How can I project how many users a site will need before it can anticipate robust ad sales?
We hand invited the publishers that join our market because, as your question suggests, there is some threshold between who should and should not try direct sales.
There are no hard rules, just guidelines.
The superseding one is this: Do you have inventory (audience) an advertiser would take the time to specifically work with you for? If you open a "store" and starting selling this stuff, do people want to buy it?
One measure is traffic, but that's not enough. In general we like to look for sites with 100,000 page views a month or more.
But it can depend on the content and vertical. For example, we power a website that gets 25k hits a month but is the only site covering the voice over talent industry in Hollywood - so its super nichey and there is a market for those advertisers.
Other examples of small but successful premium properties include some hyperlocal ones (www.queensmamas.com, www.brooklynheightsblog.com, www.brokelyn.com, etc), the largest blog for truckers, largest blog for prison wardens, etc.
The conflicting examples are sites with large traffic but bad audiences/verticals. We reject a lot of "tech blog" also-rans that just copy and paste content from TechCrunch but get a lot of SEO traffic from it. Or even if it's a legit site, it can be in a bad brand-advertiser vertical like home finance / mortgages (which is mostly lead gen advertisers)