Assessment of wood smoke induced pulmonary toxicity in normal- and chronic bronchitis-like bronchial and alveolar lung mucosa models at air-liquid interface.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) has the highest increased risk due to household air pollution arising from biomass fuel burning. However, knowledge on COPD patho-mechanisms is mainly limited to tobacco smoke exposure. In this study, a repeated direct wood smoke (WS) exposure was performed using normal- (bro-ALI) and chronic bronchitis-like bronchial (bro-ALI-CB), and alveolar (alv-ALI) lung mucosa models at air-liquid interface (ALI) to assess broad toxicological end points. METHODS: The bro-ALI and bro-ALI-CB models were developed using human primary bronchial epithelial cells and the alv-ALI model was developed using a representative type-II pneumocyte cell line. The lung models were exposed to WS (10 min/exposure; 5-exposures over 3-days; n = 6-7 independent experiments). Sham exposed samples served as control. WS composition was analyzed following passive sampling. Cytotoxicity, total cellular reactive oxygen species (ROS) and stress responsive NFkB were assessed by flow cytometry. WS exposure induced changes in gene expression were evaluated by RNA-seq (p ≤ 0.01) followed by pathway enrichment analysis. Secreted levels of proinflammatory cytokines were assessed in the basal media. Non-parametric statistical analysis was performed. RESULTS: 147 unique compounds were annotated in WS of which 42 compounds have inhalation toxicity (9 very high). WS exposure resulted in significantly increased ROS in bro-ALI (11.2%) and bro-ALI-CB (25.7%) along with correspondingly increased NFkB levels (bro-ALI: 35.6%; bro-ALI-CB: 18.1%). A total of 1262 (817-up and 445-down), 329 (141-up and 188-down), and 102 (33-up and 69-down) genes were differentially regulated in the WS-exposed bro-ALI, bro-ALI-CB, and alv-ALI models respectively. The enriched pathways included the terms acute phase response, mitochondrial dysfunction, inflammation, oxidative stress, NFkB, ROS, xenobiotic metabolism of AHR, and chronic respiratory disorder. The enrichment of the 'cilium' related genes was predominant in the WS-exposed bro-ALI (180-up and 7-down). The pathways primary ciliary dyskinesia, ciliopathy, and ciliary movement were enriched in both WS-exposed bro-ALI and bro-ALI-CB. Interleukin-6 and tumor necrosis factor-α were reduced (p < 0.05) in WS-exposed bro-ALI and bro-ALI-CB. CONCLUSION: Findings of this study indicate differential response to WS-exposure in different lung regions and in chronic bronchitis, a condition commonly associated with COPD. Further, the data suggests ciliopathy as a candidate pathway in relation to WS-exposure.

Heated Tobacco Products: Insights into Composition and Toxicity.

Heated tobacco products (HTPs) are novel products that allow users to inhale nicotine by heating (350 °C) reconstituted tobacco rather than combustion (900 °C) as in conventional cigarettes. HTP sticks containing reconstituted tobacco come in various flavours such as menthol, citrus, etc., like electronic cigarette liquids. Thus, the composition of HTP aerosol will also vary according to the flavouring agents added. Overall, the content of toxic chemicals in HTP aerosol appears to be lower than in cigarette smoke. However, the concentrations of more than twenty harmful and potentially harmful constituents have been reported to be higher in HTP aerosol than in cigarette smoke. Further, several toxic compounds not detected in cigarette smoke are also reported in HTP aerosol. Thus, the risks of HTP use remain unknown. Most of the available data on the composition and health effects of mainstream HTP aerosol exposure are generated by the tobacco industry. Few independent studies have reported short-term pathophysiological effects of HTP use. Currently available HTP toxicity data are mainly on the pulmonary and cardiovascular systems. Moreover, there are no long-term toxicity data and, therefore, the claims of the tobacco industry regarding HTPs as a safer alternative to traditional combustible cigarettes are unsubstantiated. Furthermore, HTP aerosol contains the highly addictive substance nicotine, which is harmful to the adolescent brain, developing foetuses, pregnant women, and also adults. Hence, comprehensive studies addressing the safety profiling related to long-term HTP use are warranted. With this background, the following review summarizes the current state of knowledge on HTP toxicity on four broad lines: composition of mainstream HTP aerosol compared to traditional combustible cigarette smoke, biomarkers of HTP exposure, health effects of HTP exposure, and the harm reduction aspect.

Overcrowding and Hazardous Dwelling Condition Characteristics: A Systematic Search and Scoping Review of Relevance for Health.

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.

Insight into the pulmonary molecular toxicity of heated tobacco products using human bronchial and alveolar mucosa models at air-liquid interface.

Heated tobacco products (HTP) are novel nicotine delivery products with limited toxicological data. HTP uses heating instead of combustion to generate aerosol (HTP-smoke). Physiologically relevant human bronchial and alveolar lung mucosa models developed at air-liquid interface were exposed to HTP-smoke to assess broad toxicological response (n = 6-7; ISO puffing regimen; compared to sham; non-parametric statistical analysis; significance: p < 0.05). Elevated levels of total cellular reactive oxygen species, stress responsive nuclear factor kappa-B, and DNA damage markers [8-hydroxy-2'-deoxyguanosine, phosphorylated histone H2AX, cleaved poly-(ADP-Ribose) polymerase] were detected in HTP-smoke exposed bronchial and/or alveolar models. RNA sequencing detected differential regulation of 724 genes in the bronchial- and 121 genes in the alveolar model following HTP-smoke exposure (cut off: p ≤ 0.01; fold change: ≥ 2). Common enriched pathways included estrogen biosynthesis, ferroptosis, superoxide radical degradation, xenobiotics, and α-tocopherol degradation. Secreted levels of interleukin (IL)1ꞵ and IL8 increased in the bronchial model whereas in the alveolar model, interferon-γ and IL4 increased and IL13 decreased following HTP-smoke exposure. Increased lipid peroxidation was detected in HTP-smoke exposed bronchial and alveolar models which was inhibited by ferrostatin-1. The findings form a basis to perform independent risk assessment studies on different flavours of HTP using different puffing topography and corresponding chemical characterization.

Differential Effect of SARS-CoV-2 Spike Glycoprotein 1 on Human Bronchial and Alveolar Lung Mucosa Models: Implications for Pathogenicity.

BACKGROUND: The SARS-CoV-2 spike protein mediates attachment of the virus to the host cell receptor and fusion between the virus and the cell membrane. The S1 subunit of the spike glycoprotein (S1 protein) contains the angiotensin converting enzyme 2 (ACE2) receptor binding domain. The SARS-CoV-2 variants of concern contain mutations in the S1 subunit. The spike protein is the primary target of neutralizing antibodies generated following infection, and constitutes the viral component of mRNA-based COVID-19 vaccines. METHODS: Therefore, in this work we assessed the effect of exposure (24 h) to 10 nM SARS-CoV-2 recombinant S1 protein on physiologically relevant human bronchial (bro) and alveolar (alv) lung mucosa models cultured at air-liquid interface (ALI) (n = 6 per exposure condition). Corresponding sham exposed samples served as a control. The bro-ALI model was developed using primary bronchial epithelial cells and the alv-ALI model using representative type II pneumocytes (NCI-H441). RESULTS: Exposure to S1 protein induced the surface expression of ACE2, toll like receptor (TLR) 2, and TLR4 in both bro-ALI and alv-ALI models. Transcript expression analysis identified 117 (bro-ALI) and 97 (alv-ALI) differentially regulated genes (p ≤ 0.01). Pathway analysis revealed enrichment of canonical pathways such as interferon (IFN) signaling, influenza, coronavirus, and anti-viral response in the bro-ALI. Secreted levels of interleukin (IL) 4 and IL12 were significantly (p < 0.05) increased, whereas IL6 decreased in the bro-ALI. In the case of alv-ALI, enriched terms involving p53, APRIL (a proliferation-inducing ligand) tight junction, integrin kinase, and IL1 signaling were identified. These terms are associated with lung fibrosis. Further, significantly (p < 0.05) increased levels of secreted pro-inflammatory cytokines IFNγ, IL1ꞵ, IL2, IL4, IL6, IL8, IL10, IL13, and tumor necrosis factor alpha were detected in alv-ALI, whereas IL12 was decreased. Altered levels of these cytokines are also associated with lung fibrotic response. CONCLUSIONS: In conclusion, we observed a typical anti-viral response in the bronchial model and a pro-fibrotic response in the alveolar model. The bro-ALI and alv-ALI models may serve as an easy and robust platform for assessing the pathogenicity of SARS-CoV-2 variants of concern at different lung regions.

Management of bias and conflict of interest among occupational exposure limit expert groups.

Our aim was to evaluate policies and procedures for management of conflict of interest (CoI) and other sources of bias, implemented in Occupational Exposure Limit (OEL) expert groups. First, we compiled procedural criteria applicable to OEL-setting, based on literature on CoI and systematic reviews. Second, we identified 58 global OEL-sources and sought the underlying expert groups and operating procedures. We identified eleven active groups, of which five have documented CoI policies. In all five, CoI management is based on declarations of interests (DoIs) and removal of experts from decisions in which they have an interest. Notable differences include publication of DoIs (three of five groups), limitation of DoI to current interests (two groups), quantitative limits for financial interests (none specified to ≥€10,000 per interest), control procedures for undisclosed CoI (one group), and procedures in case of discovery of undisclosed CoI (three groups). Methods to evaluate study quality are described by three groups, while reproducible and comprehensive strategies to identify and select data receive less attention. We conclude that procedures to manage CoI and bias are not broadly implemented, or at least not openly and transparently communicated. This lack of visible procedures is remarkable, considering OEL's impact on health and economy.

Addressing the challenges of E-cigarette safety profiling by assessment of pulmonary toxicological response in bronchial and alveolar mucosa models.

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.

Analysis of Acrolein Exposure Induced Pulmonary Response in Seven Inbred Mouse Strains and Human Primary Bronchial Epithelial Cells Cultured at Air-Liquid Interface.

BACKGROUND: Acrolein is a major component of environmental pollutants, cigarette smoke, and is also formed by heating cooking oil. We evaluated the interstrain variability of response to subchronic inhalation exposure to acrolein among inbred mouse strains for inflammation, oxidative stress, and tissue injury responses. Furthermore, we studied the response to acrolein vapor in the lung mucosa model using human primary bronchial epithelial cells (PBEC) cultured at an air-liquid interface (ALI) to evaluate the findings of mouse studies. METHODS: Female 129S1/SvlmJ, A/J, BALB/cByJ, C3H/HeJ, C57BL/6J, DBA/2J, and FVB/NJ mice were exposed to 1 part per million (ppm) acrolein or filtered air for 11 weeks. Total cell counts and protein concentrations were measured in bronchoalveolar lavage (BAL) fluid to assess airway inflammation and membrane integrity. PBEC-ALI models were exposed to acrolein vapor (0.1 and 0.2 ppm) for 30 minutes. Gene expression of proinflammatory, oxidative stress, and tissue injury-repair markers was assessed (cut off: ≥2 folds; p < 0.05) in the lung models. RESULTS: Total BAL cell numbers and protein concentrations remained unchanged following acrolein exposure in all mouse strains. BALB/cByJ, C57BL/6J, and 129S1/SvlmJ strains were the most affected with an increased expression of proinflammatory, oxidative stress, and/or tissue injury markers. DBA/2J, C3H/HeJ, A/J, and FVB/NJ were affected to a lesser extent. Both matrix metalloproteinase 9 (Mmp9) and tissue inhibitor of metalloproteinase 1 (Timp1) were upregulated in the strains DBA/2J, C3H/HeJ, and FVB/NJ indicating altered protease/antiprotease balance. Upregulation of lung interleukin- (IL-) 17b transcript in the susceptible strains led us to investigate the IL-17 pathway genes in the PBEC-ALI model. Acrolein exposure resulted in an increased expression of IL-17A, C, and D; IL-1B; IL-22; and RAR-related orphan receptor A in the PBEC-ALI model. CONCLUSION: The interstrain differences in response to subchronic acrolein exposure in mouse suggest a genetic predisposition. Altered expression of IL-17 pathway genes following acrolein exposure in the PBEC-ALI models indicates that it has a central role in chemical irritant toxicity. The findings also indicate that genetically determined differences in IL-17 signaling pathway genes in the different mouse strains may explain their susceptibility to different chemical irritants.

Evaluation of diacetyl mediated pulmonary effects in physiologically relevant air-liquid interface models of human primary bronchial epithelial cells.

Diacetyl is an artificial flavouring agent, known to cause bronchiolitis obliterans. Diacetyl-induced pulmonary effects were assessed in human primary bronchial epithelial cells (PBEC) cultured at air-liquid interface (ALI). The PBEC-ALI models were exposed to clean air (sham) and diacetyl vapour (1, 3, 10 and 30 ppm) for 30 min. At 6 and 24 h post-exposure, cell medium was sampled for assessment of cytotoxicity measurement, and CXCL8, MMP9 secretion by ELISA. Pro-inflammatory, oxidative stress, tissue injury/repair, anti-protease and beta-defensin markers were assessed using qRT-PCR. Additionally, epidermal growth factor receptor ligands (amphiregulin) and anti-protease (SLPI) were analysed at 6 h, 8 h and 24 h post exposure to 1 and 10 ppm diacetyl. No significant cytotoxicity was observed at any exposure level. MMP9 was significantly increased in both apical and basal media at 24 h. Both SLPI and amphiregulin secretion were significantly increased following exposure to 10 ppm diacetyl. Exposure of PBEC-ALI model to diacetyl vapour resulted in significantly altered transcript expression of pro-inflammatory, oxidative stress, anti-protease, tissue injury/repair markers. Changes in transcript expression of significantly altered markers were more prominent 24 h post-exposure compared to 6 h. This study warrants further mechanistic investigations to elucidate the pulmonary effects of inhaled diacetyl vapour using physiologically relevant in vitro models.

Will worker DNELs derived under the European REACH regulation extend the landscape of occupational exposure guidance values?

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.

Down-regulation of the inflammatory response after short-term exposure to low levels of chemical vapours.

OBJECTIVE: To investigate the relation between signs and symptoms of irritation and biomarkers of inflammatory markers in blood in healthy volunteers exposed to different chemical vapours for 2 or 4 hours in an exposure chamber. METHODS: The investigated chemicals were: acetic acid (5 and 10 ppm), acrolein (0.05 and 0.1 ppm), 1,4-dioxane (20 ppm), n-hexanal (2 and 10 ppm), hydrogen peroxide (0.5 and 2.2 ppm), 2-propanol (150 ppm), m-xylene (50 ppm), standard and dearomatised white spirit (100 and 300 mg/m3). C reactive protein (CRP), serum amyloid A protein and interleukin 6 were measured in plasma immediately before and 2 or 4 hours after the exposures. Symptoms were rated from 0 to 100 mm in Visual Analogue Scales and covered 10 questions whereof four related to irritation: discomfort in the eyes, nose and throat and dyspnoea. The effect measurements included blink frequency by electromyography, nasal swelling by acoustic rhinometry and lung function by spirometry. RESULTS: Logistic quantile regression analyses revealed no significant associations except a negative relation between ratings of irritation and CRP. CONCLUSION: The results suggest a down-regulation of CRP after short-term exposure to low levels of vapours of irritating chemicals. This response might be mediated by the cholinergic anti-inflammatory pathway and further studies are recommended in order to refute or confirm this hypothesis.

Silica, silicosis and lung cancer: what level of exposure is acceptable?

Silica, silicosis and lung cancer: what level of exposure is acceptable?

Use of uncertainty factors by the European Commission Scientific Committee on Occupational Exposure Limits: a follow-up.

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.

Inflammatory effects of acrolein, crotonaldehyde and hexanal vapors on human primary bronchial epithelial cells cultured at air-liquid interface.

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/m3), crotonaldehyde (1.5-15mg/m3) or hexanal (22-221mg/m3) or under submerged conditions to acrolein (0.1 and 0.2mg/L), crotonaldehyde (1 and 2mg/L) or hexanal (10 and 20mg/L). Cell culture medium was collected 8h and 24h post-exposure and analyzed for interleukin-8 (IL-8) and matrix metalloprotein-9 (MMP-9). The gene expression of inflammatory and oxidative stress markers were measured 6h post-exposure. In the ALI setup, all three aldehydes caused increased secretion of IL-8, acrolein and crotonaldehyde also increased the gene expression of inflammatory and oxidative stress markers. In contrast, exposure under submerged conditions resulted in significantly reduced IL-8 secretion. The inflammatory response seen in the air phase exposures correspond well with previous in vivo studies. This indicates that lung models cultured at ALI are more suitable than submerged cell cultures in toxicity assessment studies of inhaled agents.

Measures of odor and lateralization thresholds of acrolein, crotonaldehyde, and hexanal using a novel vapor delivery technique.

INTRODUCTION: Humans are exposed to aldehydes in a variety of environmental situations. Aldehydes generally have a strong odor and are highly irritating to the mucous membranes. Knowledge about odor perception and especially irritation potency in humans is thus essential in risk assessment and regulation, e.g. setting occupational exposure limits. However, data on odor and irritation are lacking or limited for several aldehydes. The aim of the study was to determine the odor and lateralization thresholds of some commonly occurring aldehydes. Acrolein and crotonaldehyde where chosen as they are formed when organic material is heated or burned, e.g. during cigarette smoking. n-Hexanal was also included as it is emitted from wood pellets and fibreboard. MATERIAL AND METHODS: To study odor and lateralization thresholds of these aldehydes, a novel, inexpensive olfactometer was designed to enable delivery of reliable and stable test concentrations and thus valid measures of thresholds. The delivery system consists of seven syringe pumps, each connected to a Tedlar bag containing a predefined concentration of the tested aldehyde vapor. To validate the threshold measures, a test-retest was performed with a separate method, namely odor delivery via amber bottles. Twenty healthy naïve individuals were tested. RESULTS: The median odor thresholds of acrolein, crotonaldehyde and hexanal were 17, 0.8, and 97 ppb, respectively. No lateralization threshold could be identified for acrolein (highest tested concentration was 2 940 ppb in 5 subjects), whereas the medians were 3 and 390 ppb for the latter two. In addition, odor thresholds for n-hexanal were also determined using two methods where similar results were obtained, suggesting that the olfactometer presentation method is valid. CONCLUSION: We found olfactory detection and lateralization thresholds (except for acrolein) in alliance with, or lower than, previously reported in naïve subjects. The new olfactometer allows better control of presentations timing and vapor concentration.

Occurrence of Fumigants and Hazardous Off-gassing Chemicals in Shipping Containers Arriving in Sweden.

Containerized cargo shipment makes up the backbone of international trade. The principal aim of this cross-sectional study was to establish a qualitative and quantitative description of gaseous fumigants and volatile off-gassing substances facing workers tasked with entering shipping containers. A total of 372 packed and 119 empty shipping containers were sampled in six ports and two distribution centers in Sweden. Fourier-transform infrared spectrometry (FTIR) and photoionization detection (PID) were the analytical methods applied to the bulk of samples. A small number of adsorbent samples were analyzed using gas chromatography-mass spectrometry (GC-MS). The results were compared to Swedish occupational exposure limits (OELs), the closest parallel to relevant work situations. Based on the FTIR analyses, 30 of 249 (12%) containers arrived with concentrations of fumigants and off-gassing substances above the 8-h OELs and close to 7% were above the short-term exposure limits. Eight detected chemicals were classified as carcinogens and 4% of the containers arrived with levels of carcinogens above the OELs, at a maximum 30 times the 8-h OEL. Considerable differences were observed between ports, ranging from 0 to 33% of containers arriving with concentrations above the OELs. It is believed that all observation results, apart from a single instance of a confirmed fumigant, phosphine, at 3 p.p.m., and possibly three instances of carbon dioxide, can be attributed to off-gassing substances. The FTIR methodology proved useful for quick preliminary checks and in-depth screening and identification. The PID method produced both false-negative and false-positive results where only 48% matched the FTIR observations. Adsorbent sampling with GC-MS analysis was useful for confirming volatile organic compounds but was deemed too slow for day-to-day screening. The high frequency of contaminated containers, the detection of several carcinogens, and the sporadic occurrences of high levels of fumigants are serious concerns that need to be properly recognized in order to protect the workers at risk.

Physiologically-based toxicokinetic model for cadmium using Markov-chain Monte Carlo analysis of concentrations in blood, urine, and kidney cortex from living kidney donors.

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.

Using population physiologically based pharmacokinetic modeling to determine optimal sampling times and to interpret biological exposure markers: The example of occupational exposure to styrene.

BACKGROUND: Biomonitoring of chemicals in the workplace provides an integrated characterization of exposure that accounts for uptake through multiple pathways and physiological parameters influencing the toxicokinetics. OBJECTIVES: We used the case of styrene to (i) determine the best times to sample venous blood and end-exhaled air, (ii) characterize the inter-individual variability in biological levels following occupational exposure and (iii) propose biological limit values using a population physiologically based pharmacokinetic (PBPK) model. METHODS: We performed Monte Carlo simulations with various physiological, exposure and workload scenarios. Optimal sampling times were identified through regression analyses between levels in biological samples and 24-h area under the arterial blood concentration vs. time curve. We characterized the variability in levels of styrene in biological samples for exposures to a time weighted average (TWA) of 20ppm. RESULTS: Simulations suggest that the best times to sample venous blood are at the end of shift in poorly ventilated workplaces and 15min after the shift in highly ventilated workplaces. Exhaled air samples are most informative 15min after the shift. For a light workload, simulated styrene levels have a median (5th-95th percentiles) of 0.4mg/l (0.2-0.6) in venous blood at the end of shift and 0.5ppm (0.3-0.8) in exhaled air 15min after the end of shift. CONCLUSION: This study supports the current BEI(®) of the ACGIH of 0.2mg/l of styrene in venous blood at the end of shift and indicates a biological limit value of 0.3ppm in end-exhaled air 15min after the end of shift.