Evaluation of BBB permeable nucleolipid (NLDPU): A di-C15-ketalised palmitone appended uridine as neuro-tracer for SPECT.

Despite being in routine for onco-diagnostics for years, the applicability of nucleosidic molecular imaging probes is severely restricted in neurological applications due to their low permeability across blood-brain-barrier (BBB). For extending nucleoside tracers utility for neuro-onco early diagnostics, suitable modification which enhances their BBB permeation needs investigation. Among various modifications, lipidization of nucleosides has been reported to enhance cellular permeability. Extending the concept, the aim was to exemplify the possibility of lipidized nucleosides as potential brain tracer with capability to cross intact BBB and evaluate as metal based neuro-imaging SPECT agent. Uridine based non-lipidic (NSDAU) and di-C15-ketal appended lipidic (NLDPU) ligands were conjugated to chelator, DTPA (DTPA-NSDAU and DTPA-NLDPU) using multi-step chemistry. The ligands were evaluated in parallel for comparative physical and biological parameters. Additionally, effects of enhanced lipophilicity on UV-absorption, acid strength, fluorescence and non-specific protein binding were evaluated. Fluorescence quenching of BSA indicated appreciable interaction of DTPA-NLDPU with protein only above 10 mM without inducing conformational changes. In addition, DTPA-NLDPU was found to be haematocompatible and cytocompatible with low dose-dependent toxicity in HEK-cells. The chelator DTPA was used for 99mTc-complexation for SPECT imaging. Optimized 99mTc-radiolabeling parameters resulted in quantitative (≥97%) labeling with good stability parameters in in-vitro serum and cysteine challenge studies. We demonstrate that the nucleolipid radiotracer (99mTc-DTPA-NLDPU) was successfully able to permeate the BBB with brain uptake of 0.2% ID/g in normal mice as compared to 0.06% ID/g uptake of 99mTc-DTPA-NSDAU at 5 min. Blood kinetics indicate biphasic profile and t1/2(distribution) 46 min for 99mTc-DTPA-NLDPU. The preferential accumulation of 99mTc-DTPA-NLDPU in brain tumor intracranial xenograft indicate the targeting capability of the nucleoside. We conclude that as first-of-its-kind, this work presents the potential of the biocompatible nucleolipidic system for brain targeting and early diagnostics.

Prediction of bioavailability and toxicity of complex chemical mixtures through machine learning models.

Empirical data from a 6-month mesocosms experiment were used to assess the ability and performance of two machine learning (ML) models, including artificial neural network (NN) and random forest (RF), to predict temporal bioavailability changes of complex chemical mixtures in contaminated soils amended with compost or biochar. From the predicted bioavailability data, toxicity response for relevant ecological receptors was then forecasted to establish environmental risk implications and determine acceptable end-point remediation. The dataset corresponds to replicate samples collected over 180 days and analysed for total and bioavailable petroleum hydrocarbons and heavy metals/metalloids content. Further to this, a range of biological indicators including bacteria count, soil respiration, microbial community fingerprint, seeds germination, earthworm's lethality, and bioluminescent bacteria were evaluated to inform the environmental risk assessment. Parameters such as soil type, amendment (biochar and compost), initial concentration of individual compounds, and incubation time were used as inputs of the ML models. The relative importance of the input variables was also analysed to better understand the drivers of temporal changes in bioavailability and toxicity. It showed that toxicity changes can be driven by multiple factors (combined effects), which may not be accounted for in classical linear regression analysis (correlation). The use of ML models could improve our understanding of rate-limiting processes affecting the freely available fraction (bioavailable) of contaminants in soil, therefore contributing to mitigate potential risks and to inform appropriate response and recovery methods.

Arsenic-containing hydrocarbons: effects on gene expression, epigenetics, and biotransformation in HepG2 cells.

Arsenic-containing hydrocarbons (AsHCs), a subgroup of arsenolipids found in fish and algae, elicit substantial toxic effects in various human cell lines and have a considerable impact on cellular energy levels. The underlying mode of action, however, is still unknown. The present study analyzes the effects of two AsHCs (AsHC 332 and AsHC 360) on the expression of 44 genes covering DNA repair, stress response, cell death, autophagy, and epigenetics via RT-qPCR in human liver (HepG2) cells. Both AsHCs affected the gene expression, but to different extents. After treatment with AsHC 360, flap structure-specific endonuclease 1 (FEN1) as well as xeroderma pigmentosum group A complementing protein (XPA) and (cytosine-5)-methyltransferase 3A (DNMT3A) showed time- and concentration-dependent alterations in gene expression, thereby indicating an impact on genomic stability. In the subsequent analysis of epigenetic markers, within 72 h, neither AsHC 332 nor AsHC 360 showed an impact on the global DNA methylation level, whereas incubation with AsHC 360 increased the global DNA hydroxymethylation level. Analysis of cell extracts and cell media by HPLC-mass spectrometry revealed that both AsHCs were considerably biotransformed. The identified metabolites include not only the respective thioxo-analogs of the two AsHCs, but also several arsenic-containing fatty acids and fatty alcohols, contributing to our knowledge of biotransformation mechanisms of arsenolipids.

Accumulation of mineral oil saturated hydrocarbons (MOSH) in female Fischer 344 rats: Comparison with human data and consequences for risk assessment.

Female Fischer 344 rats were orally exposed to a mixture of mineral oil saturated hydrocarbons (MOSH) of broad molecular mass range at doses of 40, 400 and 4000mg/kg feed. Amounts and compositions of the MOSH were analyzed in liver, spleen, adipose tissue and the carcass after exposure during 30, 60, 90 and 120d as well as after 90d exposure followed by 30d depuration. At 40mg/kg in the feed, after 30d of exposure, 10.9% of the ingested MOSH were recovered from the animal body; after 90d plus 30d depuration it was 3.9%. In liver and spleen, the maximum retention in terms of molecular mass (simulated distillation) was at n-C29; in adipose tissue and carcass it was at n-C15/16. The differentiation between MOSH below and above n-C25 (Class I versus Class II and III oils), used for present regulation, is not supported by the present data on accumulation; structural characteristics seem more pertinent than molecular mass. Concentrations in the tissues increased far less than proportionally with the dose, rendering linear extrapolation to low doses questionable. No steady state was reached after 120d. In fact, comparing with the concentrations in human tissues at the estimated exposure, extrapolation from animal experiments seems to grossly underestimate human internal exposure. Comprehensive two-dimensional gas chromatography (GCxGC) was used to characterize the MOSH residues in the tissues with the aim of identifying the most strongly accumulated types. In the liver and spleen, the highly branched hydrocarbons dominated, whereas in the adipose tissue it was the n-alkanes and species with main n-alkyl moieties. Strong MOSH accumulation is not of concern per se, but the safety at the high concentrations in human tissues needs to be re-evaluated, possibly taking into account also end points other than granuloma formation.

Biophysical determinants for cellular uptake of hydrocarbon-stapled peptide helices.

Hydrocarbon-stapled peptides are a class of bioactive alpha-helical ligands developed to dissect and target protein interactions. While there is consensus that stapled peptides can be effective chemical tools for investigating protein regulation, their broader utility for therapeutic modulation of intracellular interactions remains an active area of study. In particular, the design principles for generating cell-permeable stapled peptides are empiric, yet consistent intracellular access is essential to in vivo application. Here, we used an unbiased statistical approach to determine which biophysical parameters dictate the uptake of stapled-peptide libraries. We found that staple placement at the amphipathic boundary combined with optimal hydrophobic and helical content are the key drivers of cellular uptake, whereas excess hydrophobicity and positive charge at isolated amino acid positions can trigger membrane lysis at elevated peptide dosing. Our results provide a design roadmap for maximizing the potential to generate cell-permeable stapled peptides with on-mechanism cellular activity.

Quantitative cancer risk assessment for occupational exposures to asphalt fumes during built-up roofing asphalt (BURA) operations.

The International Agency for Research on Cancer qualitatively characterized occupational exposure to oxidized bitumen emissions during roofing as probably carcinogenic to humans (Group 2A). We examine chemistry, exposure, epidemiology and animal toxicity data to explore quantitative risks for roofing workers applying built-up roofing asphalt (BURA). Epidemiology studies do not consistently report elevated risks, and generally do not have sufficient exposure information or adequately control for confounders, precluding their use for dose-response analysis. Dermal carcinogenicity bioassays using mice report increased tumor incidence with single high doses. In order to quantify potential cancer risks, we develop time-to-tumor model methods [consistent with U.S. Environmental Protection Agency (EPA) dose-response analysis and mixtures guidelines] using the dose-time-response shape of concurrent exposures to benzo[a]pyrene (B[a]P) as concurrent controls (which had several exposure levels) to infer presumed parallel dose-time-response curves for BURA-fume condensate. We compare EPA relative potency factor approaches, based on observed relative potency of BURA to B[a]P in similar experiments, and direct observation of the inferred BURA dose-time-response (scaled to humans) as means for characterizing a dermal unit risk factor. We apply similar approaches to limited data on asphalt-fume inhalation and respiratory cancers in rats. We also develop a method for adjusting potency estimates for asphalts that vary in composition using measured fluorescence. Overall, the various methods indicate that cancer risks to roofers from both dermal and inhalation exposure to BURA are within a range typically deemed acceptable within regulatory frameworks. The approaches developed may be useful in assessing carcinogenic potency of other complex mixtures of polycyclic aromatic compounds.

Cellular Uptake and Ultrastructural Localization Underlie the Pro-apoptotic Activity of a Hydrocarbon-stapled BIM BH3 Peptide.

Hydrocarbon stapling has been applied to restore and stabilize the α-helical structure of bioactive peptides for biochemical, structural, cellular, and in vivo studies. The peptide sequence, in addition to the composition and location of the installed staple, can dramatically influence the properties of stapled peptides. As a result, constructs that appear similar can have distinct functions and utilities. Here, we perform a side-by-side comparison of stapled peptides modeled after the pro-apoptotic BIM BH3 helix to highlight these principles. We confirm that replacing a salt-bridge with an i, i + 4 hydrocarbon staple does not impair target binding affinity and instead can yield a biologically and pharmacologically enhanced α-helical peptide ligand. Importantly, we demonstrate by electron microscopy that the pro-apoptotic activity of a stapled BIM BH3 helix correlates with its capacity to achieve cellular uptake without membrane disruption and accumulate at the organellar site of mechanistic activity.

Arsenic-containing hydrocarbons and arsenic-containing fatty acids: Transfer across and presystemic metabolism in the Caco-2 intestinal barrier model.

SCOPE: Arsenic-containing hydrocarbons (AsHCs) and arsenic-containing fatty acids (AsFAs) represent two classes of arsenolipids occurring naturally in marine food. Toxicological data are yet scarce and an assessment regarding the risk to human health has not been possible. Here, we investigated the transfer and presystemic metabolism of five arsenolipids in an intestinal barrier model. METHODS AND RESULTS: Three AsHCs and two AsFAs were applied to the Caco-2 intestinal barrier model. Thereby, the short-chain AsHCs reached up to 50% permeability. Transport is likely to occur via passive diffusion. The AsFAs showed lower intestinal bioavailability, but respective permeabilities were still two to five times higher as compared to arsenobetaine or arsenosugars. Interestingly, AsFAs were effectively biotransformed while passing the in vitro intestinal barrier, whereas AsHCs were transported to the blood-facing compartment essentially unchanged. CONCLUSION: AsFAs can be presystemically metabolised and the amount of transferred arsenic is lower than that for AsHCs. In contrast, AsHCs are likely to be highly intestinally bioavailable to humans. Since AsHCs exert strong toxicity in vitro and in vivo, toxicity studies with experimental animals as well as a human exposure assessment are needed to assess the risk to human health related to the presence of AsHCs in seafood.

Role of entrained droplet oil on the bioavailability of petroleum substances in aqueous exposures.

Bioavailability of petroleum substances is a complex issue that is affected by substance composition, the physicochemical properties of the individual constituents, and the exposure preparation system. The present study applies mechanistic fate and effects models to characterize the role of droplet oil on dissolved exposure and predicted effects from both neat and weathered crude oils, and refined fuel oils. The main effect from droplet oil is input of additional dissolved hydrocarbons to the exposure system following preparation of the initial stock solution. Toxicity was characterized using toxic units (TU) and shows that replenishment of bioavailable hydrocarbons by droplets in toxicity tests with low droplet content (e.g., <1mg/L) is negligible, consistent with typical exposure conditions following open ocean oil spills. Further, the use of volumetric exposure metrics (e.g., mg/L) introduces considerable variability and the bioavailability-based metrics (e.g., TUs) provide a more consistent basis for understanding oil toxicity data.

Biodegradation of aliphatic hydrocarbons in the presence of hydroxy cucurbit[6]uril.

Aliphatic hydrocarbons are one of the major environmental pollutants with reduced bioavailability. The present study focuses on the effect of hydroxy cucurbit[6]uril on the bioavailability of hydrocarbons. A bacterial consortium was used for biodegradation studies under saline and non-saline conditions. Based on denaturing gradient gel electrophoresis results it was found that the consortium under saline conditions had two different strains. The experiment was conducted in microcosms with tetradecane, hexadecane, octadecane and mixture of the mentioned hydrocarbons as the sole carbon source. The residual hydrocarbon was quantified using gas chromatography every 24h. It was found that biodegradation of tetradecane and hexadecane, as individual carbon source increased in the presence of hydroxy CB[6], probably due to the increase in their bioavailability. In case of octadecane this did not happen. Bioavailability of all three aliphatic hydrocarbons was increased when provided as a mixture to the consortium under saline conditions.

Phytoremediation of soils co-contaminated by organic compounds and heavy metals: bioassays with Lupinus luteus L. and associated endophytic bacteria.

In the central part of the Iberian Peninsula there are old sealed landfills containing soils co-contaminated by several heavy metals (Cu, Zn, Pb, Cd, Ni, As, Cr, Fe, Al, Mn) and organic pollutants of different families (hydrocarbons, polycyclic aromatic hydrocarbons, polychlorinated biphenyls, pesticides and other organochlorinated compounds, phenols and volatile compounds), which this work will address. We have focused on phytoremedial plants that are able to deal with this type of complex pollution, not only species that tolerate the joint effect of heavy metals in the soil, but also those that can take advantage of associated bacteria to efficiently break down organic compounds. This study was carried out with Lupinus luteus and its endophytes in two greenhouse experiments: A) growing in a substrate artificially contaminated with benzo(a)pyrene (BaP), and B) using real co-contaminated landfill soils. Endophytes of roots and shoots were isolated in both bioassays. Plant growth-promotion tests and organic pollutant tolerance and degradation tests were conducted on all strains isolated in bioassay A), and on those proving to be pure cultures from bioassay B). The selected landfill is described as are isolation and test procedures. Results indicate that plants did not show toxicity symptoms when exposed to BaP but did when grown in landfill soil. Some endophytes demonstrated plant growth-promotion capacity and tolerance to BaP and other organic compounds (diesel and PCB commercial mixtures). A few strains may even have the capacity to metabolize those organic pollutants. The overall decline in plant growth-promotion capacity in those strains isolated from the landfill soil experiment, compared with those from the bioassay with BaP, may indicate that lupin endophytes are not adapted to metal concentration in roots and shoots and fail to grow. As a result, most isolated root endophytes must have colonized root tissues from the soil. While preliminary degradation tests showed promising results (some strains exhibiting the potential to use organic pollutants as their sole source of carbon), these are not conclusive and further in-depth degradation assays need to be performed.

In vitro toxicological characterisation of three arsenic-containing hydrocarbons.

Arsenic-containing hydrocarbons are one group of fat-soluble organic arsenic compounds (arsenolipids) found in marine fish and other seafood. A risk assessment of arsenolipids is urgently needed, but has not been possible because of the total lack of toxicological data. In this study the cellular toxicity of three arsenic-containing hydrocarbons was investigated in cultured human bladder (UROtsa) and liver (HepG2) cells. Cytotoxicity of the arsenic-containing hydrocarbons was comparable to that of arsenite, which was applied as the toxic reference arsenical. A large cellular accumulation of arsenic, as measured by ICP-MS/MS, was observed after incubation of both cell lines with the arsenolipids. Moreover, the toxic mode of action shown by the three arsenic-containing hydrocarbons seemed to differ from that observed for arsenite. Evidence suggests that the high cytotoxic potential of the lipophilic arsenicals results from a decrease in the cellular energy level. This first in vitro based risk assessment cannot exclude a risk to human health related to the presence of arsenolipids in seafood, and indicates the urgent need for further toxicity studies in experimental animals to fully assess this possible risk.

Bioaccumulation of petroleum hydrocarbons in fiddler crabs (Uca minax) exposed to weathered MC-252 crude oil alone and in mixture with an oil dispersant.

The Deepwater Horizon accident in the Gulf of Mexico resulted in a sustained release of crude oil, and weathered oil was reported to have washed onto shorelines and marshes along the Gulf coast. One strategy to minimize effects of tarballs, slicks, and oil sheen, and subsequent risk to nearshore ecosystem resources was to use oil dispersants (primarily Corexit® 9500) at offshore surface and deepwater locations. Data have been generated reporting how Corexit® 9500 and other dispersants may alter the acute toxicity of crude oil (Louisiana sweet crude) to marine organisms. However, it remains unknown how oil dispersants may influence bioaccumulation of petroleum hydrocarbons in nearshore crustaceans. We compare bioaccumulation of petroleum hydrocarbons in fiddler crabs (Uca minax) from exposures to the water accommodated fraction (WAF) of weathered Mississippi Canyon 252 oil (~30 d post spill) and chemically-enhanced WAF when mixed with Corexit® EC9500A. Whole body total petroleum hydrocarbon (TPH) concentrations were greater than background for both treatments after 6h of exposure and reached steady state at 96 h. The modeled TPH uptake rate was greater for crabs in the oil only treatment (k(u)=2.51 mL/g/h vs. 0.76 mL/g/h). Furthermore, during the uptake phase TPH patterns in tissues varied between oil only and oil+dispersant treatments. Steady state bioaccumulation factors (BAFs) were 19.0 mL/g and 14.1 mL/g for the oil only and oil+Corexit treatments, respectively. These results suggest that the toxicokinetic mechanisms of oil may be dependent on oil dispersion (e.g., smaller droplet sizes). The results also indicate that multiple processes and functional roles of species should be considered for understanding how dispersants influence bioavailability of petroleum hydrocarbons.

Application of data fusion in human health risk assessment for hydrocarbon mixtures on contaminated sites.

The exposure and toxicological data used in human health risk assessment are obtained from diverse and heterogeneous sources. Complex mixtures found on contaminated sites can pose a significant challenge to effectively assess the toxicity potential of the combined chemical exposure and to manage the associated risks. A data fusion framework has been proposed to integrate data from disparate sources to estimate potential risk for various public health issues. To demonstrate the effectiveness of the proposed data fusion framework, an illustrative example for a hydrocarbon mixture is presented. The Joint Directors of Laboratories Data Fusion architecture was selected as the data fusion architecture and Dempster-Shafer Theory (DST) was chosen as the technique for data fusion. For neurotoxicity response analysis, neurotoxic metabolites toxicological data were fused with predictive toxicological data and then probability-boxes (p-boxes) were developed to represent the toxicity of each compound. The neurotoxic response was given a rating of "low", "medium" or "high". These responses were then weighted by the percent composition in the illustrative F1 hydrocarbon mixture. The resulting p-boxes were fused according to DST's mixture rule of combination. The fused p-boxes were fused again with toxicity data for n-hexane. The case study for F1 hydrocarbons illustrates how data fusion can help in the assessment of the health effects for complex mixtures with limited available data.

Phytoassessment of a waste engine oil-polluted soil exposed to two different intervals of monitored natural attenuation using African yam bean (Sphenostylis stenocarpa).

The present study comparatively investigated the phytotoxic effects of waste engine oil (WEO)-polluted soil exposed to monitored natural attenuation up to 5 and 14 months respectively. Soil was previously polluted with WEO at 0, 1, 2.5, 5 and 10% w/w oil in soil. Although, there was significant reduction in heavy metal concentration of soil as well as total hydrocarbon contents, performance of Sphenostylis stenocarpa was greatly retarded when sown at 5 months after pollution (MAP), with death of all seedlings except in the control. However, growth and yield performances were significantly (p > 0.05) enhanced at 14 MAP. Computation of hazard quotient showed that ecological risk factor initially posed by the presence of heavy metals in the soil at 5 MAP was significantly (p > 0.05) reduced to safe levels at 14 MAP.

Evaluation and comparison of urinary metabolic biomarkers of exposure for the jet fuel JP-8.

A study of workers exposed to jet fuel propellant 8 (JP-8) was conducted at U.S. Air Force bases and included the evaluation of three biomarkers of exposure: S-benzylmercapturic acid (BMA), S-phenylmercapturic acid (PMA), and (2-methoxyethoxy)acetic acid (MEAA). Postshift urine specimens were collected from various personnel categorized as high (n = 98), moderate (n = 38) and low (n = 61) JP-8 exposure based on work activities. BMA and PMA urinary levels were determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), and MEAA urinary levels were determined by gas chromatography-mass spectrometry (GC-MS). The numbers of samples determined as positive for the presence of the BMA biomarker (above the test method's limit of detection [LOD = 0.5 ng/ml]) were 96 (98.0%), 37 (97.4%), and 58 (95.1%) for the high, moderate, and low (control) exposure workgroup categories, respectively. The numbers of samples determined as positive for the presence of the PMA biomarker (LOD = 0.5 ng/ml) were 33 (33.7%), 9 (23.7%), and 12 (19.7%) for the high, moderate, and low exposure categories. The numbers of samples determined as positive for the presence of the MEAA biomarker (LOD = 0.1 µ g/ml) were 92 (93.4%), 13 (34.2%), and 2 (3.3%) for the high, moderate, and low exposure categories. Statistical analysis of the mean levels of the analytes demonstrated MEAA to be the most accurate or appropriate biomarker for JP-8 exposure using urinary concentrations either adjusted or not adjusted for creatinine; mean levels of BMA and PMA were not statistically significant between workgroup categories after adjusting for creatinine.

Effect-directed assessment of the bioaccumulation potential and chemical nature of Ah receptor agonists in crude and refined oils.

Recent studies have indicated that in addition to narcosis certain chemicals in crude oils and refined petroleum products may induce specific modes of action, such as aryl hydrocarbon receptor (AhR) agonism. The risks these toxic compounds pose to organisms depend on internal exposure levels, as driven by the chemicals' bioaccumulation potential. Information on this potential however is lacking, as the chemicals' identity mostly is unknown. This study showed that AhR agonists bioaccumulate from oil-spiked sediments into aquatic worms and persist in the worms for at least several weeks. Chemical fractionations of eight pure oils into saturates, aromatics, resins, and asphaltenes (SARA), followed by effect-directed analyses using in vitro reporter gene assays revealed that the agonists predominantly are aromatic and resin-like chemicals. Some of the compounds were easily metabolized in vitro, while others were resistant to biotransformation. HPLC-assisted hydrophobicity profiling subsequently indicated that the AhR-active chemicals had a high to extremely high bioaccumulation potential, considering their estimated logK(ow) values of 4 to >10. Most of the AhR agonism, however, was assigned to compounds with logK(ow) of 5-8. These compounds were present mainly in the mid to high boiling point fractions of the oils (C(14)-C(32) alkane range), which are usually not being considered (the most) toxic in current risk assessment. The fractionations further revealed considerable oil and fraction-dependent antagonism in pure oils and SARA fractions. The results of this study clearly demonstrate that crude oils and refined petroleum products contain numerous compounds that can activate the AhR and which because of their likely persistence and extremely high bioaccumulation potential could be potential PBT (persistent, bioaccumulative and toxic) or vPvB (very persistent and very bioaccumulative) substance candidates. Many chemicals were identified by GC-MS, but the responsible individual compounds could not be exactly identified in the complex mixtures of thousands of compounds. Because this obstructs a classical PBT risk assessment, our results advocate an adapted risk assessment approach for complex mixtures in which low concentrations of very potent compounds are responsible for mixture effects.

Development of a physiologically based pharmacokinetic model for inhalation of jet fuels in the rat.

The pharmacokinetic behavior of the majority of jet fuel constituents has not been previously described in the framework of a physiologically based pharmacokinetic (PBPK) model for inhalation exposure. Toxic effects have been reported in multiple organ systems, though exposure methods varied across studies, utilizing either vaporized or aerosolized fuels. The purpose of this work was to assess the pharmacokinetics of aerosolized and vaporized fuels, and develop a PBPK model capable of describing both types of exposures. To support model development, n-tetradecane and n-octane exposures were conducted at 89 mg/m(3) aerosol+vapor and 1000-5000 ppm vapor, respectively. Exposures to JP-8 and S-8 were conducted at ~900-1000 mg/m(3), and ~200 mg/m(3) to a 50:50 blend of both fuels. Sub-models were developed to assess the behavior of representative constituents and grouped unquantified constituents, termed "lumps", accounting for the remaining fuel mass. The sub-models were combined into the first PBPK model for petroleum and synthetic jet fuels. Inhalation of hydrocarbon vapors was described with simple gas-exchange assumptions for uptake and exhalation. For aerosol droplets systemic uptake occurred in the thoracic region. Visceral tissues were described using perfusion and diffusion-limited equations. The model described kinetics at multiple fuel concentrations, utilizing a chemical "lumping" strategy to estimate parameters for fractions of speciated and unspeciated hydrocarbons and gauge metabolic interactions. The model more accurately simulated aromatic and lower molecular weight (MW) n-alkanes than some higher MW chemicals. Metabolic interactions were more pronounced at high (~2700-1000 mg/m(3)) concentrations. This research represents the most detailed assessment of fuel pharmacokinetics to date.

A quantitative method for estimating dermal benzene absorption from benzene-containing hydrocarbon liquids.

This study examines a method for estimating the dermal absorption of benzene contained in hydrocarbon liquids that contact the skin. This method applies to crude oil, gasoline, organic solvents, penetrants, and oils. The flux of benzene through occluded skin as a function of the percent vol/vol benzene in the liquid is derived by fitting a curve to experimental data; the function is supralinear at benzene concentrations < or = 5% vol/vol. When a liquid other than pure benzene is on nonoccluded skin, benzene may preferentially evaporate from the liquid, which thereby decreases the benzene flux. We present a time-averaging method here for estimating the reduced dermal flux during evaporation. Example calculations are presented for benzene at 2% vol/vol in gasoline, and for benzene at 0.1% vol/vol in a less volatile liquid. We also discuss other factors affecting dermal absorption.

Urinary metabolites of polycyclic aromatic hydrocarbons in workers exposed to vapours and aerosols of bitumen.

Urinary hydroxylated metabolites of polycyclic aromatic hydrocarbons (PAH) were investigated as potential biomarkers of bitumen exposure in a cross-shift study in 317 exposed and 117 non-exposed workers. Personal measurements of the airborne concentration of vapours and aerosols of bitumen during a working shift were weakly associated with post-shift concentrations of 1-hydroxypyrene (1-OHP) and 1-, 2+9-, 3- and 4-hydroxyphenanthrenes (further referred to their sum as OHPHE), but not 1- and 2-hydroxynaphthalene (OHNA). Smoking showed a strong influence on the metabolite concentrations, in particular on OHNA. Pre-shift concentrations of 1-OHP and OHPHE did not differ between the study groups (P = 0.16 and P = 0.89, respectively). During shift, PAH metabolite concentrations increased in exposed workers and non-exposed smokers. Statistical modelling of post-shift concentrations revealed a small increase in 1-OHP by a factor of 1.02 per 1 mg/m(3) bitumen (P = 0.02) and 1.04 for OHPHE (P < 0.001). A group difference was observed that was diminished in non-smokers. Exposed non-smokers had a median post-shift 1-OHP concentration of 0.42 µg/l, and non-smoking referents 0.13 µg/l. Although post-shift concentrations of 1-OHP and OHPHE were slightly higher than those in the general population, they were much lower than in coke-oven workers. The small content of PAHs in vapours and aerosols of bitumen, the increasing use of additives to asphalt mixtures, the strong impact of smoking and their weak association with airborne bitumen limit the use of PAH metabolites as specific biomarkers of bitumen exposure.