title: Integrated analysis of toxicity data of two pharmaceutical immunosuppressants and two environmental pollutants with immunomodulating properties to improve the understanding of side effects-A toxicopathologist׳s view.
abstract: Data in a toxicity test are evaluated generally per parameter. Information on the response per animal in addition to per parameter can improve the evaluation of the results. The results from the six studies in rats, described in the paper by Kemmerling, J., Fehlert, E., Rühl-Fehlert, C., Kuper, C.F., Stropp, G., Vogels, J., Krul, C., Vohr, H.-W., 2015. The transferability from rat subacute 4-week oral toxicity study to translational research exemplified by two pharmaceutical immunosuppressants and two environmental pollutants with immunomodulating properties (In this issue), have been subjected to principal component analysis (PCA) and principal component discriminant analysis (PC-DA). The two pharmaceuticals azathioprine (AZA) and cyclosporine A (CSA) and the two environmental pollutants hexachlorobenzene (HCB) and benzo(a)pyrene (BaP) all modulate the immune system, albeit that their mode of immunomodulation is quite diverse. PCA illustrated the similarities between the two independent studies with AZA (AZA1 and AZA2) and CSA (CSA1 and CSA2). The PC-DA on data of the AZA2 study did not increase substantially the information on dose levels. In general, the no-effect levels were lower upon single parameter analysis than indicated by the distances between the dose groups in the PCA. This was mostly due to the expert judgment in the single parameter evaluation, which took into account outstanding pathology in only one or two animals. The PCA plots did not reveal sex-related differences in sensitivity, but the key pathology for males and females differed. The observed variability in some of the control groups was largely a peripheral blood effect. Most importantly, PCA analysis identified several animals outside the 95% confidence limit indicating high-responders; also low-to-non-responders were identified. The key pathology enhanced the understanding of the response of the animals to the four model compounds.
authors.affiliation: TNO, PO Box 360, 3700 AJ Zeist, The Netherlands. Electronic address: frieke.kuper@tno.nl.
authors.forename: C Frieke
authors.initials: CF
authors.lastname: Kuper
authors.affiliation: TNO, PO Box 360, 3700 AJ Zeist, The Netherlands.
authors.forename: Jack
authors.initials: J
authors.lastname: Vogels
authors.affiliation: Bayer Pharma AG, GDD-GED-TOX-IT-Immunotoxicology, Aprather Weg, 42096 Wuppertal, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Kemmerling
authors.affiliation: Department of Medicine IV, Eberhard-Karls University, Otfried-Mueller Strasse 10, 72076 Tuebingen, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Fehlert
authors.affiliation: Bayer Pharma AG, GDD-GED-TOX-P&CP Pathology, Aprather Weg, 42096 Wuppertal, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Rühl-Fehlert
authors.affiliation: Bayer Pharma AG, GDD-GED-TOX-IT-Immunotoxicology, Aprather Weg, 42096 Wuppertal, Germany.
authors.forename: Hans-Werner
authors.initials: HW
authors.lastname: Vohr
authors.affiliation: TNO, PO Box 360, 3700 AJ Zeist, The Netherlands.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Krul
mesh_terms: D000818:Animals; D001379:Azathioprine / Q000633:toxicity; D001564:Benzo(a)pyrene / Q000633:toxicity; D016572:Cyclosporine / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D006581:Hexachlorobenzene / Q000633:toxicity; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity*; D008221:Lymphoid Tissue / Q000187:drug effects* / Q000276:immunology / Q000473:pathology*; D008297:Male; D015999:Multivariate Analysis; D025341:Principal Component Analysis; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D012737:Sex Factors; D059551:Toxicity Tests, Subacute / Q000379:methods*; D057170:Translational Research, Biomedical / Q000379:methods* / Q000706:statistics & numerical data
chemical_list: D004785:Environmental Pollutants; D007166:Immunosuppressive Agents; D001564:Benzo(a)pyrene; D006581:Hexachlorobenzene; D016572:Cyclosporine; D001379:Azathioprine
keywords: Discriminant analysis; High responders; Nonresponders; Outliers; Principal component analysis