Sticking with just part 1, I think the creation of a weapon/android that utilises radiation would be a difficult opponent to counter, perhaps even for Z era characters. After all, we never saw a character outright counter poisoning techniques until Super, and that was as result of advanced Ki control Part 1 characters don't have.
Most of the Z-Senshi also can't survive without oxygen. Piccolo may be an exception for Z characters, though doubtful since he still requires water to survive. Having a villain that can somehow launch them into the vacuum of space could work. Maybe by luring them into a base which is actually a disguised ship and sending it into orbit once they arrive at the right part of it, or by creating a space station with enough firepower to attack from a distance, which would prove a threat for the main cast until after the Freeza Arc due to Goku lacking Shunkan Ido.
Personally, I would've introduced a kryptonite like element which limit's one's Ki and have this element weaponised. Perhaps have someone discover katchin and make an armour and weaponry out of it.