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There are no specific studies on the streams in the C4, high 1,3 -butadiene category (CAS Numbers; 68476-52-8, 68477-42-9, 68955-28-2, 87741-01-3, 92045-23-3) but data are available on the component substances.

 

Butane, isobutane, and butene isomers (butenes):

 

Dahl et al (1988) investigated the comparative rates of uptake of 19 hydrocarbon vapours by rats. Representative compounds from the chemical classes of alkenes, alkynes, straight-chain and branched alkanes, alicyclics, and aromatics were examined. It was concluded that absorption tends to increase with molecular weight, so that straight chain molecules are more highly absorbed than branched isomers, and aromatic molecules are more highly absorbed than paraffins. Thus short chain C1-C4 alkanes which exist as a vapour at room temperature, are very poorly absorbed, and if absorbed, are normally rapidly exhaled. Isobutane absorption following inhalation exposure is low (uptake 0.6 -1.0 nmol/kg/min/ppm, lower than butane). Butane absorption following inhalation exposure at 100ppm (240 mg/m3) is low (uptake 1.5 -1.8 nmol/kg/min/ppm) or 0.09 -0.1 micrograms/kg/min/ppm). From this the Health Council of the Netherlands (2004) calculated that approximately 10% is absorbed.

 

Unsaturated compounds are absorbed better than saturated ones (Dahl, 1988), this is supported by the butenes database. Members of the butenes category are absorbed, widely distributed metabolised and excreted in rats and mice (Eide et al, 1995). Rats exposed to 300 ppm (688 mg/m3) of 1-alkenes (from C2-C8, including 1-butene) for 12h per day for 3 days had increased concentrations of the alkenes in blood and tissues, proportional to increasing numbers of carbon atoms. In contrast, levels of haemoglobin and DNA adducts decreased with increasing numbers of carbon atoms. The 1-alkenes were widely distributed within the body with the lowest concentrations in blood and the highest in fat.

 

More extensive metabolism and distribution studies have been carried out on the butene isomer, 2-methylpropene (isobutene). A higher rate of metabolism in the mouse and saturation of metabolism in rats and mice have been demonstrated in vivo by Csanady et al (1991) and Henderson et al (1993). In the study of Csanady et al (1991), rats and mice were exposed to 2-methylpropene, at concentrations up to 500 ppm (1147 mg/m3), metabolic elimination was first order. The maximal metabolic elimination rates were 340 µmol/kg/h for rats and 560 µmol/kg/h for mice. The atmospheric concentration at which Vmax/2 was reached was 1200 ppm (2754 mg/m3) for rats and 1800 ppm (4131 mg/m3) for mice. The metabolism was saturable in both species and was blocked by inhibitors of P450 enzymes. In the study of Henderson et al (1993), rats were exposed to 2-methylpropene at concentrations from 40 to 4000 ppm (91.8-9180 mg/m3). Rapid metabolism to oxidised metabolites excreted in the urine occurred and isobutenediol and 2-hydroxyisobutyric acid were identified as metabolites. Blood levels of 2-methylpropene were linearly related to exposure up to 400ppm (918 mg/m3) but were supralinear at 4000 ppm (9180 mg/m3) indicating saturation of metabolism at this higher dose level.

 

Similar findings were reported during a carcinogenicity study on 2-methylpropene (NTP, 1988). The major urinary metabolite of 2-methylpropene (2-hydroxyisobutyric acid: HIBA) was measured in the urine of rats and mice as an indicator of exposure. F344/N rats and B6C3F1 mice were exposed to 2-methylpropene at concentrations of 0, 500, 2,000 or 8,000 ppm, (1147, 4589, 18,359 mg/m3) for 105 weeks. In both species, the amount excreted increased with increasing exposure concentration but when HIBA concentration was normalized to isobutene exposure concentration, the relative amount of HIBA excreted decreased with increasing exposure concentration, implying nonlinear kinetics (NTP, 1988).

 

The in vivo metabolism studies are supported by extensive in vitro metabolism studies. Cornet et al (1991) showed that 2-methylpropene was metabolised to its epoxide 2-methyl-1,2-epoxypropane in a mouse liver in vitro system. The epoxide was rapidly further metabolised by epoxide hydrolase to methyl-1,2-propanediol and by glutathione-S-transferase to the glutathione conjugate. Further studies (Cornet et al, 1995) using in vitro rat, mouse and human liver systems demonstrated that the lowest rates of biotransformation to the epoxide metabolite were found in human liver, followed by rat then mouse. Quantification of levels of epoxide hydrolase, the major enzyme responsible for the detoxification of the epoxide, in these species revealed that human liver has the highest level followed by rats then mice. In contrast, levels of P450 were lowest in humans. These results demonstrate a clear species difference in the metabolism of 2-methylpropene and suggest that mice and rats are not good models for the metabolism of 2-methylpropene in species where concentrations of the primary epoxide metabolite are likely to be lower than in these rodent species.

 

 

1,3-Butadiene:

There are too many references concerning the toxicokinetics of 1,3-butadiene in laboratory animals and humans to be all listed here.The EU Risk Assessment Report (EU RAR, 2002) contains a comprehensive review of the toxicokinetic information on 1,3-butadiene that is still current. As this document has been peer-reviewed and adopted by the European Commission and representatives of its Member States under Council Regulation (EEC) No. 793/93, parts of the summary section are reproduced here. Text within quotation marks indicates text from EU RAR (2002). Some additional references that post-date the EU RAR (2002) have been added and are listed below. These references do not change the overall conclusion but strengthen it.

In Vivo Studies - Non-Human Information

 “Studies in rodents and non-human primates have shown that 1,3-butadiene is absorbed via the lungs. In rodents, uptake and metabolism of 1,3-butadiene obeys simple first order kinetics at concentrations up to about 1,500 ppm, above which saturation of the process appears to occur. 1,3-Butadiene is widely distributed throughout the body. The first step in the metabolic pathway is the formation of epoxybutene, catalysed by mixed function oxygenases. The further metabolism of epoxybutene can proceed by a number of different pathways. There is some conjugation with glutathione. A second possible pathway is hydrolysis to butenediol, catalysed by epoxide hydrolase. Another possibility is further epoxidation to diepoxybutane. Further epoxidation and/or hydrolysis reactions can then occur, which ultimately lead to erythritol formation”.

“There are quantitative species differences in the toxicokinetics of 1,3-butadiene. In comparison with the rat, the mouse absorbs and retains approximately 4-7 fold higher concentrations of 1,3-butadiene per kg bodyweight. The mouse also produces approximately 2-20 fold higher concentrations of the metabolite, epoxybutene, than does the rat, for equivalent exposures. Very low concentrations of the diepoxide metabolite have been detected in the blood and various tissues of rats and mice at relatively high 1,3-butadiene exposures. ” “Where measurements are available, tissue levels of diepoxybutane are generally higher in mice compared with rats, by up to 163-fold. ” More recent studies using 1,3-butadiene exposures at 1 ppm 1,3-butadiene for 4 weeks, which are more occupationally relevant, showed that the concentration of the haemoglobin adduct of the diepoxide metabolite (pyr-Val) was greater than 30-fold in the blood of mice compared to that in rats (Swenberg et al. 2007).Georgieva et al (2010) also exposed rats and mice to 1,3-butadiene at 0.1 to 625 ppm for 10 or 20 days and showed that mice formed 10- to 60-fold more of the haemoglobin adduct compared to rats at similar exposures. 

In Vitro Studies - Non-Human Information

“In vitro studies indicate that in the mouse, lung and liver tissue have similar capacity for 1,3-butadiene metabolism while in rats and humans, liver tissue has a greater capacity for metabolism than does lung tissue, although some metabolism does take place in lung tissue. Detoxification pathways are kinetically favoured over activation pathways in rodent and human tissue, although the ratio of activation: detoxification is highest in mouse tissue compared with rat or human tissue. ” A recent study (Filser et al, 2010) showed a qualitative species difference in the metabolism of 1,3-butadiene in isolated perfused livers from rats and mice. In 1,3-butadiene perfusions, predominantly epoxybutene and butenediol were found in both species but diepoxybutane was only detected in mouse livers. “From the limited comparative information available from in vitro and in vivo studies, it appears that in relation to the formation of epoxide metabolites, the metabolism of 1,3-butadiene in humans is quantitatively more similar to that in the rat, rather than the mouse. However, in vitro studies have demonstrated considerable inter-individual variability in the oxidative metabolism of 1,3-butadiene ”

In Vivo Studies - Human Information

“In workers exposed by inhalation to 3-4 ppm 1,3-butadiene, metabolism to epoxybutene with subsequent hydrolysis to butenediol occurs. In one study, the mercapturic acid (glutathione) conjugate of butenediol has been identified as a urinary metabolite although no detectable levels of the epoxybutene mercapturate were found in the same study. This suggests that detoxification of epoxybutene proceeds by hydrolysis to butenediol, with subsequent conjugation. ”

 Haemoglobin adducts from various metabolites of 1,3-butadiene have been identified and measured in humans (Albertini et al., 2004). Elevated levels of the haemoglobin adducts of epoxybutene have been reported in the blood of occupationally exposed workers (EU RAR, 2002; Bergemann et al., 2001). No difference has been seen between genders in the pattern of 1,3-butadiene detoxification, as evidenced by urinary metabolite levelsbutadiene and 1-dihydroxy-2-(N-acetylcysteinyl)-3-butene]. Females, however, appear to absorb less 1,3-buadiene per unit of exposure, as reflected by urine metabolite concentrations (Albertini et al, 2007). Analytical techniques have recently been developed to measure the haemoglobin adduct of the diepoxide metabolite of 1,3-butadiene N, N-(2,3-dihydroxy-1,4-butadiyl) valine (pyr-Val). In one study, the pyr-Val adduct was not quantifiable in human blood samples from workers with cumulative occupational exposures of up to 6.3 ppm-weeks (Swenberg et al., 2007). In a subsequent study in which improvements were made to the technique to improve the sensitivity, quantifiable amounts of pyr-Val were found in the blood of occupationally exposed workers. At exposures between 0.1 and 1.0 ppm humans form ~10% of the quantities of the pyr-Val adduct formed by rats (Georgieva et al., 2010). This indicates that the diepoxide metabolite is produced in humans, albeit in very low amounts.

 

Additional references

 

EU RAR (2002). European Union Risk Assessment Report for 1,3-butadiene. Vol. 20. European Chemicals Bureau (http: //ecb. jrc. ec. europa. eu/DOCUMENTS/Existing-Chemicals/RISK_ASSESSMENT/REPORT/butadienereport019. pdf) 

Albertini R (2004). Mechanistic insights from biomarker studies: somatic mutations and rodent/human comparisons following exposures to potential carcinogens, in: R. J. Buffler P, Bann R, Bird M, Bofetta P (Ed.), Mechanisms Epidemiology, IARC Sci Publ, pp. 33-40.

Bergemann, P, Sram RJ and Neumann HG. (2001). Hemoglobin adducts of epoxybutene in workers occupationally exposed to 1,3-butadiene. Arch Toxicol 74: 680-87.

Filser JG, Bhowmik S, Faller TH, Hutzler C, Kessler W, Midpanon S, Pütz C, Schuster A, Semder B, V, Csanády GA (2010). Quantitative investigation on the metabolism of 1,3-butadiene and of its oxidized metabolites in once-through perfused livers of mice and rats. Tox Sci, 114, 25-37.

Georgieva, NL, G Boysen, Bordeerat N, Walker VE and Swenberg JA. (2010). Exposure-response of 1,2:3,4-diepoxybutane-specific N-terminal valine adducts in mice and rats after inhalation exposure to 1,3-butadiene.Toxicol Sci,115, 322-329.

Swenberg JA, Boysen G, Georgieva N, Bird MG, Lewis RJ. (2007). Future directions in butadiene risk assessment and the role of cross-species internal dosimetry. Chem Biol Interact. 166: 78-83.