title: Chemical applicability domain of the Local Lymph Node Assay (LLNA) for skin sensitisation potency. Part 2. The biological variability of the murine Local Lymph Node Assay (LLNA) for skin sensitisation.
abstract: The Local Lymph Node Assay (LLNA) is the most common in vivo regulatory toxicology test for skin sensitisation, quantifying potency as the EC3, the concentration of chemical giving a threefold increase in thymidine uptake in the local lymph node. Existing LLNA data can, along with clinical data, provide useful comparator information on the potency of sensitisers. Understanding of the biological variability of data from LLNA studies is important for those developing non-animal based risk assessment approaches for skin allergy. Here an existing set of 94 EC3 values for 12 chemicals, all tested at least three times in the same vehicle have been analysed by calculating standard deviations (SD) for logEC3 values. The SDs range from 0.08 to 0.22. The overall SD for the 94 logEC3 values is 0.147. Thus the 95% confidence limits (2xSD) for LLNA EC3 values are within a factor of 2, comparable to those for physico-chemical measurements such as partition coefficients and solubility. The residual SDs of Quantitative Mechanistic Models (QMMs) based on physical organic chemistry parameters are similar to the overall SD of the LLNA, indicating that QMMs of this type are unlikely to be bettered for predictive accuracy.
authors.affiliation: School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, L3 3AF, United Kingdom. Electronic address: D.W.Roberts@ljmu.ac.uk.
authors.forename: David W
authors.initials: DW
authors.lastname: Roberts
authors.affiliation: Research Institute for Fragrance Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, United States.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Api
authors.affiliation: Unilever Safety and Environmental Assurance Centre, Colworth Science Park, Sharnbrook, Bedford, MK44 1LQ, United Kingdom.
authors.forename: Aynur O
authors.initials: AO
authors.lastname: Aptula
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D057225:Data Mining; D016208:Databases, Factual; D017449:Dermatitis, Allergic Contact / Q000209:etiology* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007509:Irritants / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D023441:Local Lymph Node Assay; D008198:Lymph Nodes / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D015203:Reproducibility of Results; D012867:Skin / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D012869:Skin Absorption; D013045:Species Specificity; D013329:Structure-Activity Relationship
chemical_list: D007509:Irritants
keywords: Biological variability; LLNA; Non-animal prediction; QMM