XENOBIOTICA,

1991, VOL. 21, NO. 1, 111-120

Kinetics of distribution and elimination of DDE in rats S. MUHLEBACH, M. J. MOOR, P. A. WYSSt and M. H. BICKELf Department of Pharmacology, University of Berne, Friedbuhlstrasse 49, CH-3010 Berne, Switzerland

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Received 26 March 1990; accepted 12 July 1990 1. Rats were given single i.v. doses of I4C-DDE, and total drug (I4C) and unchanged DDE (g.1.c.) were measured for up to 14 days in blood, tissues, and excreta. The I4C recoveries amounted to 90.0 & 108 (SD) % dose. 2. DDE underwent redistribution from blood to liver, muscle, skin and, ultimately, adipose tissue. The tissue/blood concentration ratios were 6 for liver and muscle, 35 for skin, 400 for adipose tissue. Concentrations in blood and lean tissues declined biphasically with fi-half-lives of 8-12 days. The half-lives for adipose tissue and total body burden were larger by one order of magnitude. However, due to the increase of adipose tissue mass with time, the amount of D D E stored therein remained constant at almost 60% dose. 3. Except for liver, no substantial metabolite concentrations in tissues were found. In particular, lipophilic metabolites were clearly absent. Thus, tissue kinetics and storage are controlled by unchanged DDE. 4. Of a given dose of DDE, 31% was excreted in the faeces as polar metabolites within 14 days, and 3 4 % dose as DDE. Urinary excretion was negligible. The 8-half-life of faecal excretion was equal to the one in blood and lean tissues. It is concluded that excretion is limited by the slow formation of polar metabolites of DDE.

Introduction In humans and animals the organochlorine insecticide, DDT (chlorophenothane), is slowly metabolized along a sequence of reactions to the polar metabolite, DDA, and by dehydrochlorination to the lipophilic metabolite, DDE. T h e non-insecticidal DDE is the most persistent member of the D D T family and therefore represents the major tissue residue of total D D T (Hayes 1965, Hayes and Dale 1964, Durham 1969, Geyer et al. 1986). Like other polychlorinated hydrocarbons, D D T and D D E have entered food chains and pervaded the biosphere as a result of their lipophilicity and persistence (Jensen and Jansson 1976, Bickel and Muhlebach 1980). D D E may therefore be considered as a prototype of a highly lipophilic and truly persistent xenobiotic and global pollutant. D D T and D D E are stored in adipose tissues (Hayes and Dale 1964) from where they can be mobilized, thereby eliciting toxic effects (Dale et al. 1962, To-Figueras et al. 1988). Excretion data for unchanged DDE in the rat are controversial (Ando 1982, Fawcett et ul. 1987), and the same holds true for its metabolism. D D E has been reported as a terminal metabolite (Peterson and Robinson 1964), but it has also been postulated as an intermediary product in the pathway leading from D D T to DDA and other metabolites (Datta 1970). Phenolic and other minor metabolites of D D E have also been identified (Sundstrom et al. 1975, Jensen and Jansson 1976, Fawcett et al. 1987).

t Present address: Medical College of Virginia, Division of Clinical Toxicology, Richmond, VA 23298, USA. 3 T o whom correspondence should be addressed. 0049-8254/91 $3.00 0 1991 Taylor & Francis Ltd.

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While there exists a large body of studies on bioaccumulation and residue levels of D D T and DDE, data on the pharmacokinetics and distribution are scarce and incomplete, in particular on the kinetics of DDE. In a former study (Muhlebach et al. 1985) we compared adipose tissue kinetics of DDE, thiopental and 2,4,5,2’,4’,5’-hexachlorobiphenyl (HCB). I n the present study the kinetics of distribution and elimination of D D E has been investigated during 14 days after a single intravenous dose to rats. T h e determination of both unchanged D D E by g.1.c. and total I4C allowed the establishment of a mass balance for tissues and excreta and

the differentiation between unchanged xenobiotic and its metabolites.

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Materials and methods Chemicals and drugs D D T (1,l -bis-(p-chlorophenyI)-2,2,2-trichloroethane, 2 98% purity) and D D E (1,l-bis-(pchlorophenyl)-2,2-dichloroethene, 2 99% purity) were purchased from Fluka AG, Buchs, Switzerland. Radiolabelled [phenyl-U-’4C]DDT (60-100 mCi/mmol) was obtained from the Radiochemical Centre, Amersham, UK. [Phenyl-U-14C]DDE was prepared by base-catalysed dehydrochlorination of ’“CD D T in ethanolic 1.8 M-KOHand purified by preparative t.1.c. as described by Apple (1986). T h e purity of I4C-DDE was 2 95% as confirmed by t.1.c. and g.1.c. analysis. Emulphor E L 620 was from G A F Corp. New York, NY, USA. Disposable mini-columns packed with 100pm Florisil were obtained from Baker Chemical Co., (HCB) from Analabs, North Haven, C T , Phillipsburg, NJ, USA, 2,4,5,2’,4’,5’-hexachlorobiphenyl USA. Liquid scintillation mixture Insta-Gel I1 and tissue solubilizer Soluene 350 were obtained from United Technologies Packard, Zurich, Switzerland. All other chemicals were of analytical grade and were purchased from Merck, Darmstadt, F R G or from Fluka (see above). Animals and treatment Sprague-Dawley rats (strain SIV 50, Tierzuchtinstitut, Zurich, Switzerland) of 220-230 g initial body wt. were fed ad libitum with pelleted lab diet and were kept individually during the experimental period. For drug administration, 14C-DDE and unlabelled D D E were mixed (specific radioactivity 0.5 mCi/mmol) and dissolved in a mixture of Emulphor EL 62hthanol-water (1 : 1 : 8, v/v); 5 mg/kg were administered i.v. into a surgically exposed femoral vein under ether anaesthesia. Faeces and urine samples of three animals housed in metabolic cages were collected daily over 14 days and were stored at -20°C. Prior to analysis, faeces samples were dried by lyophilization and ground with anhydr. Na,SO, (1 : 1). At 1 , 3and 24 h and 4,7 and 14 days after drug administration, three animals per time-point were killed and dissected as described previously (Miihlebach and Bickel 1981, Wyss et al. 1982). Samples included blood, liver, muscle, skin and adipose tissues (epididymal, mesenteric and subcutaneous). Except for blood and skin, samples were homogenized in phosphate buffer 005 M ( p H 74) and stored at - 20°C until further analysis. Skin samples from abdomen and ear conch were minced and ground with anhydr. Na,S04 (1 : 1). For calculation of mass balances and kinetic parameters the following relative wet wt. of large tissues were used: blood 5%, muscle 45%, skin 16%, adipose tissue 8% at 230g body wt. (9% at 2 5 0 g and 10% at 300 g body wt.) (Miihlebach and Bickel1981, Wyss et al. 1986). Final body wt. of rats in these experiments were between 250 and 300g.

G.1.c.determination of DDE The method used for sample preparation was based on our previously published procedure (Miihlebach and Bickel 1981, Wyss et al. 1986). In addition, analytical samples were further purified by solid-phase extraction, and HCB was used as an internal standard. Tissue homogenates (2.0ml), blood (1-2 ml) or 100-500mg of skin powder were extracted twice with 4ml n-hexane after addition of 200pl of a solution of internal standard. T h e combined hexane extracts were concentrated in a light stream of nitrogen to a final volume of 3.01111 and treated with 1 ml of conc. H , S 0 4 (95%). The hexane phase was dried and neutralized with a mixture of Na,SO, and Na,CO,, and 1.0 ml of the hexane phase was passed through a Florisil cartridge. T h e solid phase was washed with an additional volume of n-hexane (6 ml). Except for adipose tissue extracts, the combined organic phases were evaporated to a final volume of 1.0 ml. Extracts of adipose tissues were diluted to 10.0 ml. Aliquots of these purified hexane extracts were subsequently used for g.1.c. analysis and liquid scintillation counting. For all the tissues analysed, recoveries of DDE were between 80% and 90%. Faeces samples were processed accordingly, using faecal aliquots corresponding to 0.5 g of starting material.

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Kinetics of DDE in rats

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G.1.c. was carried out on a Hewlett-Packard H P 5890 A equipped with an on-column injector, a 63Ni electron capture detector kept at 260"C, a 530pm SE-54 fused silica capillary column and a H P 3392 A integrator unit. Temperature settings were: initial temp. 60"C, AT/min. 20"C, final temp. 250°C. Nitrogen was used as carrier gas at a flow rate of 10ml/min. Under these conditions retention times for DDE and HCB were 1 0 3 and 11.2min, respectively (figure 1). Calculation of DDE concentrations in samples of blood and tissues was based on daily re-evaluated calibration curves using DDE standard solution. In the range of 25 to 200pg, standard curves (DDE amounts vs. peak areas) were linear. Recoveries of the internal standard, HCB, were used to correct for DDE losses during the sample preparation. Using this approach, variation of measured values was between 5.5% and 7.5% (CV). Assessment of 14C-DDE radioactivity Radioactivity in blood, tissues and excreta (urine and faeces) was assessed by liquid scintillation counting with external standardization for quench correction. Tissue homogenates (200~1)and urine samples (1.0ml) were mixed with 1Oml of scintillation mixture Insta-Gel I1 and counted without further treatment. In contrast, blood (200pl), skin (50mg) and faeces (025 g) samples were solubilized with Soluene 350 in order to increase the recovery. Quenching was reduced by H,O, treatment prior to further analysis. Data analysis DDE concentration-time data in blood, liver and muscle were described by a two-compartment model (Meier et al. 1981): c= A exp ( - a t ) + B exp ( - b t )

(1)

where c is the DDE concentration at time t , A and B are ordinate intercept constants, and a and bare the corresponding first-order elimination rate constants. The time-course of DDE in adipose tissue and skin could be assessed by the following Bateman equation:

where co is the apparent drug concentration in the compartment at time zero, and kinand k,, are first-order rate constants for invasion and elimination, respectively. Parameters were estimated by nonlinear leastsquares regression analysis using the M O D F I T programs according to McIntosh and McIntosh (1980). Since adipose tissue volumes increase with time, simulations of DDE kinetics in adipose tissues were carried out. Calculations were extended beyond 14 days, assessing the growth of this compartment

11.17

k Figure 1. G.1.c. chromatogram of a rat adipose tissue sample after dosing with I4C-DDE. The peak at 1034min is DDE (about 007ng); the peak at 11.17min is HCB (internal standard).

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according to Lutz et al. (1977). The following differential equation was used to describe the kinetics of DDE in adipose tissues:

where xa is the amount of DDE in adipose tissue, V , the volume of the adipose tissue compartment at any time, and c, the DDE concentration derived from equation (2).

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Results The concentration-time profile of total drug (14C) and DDE is given in table 1. Concentrations in tissues were always greater than in blood. Between 4 and 14 days tissue/blood concentration ratios were about 6 for liver and muscle, 35 for skin, and 400 for adipose tissue. D D E concentrations peaked prior to 1 h in liver and muscle, at 3 h in skin, and between 1 and 4 days in adipose tissue. Metabolite fractions in blood and tissue homogenates were estimated indirectly by comparing the values of total I4C, I4C in hexane extracts, and unchanged DDE. T h e differences between total 14C and DDE, representing polar and lipophilic metabolites, were not always significant, except for liver (table 1). T h e differences between 14C in hexane extracts and unchanged DDE, representing lipophilic metabolites, were not significant. Thus, the presence of small amounts of polar metabolites in extrahepatic tissues is possible; however, there is no evidence for lipophilic metabolites. The distribution kinetics of D D E was characterized by a redistribution from blood to liver and muscle, to skin, and ultimately to adipose tissues. This process, which takes about 1 day, is indicated by the concentration peaks (tables 1 and 2) and the amounts in individual tissues (table 3). As is shown b y the time-course of D D E radioactivity in total tissues, the elimination of the body burden is very slow and incomplete during the first 2 weeks. Excretion in 14 days amounted to 35.5% of total administered radioactivity (table 3). The contribution of renal excretion was only 1.05% dose, most of it during the first 7 days. No unchanged DDE could be detected in urine, whereas faeces contained about 10%. No hexane-extractable lipophilic metabolites were found in faeces. Table 3 also serves as a mass balance. T h e average recovery of total drug in the tissues analysed and in excreta was 90% (74106%). The pharmacokinetic parameters for blood, tissues and the excretion processes are summarized in table 2. T h e kinetics of tissue disappearance and excretion are represented in figure 2. The b-phase half-life of DDE in blood was 12 days. T h e kinetics of faecal and urinary excretion could be described by biexponential processes (figure 3) with &half-lives of 10-1 1 days. T h e half-life for the decrease of body burden was 120 days. In adipose tissue a very slow decrease in concentration occurred during the period between its maximum and 14 days.

Discussion This single-dose (i.v,) kinetic study of distribution and elimination of D D E in rats was based on determination of both total and unchanged drug, and was controlled by mass balance. T h e high recoveries of total drug at every time-point (table 3) indicate that the most important tissues had been included and that no hidden depots exist. T h e simultaneous determination of total drug (14C) and of unchanged DDE (g.1.c.) in the same analytical sample also allowed an estimation of metabolite formation. Furthermore, a high efficiency of the clean-up procedure used

2.37 (0.17) 17.64 (0.81) 4.28 (0.60) 3.41 (0.33) 10.88 (0.61)

Total

0.96 (0.10) 9.43 (1.42) 2.46 (0.05) 4.27 (0.54) 16.85 (2.95)

I4C

DDE

1.83 (0.06) 14.30 (1.89) 3.06 (0.27) 2.56 (0.25) 8.22 (0.49)

Total

Unchanged

0.76 (0.05) 7.1 5 (1.20) 1.78 (0.05) 4.38 (0.59) 11.58 (1.57)

DDE

Unchanged

3h Unchanged

DDE 0.1 4 (0.03) 1.60 (006) 054 (0.08) 3.90 (0.31) 25.27 (7.09)

Total

I4C 019 (0.03) 2.1 5 (018) 0.80 (0.09) 4.46 (0.56) 32.46 (4.65)

24h

0.09 (0.00) 0.96 (0.06) 0.46 (0.05) 3.39 (1.08) 36.13 (1.55)

Total 14C

0.42 (0.04) 0.29 (0.06) 2.87 (0-32) 27.16 (1.93)

(0.01)

004 (0.01) 0.25 (0.05) 019 (002) 1.68 (0.27) 13.81 (2.84)

DDE

Unchanged

7 days

0.06 (0.03) 0.67 (0.1 1) 0.32 (0.02) 2.48 (0.23) 21.73 (4.49) .

I4C

DDE 0.06

Total

Unchanged

4 days

Mean values of three animals per time point, expressed as pg/g, +SD in parentheses. Dose of 14C-DDE was 5 mg/kg. Unchanged DDE was determined by g.1.c. analysis.

Adipose

Skin

Muscle

Liver

Blood

Tissue

lh

Time after dosing

0.05 (0.01) 0.38 (0.07) 0.15 (0.02) 1.16 (0.16) 22.07 (3.81)

DDE

Unchanged

14 days

0.05 (0.01) 0.58 (0.07) 0.18 (0.03) 1.46 (0.18) 2438 (2.89)

Total

Table 1. Time-course of blood and tissue concentrations after a single intravenous dose of 14C-DDE to rats (pg equiv. DDE/g).

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Table 2.

Kinetic parameters of DDE in the rat.

Blood

Liver

Muscle

2.817 04716 0.0722 0.0024

12.024 0.1155 04126 0,0009

3.689 03351 0.4153 00037

Skin

Adipose

4-240 09510 0.0042

23.305 0.3961 00004

Faeces

Urine

5.452 0.0148 2304 0.0028

0.617 0.0599 0070 0.0026

Tissue values represent unchanged DDE; excreta represent total radioactivity. Calculations for blood, liver, muscle, and excreta were based on bi-exponential equation for a two-compartment model (equation l), for skin and adipose tissue on Bateman equation (equation 2). A, B=ordinate intercepts of a- and j-phases, respectively; a, /I k,,, , k,,= first-order rate constants; co = ordinate intercept of concentration decline curve.

Table 3.

Tissue distribution, excretion, and recoveries of total 14C after intravenous dosage of "T-DDE to rats.

Time after dosage Tissue

lh

3h

24h

4 days

7 days

14 days

2.30 15.36 37.09 1055 18.90

0.93 8.41 21-39 13.22 2942

018 2.01 6.95 13.83 57.04

0.09 0.91 412 10.78 58.27

0.07 075 3.49 9.66 53.03

007 0.7 1 223 6.48 60.63

84.2

73.4

800

74.2

67.0

70.1

~

Blood Liver Muscle Skin Adipose

Total tissues Urine Faeces

Total excretion Total recovery

0.02t 030t

003t 0.59t

0.37f 6.50t

065 19.66

0.86 26.93

1.05 34.41

0.32

0.62

6.87

203 1

27.79

35.46

94.5

948

845

74.0

869

105.6

Rats were given single i.v .doses of 5 mgjkg of "C-DDE. Mean values of three animals per time-point, expressed as percentage of dose. t Calculated from regression analysis of excretion data (table 2 and figure 3).

for electron capture detection g.1.c. was shown (figure 1). T h e large number of analytical samples examined in each animal gave reliable mean concentrations of total and unchanged drug in individual tissues and excreta. T h e inter-animal variation of concentration values (table 1) was 11-16% (XCV). The bulk redistribution of DDE from rapidly perfused viscera to skin and adipose tissue takes at least 1 day. T h e corresponding time scales for thiopental and HCB are 1 h and 1 month, respectively (Miihlebach et al. 1985). A higher adipose tissue affinity for DDE than for thiopental has been shown in witro (Di Francesco and Bickel 1985). In our study, elimination of DDE from lean tissues and blood following the redistribution phase is characterized by a half-life of 8-12 days. In contrast, the decrease of adipose tissue concentrations was much slower. As a

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117

0

50

100

150

200

250

300

350

Time after dosage ( h ) Figure 2.

Tissue disappearance and excretion of D D E after a single intravenous dose of 14C-DDE to rats.

Rats were given single i.v. doses of 5 mg/kg: ( 0 )tissues, ( W ) faeces and urine. Mean values+ SD of three animals per time-point.

10

5

1

0.5

0.1

0.05

0.01

0

50

100

150

200

250

300

350

Time after dosage ( h ) Figure 3.

Rates of excretion of total

after a single intravenous dose of 14C-DDE to rats.

(m)

faeces, ( 0 )urine. Mean values in percentage dose Rats were given single i.v. doses of 5 mg/kg: per day+SD of three animals per time-point.

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consequence, the half-life for body burden was about 120 days (figure 2). Cumulative excretion of total drug in 14 days amounted to 35% dose (table 3) which, upon extrapolation, is comparable to the 64% dose in 56 days determined by Fawcett et al. (1987). As with HCB (Miihlebach and Bickel 1981, Wyss et al. 1986) and other polychlorinated compounds, excretion of DDE was predominantly by the faecal route. Kinetics of the P-phase of excretion discloses a half-life of 10 days, which agrees with the value of blood and lean tissues. Among the metabolites of DDE, lipophilic products have been identified as (phenolic) hydroxylated derivatives (Sundstrom et al. 1975, Fawcett et al. 1987) and fatty acid conjugates of 2,2-bis-(p-chlorophenyl)-ethanol(DDOH) (Leighty et al. 1980). In our study the differences in the concentrations of total drug and unchanged D D E in blood and extrahepatic tissues were relatively small or not statistically significant (table 1). In particular, there is no evidence for the formation and accumulation of lipophilic metabolites from determination of I4C in hexane extracts. Therefore, tissue kinetics and storage of D D E in the rat is determined largely by the unchanged xenobiotic. In contrast to tissues, excreta contained 32% dose as (polar) metabolites in addition to 3 4% dose as unchanged DDE. This is indicative of a rapid excretion of the slowly formed metabolites, i.e. of an excretion process limited by metabolite formation. Again, this differs from the prototypical ‘fat-seekers’, such as thiopental, which is rapidly biotransformed into renally excreted metabolites, and from HCB, which is virtually unmetabolizable in the rat and undergoes limited excretion in the faeces (Miihlebach and Bickel 1981). T h e proportion of unchanged D D E in rat faeces agrees with the study by Fawcett et al. (1987). However, these authors as well as Sundstriim et al. (1975) also found similar amounts of phenolic metabolites, whereas our study shows no evidence for the presence of lipophilic metabolites in faeces. Finally, Fawcett et al. (1987) reported unidentified metabolites, in addition to small amounts of the polar metabolite, DDA. Therefore, the bulk of polar metabolites in our study may be DDA and/or polar conjugates of hydroxylated metabolites. Definitely, these three studies demonstrate that D D E is biotransformed to polar metabolites rather than being a terminal metabolite of D D T . At 14 days after administration of D D E about 60% dose remains in adipose tissue and less than 10% dose in lean tissues (table 3). T h e slow decrease of the concentration in adipose tissue can be interpreted as a result of elimination from this tissue and/or dilution by the increase of this storage compartment by a factor of 1-5 during the period of observation (Lutz et al. 1977, Miihlebach and Bickell981). T h e constant amount of DDE in adipose tissue from day 2 to day 14 and an all-time cumulative excretion of 50% dose, as obtained by extrapolation of the excretion kinetics (table 2), are indicative that only DDE in lean tissues and blood is available for elimination during this period. However, this is unlikely to be the ultimate state, since DDE, in contrast to HCB, is metabolizable and the polar metabolites are rapidly excreted as shown by the identical rate constants of blood and excretion kinetics. In addition, unavailability of adipose-stored D D E for elimination would lead to a steady increase of adipose/blood concentration ratios which is in contrast to the results up to 14 days. Hence, it must be assumed that adipose tissue releases D D E by a slow process not yet detected prior to 14 days. Thus, D D E stored in adipose tissue will become available for metabolism and excretion so that a true terminal (third) excretion phase will lead to total excretion (100% dose). I n figure 4 curves b and c show an extrapolation of amounts of D D E in constant and increasing

119

Kinetics of DDE in rats

100

100

C M P)

0 -0

10

I0

2a

i

a

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a

1

1

0

500

1000

Time after dosage ( h ) Figure 4. Simulation of 14C-DDE kinetics in adipose tissue: ( a ) concentration vs. time (Modfit); ( b ) percentage dose vs. time, assuming constant adipose tissue mass; (c) percentage dose vs. time, assuming increasing adipose tissue mass (Lutz et al. 1977). For data see tables 1-3.

adipose tissue mass including times beyond 336h (14 days). It emerges that with increasing adipose tissue mass a substantial net efflux from this compartment would occur only from about 500 h onwards. In contrast, the concentration curve a would not differentiate between increasing and constant adipose tissue mass. As has also been shown with HCB (Wyss et al. 1986) changes in the mass of the adipose tissue compartment may dramatically influence long-term kinetics of persistent xenobiotics.

Acknowledgements This work was supported by the Swiss National Science Foundation. T h e authors are indebted to Ms H. van Hees and Dr S. Steiner for expert assistance.

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HAYES,W. J., 1965, Review of metabolism of chlorinated hydrocarbon insecticides, especially in mammals. Annual Reviews of Pharmacology and Toxicology, 5, 27-52. HAYES, W. J., J R , and DALE,W. E., 1964, Concentration of D D T in brain and other tissues in relation to symptomatology. Toxicology and Applied Pharmacology, 6 , 349. JENSEN, S., and JANSSON, B., 1976, Methyl sulfone metabolites of PCB and DDE. Ambio, 5 , 257-260. LEIGHTY, E. G., FENTIMAN, JR, A. F., and THOMPSON, R. M., 1980, Conjugation of fatty acids to D D T in the rat: possible mechanism for retention. Toxicology, 15, 77-82, LUTZ,R. J., DEDRICK, R. L., MATTHEWS, H. B., ELING,T., and ANDERSON, M. W., 1977, A preliminary pharmacokinetic model for several isomers of polychlorinated biphenyls in the rat. Drug Metabolism and Disposition, 5, 386-396. J . E. A., and MCINTOSH, R.P., 1980,Mathematical Modelling and Computers in Endocrinology MCINTOSH, (Berlin-Heidelberg: Springer). MEIER,J . , RETTING, H., and HESS,H., 1981, Biopharmaaie. Theorie und Praxis der Pharmakokinetik (Stuttgart: Thieme). S.,Cand M. H., 1981, Pharmacokinetics in rats of 2,4,5,2’,4‘,5’-hexachlorobiphenyl, M~~HLEBA H , BICKEL, an unmetabolizable lipophilic model compound. Xenobiotica, 11, 249-257. S., WYSS,P. A., and BICKEL, M. H., 1985, Comparative adipose tissue kineticsof thiopental, M~IHLEBACH, DDE, and 2,4,5,2’,4‘,5’-hexachlorobiphenyl in the rat. Xenobiotica, 15, 485-491. J. E., and ROBINSON, W. H., 1964, Metabolic products of p,p’-DDT in the rat. Toxicology and PETERSON, Applied Pharmacology, 6 , 321-327. S U N D S T RG., ~ MJANSSON, , B., andJENsEN, S., 1975, Structure of phenolic metabolites ofp,p’-DDE in rat, wild seal and guillemot. Nature, 255, 627428. TO-FIGUERAS, J., GOMEZ-CATALAN, J., RODAMILANS, M., and CORBELLA, J., 1988, Mobilization of stored during partial starvation in rats. hexachlorobenzene and p,p’-dichlorodiphenylcholoroethylene Toxicology Letters, 42, 79-86. S., and BICKEL,M. H., 1982, Pharmacokinetics of 2,2’,4,4’,5,5’-hexaWYSS,P. A,, M~~HLEBACH, chlorobiphenyl (6-CB) in rats with decreasing adipose tissue mass. I. Effects of restricting food intake two weeks after administration. Drug Metabolism and Disposition, 10, 657-661. WYSS,P. A., MUHLEBACH, S., and BICKEL,M. H., 1986, Long-term pharmacokinetics of 2,2’,4,4’,5,5’hexachlorobiphenyl (6-CB) in rats with constant adipose tissue mass. Drug Metabolism and Disposition, 14, 361-365.

Kinetics of distribution and elimination of DDE in rats.

1. Rats were given single i.v. doses of 14C-DDE, and total drug (14C) and unchanged DDE (g.l.c.) were measured for up to 14 days in blood, tissues, an...
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