Small fragments of
silicone gels injected intraperitoneally have been used to induce
plasmacytomas in genetically susceptible mice.
Silicone oils, in contrast to
silicone gels, are apparently not tumorigenic in the mouse
plasmacytoma system. The reason for this difference as well as the mechanism of
silicone gel-induced
plasmacytoma development is poorly understood. We chose to examine the possibility that low molecular wt
silicone compounds such as
siloxanes, leaking from the complex
silicone gel matrix into the surrounding tissue, may be mutagenic. We postulate that this mutagenicity may be a critical determinant of the
plasmacytoma inducing potency of
silicone gels. Six
siloxane compounds, either linear or cyclic di-, tri-, or tetrasiloxanes substituted with methyl or vinyl moieties, were selected as model compounds to study mutagenicity in Rat2lambda lacI fibroblasts in vitro. Using phage lambda-derived lacI/lacZ genes as target/reporter genes to quantitate mutagenesis, and
gamma-cyclodextrin as vehicle to effectively deliver
siloxanes, we found that exposure to 50 microM of
tetravinyl-tetramethylcyclo-tetrasiloxane (
tetravinyl D4) resulted in a modest 1.7-fold increase of mutant frequencies over controls in Rat2lambda lacI cells. In related toxicity experiments,
tetravinyl D4 was shown to perturb
lipid membranes leading to a loss of cytosolic
glutathione (GSH), which by itself resulted in a 1.5-fold increased mutant rate in Rat2lambda lacI cells. We conclude that certain
siloxanes may act as direct
mutagens in mammalian cells. In addition,
siloxane-induced mutagenicity may be enhanced by the depletion of intracellular GSH caused by the interaction of lipophilic
siloxanes with cell membranes.