Distributions for time, interspecies and intraspecies extrapolation for deriving occupational exposure limits.

This work aimed at improving the empirical database of time (i.e., exposure duration), interspecies and intraspecies extrapolation when deriving occupational exposure limits (OELs). For each extrapolation step, a distribution was derived, which can be used to model the associated uncertainties. For time and interspecies extrapolation, distributions of ratios of dose descriptors were derived from studies of different length or species. National Toxicology Program (NTP) study data were manually assessed, and data from REACH (Registration, Evaluation and Authorisation of Chemicals) registration dossiers were evaluated semi-automatically. Intraspecies extrapolation was investigated by compiling published studies on human toxicokinetic and toxicodynamic variability. A new database was established for toxicokinetic differences in interindividual susceptibility, including many inhalation studies. Using NTP data produced more reliable results than using REACH data. The geometric mean (GM) for time extrapolation subacute/chronic agreed with previous evaluations (GM = 4.11), whereas the GM for subchronic/chronic extrapolation was slightly higher (GM = 2.93) than the GMs found by others. No significant differences were observed between systemically and locally acting substances. Observed interspecies differences confirmed the suitability of allometric scaling, with the derived distribution describing remaining uncertainty. Distributions of intraspecies variability at the 1% and 5% incidence level had medians of 7.25 and 3.56, respectively. When compared with assessment factors (AFs) currently used in the EU, probabilities that these AFs are protective enough span a wide range from 10% to 95%, depending on the extrapolation step. These results help to select AFs in a transparent and informed way and, by allowing to compare protection levels achieved, to harmonise methods for deriving OELs.

Derivation of occupational exposure limits: Differences in methods and protection levels.

Frameworks for deriving occupational exposure limits (OELs) and OEL-analogue values (such as derived-no-effect levels [DNELs]) in various regulatory areas in the EU and at national level in Germany were analysed. Reasons for differences between frameworks and possible means of improving transparency and harmonisation were identified. Differences between assessment factors used for deriving exposure limits proved to be one important reason for diverging numerical values. Distributions for exposure time, interspecies and intraspecies extrapolation were combined by probabilistic methods and compared with default values of assessment factors used in the various OEL frameworks in order to investigate protection levels. In a subchronic inhalation study showing local effects in the respiratory tract, the probability that assessment factors were sufficiently high to protect 99% and 95% of the target population (workers) from adverse effects varied considerably from 9% to 71% and 17% to 87%, respectively, between the frameworks. All steps of the derivation process, including the uncertainty associated with the point of departure (POD), were further analysed with two examples of full probabilistic assessments. It is proposed that benchmark modelling should be the method of choice for deriving PODs and that all OEL frameworks should provide detailed guidance documents and clearly define their protection goals by stating the proportion of the exposed population the OEL aims to cover and the probability with which they intend to provide protection from adverse effects. Harmonisation can be achieved by agreeing on the way to perform the methodological steps for deriving OELs and on common protection goals.

Lung function and self-rated symptoms in healthy volunteers after exposure to hydrotreated vegetable oil (HVO) exhaust with and without particles.

BACKGROUND: Diesel engine exhaust causes adverse health effects. Meanwhile, the impact of renewable diesel exhaust, such as hydrotreated vegetable oil (HVO), on human health is less known. Nineteen healthy volunteers were exposed to HVO exhaust for 3 h in a chamber with a double-blind, randomized setup. Exposure scenarios comprised of HVO exhaust from two modern non-road vehicles with 1) no aftertreatment system ('HVOPM+NOx' PM1: 93 µg m-3, EC: 54 µg m-3, NO: 3.4 ppm, NO2: 0.6 ppm), 2) an aftertreatment system containing a diesel oxidation catalyst and a diesel particulate filter ('HVONOx' PM1: ~ 1 µg m-3, NO: 2.0 ppm, NO2: 0.7 ppm) and 3) filtered air (FA) as control. The exposure concentrations were in line with current EU occupational exposure limits (OELs) of NO, NO2, formaldehyde, polycyclic aromatic hydrocarbons (PAHs), and the future OEL (2023) of elemental carbon (EC). The effect on nasal patency, pulmonary function, and self-rated symptoms were assessed. Calculated predicted lung deposition of HVO exhaust particles was compared to data from an earlier diesel exhaust study. RESULTS: The average total respiratory tract deposition of PM1 during HVOPM+NOx was 27 µg h-1. The estimated deposition fraction of HVO PM1 was 40-50% higher compared to diesel exhaust PM1 from an older vehicle (earlier study), due to smaller particle sizes of the HVOPM+NOx exhaust. Compared to FA, exposure to HVOPM+NOx and HVONOx caused higher incidence of self-reported symptoms (78%, 63%, respectively, vs. 28% for FA, p < 0.03). Especially, exposure to HVOPM+NOx showed 40-50% higher eye and throat irritation symptoms. Compared to FA, a decrement in nasal patency was found for the HVONOx exposures (- 18.1, 95% CI: - 27.3 to - 8.8 L min-1, p < 0.001), and for the HVOPM+NOx (- 7.4 (- 15.6 to 0.8) L min-1, p = 0.08). Overall, no clinically significant change was indicated in the pulmonary function tests (spirometry, peak expiratory flow, forced oscillation technique). CONCLUSION: Short-term exposure to HVO exhaust concentrations corresponding to EU OELs for one workday did not cause adverse pulmonary function changes in healthy subjects. However, an increase in self-rated mild irritation symptoms, and mild decrease in nasal patency after both HVO exposures, may indicate irritative effects from exposure to HVO exhaust from modern non-road vehicles, with and without aftertreatment systems.

Occupational exposure to volatile organic compounds affects microRNA profiling: Towards the identification of novel biomarkers.

In the framework of a project aimed at finding novel predictive biomarkers of VOCs exposure-related diseases, the effect of exposure to ethylbenzene, toluene, and xylene has been analyzed in a group of painters (spray- and roller-painters) working in the shipyard industry. Airborne levels of solvents were higher in spray- than in roller-painters, and comparable to the Occupational Exposure Limits (OELs), particularly for toluene and xylene. The urinary concentration of each volatile organic compound (VOC) and of the corresponding metabolites were also concurrently measured. A set of oxidative stress biomarkers, i.e., the products of DNA and RNA oxidation, RNA methylation, and protein nitration, were measured, and found significantly higher at the end of the work shift. MicroRNA (MiRNA) expression was analyzed in the VOC-exposed workers and in a control group, finding 56 differentially expressed (DE) miRNAs at a statistically significant level (adjusted p ≤ 0.01). The Receiver-Operating Characteristic curves, computed for each identified miRNA, showed high sensitivity and specificity. A pathway analysis in the Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that miRNA-1, which was found downregulated in exposed workers, is involved in the lung cancer oncogenesis. A subset of 10 miRNAs (out of the 56 DE) was selected, including those with the highest correlation to the urinary dose biomarkers measured at the end of work-shift. Multivariate ANOVA analysis showed a statistically significant correlation between the urinary dose biomarkers (both the VOCs urinary concentration and the VOCs' metabolite concentration), and the identified miRNA subset, indicating that the exposure to low VOC doses may be sufficient to activate the miRNA response. Four miRNAs belonging to the subset strongly related to the VOCs and VOCs' metabolites concentration were individuated, miR-589-5p, miR-941, miR-146b-3p and miR-27a-3p, with well-known implications in oxidative stress and inflammation processes.

Threshold and non-threshold chemical carcinogens: A survey of the present regulatory landscape.

For the proper regulation of a carcinogenic material it is necessary to fully understand its mode of action, and in particular whether it demonstrates a threshold of effect. This paper explores our present understanding of carcinogenicity and the mechanisms underlying the carcinogenic response. The concepts of genotoxic and non-genotoxic and threshold and non-threshold carcinogens are fully described. We provide summary tables of the types of cancer considered to be associated with exposure to a number of carcinogens and the available evidence relating to whether carcinogenicity occurs through a threshold or non-threshold mechanism. In light of these observations we consider how different regulatory bodies approach the question of chemical carcinogenesis, looking in particular at the definitions and methodologies used to derive Occupational Exposure Levels (OELs) for carcinogens. We conclude that unless proper differentiation is made between threshold and non-threshold carcinogens, inappropriate risk management measures may be put in place - and lead also to difficulties in translating carcinogenicity research findings into appropriate health policies. We recommend that clear differentiation between threshold and non-threshold carcinogens should be made by all expert groups and regulatory bodies dealing with carcinogen classification and risk assessment.

Influence of frying oil type and chill storage on the nutritional quality of farmed great sturgeon (Huso huso) / Influência do tipo de óleo de fritura e armazenamento a frio na qualidade nutricional do esturjão branco (Huso huso) de cativeiro

OBJECTIVE: The objective of this study was to investigate the effect of frying oils (canola, hydrogenated sunflower and soybean oils) available commercially and chill storage on the proximate and fatty acid composition of fried slices of farmed great sturgeon (Huso huso). METHODS: Slices of farmed great sturgeon were fried for four minutes at 160ºC in a deep-fryer using different frying oils (canola, hydrogenated sunflower and soybean oils). The oil-to-slice ratio was 2:1. After frying, the slices were allowed to be air cooled for two minutes prior to analysis. For performing the analysis, each of the abovementioned batches was divided into two groups: one group was analysed immediately after frying and the second group was chill-stored at 4ºC for three days and then analysed. RESULTS: After frying, the moisture content decreased while that of fat increased. Fatty acid composition of the slices is affected by type of frying oil. Frying increased the omega-6-to-omega-3 (n-6:n-3) fatty acid ratio while decreased Eicosapentaenoic Acid (C20:5 n-3) and Docosahexaenoic Acid (C22:6 n-3) contents. Proximate and fatty acid composition of raw slices did not change after chill storage. However, in fried- and chill-stored slices, Eicosapentaenoic Acid and Docosahexaenoic Acid contents decreased, while linoleic acid content increased. CONCLUSION: The fatty acid composition of the fried slices tended to resemble that of the frying oils, indicating fatty-acid equilibrium between oils and slices and, during chill storage, it is influenced by the type of frying oil. Slices fried with canola oil had omega-6-to-omega-3 ratios in the ranges recommended for human health.

OBJETIVO: O objetivo deste estudo foi investigar o efeito de óleos de fritura (canola, girassol hidrogenado e soja) disponíveis comercialmente e do armazenamento a frio em postas fritas de beluga (Huso huso), e na composição centesimal e lipídica. MÉTODOS: Postas de beluga de cativeiro foram fritas por imersão durante quatro minutos a 160ºC utilizando-se óleos de fritura diferentes (canola, girassol hidrogenado e soja). A razão entre óleo e postas foi de 2:1. Após a fritura, permitiu-se que as postas esfriassem a temperatura ambiente por dois minutos antes da análise. Para a análise, cada um dos grupos acima foi dividido em dois subgrupos: um subgrupo foi analisado imediatamente após a fritura e o segundo subgrupo foi armazenado resfriado a uma temperatura de 4ºC por três dias e então analisado. RESULTADOS: Após a fritura, o conteúdo da umidade diminuiu enquanto que da gordura aumentou. A composição dos ácidos graxos das postas foi afetada pelo tipo de óleo utilizado na fritura. A fritura aumentou a razão omega-6 para omega-3 e diminuiu os conteúdos dos Ácidos Eicosapentaenoico (C20:5 n-3) e Docosahexaenoico (C22:6 n-3). As composições centesimal e lipídica das postas cruas não se alteraram após o armazenamento a frio. Porém, os conteúdos de Ácidos Eicosapentaenoico e Docosahexaenoico nas postas fritas e resfriadas diminuíram, enquanto que de ácido linoleico aumentou. CONCLUSÃO: A composição lipídica das postas fritas tendeu à semelhança do óleo utilizado para a fritura, indicando um equilíbrio de ácidos graxos entre os óleos e as postas. A composição lipídica das postas durante o armazenamento a frio é influenciada pelo tipo de óleo de fritura. Postas fritas com óleo de canola continham uma razão de ômega-6 para ômega-3 dentro do intervalo recomendado para a saúde humana.