| 1. |
- Nordberg, Gunnar F, et al.
(författare)
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Interactions and Mixtures in Metal Toxicology
- 2015. - 4
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Ingår i: Handbook on the Toxicology of Metals. - : Academic Press. - 9780123982926 ; , s. 213-238
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Bokkapitel (refereegranskat)abstract
- Human exposures to metals, metalloids, and their compounds frequently occur as mixtures, and hence it is important to consider the joint action of these elements in terms of both mechanisms of action and risk assessment purposes. The joint action of these elements may produce additive, synergistic/potentiating, or antagonistic effects that may be manifested as direct cellular toxicity (necrosis or apoptosis) or carcinogenicity. Dose-response relationships may be further influenced by constitutive factors such as age, sex, and the expression of specific proteins. Mechanisms of importance for the development of potentiated or antagonistic toxicity are the expression of metal-binding proteins (metallothioneins or lead-binding proteins) and interference with metal transporters such as DMT-1 and ZIP. Compared to men, women of childbearing age absorb more Cd from the gastrointestinal tract because they have lower iron stores than men. Another example of synergism that occurs in humans is the one between inorganic arsenic and cadmium in inducing kidney toxicity. In many cases, however, direct primary data on the joint action of toxic or essential elements are lacking, and so innovative derivative methods such as the binary weight-of-evidence method have been used to predict potential interactions among groups of metals and metalloids. At present, there is much to be learned about the joint action of both toxic and essential elements, and this is clearly a critical area of research.
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| 2. |
- Nordberg, Gunnar F., et al.
(författare)
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Interactions in Metal Toxicology
- 2007. - 3
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Ingår i: Handbook on the Toxicology of Metals, 3rd Edition. - San Diego : Elsevier. - 9780123694133 ; , s. 117-145
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Human exposures to metals and metalloids such as arsenic frequently occur as mixtures, and hence it is important to consider interactions among these elements in terms of both mechanisms of action and for risk assessment purposes. Interactions among these elements may produce additive, synergistic/potentiative, or antagonistic effects that may be manifested as direct cellular toxicity (necrosis or apoptosis) or carcinogenicity. Dose-response relationships may further be influenced by constitutive factors such as age, sex, and the expression of specific proteins. The roles of molecular factors regulated by specific genes (so called gene-environment interactions) for the expression of metal toxicity are known only to a limited extent for most metals. However, for chronic beryllium disease causing fibrosis of the lung, it has been shown that beryllium sensitization, a prerequisite for developing the disease, depends on an antigen-specific immune response occurring predominantly among persons with a specific HLA-DBP1 genotype. Some gene-environment interactions in terms of genetic polymorphisms have been demonstrated such as those involving ALAD and arsenic methyl transferases, but the importance of these observations for development of human diseases has not been fully explored. Mechanisms of importance for interactions and the development of toxicity are the expression of metal-binding proteins (metallothioneins or lead-binding proteins). In many cases, direct primary data on interactions among toxic or essential elements are lacking, and so innovative derivative methods such as the binary weight of evidence (BINWOE) method have been used to predict potential interactions among groups of metals and metalloids. At present, there is much to be learned about interactions among both toxic and essential elements, but this is clearly a critical area of research.
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| 3. |
- Zwickl, Craig M., et al.
(författare)
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Principles and procedures for assessment of acute toxicity incorporating in silico methods
- 2022
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Ingår i: COMPUTATIONAL TOXICOLOGY. - : Elsevier. - 2468-1113. ; 24
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Tidskriftsartikel (refereegranskat)abstract
- Acute toxicity in silico models are being used to support an increasing number of application areas including (1) product research and development, (2) product approval and registration as well as (3) the transport, storage and handling of chemicals. The adoption of such models is being hindered, in part, because of a lack of guidance describing how to perform and document an in silico analysis. To address this issue, a framework for an acute toxicity hazard assessment is proposed. This framework combines results from different sources including in silico methods and in vitro or in vivo experiments. In silico methods that can assist the prediction of in vivo outcomes (i.e., LD50) are analyzed concluding that predictions obtained using in silico approaches are now well-suited for reliably supporting assessment of LD50- based acute toxicity for the purpose of the Globally Harmonized System (GHS) classification. A general overview is provided of the endpoints from in vitro studies commonly evaluated for predicting acute toxicity (e.g., cytotoxicity/cytolethality as well as assays targeting specific mechanisms). The increased understanding of pathways and key triggering mechanisms underlying toxicity and the increased availability of in vitro data allow for a shift away from assessments solely based on endpoints such as LD50, to mechanism-based endpoints that can be accurately assessed in vitro or by using in silico prediction models. This paper also highlights the importance of an expert review of all available information using weight-of-evidence considerations and illustrates, using a series of diverse practical use cases, how in silico approaches support the assessment of acute toxicity.
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