title: Developmental immunotoxicity testing of 4-methyl anisole.
abstract: The developmental immunotoxicity of 4-methyl anisole (4MA) was investigated in the rat. Four study designs were used, with either premating or post-weaning onset of exposure, continued to postnatal day 50, and with or without additional oral gavage of pups from postnatal day 10 onward. Reduced litter size (benchmark dose lower confidence limit (BMDL) 80mg/kg bw/day) was the most sensitive developmental parameter, with pup relative organ weight effects observed at similar BMDLs, in the absence of maternal toxicity. Eosinophil numbers were reduced at lower doses (BMDL 16mg/kg bw/day). KLH challenge resulted in increased IL-13 and TNF-α responses, and variably reduced IgG production (BMDL 27mg/kg bw/day). T4 levels were reduced by 11% at maximum with a BMDL of 73mg/kg bw/day. Differences between exposure cohorts were limited and were considered to be without biological significance. This study shows that 4MA induces developmental immunotoxicity at doses below those inducing developmental and general toxicity. These observations being independent of the study designs applied suggest that the post-weaning period, included in all designs, is the most relevant sensitive period for inducing 4MA mediated developmental immunotoxicity. Moreover, this study stresses the importance of including developmental immunotoxicity testing by default in regulatory toxicology.
authors.affiliation: Center for Health Protection, National Institute for Public Health and the Environment (RIVM), Leeuwenhoeklaan 9, 3720 BA Bilthoven, The Netherlands.
authors.forename: Elisa C M
authors.initials: EC
authors.lastname: Tonk
authors.affiliation: Center for Health Protection, National Institute for Public Health and the Environment (RIVM), Leeuwenhoeklaan 9, 3720 BA Bilthoven, The Netherlands.
authors.forename: Aart
authors.initials: A
authors.lastname: Verhoef
authors.affiliation: Center for Health Protection, National Institute for Public Health and the Environment (RIVM), Leeuwenhoeklaan 9, 3720 BA Bilthoven, The Netherlands.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Gremmer
authors.affiliation: Center for Health Protection, National Institute for Public Health and the Environment (RIVM), Leeuwenhoeklaan 9, 3720 BA Bilthoven, The Netherlands.
authors.forename: Henk
authors.initials: H
authors.lastname: van Loveren
authors.affiliation: Center for Health Protection, National Institute for Public Health and the Environment (RIVM), Leeuwenhoeklaan 9, 3720 BA Bilthoven, The Netherlands; Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands. Electronic address: aldert.piersma@rivm.nl.
authors.forename: Aldert H
authors.initials: AH
authors.lastname: Piersma
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000840:Anisoles / Q000633:toxicity*; D016207:Cytokines / Q000378:metabolism; D004804:Eosinophils / Q000166:cytology; D005260:Female; D007074:Immunoglobulin G / Q000276:immunology; D007155:Immunologic Factors / Q000633:toxicity*; D007958:Leukocyte Count; D008098:Litter Size / Q000187:drug effects; D008431:Maternal-Fetal Exchange; D009929:Organ Size / Q000187:drug effects; D010976:Platelet Count; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D017208:Rats, Wistar; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D013974:Thyroxine / Q000097:blood
chemical_list: D000840:Anisoles; D016207:Cytokines; D007074:Immunoglobulin G; D007155:Immunologic Factors; C008412:4-methyl anisole; D013974:Thyroxine
keywords: 4-Methyl anisole; Benchmark dose; Developmental immunotoxicity; Developmental toxicity; Prenatal exposure