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Imagine you are a construction worker on the flat roof of a tall building. There is a guardrail at the very periphery of the roof. If you walk past the guardrail, you will fall off and get severely hurt or die. This often is the representation some people have of the so-called occupational exposure limit (OEL) values of chemicals: a fine line between safe and unsafe. However, those who are knowledgeable in the field of occupational health and safety, especially people working on expert committees recommending such values, know that this is not so. Hence the use of the word guideline is used instead of limit in the title of this chapter. However, since the expression Occupational Exposure Limit and its abbreviation OEL are widespread, they will be used in this chapter.

International audience; Adequate interpretation of biomonitoring results of occupational exposures to chemicals requires comparison values also referred to as biological interpretation values. Among these values are those derived in France by Anses, which are based on a structured approach led collectively by independent and multidisciplinary groups of scientific experts. Two types of occupational biological values are recommended by Anses: biological limit values and biological reference values. These values are derived from the data available in the scientific literature. The article first shows that the derivation by Anses of the biological values to be used for biomonitoring of occupational exposures is linked to the nature of the chemical examined. Depending upon whether the substance is a threshold or non-threshold toxicant, such as genotoxic carcinogens, the approach will be different. Next, some specific examples are presented (cadmium, styrene, 2-butoxyethanol and acrylamide) to help occupational physicians with the informed interpretation of biomonitoring results collected in workplaces. (C) 2017 Societe Francaise de Toxicologie Analytique. Published by Elsevier Masson SAS. All rights reserved.; Pour être interprétés, les résultats de la surveillance biologique des expositions professionnelles aux agents chimiques doivent pouvoir être comparés à des valeurs biologiques d'interprétation. Parmi ces valeurs figurent les valeurs élaborées en France par l'Anses selon une * Auteur correspondant. Adresse

De multiples appellations designent des valeurs dites limites pour les mesures de biosurveillance. Cela peut traduire des philosophies diverses de la part des organismes. Nous les passerons brievement en revue dans cette presentation. Le jugement professionnel a l’egard de la biosurveillance s’exerce a deux niveaux : au moment de l’elaboration de ces valeurs – que j’appellerai valeurs guides (VG) ici – et au moment de leur utilisation par les medecins du travail et autres preventeurs. La premiere etape de l’elaboration des VG concerne la recherche dans la litterature scientifique des effets deleteres de la substance. Le choix des equations de recherche dans les bases de donnees est critique autant que la definition de « effets deleteres ». On cherche celui qui survient a la plus faible dose d’exposition. La dose la plus elevee qui ne produit pas cet effet est alors designee « NOAEL » ou « No Observed Adverse Effect Level ». Son identification depend du devis de l’etude. La NOAEL constitue ce qu’on appelle un « point de depart » (PD). Il faut ensuite transformer ce PD en VG en utilisant divers facteurs d’appellations encore diverses : facteurs d’incertitude, de securite, d’estimation, d’ajustement. On tient compte ici de l’incertitude et de la variabilite associees a la determination d’une VG. Si le PD provient d’une etude animale, on le divisera par un facteur allant de 1 a 10, selon le jugement des experts, pour transformer ce PD animal en un PD humain. Ensuite, on prend en compte l’existence d’une variabilite entre les individus. On cherchera a proteger ceux qui sont potentiellement plus sensibles en divisant la valeur precedemment obtenue par un facteur additionnel allant de 1 a 5, toujours selon le jugement des experts. Pour certaines substances, de multiples VG existent. Dans le cas du plomb, l’ANSES a determine que pour prevenir l’insuffisance renale dans la population generale, une VG plombemie de 15 μg/L devait s’appliquer. En milieu de travail, la VG qui protege des effets repertories en milieux professionnels est de 180 μg/L. Comme points de reperes additionnels, le 95e percentile des valeurs observees en population generale est de 85 μg/L pour les hommes et de 60 μg/L pour les femmes, a l’exception des femmes susceptibles de procreer pour lesquelles une valeur de 45 μg/L a ete determinee. Tout ceci est information utile ou source de confusion ? Equations de recherche, definition d’effets deleteres, identification d’un PD, application selon le jugement expert de facteurs aboutissant a une VG, multiplicite des VG elles-memes : les VG ne sont pas des frontieres absolues entre toxicite et securite. Elles font appel au jugement tant des experts qui les elaborent que de ceux qui les appliquent.

Measurements of 3-hydroxybenzo(a)pyrene (3-OHBaP) in urine has been proposed for the biomonitoring of exposure to benzo(a)pyrene (BaP) in workers. To allow a better understanding of the toxicokinetics of BaP and its key biomarker, a multicompartment model was developed based on rat data previously obtained by this group. According to the model, iv injected BaP is rapidly distributed from blood to tissues (t₁/₂ = 3.65 h), with particular affinity for tissue lipid components and liver and lung proteins. BaP is then rapidly distributed to lungs, where significant tissue uptake occurs, followed by the skin, liver, and adipose tissues. Once in liver, BaP is readily metabolized, and 3-OHBaP is formed with a t₁/₂ of 3.32 h. Lung metabolism of BaP was also accounted for, but its contribution to the whole kinetics was found to be negligible. Once formed, 3-OHBaP is distributed from blood to the various organs almost as fast as the parent compound (t₁/₂ = 2.26 h). In kidneys, 3-OHBaP builds up as a result of the smaller rate of 3-OHBaP urinary excretion (t₁/₂ = 4.52 h) as compared with its transfer rate from blood to kidneys (t₁/₂ = 27.8 min). However, overall clearance of 3-OHBaP from the body is driven by its biliary transfer from liver to the gastrointestinal tract (t₁/₂ = 3.81 h). The model provides a great fit to independent sets of published data on 3-OHBaP urinary excretion time course (χ² = 0.019). This model proves useful in establishing the main biological determinants of the overall kinetics of these compounds.

A longitudinal biomonitoring study was conducted to assess exposure to polycyclic aromatic hydrocarbons (PAH) in non-occupationally exposed nonsmoking adults living in the vicinity of an aluminum plant. Metabolites of several PAH (pyrene, naphthalene, chrysene, fluoranthene, benz[a]anthracene) were measured in the urine of the participants, including 1-hydroxypyrene (1-OHP) as a validated biomarker and pyrene diones as novel biomarkers. In total, 73 individuals living about 1 km away from the plant (taken as the exposed group) were compared repeatedly with 71 individuals living at least 11 km from the smelter (used as the control group). Complete first morning voids were collected twice, at a 2-wk interval, in the fall of 2005 and twice weekly for 2 consecutive weeks in the spring of 2006. Urinary biomarker concentrations were then measured by an ultra-performance liquid chromatography (UPLC) method with time-of-flight mass spectrometry detection (MS-TOF) (UPLC-MS-TOF). For most sampling days, individuals living near the plant showed significantly higher excretion values of both 1-OHP and pyrene diones (mean ratio up to 2- and 2.4-fold, respectively) than individuals living further from the plant. In the group living near the plant, geometric mean concentrations of 1-OHP varied from 0.047 to 0.058 micromol/mol creatinine, depending on the sampling day, as compared to 0.025 to 0.04 micromol/mol creatinine in the reference group. Corresponding mean values for pyrene diones were 0.017-0.056 micromol/mol creatinine and 0.014-0.039 micromol/mol creatinine, respectively. Urinary 1- and 2-naphthols were also measured as a reference and showed no significant differences between the two groups for most sampling days; metabolite concentrations of the other monitored PAH (chrysene, fluoranthene, benz[a]anthracene) were mostly below the analytical limit of detection of 0.005 to 0.01 microg/L, depending on the metabolite, with a detection rate varying from 0 to at most 21%. Individuals living near the aluminum plant thus appeared to be repeatedly exposed to higher pyrene levels than the control group, on the basis of both 1-OHP and pyrene dione excretions. However, 1-OHP concentrations observed in this first group were similar to those of other reference populations of nonsmokers studied in the past. Uptake of the other PAH associated with plant emissions was too small to significantly increase the excretion of their metabolites.

Biomonitoring Equivalents (BEs) are screening tools for interpreting biomonitoring data. However, the development of BEs brings to the public a relatively novel concept in the field of health risk assessment and presents new challenges for environmental risk communication. This paper provides guidance on methods for conveying information to the general public, the health care community, regulators and other interested parties regarding how chemical-specific BEs are derived, what they mean in terms of health, and the challenges and questions related to interpretation and communication of biomonitoring data. Key communication issues include: (i) developing a definition of the BE that accurately captures the BE concept in lay terms, (ii) how to compare population biomonitoring data to BEs, (iii) interpreting biomonitoring data that exceed BEs for a specific chemical, (iv) how to best describe the confidence in chemical-specific BEs, and (v) key requirements for effective communication with health care professionals. While the risk communication literature specific to biomonitoring is sparse, many of the concepts developed for traditional risk assessments apply, including transparency and discussions of confidence and uncertainty. Communication of BEs will require outreach, education, and development of communication materials specific to several audiences including the lay public and health care providers.

Organic solvents can cause hearing loss themselves or promote noise-induced hearing loss. The objective of this study was to review the literature on the effects of low-level exposure to trichloroethylene on the auditory system and consider its relevance for the occupational settings. Both human and animal investigations were evaluated only for realistic exposure concentrations based on the Quebec permissible exposure limits: 50 ppm 8-h time-weighed average exposure value (TWAEV) and 200 ppm short-term exposure value (STEV). In humans, the upper limit for considering ototoxicity data relevant to the occupational exposure situation was set at the STEV. Animal data were evaluated only for exposure concentrations up to 100 times the TWAEV. There is no convincing evidence of trichloroethylene-induced hearing losses in workers. In rats, trichloroethylene affects the auditory function mainly in the cochlear mid- to high-frequency range with a lowest observed adverse effect level (LOAEL) of 2000 ppm. No studies on ototoxic interaction after combined exposure to noise and trichloroethylene were identified in humans. In rats, supra-additive interaction was reported. Further studies with sufficient data on the trichloroethylene exposure of workers are necessary to make a definitive conclusion. In the interim, we recommend considering trichloroethylene as an ototoxic agent.

Biomonitoring is one of the best available tools for the prevention of deleterious effects resulting from occupational exposure to chemicals. The availability of analytical techniques having low detection limits allows for the measurement of numerous biomarkers. Complemented with quality control programs, our ability to collect validated information on exposure to toxicants improves. This is important as exposure doses tend to decrease in workplaces. Concurrently, there is an increasing preoccupation towards skin exposure, which cannot currently be reliably assessed through external measurements. Furthermore, as lower exposure doses are encountered, background concentrations of some biomarkers become a serious limitation to their use. This prompts researchers to seek for minor, more specific metabolites, that may however be produced through metabolic pathways that are prone to larger inter-individual variations. Assessment of exposure to complex mixtures of chemicals is another major challenge. There is a growing interest towards ethical issues in biomonitoring. The understanding of the advantages and of the limits of this preventive approach may be very different among occupational health professionals, but more importantly, between health professionals and those they are seeking to protect, i.e., the workers themselves. Many organizations have proposed guideline values for biomarker concentrations, but these seldom find their way in the various countries' bylaws. One underlying reason might be the greater complexity of the scientific aspects of biomarkers, whose understanding is required to set limit values, compared to the process of setting airborne limit concentrations. But the fact that the latter does not consider all aspects of biological complexity does not make it more reliable.

A recent in vivo mass-balance study on the disposition of 14C-labelled pyrene in rats suggests that 1-hydroxypyrene (1-OHP) is not the major excreted metabolite. In that report, specific metabolites other than 1-OHP were not identified. The purpose of this study was to identify and quantify these unknown metabolites of pyrene in animal and human urine. Using a high-performance liquid chromatography (HPLC)-electrospray-mass spectrometry method, it was observed that dioxygenated pyrene metabolites (m/z 233) were present in significant amounts in urine samples of rats treated with pyrene. An HPLC method with fluorescence detection was then developed for the simultaneous determination of pyrene-1,6- and 1,8-dioxygenated metabolites, that is, the sum of hydroquinone, semiquinone, and quinone forms of these metabolites, after derivatization into 1,6-diacetoxypyrene (P16Da) and 1,8-diacetoxypyrene (P18Da). The mean limits of detection (+/- standard deviation) were 46 +/- 22 nmol P16Da/L and 86 +/- 32 nmol P18Da/L, as calculated from standard solution curves. The intraday coefficient of variation in rats was 5.5% for P16Da and 7.2% for P18Da; in humans, it was 6.8% for P16Da and 7.4% for P18Da (n = 36 in each case). The day-to-day coefficients of variation in rats were 12.5% for P16Da and 7.3% for P18Da; in humans, they were 10.1% for P16Da and 7.2% for P18Da (n = 12 in each case). The recovery rates of these metabolites ranged between 89 and 126% in rats and between 100 and 121% in humans (n = 36 in each case). Interestingly, rat data showed that P16Da molar amounts in 24-h urine samples (n = 4) exceeded those of 1-OHP by 64 to 121 times and P18Da amounts exceeded those of 1-OHP by 13 to 35 times. Similarly, P16Da molar concentrations in spot urine samples of human subjects (n = 4) exposed to pyrene exceeded those of 1-OHP by 4 to 12 times while P18Da concentrations were 0.4 to 2 times those of 1-OHP. Pyrene-1,6- and 1,8-dioxygenated metabolites are major metabolites of pyrene and, particularly in the case of the 1,6-isomers, potentially useful biomarkers of both environmental and occupational exposure to pyrene.

This study was aimed at investigating the correlation between biomarkers of exposure to polycyclic aromatic hydrocarbons and, more specifically, at examining the role of urinary 1-hydroxypyrene (1-OHP) as a reliable measure of internal dose linked to the electrophilic tissue burden (ETB), assessed as covalent binding of the ultimate carcinogen benzo( a)pyrene diolepoxide (BaPDE) with cellular proteins in target organs. The protocol included experimental verification of a previously proposed algorithm for adjustment of reference values for urinary 1-OHP with exposure to different mixtures of polycyclic aromatic hydrocarbons in a rat model. Hence, the relationships between ETB in liver, lung, and heart as well as the BaPDE-haemoglobin adducts level on the one hand, and urinary/faecal 1-OHP or urinary/faecal 3-hydroxybenzo( a)pyrene (3-OHBaP) on the other hand have been examined. Male Sprague-Dawley rats received intraperitoneally, once daily for 10 consecutive days, binary mixtures of benzo( a)pyrene (BaP) and pyrene (P) in three different exposure scenarios corresponding to BaP/P ratios of 0.2, 1 and 5, with three doses of BaP (2, 6 and 20 mg/kg) for each scenario. The ETB levels were measured as the ultimate analyte benzo( a)pyrene tetrol (BaPTeT) obtained after mild acid hydrolysis of BaPDE adducts with proteins. It was experimentally confirmed that: (1) urinary 1-OHP is a reliable biomarker linked to the ETB in tissues that are targets for carcinogenicity, such as lung, for the BaP/P ratios of 0.2 and 1 (linear regression p=0.0099 and 0.0293, respectively); (2) urinary 3-OHBaP is correlated with the BaPDE-haemoglobin adducts for all three exposure scenarios ( p=0.0011 for BaP/P=0.2, p0.0001 for BaP/P=1 and p=0.0099 for BaP/P=5). The experimental relationship between ETB and urinary 1-OHP was used to interpolate biological limit values for the urinary metabolite assuming three arbitrary critical levels of ETB. These were compared with the values calculated from the algorithm using the BaP/P ratio 1 mixture as a reference. The ratios of calculated to observed values varied from 1.0 to 1.6 for the BaP/P 0.2 mixture, and from 1.9 to 3.0 for the BaP/P 5 mixture. The results obtained in the present study indicate that the algorithm mentioned above applies well for two of the three exposure scenarios corresponding to realistic occupational BaP/P ratios of 0.2 and 1. This suggests that, using ETB as an endpoint, the proposed algorithm will reasonably predict the critical value of urinary 1-OHP for mixtures having different BaP/P ratios. Stronger linear relationships between ETB in all chosen tissues and 1-OHP or 3-OHBaP excretion were obtained with urinary metabolites than with their faecal analogues. Thus urinary 1-OHP and 3-OHBaP are more reliable biomarkers in biological monitoring strategies.

In 1996 the National Institute for Occupational Safety and Health (NIOSH) engaged more than 500 organizations and individuals representing labor, industry, government, and academia, in a process to...

Five healthy volunteers consumed similar amounts of identical foods for 5 consecutive days. The concentration of pyrene and of benzo(a)pyrene was determined in each of the 15 meals by a short analytical method that included sample saponification, solvent extraction, and HPLC analysis. The volunteers also provided three daily total volume 8-h urine samples for the duration of the study for the assessment of 1-hydroxypyrene, a biomarker of pyrene and polycyclic aromatic hydrocarbon (PAH) exposure. Mean recoveries were 83 and 75%, respectively, for pyrene and benzo(a)pyrene in food. Daily dietary pyrene doses varied from 0.7 to 3 microg. Excluding two outliers consisting of meals containing charbroiled pork and beef, pyrene content in the meals estimated from the published literature data was correlated to the measured pyrene, but overestimated the actual concentration by ca. 70%. Despite the identical ingested doses of pyrene, there was a 50-76% (coefficient of variation) interindividual variability in the daily-excreted amount of 1-hydroxypyrene. Urinary excretion of this metabolite was not correlated with ingested dose of pyrene under the normal feeding conditions used in this study. Bioavailability, enzymatic polymorphism, and differences in enterohepatic cycling of the metabolite may contribute to the observed variability. It was calculated that dietary pyrene intake accounts for between 87.5 and 99.8% of the sum of dietary and inhalation intake. From the presented data, unless the above-mentioned factors are taken into account, 1-hydroxypyrene might not be a reliable bioindicator of ingested pyrene (PAHs) under normal feeding conditions.

The urinary excretion kinetics of 1-hydroxypyrene (1-OHP) were studied in male Sprague-Dawley rats exposed orally, on Tuesdays and Fridays for 10 consecutive weeks, to 0.046 mg/kg/d of pyrene or 0.3, 1 or 3 mg/kg/d of polycyclic aromatic hydrocarbon (PAH) mixtures containing pyrene (0.046, 0.15, and 0.46 mg/kg/d, respectively). During the subchronic exposure, 24-h urine samples were collected on Mondays (prior to exposure) and Tuesdays (after exposure) for all exposure groups. During a 14-d period following last exposure in rats treated with 3 mg/kg/d of PAH mixture, 24-h urine samples were collected at frequent time intervals (0-24, 48-72, 96-120, 144-168, 193-217, 313-338 h). Whatever the administered dose, repeated exposures to pyrene and PAH mixtures resulted in a progressive time-dependent increase in the daily urinary excretion of 1-OHP. After 10 wk of treatment, daily excretion rates were on average 5 times higher than those observed after the first administration. Following the subchronic exposure to 3 mg/kg/d of PAH mixture, the time profile of 1-OHP excretion in rat urine showed a multiphasic elimination. An average first-order apparent elimination half-life of 26.5 h could be estimated for the 48-168 h period following the end of the exposure. The observed time-dependent increase in 1-OHP excretion values upon repeated exposures to PAHs does not appear to result from a PAH enzyme induction effect of pyrene metabolism to 1-OHP. Rather, the slow release of residual pyrene accumulated in a long-term compartment and/or the enterohepatic recirculation of 1-OHP and other pyrene metabolites may play significant roles in the observed urinary excretion kinetics of 1-OHP. Furthermore, the absence of mixture effect on the urinary excretion of 1-OHP suggests that 1-OHP is a good bioindicator of exposure to complex PAH mixtures, in the dose range used in this study.

Objectives: Wood combustion is used as a major energy source in African countries and could result in indoor, pollution-related health problems. This exploratory study was undertaken to estimate polycyclic aromatic hydrocarbon (PAH) and carbon monoxide exposure in individuals living in traditional rural houses in Burundi. Methods: Standard methods were used to determine indoor air concentrations of 12 PAHs, and carbon monoxide. The urinary excretion of 1-hydroxypyrene (1-OHP) was measured in occupants of traditional houses, and compared with that of individuals living in the town of Bujumbura, the capital of Burundi. Results: Mean airborne concentration of four volatile PAHs, naphthalene, fluorene, phenanthrene and acenaphthene, exceeded 1 μg/m3, and that of benzo(a)pyrene was 0.07 μg/m3. Naphthalene was by far the main PAH contaminant, with a mean concentration (±standard deviation) of 28.7 ± 23.4 μg/m3, representing on average 60–70% of total PAH concentration. Carbon monoxide mean concentration (±standard deviation) was 42 ± 31 mg/m3, and correlated with total PAH concentration. Geometric mean urinary 1-OHP excretion (range) in people living in traditional houses was 1.50 (0.26–15.62) μmol/mol creatinine, a value which is on average 30 times higher than that of people living in the capital (0.05 (0.009–0.17) μmol/mol creatinine). Conclusions: It appears that the substantially high concentrations of the studied contaminants constitute a potential health hazard to the rural population of Burundi.

The aim of study was to assess the uptake of polycyclic aromatic hydrocarbons (PAH) by children living in a city and its effect on 1-hydroxypyrene (1-OHP) excretion. Two groups of children ( n =11 and 13; 3–6 years old) were chosen: (1) a group from a kindergarten situated near a road with a high traffic density (‘polluted’ area); (2) a group from a kindergarten situated in a green zone (‘non polluted’ area). Food consumption was recorded in all children and PAH uptake from foodstuffs was estimated. Ambient air samples were collected on the playground and indoor of kindergartens during 3 days in summer 1997. Soil samples were collected on the playground. Urine samples were collected in the morning and in the evening. Mean outdoor total PAH concentration (sum of 12 individual PAH) in ‘polluted’ area was 12 times higher than that in ‘non polluted’ area (22.9 vs. 1.9 ng/m 3 ). However, indoor concentrations were similar (3.0 vs. 2.1 ng/m 3 ). The same trend was observed for pyrene concentrations. The contribution to the total pyrene absorbed dose from food consumption (estimated daily absorbed dose of 167 and 186 ng, respectively, in ‘polluted’ and ‘non polluted’ area) was much more important than that from inhalation (8.4 and 5.4 ng, respectively) in both areas. The estimated daily absorbed doses of pyrene from the soil were 0.061 and 0.104 ng in ‘polluted’ and ‘non polluted’ kindergarten, respectively, which correspond to 0.032 and 0.059% of the total absorbed dose. Higher urinary concentrations of 1-OHP were found in children from ‘polluted’ kindergarten. In conclusion, the food seems to be a main source of the total pyrene and total PAH uptake in small children, even under a relative high PAH air exposure in the city. Pyrene concentration in soil had a negligible contribution to the total pyrene absorbed dose. Usefulness of the urinary 1-OHP as an indicator of the environmental exposure to PAH needs further research.

Biological hazard index (BHI) is defined as biological level tolerable for exposure to mixture, and is calculated by an equation similar to the conventional hazard index. The BHI calculation, at the present time, is advocated for use in situations where toxicokinetic interactions do not occur among mixture constituents. The objective of this study was to develop an approach for calculating interactions-based BHI for chemical mixtures. The approach consisted of simulating the concentration of exposure indicator in the biological matrix of choice (e.g. venous blood) for each component of the mixture to which workers are exposed and then comparing these to the established BEI values, for calculating the BHI. The simulation of biomarker concentrations was performed using a physiologically-based toxicokinetic (PBTK) model which accounted for the mechanism of interactions among all mixture components (e.g. competitive inhibition). The usefulness of the present approach is illustrated by calculating BHI for varying ambient concentrations of a mixture of three chemicals (toluene (5-40 ppm), m-xylene (10-50 ppm), and ethylbenzene (10-50 ppm)). The results show that the interactions-based BHI can be greater or smaller than that calculated on the basis of additivity principle, particularly at high exposure concentrations. At lower exposure concentrations (e.g. 20 ppm each of toluene, m-xylene and ethylbenzene), the BHI values obtained using the conventional methodology are similar to the interactions-based methodology, confirming that the consequences of competitive inhibition are negligible at lower concentrations. The advantage of the PBTK model-based methodology developed in this study relates to the fact that, the concentrations of individual chemicals in mixtures that will not result in a significant increase in the BHI (i.e. > 1) can be determined by iterative simulation.

In an attempt to define a tolerable daily intake (TDI) for molybdenum based on a toxicological risk analysis approach, a large literature survey was conducted. In man, absorption of molybdenum after oral intake is in the range of 28-77% and urinary excretion is 17-80% of the total dose. A low order of toxicity of molybdenum compounds has been observed in humans. However, with the available data, it is not possible to calculate any dose-response or dose-effect relationships. Because molybdenum toxicity is associated with copper intake or depleted copper stores in the body, humans who have an inadequate intake of dietary copper or some dysfunction in their copper metabolism that makes them copper-deficient could be at greater risk of molybdenum toxicity. In the absence of relevant human studies, animal studies were evaluated for the derivation of the TDI. Effects of Mo on reproduction and foetal development were found to be critical effects observed in rats and mice. A dose-response relationship was observed in a study by Fungwe et al., with a 'no observed adverse effect' level (NOAEL) and a 'lowest observed adverse effect' level (LOAEL) of 0.9 and 1.6 mg Mo kg(-1) day(-1), respectively. Applying uncertainty factors of 10 for intraspecies and 10 for interspecies differences to the NOAEL, a TDI of 0.009 mg Mo kg(-1) day(-1) was calculated. The TDI is given a medium confidence rating. This TDI is more than double the upper limit of adequate intake for adolescents and adults that was derived from the Mo content of the average diet in the USA.

The tissue distribution and elimination of pyrene and 1-hydroxy-pyrene (1-OHP) were evaluated in male Sprague-Dawley rats (210–240 g) following an intravenous injection of 50 μmol/kg of [14C]pyrene. Blood and tissues were removed and urine and feces were collected at 1, 2, 4, 8, 16, and 24 h postdosing. [14C]Pyrene equivalents were measured by liquid scintillation counting, and β-glucuronidase/arylsulfatase-treated blood, tissues, and excreta were analyzed for pyrene and 1-OHP by HPLC/fluorescence. At 1 h, the largest fraction of the dose was found in adipose tissue, essentially as pyrene, and its elimination followed first-order monophasic kinetics with a half-life (t½) of 4.9 h. In blood, liver, kidney, lung, muscle, and gastrointestinal (GI) tract, kinetics of [14C]pyrene equivalents were biphasic and average t½ values for the terminal elimination phase (8 to 24 h) ranged between 6.2 and 8.7 h. Elimination of pyrene in blood and these tissues except the GI tract followed first-order biphasic kinetics with average t½ values of the terminal phase ranging between 3.6 and 5.4 h. In the GI tract, a monophasic elimination kinetics of pyrene was observed with mean t½ value of 3.1 h. Kinetics of 1-OHP in blood and liver showed a monophasic elimination with mean t½ values of 6.7 and 6.2 h, respectively. Kinetics of 1-OHP in the other tissues were biphasic with average t½ values of the terminal elimination phase ranging between 5.2 and 6.2 h. At 24 h, on average, 81.7% of the dose was recovered in the urine (57.2%), feces (18.3%), and GI tract (6.2%) as [14C]pyrene equivalents with 2.7 and 1.9% of dose excreted as total 1-OHP in urine and feces, respectively. At all time points, 1-OHP in urine represented a constant fraction of total 14C in urine and feces. These results indicate that (i) [14C]pyrene was rapidly distributed, metabolized, and eliminated from the body, and (ii) although 1-OHP represents a small percentage of total pyrene eliminated from the body, it remains a reliable indicator of systemic exposure to, and overall elimination of the 14C associated with, this polycyclic aromatic hydrocarbon.

The subchronic inhalation toxicity of a methanol/gasoline blend (85% methanol, 15% gasoline, v/v) was studied in rats. Sprague Dawley rats (10 animals per group) of both sexes were exposed to vapors of methanol/gasoline at 50/3, 500/30 and 5000/300 ppm for 6 hours per day, 5 days per week, for 13 weeks. Control animals inhaled filtered room air only. Control recovery and high dose recovery groups were also included which inhaled room air for an extra 4 weeks following the treatment period. No clinical signs of toxicity were observed in the treatment group and their growth curves were not significantly different from the control. Except for decreased forelimb grip strength in the high dose females, no treatment-related neurobehavioural effects (4-6 hours post inhalation) were observed using screening tests which included cage-side observations, righting reflex, open field activities, and forelimb and hindlimb grip strength. At necropsy, the organ to body weight ratios for the liver, kidneys, spleen, testes, thymus and lungs were not significantly different from the control group. There were no treatment-related effects in the hematological endpoints and no elevation in serum formate levels. Minimal serum biochemical changes were observed with the only treatment-related change being the decreased creatinine in the females. A dose-related increase in urinary ascorbic acid was detected in males after 2,4 and 8 weeks of exposure, but not after the 12th week, and in females only at week-2. Increased urinary albumin was observed in treated males starting at the lowest dose and at all exposure periods, but not in females. A treatment-related increase in urinary β 2-microglobulin was detected in males at week-2 only. Except for mild to moderate mucous cell metaplasia in nasal septum B, which occurred more often and with a slightly higher degree of severity in the low dose groups of both sexes, and presence of a minimal degree of interstitial lymphocyte infiltration in the prostate glands of the high dose males, no other significant microscopic changes were observed in the tissues of treated animals. Based on the marked increase in urinary ascorbic acid and albumin in the high dose males and the decreased forelimb grip strength in the high dose females, we concluded that the no-observed adverse effect level (NOAEL) of methanol/gasoline vapor is 500/30 ppm.

The effect of exposure to binary and ternary mixtures of polycyclic aromatic hydrocarbons (PAHs) on the urinary excretion kinetics of 1-hydroxypyrene (1-OHP) has been examined. Male Sprague-Dawley rats were administered intravenously 5 micromol/kg of pyrene alone or in combination with 0.5, 5 and 25 micromol/kg of either naphthalene, benzo(a)pyrene (BaP), or both. Urine samples were collected at frequent intervals over 48 h. The kinetics of 1-OHP in urine was not altered by the presence of either naphthalene or BaP in the mixtures, at least from 4 h post-dosing. Hence, none of the injected mixtures significantly modified the first-order apparent elimination half-life of 1-OHP in urine obtained for the 12 to 42 h period post injection where mean values ranged between 6.2 and 9.6 h. However, while the presence of naphthalene or the low BaP dose of 0.5 micromol/kg in the mixtures did not have a significant effect on the total excretion of 1-OHP, BaP doses of 5 and 25 micromol/kg in the mixtures significantly increased the amount of 1-OHP excreted in urine. Mean percentages of the pyrene dose excreted as 1-OHP after injection of pyrene in combination with 0.5, 5 and 25 micromol/kg BaP were respectively increased 1.3, 2.2 and 2.6 times compared to the value obtained after administration of pyrene alone. The percentages determined after concomitant administration of pyrene and 0.5, 5 and 25 micromol/kg of BaP plus naphthalene were 1.4, 1.8 and 2.4 times, respectively, the value obtained after administration of pyrene singly. The observed effect of BaP (5 or 25 micromol/kg) on 1-OHP total excretion appears to result from BaP induction of pyrene metabolism. Lack of effect of naphthalene appears to be due to its weak P450 1A1 enzyme induction capacity. Absence of significant effect of the low BaP dose in the mixtures (0.5 micromol/kg) suggests that 1-OHP in urine is useful as a bioindicator of occupational and environmental exposures to PAH mixtures.

PAN is one of a class of common air pollutants formed by the action of sunlight on volatile organic compounds and nitrogen oxides. No toxicokinetic studies have been found in the available literature. The acute toxicity of PAN is less than that of ozone, similar to NO2 and higher than SO2. The LC50 in mice and rats were 718-743 mg/m3 (for 2 h) and 470 mg/m3 (for 4 h), respectively. Following acute exposure, severe lung lesions and, at the higher levels, damage to the epithelium of upper parts of the respiratory tract were found in animals. It seems that concentrations of 1.19-1.49 mg/m3 lie not far from the threshold required for pulmonary function effects in sensitive individuals. However, these PAN concentrations are well above the maximum ambient concentrations usually experienced within the USA and Canada (0.003-0.078 mg/m3). It appears unlikely that present ambient PAN concentrations would affect pulmonary functions responses to ambient ozone. In human, the lowest level causing eye irritations was 0.64 mg/m3 for 2 h. Concentrations of 0.99 and 4.95 mg/m3 were identi-fied as no-observed-effect level (NOEL) and no-observed-adverse-effect level (NOAEL) for pathological and histo-logical changes in the respiratory system (nasal passages) of rats during subchronic exposures to PAN, but were not considered to be relevant to derivation of a RfC for chronic inhalation exposure. PAN is a weak point mutagen or clastogen. The data are not sufficient to evaluate its carcinogenicity. No study was found which could be used for the derivation of a RfC for acute or chronic inhalation exposure to PAN.

L'effet de la voie d'administration, de la dose et du moment d'echantillonnage sur l'excretion urinaire de quatre metabolites majeurs du benzo[a]pyrene (BaP), le 3-hydroxyBaP (3-OHBaP), le 9-hydroxyBaP (9-OHBaP), le trans-4,5-dihydrodiolBaP (4,5-diolBaP) et le trans-9,10-dihydrodiolBaP (9,10-diolBaP), a ete etudie chez des rats mâles Sprague-Dawley exposes a une dose aigue de 2, 6, 20 ou 60 μmol de BaP/kg par voies intraveineuse, orale et cutanee. Trois collectes urinaires consecutives de 24 h ont ete effectuees. Les resultats montrent que, pour une dose donnee et pour la periode 0-72 h, les quantites relatives des metabolites excretes etaient: 3-OHBaP > 4,5-diolBaP >> 9-OHBaP suivant administration par voies intraveineuse et orale et 3-OHBaP >> 9-OHBaP ≥ 4,5-diolBaP apres application cutanee. Le 9,10-diolBaP etait a peine decelable. Par ailleurs, pour une dose donnee, les quantites de 3-OHBaP et de 4,5-diolBaP excretees pendant la periode 0-72 h variaient selon la voie d'administration comme suit: intraveineuse ≃ orale ≥ cutanee. Celles du 9-OHBaP suivaient plutot l'ordre: orale ≥ cutanee > intraveineuse. Peu importe la voie d'administration, l'excretion du 4,5-diolBaP etait presque complete en 24 h contrairement a celle du 3-OHBaP et du 9-OHBaP. Le pic d'excretion du 3-OHBaP et du 9-OHBaP etait observe dans la periode 0-24 h suivant l'administration intraveineuse et orale et dans la periode 24-48 h suivant l'application cutanee. Donc, pour une voie d'entree et dose donnees, d'un metabolite a l'autre, des differences dans la vitesse d'elimination ont ete observees. En general, une bonne relation dose-excretion etait toutefois observee. En fonction de la voie d'administration, des variations dans l'excretion totale et dans le profil temporel d'un metabolite urinaire specifique ainsi que dans les proportions relatives des metabolites quantifies ont aussi ete notees. Les donnees suggerent qu'une mesure des ratios de concentrations des metabolites pourrait fournir des indications sur le moment et la voie majeure d'exposition.

This article reviews the published studies on urinary 1-hydroxypyrene (1-OHP) as a biomarker of exposure to polycyclic aromatic hydrocarbons (PAHs) in work environments. Sampling and analysis strategies as well as a methodology for determining biological exposure indices (BEIs) of 1-OHP in urine for different work environments are proposed for the biological monitoring of occupational exposure to PAHs. Owing to the kinetics of absorption of pyrene by different exposure routes and excretion of 1-OHP in urine, in general, 1-OHP urinary excretion levels increase during the course of a workday, reaching maximum values 3-9 h after the end of work. When the contribution of dermal exposure is important, post-shift 1-OHP excretion can however be lower than pre-shift levels in the case where a worker has been exposed occupationally to PAHs on the day prior to sampling. In addition, 1-OHP excretion levels in either pre-shift, post-shift or evening samples increase during the course of a work-week, levelling off after three consecutive days of work. Consequently, ideally, for a first characterization of a work environment and for an indication of the major exposure route, considering a 5-day work-week (Monday to Friday), the best sampling strategy would be to collect all micturitions over 24 h starting on Monday morning. Alternatively, collection of pre-shift, post-shift and evening urine samples on the first day of the work-week and at the end of the work-week is recommended. For routine monitoring, pre-shift samples on Monday and post-shift samples on Friday should be collected when pulmonary exposure is the main route of exposure. On the other hand, pre-shift samples on Monday and Friday should be collected when the contribution of skin uptake is important. The difference between beginning and end of work-week excretion will give an indication of the average exposure over the workweek. Pre-shift samples on the first day of the work-week will indicate background values, and, hence, reflect general environment exposure and body burden of pyrene and/or its metabolites. On the other hand, since PAH profile can vary substantially in different work sites, a single BEI cannot apply to all workplaces. A simple equation was therefore developed to establish BEIs for workers exposed to PAHs in different work environments by using a BEI already established for a given work environment and by introducing a correction factor corresponding to the ratio of the airborne concentration of the sum of benzo(a)pyrene (BaP) equivalent to that of pyrene. The sum of BaP equivalent concentrations represents the sum of carcinogenic PAH concentrations expressed as BaP using toxic equivalent factors. Based on a previously estimated BEI of 2.3 μmol 1-OHP mol(-1) creatinine for coke-oven workers, BEIs of 4.4, 8.0 and 9.8 μmol 1-OHP mol(-1) creatinine were respectively calculated for vertical pin Soderberg workers, anode workers and pre-bake workers of aluminium plants and a BEI of 1.2 μmol 1-OHP mol(-1) creatinine was estimated for iron foundry workers. This approach will allow the potential risk of cancer in individuals occupationally exposed to PAHs to be assessed better.

The time profiles of benzo(a)pyrenediolepoxide (BaPDE)-hemoglobin (Hb) adduct formation and 3-hydroxybenzo(a)pyrene (3-OHBaP) urinary excretion were studied in male Sprague-Dawley rats exposed to daily benzo(a)pyrene (BaP) intraperitoneal doses of 1.25, 6.25, and 31.25 μmol/kg administered Tuesday to Friday for 4 consecutive weeks. Blood was withdrawn weekly, on Tuesdays, prior to dosing. Twenty-four-hour urine samples were collected on Mondays (following 72 h without treatment) and Thursdays. Analytes were quantified by high performance liquid chromatography (HPLC)/fluorescence. Exposure to BaP resulted in the accumulation of BaPDE-Hb adducts, reaching an average of 1.2±0.3, 8.3±1.9, and 38.2±6.1 pmol/g Hb for the 1.25, 6.25, and 31.25 μmol/kg per day doses after 4 weeks of treatment. The expected saw tooth excretion profile of 3-OHBaP was observed, with peaks on Thursdays and troughs on Mondays, and showed a progressive rise on both Mondays and Thursdays. Increase in Monday values with time suggested a possible increase in BaP body burden during exposure. To verify this aspect further, the urinary excretion kinetic of 3-OHBaP following acute intraperitoneal dosing (31.25 μmol/kg) was determined. Urine samples were collected at frequent timed intervals for up to 164 h post-dosing. Two-step elimination was observed, the second step having a half-life of 25 h, presumably linked to the slow release of BaP accumulated in fatty tissues upon repeated treatment. Therefore, it seems that 1) BaPDE-Hb adducts are good indicators of repeated exposure, 2) the difference between pre- and post-exposure 3-OHBaP urinary excretion gives a measure of recent exposure, and 3) excretion levels of this latter metabolite after a non-exposure period of sufficient duration, to allow elimination of the bulk BaP from the last dose, could reflect BaP body burden.

An original and innovative approach to assess the risks associated to engineered nanoparticles is presented. The primary observations from the literature review are discussed and point out the interdependency of most risk factors. This sole fact justifies the need for an adequate analytical model to ensure a proper risk management for the development of an adaptive decision-making tool. With this objective, optimization-based modelling tests were first conducted in order to validate the feasibility of the method.

There is accumulating epidemiological evidence that exposure to some solvents, metals, asphyxiants and other substances in humans is associated with an increased risk of acquiring hearing loss. Furthermore, simultaneous and successive exposure to certain chemicals along with noise can increase the susceptibility to noise-induced hearing loss. There are no regulations that require hearing monitoring of workers who are employed at locations in which occupational exposure to potentially ototoxic chemicals occurs in the absence of noise exposure. This project was undertaken to develop a toxicological database allowing the identification of possible ototoxic substances present in the work environment alone or in combination with noise exposure. Critical toxicological data were compiled for chemical substances included in the Quebec occupational health regulation. The data were evaluated only for noise exposure levels that can be encountered in the workplace and for realistic exposure concentrations up to the short-term exposure limit or ceiling value (CV) or 5 times the 8-h time-weighted average occupational exposure limit (TWA OEL) for human data and up to 100 times the 8-h TWA OEL or CV for animal studies. In total, 224 studies (in 150 articles of which 44 evaluated the combined exposure to noise and a chemical) covering 29 substances were evaluated using a weight of evidence approach. For the majority of cases where potential ototoxicity was previously proposed, there is a paucity of toxicological data in the primary literature. Human and animal studies indicate that lead, styrene, toluene and trichloroethylene are ototoxic and ethyl benzene, n-hexane and p-xylene are possibly ototoxic at concentrations that are relevant to the occupational setting. Carbon monoxide appears to exacerbate noise-induced hearing dysfunction. Toluene interacts with noise to induce more severe hearing losses than the noise alone.

A high performance liquid chromatographic technique coupled with fluorometric detection was used to study the disappearance rate of the hemoglobin and albumin adducts of benzo(a)pyrene (BaP) in female Sprague-Dawley rats. The technique was considered adequate based on good recovery (>80%) of the analyte and satisfactory intra-assay coefficients of variations of 7.8% and 4.2% for hemoglobin and albumin adducts, respectively. The persistence of the adducts was determined in rats injected intravenously with 550 nmol BaP diolepoxide, the electrophilic metabolite of BaP. In a first experiment the isolated protein fractions were directly subjected to mild acid hydrolysis to yield the ultimate analyte, BaP tetrol. In a second experiment these fractions were first digested by proteases in order to liberate any unbound lipophilic BaP tetrol possibly “hidden” in the hydrophobic portions of the protein matrices. It was found that 70–100% of the measured tetrols originated from true adducts. The half-life of the free tetrol was 2.8 and 1.6 days in the hemoglobin and albumin fractions, respectively, compared to 10.7 and 3.6 days for the true adducts. Based on the total amount of tetrols, the mean half-life of the latter in the hemoglobin and albumin fractions determined from the two experiments was 9.0 and 2.7 days, respectively, assuming first order kinetics. The greater persistence of the hemoglobin adduct compared to that of the albumin adduct is coherent with the biological half-life of the intact proteins. However, the observed disappearance profile obtained does not fit with current models of adduct formation and removal.

Lead is a known toxicant that occurs naturally in the environment. Bisphenol A (BPA) is an industrial chemical used primarily in polycarbonate plastic and epoxy resins. It has been 30 years since lead exposure was measured at a national level, and it is the first time for a national assessment of BPA exposure.Data are from the 2007-2009 Canadian Health Measure Survey. Lead in whole blood (PbB) and urinary BPA were measured in 5319 and 5476 respondents aged 6 to 79, respectively. Geometric means (GMs) are presented by age group and sex for PbB (pg/dL), volume-based BPA (microg/L), and creatinine-standardized BPA (microg/g creatinine). Adjusted least squares geometric means (LSGMs) for PbB and BPA are presented by selected covariates.PbB was detected in 100% of the population, with a GM concentration of 1.34 microg/dL. Adults aged 60 to 79 and males had significantly higher GM PbB concentrations. Lower household income, being born outside Canada, living in a dwelling at least 50 years old, current or former smoking, and drinking alcohol at least once a week were associated with higher PbB concentrations. Urinary BPA was detected in 91% of the population, with a GM concentration of 1.16 microg/L (1.40 microg/g creatinine). Children aged 6 to 11 had significantly higher GM creatinine-standardized BPA concentrations than did other age groups.Although PbB concentrations have declined dramatically since the 1970s, socio-demographic characteristics, the age of dwellings, and certain lifestyle behaviours are associated with higher levels. Given the short half-life of orally ingested BPA and the high frequency of detection, the CHMS data suggest continual widespread exposure in the Canadian population.

Biomarkers of exposure and effect were assessed in 40 male Sprague-Dawley rats injected intravenously with 40 micromol/kg of benzo(a)pyrene (BaP) to determine which biomarkers are more representative of BaP-induced DNA damage in lung. Lung, liver, blood, and urine were collected at t = 2, 4, 8, 16, 24, 33, 48, 72, and 360 h postdosing. Specific BaP-diol epoxide (BPDE)-DNA adducts, 8-hydroxy-7,8-dihydro-2'-deoxyguanosine (8-OHdGuo), were measured in lung, liver, and mononucleated blood cells by high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS). Urinary 8-OHdGuo and 8-hydroxy-7,8-dihydroguanosine (8-OHGuo) were also determined by HPLC-MS/MS, and urinary 3-hydroxybenzo(a)pyrene was measured by HPLC/fluorescence. Between 2 and 72 h postdosing, BPDE-DNA adducts were significantly increased in lung, liver, and mononucleated blood cells of BaP-treated rats as compared to controls, with the highest levels found in lung. 8-OHdGuo levels also increased in lung of BaP-treated rats with values reaching statistical significance at 2, 8, and 16 h postinjection. No influence of BaP treatment was found on 8-OHdGuo and 8-OHGuo urinary excretions. BPDE-DNA adducts in lung were strongly correlated to urinary 3-OHBaP (r = 0.936 and p < 0.001) and to a lesser extent to blood BPDE-DNA adducts (r = 0.636 and p < 0.001), the latter of which were correlated to each other (r = 0.573 and p = 0.002). Urinary 3-OHBaP and BPDE-DNA adducts in mononucleated blood cells appear as relevant biomarkers of BaP genotoxic exposure and are highly promising for health risk assessment in humans.

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The toxicokinetics of benzo(a)pyrene (BaP) and 3-hydroxybenzo(a)pyrene (3-OHBaP) were assessed in 36 male Sprague-Dawley rats injected intravenously with 40 micromol kg(1) of BaP to explain the reported atypical urinary excretion profile of 3-OHBaP. Blood, liver, kidney, lung, adipose tissue, skin, urine and feces were collected at t = 2, 4, 8, 16, 24, 33, 48, 72 h post-dosing. BaP and 3-OHBaP were measured by high-performance liquid chromatography/fluorescence. A biexponential elimination of BaP was observed in blood, liver, skin and kidney (t((1/2)) of 4.2-6.1 h and 12.3-14.9 h for initial and terminal phases, respectively), while a monoexponential elimination was found in adipose tissue and lung (t((1/2)) of 31.2 and 31.5 h, respectively). A biexponential elimination of 3-OHBaP was apparent in blood, liver and skin (t((1/2)) of 7.3-11.7 h and 15.6-17.8 h for initial and terminal phases, respectively), contrary to adipose tissue, lung and kidney. In adipose tissue and lung, a monophasic elimination of 3-OHBaP was observed (t((1/2)) of 27.0 h and 24.1 h, respectively). In kidney, 3-OHBaP kinetics showed a distinct pattern with an initial buildup during the first 8 h post-dosing followed by a gradual elimination (t((1/2)) of 15.6 h). In the 72-h post-treatment, 0.21 +/- 0.09% (mean +/- SD) of dose was excreted as 3-OHBaP in urine and 12.9 +/- 1.0% in feces while total BaP in feces represented 0.40 +/- 0.16% of dose. This study allowed the identification of the kidney as a retention compartment governing 3-OHBaP atypical urinary excretion.

Questions that are central to the examination of ethical issues in the risk-assessment process are: Who needs to be protected, against what and how? These questions attract attention to the value-laden judgement of the risk-assessment process itself. This is the background upon which potential ethical pitfalls associated with the professional act of risk assessment are examined. Scientific risk assessments should contribute to improving public health rather than to serving pure ideology of interest groups. Toxicological risk assessment is the art of translating basic toxicological and epidemiological information into recommendations for risk-management decisions. The framing of the risk questions shapes the risk assessment itself and is therefore subjected to the biases and values of those who launch the risk-management process. Ill-defined risk questions will result in ill-assessed risks. Risk questions are, in essence, complex, and attempts to simplify them may severely distort the real questions that need to be addressed. Beyond biomedical aspects, risks to health include social components that are intrinsically part of the risk and should be given appropriate consideration. The controversial precautionary principle can be used as a sound evolutionary approach to risk decision-making provided it is approached in a consistent, transparent manner. Keywords: ethical pitfall; complexity; risk assessment; precautionary principle

Biological monitoring (BM or biomonitoring) deals with the assessment of individual human exposure, effect and susceptibility to occupational risk factors. It is a fundamental tool in occupational health risk assessment (OHRA) and occupational health practice (OHP) and it has become one of the most, if not the most active area in occupational health (OH) research today. From the few hundred BM papers published in the 80s, there are now several tens of thousand papers published in the peer review literature each year, and the trend is still rising exponentially. As a result, BM has become a priority for the Scientific Committee on Occupational Toxicology (SCOT) of the International Commission on Occupational Health (ICOH). Moreover, there has been a long-term interest in biological monitoring by other SCs of ICOH such as the Scientific Committees on Toxicology of Metals (SCTM) and on Rural Health (SCRH). Despite its current popularity, though, BM is not always correctly used or interpreted by those involved in OHRA or OHP. The present review has been prepared to fill this gap and to help preventing misuse and misinterpretation of data. Although the document is meant to be a reference primarily for those involved in OH research and/or practice, it might become of interest for a wider audience within and outside ICOH, including scientists, occupational physicians, industrial hygienists and occupational or public health professionals in general, involved in chemical risk assessment for occupational health. The mission of SCOT and also of other SCs of ICOH, such as SCTM and SCRH, is indeed to promote the advancement and diffusion of knowledge on biological monitoring and other relevant occupational toxicology aspects and to make them available and useful to the entire OH scientific community. All articles retrieved as of 3 January, 2007 as "Review" with the combined key words "biological monitoring" in PubMed from 2000 to 2007 have been scanned individually. This yielded a total of 1400 articles from a grand total of 2486 (excluding limitation on year of publication). When the title was related to human occupational biological monitoring, the abstract was read and its content was included. Articles outside the 2000-2007 time frame or that are not classified as "Review" in PubMed have also been included, when relevant. The review is in four parts: (a) the introduction, containing the basic principles and definitions of BM and the different types of biomarkers (BMK), their toxicological significance, practical use and limitations, (b) the methodological and analytical aspects of BM in exposed workers, (c) the interpretation and management of BM data, including a number of recommendations to be considered when planning, performing and interpreting BM results and, finally, (d) the ethical aspects of BM. A list of key references to relevant papers or documents has been included. The BM of specific chemicals or groups of chemicals is outside the purpose of the review. The document is aimed to represent the state of the art on biological monitoring in occupational risk assessment. We expect that reference to its content will be made, whenever appropriate, by those involved in occupational health practice and research when dealing with BM issues. The document is not meant, though, to represent a rigid nor a permanent set of rules and it will be periodically updated according to new developments and any significant advance in BM science. Any part of the document, therefore, is open to suggestions by scientifically qualified persons or institutions officially involved in BM and comments should be sent directly to the authors. A preliminary draft of the document has been presented at the 7th International Symposium on Biological Monitoring, Beijing, 10-12 September, 2007.

Male rats are more sensitive to the nephrocarcinogenic effect of hexachlorobenzene (HCB) than are female rats. The purpose of this study was to shed light on this phenomenon by investigating mechanisms of subchronic nephrotoxicity of HCB. Groups of rats were administered HCB in corn oil (po) at 100 mg/kg, 5 days per week for 15 days or at 50 mg/kg, 5 days per week for 50 days. Urine was collected on Days 1, 8, and 15 for the 15-day treatment and on Day 50 for the 50-day treatment. Glucosuria, proteinuria, and enzymuria (gamma-glutamyl transpeptidase) were measured to assess renal function. Twenty-four hours after the last HCB treatment, the animals were killed and kidneys were removed for histopathological evaluation. Urine analyses showed no indication of renal dysfunction in treated animals compared to controls during the 15-day treatment. However, histology of male rat kidneys revealed degenerative and regenerative cellular foci accompanied by an increased accumulation of protein droplets in epithelial cells of the proximal tubules. The same histological observations were also made in male rats after a 50-day HCB treatment but this time they were accompanied by renal function alterations. In female rats, no such renal functional or histological alterations were observed. The histopathological observations in male rats correspond well with the protein droplet nephropathy; the latter is characteristic of the accumulation in kidney cells of alpha 2u-globulin probably caused by the reversible binding of a chemical to alpha 2u that renders the protein indigestible to kidney proteases. alpha 2u-Globulin was measured in the cytosol of male rats and was found to be increased 11-fold compared to controls. Also, HCB was found to be bound reversibly to alpha 2u. These results suggest that HCB induces a male rat specific nephropathy that could explain the higher incidence of kidney tumors in male rats compared to female rats.

Organic solvents can produce ototoxic effects in both man and experimental animals. The objective of this study was to review the literature on the effects of low-level exposure to ethyl benzene on the auditory system and consider its relevance for the occupational settings. Both human and animal investigations were evaluated only for realistic exposure concentrations based on the permissible exposure limits. In Quebec, the Time-Weighed Average Exposure Value for 8 h (TWAEV) is 100 ppm (434 mg/m3) and the Short-Term Exposure Value for 15 min (STEV) is 125 ppm (543 mg/m3). In humans, the upper limit for considering ototoxicity data relevant to the occupational exposure situation was set at STEV. Animal data were evaluated only for exposure concentrations up to 100 times the TWAEV. In workers, there is no evidence of either ethyl benzene-induced hearing losses or ototoxic interaction after combined exposure to ethyl benzene and noise. In rats, ethyl benzene affects the auditory function mainly in the cochlear mid-frequency range and ototoxic interaction was observed after combined exposure to noise and ethyl benzene. Further studies with sufficient data on the ethyl benzene exposure of workers are necessary to make a definitive conclusion. Given the current evidence from animal studies, we recommend considering ethyl benzene as an ototoxic agent.

The ability of chemicals to produce hearing loss themselves or to promote noise-induced hearing loss has been reported for some organic solvents. The objective of this study was to review the literature on the effects of low-level exposure to n-hexane on the auditory system and consider its relevance for occupational settings. Both human and animal investigations were evaluated only for realistic exposure concentrations based on the permissible inhalation exposure limits. In Quebec, the time-weighted average exposure value (TWAEV) for 8 h is 50 ppm. In humans, the upper limit for considering ototoxicity data relevant to the occupational exposure situation was set at five times the TWAEV. Animal data were evaluated only for exposure concentrations up to 100 times the TWAEV. There is no convincing evidence of n-hexane-induced hearing loss in workers. In rats, n-hexane seems to affect auditory function; however, the site of these alterations cannot be determined from the present data. Further studies with sufficient data on the exposure of workers to n-hexane are necessary to make a definitive conclusion. In the interim, we recommend considering n-hexane as a possibly ototoxic agent.

Biomonitoring Equivalents (BEs) are defined as the concentration of a chemical (or metabolite) in a biological medium (blood, urine, human milk, etc.) consistent with defined exposure guidance values or toxicity criteria including reference doses and reference concentrations (RfD and RfCs), minimal risk levels (MRLs), or tolerable daily intakes (TDIs) [Hays, S.M., Becker, R.A., Leung, H.W., Aylward, L.L., Pyatt, D.W., 2007. Biomonitoring equivalents: a screening approach for interpreting biomonitoring results from a public health risk perspective. Regul. Toxicol. Pharmacol. 47(1), 96-109]. The utility of the BE is to provide a screening tool for placing biomonitoring data into a health risk context. A Panel of experts took part in the Biomonitoring Equivalents Expert Workshop to discuss the various technical issues associated with calculating BEs and developed a set of guidelines for use in the derivation of BEs. Issues addressed included the role of the point of departure (POD) in BE derivation, the appropriate application of human and animal kinetic data and models, consideration of default uncertainty factor components in the context of internal dose-based extrapolations, and relevance of mode of action to technical choices in kinetic modeling and identification of screening values. The findings from this Expert Panel Workshop on BE derivation are presented and provide a set of guidelines and considerations for use in BE derivation.

The urinary excretion time courses of pyrene-1,6-dione (P16D), pyrene-1,8-dione (P18D) and 1-hydroxypyrene (1-OHP) were compared in Sprague-Dawley and Wistar rats. Groups of five male rats, of about 200 g of body weight, were injected intravenously with 0.05, 0.5, 5 and 50 micromol pyrene kg-1 of body weight. Urine was collected at 2, 4, 6, 8, 10, 12, 18, 24, 30, 42 and 48 h post-dosing. Pyrene metabolites were measured by high-performance liquid chromatography (HPLC)/fluorescence after enzymatic hydrolysis of the glucurono- and sulfo-conjugates, extraction on Sep-Pak C18 cartridges and, for the analysis of dione metabolites, derivatization to stable diacetoxypyrene molecules. Over the 48-h sampling period, on average 17.4-25.6% of the injected pyrene was excreted overall as P16D, 6.4-8.8% as P18D and 0.6-0.8% as 1-OHP in the urine of Sprague-Dawley rats. By comparison, on average 10.3-14.7% of the intravenous pyrene dose was recovered as P16D, 4.8-6.4% as P18D and 0.3-0.4% as 1-OHP in the urine of Wistar rats. In both strains of rats there was no clear effect of the dose on the 0-48-h cumulative urinary excretion of P18D and 1-OHP over the entire dose range, while the percentage of dose recovered overall as P16D in urine at the highest dose (50 micromol kg-1) was statistically lower than at the other doses. The 0-48-h cumulative percentage of pyrene dose excreted as metabolites in the urine of Sprague-Dawley rats was also significantly higher than in Wistar rats (p0.01) exposed under identical conditions. As for the urinary excretion-time courses of the different metabolites, for a given dose and strain of rats, excretion curves of P16D, P18D and 1-OHP generally evolved in parallel. There was also no clear effect of the dose on the excretion rate, thus half-life, of pyrene metabolites, except for P16D in Sprague-Dawley rats at the highest dose where elimination tended to be slower compared with the other doses (p0.01). The average first-order elimination half-life of P16D, P18D and 1-OHP was 4.0, 5.7 and 4.1 h, respectively, in Sprague-Dawley rats, and 5.1, 6.1 and 5.1 h, respectively, in Wistar rats (all doses combined but excluding the highest dose for P16D). This study showed the relative importance of metabolic pathways leading to diones compared with 1-OHP. These dioxygenated metabolites appear to be interesting biomarkers of pyrene exposure at environmentally and occupationally relevant doses. Their adequacy as biomarkers of human exposure has yet to be confirmed.

This research aimed to understand how occupational health stakeholders represented the various ethical concerns raised by the use of biomarkers of exposure, effects and susceptibility to harmful agents. These representations were investigated by seven homogeneous focus group interviews and an Internet discussion forum. The following stakeholders took part in this research: workers, physicians, nurses, researchers, employers, industrial hygienists, trade-union representatives and employees of the Quebec Board of Health and Safety in the Workplace. The data were analyzed qualitatively using a constant comparison technique. The main ethical problems raised by the stakeholders were organized around three emergent themes: a narrative of science, the validation of biomarkers and the protection of workers. From these themes emanate the principal ethical problems raised by the stakeholders: confidentiality, the interpretation of data, consent and information, as well as an advantages/disadvantages ratio. These problems are described as ethical tension zones. The analysis also takes into account the impact of the representations that each group of stakeholders has of each other and the ethical problems that can arise. Because it is drawn from a study of stakeholders' representations, the resulting analytical model might also be used to anticipate the root of ethical problems generated by the use of the biomarkers in an occupational health context.

We assessed the lung cancer risk in six localities with aluminium smelting activities and five with other polycyclic aromatic hydrocarbon (PAH) pollution sources, using two quantitative risk assessment (QRA) approaches for PAH mixtures and compared their risk predictions against actual cancer incidence. In the first approach, carcinogen exposure was estimated from animal-derived BaP toxic equivalents (BaPeq) of individual PAHs. The upper bound lifetime risk estimates ranged between 0.012-4.7×10-5 and 0.019-0.94×10-5 in the aluminium and other localities, respectively. The second approach assumed that the potency of PAH mixtures was linked to their BaP content and lifetime lung cancer unit risk gradients were estimated from epidemiological studies based on BaP exposure measurements. Lifetime risks ranged between 0.02-89×10-5 and 0.06-6.8×10-5 in the aluminium and other localities, respectively. Predicted risks were generally higher in smelter towns, and higher when based on epidemiological studies than on BaPeq. In smelting communities, there was a linear relationship (R2≈0.8) between female lung cancer rates and PAH exposure estimates. To conclude, animal/BaPeq-based QRAs predicted lower risks than occupational/BaP-based QRAs. Epidemiological validation of the QRA could be performed for elevated past exposure to PAHs, but not for currently lower concentrations.

During biological monitoring of exposure to a chemical, a possible source of interindividual variability in the measurement of a urinary metabolite that undergoes enterohepatic cycling is the presence of dietary fiber in the gastrointestinal tract. This study examined the effect of diets containing either the insoluble fiber Alphacel (nonnutritive bulk cellulose) or the soluble pectin (from citrus fruit, MW 20,000-40,000). Five groups of male Sprague-Dawley rats received one of the following diets: poor (5% w/w) or rich (15% w/w) in Alphacel, poor (5% w/w) or rich (15% w/w) in pectin, or no fiber (NF). Five micromol/kg of pyrene was administered by iv injection immediately after feeding the animals with their respective diet, and urine and feces collections started for the determination of 1-hydroxypyrene (1-OHP), a metabolite of pyrene. The type of fiber had no influence on the results. The rats receiving diets both poor and rich in fiber excreted less 1-OHP (18 +/- 8 and 15 +/- 7 pmol per g of rat, respectively) in the 24-h urine samples than the NF group (28 +/- 6 pmol/g). There was a nonstatistically significant trend towards increased fecal and total (urinary + fecal) 1-OHP excretion with increasing amount of fiber in the diet. An in vitro experiment showed an inverse correlation (r(2) = 0.98) between the amount of Alphacel in suspension in a 1-OHP aqueous solution and the recovery of 1-OHP from the soluble fraction. The reduction in urinary output of the metabolite due to fiber reaching approximately 40% may contribute to its interindividual variability observed in occupational and environmental studies.

The aim of this study was to investigate the electrophilic tissue burden (ETB) formation, assessed as covalent binding of the ultimate carcinogen benzo( a)pyrene diolepoxide (BaPDE) with cellular proteins, in liver, lung and heart, as well as with haemoglobin (Hb) following repeated exposure to binary mixtures of benzo( a)pyrene (BaP) and pyrene (P). Male Sprague-Dawley rats were injected intraperitoneally, once daily for 10 consecutive days, with binary mixtures of BaP and P in three different exposure scenarios corresponding to BaP/P ratios of 0.2, 1 and 5 and with three dose levels of BaP (2, 6 and 20 mg/kg) for each scenario. ETB levels were measured as the ultimate analyte benzo( a)pyrene tetrol (BaPTeT) obtained after mild acid hydrolysis of BaPDE-adducts with proteins. A high-performance liquid chromatography fluorescence technique was used to quantify the analyte. Similar ETB levels (within a factor of 4) were observed in all tissues studied at any given binary dose. However, the ETB generally tended to be somewhat higher in metabolically active tissues (i.e. liver and lung) than in metabolically non-active tissues (i.e. heart and Hb). Lack of influence of pyrene on ETB levels in all tissues was confirmed over the binary dose range examined. Linear BaP-dose-dependent ETB formation in all tissues (at P/=0.05) was observed. Linear regressions were found for all between-tissue relationships of ETB over the exposure doses, with best linear correlations obtained for ETB in heart versus Hb ( R(2)=0.709; P0.0001) and ETB in lung versus Hb ( R(2)=0.507; P0.0001). The results thus suggest that BaPDE-Hb adducts could serve as a surrogate of the ETB, namely in tissues that are potential targets for carcinogenicity such as lung. The results obtained in this study indicate the role of the ETB as a promising molecular biomarker of the potential cellular damage resulting from intracellular covalent binding in animal studies.

To compare the apparent urinary excretion rates of both creatinine and 1-hydroxypyrene (1-OHP) and to assess the value of creatinine normalization for both toxicokinetic analysis and the routine examination of workers.All urine samples were collected from individuals who had been exposed to polycyclic aromatic hydrocarbons (PAHs), occupationally and non-occupationally, for at least 24 consecutive hours. Urinary creatinine and 1-OHP were determined. 1-OHP excretion rates were expressed either as a function of creatinine excretion rate or as unadjusted values. Theoretical relationships between creatinine-normalized excretion of metabolites and body weight-adjusted inhaled dose were drawn for men with a constant body mass index.Creatinine excretion rate paralleled 1-OHP excretion rate. The plot of creatinine excretion rate-adjusted excretion rate of 1-OHP vs time led to smooth curves for determination of toxicokinetic parameters. Creatinine normalization was adequate, even for samples with a urinary creatinine concentration below 0.5 g/l or above 3 g/l. A theoretical analysis revealed that men weighing between 50 kg and 100 kg, exposed to a constant dose of a pollutant producing a urinary metabolite excreted by the same mechanism as creatinine, would exhibit a body weight-adjusted dose span of 2 with an accompanying creatinine-normalized metabolite excretion span of 2.23-fold.The kinetics of creatinine excretion parallels that of 1-OHP, and a creatinine excretion rate-normalized excretion rate of 1-OHP appears to allow for a better determination of the toxicokinetic parameters of 1-OHP urinary excretion. At least in the case of 1-OHP, creatinine normalization seems valid, even for very dilute or very concentrated urine samples. Finally, because creatinine normalization not only compensates for variable diuresis but also correlates better with the body weight-adjusted dose of the parent compound, it should be used in biological monitoring of exposure to (PAHs) pyrene and to other substances whose urinary biomarker excretion kinetics parallel that of creatinine.