title: A Dose-Response Modeling Approach Shows That Effects From Mixture Exposure to the Skin Sensitizers Isoeugenol and Cinnamal Are in Line With Dose Addition and Not With Synergism.
abstract: Currently, hazard characterization of skin sensitizers is based on data obtained from studies examining single chemicals. Many consumer products, however, contain mixtures of sensitizers that might interact in such a way that the response induced by a substance is higher than predicted in the hazard assessment. To assess interaction of skin sensitizers in a mixture, a dose-response modeling approach is applied. With this approach, it is possible to assess whether or not responses from mixtures of sensitizers can be predicted from the dose-response information obtained from individual chemicals using dose addition. We selected the skin sensitizers isoeugenol and cinnamal, frequently occurring together in consumer products, to be examined in an adjusted local lymph node assay (LLNA). Cell number and cytokine production (IL-10 and IFN-γ) of the auricular lymph nodes were measured as hallmarks of the skin sensitization response. We found that dose addition for these 2 skin sensitizers closely predicted the effects from mixtures of both chemicals across the broad dose range tested. Hence, isoeugenol and cinnamal show no synergistic effects in the LLNA. Therefore, hazard assessment and risk assessment of these substances can be performed without taking into account mixture exposure.
authors.affiliation: *Centre for Health Protection and.
authors.forename: Anne S
authors.initials: AS
authors.lastname: Kienhuis
authors.affiliation: Centre for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment (RIVM), 3721 MA Bilthoven, The Netherlands.
authors.forename: Wout
authors.initials: W
authors.lastname: Slob
authors.affiliation: *Centre for Health Protection and.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Gremmer
authors.affiliation: *Centre for Health Protection and.
authors.forename: Jolanda P
authors.initials: JP
authors.lastname: Vermeulen
authors.affiliation: *Centre for Health Protection and janine.ezendam@rivm.nl.
authors.forename: Janine
authors.initials: J
authors.lastname: Ezendam
mesh_terms: D000171:Acrolein / Q000031:analogs & derivatives* / Q000633:toxicity; D000465:Algorithms; D000818:Animals; D045424:Complex Mixtures / Q000633:toxicity*; D016207:Cytokines / Q000096:biosynthesis; D017449:Dermatitis, Allergic Contact / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004357:Drug Synergism; D005054:Eugenol / Q000031:analogs & derivatives* / Q000633:toxicity; D005260:Female; D023441:Local Lymph Node Assay; D008198:Lymph Nodes / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D018570:Risk Assessment
chemical_list: D045424:Complex Mixtures; D016207:Cytokines; D005054:Eugenol; C036643:isoeugenol; D000171:Acrolein; C012843:cinnamaldehyde
keywords: LLNA; dose addition; dose response; mixture; skin sensitization; synergism