A mechanistic approach to modelling the risk of liver tumours in mice exposed to fumonisin B1 in the diet.
Data from the National Toxicology Program's carcinogenesis study of fumonisin B1 in B6C3F1 mice, conducted at the National Center for Toxicological Research, were used to fit the Moolgavkar-Venzon-Knudson (MVK) two-stage, clonal-expansion model of carcinogenesis. In addition to tumour data from the conventional 2-year bioassay, the study included data on tissue weights, cell proliferation, cell death, and sphingolipid metabolism in primary target organs. The model was used to predict 2-year liver tumour rates in female and male mice based on differences among dose groups in the effect of fumonisin B1 on the growth of normal tissue and on the proliferation of preneoplastic cells as a compensatory response to sphinganine-induced cell death. Fumonisin B1 was assumed to be non-genotoxic, i.e. the model did not include any effect of fumonisin B1 on either of the two mutation rates of the MVK model. The model was able to reproduce reasonably well the observed tumour rates in both female and male mice, predicting substantially increased rates above background only at the highest doses of fumonisin B1 in females.
Kodell
R L
RL
National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA. Rkodell@nctr.fda.gov
Young
J F
JF
Delongchamp
R R
RR
Turturro
A
A
Chen
J J
JJ
Gaylor
D W
DW
Howard
P C
PC
Zheng
Q
Q
D000818:Animals; D001835:Body Weight; D002264:Carboxylic Acids / Q000633:toxicity*; D002274:Carcinogens, Environmental / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D004305:Dose-Response Relationship, Drug; D005260:Female; D005506:Food Contamination; D037341:Fumonisins; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008954:Models, Biological; D009183:Mycotoxins / Q000633:toxicity; D009929:Organ Size / Q000187:drug effects; D018570:Risk Assessment / Q000379:methods; D012737:Sex Factors; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism
D002264:Carboxylic Acids; D002274:Carcinogens, Environmental; D037341:Fumonisins; D009183:Mycotoxins; C056933:fumonisin B1; D013110:Sphingosine; C005682:safingol