The role of mode of action studies in extrapolating to human risks in toxicology.
The US Environmental Protection Agency (EPA) in 1999 issued draft guidelines on carcinogen risk assessment, which included the use mode of action information in the risk assessment process. We have used the five stages of induction of toxicity as described by Aldridge to illustrate in the case of two drugs, tamoxifen and NTBC, how mode of action information played a key role in assessing the risk of cancer and target organ toxicity, respectively.
Lock
Edward A
EA
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, SK10 4TJ, Cheshire, UK. ted.lock@syngenta.com
Smith
Lewis L
LL
D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity*; D003512:Cyclohexanones / Q000493:pharmacokinetics / Q000633:toxicity*; D017408:Guidelines as Topic; D006207:Half-Life; D006801:Humans; D009579:Nitrobenzoates / Q000493:pharmacokinetics / Q000633:toxicity*; D018570:Risk Assessment / Q000379:methods; D013629:Tamoxifen / Q000493:pharmacokinetics / Q000633:toxicity*; D014481:United States; D014484:United States Environmental Protection Agency
D002273:Carcinogens; D003512:Cyclohexanones; D009579:Nitrobenzoates; D013629:Tamoxifen; C077073:nitisinone