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Uncertainty factors (UFs) are used to account for uncertainties and variability when setting exposure limits or guidance values. Starting from a proposal of a single UF of 100 to extrapolate from an animal NOAEL to a human acceptable exposure, the aspects of uncertainty and number of UFs have diversified and today there are several risk assessment guidelines that contain schemes of default UFs of varying complexity. In the present work, we scoped the scientific literature on default UFs to map developments regarding recommendations and evaluations of these. We identified 91 publications making recommendations for one or several UFs and 55 publications evaluating UFs without making explicit recommendations about numerical values; these were published between 1954 and 2021. The 2000s was the decade with the largest number of publications, interspecies differences and intraspecies variability being the most frequent topics. The academic sector has been the most active (76 out of 146 publications). Authors from the private sector more often presented UF recommendations, but differences between sectors regarding size of recommendations were not statistically significant. The empirical underpinning of the reviewed recommendations ranges from four to 462 chemicals, that is, relatively low numbers compared with the range of chemicals these default UFs are expected to cover. The recommended UFs have remained remarkably constant, with merely a slight decrease over time. Although chemical specific UFs are preferable, the widespread use of default UFs warrants further attention regarding their empirical and normative basis.

Approximately 11 million people work as welders worldwide and an additional 110 million are exposed to welding fumes at work (1). Several countries have an occupational exposure limit (OEL) for welding fumes of 5 mg/m^3 (1, 2) and similar OEL for respirable dust (2). Given the accumulating evidence on serious health effects from welding fumes

Limited toxicity data on electronic cigarette (ECIG) impede evidence-based policy recommendations. We compared two popular mixed fruit flavored ECIG-liquids with and without nicotine aerosolized at 40 W (E-smoke) with respect to particle number concentrations, chemical composition, and response on physiologically relevant human bronchial and alveolar lung mucosa models cultured at air–liquid interface. E-smoke was characterized by significantly increased particle number concentrations with increased wattage (25, 40, and 55 W) and nicotine presence. The chemical composition of E-smoke differed across the two tested flavors in terms of cytotoxic compounds including p-benzoquinone, nicotyrine, and flavoring agents (for example vanillin, ethyl vanillin). Significant differences in the expression of markers for pro-inflammation, oxidative stress, tissue injury/repair, alarm anti-protease, anti-microbial defense, epithelial barrier function, and epigenetic modification were observed between the flavors, nicotine content, and/ or lung models (bronchial or alveolar). Our findings indicate that ECIG toxicity is influenced by combination of multiple factors including flavor, nicotine content, vaping regime, and the region of respiratory tree (bronchial or alveolar). Toxic chemicals and flavoring agents detected in high concentrations in the E-smoke of each flavor warrant independent evaluation for their specific role in imparting toxicity. Therefore, multi-disciplinary approaches are warranted for comprehensive safety profiling of ECIG.

Gold nanoparticles (AuNPs) are readily functionalized and considered biocompatible making them useful in a wide range of applications. Upon human exposure, AuNPs will to a high extent reside in macrophages, cells that are designed to digest foreign materials. To better understand the fate of AuNPs in the human body, their possible dissolution needs to be explored. In this study, we tested the hypothesis that macrophages, and especially stimulated macrophages, can impact the dissolution of AuNPs in a size-dependent manner. We developed an in vitro method to compare the dissolution of citrate coated 5 and 50 nm-sized AuNPs, in terms of released gold ions as measured by inductive coupled mass spectrometry (ICP-MS), in (i) cell medium (alone) (ii) in medium with macrophages present and (iii) in medium with lipopolysaccharide (LPS) triggered macrophages (simulating inflammatory conditions). We found an evident, time-dependent dissolution of AuNPs in cell medium, corresponding to 3% and 0.6% of the added amounts of 5 and 50 nm AuNPs, respectively, after 1 week (168 h) of incubation. The dissolution of 5 nm AuNPs was further increased to 4% in the presence of macrophages and, most strikingly, 14% was dissolved in case of LPS-triggering. In contrast, only a minor increase was observed for 50 nm AuNPs after 1 week in the presence of LPS-triggered macrophages compared to medium alone. Dissolution experiments in the absence of cells highlighted the importance of biomolecules. Our findings thus show dissolution of citrate coated AuNPs that is dependent on size, presence of macrophages, and their inflammatory state. These findings have implications for understanding the transformation/dissolution and fate of AuNPs.

Contaminated drinking water (DW) is a major source of exposure to per- and polyfluoroalkyl substances (PFAS) at locations around PFAS production/use facilities and military airports. This study aimed to investigate quantitative relationships between concentrations in DW and serum of nine perfluoroalkyl acids (PFAAs) in Swedish adult populations living near contamination hotspots. Short-chained (PFPeA, PFHxA, PFHpA, and PFBS) and long-chained PFAAs (PFOA, PFNA, PFDA, PFHxS and PFOS) were measured in DW and serum. We matched DW and serum concentrations for a total of 398 subjects living or working in areas receiving contaminated DW and in one non-contaminated area. Thereafter, linear regression analysis with and without adjustments for co-variates was conducted. This enabled to derive (i) serum concentrations at background exposure (CB) from sources other than local DW exposure (i.e. food, dust and textiles) at 0 ng/L DW concentration, (ii) population-mean PFAA serum:water ratios (SWR) and (iii) PFAA concentrations in DW causing observable elevated serum PFAA concentrations above background variability. Median concentrations of the sum of nine PFAAs ranged between 2.8 and 1790 ng/L in DW and between 7.6 and 96.9 ng/mL in serum. DW concentration was the strongest predictor, resulting in similar unadjusted and adjusted regression coefficients. Mean CB ranged from

Introduction: Breath analyzers are commonly used to test for alcohol intoxication, i.e., elevated systemic levels of ethanol, at workplaces and among vehicle drivers. However, local low-dos...

Crowding in dwellings is an important public health issue. We hypothesize that overcrowding may cause indirect health effects by adversely affecting the dwelling itself, for example, by increasing dampness leading to mold. We therefore performed a systematic search and a scoping review on overcrowding leading to dwelling condition characteristics of relevance for health. A literature search was performed using the PubMed and Scopus databases up to 5 March 2021. The search yielded 100 records with relevant information. We found that overcrowding is defined in numerous ways and often address “socially deprived” populations. Six studies report associations of overcrowding with at least one dwelling condition characteristic, namely lead, cadmium, microorganism distribution, dust mite and cockroach allergens in dust, cockroach infestation, peeling paint, and mold. One of the studies reports associations between several characteristics, e.g., association of mold with cleanliness and rodent infestation, and points out the common use of pesticides. Additional characteristics were extracted from the remaining 94 records, without data on statistical associations with overcrowding. Our review suggests that multiple potentially hazardous dwelling condition characteristics often coincide in overcrowded dwellings. The epidemiological attribution of health effects to any characteristic is therefore difficult. Causal relationships are even more difficult to establish, as overcrowding is also associated with a range of social and other circumstances that may affect health. The complexity should be considered by scientists and practitioners dealing with overcrowding in dwellings.

Background: The filaggrin protein is important for skin barrier structure and function. Loss-of-function (null) mutations in the filaggrin gene FLG may increase dermal absorption of chemicals. Objective: The objective of the study was to clarify if dermal absorption of chemicals differs depending on FLG genotype. Method: We performed a quantitative real-time polymerase chain reaction (qPCR)-based genetic screen for loss-of-function mutations (FLG null) in 432 volunteers from the general population in southern Sweden and identified 28 FLG null carriers. In a dermal exposure experiment, we exposed 23 FLG null and 31 wild-type (wt) carriers to three organic compounds common in the environment: the polycyclic aromatic hydrocarbon pyrene, the pesticide pyrimethanil, and the ultraviolet-light absorber oxybenzone. We then used liquid-chromatography mass-spectrometry to measure the concentrations of these chemicals or their metabolites in the subjects’ urine over 48 h following exposure. Furthermore, we used long-range PCR to measure FLG repeat copy number variants (CNV), and we performed population toxicokinetic analysis. Results: Lag times for the uptake and dermal absorption rate of the chemicals differed significantly between FLG null and wt carriers with low (20–22 repeats) and high FLG CNV (23–24 repeats). We found a dose-dependent effect on chemical absorption with increasing lag times by increasing CNV for both pyrimethanil and pyrene, and decreasing area under the urinary excretion rate curve (AUC(0–40h)) with increasing CNV for pyrimethanil. FLG null carriers excreted 18% and 110% more metabolite (estimated by AUC(0–40h)) for pyrimethanil than wt carriers with low and high CNV, respectively. Conclusion: We conclude that FLG genotype influences the dermal absorption of some common chemicals. Overall, FLG null carriers were the most susceptible, with the shortest lag time and highest rate constants for skin absorption, and higher fractions of the applied dose excreted. Furthermore, our results indicate that low FLG CNV resulted in increased dermal absorption of chemicals. https://doi.org/10.1289/EHP7310

This report summarizes the outcome of a workshop held in Mysuru, India in January 2020 addressing the adverse health effects of exposure to biomass smoke (BMS). The aim of the workshop was to identify uncertainties and gaps in knowledge and possible methods to address them in the Mysuru study on Determinants of Health in Rural Adults (MUDHRA) cohort. Specific aims were to discuss the possibility to improve and introduce new screening methods for exposure and effect, logistic limitations and other potential obstacles, and plausible strategies to overcome these in future studies. Field visits were included in the workshop prior to discussing these issues. The workshop concluded that multi-disciplinary approaches to perform: (a) indoor and personalized exposure assessment; (b) clinical and epidemiological field studies among children, adolescents, and adults; (c) controlled exposure experiments using physiologically relevant in vitro and in vivo models to understand molecular patho-mechanisms are warranted to dissect BMS-induced adverse health effects. It was perceived that assessment of dietary exposure (like phytochemical index) may serve as an important indicator for understanding potential protective mechanisms. Well trained field teams and close collaboration with the participating hospital were identified as the key requirements to successfully carry out the study objectives.

Numerous shipping containers arrive with high levels of hazardous volatile chemicals in the interior air. This may constitute a health risk during inspection and unstuffing. The problem remains largely unaddressed due to ignorance, lack of suitable field instruments for chemical identification, and lack of easy to use, effective ventilation methods. Here, we present a novel ventilation approach based on extraction of air from the closed container via the existing top corner ventilators. A suction plate was developed to fit tightly over the corner ventilator and connected with a flexible hose to an extraction fan. Air flow rates and vacuum under the plate were measured in the lab with five different types of extraction fans. The vacuum produced under the suction plate held it securely in place. Washout of air contaminants under different configurations and ventilation scenarios was studied in an experimental 20-ft container stuffed with acetone emitting cardboard boxes and in the field with containers stuffed with commercial goods. Volatiles in container air were continuously recorded with logging photoionization detectors in various positions before, during and after ventilation. A maximum air flow through the ventilator of 186 m3/h was achieved. At 100 m3/h, the initial acetone levels were reduced to 11% and 4.9% in the tightly stuffed and to 6.0% and 3.1% in the loosely stuffed (pallets) experimental container after 1 h and 4 h, respectively, as measured inside the closed door (mean values). As expected, the washout was somewhat slower in nine 40-ft field containers and reached 22% and 11%, respectively. In both experimental and field containers the concentration rose quickly when ventilation ceased. In conclusion, the new ventilation method allows for convenient, safe and efficient ventilation of risk containers. The container should be continuously ventilated until it is opened, or rapid re-accumulation of volatiles will occur.

Ulrika Carlander,1 Tshepo Paulsen Moto,2 Anteneh Assefa Desalegn,1 Robert A Yokel,3 Gunnar Johanson1 1Unit of Work Environment Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Solna, Sweden; 2Faculty ofHealth Sciences, School of Health Systems and Public Health, University of Pretoria, Pretoria, South Africa; 3Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, USA Background: Cerium dioxide nanoparticles (nanoceria) are increasingly being used in a variety of products as catalysts, coatings, and polishing agents. Furthermore, their antioxidant properties make nanoceria potential candidates for biomedical applications. To predict and avoid toxicity, information about their biokinetics is essential. A useful tool to explore such associations between exposure and internal target dose is physiologically based pharmacokinetic (PBPK) modeling. The aim of this study was to test the appropriateness of our previously published PBPK model developed for intravenous (IV) administration when applied to various sizes of nanoceria and to exposure routes relevant for humans. Methods: Experimental biokinetic data on nanoceria (obtained from various exposure routes, sizes, coatings, doses, and tissues sampled) in rats were collected from the literature and also obtained from the researchers. The PBPK model was first calibrated and validated against IV data for 30 nm citrate coated ceria and then recalibrated for 5 nm ceria. Finally, the model was modified and tested against inhalation, intratracheal (IT) instillation, and oral nanoceria data.Results: The PBPK model adequately described nanoceria time courses in various tissues for 5 nm ceria given IV. The time courses of 30 nm ceria were reasonably well predicted for liver and spleen, whereas the biokinetics in other tissues were not well captured. For the inhalation, IT instillation, and oral exposure routes, re-optimization was difficult due to low absorption and, hence, low and variable nanoceria tissue levels. Moreover, the nanoceria properties and exposure conditions varied widely among the inhalation, IT instillation, and oral studies, making it difficult to assess the importance of different factors. Conclusion: Overall, our modeling efforts suggest that nanoceria biokinetics depend largely on the exposure route and dose. Keywords: biodistribution, cerium dioxide, inhalation, instillation, intravenous, oral

NanoImpact : an international journal of nanosafety research 6, 69-80 (2017). doi:10.1016/j.impact.2017.03.003, Published by Elsevier, Amsterdam

We recently reported that mold odor may be explained by chloroanisoles (CAs) formed by microbial biotransformation of chlorophenols (CPs) in legacy wood preservatives. Here we examine psychophysical aspects of CAs and trace their historic origins in buildings. Our exposure of healthy volunteers shows that 2,4,6-triCA is often perceived as unpleasant, characterized as musty or moldy and is detected at 13 ng/m3 or lower. Similar concentrations are reported in buildings with odor complaints. Scrutiny of written records reveal that new building construction methods were introduced in the 1950s, namely crawlspaces and concrete slabs on the ground. These constructions were prone to dampness and attack from wood decay fungi, prompting chemical companies and authorities to advocate preservatives against rot. Simultaneously, CPs became household chemicals used for example in indoor paints. When large-scale odor problems evolved, the authorities that once approved the preservatives attributed the odor to hidden mold, with no evidence that substantial microbial biomass was necessary for odor formation. Thereby the public remained unaware of problematic exposure to CPs and CAs. We conclude that the introduction of inappropriate designs of house foundations and CP-based preservatives once ignited and still provide impetus for indoor air research on “dampness and mold”.

Perfluorinated alkyl acids (PFAA) are highly persistent and bioaccumulative and have been associated with several adverse health effects. The chemical structure mainly differs in two ways: the length of the hydrophobic alkyl chain and the type of hydrophilic end group. Little is known how the chemical structure affects the toxicokinetics (TK) in different organisms. We studied the TK of four PFAA (PFOS, PFHxS, PFOA, and PFBA) with different chain lengths (4-8 carbons) and functional groups (sulfonic and carboxylic acid) in zebrafish ( Danio rerio) embryo. The time courses of the external (ambient water) and internal concentrations were determined at three exposure concentrations from 2 up to 120 h postfertilization (hpf). Three of the four PFAA showed a biphasic uptake pattern with slow uptake before hatching (around 48 hpf) and faster uptake thereafter. A two-compartment TK model adequately described the biphasic uptake pattern, suggesting that the chorion functions as an uptake barrier until 48 hpf. The bioconcentration factors (BCF) determined at 120 hpf varied widely between PFAA with averages of approximately 4000 (PFOS), 200 (PFHxS), 50 (PFOA), and 0.8 (PFBA) L kg dry weight-1, suggesting that both the alkyl chain length and the functional group influence the TK. The differences in toxic potency were reduced by 3 orders of magnitude when comparing internal effect concentrations instead of effective external concentrations.

Asthma, a chronic respiratory disease, can be aggravated by exposure to certain chemical irritants. The objectives were first to investigate the extent to which experimental observations on asthmatic subjects are taken into consideration in connection with the registration process under the EU REACH regulation, and second, to determine whether asthmatics are provided adequate protection by the derived no‐effect levels (DNELs) for acute inhalation exposure. We identified substances for which experimental data on the pulmonary functions of asthmatics exposed to chemicals under controlled conditions are available. The effect concentrations were then compared with DNELs and other guideline and limit values. As of April 2015, only 2.6% of 269 classified irritants had available experimental data on asthmatics. Fourteen of the 22 identified substances with available data were fully registered under REACH and we retrieved 114 reliable studies related to these. Sixty‐three of these studies, involving nine of the 14 substances, were cited by the REACH registrants. However, only 17 of the 114 studies, involving four substances, were regarded as key studies. Furthermore, many of the DNELs for acute inhalation were higher than estimated effect levels for asthmatics, i.e., lowest observed adverse effect concentrations or no‐observed adverse effect concentrations, indicating low or no safety margin. We conclude that REACH registrants tend to disregard findings on asthmatics when deriving these DNELs. In addition, we found examples of DNELs, particularly among those derived for workers, which likely do not provide adequate protection for asthmatics. Copyright © 2016 The Authors Journal of Applied Toxicology Published by John Wiley & Sons Ltd., We investigate the extent to which experimental observations on asthmatic subjects are taken into consideration by REACH registrants and determine whether asthmatics are provided adequate protection by the acute inhalation Derived No‐Effect Levels. Of 114 studies concerning 14 substances fulfilling our inclusion criteria, 63 studies, involving nine substances, were cited by the REACH registrants. However, only 17 of the 114 studies, involving four substances, were regarded as key studies. Furthermore, many of the Derived No‐Effect Levels were higher than Lowest‐ or No‐Observed Adverse Effect Concentrations values from these studies.

At the 8th conference of Occupational and Environmental Exposure of the Skin to Chemicals (OEESC) (16–18 September 2019) in Dublin, Ireland, several researchers performing skin permeation assays convened to discuss in vitro skin permeability experiments. We, along with other colleagues, all of us hands-on skin permeation researchers, present here the results from our discussions on the available OECD guidelines. The discussions were especially focused on three OECD skin absorption documents, including a recent revision of one: i) OECD Guidance Document 28 (GD28) for the conduct of skin absorption studies (OECD, 2004), ii) Test Guideline 428 (TGD428) for measuring skin absorption of chemical in vitro (OECD, 2004), and iii) OECD Guidance Notes 156 (GN156) on dermal absorption issued in 2011 (OECD, 2011). GN156 (OECD, 2019) is currently under review but not finalized. A mutual concern was that these guidance documents do not comprehensively address methodological issues or the performance of the test, which might be partially due to the years needed to finalize and update OECD documents with new skin research evidence. Here, we summarize the numerous factors that can influence skin permeation and its measurement, and where guidance on several of these are omitted and often not discussed in published articles. We propose several improvements of these guidelines, which would contribute in harmonizing future in vitro skin permeation experiments.

Asthma is a heterogeneous inflammatory disease characterized by increased airway hyper-responsiveness to external stimuli such as irritants. One may speculate that asthmatics are more sensitive to irritants in the air than healthy subjects, i.e. react at lower concentrations. We reviewed the scientific support for this speculation and investigated to what extent asthma is considered when setting exposure limits and guidance values. We found that the experimental studies comparing healthy and asthmatic subjects are often inconclusive. Still, the available studies are underused, by expert committees and industry alike. Data for a few irritants suggest that asthmatics are up to three-fold more sensitive than the healthy. The most abundant data were found for sulfur dioxide. Here, a benchmark concentration analysis suggests a nine-fold difference in sensitivity. Based on these data a default assessment factor of 10 is suggested when setting exposure limits and guidance values for irritants.

Derived no-effect levels for workers (wDNELs) under the European REACH legislation have many aspects in common with occupational exposure limits (OELs). In an attempt to examine under which circumstances wDNELs might be used as exposure guidance outside their intended application, we compared derivation methods, coverage of substances and numerical values of wDNELs against two regulatory OEL lists (European Commission and Sweden) and three sets of recommendations (European SCOEL, German MAK and US ACGIH). Finally, we looked closer at wDNELs where SCOEL concluded that data were insufficient to derive an OEL. Major differences between wDNELs and OELs include regulatory background, intended use, actors involved, substance selection criteria, transparency and procedure of derivation, and operationalisation in terms of risk management measures. As of summer 2018, approximately five times more substances were covered by wDNELs than by the five sets of OELs examined herein. Meanwhile, many occupationally relevant pollutants were not covered by wDNELs, e.g. one-third of Swedish OELs lack corresponding wDNELs. We also note that wDNELs and OELs for the same substance may vary considerably, up to several orders of magnitude. In conclusion, with extensive substance coverage, wDNELs extend the landscape beyond the OELs. That said, important limitations are (1) that many air pollutants relevant for workers' health are not covered by REACH, and (2) concerns for inconsistencies in the derivation of wDNELs and in their level of protection. In particular, that route-to-route extrapolation is a common practice that may be grossly misleading when the effect of concern is local, e.g. sensitisation. QC 20190620

Computational modeling together with experimental data are essential to assess the risk for particulate matter mediated lung toxicity and to predict the efficacy, safety and fate of aerosolized drug molecules used in inhalation therapy. In silico models are widely used to understand the deposition, distribution, and clearance of inhaled particles and aerosols in the human lung. Exacerbations of chronic obstructive pulmonary disease (COPD) have been reported due to increased particulate matter related air pollution episodes. Considering the profound functional, anatomical and structural changes occurring in COPD lungs, the relevance of the existing in silico models for mimicking diseased lungs warrants reevaluation. Currently available computational modeling tools were developed for the healthy adult (male) lung. Here, we analyze the major alterations occurring in the airway structure, anatomy and pulmonary function in the COPD lung, as compared to the healthy lung. We also scrutinize the various physiological and particle characteristics that influence particle deposition, distribution and clearance in the lung. The aim of this review is to evaluate the availability of the fundamental knowledge and data required for modeling particle deposition in a COPD lung departing from the existing healthy lung models. The extent to which COPD pathophysiology may affect aerosol deposition depends on the relative contribution of several factors such as altered lung structure and function, bronchoconstriction, emphysema, loss of elastic recoil, altered breathing pattern and altered liquid volumes that warrant consideration while developing physiologically relevant in silico models.

Decision on the safety margin, for instance by using uncertainty factors (UFs), is a key aspect in setting Occupational Exposure Limits (OELs). We analyzed the UFs in 128 OEL recommendations from the European Commission's Scientific Committee on Occupational Exposure Limits (SCOEL). We investigated factors expected to potentially influence the UFs, as well as a selection of factors that might influence how expert groups perceive quality or reliability of key studies. We extracted UFs explicitly stated in the recommendations (EUFs) and, when EUFs were missing, calculated an implicit safety margin (ISM) by dividing the point of departure (PoD) by the OEL. EUFs and ISMs were lower for recommendations based on human data than those based on animal data. EUFs and ISMs were also lower for No-Observed Adverse Effect Concentrations (NOAECs) than Lowest Observed Adverse Effect Concentrations (LOAECs). We saw no differences based on local vs systemic critical effects. Acute data resulted in lower EUFs and ISMs than subchronic. We saw no influence from status of key study (publication status, performer or funder), but high tonnage substances (1,000,000+ tonnes) have lower EUFs and ISMs than substances currently not registered under REACH. Although SCOEL methodology stated that UF should be documented, only 65 out of 128 OEL recommendations included an EUF. Indeed, the ratio of EUFs to ISMs even decreased from 1991-2003 to 2004-2017. Additionally, EUFs were, on average, 1.8 times higher than ISMs. We conclude that a more articulate framework for using UFs could enhance consistency and transparency of the SCOEL recommendations.

Environmental science / Nano 5(1), 48-63 (2018). doi:10.1039/C7EN00594F, Published by Cambridge

The cytotoxicity of aldehydes was studied using human primary bronchial epithelial cells (PBEC) cultured at the air-liquid interface (ALI) or under submerged conditions. PBEC were exposed for 30min via the air phase to acrolein (0.1-1mg/m

Objective: It has been suggested that asthmatics are more susceptible than healthy individuals to airborne irritating chemicals in general. However, there is limited human data available to support this hypothesis due to ethical and practical difficulties. We explored a murine model of ovalbumin (OVA)-induced airway inflammation to study susceptibility during acute exposure to chemicals with chlorine as a model substance. Methods: Naïve and OVA sensitized female BALB/c mice were exposed to chlorine at four different concentrations (0, 5, 30 and 80 ppm) for 15 minutes with online recording of the respiratory function by plethysmography. The specific effects on respiratory mechanics, inflammatory cells and inflammatory mediators (cytokines and chemokines) of the airways were measured 24 hours after the chlorine exposure as well as histopathological examination of the lungs. Results: Similar concentration-dependent reductions in respiratory frequency were seen in the two groups, with a 50% reduction (RD50) slightly above 5 ppm. Decreased body weight 24 hours after exposure to 80 ppm was also observed in both groups. Naïve, but not OVA-sensitized, mice showed increased bronchial reactivity and higher number of neutrophils in bronchoalveolar lavage fluid at 80 ppm. Conclusions: The results do not support an increased susceptibility to chlorine among OVA-sensitized mice. This animal model, which represents a phenotype of eosinophilic airway inflammation, seems unsuitable to study susceptibility to inhalation of irritants in relation to asthma.

The health effects of low-level chronic exposure to cadmium are increasingly recognized. To improve the risk assessment, it is essential to know the relation between cadmium intake, body burden, and biomarker levels of cadmium. We combined a physiologically-based toxicokinetic (PBTK) model for cadmium with a data set from healthy kidney donors to re-estimate the model parameters and to test the effects of gender and serum ferritin on systemic uptake. Cadmium levels in whole blood, blood plasma, kidney cortex, and urinary excretion from 82 men and women were used to calculate posterior distributions for model parameters using Markov-chain Monte Carlo analysis. For never- and ever-smokers combined, the daily systemic uptake was estimated at 0.0063 μg cadmium/kg body weight in men, with 35% increased uptake in women and a daily uptake of 1.2 μg for each pack-year per calendar year of smoking. The rate of urinary excretion from cadmium accumulated in the kidney was estimated at 0.000042 day(-1), corresponding to a half-life of 45 years in the kidneys. We have provided an improved model of cadmium kinetics. As the new parameter estimates derive from a single study with measurements in several compartments in each individual, these new estimates are likely to be more accurate than the previous ones where the data used originated from unrelated data sets. The estimated urinary excretion of cadmium accumulated in the kidneys was much lower than previous estimates, neglecting this finding may result in a marked under-prediction of the true kidney burden.

Benchmark dose (BMD) modeling is increasingly used as the preferred approach to define the point-of-departure for health risk assessment of chemicals. As data are inherently variable, there is always a risk to select a model that defines a lower confidence bound of the BMD (BMDL) that, contrary to expected, exceeds the true BMD. The aim of this study was to investigate how often and under what circumstances such anomalies occur under current modeling practice. Continuous data were generated from a realistic dose–effect curve by Monte Carlo simulations using four dose groups and a set of five different dose placement scenarios, group sizes between 5 and 50 animals and coefficients of variations of 5–15%. The BMD calculations were conducted using nested exponential models, as most BMD software use nested approaches. “Non-protective” BMDLs (higher than true BMD) were frequently observed, in some scenarios reaching 80%. The phenomenon was mainly related to the selection of the non-sigmoidal exponential model (Effect = a · e b ·dose ). In conclusion, non-sigmoid models should be used with caution as it may underestimate the risk, illustrating that awareness of the model selection process and sound identification of the point-of-departure is vital for health risk assessment.

The availability of experimental data suitable as a basis to quantify human variability in response to chemical exposure has increased in recent years. It has enabled scientifically based, data driven adjustment factors (AF) to be deployed in the risk assessment process. As part of this development, we derive AF for human toxicokinetic variability (HK) for three lipophilic organic solvents; toluene, styrene and methyl chloride using physiologically based pharmacokinetic (PBPK) models in a population framework. The Monte Carlo simulations cover the influence of age and gender on toxicokinetic variability in the general population, as well as workplace ventilation rates and fluctuations in exposure level and workload in adult male and female workers. The derived AFHK are below 2.2 (95th percentile) for all subpopulations, exposure scenarios and chemicals, except for markers of acute effects in workers, where the factors are up to 5.0.

The content of aromatic hydrocarbons in solvent mixtures, such as white spirits (WS), has been assumed a major contributor to the neurotoxic effects of these compounds. Hence, dearomatized WS have been introduced to the market rapidly in the last decade. Studies investigating other aromatic hydrocarbons (toluene) and animal models have supported the aforementioned assumption, but the current study is the first one to compare acute neurobehavioral effects of exposure to aromatic and dearomatized WS (aWS, daWS) content in human volunteers at current occupational exposure limit values. In a pseudo-randomized crossover design, six female and six male healthy volunteers were exposed to aWS and daWS at two concentrations (100 and 300 mg/m(3)) and to clean air for 4 h at rest. During each of the five exposure conditions, volunteers performed five neurobehavioral tasks that were selected following a multidisciplinary approach that accounted for findings from the cognitive neurosciences and mechanisms of solvent toxicity. Two of the tasks indicated performance changes during aromatic WS exposure, the working memory (WM) and the response shifting task, but both effects are difficult to interpret due to low mean accuracy in the WM task and due to a lack of dose-response relationship in the response shifting task. Healthy human volunteers showed weak and inconsistent neurobehavioral impairment after 4-h exposures to 100 and 300 mg/m(3) aromatic or dearomatized WS. Our multidisciplinary approach of selecting neurobehavioral test methods may guide the test selection strategies in future studies.