Approaches to interspecies extrapolation of inhalation toxic doses (literature review)

In toxicity studies on laboratory animals, a priority task is to establish reliable toxicometric characteristics of compounds, including threshold, effective (ED), and lethal (LD) doses, in accordance with the objectives of the experiment. In the case of inhalation exposure to a toxicant, there are difficulties in calculating absorbed doses, which are related both to the influence of the physical and chemical properties of the toxicant and to the species-specific characteristics of the biological test subjects used in the study. This feature poses a challenge in the interspecies extrapolation of inhalation doses to humans, making it difficult to plan and conduct further experiments. This study aims to review the domestic and foreign literature on the interspecies extrapolation of inhalation doses. The main databases used for searching scientific publications were PubMed, Google Scholar, and Web of Science. The study provides an analysis of the key biological determinants that influence the efficacy of toxicants, including anatomical and morphological features, physiological parameters, and pathological changes in laboratory animals. Additionally, the study highlights the main physical and chemical properties of compounds that affect the interaction of the system with the xenobiotic. Special attention is given to aerosol generation parameters, which are essential for assessing the risks of toxicant exposure on biological subjects. Based on the analysis, the most optimal method for calculating absorbed doses is proposed, taking into account the specific features of the respiratory systems of living organisms during experimental studies. Furthermore, key approaches for extrapolating inhalation doses to humans are outlined, including the allometric approach, the use of interspecies and dosimetric coefficients, and the physiologically based pharmacokinetic model (PBPK).

Authors’ contribution:
Popov N.S. – the concept and design of the study, collection of material, writing a text;
Konshakov Yu.O. – the concept and design of the study, editing;
Ustinova T.M. – collection of material;
Vengerovich N.G. – editing.
All co-authors – are responsible for the integrity of all parts of the manuscript and approval of the manuscript final version.

Conflict of interest. The authors declare no apparent and potential conflicts of interest in relation to the publication of this article.

Funding. The study had no sponsorship.

Received: May 25, 2025 / Revised: June 27, 2025 / Accepted: March 27, 2026 / Published: April 30, 2026

1. Basil M.C., Morrisey E.E. Lung regeneration: a tale of mice and men. Semin. Cell Dev. Biol. 2020; 100: 88–100. https://doi.org/10.1016/j.semcdb.2019.11.006

2. Rogers T.D., Button B., Kelada S.N.P., Ostrowski L.E., Livraghi-Butrico A., Gutay M.I., et al. Regional differences in mucociliary clearance in the upper and lower airways. Front. Physiol. 2022; 13: 842592. https://doi.org/10.3389/fphys.2022.842592

3. Kargopoltceva D.R., Katelnikova A.E., Kryshen K.L., Guschin Ya.A. Features of the respiratory system of animals used in pre-clinical studies which should be taken account of the modeling lung pathologies. Laboratornye zhivotnye dlya nauchnykh issledovanii. 2020; (4): 71–85. https://doi.org/10.29296/2618723X-2020-04-08 https://elibrary.ru/kcvtrp (in Russian)

4. Froehlich E. Replacement strategies for animal studies in inhalation testing. Sci. 2021; 3(4): 45. https://doi.org/10.3390/sci3040045

5. Price D.N., Kunda N.K., Muttil P. Challenges associated with the pulmonary delivery of therapeutic dry powders for preclinical testing. KONA Powder Part. J. 2019; 36: 129–44. https://doi.org/10.14356/kona.2019008

6. Stucki A.O., Sauer U.G., Allen D.G., Kleinstreuer N.C., Perron M.M., Yozzo K.L., et al. Differences in the anatomy and physiology of the human and rat respiratory tracts and impact on toxicological assessments. Regul. Toxicol. Pharmacol. 2024; 150: 105648. https://doi.org/10.1016/j.yrtph.2024.105648

7. Roth D., Şahin A.T., Ling F., Tepho N., Senger C.N., Quiroz E.J., et al. Structure and function relationships of mucociliary clearance in human and rat airways. Nat. Commun. 2025; 16(1): 2446. https://doi.org/10.1038/s41467-025-57667-z

8. Jekl V. Respiratory disorders in rabbits. Vet. Clin. North Am. Exot. Anim. Pract. 2021; 24(2): 459–82. https://doi.org/10.1016/j.cvex.2021.01.006

9. Tanner L., Single A.B. Animal models reflecting chronic obstructive pulmonary disease and related respiratory disorders: translating pre-clinical data into clinical relevance. J. Innate Immun. 2020; 12(3): 203–25. https://doi.org/10.1159/000502489

10. Khokhlova N.A., Vostroilova N.A., Fedorova N.M., Lobodina T.E. Study of the allergenic properties of the drug aminoseleton. Teoreticheskie i prikladnye aspekty sovremennoi nauki. 2015; (8-1): 98–101. https://elibrary.ru/tlhxsv (in Russian)

11. Yarto-Jaramillo E. Respiratory system anatomy, physiology, and disease: Guinea pigs and chinchillas. Vet. Clin. North Am. Exot. Anim. Pract. 2011; 14(2): 339–55. https://doi.org/10.1016/j.cvex.2011.03.008

12. Budnevskiy A.V., Avdeev S.N., Ovsyannikov E.S., Feygelman S.N. A modern view of cough pathophysiology. Tuberkulez i bolezni legkikh. 2024; 102(6): 118–26. https://doi.org/10.58838/2075-1230-2024-102-6-118-126 https://elibrary.ru/wsewxv (in Russian)

13. Lunney J.K., Van Goor A., Walker K.E., Hailstock T., Franklin J., Dai C. Importance of the pig as a human biomedical model. Sci. Transl. Med. 2021; 13(621): eabd5758. https://doi.org/10.1126/scitranslmed.abd5758

14. Kutsenko S.A. Fundamentals of Toxicology [Osnovy toksikologii]. St. Petersburg: Foliant; 2004. https://elibrary.ru/qkmwib (in Russian)

15. Rathod H.K.K., Katekar V.A., Dhole Y.R., Nalinde P.S. Pulmonary drug delivery system: A review. GSC Biol. Pharm. Sci. 2023; 25(03): 148–59. https://doi.org/10.30574/gscbps.2023.25.3.0473

16. Scott A.K. Stereoisomers and drug toxicity. The value of single stereoisomer therapy. Drug Saf. 1993; 8(2): 149–59. https://doi.org/10.2165/00002018-199308020-00005

17. Kuentz M.T., Arnold Y. Influence of molecular properties on oral bioavailability of lipophilic drugs – mapping of bulkiness and different measures of polarity. Pharm. Dev. Technol. 2009; 14(3): 312–20. https://doi.org/10.1080/10837450802626296

18. Manallack D.T., Prankerd R.J., Yuriev E., Oprea T.I., Chalmers D.K. The significance of acid/base properties in drug discovery. Chem. Soc. Rev. 2013; 42(2): 485–96. https://doi.org/10.1039/c2cs35348b

19. Charifson P.S., Walters W.P. Acidic and basic drugs in medicinal chemistry:a perspective. J. Med. Chem. 2014; 57(23): 9701–17. https://doi.org/10.1021/jm501000a

20. Kuehl P.J., Anderson T.L., Candelaria G., Gershman B., Harlin K., Hesterman J.Y., et al. Regional particle size dependent deposition of inhaled aerosols in rats and mice. Inhal. Toxicol. 2012; 24(1): 27–35. https://doi.org/10.3109/08958378.2011.632787

21. Perfilieva K.G., Zolotorev N.N. Experimental study of the surface tension effect on regularities of liquid dispersion by ejective sprayer. In: Prospects for the Development of Fundamental Sciences. Collection of Scientific Papers of the XX International Conference of Students, Postgraduates and Young Scientists. Volume 1 [Perspektivy razvitiya fundamental’nykh nauk. Sbornik nauchnykh trudov XX Mezhdunarodnoi konferentsii studentov, aspirantov i molodykh uchenykh. Tom 1]. Tomsk; 2023: 303–5. https://elibrary.ru/xhryaj (in Russian)

22. Ghazanfari T., Elhissi A.M., Ding Z., Taylor K.M. The influence of fluid physicochemical properties on vibrating-mesh nebulization. Int. J. Pharm. 2007; 339(1-2): 103–11. https://doi.org/10.1016/j.ijpharm.2007.02.035

23. Arkhipov V.A., Basalaev S.A., Matvienko O.V., Perfileva K.G., Usanina A.S. Generation and Evolution of a Liquid-Droplet Aerosol Cloud in a Gravity Field [Generatsiya i evolyutsiya zhidko-kapel’nogo aerozol’nogo oblaka v pole sily tyazhesti]. Tomsk; 2022. https://elibrary.ru/issbpe (in Russian)

24. Kudryashova O.B., Antonnikova A.A., Korovina N.V., Vorozhtsov B.I. Evaporation of finely dispersed water aerosol under different external conditions. Polzunovskii vestnik. 2013; (3): 111–4. https://elibrary.ru/rddxfd (in Russian)

25. Piskunov V.N. Aerosol Dynamics [Dinamika aehrozolei]. Moscow: Fizmatlit; 2010. https://elibrary.ru/ryrslr (in Russian)

26. Alexander D.J., Collins C.J., Coombs D.W., Gilkison I.S., Hardy C.J., Healey G., et al. Association of Inhalation Toxicologists (AIT) working party recommendation for standard delivered dose calculation and expression in non-clinical aerosol inhalation toxicology studies with pharmaceuticals. Inhal. Toxicol. 2008; 20(13): 1179–89. https://doi.org/10.1080/08958370802207318

27. Phillips J.E. Inhaled efficacious dose translation from rodent to human: A retrospective analysis of clinical standards for respiratory diseases. Pharmacol. Ther. 2017; 178: 141–7. https://doi.org/10.1016/j.pharmthera.2017.04.003

28. Chapell W.R., Mordenti J. Extrapolation of toxicological and pharmacological data from animals to humans. Adv. Drug Res. 1991; 20: 1–116. https://doi.org/10.1016/B978-0-12-013320-8.50005-8

29. EPA. Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry; 1994. Available at: https://epa.gov/risk/methods-derivation-inhalation-reference-concentrations-and-application-inhalation-dosimetry

30. Lancheros Porras K.D., Alves I.A., Novoa D.M.A. PBPK modeling as an alternative method of interspecies extrapolation that reduces the use of animals: a systematic review. Curr. Med. Chem. 2024; 31(1): 102–26. https://doi.org/10.2174/0929867330666230408201849

31. Shekunova E.V., Kovaleva M.A., Makarova M.N., Makarov V.G. Dose selection in preclinical studies: cross-species dose conversion. Vedomosti nauchnogo tsentra ekspertizy sredstv meditsinskogo primeneniya. 2020; 10(1): 19–28. https://doi.org/10.30895/1991-2919-2020-10-1-19-28 https://elibrary.ru/kvzbbv (in Russian)

32. Dedrick R.L. Animal scale-up. J. Pharmacokinet. Biopharm. 1973; 1(5): 435–61. https://doi.org/10.1007/BF01059667

33. Boxenbaum H. Interspecies scaling, allometry, physiological time, and the ground plan of pharmacokinetics. J. Pharmacokinet. Biopharm. 1982; 10(2): 201–27. https://doi.org/10.1007/BF01062336

34. Mahmood I. Interspecies scaling of Antibody-Drug Conjugates (ADC) for the prediction of human clearance. Antibodies (Basel). 2021; 10(1): 1. https://doi.org/10.3390/antib10010001

35. Gus’kova T.A., Arzamastsev E.V., Rudakov A.G., Liberman S.S., Verstakova O.L., Lyubimov B.I. Methodological recommendations for studying the general toxic effect of pharmacological agents. Vedomosti farmakologicheskogo fakul’teta. 1998; (1): 27–32. (in Russian)

36. Kuempel E.D., Sweeney L.M., Morris J.B., Jarabek A.M. Advances in inhalation dosimetry models and methods for occupational risk assessment and exposure limit derivation. J. Occup. Environ. Hyg. 2015; 12(Suppl. 1): S18–40. https://doi.org/10.1080/15459624.2015.1060328

37. Boddu R., Kollipara S., Vijaywargi G., Ahmed T. Power of integrating PBPK with PBBM (PBPK-BM): a single model predicting food effect, gender impact, drug-drug interactions and bioequivalence in fasting & fed conditions. Xenobiotica. 2023; 53(4): 260–78. https://doi.org/10.1080/00498254.2023.2238048

38. Huang H., Zhao W., Qin N., Duan X. Recent Progress on Physiologically Based Pharmacokinetic (PBPK) model: a review based on bibliometrics. Toxics. 2024; 12(6): 433. https://doi.org/10.3390/toxics12060433

39. Sarangapani R., Teeguarden J.G., Gentry P.R., Clewell H.J. 3rd, Barton H.A., Bogdanffy M.S. Interspecies dose extrapolation for inhaled dimethyl sulfate: a PBPK model-based analysis using nasal cavity N7-methylguanine adducts. Inhal. Toxicol. 2004; 16(9): 593–605. https://doi.org/10.1080/08958370490464562

40. Lin Z., Monteiro-Riviere N.A., Kannan R., Riviere J.E. A computational framework for interspecies pharmacokinetics, exposure and toxicity assessment of gold nanoparticles. Nanomedicine (Lond.). 2016; 11(2): 107–19. https://doi.org/10.2217/nnm.15.177

41. Hall C., Lueshen E., Mošat’ A., Linninger A.A. Interspecies scaling in pharmacokinetics: a novel whole-body physiologically based modeling framework to discover drug biodistribution mechanisms in vivo. J. Pharm. Sci. 2012; 101(3): 1221–41. https://doi.org/10.1002/jps.22811

42. Kirman C.R., Sweeney L.M., Meek M.E., Gargas M.L. Assessing the dose-dependency of allometric scaling performance using physiologically based pharmacokinetic modeling. Regul. Toxicol. Pharmacol. 2003; 38(3): 345–67. https://doi.org/10.1016/j.yrtph.2003.07.004

43. Yu R., Jusko W.J. Physiologically-based modeling of methylprednisolone pharmacokinetics across species with extrapolations to humans. J. Pharm. Sci. 2025; 114(5): 103719. https://doi.org/10.1016/j.xphs.2025.103719

44. Taverne F.J., van Geijlswijk I.M., Heederik D.J., Wagenaar J.A., Mouton J.W. Modelling concentrations of antimicrobial drugs: comparative pharmacokinetics of cephalosporin antimicrobials and accuracy of allometric scaling in food-producing and companion animals. BMC Vet. Res. 2016; 12(1): 185. https://doi.org/10.1186/s12917-016-0817-2