Discovery that might help someone; I couldn't find anything on it. If anyone can give me a reason and a better fix, that'd be cool.

Just moved a working but old 4.6.1 site from a Server 2003 32 bit machine to a Server 2008 64 bit machine.

Spun up the site, and first visit works fine, every subsequent request generated:

Exception: System.IO.IOException

Message: The process cannot access the file 'C:\PROJECTS\cfront\App_Data\umbraco.config' because it is being used by another process.

Followed by:

Description: The process was terminated due to an unhandled exception.
Exception Info: System.IO.IOException
Stack:
at System.IO.__Error.WinIOError(Int32, System.String)
at System.IO.File.InternalDelete(System.String, Boolean)
at System.IO.File.Delete(System.String)
at umbraco.content.DeleteXmlCache()
at umbraco.content.PersistXmlToFile(System.Xml.XmlDocument)
...

Followed by the worker process crashing and stopping:

Faulting application name: w3wp.exe, version: 7.5.7601.17514, time stamp: 0x4ce7a5f8
Faulting module name: KERNELBASE.dll, version: 6.1.7601.17651, time stamp: 0x4e211319
Exception code: 0xe0434352
Fault offset: 0x0000b9bc
Faulting process id: 0x3c8
Faulting application start time: 0x01cf233feee21a70
Faulting application path: C:\WINDOWS\SysWOW64\inetsrv\w3wp.exe
Faulting module path: C:\WINDOWS\syswow64\KERNELBASE.dll

Fixed this by changing the AppPool settings to Allow 32 bit applications = true

I have later version Umbraco sites moved onto there that run fine.