Who knows? Nobody knows. It depends on the sequence and is difficult to predict. Sometimes RNAi just isn't "clean" even when the primer sequences seem perfect.
It's prudent to be cautious when it comes to RNAi because we know so little about the function of RNA. RNA is not just a message, it can also be an enyme, and a signal. microRNA's, for example, can act like transcription factors and regulate coordinated gene expression, having profound effects on development or cellular function --and were only recently discovered. Here are some hypotheticals: even when you have no "off target" effects, the si could interfere with the function of non-coding RNA's, or the degradation of target mRNA could create mRNA fragments that have adverse cellular effects. Who knows how it happens, but occasionally si just makes cells sick.
RNAi can be a great tool. Its the new thing and has recieved alot of positive press, but it's not a magic bullet and it doesn't always work so well. It's adverse effects can be a bit mysterious. That's all I'm trying to say.
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