Changing a 16" tire is certainly doable for normal people, though they are a bit on the heavy side. The lug nuts on the E450 are torqued to around 140 ft-lbs (I think the exact value may have varied over the years), fairly tight but not at all beyond what can be done up and undone using e.g. a 2' breaker bar.
Compared to my Honda Fit, my motorhome is most definitely harder to change a tire on. Compared to a diesel pusher with 22.5" wheels, it's a piece of cake. Whether or not you would prefer to call roadside assistance of course depends on your own abilities and the situation you're in and such like. Having the option of doing it yourself is very nice indeed, if only because there are places where getting ahold of roadside assistance is iffy at best.