Correlation between the results of in vitro and in vivo chromosomal damage tests in consideration of exposure levels of test chemicals

Table 4 Comparison of parameters between in vivo positive and in vivo negative compounds - in vivo negative case with C_max and/or AUC_vivo being less than in vitro LEC and AUC_vitro -

Compound	LEC (μg/mL)	C_max (μg/mL)	AUC_vitro (μg·h/mL)	AUC_vivo (μg·h/mL)	the highest dose in vivo	t_max (h)	PPB (%)	in vitro positive condition	CS at LEC^a (%)	Fold Increase^b
I	250	25.1	1500	181	MTD	0.3	90.9	short (+/− S9)	RCC: 83 (RICC: 75)**	9.7
J	22.5	0.8	540	12.6	MFD	8.0	90.1	continuous	RMI: 70	ND
K	300	22.9	1800	205	MTD	2.0	92.1	short (− S9)	RCC: 42 (RICC: 14)**	ND
L	95	9.6	570	138	MFD	8.0	96.3	short (+*/− S9)	RCC: 55 (RICC: 33)**	ND
M	392	16.7	2350	204	MTD	–	92.8	short (+*/− S9)	RCC: 57 (RICC: 43)**	24.7
N	26	11.1	156	196	MFD	7.0	98.7	short (− S9)	RCC: 46 (RICC: 28)**	18
O	120	28.5	2880	475	MTD	4.3	83.0	short (+/− S9) continuous*	RPD: 57	ND
P	35.1	14.2	913	229	MFD	3.0	67.2	continuous	RICC: 67	3.4
Q	407	40.5	2442	441	MFD	3.0	89.6	short (+ S9)	RICC: 70	3.1
R	233	30.3	1398	400	MTD	1.0	93.9	short (+*/− S9)	RICC: 65	6

LEC, the lowest effective (positive) concentration in the in vitro test; C_max, maximum plasma concentration; AUC, area under the concentration time curve; MFD, the maximum feasible dose (2000 mg/mg); MTD, the maximum tolerated dose; t_max, time to maximum plasma concentration; PPB, the ratio of plasma protein binding; CS, the ratio of cell survival; short (+/− S9), short-term with/without S9 mix; continuous, continuous without S9 mix; ND, not determined due to the vehicle control value “0”
^aCell survival ratio at LEC compared to concurrent vehicle control. RCC, relative cell survival; RMI, relative mitotic index; RICC, relative increase in cell count; RPD, relative population doubling
^bMaximum fold increases of the incidence of micronucleated cells or cells with chromosomal aberration compared to the concurrent vehicle control value
^*The data of marked treatment condition showing positive responses with the lowest exposure levels were adopted for the comparison. The lowest exposure levels were same for compound J in the short-term treatment conditions with and without S9 mix
**Estimated RICC from RCC data

ISSN: 1880-7062