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ToxSci Advance Access published online on April 15, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg074
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received November 26, 2002; accepted February 21, 2003
© 2003 Society of Toxicology

Immunotoxicology

Immunotoxicity of Aflatoxin B1 in Rats: Effects on Lymphocytes and the Inflammatory Response in a Chronic Intermittent Dosing Study

D. M. Hinton 1*, M. J. Myers 2, R. A. Raybourne 1, S. Francke-Carroll 1, R. E. Sotomayor 1, J. Shaddock 3, A. Warbritton 3, M. Chou 3

1 USFDA, CFSAN, Laurel, MD 20708
2 USFDA, CVM, Laurel, MD, 20708
3 USFDA, NCTR, Jefferson, AR., 72079

* To whom correspondence should be addressed. E-mail: dhinton{at}cfsan.fda.gov.


  Abstract

We investigated the effects of aflatoxin B1 (AFB1) on isolated splenic lymphocytes and the histo-morphologic changes in the spleens and liver and 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 2nd dosing cycle (12 weeks) and the 2nd "off" cycle (16 weeks) at the higher doses. Inflammatory infiltrates were seen in the liver after 8 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.

Aflatoxin B1, Immunotoxicity, Inflammatory Response, Intermittent Dosing .


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