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- Cao, Yang, Associate Professor, 1972-, et al.
(författare)
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Comparison of piecewise structural equation modeling and Bayesian network for de novo construction of a quantitative adverse outcome pathway network
- 2023
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Ingår i: Altex. - : Springer Spektrum. - 1868-596X .- 1868-8551. ; 40:2, s. 287-298
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Tidskriftsartikel (refereegranskat)abstract
- Quantitative adverse outcome pathway network (qAOPN) is gaining momentum due to the predictive nature, alignment with quantitative risk assessment and great potential as a computational new approach methodology (NAM) to reduce laboratory animal tests. The present work aimed to demonstrate two advanced modeling approaches, piecewise structural equation modeling (PSEM) and Bayesian network (BN), for de novo qAOPN model construction based on routine ecotoxicological data. A previously published AOP network comprised of four linear AOPs linking excessive reactive oxygen species production to mortality in aquatic organisms was employed as a case study. The demonstrative case study intended to answer: Which linear AOP in the network contributed the most to the AO? Can any of the upstream KEs accurately predict the AO? What are the advantages and limitations of PSEM or BN in qAOPN development? The outcomes from the two approaches showed that both PSEM and Bayesian network were suitable for constructing a complex qAOPN based on limited experimental data. Besides quantification of response-response relationships, both approaches were capable of identifying the most influencing linear AOP in a complex network and evaluating the predictive ability of the AOP, albeit some discrepancies in predictive ability were identified for the two approaches using this specific dataset. The PROs and CONs of the two approaches for qAOPN construction were discussed in detail and suggestions on optimal workflows of PSEM and BN were provided to guide future qAOPN development.
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- Krebs, Alice, et al.
(författare)
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Template for the Description of Cell-Based Toxicological Test Methods to Allow Evaluation and Regulatory Use of the Data
- 2019
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Ingår i: Altex. - : ALTEX Edition. - 1868-596X .- 1868-8551. ; 36:4, s. 682-699
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Only few cell-based test methods are described by Organisation for Economic Co-operation and Development (OECD) test guidelines or other regulatory references (e.g., the European Pharmacopoeia). The majority of toxicity tests still falls into the category of non-guideline methods. Data from these tests may nevertheless be used to support regulatory decisions or to guide strategies to assess compounds (e.g., drugs, agrochemicals) during research and development if they fulfill basic requirements concerning their relevance, reproducibility and predictivity. Only a method description of sufficient clarity and detail allows interpretation and use of the data. To guide regulators faced with increasing amounts of data from non-guideline studies, the OECD formulated Guidance Document 211 (GD211) on method documentation for the purpose of safety assessment. As GD211 is targeted mainly at regulators, it leaves scientists less familiar with regulation uncertain as to what level of detail is required and how individual questions should be answered. Moreover, little attention was given to the description of the test system (i.e., cell culture) and the steps leading to it being established in the guidance. To address these issues, an annotated toxicity test method template (ToxTemp) was developed (i) to fulfill all requirements of GD211, (ii) to guide the user concerning the types of answers and detail of information required, (iii) to include acceptance criteria for test elements, and (iv) to define the cells sufficiently and transparently. The fully annotated ToxTemp is provided here, together with reference to a database containing exemplary descriptions of more than 20 cell-based tests.
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- Lindsjö, Johan, et al.
(författare)
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The 3Rs in Animal Welfare Bodies at Swedish Universities - Knowledge, Attitudes, Implementation
- 2021
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Ingår i: Altex. - : ALTEX Edition. - 1868-596X .- 1868-8551. ; 38, s. 477-489
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Tidskriftsartikel (refereegranskat)abstract
- The implementation of the 3Rs (replacement, reduction and refinement) is emphasized in EU Directive 2010/63.16 task of the animal welfare bodies (AWB) is to strengthen animal welfare and develop the 3Rs at research animal facilities. In 2016, we surveyed the knowledge on, attitudes towards and implementation of the 3Rs within AWBs at eight major Swedish universities. Based on responses of 34 closed-ended questions from 44 of 90 AWB members, the overall attitude towards the 3Rs was positive. AWB members did not believe that the 3Rs slow down innovation or result in increased costs, and refinement was considered beneficial for research quality. AWB members were particularly positive towards refinement questions in the survey. A majority of the AWB members predicted that alternative methods will never replace animal use. Researchers as a group represented in the AWBs were significantly less positive towards the 3Rs compared to the group of veterinarians. The tasks of the AWBs, e.g., giving advice on the 3Rs and following up on animal use in projects, were often not carried out in the AWB or not known by the respondents. Our results indicate a need for more practical and regulatory guidance and support to the AWBs. To reach the goal of the EU Directive to phase out animal use in research and education, we suggest that technical expertise in replacement techniques is included in the AWBs. We emphasize the need to strengthen the awareness of the 3Rs among researchers at Swedish universities.
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- Ringblom, J., et al.
(författare)
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Assigning ethical weights to clinical signs observed during toxicity testing
- 2017
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Ingår i: Altex. - : Elsevier GmbH. - 1868-596X .- 1868-8551. ; 34:1, s. 148-156
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Tidskriftsartikel (refereegranskat)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.
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- Silva, Antero Vieira, et al.
(författare)
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Associations between clinical signs and pathological findings in toxicity testing
- 2021
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Ingår i: Altex. - : ALTEX Edition. - 1868-596X .- 1868-8551. ; 38:2, s. 198-214
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Tidskriftsartikel (refereegranskat)abstract
- 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. It was 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 decrease of pain and distress experienced during animal experiments. To this end, data from three sequential toxicity studies in rats were analyzed using the multivariate partial least squares (PLS) regression method. Associations with correct prediction 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 showed the strongest associations to 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's welfare and toxicity testing. These clinical signs may also enable Reduced animal use due to their informative potential to support scientific decisions regarding drug candidate selection, dose setting, study design and toxicity assessment.
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- van der Stel, Wanda, et al.
(författare)
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New Approach Methods (NAMs) Supporting Read-Across : Two Neurotoxicity AOP-based IATA Case Studies
- 2021
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Ingår i: Altex. - : ALTEX Edition. - 1868-596X .- 1868-8551. ; 38:4, s. 615-635
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Tidskriftsartikel (refereegranskat)abstract
- Read-across approaches are considered key in moving away from in vivo animal testing towards addressing data-gaps using new approach methods (NAMs). Ample successful examples are still required to substantiate this strategy. Here we present and discuss the learnings from two OECD IATA endorsed read-across case studies. They involve two classes of pesticides - rotenoids and strobilurins - each having a defined mode-of-action that is assessed for its neurological hazard by means of an AOP-based testing strategy coupled to toxicokinetic simulations of human tissue concentrations. The endpoint in question is potential mitochondrial respiratory chain mediated neurotoxicity, specifically through inhibition of complex I or III. An AOP linking inhibition of mitochondrial respiratory chain complex I to the degeneration of dopaminergic neurons formed the basis for both cases but was deployed in two different regulatory contexts. The two cases also exemplify several different read-across concepts: analogue versus category approach, consolidated versus putative AOP, positive versus negative prediction (i.e., neurotoxicity versus low potential for neurotoxicity), and structural versus biological similarity. We applied a range of NAMs to explore the toxicodynamic properties of the compounds, e.g., in silico docking as well as in vitro assays and readouts - including transcriptomics - in various cell systems, all anchored to the relevant AOPs. Interestingly, although some of the data addressing certain elements of the read-across were associated with high uncertainty, their impact on the overall read-across conclusion remained limited. Coupled to the elaborate regulatory review that the two cases underwent, we propose some generic learnings of AOP-based testing strategies supporting read-across.
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| 16. |
- von Hellfeld, Rebecca, et al.
(författare)
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Zebrafish embryo neonicotinoid developmental neurotoxicity in the FET test and behavioral assays
- 2022
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Ingår i: Altex. - : ALTEX Edition. - 1868-596X .- 1868-8551. ; 39:3, s. 367-387
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Tidskriftsartikel (refereegranskat)abstract
- The need for reliable, sensitive (developmental) neurotoxicity testing of chemicals has steadily increased. Given the limited capacities for routine testing according to accepted regulatory guidelines, there is potential risk to human health and the environment. Most toxicity studies are based on mammalian test systems, which have been questioned for low sensitivity, limited relevance for humans, and animal welfare considerations. This increased the need for alternative models, one of which is the zebrafish (Danio rerio) embryo. This study assessed selected neonicotinoids at sub-lethal concentrations for their effects on embryonic development and behavior. The fish embryo acute toxicity test (OECD TG 236) determined the lowest observable effective concentrations, which were used as the highest test concentrations in subsequent behavioral assays. In the FET test, no severe compound-induced sublethal effects were seen at < 100 µM. In the coiling assay, exposure to ≥ 1.25 µM nicotine (positive control) affected both the burst duration and burst count per minute, whereas ≥ 50 µM thiacloprid affected the mean burst duration. Exposure to ≥ 50 µM acetamiprid and imidacloprid induced significant alterations in both mean burst duration and burst count per minute. In the swimming assay, 100 µM acetamiprid induced alterations in the frequency and extent of movements, whilst nicotine exposure only induced non-significant changes. All behavioral changes could be correlated to findings in mammalian studies. Given the quest for alternative test methods of (developmental) neurotoxicity, zebrafish embryo behavior testing could be integrated into a future tiered testing scheme.
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| 19. |
- Zeller, Kathrin S., et al.
(författare)
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The GARD platform for potency assessment of skin sensitizing chemicals
- 2017
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Ingår i: ALTEX Alternatives To Animal Experimentation. - : ALTEX Edition. - 1868-596X .- 1868-8551. ; 34:4, s. 539-559
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Tidskriftsartikel (refereegranskat)abstract
- Contact allergy induced by certain chemicals is a common health concern, and several alternative methods have been developed to fulfill the requirements of European legislation with regard to hazard assessment of potential skin sensitizers. However, validated methods, which provide information about the potency of skin sensitizers, are still lacking. The cell-based assay Genomic Allergen Rapid Detection (GARD), targeting key event 3, dendritic cell activation, of the skin sensitization AOP, uses gene expression profiling and a machine learning approach for the prediction of chemicals as sensitizers or non-sensitizers. Based on the GARD platform, we here expanded the assay to predict three sensitizer potency classes according to the European Classification, Labelling and Packaging (CLP) Regulation, targeting categories 1A (strong), 1B (weak) and no cat (non-sensitizer). Using a random forest approach and 70 training samples, a potential biomarker signature of 52 transcripts was identified. The resulting model could predict an independent test set consisting of 18 chemicals, six from each CLP category and all previously unseen to the model, with an overall accuracy of 78%. Importantly, the model was shown to be conservative and only underestimated the class label of one chemical. Furthermore, an association of defined chemical protein reactivity with distinct biological pathways illustrates that our transcriptional approach can reveal information contributing to the understanding of underlying mechanisms in sensitization.
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