Thread safety really has nothing to do with MODx and everything to do with PHP, the web server, the OS, etc. Read Jason Lester’s comment at the bottom of this page here:
http://neosmart.net/blog/2008/dont-believe-the-lies-php-isnt-thread-safe-yet/#comment-392079
Might also run through this perspective:
http://brian.moonspot.net/2008/02/13/apache-worker-and-php/
As for any real advice on these topics, I’ll have to defer to a real server administrator. I know we get quite a lot of traffic on our single massive box that is hosting modxcms.com (and a handful of other sites with PHP/MySQL-based applications, yes, mostly MODx) and we are running both an Apache 1.3 and an Apache 2 instance using server API, both prefork, with the same compile of PHP (thread safety disabled), and we’re running pretty smoothly, save for the occasional traffic peaks (usually a lame DDOS attempt) causing us to run out of db connections.
Ultimately though, it depends on the requests per second you need to be able to handle, i.e. if all of your traffic is concentrated into a small amount of time, your going to need more than a single box to handle it, and that means a lot of additional issues and constraints. If this traffic is spread out and you are having problems, I would venture to say it may be application specific (maybe a slow query? have you tried turning on the mysql slow_query_log feature for instance?).