Recommendations on dose level selection for repeat dose toxicity studies
Tóm tắt
Prior to registering and marketing any new pharmaceutical, (agro)chemical or food ingredient product manufacturers must, by law, generate data to ensure human safety. Safety testing requirements vary depending on sector, but generally repeat-dose testing in animals form the basis for human health risk assessments. Dose level selection is an important consideration when designing such studies, to ensure that exposure levels that lead to relevant hazards are identified. Advice on dose level selection is provided in test guidelines and allied guidance documents, but it is not well harmonised, particularly for selection of the highest dose tested. This paper further builds on concepts developed in a technical report by the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) which recommends pragmatic approaches to dose selection considering regulatory requirements, animal welfare and state of the art scientific approaches. Industry sectors have differing degrees of freedom to operate regarding dose level selection, depending on the purpose of the studies and the regulatory requirements/legislation, and this is reflected in the overall recommended approaches. An understanding of systemic exposure should be utilised where possible (e.g., through toxicokinetic approaches) and used together with apical endpoints from existing toxicity studies to guide more appropriate dose level selection. The highest dose should be limited to a reasonable level, causing minimal but evident toxicity to the test animals without significantly compromising their well-being. As the science of predictive human exposure further develops and matures, this will provide exciting and novel opportunities for more human-relevant approaches to dose level selection.
Tài liệu tham khảo
Barile FA, Berry SC, Blaauboer B et al (2021) The EU chemicals strategy for sustainability: in support of the BfR position. Arch Toxicol 95:3133–3136. https://doi.org/10.1007/s00204-021-03125-w
Beyer BK, Chernoff N, Danielsson BR, Davis-Bruno K, Harrouk W, Hood RD, Janer G, Liminga UW, Kim JH, Rocca M, Rogers J, Scialli AR (2011) ILSI/HESI maternal toxicity workshop summary: maternal toxicity and its impact on study design and data interpretation. Birth Def Res B 92:36–51
Chapman K, Sewell F, Allais L, Delongeas JL, Donald E, Festag M, Kervyn S, Ockert D, Nogues V, Palmer H, Popovic M, Roosen W, Schoenmakers A, Somers K, Stark C, Stei P, Robinson S (2013) A global pharmaceutical company initiative: an evidence-based approach to define the upper limit of body weight loss in short term toxicity studies. Regul Toxicol Pharmacol 67:27–38
Chapman K, Burnett J, Corvaro M, Mitchell D, Robinson S, Sangster T, Sparrow S, Spooner N, Wilson A (2014) Reducing pre-clinical blood volumes for toxicokinetics: toxicologists, pathologists and bioanalysts unite. Bioanalysis 6:2965–2968
ECHA (2017) European chemical agency guidance for the implementation of REACH. Guidance on information requirements and chemical safety assessment, chapter R.7C: endpoint specific guidance Version 3.0 (ECHA-17-G-11-EN). EChA, Helsinki, 2017. https://echa.europa.eu/documents/10162/17224/information_requirements_r7c_en.pdf/e2e23a98-adb2-4573-b450-cc0dfa7988e5?t=1498476107907
ECHA (2021) European chemical agency. Critical aspects for designing and conducting extended one-generation reproductive toxicity (EOGRT) studies under REACH. EChA, Helsinki, 2021. https://echa.europa.eu/documents/10162/17228/critical_eogrts_info_en.pdf/3968d81b-51f0-a114-5246-8919954a5efc?t=1625565738753
ECHA (2022a) European chemical agency. Advice on dose-level selection for the conduct of sub-acute and sub-chronic assays under REACH. EChA, Helsinki, 2022. https://echa.europa.eu/documents/10162/17220/211221_echa_advice_dose_rdt_en.pdf/63e6d895-a80c-f6f4-99c8-c5a3248ce02a?t=1640082455790
ECHA (2022b) European chemical agency. Advice on dose-level selection for the conduct of reproductive toxicity studies (OECD TGs 414, 421/422 and 443) under REACH. EChA, Helsinki, 2022. https://echa.europa.eu/documents/10162/17220/211221_echa_advice_dose__repro_en.pdf/27159fb1-c31c-78a2-bdef-8f423f2b6568?t=1640082455275
ECETOC (2021) European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) Guidance on Dose Selection. Technical report No. 138. Brussels, March 2021. ISSN-2079-1526-138 (online). https://www.ecetoc.org/wpcontent/uploads/2021/03/ECETOC-TR-138-Guidance-on-Dose-Selection.pdf
EU (2020) Communication from the commission to the european parliament, the council, the european economic and social committee and the committee of the regions. Chemicals strategy for sustainability: towards a toxic-free environment. COM(2020) 667 final. https://ec.europa.eu/environment/pdf/chemicals/2020/10/Strategy.pdf
EU (2021) Consolidated text: regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending regulation (EC) No 1907/2006 (Text with EEA relevance). https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A02008R1272-20211001
FELASA (1994) Pain and distress in laboratory rodents and loagomorphs. Report of the federation of European laboratory animal science associations (FELASA) working group on pain and distress. Lab Anim 28:97–112
Guillen J (2012) FELASA guidelines and recommendations. J Am Assoc Lab Anim Sci: JAALAS 51(3):311–321
Hawkins et al (2016) A good death? Report of the second Newcastle meeting on laboratory animal euthanasia. Animals 6(9): 50. https://www.mdpi.com/2076-2615/6/9/50
Heringa MB, Cnubben N, Slob W, Pronk M, Muller A, Woutersen M, Hakkert BC (2020) Use of the kinetically-derived maximum dose concept in selection of top doses for toxicity studies hampers proper hazard assessment and risk management. Regul Toxicol Pharmacol: RTP 114:104659. https://doi.org/10.1016/j.yrtph.2020.104659
Herzler M, Marx-Stoelting P, Pirow R, Riebeling C, Luch A, Tralau T, Schwerdtle T, Hensel A (2021) The “EU chemical strategy for sustainability” questions regulatory toxicology as we know it: is it all rooted in sound scientific evidence? Arch Toxicol 95:2589–2601
LASA/NC3Rs (2009) Guidance on dose level selection for regulatory general toxicology studies for pharmaceuticals. NC3Rs, London
Leary et al (2020) Members of the panel on euthanasia, AVMA guidelines for the euthanasia of animals: 2020 edition. Available from Internet: https://www.avma.org/sites/default/files/2020-01/2020_Euthanasia_Final_1-15-20.pdf
OECD (2002a) Guidance notes for analysis and evaluation of chronic toxicity and carcinogenicity studies, OECD series on testing and assessment, no. 35. OECD Publishing, Paris. https://doi.org/10.1787/9789264078499-en
OECD (2002b) Guidance document on the recognition, assessment and use of clinical signs as human endpoints for experimental animals used in safety evaluation, OECD series on testing and assessment, no. 19. OECD Publishing, Paris
OECD (2014) Guidance document 116 on the conduct and design of chronic toxicity and carcinogenicity studies, supporting test guidelines 451, 452 and 453: second edition, OECD Series on testing and assessment, No. 116. OECD Publishing, Paris. https://doi.org/10.1787/9789264221475-en
OECD (2018a) Test no. 408: repeated dose 90-day oral toxicity study in rodents, OECD guidelines for the testing of chemicals, section 4. OECD Publishing, Paris
OECD (2018b) Test no. 443: extended one-generation reproductive toxicity study, OECD guidelines for the testing of chemicals, section 4. OECD Publishing, Paris
OECD (2021) QSAR toolbox https://www.oecd.org/chemicalsafety/risk-assessment/oecd-qsar-toolbox.htm
Russell WMS, Burch RL (1959) The principles of humane experimental technique. Methuen, London
Sewell F, Ragan I, Marczylo T, Anderson B, Braun A, Casey W, Dennison N, Griffiths D, Guest R, Holmes T, van Huygevoort T, Indans I, Kenny T, Kojima H, Lee K, Prieto P, Smith P, Smedley J, Stokes WS, Wnorowski G, Horgan G (2015) A global initiative to refine acute inhalation studies through the use of “evident toxicity” as an endpoint: towards adoption of the fixed concentration procedure. Regul Toxicol Pharmacol 73(3):770–779. https://doi.org/10.1016/j.yrtph.2015.10.018
Sewell F, Aggarwal M, Bachler G, Broadmeadow A, Gellatly N, Moore E, Robinson S, Rooseboom M, Stevens A, Terry C, Burden N (2017) The current status of exposure-driven approaches for chemical safety assessment: A cross-sector perspective. Toxicology 389:109–117. https://doi.org/10.1016/j.tox.2017.07.018
Sewell F, Kimber I, Boobis AR (2020) Letter to the editor: use of the kinetically-derived maximum dose: opportunities for delivering 3rs benefits. Regul Toxicol Pharmacol 116:104734. https://doi.org/10.1016/j.yrtph.2020.104734
Sewell F, Lewis R, Mehta J, Terry C, Kimber I (2021) Rethinking agrochemical safety assessment: a perspective. Regul Toxicol Pharmacol. https://doi.org/10.1016/j.yrtph.2021.105068
Slob W, Zeilmaker MJ, Hoogenveen RT (2020) The relationship between internal and external dose: some general results based on a generic compartmental model. Toxicol Sci 177(1):60–70. https://doi.org/10.1093/toxsci/kfaa082 (PMID: 32514576)
Smith CJ, Perfetti TA (2020) Letter to the editors regarding Heringa et al. Regul Toxicol Pharmacol 116:104722. https://doi.org/10.1016/j.yrtph.2020.104722
Tan YM, Barton H, Boobis A, Brunner R, Clewell H, Cope R, Dawson J, Domoradzki J, Egeghy P, Gulati P, Ingle B, Kleinstreuer N, Lowe K, Lowit A, Mendez E, Miller D, Minucci J, Nguyen J, Paini A, Perron M, Phillips K, Qian H, Ramanarayanan T, Sewell F, Villanueva P, Wambaugh J, Embry M (2021) Opportunities and challenges related to saturation of toxicokinetic processes: implications for risk assessment. Regul Toxicol Pharmacol 127:105070
Terry C, Domoradzki J, Fleming C, Gehen S, Mingoia R, Murphy L, Bartels M (2020) Letter to the editor. Regul Toxicol Pharmacol 117:104765
United Nations (2021) Globally harmonized system of classification and labelling of chemicals (GHS); 9th revised edition. ST/SG/AC.10/30/rev.9. United Nations, New York
Woutersen M, Muller A, Pronk M, Cnubben N, Hakkert BC (2020) Regulating human safety: how dose selection in toxicity studies impacts human health hazard assessment and subsequent risk management options. Regul Toxicol Pharmacol: RTP 114:104660. https://doi.org/10.1016/j.yrtph.2020.104660