Objective: It has been suggested that asthmatics are more susceptible than healthy individuals to... more 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 (RD 50 ) 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.
Increasingly, dose-response data are being evaluated with the benchmark dose (BMD) approach rathe... more 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.
Asthma, a chronic respiratory disease, can be aggravated by exposure to certain chemical irritant... more 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.
Chemical safety management is an iterative process where reviews of safety deficiencies (e.g., in... more Chemical safety management is an iterative process where reviews of safety deficiencies (e.g., inspection notes) and failures (e.g., injuries) guide improvement efforts. The present work investigates safety in the school chemistry laboratory through two substudies. First, we interviewed 10 Swedish middle and high school chemistry teachers about how they work with safety and accident prevention in the chemistry laboratory. Second, we analyzed the call records of the Swedish Poisons Information Centre (PIC) concerning 10-19 olds and reports regarding severe injuries and accidents submitted to the Swedish Work Environment Authority (SWEA). The interviewed teachers encounter problems with chemical safety related to deficiencies in organizational support, such as lack of time and resources for preventive risk management and assignment to groups that are too large. The major safety challenge was reported to lie in students' safety behavior. Although facilities were generally well-equipped we noted outdated safety data sheets and missing written risk assessments. For 2010-2014, the PIC records identified 637 cases of chemical exposures at schools; of these, 243 (38%) concerned laboratory chemicals at school. The PIC experts on call judged 70% of the cases involving laboratory chemicals to pose a risk to the exposed students, mainly due to acids and alkali. Inhalation was the most frequent exposure route, although skin and eyes were almost equally frequent. Strikingly, PIC data identified 10 times as many cases as the SWEA injury/incident data. Hence, PIC data can provide knowledge about chemical safety incidents at schools not otherwise available.
Regulatory Toxicology and Pharmacology, Aug 1, 2012
Guideline values for emergency planning and response are aimed to protect the general public, inc... more Guideline values for emergency planning and response are aimed to protect the general public, including asthmatics and other susceptible groups, during sudden airborne releases of chemicals. A precondition of asthma may increase the individual susceptibility to acute exposures. This paper studies to what extent experimental data on asthmatics are included in the rationale and derivation of guideline values. An analysis of the Technical Support Documents (TSDs) of the Acute Exposure Guideline Levels (AEGLs) shows that only 23 of the 176 TSDs include references to experimental studies on asthmatics, 30 include a statement on asthmatics but no reference to experimental data, and 123 lack any explicit statement on asthmatics. The TSDs were further compared with the support documents of nine other programs for acute or occupational short-term values. All programs were incomplete with respect to experimental data on asthmatics. Omission of asthmatics may interfere with trustful and efficient health protective actions. We suggest that the availability of data on asthmatics should be carefully examined in the development of guideline values, and that the lack of such data should be explicitly noted. In the latter case, available data for other irritants may be used to justify an appropriate assessment factor.
We present a retrospective analysis of records on occupational accidents from the Swedish Poisons... more We present a retrospective analysis of records on occupational accidents from the Swedish Poisons Information Centre. The aim was to explore these data as a means for surveillance of accidents and incidents with chemicals at the workplace. We extracted data on all telephone consultations regarding occupational incidents (n = 8240) during 2010-2014. One third of the calls were made by health care staff (31%) and two thirds were made by the public (69%). For the latter group, about half (54%) received advice on how to manage on site. One out of five workplace incidents were assessed by the operating expert (pharmacists and physicians) as a major risk for severe symptoms. The three most commonly reported chemical groups were alkali (n = 1510, excluding ammonia), hydrocarbons (n = 1129, including halogenated hydrocarbons) and acids (n = 984). Eye exposure was the most common exposure route recorded (n = 3049), followed by inhalation (n = 2635) and skin (n = 1438). Data from the Swedish Poisons Information Centre offers insights about occupational accidents and incidents with chemical products and also include a higher number of accidents in absolute numbers as compared with the official injury statistics. With a clear focus on type of poisoning agent, treatment and health effects, poisons information data may serve as a means for surveillance on chemical incidents at the workplace.
Regulatory Toxicology and Pharmacology, Jul 1, 2014
Benchmark dose (BMD) modeling is increasingly used as the preferred approach to define the point-... more Benchmark dose (BMD) modeling is increasingly used as the preferred approach to define the point-of-departure for health risk assessment of chemicals. As data are inherently variable, there is always a risk to select a model that defines a lower confidence bound of the BMD (BMDL) that, contrary to expected, exceeds the true BMD. The aim of this study was to investigate how often and under what circumstances such anomalies occur under current modeling practice. Continuous data were generated from a realistic dose-effect curve by Monte Carlo simulations using four dose groups and a set of five different dose placement scenarios, group sizes between 5 and 50 animals and coefficients of variations of 5-15%. The BMD calculations were conducted using nested exponential models, as most BMD software use nested approaches. ''Non-protective'' BMDLs (higher than true BMD) were frequently observed, in some scenarios reaching 80%. The phenomenon was mainly related to the selection of the non-sigmoidal exponential model (Effect = a Á e bÁdose ). In conclusion, non-sigmoid models should be used with caution as it may underestimate the risk, illustrating that awareness of the model selection process and sound identification of the point-of-departure is vital for health risk assessment.
High throughput screening of bisphenols and their mixtures under conditions of low-intensity adipogenesis of human mesenchymal stem cells (hMSCs)
Food and Chemical Toxicology, 2022
In vitro models of adipogenesis are phenotypic assays that most closely mimic the increase of adi... more 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.
Background: Asthmatic individuals constitute a large sub-population that is often considered part... more 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 (EDRF41) 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.
This study assesses whether estimating children's exposure from information on adult smoking and ... more This study assesses whether estimating children's exposure from information on adult smoking and exposure to ETS makes international comparisons more reliable. Methods. The exposure among children was estimated using three different combinations (models) based on different sets of information on adult smoking, household composition or adult exposure to ETS at home in three cross-sectional nationally representative samples drawn from data sets from Estonia (n = 2650), Finland (n = 2829) and Latvia (n = 5440) in the years 2002 and 2004. The first two models were based on adult smoking and the third also included ETS exposure. Results. The parental smoking rate was similar to the general smoking prevalence. ETS exposure in nonsmoking parents ranged from 22% in Finland to 60% in Latvia. All models gave rather comparative ranges except in Latvia, where the proportion of children with exposure varied from 67% with the simplest model to 81% with the most complex one. Conclusions. Adult exposure at home or adult smoking prevalence, preferably among people with children, could be used as a proxy for children's exposure to ETS. It is recommended that population questionnaires include detailed information on exposure and household composition.
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Papers by Mattias Öberg