Isoprene

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - dermal (%):

0.3

Absorption rate - inhalation (%):

10

Additional information

Endogenous Production

Isoprene is formed endogenously in humans; the sources proposed include mevalonic acid via the intermediate product dimethylallyl pyrophosphate (precursors of cholesterol), the peroxidation of squalene, and from the decomposition of farnesyl (3 isoprene units) or geranylgeranyl residue (4 isoprene units) of prenylated proteins. Isoprene is found in the exhaled air of humans and is the major (30-70%) hydrocarbon component. It has been reported that the amounts of isoprene exhaled within a 24-hour period were determined to be 0.36 to 9.36 mg (Conkle et al., 1975) and 2 to 4 mg (Gelmont et al., 1981). The mean endogenous blood concentration of isoprene was 37 +/- 25 nmol/L.

Concentrations of isoprene in exhaled air from untreated rats and mice were originally reported by Peters et al. (1987). Subsequently, it was found that the gas chromatography and flame ionisation detection method used employed a column packing material which was unable to differentiate between endogenously produced isoprene and acetone (Filser et al.,1996). Using a different gas chromatography and mass detection technique, very low concentrations of isoprene (some ppb values) were found in the exhaled air of rats.

 

Toxicokinetics

Isoprene exhibits saturation kinetics in rats and mice. The rate of metabolism was directly proportional to the exposure concentration at concentrations up to 300 ppm. However, both species exhibited saturation kinetics when exposed to isoprene at concentrations above 300 ppm. Saturation of isoprene metabolism was nearly complete at about 1000 ppm in rats and at about 2000 ppm in mice. The maximal metabolic elimination rate in mice was determined to be at least 400 µmol/hr/kg, which is about three times faster than that found in rats (130 µmol/hr/kg). The whole body half-life of isoprene was 6.8 minutes in rats and 4.4 minutes in mice.

The internal dose of isoprene was found to be greater in mice than rats after exposure to the same concentration. At concentrations above 1000 ppm, mice absorb three times more isoprene per kg body weight compared to rats, though at lower concentrations, the species difference in uptake became smaller (approx. two-fold at 700 ppm). 

Metabolites of isoprene were detected in the blood, nose, lungs, liver, kidneys, and fat of male F344/N rats exposed to 1,480 ppm [14C]-labelled isoprene.

 

Metabolism

In liver microsomes, isoprene is metabolized by cytochrome P450 oxidation to the monoepoxide metabolites, 3,4-epoxy-3-methyl-butene and 3,4 -epoxy-2-methyl-butene. Both monoepoxides can be further metabolized to the diepoxide metabolite, 1,2:3,4-diepoxy-2-methyl-butane. The epoxides can also be hydrolysed or can be conjugated with glutathione. It is also expected that epoxide diols can be formed.

 

Physiologically-based Toxicokinetic Model

A physiologically-based toxicokinetic (PT)-model has been constructed and used to simulate the inhalation of isoprene, its distribution by the blood flow, its metabolism, endogenous production, and exhalation as unchanged isoprene (Filser et al., 1996; Csanady and Filser, 2001). The model compartments consist of air, lung, richly perfused tissues, fat, muscle, and liver. Mouse, rat and human partition coefficients were determined experimentally. The endogenous production of isoprene was considered to occur only in the human liver and was described by zero-order kinetics. Metabolism was assumed to follow Michaelis-Menten kinetics and was allocated to hepatic and also to extrahepatic tissues. Toxicokinetic parameters were derived from reanalysing closed-chamber data measured in rodents (Peter et al., 1987) by means of a two-compartment model. This calculation was based on the assumption that in rodents the endogenous production of isoprene can be neglected quantitatively (Filser et al., 1996). The maximum rate of metabolism (V_max) was directly incorporated into the PT model; the value of K_mwas scaled. In order to predict toxicokinetics if isoprene in humans, the maximum rate of metabolism was extrapolated allometrically from rats based on body weight to ¾ power. Rat and humans were used to have identical K_mvalues. The rate of endogenous production in humans was estimated from the atmospheric plateau concentration of isoprene measured in a spirometer system (Filser et al., 1996).

In the low exposure concentration range, isoprene metabolism was limited by transport to the metabolizing enzymes and not by metabolic capacity. Taking into account species-specific partition coefficients and physiological processes (ventilation or blood flow), pulmonary uptake, accumulation in the blood and tissues, exhalation and rates of isoprene metabolism were comparable in rodents and humans. The PT model predicted that for exposure concentrations up to 50 ppm, the rate of isoprene metabolism are about 14 times faster in mice and about 8 times faster in rats than in humans.   

At 0 ppm atmospheric isoprene, the rate of metabolism in humans is 0.31 µmol/hr/kg body weight and represents the part of endogenously produced isoprene that is metabolized. About 90% of the endogenously produced isoprene is metabolized, and only about 10% is exhaled unchanged.

Lower steady-state concentrations of isoprene are predicted in venous blood of humans compared to the mouse and the rat due to the relatively comparatively faster uptake of isoprene in rodents and because isoprene metabolism is perfusion limited. This can also be predicted from the blood:air partition coefficients which are significantly larger in rodents than in humans. Because of the rapid isoprene metabolism, Csanady and Filser (2001) concluded that isoprene cannot accumulate in humans at low exposure concentrations.   

Using the PT model, the area under the blood concentration-time curve (AUC) following an 8 hour exposure to 10 ppm isoprene was calculated to be about 4 times higher than the AUC resulting from the 24 hour exposure to endogenous isoprene (Filser et al., 1996; Filser and Csanady, 2001).

Discussion on absorption rate:

The dermal absorption of isoprene was predicted using a model which considers dermal absorption as a two stage process, permeation of the stratum corneum followed by transfer from the stratum corneum to the epidermis. The model predicted a maximum flux = 0.000638 mg/cm²/min giving an absorption of approximately 0.3% (ten Berge, 2009).