Refining in vitro and in silico neurotoxicity approaches by accounting for interspecies and interindividual differences in toxicodynamics

Figures & data

Figure 1. Representation of the uncertainty factors applied in toxicology. The default uncertainty factor is 100, which is divided into two factors of 10, one for interspecies differences and one for interindividual or intraspecies differences. These factors of 10 are again divided into two factors, one for variability in toxicokinetics (TK) and one for variability in toxicodynamics (TD) [11]

Table 1. Comparison of interspecies differences for a selection of neurotoxicological compounds assessed using in vitro assays. The investigated compound, the parameter that is compared, the animal species that was used and the values derived for the animal species and for humans are indicated. Furthermore, the most sensitive species based on that data and the interspecies differences are shown

Compound	Parameter compared	Animal species	Animal species value	Human value	Most sensitive species	Interspecies difference	Reference
BzATP	EC50 P2X7	Rat	1.3 µM	5.5 µM	Rat	4.2	[42]
BzATP	EC50 P2X7	Mouse	83 µM	5.5 µM	Human	15	[42]
4-aminopyridine	LOEC MEA	Rat	>100 µM	100 µM	Human	>1	[41]
Amphetamine	30 µM MEA	Rat	~90% activity	~65% activity	Human	1.4	[34,39]
Amoxapine	LOEC MEA	Rat	1 µM	1 µM	Comparable	1	[38]
AT-1001	Ki α3β4 receptor	Rat	1.9 nM	0.092 nM	Human	21	[43]
AT-1001	Ki α4β2 receptor	Rat	78 nM	91 nM	Rat	1.2	[43]
Chlorpromazine	LOEC MEA	Rat	1 µM	1 µM	Comparable	1	[38]
Cocaine ([^3H]CFT)	Bmax (binding)	Rat	156 fmol/10^5 cells	330 fmol/10^5 cells	Human	2.1	[44]
Cocaine ([^3H]CFT)	Bmax (binding)	Bovine	35 fmol/10^5 cells	330 fmol/10^5 cells	Human	9.4	[44]
Endosulfan	LOEC MEA	Rat	0.3 µM	1 µM	Rat	3.33	[34]
Enoxacin	LOEC MEA	Rat	3 µM	>10 µM	Rat	>3.33	[38]
Linopirdine	LOEC MEA	Rat	>100 µM	10 µM	Human	>10	[38]
Manganese chloride (MnCl2)	EC50 cytotoxicity	Rat	1.3 mM; 17 mM	0.71 mM; 5 mM	Human	1.8–24	[46]
Methoxetamine (MXE)	IC50 MEA	Rat	0.5 µM	>10 µM	Rat	>20	[25]
Methylmercury (MeHg)	30 µM MEA	Rat	0% activity	No effect	Rat	>30*	[36,37]
Methylmercury (MeHg)	EC50 cytotoxicity	Rat	2.2 µM	2.1 µM; 8.2 µM	Rat	<1-3.7	[46]
MPP^+	Uptake	Rat	68 fmol/10^5 cells	118 fmol/10^5 cells	Human	1.7	[44]
MPP^+	Uptake	Bovine	5 fmol/10^5 cells	118 fmol/10^5 cells	Human	24	[44]
Pentylenetetrazol	LOEC MEA	Rat	3 mM	>3 mM	Rat	>1	[38]
Perfluorooctanoic acid (PFOA)	LOEC MEA	Rat	>100 µM	1 µM	Human	>100	[40]
Perfluoorooctane sulfonate (PFOS)	LOEC MEA	Rat	100 µM	0.1–100 µM	Human	1–1000	[40]
Phenytoin	LOEC MEA	Rat	30 µM	100 µM	Rat	3.33	[38]
Picrotoxin	LOEC MEA	Rat	1 µM	1 µM/>10 µM^#	Comparable	1	[41]
Pilocarpine	LOEC MEA	Rat	>30 µM	1 µM	Human	>30	[38]
R-styrene oxide	EC50 cytotoxicity	Rat	6.6 µM; 60 µM; 110 µM	29 µM; 20 µM	Human	<1-5.5	[46]
Strychnine	LOEC MEA	Rat	3 µM	0.3–30 µM^#	Human	<1-10	[41]
S-styrene oxide	EC50 cytotoxicity	Rat	0.016 mM; 0.12 mM; 0.44 mM	0.58 mM; 0.041 mM	Human	<1-10	[46]
Tetrodotoxin (TTX)	IC50 MEA	Rat	7 nM	10 nM	Rat	1.4	[24]

*The LOEC for the rat was 1 µM; ^#depending on the model, 2 out of 3 models suggest humans are more sensitive.

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