Ch. Schlatter

Pharmacokinetics of 2,3,7,8-TCDD in man

Abstract A single dose of 1.14 ng of 3H-2,3,7,8-TCDD/kg bw, ingested by a human volunteer, was absorbed almost completely from the intestine (> 87 %). The resulting adipose tissue levels, measured 13 and 69 days after dosage were 3.09±0.05 and 2.85±0.28 ppt, respectively. The dioxin was cleared from the body with a half life of elimination of 2120 days.

Influence of solvents and adsorbents on dermal and intestinal absorption of TCDD.

The liver concentration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was measured as a means of following the uptake of this chemical by the intestinal and dermal routes. Accumulation of the (radiolabelled) compound in the liver was found to provide a good and reproducible method of comparing TCDD uptake from different formulations. After oral administration of 14·7 ng TCDD using 50% ethanol as vehicle, 36·7% of the total dose was found in the liver after 24 hr. When the compound was administered in a mixture with soil particles, adsorption occurred and only about half of this amount was found in the liver. The liver level also decreased with increasing duration of contact between the soil and the dioxin. Adsorption onto activated carbon almost completely prevented uptake of the compound. Similar effects were observed after dermal application of TCDD in the various formulations. The highest liver content, 14·8% of the dose, was found after contact of the pure compound with the skin surface. The inhibiting effects of soil and activated carbon were even more pronounced. After incorporation of the dioxin into vaseline (a lipophilic ointment), 1·4% of the dose was found in the liver, whereas, after incorporation into polyethylene glycol 1500 (a hydrophilic ointment) containing 15% water, 14·1% was found in the liver. The potency of TCDD (applied in similar formations) to produce chloracne in the rabbit ear was tested. Threshold levels for the induction of lesions were between 1 μg for the pure compound and 160 μg when the compound was adsorbed onto charcoal.

Mechanism of the carcinogenic action of benzene: irreversible binding to rat liver DNA.

Introduction It has been established that exposure of animals and men to benzene (see Ref. 1 for a recent review on benzene toxicity) can result in darnage to the haematopoietic system and a relationship between such exposure and the development of leukemia is suggested by many case reports [2]. Since a common feature of chemical carcinogens is their interaction with biological macromolecules [ 3] , most probably a covalent binding of a reactive metabolite to DN A, and since the carcinogenicity of benzene to animals has not yet been unequivocally proved, we thought it necessary to examine the interaction of benzene with DNA. We have exposed adult male rats to radioactive benzene (tritium or carbon-14 label) in a closed inhalation chamber and were able to show for the first time a covalent binding of a benzene metabolite to DN A in vivo. The liver was chosen as a model system since it is the main organ for the metabolism of foreign compounds containing all the enzymes necessary for an activation and since this organ provides ample DN A for the determination of low specific radioactivity.

The Effect of Pregnancy on the Pharmacokinetics of Caffeine

Individual variation in the half-life of caffeine in the body was measured by HPLC analysis of saliva samples. The mean for adult males and non-pregnant females was 3.4 h (range 2-5 h, n = 25), and 8.3 h (range 3-16 h, n = 57) for pregnant women. After delivery, in most cases the values returned to normal within one month. The individual values could not be correlated with age, weight or consumption of coffee. Women drinking large quantities of coffee should be aware of the side effects of coffee during pregnancy, as they may occur at a lower rate of consumption than in the non-pregnant state.

SACCHARIN DOES NOT BIND TO DNA OF LIVER OR BLADDER IN THE RAT

Introduction Saccharin was found to induce bladder tumours in male rats of the first and the second generation after life-long feeding of a diet containing 5% saccharin [1]. On the other band, with lower doses, and in epidemiological sturlies on the human consumption as sweetening agent there is no clear evidence for a carcinogenic activity despite the long and widespread use [ 2] . This controversy prompted us to investigate the interaction of saccharin with DNA in an intact mammalian organism. Most of the known chemical carcinogens undergo a covalent binding to DNA [3], and the resulting darnage can lead to a mutation. Saccharin has not been found to be mutagenic [ 4,5] and the present study shows that it does not undergo a covalent binding to DNA of the liver or the bladder of male rats either. The tumor induction is therefore probably due to a secondary darnage to the bladder.

Structure Elucidation of Mammalian TCDD-Metabolites

Biotransformation products of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) excreted in dog and rat bile were isolated and examined by combined gas chromatography-mass spectrometry (GC-MS). In the dog, hydroxylation of the TCDD molecule at the lateral position with shift of a chlorine atom to the peri-position and chlorine displacement were found to be the main routes of metabolism. The major metabolite formed was 2-hydroxy-l,3,7,8-tetrachlorodibenzo- p-dioxin. Dihydroxy-trichlorodibenzo-p-dioxins were also identified as well as metabolites formed via cleavage of one or both ether bonds. In the rat, only one metabolite has been characterized so far. It was tentatively identified as a tetrachlorodihydroxy-diphenyl ether. At least one additional metabolite was present which has not yet been investigated. A preliminary metabolic breakdown scheme of TCDD is presented.

Subchronic toxicity of some chlorinated dibenzofurans (PCDFs) and a mixture of PCDFs and chlorinated dibenzodioxins (PCDDs) in rats

Abstract Groups of 6 male and 6 female rats were maintained for 13 weeks on diets containing 12378-PeCDF (2, 20 and 200 μg/kg), 12348-PeCDF (600 and 6000 μg/kg), 123678-HxCDF (2, 20 and 200 μg/kg) and 2,3,7,8-TCDD (2 μg/kg). In addition, a mixture of 23478-PeCDF, 12378-PeCDD, 123678-HxCDF and 2378-TCDD was administered in the diet (20, 10, 10 and 2 μg/kg, respectively, and tenfold diluted). The parameters investigated included body weight development, food consumption, terminal organ weights, hematology and blood chemistry. Tissues were also examined microscopically. The expected toxic syndrome was observed with the toxic isomers, but dosage required to produce the same degree of lesions was quite different. The toxic potency of the isomers relative to TCDD was estimated as follows: (TCDD: 1); 12378-PeCDF: 0.01; 123678-HxCDF: 0.1; 12348-PeCDF:

Pyrrolizidine alkaloids from Symphytum officinale L. and their percutaneous absorption in rats.

An analysis of a commercial sample of Symphyti radix originating from Poland with a total alkaloid content of 0.07% revealed the presence of 7 pyrrolizidine alkaloid-N-oxides: 7-acetyl intermedine, 7-acetyl lycopsamine as the main constituents and lycopsamine, intermedine, symphytine and traces of 2 further not yet identified alkaloids. The percutaneous absorption of these alkaloids was investigated in rats, using a crude alcoholic extract of the plant corresponding to a dose of 194 mg alkaloid-N-oxides/kg b.wt. The excretion of N-oxides in the urine during 2 days was in the range of 0.1–0.4% of the dose. The dermally absorbed N-oxides are not or only to a small extent converted to the free alkaloids in the organism. The oral application led to a 20–50 times higher excretion of N-oxides and free alkaloids in the urine.

Zur Biosynthese des Cantharidins. I

In contrast to the female, the adult males ofLytta vesicatoria (Coleopt. Meloidae) produced radioactive cantharidine on injection with14C-1-acetate and14C-2-mevalonate solutions. A partial degradation of the cantharidine showed that in the acetate experiment approximately ⅔ of the activity occurred at C atoms 2 + 3 whereas with mevalonate approximately ⅛ of the activity was at C atoms 8 + 9 and ⅙ at C atoms 10 + 11. These results show that cantharidine is not formed by a tail to tail linkage of 2 isoprene units.

The metabolism of some pentachlorodibenzofurans in the rat

Three pentachlorodibenzofurans (23478-, 12378- and 12348-penta-CDF) were prepared by isomer-specific syntheses and administered to bile duct-cannulated rats in single oral doses. All three compounds were metabolized and metabolites excreted in the bile. Metabolites were identified by g.l.c.-mass spectrometry after clean-up and methylation of bile samples. Phenolic metabolites (identified as methyl ether derivatives) were formed from all three penta-CDFs by aromatic hydroxylation or by hydrolytic dechlorination. Cleavage of the ether bond with formation of a biphenyl derivative was observed with 23478-penta-CDF; from this compound small amounts of a sulphur-containing metabolite were also formed. All three penta-CDFs followed a common metabolic pathway but differed in the distribution of the metabolites. 12348-CDF was biotransformed more efficiently than the two other isomers. Unmetabolized penta-CDFs were also excreted in the bile.