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The Local Lymph Node Assay

  • David A. Basketter
  • Ian Kimber
  • G. Frank Gerberick
Chapter

Abstract

The local lymph node assay (LLNA) was the first alternative method to undergo formal validation for skin sensitisation hazard identification, followed by the challenges of regulatory acceptance, and so provided lessons for the entire process. What ensued has been instructive for test developers and those involved in validation and acceptance: widespread use of the LLNA led to questions and challenges not anticipated in the development and validation activity; the LLNA was applied to regulatory toxicology, such as in testing of formulations, despite no evidence of functionality for that purpose; perceived imperfections with the assay led some to view the preceding guinea pig methods with rosy nostalgia, even though those methods had not been validated. However, for the toxicology community, the main interest was the evolution of the LLNA from a hazard identification tool to a technique for measurement of the relative potency of skin sensitising chemicals. It is in this manifestation that the LLNA has proven of greatest utility in terms of driving improvements in risk assessment, risk management and protection of human health.

References

  1. 1.
    Botham PA, Basketter DA, Maurer T, Mueller D, Potokar M, Bontinck WJ. Skin sensitization - a critical review of predictive test methods in animal and man. Food Chem Toxicol. 1991;29:275–86.CrossRefPubMedGoogle Scholar
  2. 2.
    Kimber I, Weisenberger C. A murine local lymph node assay for the identification of contact allergens. Arch Toxicol. 1989;63:274–82.Google Scholar
  3. 3.
    Kimber I, Basketter DA. The murine local lymph node assay; collaborative studies and new directions: a commentary. Food Chem Toxicol. 1992;30:165–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Kimber I, Hilton J, Botham PA, Basketter DA, Scholes EW, Miller K, Robbins MC, Gray TJB, Waite SJ. The murine local lymph node assay. Results of an interlaboratory trial. Toxicol Lett. 1991;55:203–13.CrossRefPubMedGoogle Scholar
  5. 5.
    Basketter DA, Scholes EW, Kimber I, Botham PA, Hilton J, Miller K, Robbins MC, Harrison PTC, Waite SJ. Interlaboratory evaluation of the local lymph node assay with 25 chemicals and comparison with guinea pig tests. Toxicol Methods. 1991;1:30–43.CrossRefGoogle Scholar
  6. 6.
    Scholes EW, Basketter DA, Sarll AE, Kimber I, Evans CD, Miller K, Robbins MC, Harrison PTC, Waite SJ. The local lymph node assay: results of a final interlaboratory validation under field conditions. J Appl Toxicol. 1992;12:217–22.CrossRefPubMedGoogle Scholar
  7. 7.
    Basketter DA, Selbie E, Scholes EW, Lees D, Kimber I, Botham PA. Results with OECD recommended positive control sensitizers in the maximisation, Buehler and local lymph node assays. Food Chem Toxic. 1993;31:63–7.CrossRefGoogle Scholar
  8. 8.
    Kimber I, Hilton J, Dearman RJ, Gerberick GF, Ryan CA, Basketter DA, Scholes EW, Ladics GS, Loveless SE, House RV, Guy A. An international evaluation of the local lymph node assay and comparison of modified procedures. Toxicology. 1995;103:63–73.CrossRefPubMedGoogle Scholar
  9. 9.
    Kimber I, Hilton J, Dearman RJ, Gerberick GF, Ryan CA, Basketter DA, Lea L, House RV, Ladics GS, Loveless SE, Hastings KL. Assessment of the skin sensitization potential of topical medicaments using the local lymph node assay: an interlaboratory exercise. J Toxicol Environ Health. 1998;53:563–79.CrossRefGoogle Scholar
  10. 10.
    Loveless SE, Ladics GS, Gerberick GF, Ryan CA, Basketter DA, Scholes EW, House RV, Hilton J, Dearman RJ, Kimber I. Further evaluation of the local lymph node assay in the final phase of an international collaborative trial. Toxicology. 1996;108:141–52.CrossRefPubMedGoogle Scholar
  11. 11.
    Dearman RJ, Hilton J, Evans P, Harvey P, Basketter DA, Kimber I. Temporal stability of local lymph node assay responses to hexyl cinnamic aldehyde. J Appl Toxicol. 1998;18:281–4.CrossRefPubMedGoogle Scholar
  12. 12.
    Basketter DA, Gerberick GF, Kimber I, Loveless SE. The local lymph node assay - a viable alternative to currently accepted skin sensitisation tests. Food Chem Toxicol. 1996;34:985–97.CrossRefPubMedGoogle Scholar
  13. 13.
    Chamberlain M, Basketter DA. The local lymph node assay: status of validation. Food Chemical Toxicol. 1996;34:999–1002.CrossRefGoogle Scholar
  14. 14.
    Dean JH, Twerdok LE, Tice RR, Sailstad DM, Hattan DG, Stokes WS. ICCVAM evaluation of the murine local lymph node assay. II conclusions and recommendations of an independent scientific peer review panel. Reg Toxicol Pharmacol. 2001;34:258–73.CrossRefGoogle Scholar
  15. 15.
    Sailstad DM, Hattan D, Hill RN, Stokes WS. ICCVAM evaluation of the murine local lymph node assay. I. The ICCVAM review process. Reg Toxicol Pharmacol. 2001;34:249–57.CrossRefGoogle Scholar
  16. 16.
    Gerberick GF, Ryan CA, Kimber I, Dearman RJ, Lea LJ, Basketter DA. Local lymph node assay validation assessment for regulatory purposes. Am J Cont Derm. 2000;11:3–18.CrossRefGoogle Scholar
  17. 17.
    OECD. Local lymph node assay test guideline no 429. Paris: Organisation for Economic Cooperation and Development; 2002.Google Scholar
  18. 18.
    OECD. Test guideline 429: The local lymph node assay. Paris: Organisation for Economic Cooperation and Development; 2010a.CrossRefGoogle Scholar
  19. 19.
    Basketter DA, Blaikie L, Dearman RJ, Kimber I, Ryan CA, Gerberick GF, Harvey P, Evans P, White IR, Rycroft RJG. Use of the local lymph node assay for the estimation of relative contact allergenic potency. Contact Dermatitis. 2000;42:344–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Balls M, Amcoff P, Bremer S, Casati S, Coecke S, Clothier R, et al. Zuang V; ECVAM. The principles of weight of evidence validation of test methods and testing strategies. The report and recommendations of ECVAM workshop 58. Altern Lab Anim. 2006;34(6):603–20.Google Scholar
  21. 21.
    Basketter DA, Gerberick GF, Kimber I. Strategies for identifying false positive responses in predictive sensitisation tests. Food Chem Toxicol. 1998;36:327–33.Google Scholar
  22. 22.
    Basketter DA, Cockshott A, Corsini E, Gerberick GF, Idehara K, Kimber I, et al. An evaluation of performance standards and non-radioactive endpoints for the local lymph node assay. ATLA. 2008;36:243–57.Google Scholar
  23. 23.
    Basketter DA, Ball N, Cagen S, Carrillo J-C, Certa H, Eigler D, et al. Application of a weight of evidence approach to analysing discordant sensitization datasets: implication for REACH. Regul Toxicol Pharmacol. 2009a;55:90–6.Google Scholar
  24. 24.
    Kreiling R, Hollnagel HM, Hareng L, Eigler D, Lee MS, Griem P, et al. Comparison of the skin sensitizing potential of unsaturated compounds as assessed by the murine local lymph node assay (LLNA) and the guinea pig maximization test (GPMT). Food Chem Toxicol. 2008;46(6):1896–904.CrossRefPubMedGoogle Scholar
  25. 25.
    Basketter DA, McFadden JF, Gerberick GF, Cockshott A, Kimber I. Nothing is perfect, not even the local lymph node assay. A commentary and the implications for REACH. Contact Dermatitis. 2009b;60:65–9.CrossRefPubMedGoogle Scholar
  26. 26.
    OECD. Guidelines for test of chemicals nos 442a and 442b. Paris: Organisation for Economic Cooperation and Development; 2010b.Google Scholar
  27. 27.
    ECHA. Guidance on the Application of the CLP Criteria. 2013. Version 4.0 November 2013. www.echa.europa.eu/documents/10162/13562/clp_en.pdf. Last accessed 20 oct 2014.
  28. 28.
    Basketter DA, Roberts DW, Cronin M, Scholes EW. The value of the local lymph node assay in quantitative structure activity investigations. Contact Dermatitis. 1992;27:137–42.CrossRefPubMedGoogle Scholar
  29. 29.
    Basketter DA, Lea L, Cooper K, Dickens A, Briggs D, Pate I, Dearman RJ, Kimber I. A comparison of statistical approaches to derivation of EC3 values from local lymph node assay dose responses. J Appl Toxicol. 1999;19:261–6.CrossRefPubMedGoogle Scholar
  30. 30.
    Kimber I, Basketter DA. Contact sensitization: a new approach to risk assessment. Hum Ecol Risk Assess. 1997;3:385–95.CrossRefGoogle Scholar
  31. 31.
    Kimber I, Basketter DA, Berthold K, Butler M, Garrigue JL, Lea LJ, Newsome C, Roggeband R, Steiling W, Stropp G, Waterman S, Wiemann C. Skin sensitisation testing in potency and risk assessment. Toxicol Sci. 2001;59:198–208.CrossRefPubMedGoogle Scholar
  32. 32.
    Gerberick GF, Robinson MK, Ryan CA, Dearman RJ, Kimber I, Basketter DA, Wright Z, Marks JG. Contact allergenic potency: correlation of human and local lymph node assay data. Am J Cont Derm. 2001;12:156–61.Google Scholar
  33. 33.
    Ryan CA, Gerberick GF, Cruse LW, Basketter DA, Lea LJ, Blaikie L, Dearman RJ, Warbrick EV, Kimber I. Activity of human contact allergens in the murine local lymph node assay. Contact Dermatitis. 2000;43:95–102.CrossRefPubMedGoogle Scholar
  34. 34.
    Basketter DA. The human repeated insult patch test in the 21st century: a commentary on ethics and validity. Cutan Ocul Toxicol. 2009;28:49–53.CrossRefPubMedGoogle Scholar
  35. 35.
    Basketter DA, Andersen KE, Lidén C, van Loveren H, Boman A, Kimber I, Alanko K, Berggren E. Evaluation of the skin sensitising potency of chemicals using existing methods and considerations of relevance for elicitation. Contact Dermatitis. 2005a;52:39–43.CrossRefPubMedGoogle Scholar
  36. 36.
    Basketter DA, Gerberick GF, Kimber I. The local lymph node assay EC3 value: status of validation. Contact Dermatitis. 2007;57:70–5.CrossRefPubMedGoogle Scholar
  37. 37.
    Gerberick GF, Ryan CA, Kern PS, Schlatter H, Dearman RJ, Kimber I, Patlewicz G, Basketter DA. Compilation of historical local lymph node assay data for the evaluation of skin sensitization alternatives. Dermatitis. 2005;16:157–202PubMedPubMedCentralGoogle Scholar
  38. 38.
    Kern PS, Gerberick GF, Ryan CA, Kimber I, Aptula A, Basketter DA. Historical local lymph node data for the evaluation of skin sensitization alternatives: a second compilation. Dermatitis. 2010;21:8–32.PubMedGoogle Scholar
  39. 39.
    Api AM, Basketter DA, Lalko J. Correlation between experimental human and murine skin sensitization induction thresholds. Cutan Ocul Toxicol. 2014;28:1–5.Google Scholar
  40. 40.
    Basketter DA, Clapp C, Jefferies D, Safford RJ, Ryan CA, Gerberick GF, Dearman RJ, Kimber I. Predictive identification of human skin sensitisation thresholds. Contact Dermatitis. 2005b;53:260–7.CrossRefPubMedGoogle Scholar
  41. 41.
    Basketter DA, McFadden JP. Cutaneous allergies. In: Dietert RR, Luebke RW, editors. Immunotoxicity, immune dysfunction and chronic disease. New York: Humana Press; 2012. p. 103–26.CrossRefGoogle Scholar
  42. 42.
    Griem P, Goebel C, Scheffler H. Proposal for a risk assessment methodology for skin sensitization based on sensitization potency data. Regul Toxico Pharmaol. 2003;38:269–90.CrossRefGoogle Scholar
  43. 43.
    Schneider K, Akkan Z. Quantitative relationship between the local lymph node assay and human skin sensitization assays. Regul Toxicol Pharmacol. 2004;39:245–55.CrossRefPubMedGoogle Scholar
  44. 44.
    Api AM, Basketter DA, Cadby PA, Cano M-F, Ellis G, Gerberick GF, Griem P, McNamee PM, Ryan CA, Safford B. Dermal sensitization quantitative risk assessment (QRA) for fragrance ingredients. Regul Toxicol Pharmacol. 2008;52:3–23.CrossRefPubMedGoogle Scholar
  45. 45.
    Robinson MK, Gerberick GF, Ryan CA, McNamee P, White I, Basketter DA. The importance of exposure assessment of skin sensitization risk. Contact Dermatitis. 2000;42:251–9.CrossRefPubMedGoogle Scholar
  46. 46.
    Vocanson M, Nicolas J-F, Basketter DA. In vitro approaches to the identification and characterization of skin sensitisers. Exp Rev Dermatol. 2013;8:395–405.CrossRefGoogle Scholar
  47. 47.
    Natsch A, Emter R, Gfeller H, Haupt T, Ellis G. Predicting skin sensitizer potency based on in vitro data from KeratinoSens and kinetic peptide binding: global versus domain-based assessment. Toxicol Sci. 2015;143:319–32.CrossRefPubMedGoogle Scholar
  48. 48.
    Jaworska JS, Natsch A, Ryan C, Strickland J, Ashikaga T, Miyazawa M. Bayesian integrated testing strategy (ITS) for skin sensitization potency assessment: a decision support system for quantitative weight of evidence and adaptive testing strategy. Arch Toxicol. 2015;89(12):2355–83.CrossRefPubMedGoogle Scholar
  49. 49.
    Tsujita-Inoue K, Hirota M, Ashikaga T, Atobe T, Kouzuki H, Aiba S. Skin sensitization risk assessment model using artificial neural network analysis of data from multiple in vitro assays. Toxicol In Vitro. 2014;28:626–39.CrossRefPubMedGoogle Scholar
  50. 50.
    Basketter DA, White IR, McFadden JP, Kimber I. Skin sensitization: integration of clinical data into hazard identification and risk assessment. Human Exp Toxicol. 2015;34(12):1222–30.CrossRefGoogle Scholar
  51. 51.
    IFRA. International dialogue for the evaluation of allergens. 2014. http://www.ideaproject.info/uploads/Modules/Documents/idea-annual-review-2014---summary-distributed-to-the-participants.pdf. Last accessed 10 February 2015.
  52. 52.
    Basketter DA, Alepee N, Ashikaga T, Barroso J, Gilmour N, Goebel C, Hibatallah J, Hoffmann S, Kern P, Martinozzi-Teissier S, Maxwell G, Millet M, Reisinger K, Sakaguchi H, Schepky A, Tialhardat M, Templier M. Categorisation of chemicals according to their relative human skin sensitizing potency. Dermatitis. 2014;25:11–21.CrossRefPubMedGoogle Scholar
  53. 53.
    EU. Directive 2003/15/EC of the European parliament and the council of 27 February 2003 amending council directive 76/768/ EEC on the approximation of the laws of the members states relating to cosmetic products. Off J Eur Union. 2003;L66:26–35.Google Scholar
  54. 54.
    OECD. Guidelines for test of chemicals nos 442c and 442d. Paris: Organisation for Economic Cooperation and Development; 2015.Google Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • David A. Basketter
    • 1
  • Ian Kimber
    • 2
  • G. Frank Gerberick
    • 3
  1. 1.DABMEB Consultancy LtdSharnbrookUK
  2. 2.Faculty of Life SciencesUniversity of ManchesterManchesterUK
  3. 3.The Procter and Gamble Company, Central Product SafetyMasonUSA

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