- Email: [email protected]
Urinary metabolites and haemoglobin adducts as biomarkers of exposure to 1,3-butadiene: a basis for 1,3-butadiene cancer risk assessment.
Chemico-Biological Interactions 135– 136 (2001) 695– 701
www.elsevier.com/locate/chembiont
Urinary metabolites and haemoglobin adducts as biomarkers of exposure to 1,3-butadiene: a basis for 1,3-butadiene cancer risk assessment. Peter J. Boogaard *, Nico J. van Sittert, Hendricus J.J.J. Megens Molecular Toxicology, Shell Research & Technology Centre, Amsterdam The Netherlands
Abstract Since 1,3-butadiene (BD) is a suspected human carcinogen, exposure to BD should be minimised and controlled. This study aimed at comparing the suitability of biomarkers for low levels of exposure to BD, and at exploration of the relative pathways of human metabolism of BD for comparison with experimental animals. Potentially sensitive biomarkers for BD are its urinary metabolites 1,2-dihydroxybutyl mercapturic acid (DHBMA, also referred to as MI) and 1- and 2-monohydroxy-3-butenyl mercapturic acid (MHBMA, also referred to as MII) and its haemoglobin (Hb) adducts 1- and 2-hydroxy-3-butenyl valine (MHBVal). In two field studies in BD-workers, airborne BD, MHBMA, DHBMA and MHBVal were determined. MHBMA proved more sensitive than DHBMA for monitoring recent exposures to BD and could measure 8-h time weighted average exposures as low as 0.13 ppm (0.29 mg/m3). The sensitivity of DHBMA was restricted by relatively high natural background levels in urine, of which the origin is currently unknown. MHBVal proved a sensitive method for monitoring cumulative exposures to BD at or above 0.35 ppm (0.77 mg/m3). Statistically significant relationships were found between either MHBMA or DHBMA and 8-h airborne BD levels, and between MHBVal adducts and average airborne BD levels over 60 days. The data showed a much higher rate of hydrolytic metabolism of BD in humans compared to animals, which was reflected in a much higher DHBMA/ (MHBMA+ DHBMA) ratio, and in much lower levels of MHBVal in humans, confirming in 6itro results. Assuming a genotoxic mechanism, the data of this study coupled with our recent data on DNA and Hb binding in rodents, suggest that the cancer risk for humans
* Corresponding author. Shell International B.V., Health Services, P.O.Box 162, 2501 AN, ;The Hague; The Netherlands; Tel.: +31-70-3772123; fax: +31-70-3776380. E-mail address: [email protected] (P.J. Boogaard). 0009-2797/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S0009-2797(01)00205-8
696
P.J. Boogaard et al. / Chemico-Biological Interactions 135–136 (2001) 695–701
from exposure to BD will be less than for the rat, and much less than for the mouse. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: 1,3-Butadiene; Biomarkers; Risk assessment; Haemoglobin adducts; Urinary metabolites; Exposure monitoring
1. Introduction 1,3-Butadiene (BD) is a major industrial chemical used in the manufacture of a wide variety of synthetic rubbers and resins. Occupational exposure to BD may occur during the production of BD and its derivatives. In addition, the general population may be exposed to BD because it is a ubiquitous environmental pollutant. Since the International Agency for Research on Cancer (IARC) has classified BD as category 2A, ‘Probably carcinogenic to Humans’ [1], human exposure to BD should be minimised and controlled. Sensitive biomarkers are needed for proper control of exposure. The primary metabolite of BD is 1,2-epoxy-3-butene (EB). EB may be oxidised to 1,2:3,4-diepoxybutane (DEB) or hydrolysed to 1,2-dihydroxy-3-butene (DHB). Hydrolysis of DEB yields 3,4-epoxy-1,2-butanediol (EBD), which may also be formed from DHB by epoxidation of the double bond. The epoxides (EB, DEB, and EBD) have the potential to react with DNA and proteins, such as haemoglobin (Hb). Alternatively, they may be inactivated via hydrolysis or conjugation with glutathione (GSH). In our recent studies on the metabolism of BD in rats and mice exposed to 200 ppm [2,3-14C]-BD for 6 h, no urinary metabolites other than those formed through an epoxide intermediate were found [2]. In both species, major metabolites derived from EB were: 1,2-dihydroxybutyl mercapturic acid (DHBMA, also referred to as MI), formed by hydrolysis of EB to DHB followed by subsequent metabolism to DHBMA, and an isomeric mixture of 1- and 2-monohydroxy-3-butenyl mercapturic acid (MHBMA, also referred to as MII), formed via direct conjugation of EB with GSH. In blood, EB may react with the N-terminal valine of Hb which leads to the formation of MHBVal, a stable Hb adduct. Mercapturic acids and Hb adducts have proved to be suitable biomarkers for human exposure to a variety of industrial chemicals [3–5]. Assays for the measurement of MHBMA and DHBMA in urine and MHBVal in blood of workers occupationally exposed to BD were developed, but lacked sensitivity to measure low BD exposures [5– 7]. In the present study, the assays for MHBMA, DHBMA and MHBVal were modified to improve sensitivity and applied to monitor exposure to BD of workers engaged in manufacture and use of BD. The specific aims of this part of the study were to: (1) investigate the sensitivity of these biomarkers as indicators of exposure to BD, (2) establish the relationship between airborne BD and the selected biomarker(s), and (3) investigate the relative pathways of detoxification, i.e. hydrolysis 6s. GSH conjugation, for comparison with data from experimental animals exposed to BD.
P.J. Boogaard et al. / Chemico-Biological Interactions 135–136 (2001) 695–701
697
2. Experimental
2.1. Study design The first study took place from 1994 to 1997 in a BD monomer production facility in The Netherlands. Blood samples for MHBVal measurements were collected from 44 male workers engaged in the loading of BD in ships and tankers. MHBVal was also measured in 28 male administrative workers from the same plant without occupational exposure to BD (controls). Personal air monitoring was performed during loading activities on 11 workers, using passive dosimeters (3M gas diffusion badges, type 3520). The second study took place in 1998 in a BD monomer and a styrene-butadiene-rubber (SBR) production facility in the Czech Republic. Blood and urine samples (before and after the shift) were collected from male workers: 24 from a BD monomer unit, 34 from a SBR unit, and 25 from an administrative unit without occupational exposure to BD (controls). Personal air monitoring was performed using diffusive solid sorbent tubes during 10 full 8-h shifts on each of the 58 exposed workers over a 60-day period and during 1 or 2 random days on the controls.
2.2. Urinary analyses Urine samples were frozen (−70°C), shipped to the laboratory in liquid nitrogen and stored frozen until analysis. After thawing, the samples were homogenised and an aliquot was analysed after addition of internal standards, [d6]-MHBMA and dihydroxypropyl mercapturic acid, synthesised as previously described [8]. The mercapturic acids were extracted and subsequently methylated and pentafluorobenzoylated and analysed by GC-MS-MS with negative chemical ionisation and multiple reaction monitoring as previously described [8].
2.3. Blood analyses Erythrocytes were isolated from the blood samples, washed with isotonic saline twice, frozen (− 70°C), shipped to the laboratory in liquid nitrogen and stored frozen until analysis. MHBVal in the samples was analysed as its phenylthiohydantoin by GC-MS-MS as described previously [5,9], except that [d6]-MHBVal, synthesised as previously described [8], was used as internal standard.
3. Results and discussion In the first study, airborne Bd levels ranged from B0.2 to 9.5 ppm (median 0.5 ppm, equivalent to 1.1 mg/m3) (8-h TWA) during loading activities and MHBVal ranged from 0.6 to 3.8 (median 1.2) pmol/g Hb in the exposed workers. In the controls, MHBVal ranged from B 0.1 to 1.2 (median B 0.1) pmol/g Hb. There was no influence from smoking on MHBVal levels. In the second study, the
698
P.J. Boogaard et al. / Chemico-Biological Interactions 135–136 (2001) 695–701
airborne BD ranged from 0.000 to 0.038 (median 0.007, equivalent to 0.015 mg/m3) in the controls, from 0.02 to 1.6 ppm (median 0.17 ppm, equivalent to 0.37 mg/m3) in the monomer workers and from 0.02 to 4.2 (median 0.50 ppm, equivalent to 1.1 mg/m3) in the SBR workers. There was a strong correlation between MHBVal and the 60-day average airborne BD concentration (Fig. 1). MHBVal proved a sensitive method for monitoring cumulative exposures to BD at or above 0.35 ppm (0.77 mg/m3). In the controls MHBMA ranged from B 0.1 to 7.3 (median 1.6) mg/l and DHBMA from 197 to 747 (median 355) mg/l. In the monomer and polymer workers MHBMA ranged from B0.1 to 44 (median 3.6) mg/l and from 1.7 to 962 (median 20) mg/l, respectively in end-of-shift urines. DHBMA ranged from 52 to 3522
Fig. 1. Relation between airborne BD (60-day average) and MHBVal levels in Hb (83 workers). The regression line is shown with 95% confidence intervals for individual (outer dashed line) and group values (inner dashed line).
P.J. Boogaard et al. / Chemico-Biological Interactions 135–136 (2001) 695–701
699
Fig. 2. Relation between airborne BD (8-h TWA) and MHBMA (upper panel) and DHBMA (lower panel) levels in end-of-shift urine (21 workers). The regression line with 95% confidence intervals for individual (outer dashed line) and group values (inner dashed line) is shown.
(median 508) mg/l in the monomer workers and from 190 to 26207 (median 1479) mg/l in the polymer workers. For both MHBMA and DHBMA there was a strong correlation with 8-h airborne BD levels (Fig. 2). MHBMA proved more sensitive than DHBMA for monitoring recent exposures to BD and could measure 8-h TWA exposures as low as 0.13 ppm (0.29 mg/m3). The sensitivity of DHBMA was restricted by relatively high natural background levels in urine, of which the origin is currently unknown. As shown in Table 1, humans have a much higher rate of hydrolytic metabolism of BD than animals, which is reflected in a much higher DHBMA/(MHBMA + DHBMA) ratio, and in much lower levels of MHBVal in humans. This is fully in line with the results of in 6itro studies on the detoxification of EB and DEB [10] and suggest that the circulating levels of reactive epoxides will decrease in the following order: mice \rats \monkeys \ humans. Assuming a genotoxic mechanism, the data of this study coupled with our recent data on Hb and DNA binding in rodents [8,9,11], hence suggest that the cancer risk for humans from exposure to BD will be less than for the monkey and rat, and much less than for the mouse.
Acknowledgements This study was supported by the Health Effects Institute (HEI), the European Chemical Industry Council (CEFIC) and Shell International Chemicals B.V. We like to thank Dr R. Albertini (Univ. of Vermont) and Dr R.J. S& ra`m (Czech Academy of Sciences) for coordination of Study 2.
700
Exposure
MHBMA (GSH pathway of EB) DHBMA (Hydrolysis of EB) DHBMA/ (MHBMA+DHBMA)*
8 h, 1.0 ppm (2.2 mg/m3) [present study]
2 h, 300 ppm (660 mg/m3) [6]
4 h, 11.7 ppm (25.7 mg/m3) [7]
6 h, 200 ppm (440 mg/m3) 14C-BD [2]
Metabolites (mg/l)
Metabolites (% of total)
Metabolites (nmol)
Metabolites (% of total)
Human
Monkey
Rat
Mouse
Rat
Mouse
39
6
150
34
18.6
16.6
2213
55
156
10.3
17.5
10.1
0.983
0.90
* GSH conjugation as part of the total detoxification by GSH conjugation and hydrolysis
0.51
0.23
0.485
0.378
P.J. Boogaard et al. / Chemico-Biological Interactions 135-136 (2001) 695–701
Table 1 Comparison of urinary metabolite excretion and metabolite ratios between human, rat and mouse following BD exposure (mean values)
P.J. Boogaard et al. / Chemico-Biological Interactions 135–136 (2001) 695–701
701
References [1] IARC, Re-evaluation of some organic chemicals hydrazine and hydrogen peroxide: phenyl glycidyl ether, IARC Monogr. 71 (1999) (1999) 109 – 226. [2] K.A. Richardson, M.M.C.G. Peters, B.A. Wong, H.J.J.J. Megens, P.A. van Elburg, E.D. Booth, P.J. Boogaard, J.A. Bond, M.A. Medinsky, W.P. Watson, N.J. van Sittert, Quantitative and qualitative differences in the metabolism of 14C-1,3-butadiene, Toxicol. Sci. 49 (1999) 186 – 201. [3] P.J. Boogaard, N.J. van Sittert, Biological monitoring of exposure to benzene: a comparison between S-phenylmercapturic acid, trans,trans-muconic acid and phenol, Occup. Environ. Med. 52 (1995) 611 –620. [4] P.J. Boogaard, P.S.J. Rocchi, N.J. van Sittert, Biomonitoring of exposure to ethylene oxide and propylene oxide by determination of hemoglobin adducts: correlations between airborne exposure and adduct levels, Int. Arch. Occup. Environ. Health 72 (1999) 142 – 150. [5] N.J. van Sittert, E.W.N. van Vliet, Monitoring occupational exposure to some industrial chemicals by determining hemoglobin adducts, Clin. Chem. 40 (1994) 1472 – 1475. [6] P.J. Sabourin, L.T. Burka, W.E. Bechtold, A.R. Dahl, M.D. Hoover, I.-Y. Chang, R.F. Henderson, Species differences in urinary butadiene metabolites: Identification of 1,2-dihydroxy-4-(N-acetylcysteinyl)-butane, a novel metabolite from 1,3-butadiene, Carcinogenesis 13 (1992) 1633 – 1638. [7] W.E. Bechtold, M.R. Strunk, I.Y. Chang, J.B. Ward, R.F. Henderson, Species differences in urinary butadiene metabolites: comparisons of metabolite ratios between mice, rats and humans, Toxicol. Appl. Pharmacol. 127 (1994) 44 – 49. [8] N.J. van Sittert, H.J.J.J. Megens, W.P. Watson, P.J. Boogaard, Biomarkers of exposure to 1,3-butadiene as a basis for cancer risk assessment, Toxicol. Sci. 56 (2000) 189 – 202. [9] K.A. Richardson, H.J.J.J. Megens, J.D. Webb, N.J. van Sittert, Biological monitoring of butadiene exposure by measurement of hemoglobin adducts, Toxicology 113 (1996) 112 – 118. [10] P.J. Boogaard, J.A. Bond, The role of hydrolysis in the detoxification of 1,2:3,4-diepoxybutane by human, rat, and mouse liver and lung in vitro, Toxicol. Appl. Pharmacol. 141 (1996) 617 – 627. [11] P.J. Boogaard, K.P. de Kloe, N.J. van Sittert, N7-(1-(Hydroxymethyl)-2,3-dihydroxypropyl)guanine is the major DNA adduct after exposure to 1,3-butadiene but not 1,2-epoxy-3-butene, Toxicol. Sci. 54 (2000) S229.
.
www.elsevier.com/locate/chembiont
Urinary metabolites and haemoglobin adducts as biomarkers of exposure to 1,3-butadiene: a basis for 1,3-butadiene cancer risk assessment. Peter J. Boogaard *, Nico J. van Sittert, Hendricus J.J.J. Megens Molecular Toxicology, Shell Research & Technology Centre, Amsterdam The Netherlands
Abstract Since 1,3-butadiene (BD) is a suspected human carcinogen, exposure to BD should be minimised and controlled. This study aimed at comparing the suitability of biomarkers for low levels of exposure to BD, and at exploration of the relative pathways of human metabolism of BD for comparison with experimental animals. Potentially sensitive biomarkers for BD are its urinary metabolites 1,2-dihydroxybutyl mercapturic acid (DHBMA, also referred to as MI) and 1- and 2-monohydroxy-3-butenyl mercapturic acid (MHBMA, also referred to as MII) and its haemoglobin (Hb) adducts 1- and 2-hydroxy-3-butenyl valine (MHBVal). In two field studies in BD-workers, airborne BD, MHBMA, DHBMA and MHBVal were determined. MHBMA proved more sensitive than DHBMA for monitoring recent exposures to BD and could measure 8-h time weighted average exposures as low as 0.13 ppm (0.29 mg/m3). The sensitivity of DHBMA was restricted by relatively high natural background levels in urine, of which the origin is currently unknown. MHBVal proved a sensitive method for monitoring cumulative exposures to BD at or above 0.35 ppm (0.77 mg/m3). Statistically significant relationships were found between either MHBMA or DHBMA and 8-h airborne BD levels, and between MHBVal adducts and average airborne BD levels over 60 days. The data showed a much higher rate of hydrolytic metabolism of BD in humans compared to animals, which was reflected in a much higher DHBMA/ (MHBMA+ DHBMA) ratio, and in much lower levels of MHBVal in humans, confirming in 6itro results. Assuming a genotoxic mechanism, the data of this study coupled with our recent data on DNA and Hb binding in rodents, suggest that the cancer risk for humans
* Corresponding author. Shell International B.V., Health Services, P.O.Box 162, 2501 AN, ;The Hague; The Netherlands; Tel.: +31-70-3772123; fax: +31-70-3776380. E-mail address: [email protected] (P.J. Boogaard). 0009-2797/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S0009-2797(01)00205-8
696
P.J. Boogaard et al. / Chemico-Biological Interactions 135–136 (2001) 695–701
from exposure to BD will be less than for the rat, and much less than for the mouse. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: 1,3-Butadiene; Biomarkers; Risk assessment; Haemoglobin adducts; Urinary metabolites; Exposure monitoring
1. Introduction 1,3-Butadiene (BD) is a major industrial chemical used in the manufacture of a wide variety of synthetic rubbers and resins. Occupational exposure to BD may occur during the production of BD and its derivatives. In addition, the general population may be exposed to BD because it is a ubiquitous environmental pollutant. Since the International Agency for Research on Cancer (IARC) has classified BD as category 2A, ‘Probably carcinogenic to Humans’ [1], human exposure to BD should be minimised and controlled. Sensitive biomarkers are needed for proper control of exposure. The primary metabolite of BD is 1,2-epoxy-3-butene (EB). EB may be oxidised to 1,2:3,4-diepoxybutane (DEB) or hydrolysed to 1,2-dihydroxy-3-butene (DHB). Hydrolysis of DEB yields 3,4-epoxy-1,2-butanediol (EBD), which may also be formed from DHB by epoxidation of the double bond. The epoxides (EB, DEB, and EBD) have the potential to react with DNA and proteins, such as haemoglobin (Hb). Alternatively, they may be inactivated via hydrolysis or conjugation with glutathione (GSH). In our recent studies on the metabolism of BD in rats and mice exposed to 200 ppm [2,3-14C]-BD for 6 h, no urinary metabolites other than those formed through an epoxide intermediate were found [2]. In both species, major metabolites derived from EB were: 1,2-dihydroxybutyl mercapturic acid (DHBMA, also referred to as MI), formed by hydrolysis of EB to DHB followed by subsequent metabolism to DHBMA, and an isomeric mixture of 1- and 2-monohydroxy-3-butenyl mercapturic acid (MHBMA, also referred to as MII), formed via direct conjugation of EB with GSH. In blood, EB may react with the N-terminal valine of Hb which leads to the formation of MHBVal, a stable Hb adduct. Mercapturic acids and Hb adducts have proved to be suitable biomarkers for human exposure to a variety of industrial chemicals [3–5]. Assays for the measurement of MHBMA and DHBMA in urine and MHBVal in blood of workers occupationally exposed to BD were developed, but lacked sensitivity to measure low BD exposures [5– 7]. In the present study, the assays for MHBMA, DHBMA and MHBVal were modified to improve sensitivity and applied to monitor exposure to BD of workers engaged in manufacture and use of BD. The specific aims of this part of the study were to: (1) investigate the sensitivity of these biomarkers as indicators of exposure to BD, (2) establish the relationship between airborne BD and the selected biomarker(s), and (3) investigate the relative pathways of detoxification, i.e. hydrolysis 6s. GSH conjugation, for comparison with data from experimental animals exposed to BD.
P.J. Boogaard et al. / Chemico-Biological Interactions 135–136 (2001) 695–701
697
2. Experimental
2.1. Study design The first study took place from 1994 to 1997 in a BD monomer production facility in The Netherlands. Blood samples for MHBVal measurements were collected from 44 male workers engaged in the loading of BD in ships and tankers. MHBVal was also measured in 28 male administrative workers from the same plant without occupational exposure to BD (controls). Personal air monitoring was performed during loading activities on 11 workers, using passive dosimeters (3M gas diffusion badges, type 3520). The second study took place in 1998 in a BD monomer and a styrene-butadiene-rubber (SBR) production facility in the Czech Republic. Blood and urine samples (before and after the shift) were collected from male workers: 24 from a BD monomer unit, 34 from a SBR unit, and 25 from an administrative unit without occupational exposure to BD (controls). Personal air monitoring was performed using diffusive solid sorbent tubes during 10 full 8-h shifts on each of the 58 exposed workers over a 60-day period and during 1 or 2 random days on the controls.
2.2. Urinary analyses Urine samples were frozen (−70°C), shipped to the laboratory in liquid nitrogen and stored frozen until analysis. After thawing, the samples were homogenised and an aliquot was analysed after addition of internal standards, [d6]-MHBMA and dihydroxypropyl mercapturic acid, synthesised as previously described [8]. The mercapturic acids were extracted and subsequently methylated and pentafluorobenzoylated and analysed by GC-MS-MS with negative chemical ionisation and multiple reaction monitoring as previously described [8].
2.3. Blood analyses Erythrocytes were isolated from the blood samples, washed with isotonic saline twice, frozen (− 70°C), shipped to the laboratory in liquid nitrogen and stored frozen until analysis. MHBVal in the samples was analysed as its phenylthiohydantoin by GC-MS-MS as described previously [5,9], except that [d6]-MHBVal, synthesised as previously described [8], was used as internal standard.
3. Results and discussion In the first study, airborne Bd levels ranged from B0.2 to 9.5 ppm (median 0.5 ppm, equivalent to 1.1 mg/m3) (8-h TWA) during loading activities and MHBVal ranged from 0.6 to 3.8 (median 1.2) pmol/g Hb in the exposed workers. In the controls, MHBVal ranged from B 0.1 to 1.2 (median B 0.1) pmol/g Hb. There was no influence from smoking on MHBVal levels. In the second study, the
698
P.J. Boogaard et al. / Chemico-Biological Interactions 135–136 (2001) 695–701
airborne BD ranged from 0.000 to 0.038 (median 0.007, equivalent to 0.015 mg/m3) in the controls, from 0.02 to 1.6 ppm (median 0.17 ppm, equivalent to 0.37 mg/m3) in the monomer workers and from 0.02 to 4.2 (median 0.50 ppm, equivalent to 1.1 mg/m3) in the SBR workers. There was a strong correlation between MHBVal and the 60-day average airborne BD concentration (Fig. 1). MHBVal proved a sensitive method for monitoring cumulative exposures to BD at or above 0.35 ppm (0.77 mg/m3). In the controls MHBMA ranged from B 0.1 to 7.3 (median 1.6) mg/l and DHBMA from 197 to 747 (median 355) mg/l. In the monomer and polymer workers MHBMA ranged from B0.1 to 44 (median 3.6) mg/l and from 1.7 to 962 (median 20) mg/l, respectively in end-of-shift urines. DHBMA ranged from 52 to 3522
Fig. 1. Relation between airborne BD (60-day average) and MHBVal levels in Hb (83 workers). The regression line is shown with 95% confidence intervals for individual (outer dashed line) and group values (inner dashed line).
P.J. Boogaard et al. / Chemico-Biological Interactions 135–136 (2001) 695–701
699
Fig. 2. Relation between airborne BD (8-h TWA) and MHBMA (upper panel) and DHBMA (lower panel) levels in end-of-shift urine (21 workers). The regression line with 95% confidence intervals for individual (outer dashed line) and group values (inner dashed line) is shown.
(median 508) mg/l in the monomer workers and from 190 to 26207 (median 1479) mg/l in the polymer workers. For both MHBMA and DHBMA there was a strong correlation with 8-h airborne BD levels (Fig. 2). MHBMA proved more sensitive than DHBMA for monitoring recent exposures to BD and could measure 8-h TWA exposures as low as 0.13 ppm (0.29 mg/m3). The sensitivity of DHBMA was restricted by relatively high natural background levels in urine, of which the origin is currently unknown. As shown in Table 1, humans have a much higher rate of hydrolytic metabolism of BD than animals, which is reflected in a much higher DHBMA/(MHBMA + DHBMA) ratio, and in much lower levels of MHBVal in humans. This is fully in line with the results of in 6itro studies on the detoxification of EB and DEB [10] and suggest that the circulating levels of reactive epoxides will decrease in the following order: mice \rats \monkeys \ humans. Assuming a genotoxic mechanism, the data of this study coupled with our recent data on Hb and DNA binding in rodents [8,9,11], hence suggest that the cancer risk for humans from exposure to BD will be less than for the monkey and rat, and much less than for the mouse.
Acknowledgements This study was supported by the Health Effects Institute (HEI), the European Chemical Industry Council (CEFIC) and Shell International Chemicals B.V. We like to thank Dr R. Albertini (Univ. of Vermont) and Dr R.J. S& ra`m (Czech Academy of Sciences) for coordination of Study 2.
700
Exposure
MHBMA (GSH pathway of EB) DHBMA (Hydrolysis of EB) DHBMA/ (MHBMA+DHBMA)*
8 h, 1.0 ppm (2.2 mg/m3) [present study]
2 h, 300 ppm (660 mg/m3) [6]
4 h, 11.7 ppm (25.7 mg/m3) [7]
6 h, 200 ppm (440 mg/m3) 14C-BD [2]
Metabolites (mg/l)
Metabolites (% of total)
Metabolites (nmol)
Metabolites (% of total)
Human
Monkey
Rat
Mouse
Rat
Mouse
39
6
150
34
18.6
16.6
2213
55
156
10.3
17.5
10.1
0.983
0.90
* GSH conjugation as part of the total detoxification by GSH conjugation and hydrolysis
0.51
0.23
0.485
0.378
P.J. Boogaard et al. / Chemico-Biological Interactions 135-136 (2001) 695–701
Table 1 Comparison of urinary metabolite excretion and metabolite ratios between human, rat and mouse following BD exposure (mean values)
P.J. Boogaard et al. / Chemico-Biological Interactions 135–136 (2001) 695–701
701
References [1] IARC, Re-evaluation of some organic chemicals hydrazine and hydrogen peroxide: phenyl glycidyl ether, IARC Monogr. 71 (1999) (1999) 109 – 226. [2] K.A. Richardson, M.M.C.G. Peters, B.A. Wong, H.J.J.J. Megens, P.A. van Elburg, E.D. Booth, P.J. Boogaard, J.A. Bond, M.A. Medinsky, W.P. Watson, N.J. van Sittert, Quantitative and qualitative differences in the metabolism of 14C-1,3-butadiene, Toxicol. Sci. 49 (1999) 186 – 201. [3] P.J. Boogaard, N.J. van Sittert, Biological monitoring of exposure to benzene: a comparison between S-phenylmercapturic acid, trans,trans-muconic acid and phenol, Occup. Environ. Med. 52 (1995) 611 –620. [4] P.J. Boogaard, P.S.J. Rocchi, N.J. van Sittert, Biomonitoring of exposure to ethylene oxide and propylene oxide by determination of hemoglobin adducts: correlations between airborne exposure and adduct levels, Int. Arch. Occup. Environ. Health 72 (1999) 142 – 150. [5] N.J. van Sittert, E.W.N. van Vliet, Monitoring occupational exposure to some industrial chemicals by determining hemoglobin adducts, Clin. Chem. 40 (1994) 1472 – 1475. [6] P.J. Sabourin, L.T. Burka, W.E. Bechtold, A.R. Dahl, M.D. Hoover, I.-Y. Chang, R.F. Henderson, Species differences in urinary butadiene metabolites: Identification of 1,2-dihydroxy-4-(N-acetylcysteinyl)-butane, a novel metabolite from 1,3-butadiene, Carcinogenesis 13 (1992) 1633 – 1638. [7] W.E. Bechtold, M.R. Strunk, I.Y. Chang, J.B. Ward, R.F. Henderson, Species differences in urinary butadiene metabolites: comparisons of metabolite ratios between mice, rats and humans, Toxicol. Appl. Pharmacol. 127 (1994) 44 – 49. [8] N.J. van Sittert, H.J.J.J. Megens, W.P. Watson, P.J. Boogaard, Biomarkers of exposure to 1,3-butadiene as a basis for cancer risk assessment, Toxicol. Sci. 56 (2000) 189 – 202. [9] K.A. Richardson, H.J.J.J. Megens, J.D. Webb, N.J. van Sittert, Biological monitoring of butadiene exposure by measurement of hemoglobin adducts, Toxicology 113 (1996) 112 – 118. [10] P.J. Boogaard, J.A. Bond, The role of hydrolysis in the detoxification of 1,2:3,4-diepoxybutane by human, rat, and mouse liver and lung in vitro, Toxicol. Appl. Pharmacol. 141 (1996) 617 – 627. [11] P.J. Boogaard, K.P. de Kloe, N.J. van Sittert, N7-(1-(Hydroxymethyl)-2,3-dihydroxypropyl)guanine is the major DNA adduct after exposure to 1,3-butadiene but not 1,2-epoxy-3-butene, Toxicol. Sci. 54 (2000) S229.
.