ABSTRACT
Phthalates are endocrine disrupting chemicals (EDCs) found in common consumer products such as soft plastics and cosmetics. Although the knowledge regarding the adverse effects of phthalates on female fertility are accumulating, information on the hormone sensitive endometrium is still scarce. Here, we studied the effects of phthalates on endometrial cell proliferation and gene expression. Human endometrial primary epithelial and stromal cells were isolated from healthy fertile-aged women (n=3), and were compared to endometrial cell lines T-HESC and Ishikawa. Three different epidemiologically relevant phthalate mixtures were used, defined by urine samples in the Midlife Women Health Study (MWHS) cohort. Mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) was used as a single phthalate control. Cells were harvested for proliferation testing and transcriptomic analyses after 24â¯h exposure. Even though all cell models responded differently to the phthalate exposures, many overlapping differentially expressed genes (DEGs, FDR<0.1), related to cell adhesion, cytoskeleton and mitochondria were found in all cell types. The qPCR analysis confirmed that MEHHP significantly affected cell adhesion gene vinculin (VCL) and NADH:ubiquinone oxidoreductase subunit B7 (NDUFB7), important for oxidative phosphorylation. Benchmark dose modelling showed that MEHHP had significant concentration-dependent effects on cytoskeleton gene actin-beta (ACTB). In conclusion, short 24â¯h phthalate exposures significantly altered gene expression cell-specifically in human endometrial cells, with six shared DEGs. The mixture effects were similar to those of MEHHP, suggesting MEHHP could be the main driver in the mixture. Impact of phthalate exposures on endometrial functions including receptivity should be addressed.
ABSTRACT
Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals used in various industrial and consumer products. They have gained attention due to their ubiquitous occurrence in the environment and potential for adverse effects on human health, often linked to immune suppression, hepatotoxicity, and altered cholesterol metabolism. This study aimed to explore the impact of ten individual PFAS, 3â¯H-perfluoro-3-[(3-methoxypropoxy) propanoic acid] (PMPP/Adona), ammonium perfluoro-(2-methyl-3-oxahexanoate) (HFPO-DA/GenX), perfluorobutanoic acid (PFBA), perfluorobutanesulfonic acid (PFBS), perfluorodecanoic acid (PFDA), perfluorohexanoic acid (PFHxA), perfluorohexanesulfonate (PFHxS), perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), and perfluorooctanesulfonic acid (PFOS) on the lipid metabolism in human hepatocyte-like cells (HepaRG). These cells were exposed to different concentrations of PFAS ranging from 10⯵M to 5000⯵M. Lipids were extracted and analyzed using liquid chromatography coupled with mass spectrometry (LC- MS-QTOF). PFOS at 10⯵M and PFOA at 25⯵M increased the levels of ceramide (Cer), diacylglycerol (DAG), N-acylethanolamine (NAE), phosphatidylcholine (PC), and triacylglycerol (TAG) lipids, while PMPP/Adona, HFPO-DA/GenX, PFBA, PFBS, PFHxA, and PFHxS decreased the levels of these lipids. Furthermore, PFOA and PFOS markedly reduced the levels of palmitic acid (FA 16.0). The present study shows distinct concentration-dependent effects of PFAS on various lipid species, shedding light on the implications of PFAS for essential cellular functions. Our study revealed that the investigated legacy PFAS (PFOS, PFOA, PFBA, PFDA, PFHxA, PFHxS, and PFNA) and alternative PFAS (PMPP/Adona, HFPO-DA/GenX and PFBS) can potentially disrupt lipid homeostasis and metabolism in hepatic cells. This research offers a comprehensive insight into the impacts of legacy and alternative PFAS on lipid composition in HepaRG cells.
Subject(s)
Fluorocarbons , Hepatocytes , Lipid Metabolism , Humans , Fluorocarbons/toxicity , Lipid Metabolism/drug effects , Hepatocytes/drug effects , Hepatocytes/metabolism , Cell Line , Environmental Pollutants/toxicity , Alkanesulfonic Acids/toxicityABSTRACT
Chemical health risk assessment is based on single chemicals, but humans and wildlife are exposed to extensive mixtures of industrial substances and pharmaceuticals. Such exposures are life-long and correlate with multiple morbidities, including infertility. How combinatorial effects of chemicals should be handled in hazard characterization and risk assessment are open questions. Further, test systems are missing for several relevant health outcomes including reproductive health and fertility in women. Here, our aim was to screen multiple ovarian cell models for phthalate induced effects to identify biomarkers of exposure. We used an epidemiological cohort study to define different phthalate mixtures for in vitro testing. The mixtures were then tested in five cell models representing ovarian granulosa or stromal cells, namely COV434, KGN, primary human granulosa cells, primary mouse granulosa cells, and primary human ovarian stromal cells. Exposures at epidemiologically relevant levels did not markedly elicit cytotoxicity or affect steroidogenesis in short 24-hour exposure. However, significant effects on gene expression were identified by RNA-sequencing. Altogether, the exposures changed the expression of 124 genes on the average (9-479 genes per exposure) in human cell models, without obvious concentration or mixture-dependent effects on gene numbers. The mixtures stimulated distinct changes in different cell models. Despite differences, our analyses suggest commonalities in responses towards phthalates, which forms a starting point for follow-up studies on identification and validation of candidate biomarkers that could be developed to novel assays for regulatory testing or even into clinical tests.
Subject(s)
Endocrine Disruptors , Phthalic Acids , Animals , Mice , Humans , Female , Ovary , Cohort Studies , Phthalic Acids/toxicity , Fertility , Endocrine Disruptors/toxicityABSTRACT
In vitro models of adipogenesis are phenotypic assays that most closely mimic the increase of adipose tissue in obesity. Current models, however, often lack throughput and sensitivity and even report conflicting data regarding adipogenic potencies of many chemicals. Here, we describe a ten-day long adipogenesis model using high content analysis readouts for adipocyte number, size, and lipid content on primary human mesenchymal stem cells (MSC) sensitive enough to compare bisphenol A derivatives quantitatively in a robust and high throughput manner. The number of adipocytes was the most sensitive endpoint capable of detecting changes of 20% and was used to develop a benchmark concentration model (BMC) to quantitatively compare eight bisphenols (tested at 0.1-100 µM). The model was applied to evaluate mixtures of bisphenols obtaining the first experimental evidence of their additive effect on human MSC adipogenesis. Using the relative potency factors (RPFs), we show how a mixture of bisphenols at their sub-active concentrations induces a significant adipogenic effect due to its additive nature. The final active concentrations of bisphenols in tested mixtures reached below 1 µM, which is within the concentration range observed in humans. These results point to the need to consider the toxicity of chemical mixtures.
Subject(s)
Adipocytes/drug effects , Adipogenesis/drug effects , Benzhydryl Compounds/toxicity , High-Throughput Screening Assays/methods , Mesenchymal Stem Cells/drug effects , Phenols/toxicity , Adaptation, Biological , Adipocytes/physiology , Adipogenesis/physiology , Cell Differentiation , HumansABSTRACT
Convergent evidence associates exposure to endocrine disrupting chemicals (EDCs) with major human diseases, even at regulation-compliant concentrations. This might be because humans are exposed to EDC mixtures, whereas chemical regulation is based on a risk assessment of individual compounds. Here, we developed a mixture-centered risk assessment strategy that integrates epidemiological and experimental evidence. We identified that exposure to an EDC mixture in early pregnancy is associated with language delay in offspring. At human-relevant concentrations, this mixture disrupted hormone-regulated and disease-relevant regulatory networks in human brain organoids and in the model organisms Xenopus leavis and Danio rerio, as well as behavioral responses. Reinterrogating epidemiological data, we found that up to 54% of the children had prenatal exposures above experimentally derived levels of concern, reaching, for the upper decile compared with the lowest decile of exposure, a 3.3 times higher risk of language delay.
Subject(s)
Endocrine Disruptors/toxicity , Language Development Disorders/epidemiology , Neurodevelopmental Disorders/epidemiology , Prenatal Exposure Delayed Effects , Transcriptome/drug effects , Animals , Autism Spectrum Disorder/epidemiology , Autism Spectrum Disorder/genetics , Brain/drug effects , Brain/embryology , Child, Preschool , Estrogens/metabolism , Female , Fluorocarbons/analysis , Fluorocarbons/toxicity , Gene Expression Profiling , Gene Expression Regulation , Gene Ontology , Humans , Locomotion/drug effects , Neural Stem Cells/drug effects , Neurodevelopmental Disorders/genetics , Organoids , Phenols/analysis , Phenols/toxicity , Phthalic Acids/analysis , Phthalic Acids/toxicity , Pregnancy , Risk Assessment , Thyroid Hormones/metabolism , Xenopus laevis , ZebrafishABSTRACT
Hazard characterization during pharmaceutical development identifies the candidate drug's potential hazards and dose-response relationships. To date, the no-observed-adverse-effect-level (NOAEL) approach has been employed to identify the highest dose which results in no observed adverse effects. The benchmark dose (BMD) modeling approach describes potential dose-response relationships and has been used in diverse regulatory domains, but its applicability for pharmaceutical development has not previously been examined. Thus, we applied BMD-modeling to all endpoints in three sequential in vivo studies in a drug development setting, including biochemistry, hematology, organ pathology and clinical observations. In order to compare the results across such a broad range of effects, we needed to standardize the choice of the critical effect size (CES) for the different endpoints. A CES of 5%, previously suggested by the European Food Safety Authority, was compared with the study NOAEL and with the General Theory of Effect Size, which takes natural variability into account. Compared to the NOAEL approach, the BMD-modeling approach resulted in more informative estimates of the doses leading to effects. The BMD-modeling approach handled well situations where effects occurred below the lowest tested dose and the study's NOAEL, and seems advantageous to characterize the potential toxicity during safety assessment. The results imply a considerable step forward from the perspective of reducing and refining animal experiments, as more information is yielded from the same number of animals and at lower doses. Taken together, employing BMD-modeling as a substitute, or as a complement, to the NOAEL approach seems appropriate.
Subject(s)
Antineoplastic Agents/toxicity , Drug Development , Endpoint Determination , Research Design , Toxicity Tests , Animals , Dose-Response Relationship, Drug , Female , Humans , Male , No-Observed-Adverse-Effect Level , Rats, Wistar , Risk AssessmentABSTRACT
Animal testing for toxicity assessment of chemicals and pharmaceuticals must take the 3R principles into consideration. During toxicity testing in vivo, clinical signs are used to monitor animal welfare and to inform about potential toxicity. This study investigated possible associations between clinical signs, body weight change and histopathological findings observed after necropsy. We hypothesized that clinical signs and body weight loss observed during experiments could be used as early markers of organ toxicity. This represents a potential for refinement in terms of improved study management and decreasing of pain and distress experienced during animal experiments. Data from three sequential toxicity studies of an anti-cancer drug candidate in rats were analyzed using the multivariate partial least squares (PLS) regression method. Associations with a predictive value over 80% were found between the occurrence of mild to severe clinical signs and histopathological findings in the thymus, testes, epididymides and bone marrow. Piloerection, eyes half shut and slightly decreased motor activity were most strongly associated with the pathological findings. A 5% body weight loss was found to be a strong empirical predictor of pathological findings but could also be predicted accurately by clinical signs. Thus, we suggest using mild clinical signs and a 5% body weight loss as toxicity markers and as a non-invasive surveillance tool to monitor research animal welfare in toxicity testing. These clinical signs may also enable reduction of animal use due to their informative potential to support scientific decisions regarding drug candidate selection, dose setting, study design, and toxicity assessment.
Subject(s)
Animal Experimentation , Toxicity Tests , Animal Welfare , Animals , RatsABSTRACT
BACKGROUND: Extensive exposure to per- and polyfluoroalkyl substances (PFAS) have been observed in many countries. Current deterministic frameworks for risk assessment lack the ability to predict the likelihood of effects and to assess uncertainty. When exposure exceeds tolerable intake levels, these shortcomings hamper risk management and communication. OBJECTIVE: The integrated probabilistic risk assessment (IPRA) combines dose-response and exposure data to estimate the likelihood of adverse effects. We evaluated the usefulness of the IPRA for risk characterization related to decreased levels of total triiodothyronine (T3) in humans following a real case of high exposure to PFAS via drinking water. METHODS: PFAS exposure was defined as serum levels from residents of a contaminated area in Ronneby, Sweden. Median levels were 270 ng/mL [perfluorooctane sulfonic acid (PFOS)] and 229 ng/mL [perfluorohexane sulfonic acid (PFHxS)] for individuals who resided in Ronneby 1 y before the exposure termination. This data was integrated with data from a subchronic toxicity study in monkeys exposed daily to PFOS. Benchmark dose modeling was employed to describe separate dose-effect relationship for males and females, and extrapolation factor distributions were used to estimate the corresponding human benchmark dose. The critical effect level was defined as a 10% decrease in total T3. RESULTS: The median probability of critical exposure, following a combined exposure to PFOS and PFHxS, was estimated to be [2.1% (90% CI: 0.4%-13.1%)]. Gender-based analysis showed that this risk was almost entirely distributed among women, namely [3.9% (90% CI: 0.8%-21.6%)]. DISCUSSION: The IPRA was compared with the traditional deterministic Margin of Exposure (MoE) approach. We conclude that probabilistic risk characterization represents an important step forward in the ability to adequately analyze group-specific health risks. Moreover, quantifying the sources of uncertainty is desirable, as it improves the awareness among stakeholders and will guide future efforts to improve accuracy. https://doi.org/10.1289/EHP6654.
Subject(s)
Drinking Water/chemistry , Environmental Exposure/statistics & numerical data , Fluorocarbons/analysis , Triiodothyronine/blood , Water Pollutants, Chemical/analysis , Water Pollution/statistics & numerical data , Adult , Alkanesulfonic Acids , Female , Humans , Male , Sulfonic Acids , SwedenABSTRACT
The number of anthropogenic chemicals, manufactured, by-products, metabolites and abiotically formed transformation products, counts to hundreds of thousands, at present. Thus, humans and wildlife are exposed to complex mixtures, never one chemical at a time and rarely with only one dominating effect. Hence there is an urgent need to develop strategies on how exposure to multiple hazardous chemicals and the combination of their effects can be assessed. A workshop, "Advancing the Assessment of Chemical Mixtures and their Risks for Human Health and the Environment" was organized in May 2018 together with Joint Research Center in Ispra, EU-funded research projects and Commission Services and relevant EU agencies. This forum for researchers and policy-makers was created to discuss and identify gaps in risk assessment and governance of chemical mixtures as well as to discuss state of the art science and future research needs. Based on the presentations and discussions at this workshop we want to bring forward the following Key Messages.
Subject(s)
Risk Assessment , Complex Mixtures , Hazardous Substances , HumansABSTRACT
Purpose. This study aimed to investigate chemical injuries caused by cleaning agents and disinfectants by reviewing poison control data. Methods. We performed a 5-year retrospective analysis of calls to the Swedish Poisons Information Centre (PIC) concerning occupational use of cleaning agents and disinfectants. In addition, callers for 17 new cases were interviewed. Results. Out of 8240 occupationally related cases handled by the PIC during 2010-2014, 24% concerned cleaning agents and disinfectants (N = 1983). Of these, one-third were classified as major risk cases, generally due to potential for corrosive eye and skin injuries. The most frequent type of workplace was restaurants and caterers. However, information about occupation was only identifiable for 30% of the cases. Follow-up interviews exemplify how limited awareness of safety data sheets and disregard of protective equipment may contribute to health-related outcomes such as absence at work. Conclusions. Management and prevention strategies for cleaning agents should be improved. PIC records hold relevant information both for designing interventions and for future research on occupational health and safety management. We suggest that systematic collection by the PIC of information on occupation and age would further improve the usefulness for occupational injury surveillance purposes.
Subject(s)
Detergents , Information Centers , Occupational Health , Poisoning/prevention & control , Adult , Aged , Female , Humans , Interviews as Topic , Male , Middle Aged , Qualitative Research , Retrospective Studies , Risk Management , Workplace , Young AdultABSTRACT
Fundamental to regulatory guidelines is to identify chemicals that are implicated with adverse human health effects and inform public health risk assessors about "acceptable ranges" of such environmental exposures (e.g., from consumer products and pesticides). The process is made more difficult when accounting for complex human exposures to multiple environmental chemicals. Herein we propose a new class of nonlinear statistical models for human data that incorporate and evaluate regulatory guideline values into analyses of health effects of exposure to chemical mixtures using so-called 'desirability functions' (DFs). The DFs are incorporated into nonlinear regression models to allow for the simultaneous estimation of points of departure for risk assessment of combinations of individual substances that are parts of chemical mixtures detected in humans. These are, in contrast to published so-called biomonitoring equivalent (BE) values and human biomonitoring (HBM) values that link regulatory guideline values from in vivo studies of single chemicals to internal concentrations monitored in humans. We illustrate the strategy through the analysis of prenatal concentrations of mixtures of 11 chemicals with suspected endocrine disrupting properties and two health effects: birth weight and language delay at 2.5â¯years. The strategy allows for the creation of a Mixture Desirability Function i.e., MDF, which is a uni-dimensional construct of the set of single chemical DFs; thus, it focuses the resulting inference to a single dimension for a more powerful one degree-of-freedom test of significance. Based on the application of this new method we conclude that the guideline values need to be lower than those for single chemicals when the chemicals are observed in combination to achieve a similar level of protection as was aimed for the individual chemicals. The proposed modeling may thus suggest data-driven uncertainty factors for single chemical risk assessment that takes environmental mixtures into account.
Subject(s)
Complex Mixtures/analysis , Endocrine Disruptors/analysis , Environmental Exposure/analysis , Hazardous Substances/analysis , Models, Statistical , Birth Weight , Child, Preschool , Complex Mixtures/standards , Endocrine Disruptors/standards , Environmental Exposure/standards , Environmental Monitoring/methods , Female , Government Regulation , Hazardous Substances/standards , Humans , Infant, Newborn , Language Development Disorders/epidemiology , Male , Maternal-Fetal Exchange , Pregnancy , Risk Assessment , UncertaintyABSTRACT
Records of injuries and incidents provide an important basis for injury prevention related to hazardous substances at the workplace. The present study aimed to review available data on injuries and incidents involving hazardous substances and investigate how data from the Poisons Information Centre could complement the records of the Swedish Work Environment Authority. We found two major obstacles for using injury/incident data based on employers' mandatory reporting. First, it was not possible to quickly and reliably identify injuries caused by hazardous substances, and second, data identifying substances or products are not systematically included. For two out of five investigated injuries with lost working days likely due to chemical injuries, we could not identify substances and/or products involved. The records based on calls to the Poisons Information Centre allow better understanding of chemical hazards and products. Besides the large share of unidentified chemical hazards in the injury statistics, the most striking difference was found for cleaning agents. Cleaning agents were implicated in one-third of the occupational cases that the consulting Poisons Information Centre expert judged to pose a major risk and in need of immediate healthcare. Only one in 10 injuries with lost days reported by employers was related to this type of product. The identification of exposures and symptoms by the Poisons Information Centre allow recognition of chemicals with problematic occupational uses. Hence, these records may serve as an important complement to official injury statistics related to incidents with hazardous substances at work.
Subject(s)
Accidents, Occupational/statistics & numerical data , Hazardous Substances/poisoning , Occupational Exposure/statistics & numerical data , Poison Control Centers/statistics & numerical data , Female , Humans , Male , Sweden , Workplace/statistics & numerical dataABSTRACT
The benchmark dose (BMD) approach is increasingly used as a preferred approach for dose-effect analysis, but standard experimental designs are generally not optimized for BMD analysis. The aim of this study was to evaluate how the use of unequally sized dose groups affects the quality of BMD estimates in toxicity testing, with special consideration of the total burden of animal distress. We generated continuous dose-effect data by Monte Carlo simulation using two dose-effect curves based on endpoints with different shape parameters. Eighty-five designs, each with four dose groups of unequal size, were examined in scenarios ranging from low- to high-dose placements and with a total number of animals set to 40, 80, or 200. For each simulation, a BMD value was estimated and compared with the "true" BMD. In general, redistribution of animals from higher to lower dose groups resulted in an improved precision of the calculated BMD value as long as dose placements were high enough to detect a significant trend in the dose-effect data with sufficient power. The improved BMD precision and the associated reduction of the number of animals exposed to the highest dose, where chemically induced distress is most likely to occur, are favorable for the reduction and refinement principles. The result thereby strengthen BMD-aligned design of experiments as a means for more accurate hazard characterization along with animal welfare improvements.
ABSTRACT
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.
Subject(s)
Allergens , Asthma , Chlorine/toxicity , Irritants/toxicity , Ovalbumin , Administration, Inhalation , Animals , Asthma/blood , Asthma/immunology , Asthma/pathology , Asthma/physiopathology , Bronchoalveolar Lavage Fluid/immunology , Cytokines/immunology , Disease Models, Animal , Female , Immunoglobulin E/blood , Lung/drug effects , Lung/immunology , Lung/pathology , Mice , Mice, Inbred BALB C , Respiratory Mechanics/drug effectsABSTRACT
Increasingly, dose-response data are being evaluated with the benchmark dose (BMD) approach rather than by the less precise no-observed-adverse-effect-level (NOAEL) approach. However, the basis for designing animal experiments, using equally sized dose groups, is still primed for the NOAEL approach. The major objective here was to assess the impact of using dose groups of unequal size on both the quality of the BMD and overall animal distress. We examined study designs with a total number of 200 animals distributed in four dose groups employing quantal data generated by Monte Carlo simulations. Placing more animals at doses close to the targeted BMD provided an estimate of BMD that was slightly better than the standard design with equally sized dose groups. In situations involving a clear dose-response, this translates into fewer animals receiving high doses and thus less overall animal distress. Accordingly, in connection with risk and safety assessment, animal distress can potentially be reduced by distributing the animals appropriately between dose groups without decreasing the quality of the information obtained.
ABSTRACT
Reducing the number of laboratory animals used and refining experimental procedures to enhance animal welfare are fundamental questions to be considered in connection with animal experimentation. Here, we explored the use of cardinal ethical weights for clinical signs and symptoms in rodents by conducting trade-off interviews with members of Swedish Animal Ethics Committees in order to derive such weights for nine typical clinical signs of toxicity. The participants interviewed represent researchers, politically nominated political nominees and representatives of animal welfare organizations. We observed no statistically significant differences between these groups with respect to the magnitude of the ethical weights assigned, though the political nominees tended to assign lower weights. Overall, hunched posture was considered the most severe clinical sign and body weight loss the least severe. The ethical weights assigned varied considerably between individuals, from zero to infinite value, indicating discrepancies in prioritization of reduction and refinement. Cardinal ethical weights may be utilized to include both animal welfare refinement and reduction of animal use in designing as well as in retrospective assessment of animal experiments. Such weights may also be used to estimate ethical costs of animal experiments.
Subject(s)
Animal Care Committees , Animal Experimentation/ethics , Toxicity Tests/ethics , Animal Testing Alternatives , Animal Welfare/ethics , Animals , Rats , SwedenABSTRACT
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.
Subject(s)
Air Pollutants, Occupational/toxicity , Asthma/chemically induced , Inhalation Exposure/analysis , Occupational Exposure/analysis , Occupational Health/legislation & jurisprudence , European Union , Government Regulation , Humans , Inhalation Exposure/legislation & jurisprudence , Inhalation Exposure/standards , Maximum Allowable Concentration , No-Observed-Adverse-Effect Level , Occupational Exposure/legislation & jurisprudence , Occupational Exposure/standards , Occupational Health/standards , Threshold Limit Values , Workplace/standardsABSTRACT
BACKGROUND: Asthmatic individuals constitute a large sub-population that is often considered particularly susceptible to the deleterious effects of inhalation of airborne chemicals. However, for most such chemicals information on asthmatics is lacking and inter-individual assessment factors (AFs) of 3-25 have been proposed for use in the derivation of health-based guideline values. OBJECTIVE: To evaluate available information in attempt to determine whether a general difference in airway response during short-term exposure between healthy and asthmatic individuals can be identified, and whether current AFs for inter-individual variability provide sufficient protection for asthmatics. METHODS: After performing systematic review of relevant documents and the scientific literature estimated differential response factors (EDRF) were derived as the ratio between the lowest observed adverse effect levels for healthy and asthmatic subjects based on studies in which both groups were tested under the same conditions. Thereafter, the concentration-response relationships for healthy and asthmatic subjects exposed separately to four extensively tested chemicals (nitrogen dioxide, ozone, sulfuric acid, sulfur dioxide) were compared on the basis of combined data. Finally, a Benchmark Concentration (BMC) analysis was performed for sulfur dioxide. RESULTS: We found evidence of higher sensitivity among asthmatics (EDRF > 1) to 8 of 19 tested chemicals, and to 3 of 11 mixtures. Thereafter, we confirmed the higher sensitivity of asthmatics to sulfuric acid and sulfur dioxide. No difference was observed in the case of ozone and nitrogen dioxide. Finally, our BMC analysis of sulfur dioxide indicated a ninefold higher sensitivity among asthmatics. CONCLUSION: Although experimental data are often inconclusive, our analyses suggest that an AF of 10 is adequate to protect asthmatics from the deleterious respiratory effects of airborne chemicals.