| 1. |
- Caporale, N., et al.
(författare)
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From cohorts to molecules: Adverse impacts of endocrine disrupting mixtures
- 2022
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 375:6582
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Tidskriftsartikel (refereegranskat)abstract
- 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. © 2022 American Association for the Advancement of Science. All rights reserved.
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| 2. |
- Drakvik, E., et al.
(författare)
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Statement on advancing the assessment of chemical mixtures and their risks for human health and the environment
- 2020
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Ingår i: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 134
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Tidskriftsartikel (refereegranskat)abstract
- 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: • We are at a turning point: multiple exposures and their combined effects require better management to protect public health and the environment from hazardous chemical mixtures. • Regulatory initiatives should be launched to investigate the opportunities for all relevant regulatory frameworks to include prospective mixture risk assessment and consider combined exposures to (real-life) chemical mixtures to humans and wildlife, across sectors. • Precautionary approaches and intermediate measures (e.g. Mixture Assessment Factor) can already be applied, although, definitive mixture risk assessments cannot be routinely conducted due to significant knowledge and data gaps. • A European strategy needs to be set, through stakeholder engagement, for the governance of combined exposure to multiple chemicals and mixtures. The strategy would include research aimed at scientific advancement in mechanistic understanding and modelling techniques, as well as research to address regulatory and policy needs. Without such a clear strategy, specific objectives and common priorities, research, and policies to address mixtures will likely remain scattered and insufficient. © 2019 The Authors
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| 3. |
- Silva, A. V., et al.
(författare)
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Dose-dependent toxicological effects in rats following a 90-day dietary exposure to PCB-156 include retinoid disruption
- 2021
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Ingår i: Toxicology Letters. - : Elsevier. - 0378-4274 .- 1879-3169. ; 350:Suppl., s. S163-S163
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The toxicity of PCB-156 (2,3,3¢,4,4¢,5-hexachlorobiphenyl) was investigated in rats following subchronic dietary exposure. Groups of 10 male and 10 female Sprague-Dawley rats were administered PCB in the diet at 0, 0.01, 0.1, 1 or 10 ppm for 13 weeks. Results were analysed by group-wise comparison and benchmark dose-modelling. The latter revealed ose-related decreases of final body weight, growth rate and thymus weight. Additionally, rats receiving PCB-156 showed dose-dependent weight increases of liver, lungs and kidneys. Biochemical changes included increases in liver EROD, PROD and UD-PGT enzymatic activities, as well as increases in uro-porphyrin. Retinoid (Vitamin A) quantification showed a clear and treatment-related reduction of the levels in the liver and lungs, as well as increased levels in the kidneys. A owest-observable-adverse-effect level (LOAEL) of 0.01 ppm was established, based on effects in the liver apolar retinoids concentration, corresponding to dietary exposure of 0.7 and 0.8 μg PCB-156/kg body weight per dayin male and female rats, respectively. Benchmark dose-modelling corroborated effects in the retinoid system, in both sexes, at even lower intake levels. The lower confidence limit (BMDL) for a 5% decrease in the concentration of liver apolar retinoids was 0.00086 (males) and 0.00068 ppm (fe-males), corresponding to a daily exposure of 0.06 μg PCB-156/kg body weight for both sexes. This BMDL5 is approximately 10-fold lower than the LOAEL for PCB-156. Based on the retinoid system’s susceptibility to PCB-156 exposure, we recommend effects on this system to be considered as critical for risk assessment of PCB-156 and other PCB congeners.
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| 4. |
- Vieira Silva, A., et al.
(författare)
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Dose-dependent toxicological effects in rats following a 90-day dietary exposure to PCB-156 include retinoid disruption
- 2022
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Ingår i: Reproductive Toxicology. - : Elsevier. - 0890-6238 .- 1873-1708. ; 107, s. 123-139
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Tidskriftsartikel (refereegranskat)abstract
- The toxicity of PCB-156 (2,3,3',4,4',5-hexachlorobiphenyl) was investigated in rats following subchronic dietary exposure. Groups of 10 male and female Sprague-Dawley rats were administered PCB-156 in the diet at 0, 0.01, 0.1, 1 or 10 ppm for 90 days. Dose-dependent increases were detected for the liver, lung and kidney weights, as well as for the liver EROD, PROD and UDPGT enzyme activities and liver uroporphyrin concentration. Dose-dependent decreases were observed in final body weight, body weight gain, and thymus weight. Apolar retinoid concentrations were decreased in the liver and lungs and increased in the kidneys. Histopathological examination of the liver, thyroid, and thymus showed mild to moderate dose-related changes.A LOAEL of 0.01 ppm was established, based on reduced apolar liver retinoid concentration. Benchmark dose-modelling corroborated the sensitivity of liver retinoid endpoints. The lower confidence limits (BMDL) for a 5% decrease in apolar liver retinoid concentrations were 0.0009 and 0.0007 ppm, respectively, in males and females, corresponding to a daily dose of 0.06 µg PCB-156 per kg body weight. Organizing dose-response data for the individual hepatic endpoints along the PCB-156 dosing scale revealed a sequence of events compatible with a causal link between depletion of apolar retinoids and the other liver biochemistry and pathology findings. Taken together, data suggest that the retinoid endpoints should be further evaluated for a causal relationship to PCB-induced liver toxicity and that retinoid system endpoints are identified and characterized to support health risk assessment in the emerging research fields of endocrine disruption and mixture toxicology.
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