physiology. The methodology involved the use of a previously validated physiologically based pharmacokinetic (PBPK) model, in which the intrinsic clearance for hepatic metabolism (CL(int)) was expressed in terms of the CYP2E1 content. The adult toluene PBPK model, with enzyme content-normalized CL(int), facilitated the calculation of child-specific CL(int) based on knowledge of hepatic CYP2E1 protein levels. The child-specific physiological parameters, except liver volume, were computed with knowledge of age and body weight, whereas physicochemical parameters for toluene were kept age-invariant based on available data. The actual individual-specific liver volume (autopsy data) was also included in the model. The resulting model was used to simulate the blood concentration profiles in children exposed by inhalation, to 1 ppm toluene for 24 h. For this exposure scenario, the area under the venous blood concentration vs. time curve (AUC) ranged from 0.30 to 1.01 microg/ml x h in neonates with low CYP2E1 concentration (<3.69 pmol/mg protein). The simulations indicated that neonates with higher levels of CYP2E1 (4.33 to 55.93 pmol/mg protein) as well as older children would have lower AUC (0.16 to 0.43 microg/ml x h). The latter values were closer to those simulated for adults. Similar results were also obtained for 7 h exposure to 17 ppm toluene, a scenario previously evaluated in human volunteers. The interindividual variability factor for each subgroup of children and adults, calculated as the ratio of the 95th and 50th percentile values of AUC, was within a factor of 2. The 95th percentile value of the low metabolizing neonate group, however, was greater than the mean adult AUC by a factor of 3.9. This study demonstrates the feasibility of incorporating subject-specific data on hepatic CYP2E1 content and physiology within PBPK models for evaluating the age, interchild and population variability of internal dose for use in risk assessment of inhaled volatile organics.

Rapid fold and structure determination of the archaeal translation elongation factor 1beta from Methanobacterium thermoautotrophicum.

The tertiary fold of the elongation factor, aEF-1beta, from Methanobacterium thermoautotrophicum was determined in a high-throughput fashion using a minimal set of NMR experiments. NMR secondary structure prediction, deuterium exchange experiments and the analysis of chemical shift perturbations were combined to identify the protein fold as an alpha-beta sandwich typical of many RNA binding proteins including EF-G. Following resolution of the tertiary fold, a high resolution structure of aEF-1beta was determined using heteronuclear and homonuclear NMR experiments and a semi-automated NOESY assignment strategy. Analysis of the aEF-1beta structure revealed close similarity to its human analogue, eEF-1beta. In agreement with studies on EF-Ts and human EF-1beta, a functional mechanism for nucleotide exchange is proposed wherein Phe46 on an exposed loop acts as a lever to eject GDP from the associated elongation factor G-protein, aEF-1alpha. aEF-1beta was also found to bind calcium in the groove between helix alpha2 and strand beta4. This novel feature was not observed previously and may serve a structural function related to protein stability or may play a functional role in archaeal protein translation.