Mind the gaps: Prioritizing activities to meet regulatory needs for acute systemic lethality

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Kristie M. Sullivan
David G. Allen
Amy J. Clippinger
Daniel M. Wilson
Stephen W. Edwards
Kyle Glover
Kamel Mansouri
Raja Settivari
Sanjeeva J. Wijeyesakere
Warren Casey

Abstract

Efforts are underway to develop and implement nonanimal approaches which can characterize acute systemic lethality. A workshop was held in October 2019 to discuss developments in the prediction of acute oral lethality for chemicals and mixtures, as well as progress and needs in the understanding and modeling of mechanisms of acute lethality. During the workshop, each speaker led the group through a series of charge questions to determine clear next steps to progress the aims of the workshop. Participants concluded that a variety of approaches will be needed and should be applied in a tiered fashion. Non-testing approaches, including waiving tests, computational models for single chemicals, and calculating the acute lethality of mixtures based on the LD50 values of mixture components, could be used for some assessments now, especially in the very toxic or non-toxic classification ranges. Agencies can develop policies indicating contexts under which mathematical approaches for mixtures assessment are acceptable; to expand applicability, poorly predicted mixtures should be examined to understand discrepancies and adapt the approach. Transparency and an understanding of the variability of in vivo approaches are crucial to facilitate regulatory application of new approaches. In a replacement strategy, mechanistically based in vitro or in silico models will be needed to support non-testing approaches especially for highly acutely toxic chemicals. The workshop discussed approaches that can be used in the immediate or near term for some applications and identified remaining actions needed to implement approaches to fully replace the use of animals for acute systemic toxicity testing.

Article Details

How to Cite
Sullivan, K. M., Allen, D. G., Clippinger, A. J., Wilson, D. M., Edwards, S. W., Glover, K., Mansouri, K., Settivari, R., Wijeyesakere, S. J. and Casey, W. (2021) “Mind the gaps: Prioritizing activities to meet regulatory needs for acute systemic lethality”, ALTEX - Alternatives to animal experimentation, 38(2), pp. 327-335. doi: 10.14573/altex.2012121.
Section
Meeting Reports
References

Al-Sabi, A., McArthur, J., Ostroumov, V. et al. (2006). Marine toxins that target voltage-gated sodium channels. Marine Drugs 4, 157-192. doi:10.3390/md403157

Ankley, G. T., Bennett, R. S., Erickson, R. J. et al. (2010). Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment. Environ Toxicol Chem 29, 730-741. doi:10.1002/etc.34

Bell, S., Abedini, J., Ceger, P. et al. (2020). An integrated chemical environment with tools for chemical safety testing. Toxicol In Vitro 67, 104916. doi:10.1016/j.tiv.2020.104916

Clippinger, A. J., Allen, D., Behrsing, H. et al. (2018). Pathway-based predictive approaches for non-animal assessment of acute inhalation toxicity. Toxicol In Vitro 52, 131-145. doi:10.1016/j.tiv.2018.06.009

Corvaro, M., Gehen, S., Andrews, K. et al. (2016). GHS additivity formula: A true replacement method for acute systemic toxicity testing of agrochemical formulations. Regul Toxicol Pharmacol 82, 99-110. doi:10.1016/j.yrtph.2016.10.007

EPA – Environmental Protection Agency (2012). Guidance for Waiving or Bridging of Mammalian Acute Toxicity Tests for Pesticides and Pesticide Products (Acute Oral, Acute Dermal, Acute Inhalation, Primary Eye, Primary Dermal, and Dermal Sensitization). https://www.epa.gov/sites/production/files/documents/acute-data-waiver-guidance.pdf

EPA (2016). Guidance for Waiving Acute Dermal Toxicity Tests for Pesticide Formulations & Supporting Retrospective Analysis. https://bit.ly/3bSAY1W

EPA (2020). Public Review Draft - Guidance for Waiving Acute Dermal Toxicity Tests for Pesticide Technical Chemicals & Supporting Retrospective Analysis, September 2020. https://bit.ly/2P4LYQI

Hamm, J., Sullivan, K., Clippinger, A. J. et al. (2017). Alternative approaches for identifying acute systemic toxicity: Moving from research to regulatory testing. Toxicol In Vitro 41, 245-259. doi:10.1016/j.tiv.2017.01.004

ICCVAM (2018). A strategic roadmap for establishing new approaches to evaluate the safety of chemicals and medical products in the United States. doi:10.22427/NTP-ICCVAM-ROADMAP2018

Isbister, G. K., Bowe, S. J., Dawson, A. et al. (2004). Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. J Toxicol Clin Toxicol 42, 277-285. doi:10.1081/clt-120037428

Kleinstreuer, N. C., Karmaus, A., Mansouri, K. et al. (2018). Predictive models for acute oral systemic toxicity: A workshop to bridge the gap from research to regulation. Comput Toxicol 8, 21-24. doi:10.1016/j.comtox.2018.08.002

Mansouri, K., Grulke, C. M., Judson, R. S. et al. (2018). Opera models for predicting physicochemical properties and environmental fate endpoints. J Cheminform 10, 10. doi:10.1186/s13321-018-0263-1

Mansouri, K., Cariello, N. F., Korotcov, A. et al. (2019). Open-source QSAR models for pKa prediction using multiple machine learning approaches. J Cheminform 11, 60. doi:10.1186/s13321-019-0384-1

Mansouri, K., Karmaus A., Fitzpatrick J. et al. (submitted). CATMoS: Collaborative acute toxicity modeling suite. Environ Health Perspectives.

OECD – Organisation for Economic Cooperation and Development (2017). Guidance Document on Considerations for Waiving or Bridging of Mammalian Acute Toxicity Tests. Series on Testing and Assessment, No. 237. OECD Publishing, Paris. doi:10.1787/9789264274754-en

PMRA Health Canada (2013). Guidance for Waiving or Bridging of Mammalian Acute Toxicity Tests for Pesticides. https://bit.ly/3cBmvXo

PMRA Health Canada (2017). Science Policy Note SPN2017-03, Acute Dermal Toxicity Study Waiver. https://bit.ly/2OZa9QT

Prieto, P., Graepel, R., Gerloff, K. et al. (2019). Investigating cell type specific mechanisms contributing to acute oral toxicity. ALTEX 36, 39-64. doi:10.14573/altex.1805181

Sowa-Rogozinska, N., Sominka, H., Nowakowska-Golacka, J. et al. (2019). Intracellular transport and cytotoxicity of the protein toxin ricin. Toxins (Basel) 11, 350. doi:10.3390/toxins11060350

Strickland, J., Clippinger, A. J., Brown, J. et al. (2018). Status of acute systemic toxicity testing requirements and data uses by U.S. regulatory agencies. Regul Toxicol Pharmacol 94, 183-196. doi:10.1016/j.yrtph.2018.01.022

UN – United Nations (2015). Globally harmonized system of classification and labelling of chemicals (GHS) – Sixth revised edition. doi:10.18356/1e984724-en

Van Cott, A., Hastings, C. E., Landsiedel, R. et al. (2018). GHS additivity formula: Can it predict the acute systemic toxicity of agrochemical formulations that contain acutely toxic ingredients? Regul Toxicol Pharmacol 92, 407-419. doi:10.1016/j.yrtph.2017.12.024

Wijeyesakere, S. A., Wilson, D., Settivari, R. S. et al. (2018). Development of a profiler for facile chemical reactivity using the open-source Konstanz information miner. Appl In Vitro Toxicol 4, 202-213. doi:10.1089/aivt.2017.0040

Wijeyesakere, S. A., Wilson, D., Auernhammer, T. R. et al. (2019). Hybrid machine-learning/smarts profiling model for mitochondrial inhibition. Appl In Vitro Toxicol 5, 196-204. doi:10.1089/aivt.2019.0010

Wilson, D., Wijeyesakere, S. A., Parks, A. K. et al. (2018). Profiling acute oral and inhalation toxicity data using a computational workflow to screen for facile chemical reactivity. Appl In Vitro Toxicol 4, 214-219. doi:10.1089/aivt.2017.0041

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