A guidance value of 1-hydroxypyrene in urine in view of acceptable occupational exposure to polycyclic aromatic hydrocarbons.

Occupational exposure limits for carcinogens are increasingly based on excess lifetime risks of cancer. Acceptable limits in some countries in Europe are set at 4/1000 (=highest tolerable risk level) and 4/100,000 (=acceptable risk level) based on 40 year working exposure for the occupational population. When an exposure metric is used that is fairly new, epidemiology does not offer dose-response data that is needed for the derivation of a science based limit value. The urinary concentration of 1-hydroxypyrene is a fairly new bioindicator of exposure to polycyclic aromatic hydrocarbons (PAH). Nowadays, measurements of 1-hydroxypyrene in urine are routinely applied to control industrial exposure to PAH as present in coke ovens and primary aluminium production and to control exposure of professionals when handling coal tar derived products. Due to lacking dose-response data from epidemiological studies, a cancer risk based limit of 1-hydroxypyrene in urine cannot be derived. An alternative derivation procedure is proposed for the limit value that can be used as guidance for the intermediate period. For the period in-between, it is suggested to take the 'no observed genotoxic effect level' (=NOGEL) in PAH-exposed workers as the point-of-departure for setting the limit value. The genotoxic endpoints are genotoxic effects in white blood cells of PAH-exposed workers (chromosomal aberrations, sister chromatid exchanges, micronuclei, comet assay, DNA adducts). In order to assess the point-of-departure for limit setting, cross-sectional studies were searched for that report on the response of early genotoxic effects in white blood cells of workers that could be related to the degree of PAH-exposure (expressed as 1-hydroxypyrene in urine). Nine cross-sectional studies were traced that met these requirements. From each study, the concentration of 1-hydroxypyrene in end-of-shift urine samples was determined, at which no genotoxic effects was found. From 4 out of 9 studies a no-observed genotoxic effect level could be derived, the lowest level was 1.0 µmol/mol creatinine. This limit level is recommended as a state-of-the-art guidance, valid when the PAH-profile in the work environment is similar to that of coke oven with a typical pyrene/BaP ratio of 2.5. For work environments with a deviating PAH-profile an adjustment procedure with the pyrene/BaP ratio is suggested.

Simulation of urinary excretion of 1-hydroxypyrene in various scenarios of exposure to polycyclic aromatic hydrocarbons with a generic, cross-chemical predictive PBTK-model.

INTRODUCTION: A physiologically based toxicokinetic (PBTK) model can predict blood and urine concentrations, given a certain exposure scenario of inhalation, dermal and/or oral exposure. The recently developed PBTK-model IndusChemFate is a unified model that mimics the uptake, distribution, metabolism and elimination of a chemical in a reference human of 70 kg. Prediction of the uptake by inhalation is governed by pulmonary exchange to blood. Oral uptake is simulated as a bolus dose that is taken up at a first-order rate. Dermal uptake is estimated by the use of a novel dermal physiologically based module that considers dermal deposition rate and duration of deposition. Moreover, evaporation during skin contact is fully accounted for and related to the volatility of the substance. Partitioning of the chemical and metabolite(s) over blood and tissues is estimated by a Quantitative Structure-Property Relationship (QSPR) algorithm. The aim of this study was to test the generic PBTK-model by comparing measured urinary levels of 1-hydroxypyrene in various inhalation and dermal exposure scenarios with the result of model simulations. EXPERIMENTAL: In the last three decades, numerous biomonitoring studies of PAH-exposed humans were published that used the bioindicator 1-hydroxypyrene (1-OH-pyrene) in urine. Longitudinal studies that encompass both dosimetry and biomonitoring with repeated sampling in time were selected to test the accuracy of the PBTK-model by comparing the reported concentrations of 1-OHP in urine with the model-predicted values. Two controlled human volunteer studies and three field studies of workers exposed to polycyclic aromatic hydrocarbons (PAH) were included. RESULTS: The urinary pyrene-metabolite levels of a controlled human inhalation study, a transdermal uptake study of bitumen fume, efficacy of respirator use in electrode paste workers, cokery workers in shale oil industry and a longitudinal study of five coke liquefaction workers were compared to the PBTK-predicted values. The simulations showed that the model-predicted concentrations of urinary pyrene and metabolites over time, as well as peak-concentrations and total excreted amount in different exposure scenarios of inhalation and transdermal exposure were in all comparisons within an order of magnitude. The model predicts that only a very small fraction is excreted in urine as parent pyrene and as free 1-OH-pyrene. The predominant urinary metabolite is 1-OH-pyrene-glucuronide. Enterohepatic circulation of 1-OH-pyrene-glucuronide seems the reason of the delayed release from the body. CONCLUSIONS: It appeared that urinary excretion of pyrene and pyrene-metabolites in humans is predictable with the PBTK-model. The model outcomes have a satisfying accuracy for early testing, in so-called 1st tier simulations and in range finding. This newly developed generic PBTK-model IndusChemFate is a tool that can be used to do early explorations of the significance of uptake of pyrene in the human body following industrial or environmental exposure scenarios. And it can be used to optimize the sampling time and urine sampling frequency of a biomonitoring program.

A generic, cross-chemical predictive PBTK model with multiple entry routes running as application in MS Excel; design of the model and comparison of predictions with experimental results.

AIM: Physiologically based toxicokinetic (PBTK) models are computational tools, which simulate the absorption, distribution, metabolism, and excretion of chemicals. The purpose of this study was to develop a physiologically based pharmacokinetic (PBPK) model with a high level of transparency. The model should be able to predict blood and urine concentrations of environmental chemicals and metabolites, given a certain environmental or occupational exposure scenario. MODEL: The model refers to a reference human of 70 kg. The partition coefficients of the parent compound and its metabolites (blood:air and tissue:blood partition coefficients of 11 organs) are estimated by means of quantitative structure-property relationship, in which five easily available physicochemical properties of the compound are the independent parameters. The model gives a prediction of the fate of the compound, based on easily available chemical properties; therefore, it can be applied as a generic model applicable to multiple compounds. Three routes of uptake are considered (inhalation, dermal, and/or oral) as well as two built-in exercise levels (at rest and at light work). Dermal uptake is estimated by the use of a dermal diffusion-based module that considers dermal deposition rate and duration of deposition. Moreover, evaporation during skin contact is fully accounted for and related to the volatility of the substance. Saturable metabolism according to Michaelis-Menten kinetics can be modelled in any of 11 organs/tissues or in liver only. Renal tubular resorption is based on a built-in algorithm, dependent on the (log) octanol:water partition coefficient. Enterohepatic circulation is optional at a user-defined rate. The generic PBTK model is available as a spreadsheet application in MS Excel. The differential equations of the model are programmed in Visual Basic. Output is presented as numerical listing over time in tabular form and in graphs. The MS Excel application of the PBTK model is available as freeware. EXPERIMENTAL: The accuracy of the model prediction is illustrated by simulating experimental observations. Published experimental inhalation and dermal exposure studies on a series of different chemicals (pyrene, N-methyl-pyrrolidone, methyl-tert-butylether, heptane, 2-butoxyethanol, and ethanol) were selected to compare the observed data with the model-simulated data. The examples show that the model-predicted concentrations in blood and/or urine after inhalation and/or transdermal uptake have an accuracy of within an order of magnitude. CONCLUSIONS: It is advocated that this PBTK model, called IndusChemFate, is suitable for 'first tier assessments' and for early explorations of the fate of chemicals and/or metabolites in the human body. The availability of a simple model with a minimum burden of input information on the parent compound and its metabolites might be a stimulation to apply PBTK modelling more often in the field of biomonitoring and exposure science.

Hydroxypyrene in urine of football players after playing on artificial sports field with tire crumb infill.

BACKGROUND: Artificial sports fields are increasingly being used for sports. Recycled rubber from automotive and truck scrap rubber tires are used as an infill material for football grounds. There are concerns that football players may be at risk due to exposure from released compounds from rubber infill. Compounds from crumb infill may be inhaled and dermal exposure may occur. A study was performed to assess the exposure of football players to polycyclic aromatic hydrocarbons due to sporting on synthetic ground with rubber crumb infill. METHODS: In this study, football players were trained and had a match on the artificial turf pitch during 2.5 h. They had an intensive skin contact with rubber infill. All urine of seven nonsmoking football players was collected over a 3-day period, the day before sporting, the day of sporting and the day after sporting. Urine samples were analyzed for 1-hydroxypyrene. Confounding exposure from environmental sources and diet was controlled for. RESULTS: The individual increase of the amount of excretion over time was used as a measure to assess the uptake of PAH. It appeared that the baseline of excreted 1-hydroxypyrene in 4 of 7 volunteers was sufficient stable and that 1 volunteer out of 4 showed after the 2.5-h period of training and match on the playground an increase in hydroxypyrene in urine. However, concomitant dietary uptake of PAH by this volunteer was observed. CONCLUSIONS: This study provides evidence that uptake of PAH by football players active on artificial grounds with rubber crumb infill is minimal. If there is any exposure, than the uptake is very limited and within the range of uptake of PAH from environmental sources and/or diet.

Validation of multimedia models assessing exposure to PAHs--the SOLEX study.

Polluted soils have become a public health problem. While population exposure to soil pollutants is generally quantified using multimedia models, their estimations have not been validated, and studies that attempted to do so are scarce. The objective of the SOLEX study was to compare the predictions of pyrene exposure levels (converted into 1 hydroxypyrene) computed by several models with the results of urinary 1-hydropyrene (1-HOP) assays among 110 employees working at three sites polluted during their past use as manufactured gas plants. Four models were used: AERIS (Canada), CalTOX (California, USA), CLEA (UK), and HESP (The Netherlands). Three occupational exposure scenarios--with office, mixed, and outdoor workers--were constructed, based upon job activities during two measurement campaigns, one in winter and one in summer. The exposure levels estimated by the four models could differ markedly (from 7 up to 80 times) according to the exposure scenario. Also, the predominant exposure routes differed according to the model (direct soil ingestion for HESP and CalTOX, inhalation for AERIS, and dermal absorption for CLEA). The predictions of CalTOX are consistent with the 1-HOP measurements for all the scenarios. For HESP, the consistency is observed for the scenarios, office and mixed, for which the pyrene level in the soil is low. AERIS and CLEA yield results that are systematically above the 1-HOP measurements. This study confirms that validation of the models is crucial and points out to the need to proceed to assess components of the models that are the most influential using appropriate statistical analysis in combination with true field data.

Biological versus ambient exposure monitoring of creosote facility workers.

Traditional methods for monitoring occupational creosote exposure have focused on inhalation. However, there is evidence that dermal exposure contributes importantly to total systemic dose, as measured by biological monitoring methods. This study was conducted to further characterize the relationships between inhalation and dermal exposures to creosote, and to compare traditional ambient exposure monitoring versus biological monitoring in 36 creosote-exposed wood treatment workers. Full-shift personal air samples were obtained, along with post-shift and next-day urine measurements for 1-hydroxypyrene. There was little or no correlation between airborne measures and urinary 1-hydroxypyrene (r2 = 0.05 to 0.35). More than 90% of 1-hydroxypyrene could be attributed to dermal exposure. These data indicate that traditional monitoring methods may be inappropriate for creosote workers, raising concerns about the adequacy of methods currently mandated by the Occupational Safety and Health Administration.