We applied the L1000 platform to study the effects of chemical perturbations of previously validated rat liver carcinogens and noncarcinogens
in HepG2 (human hepatocellular carcinoma) cell lines.
We used established unit risk estimates for carcinogens and/or chronic reference values for noncarcinogens
to set thresholds for each category.
To further identify gene expression changes that may be predictive of cancer risk, additional emphasis was placed on signaling pathways influenced by PB and PTU (carcinogens) but not NaI (noncarcinogen
where the parameter values are the following: EFr, exposure frequency = 365 days/year; [ED.sub.tot], exposure duration = 70 years, equivalent to average lifetime ; FIR, food ingestion rate = 0.345 kg/person/day [24,25]; C, concentration of metal in animal tissue in mg/kg; [RfD.sub.o], oral reference dose in mg/kg/day; [BW.sub.a], average body weight, adult = 60 kg; [AT.sub.n], average exposure time for noncarcinogens
in days (EFr (365 days/year) x [ED.sub.tot] (number of exposure years, assuming 70 years in this study); [10.sup.-3], the unit of conversion).
where EFr is the exposure frequency = 312 days/year, equivalent to average lifetime; TSIR is the tobacco snuff ingestion rate = 50.0 g/day, equivalent to 10 pouches/day, 50.0 [micro]g/pouch of TSS; C is the concentration of metal in TSS in [micro]g/g; [RfD.sub.o] is the oral reference dose in mg/kg/day; [BW.sub.a] is the average body weight, adult = 60 kg; [AT.sub.n] is the average exposure time for noncarcinogens
in days (EFr(312 days/ year) x [ED.sub.tot] (number of exposure years, assuming 70 years in this study); and [10.sup.-3] is the unit of conversion.
Thus, the common mechanism of action of diametrically different carcinogens (and noncarcinogens
) on target cells is the destruction of the plasmatic membrane.
According to the Integrated Risk Information System (IRIS) from USEPA, DBP and DiOP are noncarcinogens
, and their exposure reference doses are 1.00 x [10.sup.-1] mg/(kg x d), and 2.00 x [10.sup.-2] mg/(kg x d) respectively.
Although the in vitro test battery demonstrates a high degree of sensitivity in detecting genotoxic carcinogens, it is poor at correctly identifying noncarcinogens
. The specificity of the in vitro mammalian cell tests is particularly low, giving misleading positive results for more than 50% of noncarcinogens
(70) Although FDA has tried to evade the Delaney Clause, finding various statutory loopholes to subject carcinogens to the one-in-one million de minimis threshold instead, (71) I am not aware of evidence that the FDA has regularly subverted this safety threshold or the parallel threshold for noncarcinogens
to serve nonsafety goals.
For sources emitting noncarcinogens
, the Agency could delist ah industry if, inter alia, its emissions do not "exceed a level which is adequate to protect public health with an ample margin of safety." Id.
His team administered known carcinogens and noncarcinogens
to the novel mice.
Benzene is an interesting example as it is a nonchlorinated carcinogen, while many compounds formed by chlorine substitution -- mono-chlorobenzene, pentachlorobenzene, cresol -- are chlorinated noncarcinogens