IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

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(mainly hepatocellular carcinomas) in rodents (rats and Syrian hamsters) and non-human
primates (rhesus, cynomolgus and African green monkeys). There have been numerous
subsequent studies in aflatoxin B 1-exposed animals, especially rats, of GSTP-positive
foci in the liver. Particular emphasis has been placed on modification by different coexposures
of the development and frequency of these foci. Often, there was an increase
in the number of GSTP-positive foci by L-buthionine sulfoximine (which depletes
reduced glutathione) and inhibition of their appearance or rate of development by phenobarbital,
anti-oxidants and various sulfur compounds, including dithiolethiones (e.g.,
Bolton et al., 1993; Gopalan et al., 1993; Maxuitenko et al., 1993; Primiano et al., 1995;
Hiruma et al., 1996; Williams & Iatropoulos, 1996; Hiruma et al., 1997; Soni et al.,
1997; Maxuitenko et al., 1998).
(a) Immunosuppression
IARC MONOGRAPHS VOLUME 82
Studies on the immunosuppressive effects of aflatoxins published before 1993 were
reviewed in the previous monograph (IARC, 1993).
Aflatoxins modulate the immune system in domestic and laboratory animals after
dietary intake of up to several milligrams per kg feed (Hall & Wild, 1994; Bondy &
Pestka, 2000). The major effects involve suppression of cell-mediated immunity, most
notably impairment of delayed-type hypersensitivity, which has been a consistent observation
at low dose levels in various species (Bondy & Pestka, 2000). Other notable
effects include suppression of non-specific humoral substances, reduced antibody formation,
suppression of allograft rejection, decreased phagocytic activity and decreased
blastogenic response to mitogens (Pier & McLoughlin, 1985; Denning, 1987; WHO,
1990). Strong modification of cytokine secretion and interleukin gene expression has
also been observed in vitro with mycotoxins, including aflatoxins (Han et al., 1999;
Moon et al., 1999; Rossano et al., 1999). The immune system of developing pigs was
affected by maternal dietary exposure to aflatoxin B 1 or aflatoxin G 1 during gestation and
lactation. Motility and chemotaxis of neutrophils were inhibited in piglets from aflatoxin-treated
sows (Silvotti et al., 1997). In a further study, thymic cortical lymphocytes
were depleted and thymus weight was reduced in piglets from sows exposed to aflatoxin
B 1 (800 ppb [μg/kg] in diet) from day 60 of gestation up to day 28 of lactation
(Mocchegiani et al., 1998).
The effects of aflatoxin B 1 on growing rats have been shown to be similar to those in
adult animals. Weanling rats [strain unspecified] were given oral doses of 60, 300 or
600 μg/kg bw aflatoxin B 1 in corn oil every other day for four weeks. Aflatoxin B 1 selectively
suppressed cell-mediated immunity, assessed by measuring the delayed-type
hypersensitivity response, at the 300- and 600-μg/kg bw doses (Raisuddin et al., 1993).
In order to determine the effect of aflatoxin B 1 on the activation of toxoplasmosis,
CF1 mice were injected with the cyst-forming parasite Toxoplasma gondii one month
before aflatoxin B 1 was given by gavage daily for 50 days at 100 μg/kg bw. Cysts developed
in the brains of all mice, but the lesions were judged to be more severe in the aflatoxin
B 1-treated animals (Venturini et al., 1996).