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This work has been clarified the optical differential phase shift keying transceiver systems performance efficiency at high data rate optical systems in the presence of pr doped amplifiers. The Max optical signal power variations after fiber link versus wavelength variations at various system data rates are demonstrated. The total optical power within optical fiber at data rates from 10 to 100 Gbps are indicated. The Max electrical signal power variations against frequency after receiver variations at various system data rates are clarified. The total electrical power after receiver at various system data rates are demonstrated. The light/electrical power received, OSNR and SNR variations in relation to data rate variations are also studied.

Mesoporous silica-based nanoparticles (MSNs) have gained rapid interest as a drug delivery system (DDS) and demonstrated their versatility in delivering drugs for the treatment of various cancers. However, the drug loading efficiency of MSNs is low and is usually improved by improving textural properties through complicated synthesis methods or by post synthesis modification of the surface that can result in the loss of surface area and modify its drug release properties. In this study, we report a direct single-step synthesis of MSNs with a unique egg-yolk core-shell morphology, large pore volume and a hydrophilic surface, decorated with nitrogen rich surface functionalities for increasing its drug loading capacity. This combination of excellent textural properties and surface functionalisation was achieved by a simple soft templating method using dual surfactants and the silica sources assisted by employing either triethylamine (TEA) or triethanolamine (TEO) as the hydrolysis agent. The morphology and well-ordered mesoporous structure can simply be tuned by changing the pH of the synthesis medium that affects the self-assembly mechanism of the micelles. HRTEM image of samples clearly revealed an egg-yolk core-shell morphology with a thin mesoporous silica shell. The optimised MSN samples synthesized at a pH of 11 using either TEA or TEO depicted a higher doxorubicin (Dox) loading capacity of 425 μg mg

The elucidation of the mode of action of reproductive and developmental toxicants (RDTs) requires a better understanding of their pharmacokinetics and the characterization of the potential toxic moiety at the site of action. The measurement of the concentration of the putative toxic moiety as a function of time in the target site is not always feasible in developing organisms for all exposure routes, dose levels, and exposure scenarios. Therefore, the development of quantitative models to predict the tissue dose and kinetics of chemicals and their metabolites as a function of species, life stage, test system (e.g., in vitro), exposure route, and exposure scenario is of utmost importance. In this regard, the mechanism-based mathematical models, such as the physiologically based pharmacokinetic (PBPK) models, have a unique role to play. The motivation for the use of PBPK models in developmental and reproductive toxicology research is to uncover the biological determinants of tissue dose to the developing animal, and contribute to the refinement of the experimental protocol or risk assessments. Furthermore, the PBPK models for RDTs provide a framework for simulating maternal and lactational exposures of the past, in view of interpreting epidemiology data in the context of human health risk assessment. These models then become an essential part of any systematic approach to the evaluation of how RDTs gain entry into fetal or maternal organism and distribute within and across life stages and generations.

New generation of toxicological tests and assessment strategies require validated toxicokinetic data or models that are lacking for most chemicals. This study aimed at developing a quantitative property-property relationship (QPPR)-based human physiologically based pharmacokinetic (PBPK) modeling framework for high-throughput predictions of inhalation toxicokinetics of organic chemicals. A PBPK model was parameterized with QPPR-derived values for hepatic clearance (CLh) and partition coefficients (P) [blood:air (Pba) and tissue:air (Pta) and tissue:blood (Ptb)]. The model was initially applied to an evaluation dataset of 40 organic chemicals in the applicability domain, and then to an expanded dataset of 249 organic chemicals from diverse chemical classes. ‘Batch’ analyses were performed for rapid assessments of hundreds of chemicals. The simulations of inhalation toxicokinetics following an 8-h exposure to 1 ppm of each chemical were successful. The mean ratios of their predicted-to-experimental values were within a factor of 1.36–2.36 for Ptb and 1.18 for CLh, for 80% of the chemicals in the evaluation dataset. The predicted 24-h area under the venous blood concentration-time curve (AUC24) values were within the predicted envelopes obtained while using experimental values of Pba and considering either no or maximal hepatic extraction. The reliability analysis (based on combined sensitivity and uncertainty analyses) indicated that AUC24 predictions for 55% of the expanded dataset were moderately to highly reliable, with 46% exhibiting highly reliable values. Overall, the modeling framework suggests that molecular structure and chemical properties can together be effectively used to obtain first-cut estimates of the toxicokinetics of data-poor organic chemicals for screening and prioritization purposes.

The objectives of the present work were: (1) to assemble population-level biomonitoring data to identify the concentrations of urinary and plasma barium across the general population; and (2) to derive biomonitoring equivalents (BEs) for barium in urine and plasma in order to facilitate the interpretation of barium concentrations in the biological matrices. In population level biomonitoring studies, barium has been measured in urine in the U.S. (NHANES study), but no such data on plasma barium levels were identified. The BE values for plasma and urine were derived from U.S. EPA's reference dose (RfD) of 0.2 mg/kg bw/d, based on a lower confidence limit on the benchmark dose (BMDL05) of 63 mg/kg bw/d. The plasma BE (9 μg Ba/L) was derived by regression analysis of the near-steady-state plasma concentrations associated with the administered doses in animals exposed to barium chloride dihydrate in drinking water for 2-years in a NTP study. Using a human urinary excretion fraction of 0.023, a BE for urinary barium (0.19 mg/L or 0.25 mg/g creatinine) was derived for US EPA's RfD. The median and the 95th percentile barium urine concentrations of the general population in U.S. are below the BE determined in this study, indicating that the population exposure to inorganic barium is expected to be below the exposure guidance value of 0.2 mg/kg bw/d.

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

Polycyclic aromatic hydrocarbons (PAHs) are a class of hazardous organic contaminants that are widely distributed in nature, and many of them are potentially toxic to humans and other living organisms. Biodegradation is the major route of detoxification and removal of PAHs from the environment. Aerobic biodegradation of PAHs has been the subject of extensive research; however, reports on anaerobic biodegradation of PAHs are so far limited. Microbial degradation of PAHs under anaerobic conditions is difficult because of the slow growth rate of anaerobes and low energy yield in the metabolic processes. Despite the limitations, some anaerobic bacteria degrade PAHs under nitrate-reducing, sulfate-reducing, iron-reducing, and methanogenic conditions. Anaerobic biodegradation, though relatively slow, is a significant process of natural attenuation of PAHs from the impacted anoxic environments such as sediments, subsurface soils, and aquifers. This review is intended to provide comprehensive details on microbial degradation of PAHs under various reducing conditions, to describe the degradation mechanisms, and to identify the areas that should receive due attention in further investigations.

Population-level biomonitoring of tin in urine has been conducted by the U.S. National Health and Nutrition Examination Survey (NHANES) and the National Nutrition and Health Study (ENNS – Étude nationale nutrition santé) in France. The general population is predominantly exposed to inorganic tin from the consumption of canned food and beverages. The National Institute for Public Health and the Environment of the Netherlands (RIVM) has established a tolerable daily intake (TDI) for chronic exposure to inorganic tin based on a NOAEL of 20 mg/kg bw per day from a 2-year feeding study in rats. Using a urinary excretion fraction (0.25%) from a controlled human study along with a TDI value of 0.2 mg/kg bw per day, a Biomonitoring Equivalent (BE) was derived for urinary tin (26 μg/g creatinine or 20 μg/L urine). The geometric mean and the 95th percentile tin urine concentrations of the general population in U.S. (0.705 and 4.5 μg/g creatinine) and France (0.51 and 2.28 μg/g creatinine) are below the BE associated with the TDI, indicating that the population exposure to inorganic tin is below the exposure guidance value of 0.2 mg/kg bw per day. Overall, the robustness of pharmacokinetic data forming the basis of the urinary BE development is medium. The availability of internal dose and kinetic data in the animal species forming the basis of the assessment could improve the overall confidence in the present assessment.

This study aimed at deriving occupational thresholds of toxicological concern for inhalation exposure to systemically-acting organic chemicals using predicted internal doses. The latter were also used to evaluate the quantitative relationship between occupational exposure limit and internal dose. Three internal dose measures were identified for investigation: (i) the daily area under the venous blood concentration vs. time curve, (ii) the daily rate of the amount of parent chemical metabolized, and (iii) the maximum venous blood concentration at the end of an 8-hr work shift. A dataset of 276 organic chemicals with 8-hr threshold limit values-time-weighted average was compiled along with their molecular structure and Cramer classes (Class I: low toxicity, Class II: intermediate toxicity, Class III: suggestive of significant toxicity). Using a human physiologically-based pharmacokinetic model, the three identified dose metrics were predicted for an 8-hr occupational inhalation exposure to the threshold limit value for each chemical. Distributional analyses of the predicted dose metrics were performed to identify the percentile values corresponding to the occupational thresholds of toxicological concern. Also, simple linear regression analyses were performed to evaluate the relationship between the 8-hr threshold limit value and each of the predicted dose metrics, respectively. No threshold of toxicological concern could be derived for class II due to few chemicals. Based on the daily rate of the amount of parent chemical metabolized, the proposed internal dose-based occupational thresholds of toxicological concern were 5.61 × 10−2 and 9 × 10−4 mmol/d at the 10th percentile level for classes I and III, respectively, while they were 4.55 × 10−1 and 8.5 × 10−3 mmol/d at the 25th percentile level. Even though high and significant correlations were observed between the 8-hr threshold limit values and the predicted dose metrics, the one with the rate of the amount of chemical metabolized was remarkable regardless of the Cramer class (r2 = 0.81; n = 276). The proposed internal dose-based occupational thresholds of toxicological concern are potentially useful for screening-level assessments as well as prioritization within an integrated occupational risk assessment framework.

Over the past four decades, there has been increasing concern that perineal use of talc powder, a commonly used personal care product, might be associated with an increased risk of ovarian cancer. Objectives To critically review all available human epidemiological data on the relationship between perineal use of talc powder and ovarian cancer, with consideration of other relevant experimental evidence. Methodology We identified 30 human studies for qualitative assessment of evidence, including 27 that were retained for further quantitative analysis. Results A positive association between perineal use of talc powder and ovarian cancer was found [OR: 1.28 (95% CI: 1.20–1.37)]. A significant risk was noted in Hispanics and Whites, in women applying talc to underwear, in pre-menopausal women and in post-menopausal women receiving hormonal therapy. A negative association was noted with tubal ligation. Conclusion Perineal use of talc powder is a possible cause of human ovarian cancer.

The level of active form of a chemical in target tissue is of prime importance in determining responses in toxicological studies, and depends upon the processes of absorption, distribution, metabolism, and excretion (ADME). The characterization of ADME in biota is referred to as pharmacokinetics (PK); when it is conducted in the range of doses causing toxicity it has been referred to as toxicokinetics (TK). Since repeated measurement of chemicals and their metabolites in all treated animals is not possible, PK parameters and models are used for estimating them. These PK models range from simple, one-compartmental model to complex physiologically based models. A PK parameter, namely elimination half-life (t1/2), is key to the understanding of the amount remaining in the body after each dose and thus of direct use in determining optimal time intervals between doses. Such PK data are also critical in planning future/supplementary studies by different routes or in different species. This chapter presents the basic PK principles and models, with emphasis on their critical role in designing and interpreting toxicity studies.

Many substances in workplace do not have occupational exposure limits. The threshold of toxicological concern (TTC) principle is part of the hierarchy of approaches useful in occupational health risk assessment. The aim of this study was to derive occupational TTCs (OTTCs) reflecting the airborne concentrations below which no significant risk to workers would be anticipated. A reference dataset consisting of the 8-h threshold limit values-Time-Weighted Average for 280 organic substances was compiled. Each substance was classified into low (class I), intermediate (class II), or high (class III) hazard categories as per Cramer rules. For each chemical, n-octanol:water partition coefficient and vapor pressure along with the molecular weight were used to predict the blood:air partition coefficient. The blood:air partition coefficient along with data on water solubility and ventilation rate allowed the prediction of pulmonary retention factor and absorbed dose in workers. For each Cramer class, the distribution of the predicted doses was analyzed to identify the various percentile values corresponding to the OTTC. Accordingly, for Cramer classes I-III, the OTTCs derived in this study correspond to 0.15, 0.0085, and 0.006 mmol/d, respectively, at the 10th percentile level, while these values were 1.5, 0.09 and 0.03 mmol/d at the 25th percentile level. The proposed OTTCs are not meant to replace the traditional occupational exposure limits, but can be used in data-poor situations along with exposure estimates to support screening level risk assessment and prioritization.

The consideration of inhalation and dermal routes of exposures in developing guideline values for drinking water contaminants is important. However, there is no guidance for determining the eligibility of a drinking water contaminant for its multiroute exposure potential. The objective of the present study was to develop a 4-step framework to screen chemicals for their dermal and inhalation exposure potential in the process of developing guideline values. The proposed framework emphasizes the importance of considering basic physicochemical properties prior to detailed assessment of dermal and inhalation routes of exposure to drinking water contaminants in setting guideline values.

Information on toxicokinetics is critical for animal-free human risk assessment. Human external exposure must be translated into human tissue doses and compared with in vitro actual cell exposure associated to effects (in vitro-in vivo comparison). Data on absorption, distribution, metabolism and excretion in humans (ADME) could be generated using in vitro and QSAR tools. Physiologically-based toxicokinetic (PBTK) computer modelling could serve to integrate disparate in vitro and in silico findings. However, there are only few freely-available PBTK platforms currently available. And although some ADME parameters can be reasonably estimated in vitro or in silico, important gaps exist. Examples include unknown or limited applicability domains and lack of (high-throughput) tools to measure penetration of barriers, partitioning between blood and tissues and metabolic clearance. This paper is based on a joint EPAA--EURL ECVAM expert meeting. It provides a state-of-the-art overview of the availability of PBTK platforms as well as the in vitro and in silico methods to parameterise basic (Tier 1) PBTK models. Five high-priority issues are presented that provide the prerequisites for wider use of non-animal based PBTK modelling for animal-free chemical risk assessment.

A default uncertainty factor of 3.16 (√10) is applied to account for interindividual variability in toxicokinetics when performing non-cancer risk assessments. Using relevant human data for specific chemicals, as WHO/IPCS suggests, it is possible to evaluate, and replace when appropriate, this default factor by quantifying chemical-specific adjustment factors for interindividual variability in toxicokinetics (also referred to as the human kinetic adjustment factor, HKAF). The HKAF has been determined based on the distributions of pharmacokinetic parameters (e.g., half-life, area under the curve, maximum blood concentration) in relevant populations. This article focuses on the current state of knowledge of the use of physiologically based algorithms and models in characterizing the HKAF for environmental contaminants. The recent modeling efforts on the computation of HKAF as a function of the characteristics of the population, chemical and its mode of action (dose metrics), as well as exposure scenario of relevance to the assessment are reviewed here. The results of these studies, taken together, suggest the HKAF varies as a function of the sensitive subpopulation and dose metrics of interest, exposure conditions considered (route, duration, and intensity), metabolic pathways involved and theoretical model underlying its computation. The HKAF seldom exceeded the default value of 3.16, except in very young children (i.e.

In the risk assessment process, the reference dose, tolerable intake, or acceptable daily intake (RfD, TDI, ADI) is apportioned to specific exposure sources on the basis of a source allocation factor (AF) or relative source contribution (RSC). The U.S. Environmental Protection Agency (EPA) published an exposure decision tree framework in 2000 to guide the determination of AF (or RSC) of drinking-water contaminants (DWC). Besides that, there has not been any systematic analysis of the basis of the use of AF in DWC risk assessments. This article therefore critically reviews and integrates current knowledge and approaches for the development of AF, while focusing on its consistent use in DWC risk assessments based on consideration of (i) risk assessment endpoint, (ii) existing guidelines, (iii) exposure estimates, (iv) usage pattern and environmental fate information, (v) physicochemical properties, (vi) bounds of AF, (vii) multiroute exposures, and (viii) target population characteristics. Accordingly, for a DWC for which drinking water is not a major source of exposure and for which there is documented evidence of widespread presence in one or more of the other media (i.e., air, food, soil, or consumer products), the use of an AF value of 0.2 is suggested. For DWC for which drinking water represents nearly the single major source of exposure, a ceiling AF value of 0.8 is suggested. For other situations, chemical- and context-specific AF values can be developed based on exposure data or models, which should in turn be bounded by the floor and ceiling AF values as originally described by the U.S. EPA (i.e., 0.2-0.8). Future studies need to focus on improvements in methods for deriving AF, by basing it on the consideration of bioavailability, target tissue dose, and extent of route-specific absorption, as well as improvement in the modeling of dose received via direct/voluntary exposure through consumer products and at workplaces.

Measured concentrations of chemicals in blood or urine in biomonitoring studies provide an integrated reflection of exposures to chemicals via multiple routes and pathways. The potential significance of the measured concentrations of chemicals in the context of existing toxicology data and risk assessments can be assessed if chemical-specific quantitative screening criteria are available. This work presents the derivation of Biomonitoring Equivalents (BEs) for deltamethrin, a synthetic Type II pyrethroid. BEs are estimates of biomarker concentrations that are consistent with risk assessment-based exposure guidance values such as reference doses or acceptable daily intakes. BE values were derived for deltamethrin based on two biomarkers: deltamethrin in plasma and 3-(2,2-dibromovinyl)-2,2-dimethylcyclopropane carboxylic acid (DBCA), a specific metabolite, in urine. BE values for deltamethrin in plasma were based on extrapolation from measured deltamethrin concentrations in plasma in rats under conditions consistent with the Point of Departure in the critical study underlying the USEPA RfD. BE values for DBCA in urine were derived based on pharmacokinetic data from a study in human volunteers on the urinary excretion of deltamethrin and metabolites. BE values for deltamethrin in plasma corresponding to the USEPA RfD for adults and children are 20 and 2 μg/L, respectively. BE values for DBCA in urine corresponding to the adult and child-specific RfDs are 50 and 7 μg/L, respectively. The urinary BE value corresponding to the ADI established by the European Commission and the Joint Meeting on Pesticide Residues is 60 μg/L (as DBCA in urine). These values can be used to screen biomonitoring data in the context of current risk assessments for detlamethrin.

Biomonitoring Equivalents (BEs) are defined as the concentration or range of concentrations of a chemical or its metabolite in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline such as a reference dose (RfD) or tolerable daily intake (TDI). BE values can be used as a screening tool for the evaluation of population-based biomonitoring data in the context of existing risk assessments. This study reviews health based risk assessments and exposure guidance values for 2,2',4,4',5-pentabromodiphenylether (PBDE-99) from Health Canada and the United States Environmental Protection Agency (US EPA). Toxicokinetic data from laboratory animals and humans are reviewed. A BE value corresponding to the US EPA RfD is derived here for PBDE-99 based on the assumption of chronic steady-state exposure, distribution into body lipids, and a previously-estimated first-order half-life of elimination of 1040days. The steady-state lipid-adjusted BE(RfD) is 520ng/g lipid. Sources of uncertainty relating to the underlying toxicokinetic and toxicologic database for PBDE-99 and the simultaneous exposure to multiple PBDE congeners are discussed. The BE(RfD) value may be used as a screening tool for evaluation of population biomonitoring data for PBDE-99 in the context of the existing US EPA risk assessment and can assist in prioritization of the potential need for additional risk assessment efforts for PBDE-99 relative to other chemicals.

Biomonitoring Equivalents (BEs) are defined as the concentration or range of concentrations of a chemical or its metabolite in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline such as a reference dose (RfD) or tolerable daily intake (TDI). BE values can be used as a screening tool for the evaluation of population-based biomonitoring data in the context of existing risk assessments. This study reviews available health based risk assessments and exposure guidance values for di-isononyl phthalate (DINP) from Health Canada, the United States Consumer Product Safety Commission (US CPSC), and the European Food Safety Authority (EFSA). Controlled dosing data reporting the urinary excretion fractions of major DINP metabolites following administration of labeled DINP are reviewed, and BE values corresponding to the available exposure guidance values are derived assuming chronic, steady-state intake and excretion at those exposure values. The BE values range from 1500 to 3600μg/L (1900-4600μg/g creatinine) based on the sum of three oxidative metabolites. Sources of uncertainty relating to both the basis for the BE values and their use in evaluation of biomonitoring data, including the transience of the biomarkers relative to exposure frequency, are discussed. The BE values derived here can be used as screening tools for evaluation of population biomonitoring data for DINP in the context of existing risk assessments and can assist in prioritization of the potential need for additional risk assessment efforts for DINP relative to other chemicals.

Physiologically based pharmacokinetic modeling and occupational exposure assessment studies often use minute ventilation rates (VE), alveolar ventilation rates (VA) and cardiac outputs (Q) that are not reflective of the physiological variations encountered during the aggregate daytime activities of individuals from childhood to adulthood. These variations of VE, VA and Q values were determined for healthy normal-weight individuals aged 5–96 years by using two types of published individual data that were measured in the same subjects (n = 902), namely indirect calorimetry measurements and the disappearance rates of oral doses of deuterium (2H) and heavy-oxygen (18O) in urine monitored by gas-isotope-ratio mass spectrometry. Arteriovenous oxygen content differences (0.051–0.082 ml of O2 consumed ml−1 of blood) and ratios of the physiological dead space to the tidal volume (0.232–0.419) were determined for oxygen consumption rates (0.157–0.806 l min−1) required by minute energy expenditures ranging from 0.76 to 3.91 kcal min−1. Generally higher values for the 2.5th up to the 99th percentile for VE (0.132–0.774 l kg−1 min−1, 4.42–21.69 l m−2 min−1), VA (0.093–0.553 l kg−1 min−1, 3.09–15.53 l m−2 min−1), Q (0.065–0.330 l kg−1 min−1, 2.17 to 9.46 l m−2 min−1) and ventilation–perfusion ratios (1.12–2.16) were found in children and teenagers aged 5–

The methodology developed in our previous studies ( Brochu et al. 2006a-c ) for the determination of physiological daily inhalation rates was improved by integrating into the calculation process, both nighttime and daytime respiratory parameters, namely oxygen uptake factors (H) and ventilatory equivalents (VQ). H values during fasting (0.2057±0.0018 L of O2/kcal; mean±SD) and postprandial phases (0.2059±0.0019 L of O2/kcal) as well as VQ values for subjects at rest (27.4±4.8 to 32.2±3.1, unitless) and during the aggregate daytime activities (29.9±4.2 to 33.7±7.2) were determined and combined with published doubly labeled water measurements for the calculation of daily inhalation rates in normal-weight males and females aged 0.22-96 years (n=1235). Depending upon the unit value chosen, the highest 99th percentiles for inhalation data were found in males aged 35 to

Recent efforts worldwide have resulted in a growing database of measured concentrations of chemicals in blood and urine samples taken from the general population. However, few tools exist to assist in the interpretation of the measured values in a health risk context. Biomonitoring Equivalents (BEs) are defined as the concentration or range of concentrations of a chemical or its metabolite in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline, and are derived by integrating available data on pharmacokinetics with existing chemical risk assessments. This study reviews available health-based exposure guidance values for cyfluthrin from Health Canada, the United States Environmental Protection Agency (USEPA), and the World Health Organization/Food and Agriculture Organization. BE values corresponding to the oral reference dose (RfD), or acceptable daily intake (ADI) estimates from these agencies were derived based on data on excretion fractions of the urinary metabolite 4-fluoro-3-phenoxybenzoic acid (FPBA), which is a metabolite specific to cyfluthrin. These values may be used as screening tools for evaluation of biomonitoring data for cyfluthrin as the metabolite FPBA in the context of existing risk assessments and for prioritization of the potential need for additional risk assessment efforts for cyfluthrin relative to other chemicals.

Recent efforts worldwide have resulted in a growing database of measured concentrations of chemicals in blood and urine samples taken from the general population. However, few tools exist to assist in the interpretation of the measured values in a health risk context. Biomonitoring Equivalents (BEs) are defined as the concentration or range of concentrations of a chemical or its metabolite in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline, and are derived by integrating available data on pharmacokinetics with existing chemical risk assessments. This study reviews available health-based exposure guidance values for di-n-butyl phthalate (DBP), benzylbutyl phthalate (BzBP), and diethyl phthalate (DEP) from Health Canada, the United States Environmental Protection Agency (U.S. EPA), the Agency for Toxic Substances and Disease Registry (ATSDR), and the European Food Safety Authority (EFSA). BE values corresponding to the oral reference dose (RfD), minimal risk level (MRL) or tolerable daily intake (TDI) estimates from these agencies were derived for each compound based on data on excretion fractions of key urinary metabolites. These values may be used as screening tools for evaluation of biomonitoring data for metabolites of these three phthalate compounds in the context of existing risk assessments and for prioritization of the potential need for additional risk assessment efforts for each of these compounds relative to other chemicals.

International audience; p-tert-Octylphenol (OP) is a degradation product of alkylphenol ethoxylates. OP is an endocrine disruptor known to bind to the estrogen receptor; however, effects on males are controversial. The objective of this study was to evaluate the effects of chronic exposure to OP on male reproduction. Adult Sprague-Dawley rats were administered OP for 60 d, representing 1.5 cycles of spermatogenesis. Experimental groups included a vehicle control, and three doses of OP (25, 50, or 125 mg/kg body weight [bw]) administered daily by gavage. There was a significant decrease in body weight in the 125-mg/kg group after 60 d of treatment. Both testicular and epididymal weights and histology were not altered by treatment with OP at any of the doses administered. There were no marked differences in cauda epididymal sperm counts at any doses; however, total percent sperm motility was significantly lower in rats exposed to the intermediate dose (50 mg/kg bw). There was an increase in percent static sperm cells in all OP-treated groups, with the intermediate dose (50 mg/kg) displaying a significantly higher proportion of static cells relative to untreated controls. Caput epididymal sperm motility was unaltered by OP treatment. Gene expression profiles of testes from control and high-dose-exposed rats indicate that 14 genes were modulated by at least twofold, although these changes were not statistically significant. Taken together, results from this study indicate that OP treatment of adult rats does not appear to exert major effects on male reproductive endpoints at relevant environmental exposure doses.

Physiologically based pharmacokinetic (PBPK) models have increasingly been employed in chemical health risk assessments. By incorporating individual variability conferred by genetic polymorphisms, health conditions, and physiological changes during development and aging, PBPK models are ideal for predicting chemical disposition in various subpopulations of interest. In order to improve the parameterization of PBPK models for healthy and health-impaired elderly (herein defined as those aged 65 yr and older), physiological parameter values were obtained from the peer-reviewed literature, evaluated, and entered into a Microsoft ACCESS database. Database records include values for key age-specific model inputs such as ventilation rates, organ volumes and blood flows, glomerular filtration rates, and other clearance-related processes. In total, 528 publications were screened for relevant data, resulting in the inclusion of 155 publications comprising 1051 data records for healthy elderly adults and 115 data records for elderly with conditions such as diabetes, chronic obstructive pulmonary disease (COPD), obesity, heart disease, and renal disease. There are no consistent trends across parameters or their associated variance with age; the gross variance in body weight decreased with advancing age, whereas there was no change in variance for brain weight. The database contains some information to inform ethnic and gender differences in parameters; however, the majority of the published data pertain to Asian (mostly Japanese) and Caucasian males. As expected, the number of records tends to decrease with advancing age. In addition to a general lack of data for parameters in the elderly with various health conditions, there is also a dearth of information on blood and tissue composition in all elderly groups. Importantly, there are relatively few records for alveolar ventilation rate; therefore, the relationship between this parameter and cardiac output (usually assumed to be 1:1) in the elderly is not well informed by the database. Despite these limitations, the database represents a potentially useful resource for parameterizing PBPK models for the elderly to facilitate the prediction of dose metrics in older populations for application in risk assessment.

In vitro data on metabolism and partitioning may be integrated within physiologically-based pharmacokinetic (PBPK) models to provide simulations of the kinetics and bioaccumulation of chemicals in intact organisms. Quantitative structure-property relationship (QSPR) modelling of available in vitro data may be performed to predict metabolism rates and partition coefficients (PCs) for developing in vivo PBPK models. The objective of the present study was to develop an integrated QSPR-PBPK modelling approach for the conduct of in vitro to in vivo extrapolation. For this purpose, data on rat blood:air (P(b)) and fat:air (P(f)) PCs, as well as intrinsic metabolic clearance (CL(int)) obtained using rat liver slices for some C(5)-C(10) volatile organic compounds (VOCs) were compiled from the literature. Multilinear additive QSPR models for P(f), P(b) and CL(int) were developed based on the number and nature of molecular fragments in these VOCs (CH(3), CH(2), CH, C, C=C, H, benzene ring and H in benzene ring structure). The mean estimated/experimental (est/exp) ratios (+/-SD; range) were 1.0 (+/-0.04; 0.93 - 1.06) for log P(f), 1.08 (+/-0.26; 0.70 - 1.62) for log P(b), and 1.07 (+/- 0.21; 0.80 - 1.44) for CL(int). By accounting for the difference in the content of neutral lipids in fat and other tissues, the liver : air and muscle : air PCs of the compounds investigated in this study, with the excerption of n-decane, were adequately predicted from P(f). Integrating the QSPRs for P(f), P(b) and CL(int) within a rat PBPK model, simulations of inhalation pharmacokinetics of several VOCs were generated on the basis of molecular structure, for a given exposure scenario. The integrated QSPR-PBPK model developed in this study is a potentially useful tool for predicting in vivo kinetics and bioaccumulation of chemicals in rats under poor data situations.

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.

A sensitive and reproducible procedure using gas chromatography coupled with mass spectrometry is described for the determination of p-tert-octylphenol (OP), a persistent degradation product of alkylphenol ethoxylates that binds to the estrogen receptor in blood and tissues. The first step involved the extraction of blood (200 microL) or tissue homogenate (400 microL) with methyl tert-butyl ether, including p-tert-butylphenol (BP) as internal standard. After extraction, the sample was evaporated to dryness with a gentle stream of nitrogen at 45 degrees C, and OP and BP were derivatized with an acetylation reaction involving acetic anhydride and catalyzed by pyridine. Samples were then analyzed by a gas chromatograph equipped with a mass spectrometer (single ion monitoring) with a Varian VF-5ms capillary column. The limit of detection and the limit of quantification of the method in blood were 4.6 and 15.5 ng/mL, respectively. The linearity and reproducibility of the method were acceptable, with coefficients of variation of approximately 10% for blood and ranging between 9% and 27% for tissues. This method was applied to the determination of unchanged OP in blood and tissues obtained from Sprague-Dawley rats after oral and IV OP administration.

The derivation of reference concentrations (RfCs) for systemically acting volatile organic chemicals (VOCs) uses a default factor of 10 to account for the interindividual variability in pharmacokinetics (PK) and pharmacodynamics (PD). The magnitude of the PK component of the interindividual variability factor (IVF; also referred to as human kinetic adjustment factor (HKAF)) has previously been estimated using Monte Carlo approaches and physiologically based pharmacokinetic (PBPK) models. Since the RfC derivation considers continuous lifetime human exposure to VOCs in the environment, algorithms to compute steady-state internal dose (SS-ID), such as steady-state arterial blood concentration (Ca) and the steady-state rate of amount metabolized (RAM), can be used to derive IVF-PKs. In this context, probability-bounds (P-bounds) approach is potentially useful for computing an interval of probability distribution of SS-ID from knowledge of population distribution of input parameters. The objective of this study was therefore to compute IVF-PK using the P-bounds approach along with an algorithm for SS-ID in an adult population exposed to VOCs. The existing steady-state algorithms, derived from PBPK models, were rewritten such that SS-ID could be related, without any interdependence, to the following input parameters: alveolar ventilation (Qp), hepatic blood flow (Ql), intrinsic clearance (CLint) and blood:air partition coefficient (Pb). The IVF-PK was calculated from the P-bounds of SS-ID corresponding to the 50th and 95th percentiles. Following either specification of probability distribution-free bounds (characterized by minimal, maximal, and mean values) or distribution-defined values (mean, standard deviation and shape of probability distribution where: Qp = lognormal, Ql = lognormal, CLint = lognormal and Pb = normal) in RAMAS Risk Calc® software version 3.0 (Applied Biomathematics, Setauket, NY), the P-bound estimates of SS-ID for benzene, carbon tetrachloride, chloroform and methyl chloroform were obtained for low level exposures (1 ppm). Using probability distribution-defined inputs, the IVF-PK for benzene, carbon tetrachloride, chloroform and methyl chloroform were, respectively, 1.18, 1.28, 1.24, and 1.18 (based on P-bounds for Ca), and 1.31, 1.58, 1.30, and 1.24 (based on P-bounds for RAM). A validation of the P-bounds computation was performed by comparing the results with those obtained using Monte Carlo simulation of the steady-state algorithms. In data-poor situations, when the statistical distributions for all input parameters were not known or available, the P-bounds approach allowed the estimation of IVF-PK. The use of P-bounds method along with steady-state algorithms, as done in this study for the first time, is a practical and scientifically sound way of computing IVF-PKs for systemically acting VOCs.