Flashing in safe mode is a good idea. Having said that, I've probably done close to 100 flashes in 'normal' Windows, almost always with at least a few programs such as a web browser running in the background, and never had a problem. And at least half of those I'd say I've done in a USB enclosure, some of which are not the best enclosures. And did I mention that I usually don't reboot either? With USB I just cycle the power on/off, with internal drives sometimes I've just cycled into/out of hibernate.
Life's too short for reboots, safe mode, and DOS. (just kidding ) The above obviously increases the risk, even if only slightly with a good running system and stable programs running in the background.