No-effect Level Research Articles

Occupational exposure limits for reproductive toxicants – A comparative analysis

We investigated the level of protection of reproductive and developmental toxicity offered through occupational exposure limits (OELs) and Derived No-Effect Levels for workers’ inhalation exposure (wDNELs). We compared coverage of substances that have a harmonised classification as reproductive toxicant 1 A or 1B (Repr.1 A/B), numerical values and scientific basis of 12 lists of OELs and wDNELs from REACH Registrants’ and the Committee for Risk Assessment. Across the 14 sources of OELs and wDNELs, 53 % of the Repr1A/B-substances had at least one exposure limit (counting groups of metals as one entry). Registrants’ wDNELs covered the largest share, 40 %. The numerical values could be highly variable for the same substance across the lists. How often reproductive toxicity is identified as the critical effect varies between the examined lists, both due to different assessments of the same substance and different substance coverage. Reviewing the margin of safety to reproductive toxicity cited in the documents, we found that 15 % of safety margins were lower to reproductive toxicity than the critical effect. To conclude, neither the REACH nor work environment legislation supply wDNELs or OELs for a substantial share of known reproductive toxicants. EU OELs cover among the fewest substances in the range, and in many cases national OELs or wDNELs are set at more conservative levels.

Effects of organic degradation products on the migration behaviour of radionuclides in cementitious materials

The impact of phthalates, which might be present in a cementitious repository as degradation products of superplasticisers or PVC additives, on the migration behaviour of An(III)/Ln(III) was investigated in batch sorption experiments on hardened cement paste. In the absence of organics, An(III)/Ln(III) sorb strongly on HCP with distribution ratios, Rd, of 105 to 106 L kg−1. Above a no-effect level of ~ 10–3 mol L−1 phthalate, a distinct decrease of the An(III)/Ln(III) sorption was observed with sorption reduction factors (i.e., the ratio between the Rd values without and with organic ligand) of 100 to 1000 at phthalate concentrations of 10–1 mol L−1. This sorption reduction is attributed to the effect of Ca complexation with phthalate on the stability of calcium silicate hydrate (C–S–H) phases as main sorbing phase. These results and ongoing diffusion experiments indicate an increase in the mobility of An(III)/Ln(III) in cementitious barriers with increasing phthalate concentrations.Graphical abstract

Assessment of the suitability of selected non-measuring models for dermal exposure estimation for the purposes of assessing compliance of working conditions with restrictions 71 and 76 in Annex XVII of the REACH regulation

Occupational exposure to chemicals occurs mainly through inhalation and the skin. The inhalation exposure assessment is regulated by law, while in Poland the method of conducting measurements for dermal exposure has not been indicated in the law. However, due to the restrictions 71 and 76 from Annex XVII of REACH for 1-methyl-2-pyrrolidone (NMP) and N,N-dimethylformamide (DMF), exposure assessment by the dermal route is necessary. These restrictions require to ensure that exposure of workers is below the derived no-effect levels (DNELs) for dermal exposure. The aim of the work was assessment of suitability of selected non-measurement forecasting models for the estimation of dermal occupational exposure to chemicals for the purposes of assessing compliance of working conditions with the restrictions 71 and 76 of the REACH regulation. Three tools estimating dermal exposure, recommended by European Chemical Agency (ECHA), were selected: ECETOC TRA, RISKOFDERM and IH SkinPerm, which were used to estimate 2 exemplary workplaces. Results of the estimations of dermal exposure showed that non-measuring models are useful for fulfilling the obligations under restrictions 71 and 76 of Annex XVII of REACH. The type of exposure scenario and amount of data available for the workplace are crucial for the selection of the model. The ECETOC TRA was considered the best model for this type of analysis, whose main advantages are direct comparison of the output data in mg/kg/day with the DNEL value and use of standardized descriptors system. Exposure modeling is a good and cheap way to determine the dermal exposure magnitude at workplaces, also to comply with the requirements of restrictions 71 and 76 of Annex XVII of REACH. The application of modeling in the case of occupational exposure by the dermal route is one of the solutions when it is necessary to comply with the DNEL for dermal exposure. Med Pr Work Health Saf. 2023;74(6):487-500.

Increasing exposure to the UV filters octocrylene and 2-ethylhexyl salicylate in Germany from 1996 to 2020: Human biomonitoring in 24-h urine samples of the German Environmental Specimen Bank (ESB)

The UV filters octocrylene (OC) and 2-ethylhexyl salicylate (EHS) are commonly used in sunscreens and frequently detected in environmental media. However, knowledge on human exposures is scarce.In this human biomonitoring (HBM) study, we analyzed concentrations of exposure biomarkers specific to OC (CPAA, DOCCA, 5OH-OC) and EHS (5OH-EHS, 5oxo-EHS, 5cx-EPS) in 24-h urine samples (n = 420) from the German Environmental Specimen Bank (ESB). These samples were collected from German students (20–29 years; 30 males/30 females per year) between 1996 and 2020 (4-year intervals; collection in winter).We found continuously increasing OC and EHS exposures (Jonckheere-Terpstra; p < 0.001) documented by very few to no samples with concentrations of the most sensitive biomarkers CPAA and 5cx-EPS above the limit of quantification (LOQ) in 1996 (5 % and 0 %, respectively) and reaching 100 % and 93 % above the LOQ in 2016, with median concentrations of 4.79 and 0.071 µg/L, respectively. In 2020, biomarker concentrations slightly decreased to 3.12 µg/L CPAA (97 %>LOQ) and 0.060 µg/L 5cx-EPS (88 %>LOQ). This general trend was confirmed by the other biomarkers, however at lower detection rates. Based on metabolite excretion in the 24-h urine samples and human toxicokinetic data, we calculated maximum daily intakes (DI) of 17 µg/(kg bw * d) OC and 59 µg/(kg bw * d) EHS. Based on a derived no-effect level (DNEL) of 0.8 mg/(kg bw * d), the OC exposures of individuals in our study did not indicate any health risk. Similarly, for EHS all biomarker concentrations were well below the HBM-I values of 12 µg/L 5OH-EHS and 11 µg/L 5cx-EPS.Our data proves the general applicability of specific OC and EHS metabolites for HBM in the general population and shows clearly increasing exposures. Higher (co-)exposures must be expected in populations with increased sunscreen use such as (summer) vacationers, children and outdoor workers.

Is there a No-Effect Level (NEL) for adverse effects on electromechanical components by volatile siloxanes?

Emissions from silicone elastomers, used as seals and adhesives, may impair the function of electrical contact surfaces in electromechanical components, a phenomenon that has been known for a long time. At the same time, the automotive industry heavily relies on the very good properties of silicones. Hence, a detailed risk assessment is necessary when using silicones. Therefore, we investigated the reliability of a relays when operated in a siloxane gas atmosphere. To elucidate failure mechanisms, the failed relays were analysed by optical microscopy, SEM, EDX and FIBS. In the reliability experiments, the siloxane concentration and type, current strength, humidity and temperature were varied to evaluate their specific impact. The overall aim was to search for a No-Effect Level (NEL) below which there is no negative impact on the service life of the relay.

Risk assessment of the asthma-induction potential of substances in spray products for car cabin detailing – based on EU’s Chemical Agents Directive, using harmonised classifications and quantitative structure-activity relationship (QSAR)

Exposure to spray-formulated products for car cabin detailing is a potential risk for asthma induction. With a focus on the asthma-related endpoints sensitisation and irritation of the lungs, we performed an occupational risk assessment based on requirements in the EU Chemical Agents Directive. We identified 71 such spray products available in Denmark. We identified ingredient substances in safety data sheets and screened for harmonised classifications of respiratory sensitisation and airway irritation. For respiratory sensitisation, we also applied quantitative structure-activity relationship (QSAR). We modelled the exposure during 15 min of work inside a car cabin, and determined the risk ratio of the products by further applying occupational exposure limits – mainly derived no-effect levels (DNELs) from the European Chemicals Agency (ECHA) set on respiratory irritation. Four substances had a harmonised classification for respiratory irritation (bronopol, 2-phenoxyethanol, 2-methoxypropanol, and butan-1-ol). Seven substances were positive in the QSAR model for respiratory sensitisation (monoethanolamine, bronopol, glycerol, methyl salicylate, benzoic acid, ammonium benzoate, and sodium benzoate). Two vinyl treatment products had a risk ratio > 1 based on the level of sodium benzoate and its DNEL set on respiratory irritation. Two products had risk ratios of 0.69 and 0.73, respectively, based on 2-methyl-2 H-isothiazol-3-one and its acute DNEL set on respiratory irritation. In conclusion, 10 substances that may pose a risk for asthma induction were identified in the products. Two of the 71 products had a risk ratio > 1, meaning they may pose an asthma-induction risk in the modelled exposure scenario and using respiratory irritation DNELs from ECHA.

Monitoring the exposure to ethoxyquin between 2000 and 2021 in urine samples from the German Environmental Specimen Bank

Human Biomonitoring (HBM) of emerging chemicals gained increasing attention within the EU in recent years. After evaluating the metabolism, we established a new HBM method for ethoxyquin (EQ), a feed additive, which was banned in 2017 due to concerns regarding the possible exposure of the general population to it and its highly toxic precursor p-phenetidine. The method was applied to 250 urine samples from the Environmental Specimen Bank collected between 2000 and 2021. The major metabolite EQI was quantified in the majority of the study samples illustrating the ubiquitous exposure of the non-occupationally exposed population. A rather constant exposure was observed until 2016 with a significant decline from 2016 to 2021. This drop falls within the EU wide ban of the chemical as a feed additive from June 2017 which led to a gradual removal until its complete suspension in June 2020. The daily intake (DI) was evaluated with respect to the reported derived no-effect level (DNEL) to estimate the potential health risks from EQ exposure. The median DI of 0.0181 µg/kg bw/d corresponds to only 0.01 % of the DNEL. Even the observed maxima up to 13.1 µg/kg bw/d only accounted for 10 % of the DNEL. Nevertheless, the values suggest a general exposure with the risk of higher burden in a low fraction of the population. In regard to the EQ associated intake of the carcinogen and suspected mutagen p-phenetidine, this level of exposure cannot be evaluated as safe. The recent decrease and the broad exposure substantiate the need for future HBM campaigns in population representative studies to further investigate the observed reductions, potentially find highly exposed subgroups and clarify the impact of the ban as feed additive on EQ exposure.

Modelling the attenuation of flowback chemicals for a soil-groundwater pathway from a hypothetical spill accident

Flowback water from shale gas operations contains formation-derived compounds, including trace metals, radionuclides, and organics. While accidental releases from storage tanks with flowback water are low-probability events if multiple containment barriers are put in place, they cannot be entirely excluded. Here the natural attenuation potential of deep unsaturated zones and groundwater was explored using predictive modelling involving a hypothetical leak from a storage tank. Actual chemical concentrations from flowback water at two shale gas wells with contrasting salinity (12,300 and 105,000 ppm TDS) in the Beetaloo Sub-basin (Northern Territory, Australia) served as input to the one-dimensional HYDRUS model for simulating chemical transport through the unsaturated zone, with groundwater at 50 and 100 m depth, respectively. Subsequent chemical transport in groundwater involved the use of a three-dimensional analytical transport model. For a total of 63 chemicals the long-term attenuation from dilution and dispersion in unsaturated sediments and groundwater was calculated. Predicted environmental concentrations for aquatic receptors were compared with no-effect levels of individual chemicals to derive risk quotients (RQ) and identify chemicals of no concern to ecosystem health (i.e. RQ <1). Except for salinity and radium-228 in one of the two wells, RQ < 1 for all other chemicals. The initial approach considered testing of toxicity to individual chemicals only. When direct toxicity assessments (DTAs) were used to account for effects of chemical mixtures, the required DTA-derived safe dilution factor for 95% species protection was 1.8 to 2.5 times higher than the dilution factor accounting for dispersion and dilution only. Accounting for biodegradation, sorption and radioactive decay decreased chemical concentrations in unsaturated sediments to safe levels using the DTA for all chemicals. The study highlighted the importance of incorporating DTA in chemical risk assessments involving complex chemical mixtures. Improved understanding of fate and transport of flowback chemicals will help effectively manage water-quality risks associated with shale gas extraction.

Association between Urinary Metabolites and the Exposure of Intensive Care Newborns to Plasticizers of Medical Devices Used for Their Care Management.

Care management of newborns in the neonatal intensive care unit (NICU) requires numerous PVC (PolyVinyl Chloride) medical devices (MD) containing plasticizers that can migrate and contaminate the patient. We measured the magnitude of neonates’ exposure to plasticizers (di-ethylhexylphthalate (DEHP) and alternatives) in relation to urinary concentrations of their metabolites. Plasticizers’ exposure was evaluated (1) by calculating the amounts of plasticizers prone to be released from each MD used for care management, and (2) by measuring the patients’ urinary levels of each plasticizers’ metabolites. 104 neonates were enrolled. They were exposed to di-isononylphthalate (DINP), especially via transfusion and infusion MD, and to DEHP via ECMO (Extra Corporeal Membrane Oxygenation) and respiratory assistance MD. Mean exposure doses exceeded the derived no-effect level of DINP and DEHP by a 10-fold and a 1000-fold factor. No PVC MD were plasticized with di-isononylcyclohexane-1,2-dicarboxylate (DINCH). High urinary concentrations of DEHP metabolites were directly correlated with DEHP exposure through ECMO MD. Urinary concentrations of DINP metabolites in transfused patients were also high. DINCH metabolites were found in urine, suggesting another route of exposure. Neonates in NICU are considerably exposed to plasticizers, with magnitudes varying with the type of MD used. The high exposure to DEHP and DINP leads to a risk of their metabolites’ toxicity.

Development of a Method for Simultaneous Analysis of Allergenic Flavoring Agents in Cigarettes and Quantitative Risk Assessment for Consumer Safety.

Flavoring agents are added to cigarettes to improve taste. There are mostly permitted food additives, but some of them are restricted for use in food, cosmetics, and toys, since they can cause allergic reactions. Previous studies have investigated the levels of flavoring agents in tobacco but none has focused on their content in filter tips and capsules. Moreover, no studies have assessed the risk of adding allergenic flavoring agents in cigarettes. Here, we developed and validated a simultaneous analysis method for 25 allergenic flavoring agents and menthol with gas chromatography–tandem mass spectrometry to determine levels of flavoring agents in the tobacco, filter tips, and capsules of 54 commercial cigarettes in Korea. All cigarettes contained at least one allergenic flavoring agent regardless of the inclusion of flavoring capsules. Importantly, the filter tips and the capsules contained higher levels of flavoring agents than tobacco, highlighting the importance of the quantification of flavoring agents in these parts of cigarettes. Nevertheless, the risk assessment based on their levels in cigarettes suggested that their exposure was maintained at a safe level. However, the risk assessed from maximum menthol, linalool, and cinnamaldehyde exceeded one-tenth of derived no-effect levels, suggesting the need for further studies on their risk to human health.

Under the influence of regulations: spatio-temporal trends of the UV filter 2-Ethylhexyl-4-methoxycinnamate (EHMC) in German rivers

BackgroundGlobally, 2-Ethylhexyl-4-methoxycinnamate (EHMC) is one of the most commonly used UV filters in sunscreen and personal care products. Due to its widespread usage, the occurrence of EHMC in the aquatic environment has frequently been documented. In the EU, EHMC is listed under the European Community Rolling Action Plan (CoRAP) as suspected to be persistent, bioaccumulative, and toxic (PBT) and as a potential endocrine disruptor. It was included in the first watch list under the Water Framework Directive (WFD) referring to a sediment PNEC of 200 µg/kg dry weight (dw). In the light of the ongoing substance evaluation to refine the environmental risk assessment, the objective of this study was to obtain spatio-temporal trends for EHMC in freshwater.We analyzed samples of suspended particulate matter (SPM) retrieved from the German environmental specimen bank (ESB). The samples covered 13 sampling sites from major German rivers, including Rhine, Elbe, and Danube, and have been collected since mid-2000s.ResultsOur results show decreasing concentrations of EHMC in annual SPM samples during the studied period. In the mid-2000s, the levels for EHMC ranged between 3.3 and 72 ng/g dw. The highest burden could be found in the Rhine tributary Saar. In 2017, we observed a maximum concentration ten times lower (7.9 ng/g dw in samples from the Saar). In 62% of all samples taken in 2017, concentrations were even below the limit of quantification (LOQ) of 2.7 ng/g dw.ConclusionsThe results indicate a general declining discharge of EHMC into German rivers within the last 15 years and correspond to the market data. Although the measured levels are below the predicted no-effect level (PNEC) in sediment, further research should identify local and seasonal level of exposure, e.g., at highly frequented bathing waters especially in lakes. In addition, possible substitutes as well as their potentially synergistic effects together with other UV filters should be investigated.

Exposure Assessment of Toxicologically Relevant Volatile Organic Compounds Emitted from Polymer-Based Costume Masks.

Plastic costume masks regularly exhibit unpleasant odors that may be associated with the emissions of volatile organic compounds (VOCs). Upon inhalation, VOCs might adversely affect the wearer's health if the exposure exceeds regulatory threshold values. The VOCs emitted from a selection of costume masks (n = 12) were characterized semiquantitatively with a screening method based on GC/MS measurements in dynamic headspace sampling mode. Furthermore, odors associated with the masks were evaluated by a sensory panel. Two masks emitted particularly high concentrations of ethylbenzene, xylenes, and cyclohexanone and exhibited the most intense and unpleasant odors, which were described as rubber-like, pungent, and leather-like. To simulate and assess the inhalation exposures for wearers of these masks, an innovative experimental setup based on a doll's head was developed, with sampling of emitted volatiles on adsorption material and subsequent analysis by thermal desorption-GC/MS. The measured inhalable concentrations of cyclohexanone exceeded the derived no-effect level (DNEL) for systemic effects on the general population over several hours of wearing, and also after repeated use. Importantly, the cyclohexanone DNEL was reevaluated in relation to a recent study on inhalation toxicity in rodents and was found to be significantly lower (1.4 mg·m-3) compared to the industry-derived values (10-20 mg·m-3), thus aggravating the health risks associated with inhalation exposure from some of the costume masks tested. Finally, a comparison of the inhalable concentrations derived from the simulated exposure assessments with those derived from measurements in miniaturized emission test chambers indicate that microchambers represent a useful tool for high-throughput analysis. The influences of temperature and inhalation/exhalation flow rates on VOC exposures were also studied.

The REACH registration process: A case study of metallic aluminium, aluminium oxide and aluminium hydroxide

The European Union’s REACH Regulation requires determination of potential health and environmental effects of chemicals in commerce. The present case study examines the application of REACH guidance for health hazard assessments of three high production volume (HPV) aluminium (Al) substances: metallic aluminium, aluminium oxide, and aluminium hydroxide. Among the potential adverse health consequences of aluminium exposure, neurotoxicity is one of the most sensitive targets of Al toxicity and the most critical endpoint. This case study illustrates integration of data from multiple lines of evidence into REACH weight of evidence evaluations. This case study then explains how those results support regulatory decisions on classification and labelling. Challenges in the REACH appraisal of Al compounds include speciation, solubility and bioavailability, application of assessment factors, read-across rationale and differences with existing regulatory standards. Lessons learned from the present case study relate to identification and evaluation of toxicologic and epidemiologic data; assessing data relevance and reliability; development of derived no-effect levels (DNELs); addressing data gaps and preparation of chemical safety reports.

Human biomonitoring in urine samples from the Environmental Specimen Bank reveals a decreasing trend over time in the exposure to the fragrance chemical lysmeral from 2000 to 2018

2-(4-tert-butylbenzyl)propionaldehyde (trade names, e.g. lysmeral or lilial) is a fragrance chemical frequently used in cosmetic products where it is labelled as Butylphenyl methylpropional. A recently developed LC-MS/MS method for the analysis of four lysmeral metabolites (tert-butylbenzoic acid (TBBA), lysmerol, lysmerylic acid, and hydroxy-lysmerylic acid) was applied to 329 urine samples from the Environmental Specimen Bank collected between 2000 and 2018. The two major metabolites TBBA and lysmerol were found in quantifiable concentrations in almost all samples in this study and correlated significantly. Hence, both analytes proved to be specific biomarkers indicating the broad exposure to lysmeral. A significant decline was found for TBBA and lysmerol for the monitored years with the most pronounced decrease from 2012 to 2015. The daily intake (DI) was used to evaluate potential health risks with respect to the derived no-effect level (DNEL) as a threshold for exposure of the general population. The median DI (1.63 μg/kg bw/d) and the 95th percentile (4.69 μg/kg bw/d) corresponded to 2.6% and 7.5% of the lowest DNEL (62.5 μg/kg bw/d for oral administration), respectively. Even though a decreasing trend in exposure was observed the data still calls for efforts to reduce the exposure towards lysmeral since metabolites of lysmeral were detected in nearly all samples and adverse effects cannot be excluded. Clearly, these results need to be substantiated by HBM campaigns in population representative samples like the German Environmental Survey in adults (GerES VI) to provide more robust data for the adult population.

Non-occupational exposure to phthalates in Finland

The aim of this study was to assess phthalate exposure of non-occupationally exposed working aged population in Finland. Studied phthalates included diethyl phthalate (DEP), di-n-butyl phthalate (DnBP), diisobutyl phthalate (DiBP), benzyl butyl phthalate (BzBP), dicyclohexyl phthalate (DCHP), di(2-ethylhexyl) phthalate (DEHP), diisononyl phthalate (DiNP), diisodecyl phthalate (DiDP), di(2-propylheptyl) phthalate (DPHP), and di-n-octyl phthalate (DnOP). Sample collection campaign took place in 2015.Metabolites of DEP, DnBP and DiBP were detected in all the first morning void urine samples of the non-occupationally exposed volunteers (n = 60; 42 women and 18 men; aged 25–63). Metabolite of BBP and secondary metabolites of DEHP and DiNP were detected in >90% of the samples. MCHP (1.7%), MEHP (18.3%), cx-MiNP (8.3%) and MnOP (1.7%) were less frequently detected. MiNP and OH-MPHP were not detected in any of the urine samples.The observed levels were mostly comparable to the levels published in the adult population in Europe and the US. One notable difference was the observed higher exposure of the Finnish study population to DnBP in comparison to the German, Austrian, Norwegian and US populations. The levels of individual phthalates did not often correlate very well with each other. In most cases, higher exposure to phthalates was seen in females in comparison to males, which is in accordance with other studies.The urinary levels were compared to the biomonitoring equivalents (BEs), which were calculated on the basis of published DNELs (derived no-effect levels). The P95 levels of individual phthalates remained below the respective BEs, the highest risk characterization ratio (RCR) being 0.88 for DnBP and the second highest 0.34 for DiBP. For other phthalates, the RCRs were below 0.2. Using the P95 levels, combined exposure to DnBP, DiBP, DEHP and BBP resulted in risk characterization ratio exceeding 1. This suggests a need to limit the exposure to these phthalates.

Comparison between Communicated and Calculated Exposure Estimates Obtained through Three Modeling Tools.

This study aims to evaluate the risk assessment approach of the REACH legislation in industrial chemical departments with a focus on the use of three models to calculate exposures, and discuss those factors that can determine a bias between the estimated exposure (and therefore the expected risk) in the extended safety data sheets (e-SDS) and the expected exposure for the actual scenario. To purse this goal, the exposure estimates and risk characterization ratios (RCRs) of registered exposure scenarios (ES; “communicated exposure” and “communicated RCR”) were compared with the exposure estimates and the corresponding RCRs calculated for the actual, observed ES, using recommended tools for the evaluation of exposure assessment and in particular the following tools: (i) the European Centre for Ecotoxicology and Toxicology of Chemicals Targeted Risk Assessment v.3.1 (ECETOC TRA), (ii) STOFFENMANAGER® v.8.0 and (iii) the Advanced REACH Tool (ART). We evaluated 49 scenarios in three companies handling chemicals. Risk characterization ratios (RCRs) were calculated by dividing estimated exposures by derived no-effect levels (DNELs). Although the calculated exposure and RCRs generally were lower than communicated, the correlation between communicated and calculated exposures and RCRs was generally poor, indicating that the generic registered scenarios do not reflect actual working, exposure and risk conditions. Further, some observed scenarios resulted in calculated exposure values and RCR higher than those communicated through chemicals’ e-SDSs; thus ‘false safe’ scenarios (calculated RCRs > 1) were also observed. Overall, the obtained evidences contribute to doubt about whether the risk assessment should be performed using generic (communicated by suppliers) ES with insufficient detail of the specific scenario at all companies. Contrariwise, evidences suggested that it would be safer for downstream users to perform scenario-specific evaluations, by means of proper scaling approach, to achieve more representative estimates of chemical risk.

Assessment of respiratory and systemic toxicity of Benzalkonium chloride following a 14-day inhalation study in rats

BackgroundAlthough biocides at low concentrations have been used to control pests, they can be more harmful than industrial chemicals as humans are directly and frequently exposed to such biocides. Benzalkonium chloride (BAC or BKC) is a non-toxic substance used to control pests. Recently, BAC has been increasingly used as a component in humidifier disinfectants in Korea, raising a serious health concern. Moreover, it poses significant health hazards to workers handling the chemical because of direct exposure. In the present study, we aimed to evaluate the respiratory toxicity of BAC due to its inhalation at exposure concentrations of 0.8 (T1 group), 4 (T2 group) and 20 (T3 group) mg/m3.ResultsIn our previous study on the acute inhalational toxicity of BAC, bleeding from the nasal cavity was observed in all the rats after exposure to 50 mg/m3 BAC. Therefore, in this study, 20 mg/m3 was set as the highest exposure concentration, followed by 4 and 0.8 mg/m3 as the medium and low concentrations for 6 h/day and 14 days, respectively. After exposure, recovery periods of 2 and 4 weeks were provided. Additionally, alveolar lavage fluid was analyzed in males of the BAC-exposed groups at the end of exposure and 2 weeks after exposure to evaluate oxidative damage.In the T3 group exposed to BAC, deep breathing, hoarseness, and nasal discharge were observed along with a decline in feed intake and body weight, and nasal discharge was also observed in the T1 and T2 groups. ROS/RNS, IL-1β, IL-6, and MIP-2 levels decreased in a concentration-dependent manner in the bronchoalveolar lavage fluid. Histopathological examination showed cellular changes in the nasal cavity and the lungs of the TI, T2, and T3 groups.ConclusionsAs a result, it was confirmed that the target organs in the respiratory system were the nasal cavity and the lungs. The adverse effects were evaluated as reversible responses to oxidative damage. Furthermore, the no observed adverse effect level was found to be less than 0.8 mg/m3 and the lowest benchmark dose was 0.0031 mg/m3. Accordingly, the derived no-effect level of BAC was calculated as 0.000062 mg/m3.

Značaj i procena benchmark doze u toksikologiji

This paper aims to present the importance of the benchmark dose (BMD) as a point of departure (the lowest dose or concentration in the experiment that deviates from the response that differs from the normal response) in toxicological risk assessment, as well as to present commonly used software for its calculation (BMDS and PROAST). Benchmark dose is defined as a statistical lower confidence limit of a dose that results in a small change in effect (5-10%) in comparison with the control value. The BMD approach is considered a substitution for the NOAEL approach, which uses the highest observed no-effect level (NOAEL) to obtain the reference dose. The BMD approach is a methodically more forward-thinking technique than the NOAEL approach because it has statistical power and provides a wide range of dose-response relationships and allows the determination of their uncertainty and variability. Moreover, the BMD approach contributes to the reduction of experimental animals in toxicity studies. Therefore, the European Food Safety Authority (EFSA) recommends the use of BMDL10 values for quantal and BMDL05 for continuous data.

Actual problem of methodology and development of evidence-based health risk assessment associated with chemical exposure

Paramount problems of the development of the assessment of population health risks associated with the chemical exposure in Russia are considered on the ground of critical analysis of reports devoted to methodological issues of the risk assessment and guidelines published since 2010. Causes of the lack in progress of risk assessment are discussed. The information of executed research revealed the significant retardation number of Russian publications devoted to the evidence-based health risk assessment compare to worldwide trend. The analysis of publications according to evidence-based health risk assessment in Russia in 1998 - 2012 demonstrated methodical problems to be leading to the underestimation of the real risk to population’s health. There are demonstrated directions in the renewal of methodology and practice of hygienic standardization on the basis of the risk assessment. The comparative analysis of values of uncertainty factors (modifying factors, conversion factors) used for extrapolation and accepted in different countries and organizations was made. The system of extrapolation coefficients of DNEL (Derive No-Effect Level) is presented. The leading principles of modern toxicology and risk assessment based on strict scientific proofs are showed. Criteria of evidence-based toxicology and risk assessment are presented.Among actual problems which demand their decision there are considered: the assessment of combined action in regulatory toxicology; expansion of spheres of the application of health risk assessment methodology; the improvement ofpreparation and certification of experts in the field of health risk assessment; need of check of dispersion models and their replacement by more modern models; the improvement of exposure assessment with taking into account the international requirements; the assessment of regional exposure factors; expansion of atmospheric air monitoring in all the large cities of Russia.

Setting surface wipe limits for skin sensitizers.

Guidance for managing potential dermal exposures has historically been qualitative in nature, for example, in the form of a DSEN notation. We propose a method that can provide quantitative guidance on how to establish and use surface wipe limits for skin sensitizers. The murine local lymph node assay (LLNA) is a validated test that not only identifies potential skin sensitizers but also provides an effective concentration (EC3) value. This provides quantitative dose-response information on induction of skin sensitization that permits estimates of sensitization thresholds and potency. Building upon the previously established correlation between LLNA EC3 values and human repeat insult patch testing no-effect levels, we present a quantitative method for setting surface wipe guidelines using the LLNA EC3. These limits can be used to assign compounds to occupational exposure bands and provide handling guidance for skin sensitizers of varying potency, supporting both exposure assessment and control strategies. A table is included that suggests a band of reasonable surface wipe limits (mg/100 cm2) for potentially all chemical sensitizers. When used in conjunction with a comprehensive industrial hygiene program that includes hazard communication, engineering controls, and personal protective equipment, skin exposure and consequent skin sensitization risks in the workplace can be minimized.