I'm doing a bit of research into pre-clinical toxicology methods. Could anybody help me out or point me towards a source of info? The question on my mind is - once those in drug discovery/development have a lead and want to assess its toxicity, how do they decide what are the high/medium/low doses to administer to the animals? Surely there must be some kind of rule of thumb? What about in vitro assays? Is there a rule of thumb that says, for example "x concentration of drug in a primary hepatocyte assay is approx. equivalent to administering x amount of the drug to the animal equivalent"? Should one try and match in vitro concentrations with in vivo blood concentrations? I'm trying to get a feel for how this is all done.

Sadly there is no precise "formula" for the administration of different drugs, probably because there are a large number of variables to be addressed. If you cannot find any references for similar (families) of compounds administered in vivo or in vitro, a good place to start is to try several decades of concentrations on your target cell line (eg hepatocytes).
"x concentration of drug in a primary hepatocyte assay is approx. equivalent to administering x amount of the drug to the animal equivalent" is almost never a direct correlation, because of the physiological profile of the animal (eg mouse), the particular drug and its metabolism, mode of administration etc etc.
Any conc that gives an effect in vitro can again be tried with the decade rule (+ and 1 10 fold) in animals - start with small groups of perhaps ~3 mice/group (9 total) - this will help determine the ranges, and narrow them down. With mice, its usually amt/kg wt of animal - but this value can differ widely depending upon age, mode of administration, target etc.

Thank you so much Samm.

I did a bit more background reading and found the FDA "maximum recommended starting dose" for phase I trials. They provide a general list of conversions, which I appreciate are not the best but give a starting point I suppose. E.g. If the max safe dose of a substance in a mouse is "x" the the human max equivalent to start a phase I trial should be "x/6.2".

Is there not something similar with cell assays (even if it is very crude? I appreciate that there are so many potential confounding variables). Say hypothetically you cultured primary rat hepatocytes with 5mM acetaminophen and found cytotoxicity... what best guess dose would you say should you aim for in the rat?

Thank you again for the help. It really is appreciated.