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REACH does not specifically require toxicokinetic information but does require that the human health hazard assessment considers the toxicokinetic behaviour of a substance. There are many references concerning the toxicokinetics of 1,3-butadiene in laboratory animals and humans and too many 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. It is not clear at which stage or stages in the pathway, CO2 is formed. The main route of elimination of 1,3-butadiene and its metabolites in rodents and primates is urinary excretion or exhalation in the breath. Minor faecal excretion also occurs. In rodents, urinary excretion takes place in two phases with 77-99% of the inhaled dose excreted with a half-life of a few hours in rodents, while the remainder is excreted with a half-life of several days. There is no evidence for bioaccumulation of 1,3-butadiene. There are no data on the toxicokinetics of 1,3-butadiene following oral or dermal exposure, and although the possibility of uptake via these routes cannot be entirely discounted, their contribution to uptake and metabolism of 1,3-butadiene is anticipated to be negligible. In addition, there is no evidence of any significant potential for dermal uptake from a comparison of the results of whole-body inhalation exposure studies compared with those in which exposure was nose-only.”

 

“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; this metabolite has been tentatively identified in the blood of monkeys, in vivo. Again, where measurements are available, tissue levels of diepoxybutane are generally higher in mice compared with rats, by up to 163-fold.” More recent studies have confirmed that mice form greater quantities of the diepoxide metabolite than rats. 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.

 

The currently understood metabolic pathway for butadiene in vivo can be found in the EU RAR (2002).

 

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. In mouse liver and lung tissue, detoxification of epoxybutene appears to be mainly by conjugation with glutathione, with hydrolysis to butenediol a relatively minor pathway. In comparison, in human liver and lung, detoxification of epoxybutene is primarily by hydrolysis, with only some glutathione conjugation; this finding from in vitro studies supports the in vivo human metabolism data. Formation of the diepoxide has been demonstrated in mouse liver tissue exposed to butadiene in vitro, but not in rat or human tissue, although formation of diepoxybutane has been demonstrated in cDNA-expressed human liver microsomes exposed to epoxybutene.” 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 butadiene.” 

 

 

In Vivo Studies - Human Information

 

“There is very limited information on the toxicokinetics of 1,3-butadiene in humans. 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., 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 levels [1,2-dihydroxy-4-acetyl) butane and 1-dihydroxy-2-(N-acetylcysteinyl)-3-butene]. Females, however, appear to absorb less 1,3-butadiene 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.

“There are no data on the toxicokinetics of 1,3-butadiene following other routes of exposure. The possibility that 1,3-butadiene is absorbed and metabolised via the oral and dermal routes cannot be entirely discounted, although given its physicochemical characteristics, the potential for uptake via these routes is anticipated to be minor, particularly in relation to the inhalation route.”

 

In Vitro Studies - Human Information

 

“The only other information in relation to toxicokinetics in humans comes from in vitro studies using human tissue, which indicate that metabolism of 1,3-butadiene to epoxybutene occurs in human liver, lung and bone marrow. In the one study that has investigated further metabolism of the monoepoxide to diepoxybutane, in liver and lung tissue, no detectable levels of the diepoxide were measured. Human liver tissue has greater capacity for metabolism to epoxybutene compared with lung tissue. However, the results for lung tissue must be treated with some caution as diseased tissue was used. There is evidence for considerable inter-individual variation in the capacity of human liver tissue to metabolise 1,3-butadiene to epoxybutane, with some human liver tissue samples showing capacity for metabolism comparable to, or exceeding, that in the mouse. The involvement of specific P450 isozymes in metabolism of butadiene to the monoepoxide has been demonstrated, and raises the possibility that differences in expression of P450 isozymes may explain some of the intra-individual variability that has been seen in vitro.”

 

 

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.

Albertini, R. J., Sram, R. J., Vacek, P. M., Lynch, J., Rossner, P., Nicklas, J. A., McDonald, J. D., Boysen, G., Georgieva, N., and Swenberg, J. A. (2007). Molecular epidemiological studies in 1,3-butadiene exposed Czech workers: female-male comparisons. Chem. Biol. Interact. 166:63-77.

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 (2009). 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.