title: 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.
abstract: Exposure to chemicals may have an influence on the immune system. Often, this is an unwanted effect but in some pharmaceuticals, it is the intended mechanism of action. Immune function tests and in depth histopathological investigations of immune organs were integrated in rodent toxicity studies performed according to an extended OECD test guideline 407 protocol. Exemplified by two immunosuppressive drugs, azathioprine and cyclosporine A, and two environmental chemicals, hexachlorobenzene and benzo[a]pyrene, results of subacute rat studies were compared to knowledge in other species particular in humans. Although immune function has a high concordance in mammalian species, regarding the transferability from rodents to humans various factors have to be taken into account. In rats, sensitivity seems to depend on factors such as strain, sex, stress levels as well as metabolism. The two immunosuppressive drugs showed a high similarity of effects in animals and humans as the immune system was the most sensitive target in both. Hexachlorobenzene gave an inconsistent pattern of effects when considering the immune system of different species. In some species pronounced inflammation was observed, whereas in primates liver toxicity seemed more obvious. Generally, the immune system was not the most sensitive target in hexachlorobenzene-treatment. Immune function tests in rats gave evidence of a reaction to systemic inflammation rather than a direct impact on immune cells. Data from humans are likewise equivocal. In the case of benzo[a]pyrene, the immune system was the most sensitive target in rats. In the in vitro plaque forming cell assay (Mishell-Dutton culture) a direct comparison of cells from different species including rat and human was possible and showed similar reactions. The doses in the rat study had, however, no realistic relation to human exposure, which occurs exclusively in mixtures and in a much lower range. In summary, a case by case approach is necessary when testing immunotoxicity. Improvements for the translation from animals to humans related to immune cells can be expected from in vitro tests which offer direct comparison with reactions of human immune cells. This may lead to a better understanding of results and variations seen in animal studies.
authors.affiliation: Bayer Pharma AG, GDD-GED-TOX-IT-Immunotoxicology, Aprather Weg, 42096 Wuppertal, Germany. Electronic address: jessica.kemmerling@bayer.com.
authors.forename: Jessica
authors.initials: J
authors.lastname: Kemmerling
authors.affiliation: Department of Medicine IV, Eberhard-Karls University, Otfried-Müller Street 10, 72076 Tübingen, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Fehlert
authors.affiliation: TNO Innovation for Life, PO Box 360, 3700 AJ Zeist, The Netherlands.
authors.forename: C Frieke
authors.initials: CF
authors.lastname: Kuper
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-Product Stewardship Industrial Chemicals, Aprather Weg, 42096 Wuppertal, Germany.
authors.forename: Gisela
authors.initials: G
authors.lastname: Stropp
authors.affiliation: TNO Innovation for Life, PO Box 360, 3700 AJ Zeist, The Netherlands.
authors.forename: Jack
authors.initials: J
authors.lastname: Vogels
authors.affiliation: TNO Innovation for Life, PO Box 360, 3700 AJ Zeist, The Netherlands.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Krul
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
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001379:Azathioprine / Q000633:toxicity; D001564:Benzo(a)pyrene / Q000633:toxicity; D016572:Cyclosporine / Q000633:toxicity; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D017408:Guidelines as Topic; D006581:Hexachlorobenzene / Q000633:toxicity; D006801:Humans; D056724:Immunity, Humoral / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000633:toxicity*; D008221:Lymphoid Tissue / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009929:Organ Size / Q000187:drug effects; D009928:Organ Specificity; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D059551:Toxicity Tests, Subacute / Q000379:methods*; D057170:Translational Research, Biomedical / Q000379:methods*
chemical_list: D004785:Environmental Pollutants; D007166:Immunosuppressive Agents; D017382:Reactive Oxygen Species; D001564:Benzo(a)pyrene; D006581:Hexachlorobenzene; D016572:Cyclosporine; D001379:Azathioprine
keywords: Azathioprine; Benzo[a]pyrene; Cyclosporine A; Hexachlorobenzene; Immunotoxicity; Immunotoxicology; Test Guideline