OK, so I ended up going with paint.NET, and that seems to be meeting my needs, for the moment. I'm not an artist, so the other tools seemed to offer too much for me to work with. I'm still trying to work through how to make part of a tile transparent, but not the whole thing.
Right now, that amounts to placing black objects on a gray-shaded background, which for many tiles works ok, since I want the material to show through. (eg, white table if the workshop was made of dolomite, and brown if it was made from wood) then the object (hammer, etc.) is in black. But that is a topic for another thread.
I did try Tile Studio as well, and that's interesting, and seems to have similar features to paint.Net. So it was a question of where do I spend my learning time, and I went with the more general toolset. TS does have options and ways to break up the tiles which could actually be really, really useful for work like this...but I didn't spend the time to figure out to really use it.