A data-based assessment of alternative strategies for identification of potential human cancer hazards.
The two-year cancer bioassay in rodents remains the primary testing strategy for in-life screening of compounds that might pose a potential cancer hazard. Yet experimental evidence shows that cancer is often secondary to a biological precursor effect, the mode of action is sometimes not relevant to humans, and key events leading to cancer in rodents from nongenotoxic agents usually occur well before tumorigenesis and at the same or lower doses than those producing tumors. The International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) hypothesized that the signals of importance for human cancer hazard identification can be detected in shorter-term studies. Using the National Toxicology Program (NTP) database, a retrospective analysis was conducted on sixteen chemicals with liver, lung, or kidney tumors in two-year rodent cancer bioassays, and for which short-term data were also available. For nongenotoxic compounds, results showed that cellular changes indicative of a tumorigenic endpoint can be identified for many, but not all, of the chemicals producing tumors in two-year studies after thirteen weeks utilizing conventional endpoints. Additional endpoints are needed to identify some signals not detected with routine evaluation. This effort defined critical questions that should be explored to improve the predictivity of human carcinogenic risk.
Boobis
Alan R
AR
Imperial College London, London, United Kingdom.
Cohen
Samuel M
SM
Doerrer
Nancy G
NG
Galloway
Sheila M
SM
Haley
Patrick J
PJ
Hard
Gordon C
GC
Hess
Frederick G
FG
Macdonald
James S
JS
Thibault
Stéphane
S
Wolf
Douglas C
DC
Wright
Jayne
J
D000818:Animals; D015197:Carcinogenicity Tests / Q000379:methods*; D002273:Carcinogens / Q000633:toxicity*; D016208:Databases, Factual; D005260:Female; D006801:Humans; D055633:Immune System Phenomena / Q000187:drug effects; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D051381:Rats; D011916:Rats, Inbred F344; D018570:Risk Assessment / Q000379:methods
D002273:Carcinogens