Not really. If you decided to play the game without killing everyone and some quest related NPC dies because he's attacked by a Giant Frostspider. You'd be on the forums saying the worst thing Beth ever did was make all NPC's killable.
A ridiculous example. I have never seen one instance where a random member of a town wandered off into the wilderness and got killed by an animal. For the most part, they remain in their immediate vicinity. They simply aren't that erratic. Dragons are really the only time you have to worry about random events killing NPC's, and you can easily make special NPC's immune to dragon attacks, as has been suggested on this forum many times. Now, if you were to lure a Giant towards one of the smaller towns and watched as it killed all of the occupants, they should not be immune to such things as it was you that instigated the event.
The only other instance I can think of is random NPC's fighting each other. I've heard that this happens, but have never witnessed it personally. If it really does happen, setting immunity to everything but the player would solve the problem.