In vivo assessment of immunotoxicity

Abstract

The organs, tissues, and cells of the lymphoreticular system have received considerable attention as targets for chemicals causing adverse effects. A basic toxicological approach is described for assessing the risk of a chemical perturbing the immune system. CD-1 mice were exposed for 14 or 90 days to one of several chlorinated hydrocarbons: 1,2-dichloroethane, 1,2-dichloroethylene or 1,1,2-trichloroethylene. Other mice were exposed to dexamethasone, a known immunosuppressive agent. The immune system is evaluated against a background of the more standard toxicological parameters such as fluid consumption, body and organ weights, hematology, clinical chemistries, and blood coagulation. Reported here are the results for the male mice after 14-day exposure to three chlorinated hydrocarbons and after 90-day exposure to 1,2-dichloroethane and dexamethasone. Acute toxicity studies were performed to provide a basis for doses used in the subchronic studies. The LD50 values are reported. The status of the humoral immune system was determined by measuring the number of IgM spleen antibody-forming cells to sRBC, the serum antibody level to sRBC, and the lymphocyte response to the B-cell mitogen, LPS. Of the three chlorinated hydrocarbons, only dichloroethane produced a significant (p < 0.05) reduction in antibody-forming cells. The other two chemicals produced trends towards suppression. Mice exposed to dichloroethane in the drinking water for 90 days showed no alteration in AFC, serum antibody titers or response to the B-lymphocyte mitogen, LPS. Subchronic 90-day exposure to dexamethasone produced a dose-dependent inhibition of AFC/spleen but not AFC/106 spleen cells when measured on the peak day of response. Response to LPS was not altered, and spleen weight and spleen cell number were reduced as much as 42%. These data suggest that dexamethasone administered in the drinking water is nonspecifically cytotoxic to the spleen cells. Cell-mediated immunity was assessed by measuring the DTH response to sRBC and the response to the T-lymphocyte mitogen, concanavalin A. After 14 days of exposure, trichloroethylene produced a 15 and 60% suppression at 24 and 240 mg/kg, respectively. Dichloroethylene produced a non-dose-dependent inhibition at 4.9 and 49 mg/kg, which was slight, but significant (p < 0.05). Subchronic 90-day exposure to dichloroethane did not alter the DTH response or spleen lymphocyte response to concanavalin A. In contrast, dexamethasone produced a dose-dependent inhibition of the DTH response and a hyperresponsiveness to concanavalin A. Dichloroethane did not alter the functional activity of the reticuloendothelial system, as measured by the vascular clearance rate and tissue uptake of 51Cr sRBC. In the case of dexamethasone exposure, only the spleen and thymus showed decreased uptake of 51Cr sRBC, which was directly related to decrease in size. The approaches and results from these types of studies provide a basis for judging a chemical's potential risk to the immune system.

A Sub Acute Immunotoxicity Study in G?ttingen Minipigs? with the Immunosuppressive Compounds Cyclosporin A and Dexamethasone

“…DEX treatment resulted in a slightly reduced body weight gain in minipigs. Similar results have been found in rodent studies [36,42]. DEX did not bring about an effect on spleen weights in the minipig.…”

“…In contrary, Exon et al [42,43] using different DEX treatment schedules in male Sprague Dawley rats, observed a decreased DTH response to BSA. Also in a mice study of Munson et al [36] the DTH response to SRBC was found to be reduced upon DEX exposure levels up to 0.49 mg/kg in the drinking water for 90 days.…”

“…In humans treated with CsA, either no effect [38] or a decreased [46] mitogeninduced proliferation has been observed. In a mouse study of Munson et al [36] the ConA stimulated proliferation of spleen cells was found to be increased upon DEX exposure. Decreased PHA induced proliferation was observed in human PBMC in the presence of DEX or CsA [47].…”

“…The number of neutrophils was increased after DEX-exposure of the minipigs. Increased neutrophil count is a well known stress-related effect associated with increased corticosteroid levels [34] that is also evident upon DEX exposure in other animal species both rodents and non-rodents [28,30,31,35,36].…”

“…In contrast, reduced spleen weights were observed in rodents after DEX exposure [36,42,43], but treatment lasted longer or other treatment routes and dose levels were used making direct comparison difficult. Thymus weights of the DEX-treated minipigs were significantly reduced in both sexes, which is in line with observations made in rodents [36,42,43]. Thus, in general the effects of CsA and DEX on body and organ weights and histopathology of lymphoid organs in the minipig are in general in agreement with those observed in other species (both rodents and non-rodents).…”