Organotins

Organotins have a wide variety of industrial and commercial applications including use as wood preservatives, agricultural pesticides, chemical catalysts, plastic heat stabilizers, marine antifoulants, and curing agents (Piver 1973). Certain dialkyl-and trialkyl-substituted organotins (e.g., di-n-octyltin dichloride [DOTC] and di-n-butyltin dichloride [DBTC], and tributyltin oxide [TBTO],) alter the structure and function of the thymus and consequently affect primarily T cell-dependent immune function in rodents. There is evidence that rat natural killer (NK) cell activity is also affected by organotins (Pennicks and Pieters1995).

Early work by Seinen et al. (1977; 1979) demonstrated that pre- and/or postnatal exposure of Wistar-derived WAG rats to either DOTC or TBTO results in suppression of the DTH response, antibody response to SRBCs, and graft-vs.-host response. Female rats were dosed by gavage with 0, 5, or 15 mg DOTC/kg body wt or with 0, 1, 3, 5, or 15 mg DBTC/kg body wt starting on day 2 of pregnancy and through gestation, followed by direct dosing of the pups on PND 2 and then three times per week until immune function testing. The antibody response to SRBCs, as determined by the PFC assay and serum antibody titers, was suppressed in both 6-week-old male and female offspring dosed at 15 mg/kg DBTC (Seinen et al. 1977). In addition, the graft-vs.-host skin graft rejection response was delayed, compared to control, in 7-week-old male rats dosed at 1 and 3 mg DBTC/kg (Seinen et al. 1977). Six-

week-old female rats exposed pre- and postnatally to DOTC at 5 and 15 mg DOTC/kg had delayed skin graft rejection times in the graft-vs.-host reaction (Seinen et al. 1979). The authors of these papers concluded that it appears that DOTC and DBTC cause immune suppression in rats by a selective inhibition of T lymphocyte function, and that immune suppression is more pronounced in rats exposed to these organotins during immune system development (Seinen et al. 1977). No attempt was made in these studies to determine if the immune function deficits observed immediately following the last organotin exposure of the rats, resulted in a long-lived or persistent immunosuppression.

More recently, two studies were conducted to determine if exposure to either DOTC or TBTO during immune system development affected immune function in adult male Fischer 344 rats. In the first study (Smialowicz et al. 1988), dams were exposed to DOTC by gavage during the prenatal, both pre- and postnatal (i.e., lactation), or postnatal period(s). The offspring of these dams displayed no consistent alteration in immune function, as determined by the in vitro LP response to T and B cell mitogens or by the in vitro NK cell 51Cr-release assay. In contrast, direct gavage dosing of pups with 5, 10, or 15 mg DOTC/kg/d on PND 3 and then 3 times a week up to PND 24, for a total of 10 doses, resulted in suppression of the LP responses at up to10 weeks of age (i.e., 7 weeks after the last exposure to DOTC). LP responses returned to control levels after 10 weeks of age. In comparison, young adult (i.e., 8-week-old) rats dosed by gavage with 10 or 20 mg DOTC/kg/body wt/day, using the identical dosing schedule (i.e., 3 times per week for a total of 10 doses) showed no alteration of the LP responses one week after the last exposure (Smialowicz et al. 1988).

In the second study (Smialowicz et al. 1989), rat pups were dosed by gavage with TBTO, as described above (i.e., PND 3 through PND 24, 3 days per week, for a total of 10 doses). Rats were assessed for immune competency as determined by the in vitro LP response and NK assay, as well as mixed leukocyte response (MLR) and cytotoxic T lymphocyte (CTL) response, and the T cell-dependent antibody response to SRBCs as determined by the PFC assay. Young adult (i.e., 9-week-old) rats were similarly dosed (i.e., 3 times per week for a total of 10 times) with TBTO. LP responses were suppressed in pups dosed at 5 and 10 mg/kg/d, while in adults suppression was observed at doses of 10 and 20 mg/kg/d. No other immune function endpoints were affected. Within 3 weeks following the last exposure of adult rats, the LP responses returned to control levels. However, suppression of the LP responses in exposed pups persisted for up to 13 weeks of age (i.e., 10 weeks after the last exposure to TBTO), after which they returned to control levels.

These data (Smialowicz et al. 1988, 1989) indicate that the direct exposure of young male rat pups to DOTC or TBTO resulted in immune suppression at doses lower than those required to suppress immune function in the adult rat. Furthermore, immune suppression persisted for 7 to 10 weeks longer when pups, rather than adults, were exposed to DOTC or TBTO, respectively. It is interesting that direct early postnatal, but not perinatal (i.e., in utero and lactational) exposure to DOTC resulted in immune suppression that persisted for 7 weeks. This suggests that DOTC may not be available to the fetus via the placenta and the pup via milk at sufficient concentrations to alter immune system development. This observation underscores the importance of information relative to the pharmacokinetics of the test chemical. Such information would be extremely helpful in designing the dosing protocol for a chemical that might be considered for developmental immunotoxicity testing. Since only males were evaluated in these studies, important information relative to potential gender susceptibility to early postnatal organotin exposure was not available.

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