Stefan Scholz, Helmholtz Centre for Environmental Research - UFZ, Department of Bioanalytical Ecotoxicology, Permoserstr. 15, 04318 Leipzig, Germany, T +49 341 235 1080, email firstname.lastname@example.org
Point of Contact
- Stefan Scholz
|Author status||OECD status||OECD project||SAAOP status|
|Under development: Not open for comment. Do not cite|
This AOP was last modified on August 03, 2017 10:42
|Thiol group of chemicals interact with sulfuhydryl groups of proteins to form thiol adducts||August 03, 2017 11:25|
|Inhibition of lysyl oxidase||August 03, 2017 11:26|
|Reduction of collagen crosslinking||August 03, 2017 11:27|
|Weak collagen matrix||August 03, 2017 11:28|
|Notochord distortion or malformations||August 03, 2017 11:29|
|Reduced, Swimming performance||November 29, 2016 19:36|
|Growth, reduction||August 03, 2017 11:31|
|Decreased, survival||December 03, 2016 16:37|
|Thiol protein adducts leads to Inhibition of lysyl oxidase||August 03, 2017 11:33|
|Inhibition of lysyl oxidase leads to Reduction of collagen crosslinking||August 03, 2017 11:34|
|Reduction of collagen crosslinking leads to Weak collagen matrix||August 03, 2017 11:35|
|Weak collagen matrix leads to Notochord malformation||August 03, 2017 11:36|
|Notochord malformation leads to Reduced, Swimming performance||August 03, 2017 11:37|
|Reduced, Swimming performance leads to Growth, reduction||August 03, 2017 11:37|
|Reduced, Swimming performance leads to Decreased, survival||August 03, 2017 11:38|
|Sodium metam||August 03, 2017 10:46|
|Dimethyl dithiocarbamate||August 03, 2017 10:49|
|Thiram||August 03, 2017 10:52|
|Disulfiram||August 03, 2017 10:53|
|Ferbam||August 03, 2017 10:54|
|Dazornet||August 03, 2017 10:56|
|Pyrolidine dithiocarbamate||August 03, 2017 10:57|
|Mancozeb||August 03, 2017 10:58|
|Maneb||November 29, 2016 18:42|
|Nabam-sodium||August 03, 2017 11:00|
|Ziram||August 03, 2017 11:15|
|Zineb||August 03, 2017 11:18|
Exposure of fish embryos to various dithiocarbamates elicited specific notochord distortions. Growth inhibitions in the FELS test for thiram, ziram, maneb and NaDTMC were observed in a range of concentrations close to those causing notochord distortions in zebrafish embryos. This notochord distortion appears to be caused by inhibition of the enzyme lysyl oxidase. Notochord malformation are caused by muscle contractions due to the weak resistance of the extracellular matrix. It can be assumed that the notochord distortions affect swimming behaviour and feeding, leading to the observed reduction in survival and growth observed in the FELS test.
This optional section should be used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development. The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. Instructions To add background information, click Edit in the upper right hand menu on the AOP page. Under the “Background (optional)” field, a text editable form provides ability to edit the Background. Clicking ‘Update AOP’ will update these fields.
Summary of the AOP
Molecular Initiating Event
|Thiol group of chemicals interact with sulfuhydryl groups of proteins to form thiol adducts||Thiol protein adducts|
|Inhibition of lysyl oxidase||Inhibition of lysyl oxidase|
|Reduction of collagen crosslinking||Reduction of collagen crosslinking|
|Weak collagen matrix||Weak collagen matrix|
|Notochord distortion or malformations||Notochord malformation|
|Reduced, Swimming performance||Reduced, Swimming performance|
Relationships Between Two Key Events (Including MIEs and AOs)
|Thiol protein adducts leads to Inhibition of lysyl oxidase||Directly leads to||Weak|
|Inhibition of lysyl oxidase leads to Reduction of collagen crosslinking||Directly leads to||Strong|
|Reduction of collagen crosslinking leads to Weak collagen matrix||Directly leads to||Weak|
|Weak collagen matrix leads to Notochord malformation||Directly leads to||Weak|
|Notochord malformation leads to Reduced, Swimming performance||Directly leads to||Weak|
|Reduced, Swimming performance leads to Growth, reduction||Directly leads to||Weak|
|Reduced, Swimming performance leads to Decreased, survival||Directly leads to||Weak|
Life Stage Applicability
Graphical RepresentationClick to download graphical representation template
Overall Assessment of the AOP
The evidence for the link between lysyl oxidase inhibition and enhanced chronic toxicity has been provided only for fish and can be concluded from various publications describing the impact of dithiocarbamate fungicides on lysyl oxidase enzyme inhibition, morpholino knock-down studies and embryonic malformations in zebrafish. The link to chronic toxicity is only provided via a meta-analysis of Fish Early Life Stage (FELS) tests that showed high toxic ratios (TR) and acute-to-chronic ratios (ACR) for dithiocarbamates. There is no study available that has analysed the the whole chain of AOP events within a single study and species, which may weaken the confidence in the AOP. Of particular regulatory relevance is the observations of malformations in fish embryos which may used to infer chronic fish toxicity from short term fish embryo tests.
Domain of Applicability
Fish, embryonic, larvae, juveniles
Essentiality of the Key Events
All key events are considered as essential but the weight-of-evidence is weak to mediocre given that MIEs, KEs and AO have been partially investigated in different studies with different experimental set-up.
Weight of Evidence Summary
Strong evidence for individual KER relationships that were however, provided from individual disconnected studies with different experimental setups and species. Therefore, the overall weight of evidence is estimated as weak.
Quantitative data are available from Tilton et al. (2006) which demonstrate a clear concentration - dependency of notochord malformation in zebrafish embryos exposed to diverse dithiocarbamates.No observed effect levels were calculated for the test compounds in this study. Similar malformations were shown for selected concentrations (probably concentration-dependent but not explicitely specified in the original publication) were also observed for rainbow trout (Leeuwen et al. 1986). A concentration dependent inhibition was shown for the enzyme lysyl oxidase in zebrafish by Boxtel et al. (2010). Morpholino injection in zebrafish to confirm that the observed notochord malformation phenotype is caused by interference with lysyl oxidase has been only provided for single selected concentrations and provoke the same phenotype as lysyl oxidase inhibition.
Considerations for Potential Applications of the AOP (optional)
At their discretion, the developer may include in this section discussion of the potential applications of an AOP to support regulatory decision-making. This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. While it is challenging to foresee all potential regulatory application of AOPs and any application will ultimately lie within the purview of regulatory agencies, potential applications may be apparent as the AOP is being developed, particularly if it was initiated with a particular application in mind. This optional section is intended to provide the developer with an opportunity to suggest potential regulatory applications and describe his or her rationale. Detailing such considerations can aid the process of transforming narrative descriptions of AOPs into practical tools. In this context, it is necessarily beneficial to involve members of the regulatory risk assessment community on the development and assessment team. The Network view which is generated based on assessment of weight of evidence/degree of confidence in the hypothesized AOP taking into account the elements described in Section 7 provides a useful summary of relevant information as a basis to consider appropriate application in a regulatory context. Consideration of application needs then, to take into consideration the following rank ordered qualitative elements: Confidence in biological plausibility for each of the KERs Confidence in essentiality of the KEs Empirical support for each of the KERs and overall AOP The extent of weight of evidence/confidence in both these qualitative elements and that of the quantitative understanding for each of the KERs (e.g., is the MIE known, is quantitative understanding restricted to early or late key events) is also critical in determining appropriate application. For example, if the confidence and quantitative understanding of each KER in a hypothesised AOP are low and or low/moderate and the evidence for essentiality of KEs weak (Section 7), it might be considered as appropriate only for applications with less potential for impact (e.g., prioritisation, category formation for testing) versus those that have immediate implications potentially for risk management (e.g., in depth assessment). If confidence in quantitative understanding of late key events is high, this might be sufficient for an in depth assessment. The analysis supporting the Network view is also essential in identifying critical data gaps based on envisaged regulatory application. Instructions To edit the “Considerations for Potential Applications of the AOP” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Considerations for Potential Applications of the AOP” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page. The new text should appear under the “Considerations for Potential Applications of the AOP” section on the AOP page.
Haendel, M.A., Tilton, F., Bailey, G.S., Tanguay, R.L., 2004. Developmental Toxicity of the Dithiocarbamate Pesticide Sodium Metam in Zebrafish. Tox. Sci. 81, 390-400.
Scholz, S., Schreiber, R., Armitage, J., Mayer, P., Escher, B., Lidzba, A., Léonard, M., Altenburger, R., Meta-analysis of fish early life stage tests – association of toxic ratios and acute-to-chronic ratios with modes of action
Manuscript in preparation.
Tilton, F., La Du, J.K., Vue, M., Alzarban, N., Tanguay, R.L., 2006. Dithiocarbamates have a common toxic effect on zebrafish body axis formation. Toxicol. Appl. Pharmacol. 216, 55-68.
Van Leeuwen, C.J., Espeldoorn, A., Mol, F., 1986. Aquatic toxicological aspects of dithiocarbamates and related compounds. III. Embryolarval studies with rainbow trout (Salmo gairdneri). Aquat. Toxicol. 9, 129-145.