The 'safer' route is the one which the person driving feels safer with.
Perception is reality, and seldom changed.
I'll drive most interstates, and also am not adverse to driving US highways, or state highways.
Each leg, each day's drive is based on how I feel at the time.
Some times I'll drive I-35 through Austin, and some times I'll take US-281 which is 30 miles west, or US-77 to the east.
I avoid I-10 between Fort Stockton and Junction TX, vastly preferring US-90.
Where the interstate traffic, trucks, regularly run above 75 mph I'm not comfortable at my standard 62 mph. Especially if the run has a lot of grades. I prefer to let the rig climb at a slower pace. It can be a 25-35% cut in fuel mileage trying to stay 'safe' on interstates in hilly country.
Unless your rig is driven at very high speeds with a fuel range of four hours or more - the average speed is going to be about 50-55 mph on an interstate or on the US highways. (This is over several days driving.) There is almost no time advantage to taking interstates - except in very heavily populated areas. I didn't drive across Connecticut on local roads / US highways often. But I will in Texas, Oklahoma, Tennessee, Mississippi and states west of those. I also like US highways in central Florida, Georgia, South Carolina, North Carolina, Pennsylvania, etc.
This assumes you are able to travel at your own pace. We all know people with limited vacation time, or who have to be somewhere by a certain date - who drive 8 or 10 hours a day. I don't have to do that, and won't do it.
But, to get back around to my initial point.
There is a saying about choosing rigs and floorplans "Get one the wife likes" because she has to deal with it more than he does most of the time.
The same applies to choosing routes "Take the one the driver feels most comfortable driving".
