If you are running light, as in well under your GVWR you can get better mileage on the flats and slight down hill grades by leaving Tow Haul off. I'm not sure E-450's ever fit that description. :B
On any significant grade and often on slight extended grades engaging TH will dramatically lower your trans fluid temps. I use my Scan Gauge to monitor this critical function. If you don't have a Scan Gauge or some other device to monitor your engine functions above and beyond the idiot lights Ford supplies, you need one.
On steep downhills you always want to be in TH. I can engage TH and descend a 12 mile 6 - 8% grade and never touch the brakes and best of all won't burn a drop of fuel all the way to the bottom. Don't be concerned about the the V-10 revving as that is what it is designed to do.
A lot of folks just keep things simple by running in TH all the time and there is absolutely nothing wrong with that. You will burn a tad more fuel but your trans will stay cooler and gas is a lot cheaper than a new transmission.
:C