title: Chemical applicability domain of the Local Lymph Node Assay (LLNA) for skin sensitisation potency. Part 3. Apparent discrepancies between LLNA and GPMT sensitisation potential: False positives or differences in sensitivity?
abstract: The Local Lymph Node Assay (LLNA) is the gold standard regulatory toxicology test for skin sensitisation along with the guinea pig maximisation test (GPMT). Compared with the GPMT, LLNA uses fewer animals, it is quantitative, and it gives a numerical prediction of potency. However several concerns have been raised with this assay, mainly related to false positives and false negatives. Over the years, many authors, including the developers of the assay, have presented cases where there have been discrepancies between the GMPT and LLNA results. Several theories have been put forward for these discrepancies, the main one being the "over-sensitivity" of the GPMT. This paper analyses the data from a systematic study, published in three papers from 2008 to 2011, covering several classes of chemicals, in particular unsaturated fatty acids, sugar surfactants and ethoxylated alcohols, with many cases of chemicals testing positive in the LLNA being negative in the GPMT. Based on consideration of reaction chemistry and structural alerts, it is concluded that these discrepancies are not LLNA false positives, but can be rationalised in terms of the different protocols of the assays.
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: The University of Tennessee, College of Veterinary, 2407 River Drive, Knoxville, TN, 37996, USA.
authors.forename: Terry W
authors.initials: TW
authors.lastname: Schultz
authors.affiliation: Research Institute for Fragrance Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ, 07677, USA.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Api
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; D005189:False Positive Reactions; D006168:Guinea Pigs; 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: Autoxidation; Surfactants; Unsaturated fatty acids