Toxicokinetics of Inhaled Propylene in Mouse, Rat, and Human

Filser, Johannes G.; Schmidbauer, R.; Rampf, F.; Baur, C.; Pütz, Christian; Csanády, György A.

doi:10.1006/taap.2000.9027

Cited by 30 publications

(16 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The existing literature indicates that treatment of rats with 20 mg CPP/kg bw [Aidoo et al, 1991;Mirkes et al 1992], but not propylene at any exposure concentration, should produce a significant mutagenic response compared to spontaneous Hprt Mfs (see Introduction). These results support the conclusion that the in vivo metabolism of propylene to PO becomes saturated to yield maximum levels of PO that are insufficient to exceed a threshold for induction of mutations over the spontaneous background in the rat [Filser et al, 2000].…”

Section: Discussionsupporting

confidence: 77%

“…Svensson et al [1991] monitored the formation of hydroxypropyl adducts to N-7 guanine of DNA in several organs of male CBA mice following inhalation exposure to propylene, and found that the distribution of DNA adducts was uniform across target (lung) and nontarget (liver, kidney, testis, spleen) tissues for PO-induced cancer. Filser et al [2000] found that inhaled propylene had a very low potential to accumulate in any tissue except blood and adipose tissue.…”

Section: Introductionmentioning

confidence: 98%

“…The pharmacokinetics of inhaled propylene were studied in male Sprague-Dawley rats [NTP, 1985, Golka et al, 1989, Filser et al, 2000. In rats exposed to 50 ppm propylene by inhalation, approximately 16% was absorbed into the lungs.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Hprt mutant frequencies in splenic T‐cells of male F344 rats exposed by inhalation to propylene

Walker

Seilkop

Scott

et al. 2004

Environ and Mol Mutagen

View full text Add to dashboard Cite

Propylene is a major industrial intermediate and atmospheric pollutant to which humans are exposed by inhalation. In this study, 6-week-old male F344 rates were exposed to 0, 200, 2000, or 10,000 ppm propylene by inhalation for 4 weeks (6 h/day, 5 days/week), and mutant frequencies were determined in the Hprt gene of splenic T-lymphocytes. Twenty milligrams of cyclophosphamide monohydrate (CPP)/kg bw, given on the penultimate day of propylene exposure, was used as a positive control mutagen. Rats (n = 8/group) were necropsied for isolation of T-cells 8 weeks after the last dose, a sampling time that produced peak spleen Hprt mutant frequencies (Mfs) in a preliminary mutant manifestation study using CCP treatment. Hprt Mfs were measured via the T-cell cloning assay, which was performed without knowledge of the animal treatment groups. Mean Hprt Mfs were significantly increased over control values (mean Mf = 5.24 +/- 1.55 (SD) x 10(-6)) in CPP-treated rats (10.37 +/- 4.30 x 10(-6), P = 0.007). However, Hprt Mfs in propylene-exposed rats were not significantly increased over background, with mean Mfs of 4.90 +/- 1.84 x 10(-6) (P = 0.152), 5.05 +/- 3.70 x 10(-6) (P = 0.895), and 5.95 +/- 2.49 x10(-6) (P = 0.500) for animals exposed to 200, 2000, or 10,000 ppm propylene, respectively. No significant increase in F344 rat or B6C3F1 mouse cancer incidence was reported in the National Toxicology Program carcinogenicity studies of propylene across this same exposure range. Taken together, these findings support the conclusion that inhalation exposure of rats to propylene does not cause mutations or cancer.

show abstract

Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 98%

See 1 more Smart Citation

Hprt mutant frequencies in splenic T‐cells of male F344 rats exposed by inhalation to propylene

Walker

Seilkop

Scott

et al. 2004

Environ and Mol Mutagen

View full text Add to dashboard Cite

show abstract

“…The shortest time interval between exposures was 2 days. Exposures of the 4 volunteers were conducted using the open exposure system described in detail in Filser et al (2000, 2008). Briefly, a stream of an ET-air mixture flowed through a polytetrafluoroethene tube at a constant flow rate from an ET storage container into a chemical exhaust hood.…”

Section: Methodsmentioning

confidence: 99%

Ethylene Oxide in Blood of Ethylene-Exposed B6C3F1 Mice, Fischer 344 Rats, and Humans

Filser

Kessler

Artati

et al. 2013

Toxicological Sciences

View full text Add to dashboard Cite

The gaseous olefin ethylene (ET) is metabolized in mammals to the carcinogenic epoxide ethylene oxide (EO). Although ET is the largest volume organic chemical worldwide, the EO burden in ET-exposed humans is still uncertain, and only limited data are available on the EO burden in ET-exposed rodents. Therefore, EO was quantified in blood of mice, rats, or 4 volunteers that were exposed once to constant atmospheric ET concentrations of between 1 and 10 000 ppm (rodents) or 5 and 50 ppm (humans). Both the compounds were determined by gas chromatography. At ET concentrations of between 1 and 10 000 ppm, areas under the concentration-time curves of EO in blood (µmol × h/l) ranged from 0.039 to 3.62 in mice and from 0.086 to 11.6 in rats. At ET concentrations ≤ 30 ppm, EO concentrations in blood were 8.7-fold higher in rats and 3.9-fold higher in mice than that in the volunteer with the highest EO burdens. Based on measured EO concentrations, levels of EO adducts to hemoglobin and lymphocyte DNA were calculated for diverse ET concentrations and compared with published adduct levels. For given ET exposure concentrations, there were good agreements between calculated and measured levels of adducts to hemoglobin in rats and humans and to DNA in rats and mice. Reported hemoglobin adduct levels in mice were higher than calculated ones. Furthermore, information is given on species-specific background adduct levels. In summary, the study provides most relevant data for an improved assessment of the human health risk from exposure to ET.

show abstract

“…Subsequently, the resulting QPPR model was evaluated with experimental in vivo data on CL int⁡ for 11 additional VOCs in rats (1,1,1-trichloroethane; 1,2,4-trimethylbenzene; bromoform; dibromochloromethane; furan; halothane; o -xylene; trans -1,2-dichloroethylene; tetrachloroethylene; propylene; ethylene) [46, 48, 54–61]. These 11 chemicals outside the calibration set were also lipophilic, low-molecular-weight VOCs and likely substrates of cytochrome P450 2E1 [32, 62].…”

Section: Methodsmentioning

confidence: 99%

Quantitative Property-Property Relationship for Screening-Level Prediction of Intrinsic Clearance of Volatile Organic Chemicals in Rats and Its Integration within PBPK Models to Predict Inhalation Pharmacokinetics in Humans

Peyret

Krishnan²

2012

Journal of Toxicology

View full text Add to dashboard Cite

The objectives of this study were (i) to develop a screening-level Quantitative property-property relationship (QPPR) for intrinsic clearance (CLint) obtained from in vivo animal studies and (ii) to incorporate it with human physiology in a PBPK model for predicting the inhalation pharmacokinetics of VOCs. CLint, calculated as the ratio of the in vivo V max (μmol/h/kg bw rat) to the K m (μM), was obtained for 26 VOCs from the literature. The QPPR model resulting from stepwise linear regression analysis passed the validation step (R 2 = 0.8; leave-one-out cross-validation Q 2 = 0.75) for CLint normalized to the phospholipid (PL) affinity of the VOCs. The QPPR facilitated the calculation of CLint (L PL/h/kg bw rat) from the input data on log P ow, log blood: water PC and ionization potential. The predictions of the QPPR as lower and upper bounds of the 95% mean confidence intervals (LMCI and UMCI, resp.) were then integrated within a human PBPK model. The ratio of the maximum (using LMCI for CLint) to minimum (using UMCI for CLint) AUC predicted by the QPPR-PBPK model was 1.36 ± 0.4 and ranged from 1.06 (1,1-dichloroethylene) to 2.8 (isoprene). Overall, the integrated QPPR-PBPK modeling method developed in this study is a pragmatic way of characterizing the impact of the lack of knowledge of CLint in predicting human pharmacokinetics of VOCs, as well as the impact of prediction uncertainty of CLint on human pharmacokinetics of VOCs.

show abstract

Toxicokinetics of Inhaled Propylene in Mouse, Rat, and Human

Cited by 30 publications

References 36 publications

Hprt mutant frequencies in splenic T‐cells of male F344 rats exposed by inhalation to propylene

Hprt mutant frequencies in splenic T‐cells of male F344 rats exposed by inhalation to propylene

Ethylene Oxide in Blood of Ethylene-Exposed B6C3F1 Mice, Fischer 344 Rats, and Humans

Quantitative Property-Property Relationship for Screening-Level Prediction of Intrinsic Clearance of Volatile Organic Chemicals in Rats and Its Integration within PBPK Models to Predict Inhalation Pharmacokinetics in Humans

Contact Info

Product

Resources

About