TOXICOLOGICAL SCIENCES 70, 171–182 (2002)
Copyright © 2002 by the Society of Toxicology
Tissue Distribution and Half-Lives of Individual Polychlorinated
Biphenyls and Serum Levels of 4-Hydroxy-2,3,3⬘,4⬘,5pentachlorobiphenyl in the Rat
Mattias Öberg,* Andreas Sjödin,† ,1 Helena Casabona,* Ingrid Nordgren,* Eva Klasson-Wehler,† and Helen Håkansson* ,2
*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
This study was done to generate kinetic data on individual
congeners of chlorinated biphenyls in the low dose range, which
could be of value in the risk assessment procedure. Male
Sprague-Dawley rats were given a single oral dose of a mixture
of polychlorinated biphenyls (CBs) containing either CBs 105,
118, 138, 153, 156, 157, 170, and 180 (A-mix) or CBs 28, 52, 77,
87, and 101 (B-mix). Liver, serum, and adipose tissue were
collected after 6 h up to 135 days, from rats given the A-mix,
and after 6 h up to 4 days from rats given the B-mix. CB
concentrations were measured in liver, serum, and adipose
tissue. In addition, this study provides kinetic data of one of the
major CB metabolites, 4-hydroxy-2,3,3ⴕ,4ⴕ,5-pentachlorobiphenyl (4-OH-CB107). The low doses used resulted in serum CB
concentrations similar to human background serum concentrations. In the A-mix experiment all CBs show high initial liver
and serum concentrations followed by redistribution into adipose tissue. Differences between congeners were correlated to
molecular weight. High molecular weight correlated to lower
uptake and slower redistribution. During dynamic steady-state
the tissue concentrations decreased with a calculated first order
rate between 54 –129 days for halving the concentrations (halflife). Most of the decrease in concentration was explained by the
growth-related increase of tissue masses in general and adipose
tissue in particular. In the B-mix experiment, the concentrations of CBs in adipose tissue decreased with between 25 and
59% from day 1 to day 4. These results show that the B-mix
congeners, given at low dose, have longer half-lives than previously reported in high dose studies. Partition coefficients
between body compartments are reported and for the first time
a high and congener specific liver-to-serum ratio of CB 77 is
observed.
Key Words: distribution; partition coefficient; half-life; polychlorinated biphenyls; PCB; liver; adipose tissue; serum; rat; 4-hydroxy-2,3,3ⴕ,4ⴕ,5-pentachlorobiphenyl.
1
Present address: National Center for Environmental Health, 4770 Buford
Highway, MS F-17, Atlanta, GA 30341.
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: [email protected].
171
Polychlorinated biphenyls (PCB) are commercial products
that are prepared by the chlorination of biphenyls. PCB oil has
been widely used in industry, e.g., as heat transfer fluid, dielectric fluid, and flame retardant. The high lipophilicity and
stability of PCB results in biomagnification and bioconcentration (reviewed by Geyer et al., 2000). Today PCB are found
almost everywhere in the biosphere, including human tissues,
in spite of the fact that they have been banned in most industrialized countries. Acute PCB exposure has been seen in
accidents, such as in 1968 in Yoshu, Japan, where rice oil, by
mistake, was contaminated with PCB (Taki et al., 1969).
Accidental contamination of food is still occurring, as seen in
Belgium during the spring of 1999, when old PCB was mixed
into cattle feed, resulting in exposure to humans via animal
products (van Larebeke et al., 2001). In normal situations
humans are exposed to low chronic doses. In 1996 the average
daily PCB intake in Sweden was reported to be about 0.05
␮g/kg body weight (Darnerud et al., 1995), although in some
local areas the intake of persistent organohalogen pollutants
can be considerably higher than the average.
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-tetrachlorodibenzop-dioxin (TCDD). These CBs, which elicit similar toxic effects, probably by binding to the aryl hydrocarbon receptor
172
ÖBERG ET AL.
(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 halflives 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-hydroxy2,3,3⬘,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).
MATERIALS AND METHODS
Animals. Male Sprague-Dawley rats obtained from B & K Universal AB
(Sollentuna, Sweden), weighing approximately 225 g at the beginning of the
study, were used. The animals were housed in wire-bottomed plastic cages,
with six animals in each cage. The temperature was maintained at 21 ⫾ 1°C
and the illumination cycle (12 h light, 12 h dark) was automatically controlled.
Before treatment, the animals were kept for a 7 to 10 day acclimation period.
Throughout the experiment, the animals were provided with tap water ad
TABLE 1
Characteristics of the Chlorinated Biphenyls (CBs) Used in the
Two Mixtures and the Analyzed Hydroxy Metabolite
CB
A-mix
105
118
138
153
156
157
170
180
B-mix
28
52
77
87
101
4-OH-CB107
Chlorine substitutions
MW
Log K ow
Ortho
2,3,3⬘,4,4⬘
2,3⬘,4,4⬘,5
2,2⬘,3,4,4⬘,5⬘
2,2⬘,4,4⬘,5,5⬘
2,3,3⬘,4,4⬘,5
2,3,3⬘,4,4⬘,5⬘
2,2⬘,3,3⬘,4,4⬘,5
2,2⬘,3,4,4⬘,5,5⬘
326
326
361
361
361
361
395
395
6.65
6.74
6.83
6.92
7.18
7.18
7.27
7.36
1
1
2
2
1
1
2
2
2,4,4⬘
2,2⬘,5,5⬘
3,3⬘,4,4⬘
2,2⬘,3,4,5⬘
2,2⬘,4,5,5⬘
4-OH-2,3,3⬘,4⬘,5⬘
258
292
292
326
326
342
5.67
5.84
6.36
6.29
6.38
6.10 c
1
2
0
2
2
1
Note. Chlorine substitution pattern, molecular weight (MW), n-Octanol/
water partition coefficient (Log K ow), and number of ortho-substituents for the
13 chlorinated biphenyls (CBs) used in the two mixtures and the analyzed
hydroxy metabolite are shown. The CBs and the hydroxy metabolite are
numbered according to IUPAC. Log K ow values are from Hawker and Connell
(1988). Values for 4-OH-CB107 were calculated by H. Geyer (personal
communication).
libitum and they had free access to a standard pellet diet (R36, Lactamin AB,
Vadstena, Sweden). The experimental protocol, including animal housing and
care during the study was approved by the Stockholm Northern Animal Ethic
Committee (Stockholm, Sweden).
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.
Experimental design. Rats were given a single oral dose of a CB mixture
in corn oil containing either CBs 105, 118, 138, 153, 156, 157, 170, and 180
(A-mix) or CBs 28, 52, 77, 87, and 101 (B-mix). All A-mix congeners were
reported to have half-lives longer than 90 days (Tanabe et al., 1981). The
lower-chlorinated CBs in the B-mix were all classified into classes with short
initial half-lives of about 1 to 2 days by Tanabe et al. (1981).
The given amount per rat, was 0.03 ␮mol/CB (⫽ 47 to 56 ␮g/kg) of the
A-mix and 0.1 ␮mol/CB (⫽ 119 to 151 ␮g/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
173
KINETICS OF POLYCHLORINATED BIPHENYLS
chromatography (HPLC) as previously described (Håkansson et al., 1987). The
column used was a Nucleosil 5␮m C 18, 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 ␮M 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 ␮m 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).
t)
The data were fitted to a first order elimination curve; C t ⫽ C 0 ⫻ e (– ke , where
C t is the concentration of the CB congener in different tissues at time t 1, C 0 is
the concentration at the beginning of the decrease, k e is the elimination rate in
days –1. The half-lives (t21) in different tissues were calculated from the k e values
by the equation t21 ⫽ ln2/k e. 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 ⫻ 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).
RESULTS
Tissue Weights, Clinical and Biochemical Effects
No animals died during the study and no abnormal clinical
signs were observed. No treatment related effect on body
weight, organ weights, or organ lipid fractions were seen for
any of the two mixtures given (data not shown). The average
body weight increased from 216 at the beginning of experiments to 530 g after 135 days and liver weights increased from
9 to 17 g during the same period.
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 1.5–3.5 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).
Concentrations of CBs in Liver, Serum, and Adipose Tissue
A-mix CB congeners. Liver concentration profiles of all
A-mix CB congeners showed a biphasic course of concentration decrease (Table 2) as visualized for CB 105 in Figure 2. At
6 h, individual CB concentrations were in the range of 280 –
626 pmol/g. There was a decrease of about 80% in hepatic CB
concentrations between 6 and 24 h after exposure. Thereafter,
the concentration decreased at a slower rate during dynamic
steady-state (between days 15 and 135). The liver concentration half-lives calculated during this period were found to be in
the range of 54 –120 days (Table 3). At the end of the experiment, liver concentrations of individual congeners were in the
range of 3– 6 pmol/g for all congeners (Table 2).
Serum concentrations of all A-mix CBs were close to onetenth of the liver concentrations and showed the same biphasic
decreasing pattern (Table 2) as visualized for CB 105 in Figure
2. At 6 h, individual CB concentrations were in the range of
16 –55 pmol/g. Between 6 and 24 h after exposure the concentrations decreased by more than 80%. The serum concentration
half-lives calculated during dynamic steady-state were in the
range of 81–117 days (Table 3). After 135 days, concentrations
between 0.2 and 0.5 pmol/g were found for the A-mix CBs
(Table 2).
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 360 –709 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 115–151 pmol/g (Table 2).
174
ÖBERG ET AL.
FIG. 1. Hepatic ethoxy- and pentoxyresorufin-O-dealkylation activities (EROD and PROD), for male Sprague-Dawley rats given a single oral dose of two
different mixtures of polychlorinated biphenyls (CBs). (A) and (C) show results from the A-mix experiment including CBs 105, 118, 138, 153, 156, 157, 170,
and 180. (B) and (D) show results from the B-mix experiment including CBs 28, 52, 77, 87, and 101. *Significant difference (p ⬍ 0.05) as compared to the
corresponding control or the mean control value.
B-mix CB congeners. Hepatic CB-concentrations, 6 h after
administration to the B-mix, were in the range of 107–560
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).
Serum concentrations varied between 11 and 49 pmol/g 6 h
after treatment (Table 4). The highest initial concentration was
found for CB 101. The B-mix CB concentrations in serum
showed a rapid decrease during the first day. Between 6 and 24 h
after exposure, the CB concentrations decreased by 62– 82%. The
slowest rate of decrease was found for CB 28. Between one and
four days after exposure the concentration of CB 28 decreased
with 60%, while the concentrations of other CBs were diminished
by 67– 80%. Four days after exposure, CB 101 was still the most
abundant congener (3 pmol/g). The lowest serum concentration
was found for CB 77 throughout the experiment.
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-OHCB107 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.
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KINETICS OF POLYCHLORINATED BIPHENYLS
TABLE 2
Concentrations of Chlorinated Biphenyls (CBs) and 4-Hydroxy-2,3,3ⴕ,4ⴕ,5-pentachlorobiphenyl (4-OH-CB107)
in Male Sprague-Dawley Rats
Tissue
CB
6h
24 h
5 days a
15 days
45 days
135 days
105
118
138
153
156
157
170
180
280 ⫾ 52
285 ⫾ 56
406 ⫾ 78
397 ⫾ 87
327 ⫾ 61
355 ⫾ 69
625 ⫾ 126
626 ⫾ 144
55 ⫾ 15
61 ⫾ 14
86 ⫾ 16
80 ⫾ 15
71 ⫾ 12
76 ⫾ 15
153 ⫾ 45
146 ⫾ 47
20 ⫾ 3.6
20 ⫾ 3.9
29 ⫾ 5.2
21 ⫾ 2.9
18 ⫾ 5.2
24 ⫾ 7.2
26 ⫾ 4.5
20 ⫾ 2.2
8.5 ⫾ 1.8
8.9 ⫾ 2.1
13 ⫾ 2.7
10 ⫾ 2.3
8.9 ⫾ 2.4
11 ⫾ 3.1
11 ⫾ 2.6
11 ⫾ 1.4
6.7 ⫾ 2.2
6.6 ⫾ 2.0
7.9 ⫾ 2.0
6.4 ⫾ 1.5
4.3 ⫾ 1.4
4.9 ⫾ 1.9
6.4 ⫾ 1.8
6.3 ⫾ 1.8
4.2 ⫾ 1.3
3.3 ⫾ 1.0
4.4 ⫾ 1.4
3.0 ⫾ 1.0
4.7 ⫾ 1.6
5.1 ⫾ 1.8
5.6 ⫾ 2.1
2.8 ⫾ 0.7
105
118
138
153
156
157
170
180
16 ⫾ 3.9
26 ⫾ 5.4
31 ⫾ 10
36 ⫾ 10
33 ⫾ 13
37 ⫾ 15
36 ⫾ 14
55 ⫾ 18
0.96 ⫾ 0.79
3.1 ⫾ 0.9
4.8 ⫾ 1.4
5.6 ⫾ 1.8
6.2 ⫾ 1.7
4.1 ⫾ 1.2
5.1 ⫾ 1.5
7.2 ⫾ 2.7
9.2 ⫾ 2.9
2.5 ⫾ 1.7
1.4 ⫾ 0.1
2.2 ⫾ 0.2
2.0 ⫾ 0.3
2.0 ⫾ 0.2
1.3 ⫾ 0.3
1.8 ⫾ 0.4
1.3 ⫾ 0.3
1.6 ⫾ 0.3
6.5 ⫾ 5.4
0.7 ⫾ 0.2
1.1 ⫾ 0.2
0.9 ⫾ 0.2
0.9 ⫾ 0.2
0.6 ⫾ 0.1
0.8 ⫾ 0.2
0.6 ⫾ 0.1
0.7 ⫾ 0.2
6.5 ⫾ 4.0
0.6 ⫾ 0.1
1.0 ⫾ 0.2
0.7 ⫾ 0.1
0.8 ⫾ 0.2
0.5 ⫾ 0.1
0.6 ⫾ 0.1
0.4 ⫾ 0.1
0.5 ⫾ 0.1
0.50 ⫾ 0.15
0.3 ⫾ 0.1
0.5 ⫾ 0.1
0.4 ⫾ 0.1
0.4 ⫾ 0.1
0.2 ⫾ 0.1
0.3 ⫾ 0.1
0.2 ⫾ 0.0
0.3 ⫾ 0.0
0.20 ⫾ 0.12
105
118
138
153
156
157
170
180
224 ⫾ 48
271 ⫾ 55
171 ⫾ 35
176 ⫾ 34
164 ⫾ 33
167 ⫾ 34
124 ⫾ 25
114 ⫾ 23
356 ⫾ 112
429 ⫾ 134
286 ⫾ 88
300 ⫾ 92
270 ⫾ 86
276 ⫾ 88
211 ⫾ 65
198 ⫾ 61
584 ⫾ 92
709 ⫾ 106
485 ⫾ 77
510 ⫾ 80
465 ⫾ 80
473 ⫾ 81
379 ⫾ 65
360 ⫾ 62
320 ⫾ 80
404 ⫾ 107
293 ⫾ 90
312 ⫾ 95
280 ⫾ 86
293 ⫾ 86
236 ⫾ 69
224 ⫾ 65
224 ⫾ 53
284 ⫾ 65
214 ⫾ 42
235 ⫾ 45
204 ⫾ 48
218 ⫾ 52
178 ⫾ 38
170 ⫾ 37
115 ⫾ 19
151 ⫾ 25
128 ⫾ 20
148 ⫾ 22
123 ⫾ 20
129 ⫾ 21
119 ⫾ 21
119 ⫾ 23
Liver
Serum
4-OH-CB107 b
Adipose
Note. Concentrations (in pmol/g), over time, of chlorinated biphenyls (CBs) in liver, serum, and adipose tissue and 4-hydroxy-2,3,3⬘,4⬘,5-pentachlorobiphenyl
(4-OH-CB107) in serum of male Sprague-Dawley rats are shown. Rats were given a single oral dose of CBs 105, 118, 138, 153, 156, 157, 170, and 180 as a
mixture of 0.03 ␮mol per congener. Concentration values are arithmetic mean ⫾ SD (n ⫽ 6).
a
The exact time was 125 h.
b
4-OH-CB107 and 4⬘-OH-CB108 are not separated.
Distribution Ratios
A-mix CB congeners. Six h after administration of the Amix, 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).
B-mix CB congeners. No period of dynamic steady-state
was observed for any of the CBs in the B-mix. Six h after
exposure, the distribution ratios between liver and adipose
tissue varied between 0.2 and 1.2 for the different congeners
(based on data in Table 4). The only congener with a ratio
above one was CB 77. This liver retention of CB 77 declined
at the end of the experiment. Liver-to-serum ratios were stable
from 6 h and throughout the experiment, with the exception of
CB 77 that showed an initial liver retention. The other congeners showed average liver-to-serum distribution ratios between
3 and 18 (Table 5). The liver-to-adipose tissue ratios were in
the range of 0.2 to 2.5 after 6 h. Between days 1 and 4 the
distribution was more and more shifted to the adipose tissue
resulting in liver-to-adipose tissue ratios between 0.01 and 0.05
(based on data in Table 4).
DISCUSSION
Dose-Related Effects
The present study was performed with exposure doses that
caused minimal biochemical effects and gave no signs of
176
ÖBERG ET AL.
FIG. 2. Mean concentration over time of CB 105 in adipose tissue, liver
and serum and the hydroxy metabolite (4-OH-CB107) concentration in serum
of male Sprague-Dawley rats given a single oral dose of a mixture consisting
of CBs 105, 118, 138, 153, 156, 157, 170, and 180 (0.03 ␮mol/CB).
clinical or toxic effects. The transient hepatic EROD induction,
which measures cytochrome P450 1A (CYP1A) enzyme activity (Bandiera et al., 1982), in the A-mix experiment was
significant only before 15 days after exposure (Figs. 1A and
1B). The period of significant induction correlates with high
concentrations in the liver. No altered EROD activity was seen
during the time period when half-lives were measured. High
activities of phase one metabolic enzymes (e.g., CYP1A) may
explain the reported prolongation of half-lives with decreasing
doses that has been observed for dioxins by others (Carrier et
al., 1995b). The hepatic EROD induction seen after exposure
to the B-mix was about 15 times the control activity after 24 h
and decreased to about two times the control activity after four
days. This transient induction, which could be a result of the
non-ortho substituted CB 77, may have influenced the elimination rate. In both the A-mix and the B-mix experiments, up
to a three-fold induction of hepatic PROD activity was seen
throughout (Figs. 1C and 1D), independent of internal hepatic
CB concentrations. It has been shown that PROD activity is
related to CYP2B and can be induced by certain CBs (Connor
et al., 1995; Lubet et al., 1985a). Among the congeners in the
present study CBs 87, 101, 153, and 180 are all known to
induce CYP2B, whereas CBs 105, 118, 156, 157, 138, and 170
are known to induce both CYP1A and 2B (McFarland and
Clarke, 1989). The PROD induction is not likely to depend on
the treatment nor likely to influence the kinetics.
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 ␮g 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 ␮g/kg
(A-mix), or 0.01 ␮g 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
TABLE 3
Half-Lives (Days) Based on Decreasing Concentrations and Total Amount of Chlorinated Biphenyls (CBs) in Liver, Serum, and
Adipose Tissue of Sprague-Dawley Rats
Liver
Serum
Adipose tissue
CB
Conc. 95% C. I.
Total
Conc. 95% C. I.
Conc. 95% C. I.
Total a
105
118
138
153
156
157
170
180
118 75–283
83 56–163
71 49–127
60 43–102
120 64–1012
97 53–552
106 63–331
54 41–81
169
109
93
84
216
149
186
69
98 68–177
117 78–232
101 71–175
113 77–213
83 55–164
85 61–138
83 58–143
81 57–139
77 54–136
81 56–147
97 64–202
109 71–237
98 64–217
99 65–209
120 76–277
129 80–323
222
248
446
758
462
455
1771
NE
Note. Half-lives were calculated by fitting individual data from 15, 45, and 135 days after administration to C t ⫽ C 0 ⫻ e (– ke , where C t is the concentration
of the CB congener in different tissues at time t 1, C 0 is the concentration at the beginning of the decrease, k e is the elimination rate in days –1. The half-life (t21)
in different tissues were calculated from the k e values by the equation t21 ⫽ ln2/k e. NE ⫽ no elimination observed.
a
The calculated half-lives of total amount in adipose tissue is based on a model where adipose tissue weight is related to total body weight (BW) as
0.0199 * BW ⫹ 1.664 (Bailey et al., 1980).
t)
177
KINETICS OF POLYCHLORINATED BIPHENYLS
TABLE 4
Concentrations of Chlorinated Biphenyls (CBs) in Male Sprague-Dawley Rats
following a Single Oral Dose of CBs 28, 52, 77, 87, and 101
Tissue
CB
6h
1 day
2 days
4 days
28
52
77
87
101
222 ⫾ 24
107 ⫾ 26
560 ⫾ 148
367 ⫾ 79
542 ⫾ 90
95 ⫾ 19
28 ⫾ 7
158 ⫾ 78
63 ⫾ 16
83 ⫾ 29
54 ⫾ 15
12 ⫾ 3
30 ⫾ 15
31 ⫾ 11
49 ⫾ 27
41 ⫾ 13
8⫾2
8⫾2
22 ⫾ 10
34 ⫾ 18
28
52
77
87
101
13 ⫾ 2
34 ⫾ 4
11 ⫾ 2
39 ⫾ 6
49 ⫾ 4
5⫾1
10 ⫾ 2
4⫾4
9⫾2
9⫾3
4⫾1
4⫾1
1⫾0
5⫾2
7⫾3
2⫾1
2⫾0
1⫾0
2⫾1
3⫾1
28
52
77
87
101
872 ⫾ 236
578 ⫾ 143
458 ⫾ 181
585 ⫾ 177
608 ⫾ 168
1727 ⫾ 255
1019 ⫾ 122
550 ⫾ 144
1101 ⫾ 165
1181 ⫾ 190
1554 ⫾ 421
760 ⫾ 155
364 ⫾ 126
903 ⫾ 232
1029 ⫾ 316
1357 ⫾ 390
565 ⫾ 106
227 ⫾ 92
805 ⫾ 180
947 ⫾ 251
Liver
Serum
Adipose
Note. Concentrations (in pmol/g), over time, of chlorinated biphenyls (CBs) in liver, serum, and adipose tissue of male Sprague-Dawley rats following a single
oral dose of CBs 28, 52, 77, 87, and 101 as a mixture of 0.1 ␮mol per congener are shown. Concentration values are arithmetic mean ⫾ SD (n ⫽ 6).
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.
TABLE 5
Tissue Partition Coefficients during Dynamic Steady-State between Liver (L), Adipose Tissue (A), and Serum (S) for Chlorinated Biphenyls (CBs) in Rat
CB
L/A
A/S
L/S
28
52
77 a
87
101
105
118
138
153
156
157
170
180
—
—
—
—
—
0.03
0.02
0.04
0.03
0.03
0.03
0.05
0.03
—
—
—
—
—
400 ⫾ 84
322 ⫾ 81
326 ⫾ 61
316 ⫾ 56
517 ⫾ 141
393 ⫾ 80
483 ⫾ 114
379 ⫾ 100
18 ⫾ 3
3 ⫾ 0.5
—
8⫾2
10 ⫾ 2
12 ⫾ 3
7⫾2
12 ⫾ 2
8⫾2
16 ⫾ 6
13 ⫾ 5
22 ⫾ 8
13 ⫾ 3
Note. Partition coefficients are calculated as mean ⫾ SD from individual
data of the last three time points (15, 45, and 135 days) when dynamic
steady-state is observed. Since no dynamic steady-state is observed for CBs 28,
52, 77, 87, and 101, partition coefficients for L/S are calculated as mean ⫾ SD
at all measured time points (6 h, and 1, 2, and 4 days) when stable distribution
ratios between these body compartments are observed.
a
CB 77 did not show a stable concentration ratio between liver and serum.
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 K ow (Table 1), does not coincide with the
clusters, showing that the impact of log K ow is not as large as
reported elsewhere (van de Waterbeemd et al., 2001), even if
molecular weight partially corresponds with log K ow. 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,
178
ÖBERG ET AL.
FIG. 3. Principal Component Analysis (PCA) generated from individual
concentration data normalized to total CB concentration. The model has two
significant components (r 2 ⫽ 0.987 and Q 2 ⫽ 0.969). (A) Scores in two
components with three clusters corresponding to number of chlorine atoms. (B)
Loadings of the second component for all analyzed tissues.
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.
When dynamic steady-state was established in the A-mix
experiment, a slow and similar decrease of concentrations took
place in all examined compartments as visualized for CB 105
in Figure 2. The constant tissue distribution ratios during this
time period indicate that the diffusion between compartments
in the body is much faster than the elimination from the body
(Segel and Slemrod, 1989). In the tissue samples of rats exposed to the A-mix, concentration half-lives were found in the
range of 54 –129 days (Table 3). Relatively high variation
between individuals and a slow decreasing rate made it difficult
to determine exact and comparable values. In order to get more
accurate t12 values, experimental time periods of at least three
times the half-lives are needed, in this case about one year
(Phillips et al., 1989).
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 SpragueDawley rats has been estimated to be 0.0199 ⫻ 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
KINETICS OF POLYCHLORINATED BIPHENYLS
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 t21 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-toadipose 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-
179
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 1–2 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 metapara 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.
180
ÖBERG ET AL.
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).
Conclusions
FIG. 4. Suggested metabolic routes for formation of 4-OH-CB 107 from
CBs 105 and 118 according to Sjödin et al. (1998).
During the dynamic steady-state CBs 105, 118, 138, 153,
156, 157, 170, and 180 showed decreased concentrations with
half-lives in the range 54 to 124 days. Most of the decrease in
concentration was explained by the growth-related increase of
tissue masses in general and adipose tissue in particular. A
PCA showed a correlation between molecular weight and
bioavailability and distribution between these congeners. The
CBs 28, 52, 77, 87, and 101 were eliminated at slower rates
than previously reported and for the first time a high and
congener-specific liver-to-serum ratio of CB 77 was observed.
This study also provides serum concentration data on the
hydroxy metabolite 4-OH-CB107 that was present at concentrations similar to the parental CBs 105 and 118. The low doses
used in this study are comparable with the human background
situation. The dynamic steady-state reached makes the results
valuable in the human health risk assessment procedure.
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 12– 62% 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
␮mol/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-OHCB107 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
ACKNOWLEDGMENTS
The authors sincerely thank Ellu Manzoor for chemical analysis and Joost de
Jongh for sharing toxicokinetic knowledge. This study was supported by funds
from the Swedish Environmental Protection Agency.
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