title: Immunotoxicity of aflatoxin B1 in rats: effects on lymphocytes and the inflammatory response in a chronic intermittent dosing study.
abstract: We investigated the effects of aflatoxin B1 (AFB1) on isolated splenic lymphocytes and the histo-morphologic changes in the spleens and liver of Fisher-344 male rats. Weaned animals were fed chow diets that contained 0, 0.01, 0.04, 0.4, or 1.6 ppm AFB1, using an intermittent dosing regimen (4 weeks on and 4 weeks off AFB1), for 40 weeks. An additional group of animals was fed the 1.6 ppm AFB1 diet continuously. The intermittent dosing regimen was designed to evaluate effects of cumulative dose and exposure for risk assessment comparisons. The percentages of T and B cells were affected as shown by flow cytometric analysis after the dosing cycles. The observed changes appeared to reverse or compensate to some extent after the off cycles. Lymphocytes were stimulated in culture for analysis of the production of IL-2, IL-1, and IL-6. Significantly increased production of IL-1 and IL-6 was seen in the second dosing cycle (12 weeks) and the second "off" cycle (16 weeks) at the higher doses. Inflammatory infiltrates were seen in the liver after eight weeks of continuous and intermittent dosing and were increased in size and number at 12 weeks in both 1.6 ppm dose groups correlating with the peak production of Il-1 and IL-6. We concluded that AFB1 effects on the immune system can be either stimulatory or suppressive dependent on a critical exposure window of dose and time. Immune cells in spleen such as T-lymphocytes and macrophages, both important mediators of inflammatory responses to tissue damage, were affected differently in the continuous and intermittent exposures to AFB1.
authors.affiliation: United States Food and Drug Association, Center for Food Safety and Applied Nutrition, Laurel, Maryland 20708, USA. dhinton@cfsan.fda.gov
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Hinton
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Myers
authors.forename: Richard A
authors.initials: RA
authors.lastname: Raybourne
authors.forename: Sabine
authors.initials: S
authors.lastname: Francke-Carroll
authors.forename: Rene E
authors.initials: RE
authors.lastname: Sotomayor
authors.forename: Joseph
authors.initials: J
authors.lastname: Shaddock
authors.forename: Alan
authors.initials: A
authors.lastname: Warbritton
authors.forename: Ming W
authors.initials: MW
authors.lastname: Chou
mesh_terms: D000284:Administration, Oral; D016604:Aflatoxin B1 / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D002452:Cell Count; D002478:Cells, Cultured; D004032:Diet; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005434:Flow Cytometry; D007107:Immune System / Q000187:drug effects*; D007378:Interleukins / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D036401:Toxicity Tests, Chronic
chemical_list: D007378:Interleukins; D016604:Aflatoxin B1