* Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; and
Department of Environmental Chemistry, Stockholm University, Stockholm, Sweden
Received June 4, 2002; accepted September 10, 2002
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ABSTRACT |
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Key Words: distribution; partition coefficient; half-life; polychlorinated biphenyls; PCB; liver; adipose tissue; serum; rat; 4-hydroxy-2,3,3`,4`,5-pentachlorobiphenyl.
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INTRODUCTION |
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Since the use of PCB was banned in many countries, the levels in human milk have declined (Norén and Meironyte, 2000; Solomon and Weiss, 2002
). Nevertheless, present human background levels are suspected to adversely impact health (van Leeuwen and Younes, 1998
). Individual congeners of chlorinated biphenyls (CBs) show a broad spectrum of toxic effects. Effects of high concern for the general population are reproductive and developmental toxicity (Ahlborg et al., 1992
). In particular, children exposed in utero to background levels have shown subtle cognitive and motor developmental delays, which persist into school age (Jacobson and Jacobson, 1997
; Vreugdenhil et al., 2002
). More optimal intellectual stimulation provided by a more advantageous parental and home environment may counteract these effects (Vreugdenhil et al., 2002
). Non- and mono-ortho CB congeners with chlorine substituents in both para and at least two meta positions are approximate isostereomers of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). These CBs, which elicit similar toxic effects, probably by binding to the aryl hydrocarbon receptor (AhR; Safe, 1990
, 1994
), are hereby referred to as dioxin-like. Other CB congeners, herein referred to as nondioxin-like, cause adverse effects by other mechanisms of action, not always well investigated (Fischer et al., 1998
; Giesy and Kannan, 1998
; Seegal et al., 1990
). Lack of toxicity data for individual CBs in the low dose range still hamper a proper human health risk assessment of CBs. Even less information is available for the toxicokinetic behavior of individual CBs in the low dose range (Ahlborg et al., 1992
). Kinetic data based on previous studies with high doses of technical PCB mixtures and short followup times are of limited value for risk assessment procedure. It is known, for example, that high doses of organohalogen pollutants can cause altered kinetic behavior as a result of toxic effects, protein induction, or interactions (de Jongh et al., 1993a
; Santostefano et al., 1997
). There are few half-lives reported on CBs. In one of the most extensive studies the absorption and elimination rates of individual CB congeners in a commercial mixture (3 mg Kanechlor/day during 5 days) were examined during 90 days and the 79 analyzed congeners were classified into three classes (Tanabe et al., 1981
). Most high-chlorinated CBs were reported to have half-lives longer than 90 days. The lower-chlorinated CBs were classified into two other classes with shorter initial half-lives of about 1 to 2 days.
The present study was done to generate kinetic data for individual CB congeners in the low dose range. Such information is of value in the risk assessment procedure. The 13 selected congeners were chosen to include CBs of relevance to human exposure via common food items and with variable chlorine substitution, but without high dioxin-like toxic equivalency factors. This study reports CB concentrations in liver, serum, and adipose tissue, the rates by which CB concentrations decrease during dynamic steady-state, and tissue partition coefficients. In addition, it provides kinetic data for 4-hydroxy-2,3,3`,4`,5-pentachlorobiphenyl (4-OH-CB107), which is a major metabolite of CBs 105 and 118 (Sjödin et al., 1998). This metabolite is also important for its blood specific binding and endocrine disrupting potential. In addition, P450 activities (EROD and PROD) as well as vitamin A levels are reported to demonstrate that the study was performed at a dose level, which is unlikely to interfere with the kinetics of the given compounds. EROD have together with vitamin A been demonstrated to be among the most sensitive biochemical responses to the exposure of dioxin-like compounds (Fattore et al., 2000
; Fletcher et al., 2001
; van Birgelen et al., 1995
).
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MATERIALS AND METHODS |
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Chemicals.
The CBs used in this study were synthesized by Professor Bergman's group at the Department of Environmental Chemistry, Stockholm University, Sweden. All CBs were prepared as previously described and purified on a charcoal column (Bergman et al., 1990; Sundström, 1973
). The following CBs, as numbered by IUPAC, were used: 28, 52, 77, 87, 101, 105, 118, 138, 153, 156, 157, 170, and 180 (Table 1
). PCBs 40, 97, 137, 189, and 4-OH-CB193 were used as internal quantification standards. All other chemicals were of analytical grade and commercially obtained.
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The given amount per rat, was 0.03 µmol/CB (= 47 to 56 µg/kg) of the A-mix and 0.1 µmol/CB (= 119 to 151 µg/kg) of the B-mix. Each mixture was given in a total volume of 0.5 ml. The time points for termination of rats given the A-mix were set to 6 h, and 1, 5, 15, 45, and 135 days, whereas rats given the B-mix were terminated at 6 h, and 1, 2, and 4 days. At each time point, blood was withdrawn from the abdominal aorta under mebumal anesthesia (90 mg/kg). Every group contained six animals. Total body weights were recorded, and liver, kidneys, thymus, and peritesticular fat were collected and weighed. The collected tissues were frozen and stored at 70°C until further examination. Blood was centrifuged at 3000 rpm for 5 min and the serum was stored at 70°C. Control animals were given pure corn oil and were followed for 6 h, and 4, 15, and 135 days, respectively.
Biochemical analyses.
Vitamin A was extracted from frozen liver, kidney, and serum samples and was quantified as retinol by high pressure liquid chromatography (HPLC) as previously described (Håkansson et al., 1987). The column used was a Nucleosil 5µm C18, eluted with methanol/water (95:5). Detection of retinol was made with a JASCO 821-FP fluorescence detector.
Hepatic activities of the monooxygenase enzymes cytochrome P450 1A1 and 2B1/2 were measured, by O-dealkylation of 7-ethoxyresorufin (EROD) and 7-pentoxyresorufin (PROD), respectively. The formation of resorufin was measured fluorimetrically (ex = 522 nm,
em = 586 nm) in liver S9 fractions containing 10 µM dicumarol at 37°C using a Shimadzu RF-5000 spectrofluorometer (Burke et al., 1985
; Lubet et al., 1985b
).
Chemical analyses.
The extraction procedure for tissue samples was slightly modified from a previously published method (Hovander et al., 2000; Jensen et al., 1983
). Briefly, tissues were homogenized in acetone:hexane (7:2). The solvent was transferred to 0.1 M phosphoric acid in a 1% sodium chloride solution in water. Additional solvent, hexane:methyl tert-butyl ether (9:1) was added. After rocking the organic phase against the acidified water phase and subsequent centrifugation, the organic phase was transferred to a preweighted sample tube. Lipid content was thereafter determined gravimetrically. The extracts were treated with concentrated sulphuric acid in order to remove coextracted lipids.
Serum and adipose tissue were analyzed for CBs by gas chromatography with electron capture detector (GC-ECD) using a Varian 3400 equipped with a DB5 column (30 m, 0.25 µm stationary phase, 0.25 mm i.d.; J&W Scientific, Folsom, CA). Quantification was made using single point calibration after verification of a linear response. The injector and detector temperatures were 250 and 360°C, respectively. The GC oven was programmed from 80°C (2 min), to 300°C (10°C/min) and isothermally for 5 min. Hydrogen was used as the carrier gas and nitrogen as the makeup gas. For separation of congeners in liver tissues from rats exposed to the A-mix, a slightly different temperature program was used with a start at 150°C followed by a 4°C/min rise up to 280°C. For detection of congeners in the liver tissues a mass spectrometer (Hewlett-Packard 5970) was used. CB 28 was analyzed at m/z 256 and 258 with CB 21 as internal standard (IS). CBs 52 and 77 were analyzed at m/z 290 and 292 with CB 40 as IS. CBs 87, 101, 105, and 118 were analyzed at m/z 324 and 326 with CB 97 as IS. CBs 138, 153, 156, and 157 were analyzed at m/z 358 and 360 with CB 137 as IS. PCBs 170 and 180 were analyzed at m/z 392 and 394 with CB 189 as IS. Quantification was based on peak-height measurements using a linear standard curve.
Serum was analyzed with respect to 4-OH-CB107 by GC using the same equipment and program as for CB analysis with 4-OH-CB193 as IS. The phenolic compounds were derivatized to their corresponding methylethers by the addition of ethereal diazomethane prior to analysis as described earlier (Hovander et al., 2000).
Kinetic calculations.
Calculations of rates of decreasing CB concentrations were made using only data from observed dynamic steady-state, an assumption defined as a condition with constant partition during concentration decline in all examined compartments (Segel, 1988; Segel and Slemrod, 1989
). The data were fitted to a first order elimination curve;
, where Ct is the concentration of the CB congener in different tissues at time t1, C0 is the concentration at the beginning of the decrease, ke is the elimination rate in days-1. The half-lives (t
) in different tissues were calculated from the ke values by the equation t
= ln2/ke. The calculated half-lives of total amount in liver and adipose tissue is based on measured liver weights and a model where adipose tissue weight is related to total body weight (BW) as 0.0199 x BW + 1.664 (Bailey et al., 1980
). The TableCurve 2D from Jandel Scientific, USA, was used. Partition coefficients between body compartments were calculated as the average distribution ratios during steady-state.
Statistical analysis.
The statistical analyses were carried out with the SPSS for Windows statistical package and data from exposed rats were compared with control rats using Wilcoxon's Rank Correlation Test. Comparisons were considered significant at the p < 0.05 level. Principal Component Analysis (PCA) was used to identify systematic differences between the congeners in the A-mix experiment using normalized concentration data from all tissues and individual animals. The PCA was made using Simca-P 8.0 (Umetrics AB, Sweden).
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RESULTS |
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Transient increases in hepatic EROD activity were observed in both experiments (Figs. 1A and 1B). The maximum induction was 6- and 22-fold, respectively, in the two experiments, 24 h after exposure. For both exposures (A-mix and B-mix) during the whole time range, PROD activity showed an increase in the range 1.53.5 times the control activity. There were no treatment-related changes in either the total hepatic vitamin A content or in serum or kidney concentrations (data not shown).
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The adipose tissue concentrations of all A-mix CBs increased during the first five days followed by a slow decreasing phase from day 15 (Table 2) as visualized for CB 105 in Figure 2
. Adipose tissue concentrations were in general higher than the liver levels, with the exception for the first time point. The observed maxima of adipose tissue CB concentrations were in the range of 360709 pmol/g. The adipose tissue concentration half-lives calculated during dynamic steady-state ranged from 77 to 129 days (Table 3
). After 135 days the adipose tissue levels were in the range of 115151 pmol/g (Table 2
).
B-mix CB congeners.
Hepatic CB-concentrations, 6 h after administration to the B-mix, were in the range of 107560 pmol/g (Table 4). The highest concentration was found for CB 77 and the lowest for CB 52. The decrease of CB concentration in the liver was most rapid during the first day. Between 6 and 24 h after exposure there was a decrease of between 57 and 85%. A rapid decrease in hepatic CB concentration was observed for all five congeners, but was most prominent for CB 77. Between one and four days after exposure the concentration of CB 77 dropped by 95%, while the other showed a decrease of concentration between 57 and 71%. The slowest decrease was found for CB 28. At the end of the experiment, four days after exposure, CB 28 was found at the highest concentration (41 pmol/g), whereas CBs 77 and 52 were found at the lowest concentrations (8 pmol/g).
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The concentrations of B-mix CBs in adipose tissue increased until 24 h after exposure and decreased thereafter. The maximum concentration in adipose tissue was observed 24 h after exposure and ranged between 550 and 1727 pmol/g, with the highest concentration of CB 28 and the lowest of CB 77 (Table 4). From that time point to the end of the experiment a decrease of 20 to 59% was observed. At the end, CB concentrations in adipose tissue ranged between 227 and 1357 pmol/g.
Hydroxy metabolite.
The hydroxy metabolite 4-OH-CB107 was present in serum at all time points (Table 2). The concentration increased during the first five days, reached a plateau of about 6.5 pmol/g between days 5 and 15, and decreased thereafter (Fig. 2
). After 135 days, the concentration of this metabolite was 0.2 pmol/g. After 15 days, the ratios between serum metabolite and the parental CBs 105 and 118 concentrations were 9 and 6, respectively. At the end of the experiment the ratios were 0.7 and 0.4, respectively.
Distribution Ratios
A-mix CB congeners.
Six h after administration of the A-mix, the liver-to-adipose tissue distribution ratios were about 1 for CBs 105 and 118 (Table 2). The corresponding ratios were 2 for CBs 138, 153, 156, and 157, while for CBs 170 and 180 the ratios were 5 and 5.5, respectively. During the period of dynamic steady-state (defined as constant distribution ratios between all body compartments) distribution ratios between liver and adipose tissue were in the range of 0.02 to 0.05 (Table 5
). Liver-to-serum ratios varied between 7 and 22 for the different congeners and remained stable over the full time course of the study (Table 5
). The adipose tissue-to-serum ratios were in the range of 2 to 14 after 6 h. During the dynamic steady-state period, ratios between adipose tissue and serum ranged between 316 and 517 for the different congeners (Table 5
).
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DISCUSSION |
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In addition, the exposure was similar to present human exposure. Serum concentrations of CB during the dynamic steady-state of the A-mix experiment were found to be between 550 to 1100 ng/g lipid (Table 2
). The median plasma levels of
CB among people with low fish intake, is reported to be 780 ng/g lipid, of which 660 ng/g are from the eight CBs in the A-mix (Sjödin et al., 2000
). The doses were lower than the dose (3 µg TEQ/kg) reported to cause reciprocal kinetic influence between dioxin-like substances (Carrier et al., 1995a
). On a dioxin toxic equivalency (TEQ) basis, as defined by the World Health Organization (WHO; van Leeuwen and Younes, 1998
), the rats were exposed to a TEQ dose of 0.05 µg/kg (A-mix), or 0.01 µg TEQ/kg (B-mix). The present study was also performed at doses (0.35 and 0.60 mg
CB/kg, respectively) lower than the doses of nondioxin-like CBs that have been reported to cause shifted liver retention and potentiation of EROD activity (de Jongh et al., 1993b
). In the study performed by de Jongh et al.(1993b)
interactions were observed between CB 153 and 156 when given at doses of 99 and 15 mg/kg, respectively.
A-Mix CB Congeners
Tissue distribution and decreasing concentrations.
All the examined A-mix CBs were found to have a high initial liver and serum concentration after uptake through the gastrointestinal tract (Table 2). The following concentration decrease in liver and increase in adipose tissue demonstrates the redistribution to the adipose tissue (Fig. 2
). This redistribution occurred during the first week after administration until dynamic steady-state was established. There may have been a significant amount of metabolism and redistribution of CBs prior to the initial sampling time. The distribution results in this study generally confirm previous observations for CB 153 in the rat (Matthews and Anderson, 1975
).
A comparison of the eight individual A-mix CBs, by making a PCA for all normalized concentration data for individual rats, showed that the results were clustered in three groups in the second principal component (Fig. 3A). These groups correspond to the number of substituted chlorine atoms, which seems to be the most important quality for the differences in kinetic behavior among the CBs in the A-mix. Lipophilicity, measured as log Kow (Table 1
), does not coincide with the clusters, showing that the impact of log Kow is not as large as reported elsewhere (van de Waterbeemd et al., 2001
), even if molecular weight partially corresponds with log Kow. The loading plot of the second principal component (Fig. 3B
) summarize the differences over time in all body compartments and shows that the CB congeners differ with respect to liver, adipose tissue, and serum concentrations at early time points, and in serum concentrations at the end of the experiment. The heptachlorinated CBs 170 and 180 showed a pattern characterized by higher concentration in the liver and serum at early time points, lower concentration in adipose tissue towards the beginning of the experiment, and lower serum concentrations towards the end. The pentachlorinated CBs 105 and 118 showed the opposite pattern with lower initial liver and serum concentrations, higher initial concentration in adipose tissue, and higher serum concentrations towards the end of the experiment. The lower initial concentration of the penta-CBs in the liver and serum could be explained by a more rapid flow through the liver and into the adipose tissue. After 6 h, most of the penta-CBs may already have passed the liver. Passive diffusion has been shown to depend on permeability rather than distribution coefficients (Andersen, 1991
). Since adipose tissue is known to be the main deposit of lipophilic persistent contaminants in the body, the adipose concentrations reflect differences in the total body burden and, if the metabolism is slow, also the uptake. During the whole experimental time, most pronounced at early time points, the penta-CBs had the highest concentrations in adipose tissue and our conclusion was therefore that the lower chlorinated CBs had a higher uptake, a statement that is in accordance with previous results by Tanabe et al.(1981)
who report an absorption of almost 85% for the penta-CBs and an absorption of about 75% for the hepta-CBs.
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Concentration in a tissue is a unit inversely proportional to the mass of the tissue and decreasing concentrations of persistent pollutants has been shown to partly be an effect of dilution (Lutz et al., 1977). This dilution-effect has also been seen in children occasionally exposed to PCB (Yakushiji et al., 1984
). The Sprague-Dawley rats in the present study grew from about 350 to 500 g during the period of steady-state, i.e., 43% increase in body weight, while liver weights increased with 19% during the same time. A recalculation of the half-lives, based on total amount in the liver, showed prolonged times for all congeners by about 40% (Table 4
). A change in body composition may also alter the distribution and can cause redistribution between body compartments when a dynamic steady-state is established. While the proportion of adipose tissue increases the lipophilic pollutants are "drawn" from other parts of the body into the adipose tissue. The proportion of adipose tissue as percent per body weight (BW) in Sprague-Dawley rats has been estimated to be 0.0199 x BW + 1.664 (Bailey et al., 1980
). This means that in the present study the adipose tissue amount of rats increased from 30 to 58 g. In fact, the relative liver weight in this study decreased from 4 to 3% of total body weight. Some of the decrease of hepatic CB concentrations may be an effect of a second redistribution to the adipose tissue. Our conclusion from this study is that the decrease of CB concentrations in the tissues is mainly due to growth of the rat and specifically due to the increase of adipose tissue masses. A recalculation of half-lives based on an estimation of total amount in adipose tissue show that for several congeners almost no elimination at all could be detected during the study period (Table 3
). In rats with constant mass of adipose tissue, the excretion terminal half-life of CB 153 has been calculated to be 478 days (Wyss et al., 1986
), compared to a concentration half-life of about 100 days in this study. However, these t
values are not directly comparable. Nevertheless, the long half-live values in different tissues of the Sprague-Dawley rat calculated in this study provide good evidence for the extreme stability of these substances. Very few half-lives of the examined CBs, measured under low dose conditions, are reported in the literature. Of the congeners in the present study the previously reported half-lives for total body burden was given as > 90 days for CBs 105, 118, 153, 138, 156, 170, and 180 (Tanabe et al., 1981
). In Rhesus monkeys, half-lives for the CBs in mix-A are reported to vary between 0.5 and 1.5 years (Mes et al., 1995
) and in humans about 3.7 years (Ryan et al., 1993
). The results in the present study show that low dose elimination rates in the rat do not differ much from other species.
Partition between body compartments.
Lipophilic compounds are normally distributed in the fat depots within the body, as confirmed in the concentration order in the present study as visualized for CB 105 in Figure 2: adipose tissue > liver > serum. The same order has been reported by Lutz et al.(1977)
. The examined CBs of the A-mix all have liver-to-adipose tissue ratios of about 0.03 (Table 5
). This is in good accordance with Lutz et al.(1977)
who reported a ratio of 0.03 in rats for CB 153. The liver-to-adipose tissue ratio is often used to describe and compare partition among persistent organohalogen compounds (Haag-Grönlund et al., 1997
; van den Berg et al., 1994
). In the body, the distribution between liver and adipose tissue is dependent on an intermediary compartment, the serum. In the present study, CB 153 was found to have an adipose tissue-to-serum ratio of 316 (Table 5
). In comparison, others have reported an adipose tissue-to-serum ratio of 270 for this congener (Wolff et al., 1982
). For all examined congeners Wolff et al.(1982)
found somewhat lower human adipose tissue/serum ratios than observed in this study. The partition between liver and serum seem to be stable from the first time point, at 6 h after treatment, for all thirteen congeners, with the exception of CB 77 (Table 5
). If a compound does not follow the same distribution as similar substances, this could be a sign of specific protein binding in a special compartment. This has been reported for dioxin and the dioxin-like CBs 126 and 169, which all bind to the hepatic enzyme CYP1A2 and where a shift towards the liver is observed in liver-to-adipose tissue ratios (de Jongh et al., 1993b
; Diliberto et al., 1997a
; Santostefano et al., 1997
; Yoshimura et al., 1985
). Experiments with mice deficient for CYP1A2 do not show this shifted ratio (Diliberto et al., 1997b
). In the B-mix experiment, a liver specific initial retention for the non-ortho CB77 was observed. This retention could be explained by binding to the AhR-dependent CYP1A2 induced by the Ah-receptor. The liver retention also correlates to the AhR-dependent EROD activity.
B-Mix PCB Congeners
Tissue distribution and decreasing concentrations.
Previous data suggested that the CB congeners in the B-mix have initial half-lives in the range of 12 days (Tanabe et al., 1981). For CBs 28, 52, and 101 Tanabe et al.(1981)
reported a biphasic elimination with a second half-life (whole body) of 6, 3, and 35 days, respectively. In the same study CB 87 was reported to have a half-life of about 2 days whereas CB 77 was not included. Our results suggest that the half-lives of the B-mix CBs are significantly longer than reported by Tanabe et al.(1981)
. The previously reported short half-lives may be an effect of the relatively high dose given. The maximum accumulation in the adipose tissue occurred 24 h after administration as compared with 5 days for the congeners in the A-mix experiment. The trichlorinated CB 28 seemed to have an effective uptake, detected as a high adipose tissue concentration at early time points, and a slow elimination rate. It is known from environmental samples that CB 28 often occurs at high concentrations, but the tissue retention of this low chlorinated congener still has to be explained (Glynn et al., 2000
). A structure-related model of CB metabolism has been proposed (Parham and Portier, 1998
). This model depends mostly on the degree of chlorination, coplanarity, and chlorine free meta-para and ortho-meta sites (double positions). As in the results of this study, the proposed model gives a lower elimination rate if the number of chlorine increases, but no correlation with free double positions could be detected in the present study. For example, CB 28, which has three free double positions, shows a high tissue retention in the present study (Table 4
). Lowest concentrations were seen of the tetrachlorinated CB 52. This congener is the only congener among the ones studied with two free meta-para sites, and a clear relationship between the number of free meta-para sites and a high degree of metabolism has been shown (Tanabe et al., 1981
). This site is easily epoxidized and thereafter the congener can be conjugated and excreted. The tetrachlorinated CB 77 is characterized by a high initial relative liver concentration and a fast elimination. The high liver retention may potentiate the metabolism, since the half-lives of total body burden have been shown to depend on liver concentration (Carrier et al., 1995b
). The two pentachlorinated CBs 87 and 101 seem to have similar kinetic behavior. CB 87 is found in slightly lower concentrations and this may reflect lower uptake and/or higher metabolism. Tanabe et al.(1981)
reported that CB 87 has a much faster whole-body elimination rate compared to CB 101. Such a big difference could not be detected in this study. Due to the short study period (4 days) dynamic steady-state was not achieved for the B-mix congeners. To better describe the kinetics of these B-mix CBs the study period would need to be 40 days or more.
Hydroxy Metabolite
In this study the main hydroxy metabolite from CBs 105 and 118 was analyzed in serum (Table 2; Sjödin et al., 1998
). The possible metabolic routes are shown in Figure 4
. In humans, this serum metabolite has been shown to be one of the major hydroxylated CB metabolites, constituting 1262% of all analyzed OH-CBs (Sandau et al., 2000
; Sjödin et al., 2000
). In the present study, 4-OH-CB107 reached a concentration about 10 times higher than the parental compounds after five days. From day 15, when the parental compounds are in a dynamic steady-state condition, there was a fast, nonlinear decrease on the metabolite concentration. It is worth noting that the metabolite shows serum concentrations similar to the parental compounds at both 45 and 135 days after exposure. This is similar to previous results, where 20 days after iv exposure to 3 µmol/kg of CBs 105 and 118, the plasma concentration ratio between parent CBs and 4-OH-CB107 was found to be 0.7 and 1.4, for CBs 105 and 118, respectively (Sjödin et al., 1998
). During the last 90 days in the present study, the concentration of the OH metabolite decreased by 59%, which corresponds to a first order decrease with a half-life of about 77 days. These data confirm previous findings, which demonstrate that hydroxylated CB metabolites have a selective retention in the blood (Bergman et al., 1994
). In mouse plasma, the 4-OH-CB107 concentration was 15 times higher than the parent CB 105 concentration five days after exposure (Klasson Wehler et al., 1993
). The selective retention in blood of OH metabolites may be due to their ability to bind to transthyretin (TTR), a thyroxin and retinol transporting protein. The meta positions of the 4-OH-CB107 are halogenated in the same ring as the para-substituted hydroxy group, which allows the metabolite to compete with thyroxin for the TTR binding site (Lans et al., 1993
). By interfering with TTR the OH metabolite can disturb not only thyroxin, but also retinoid transport (Brouwer et al., 1988
).
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ACKNOWLEDGMENTS |
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NOTES |
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2 To whom correspondence should be sent at Institute of Environmental Medicine (IMM), Karolinska Institutet, P.O. Box 210, SE-171 77 Stockholm, Sweden. Fax: 46-8-34-38-49. E-mail: helen.hakansson{at}imm.ki.se.
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