Styrene metabolites

It is noteworthy that the styrene reference concentration (RfC) in the Integrated Risk Information System is based on the biomarker-response relationship found in workers (Mutti et al. 1984 EPA 1998). The Environmental Protection Agency (EPA) used the relationship of urinary biomarker to ambient-air concentration of workers to develop an RfC that was adjusted for the difference in exposure time between the workplace and the general population. That is a valid approach because it derives a workplace concentration-toxicity relationship in workers, which can then be adjusted for the general population to account for differences in exposure time and can take uncertainty factors into account. It is different from direct adjustment of the styrene BEI to evaluate human population biomonitoring data on styrene metabolites in urine, which would have the uncertainties described above and in Chapter 5. 

J.Liq.Chromatogr., 1987, 10, 2369—2382 [simultaneous metabolites, styrene metabolites vudne rat] Shihabi, Z.K. Dyer, R.D. Serum injection of the HPLC column for carbamazepine assay. 

Quantitative Determination of Urinary Styrene Metabolites by Gas Chromatography... 

PBPK models have also been used to explain the rate of excretion of inhaled trichloroethylene and its major metabolites (Bogen 1988 Fisher et al. 1989, 1990, 1991 Ikeda et al. 1972 Ramsey and Anderson 1984 Sato et al. 1977). One model was based on the results of trichloroethylene inhalation studies using volunteers who inhaled 100 ppm trichloroethylene for 4 horns (Sato et al. 1977). The model used first-order kinetics to describe the major metabolic pathways for trichloroethylene in vessel-rich tissues (brain, liver, kidney), low perfused muscle tissue, and poorly perfused fat tissue and assumed that the compartments were at equilibrium. A value of 104 L/hour for whole-body metabolic clearance of trichloroethylene was predicted. Another PBPK model was developed to fit human metabolism data to urinary metabolites measured in chronically exposed workers (Bogen 1988). This model assumed that pulmonary uptake is continuous, so that the alveolar concentration is in equilibrium with that in the blood and all tissue compartments, and was an expansion of a model developed to predict the behavior of styrene (another volatile organic compound) in four tissue groups (Ramsey and Andersen 1984). 

In contrast, a number of alkene epoxides (10.3) are chemically quite stable, i.e., intrinsically less reactive than arene oxides. Examples of epoxide metabolites that have proven to be stable enough to be isolated in the absence of degrading enzymes include 1,2-epoxyoctane (10.4), 1,2-epoxycyclohex-ane (10.5), 1-phenyl-1,2-epoxy ethane (styrene oxide, 10.6), and cis- 1,2-diphenyl-1,2-epoxyethane (cfv-stilbene oxide, 10.7) [12], The same is true of alclofenac epoxide (10.8), hexobarbital epoxide (10.9), and a few other epoxides of bioactive compounds. 

Such stability is only relative, however, given the possibility of the acid-catalyzed 1,2-shift of a proton observed in some olefin epoxides of general structure 10.10 (Fig. 10.3) [12], Such a reaction occurs in the in vivo metabolism of styrene to phenylacetic acid the first metabolite formed is styrene oxide (10.10, R = Ph, Fig. 10.3, also 10.6), whose isomerization to phenyl-acetaldehyde (10.11, R = Ph, Fig. 10.3) and further dehydrogenation to phenylacetic acid has been demonstrated by deuterium-labeling studies. A com-... 

Parkki MG, Marniemi J, Vainio H Action of styrene and its metabolites styrene oxide and styrene glycol on activities of xenobiotic biotransformation enzymes in rat liver in vivo. Toxicol Appl Pharmacol 38 59-70, 1976... 

By means of an apparent Michaelis constant (A mapp) together with a maximum rate ( max) of butadiene metabolism both obtained with human liver microsomes (Filser et al., 1992), Filser et al. (1993) constructed a human model which was later extended by Csanady et al. (1996) for the butadiene metabolites epoxybutene and diepoxybutane. For butadiene and epoxybutane, the required human tissue air partition coefficients were measured using autopsy material (Table 23). Filser et al. (1993) investigated the influence of styrene co-exposure on butadiene metabolism by assuming competitive interaction. Simulations for a 70-kg man exposed over 8 h to 5 or 15 ppm [11 or 33 mg/m3] butadiene indicated total amounts of butadiene metabolized of 0.095 and 0.285 mmol, respectively, reduced by about 19% and 37% as a result of co-exposure to 20 and 50 ppm styrene, respectively. No influence of butadiene on styrene metabolism was noted. 

Bitzenhofer, U.N., Kessler, W., Kreuzer, PE. Filser, J.G. (1994) Kinetics of styrene and its metabolite st rene-7,8-oxide in the isolated perfused rat liver (Abstract No. 390). The Toxicologist, 14. 118... 

Cochrane, J.E. Skopek, T.R. (1993) Mutagenicity of 1,3-butadiene and its epoxide metabolite in human TK6 cells and in splenic T cells isolated from exposed B6C3F1 mice. In Sorsa, M., Peltonen, K., Vainio, H. Hemminki, K., eds. Butadiene and Styrene Assessment of Health Hazards (lARC Scientific Publications No. 127), Lyon, I ARC. pp. 195-204... 

Styrene Urinary metabolites Use of worker urinary metabolite-exposure information to develop pharmacokinetic model applicable to general public Appendix B... 

Styrene Urinary metabolites Biomarker to external dose (air concentration) in workers external dose to toxicity in animals biomarker to toxicity in workers Biomarker results can estimate risk in workers but not directly applicable to general population. 

The chlorpyrifos and phthalate examples demonstrate that urinary biomarker data can be used within the context of pharmacokinetic modeling to interpret human exposure and risk. For a number of workplace urinary biomarkers, simple approaches have been used to relate biomarker concentration to exposure dose. A prime example is styrene an empirically derived relationship between urinary concentration of the metabolite, man-... 

Astier A. 1992. Simultaneous high-performance liquid chromatographic determination of urinary metabolites of benzene, nitrobenzene, toluene, xylene and styrene. J Chromatogr 573(2) 318-322. 

Ogata M, Taguchi T. 1987. Quantitation of urinary metabolites of toluene, xylene, styrene, ethylbenzene, benzene and phenol by automated high performance liquid chromatography. Int Arch Occup Environ Health 59 263-272. 

Lovley, D.R., Anaerobic benzene degradation, Biodegradation 11, 107—116, 2000 Snyder, R., Xenobiotic metabolism and the mechanism(s) of benzene toxicity. Drug Metab. Rev. 36, 531—547, 2004 Rana, S.V. and Verma, Y., Biochemical toxicity of benzene, J. Environ. Biol. 26,157—168, 2005 Lin, Y.S., McKelvey, W., Waidyanatha, S., and Rappaport, S.M., Variability of albumin adducts of 1,4-benzoquinone, a toxic metabolite of benzene, in human volunteers. Biomarkers 11,14-27, 2006 Baron, M. and Kowalewski, V.J., The liquid water-benzene system, J. Phys. Chem. A Mol. Spectrosc. Kinet. Environ. Gen. Theory 100, 7122-7129, 2006 Chambers, D.M., McElprang, D.O., Waterhouse, M.G., and Blount, B.C., An improved approach for accurate quantiation of benzene, toluene, ethylbenzene, zylene, and styrene in blood, Anal. Chem. 78, 5375-5383, 2006. 

Styrene is absorbed by all routes of exposure. Absorption through the respiratory tract is rapid and the major route of human exposure. Once absorbed, styrene is rapidly distributed throughout the body. Studies in rats and mice indicate that styrene or its metabolites are distributed to the liver, kidneys, heart, subcutaneous fat, lung, brain, and spleen. In both species, fat contained the highest concentration of styrene, suggesting that fat may act as a modest reservoir for these compounds. While there are qualitative similarities in the metabolism of styrene among species, quantitative differences have been noted. 

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