D. H. Hutson

Genetic toxicology testing of 41 industrial chemicals.

41 compounds or mixtures of diverse structure and application have been tested for genotoxic activity. The materials were tested in bacterial mutation assays, in Saccharomyces cerevisiae JD1 for mitotic gene conversion and in a cultured rat-liver cell line for structural chromosome damage. 11 compounds were bacterial mutagens, 4 induced mitotic gene conversion in yeast and 5 were positive in the chromosome assay. 5 of the materials were positive in bacteria only and 2 compounds induced chromosome damage in cultured cells in the absence of mutation in bacteria or gene conversion in yeast. The materials were tested over a 5-year period and the performance and evolution of the 3 assays during this time is evaluated. The results are considered in relation to the structure of the chemicals and the genotoxicity of related compounds.

Glutathione conjugation in the detoxication of (Z)-1,3-dichloropropene (a component of the nematocide D-D) in the rat

1. (Z)-1,3-Dichloro[2-14C]propene([14C](Z)-DCP) when dosed orally to rats gave 82-84% of the radioactivity in the urine 24 h after treatment. Most of this 14C (92%) was present as N-acetyl-S-((Z)-3-chloroprop-2-enyl)cysteine ((Z)-DCP mercapturic acid).2. When (Z)-DCP was incubated with glutathione and rat liver cytosol (containing glutathione S-alkyl transferase), very rapid loss of (Z)-DCP was observed. The product of this reaction was S-[(Z)-3-chloroprop-2-enyl)]glutathione.

The Metabolic Fate of [Vinyl-I-14C]Dichlorvos in the Rat after Oral and Inhalation Exposure

Abstract1. [Vinyl-1-14C]Dichlorvos is rapidly metabolized when administered orally to the rat, the major metabolite being [14C]carbon dioxide.2. Much of the administered radioactivity is incorporated into the pathways of intermediary metabolism and thus the residual radioactivity associated with the carcass four days after the treatment is relatively high. Most of the radioactivity retained in the livers of treated animals has been identified as [14C] glycine and [14C]serine, incorporated into liver protein. It is probable that the amino acids were synthesized via dichlorvos, dichloroacetaldehyde and glyoxylate.3. At least nine radioactive metabolites were found in urine; those identified were hippuric acid (8.3% of urinary radioactivity); desmethyldichlorvos (10.9%), dichloroethanol glucuronide (27%) and urea (3.1%).4. The rapid detoxification of dichlorvos can be attributed to hydrolytic and demethylation reactions, leading to dichloroacetaldehyde, which is then partly reduced to dichloroethanol and exc...

Xenobiotic triglyceride formation

1. When 3-phenoxy[14C]benzoic acid was dosed orally (0.76 mg/kg) to rats, 1--3% of the administered radioactivity was found in the skin four days after dosing. Approximately 90% of this residue was unchanged 3-phenoxybenzoate, 10% was a neutral compound. 2. The residue in the skins of rats dosed with 193 mg of 3-phenoxybenzoic acid over 7 days (c. 100 mg/kg per day) contained 40% 3-phenoxybenzoate and 60% neutral metabolites. 3. The components were separated and purified by gel permeation, absorption and t.l.c. and analysed by mass spectrometry. 4. 2- and 3-(3-Phenoxybenzoyl)dipalmitins were major components of the neutral metabolite.

The distribution of dichlorvos in the tissues of mammals after its inhalation or intravenous administration

Abstract No dichlorovos could be detected in the blood of rats, mice, and humans after exposure to atmospheric concentrations of dichlorvos up to 17 times that normally attained for domestic insect control. Exposure of rats to 10 μg/liter (250 times normal exposure) for 4 hr was required before dichlorvos was found present; it was then measurable only in the kidneys of the animals. At about 90 μg/liter (2000 times normal exposure) dichlorvos could be detected in most tissues of the rat. The latter dichlorvos concentration is slightly more than 60% of full saturation of air at ambient conditions. The half-life of dichlorvos in the kidneys of male rats exposed to approximately 50 μg/liter for 4 hr was 13.5 min, indicating rapid degradation. Dichlorvos administered iv to rats was rapidly distributed, as it was following inhalation exposure. When mice were exposed to the high atmospheric concentrations of dichlorvos, the compound could be detected in most of the tissues examined, but male mouse kidneys contained only one-tenth of that found in male rat kidneys. In vitro, addition of dichlorvos to blood of rats, rabbits and humans similarly revealed a rapid degradation, which was catalyzed by enzymes in the plasma.

Elimination and Accumulation of the Rodenticide Flocoumafen in Rats Following Repeated Oral Administration

1. Following multiple oral administration of 14C-flocoumafen to rats at 0.02 and 0.1 mg/kg per week, appreciable cellular accumulation was seen in the liver. 2. Residues in the liver increased with dose throughout the duration of the experiment (14 weeks) at the low dose, but reached a plateau after 4 weeks at the high dose. The major component was unchanged flocoumafen together with a minor polar metabolite seen also in faeces. 3. The data suggest the presence in rat liver of a saturable high-affinity binding site for flocoumafen and a second binding site of lower affinity. 4. Lethal anticoagulant action occurs only when the binding sites have become saturated. 5. A range of haematological and clinical chemistry measurements failed to predict the onset of anticoagulant toxicity seen in the high dose treatment group. 6. Flocoumafen was not extensively metabolised; at the low dose, approximately 30% of the cumulative administered dose was eliminated in the faeces within 3 days of each dosing, mainly as unchanged rodenticide. At the high dose, this value ranged from 18% after the first dose to 59% after the tenth dose. 7. Two more polar metabolites and a lipophilic compound were minor products in faeces. Amounts of the polar products increased with cumulative dosage received. The urinary route of elimination was a very minor one (less than 1.6%) at both doses.

The Metabolism of [14C-Methyl]Dichlorvos in the Rat and the Mouse

1. [14C-Methyl]-labelled dichlorvos (2,2-dichlorovinyl dimethyl phosphate) was administered orally to rats and mice.2. Excretion of radioactivity was rapid and similar in both species. The major routes of excretion of radioactivity were the urine (58.8–64.6%) and expired carbon dioxide (14.4–18.5%).3. Dimethyl phosphate was the major metabolite in both species, indicating that hydrolysis was an important mechanism of detoxication.4. Demethylation also represented an important route of detoxication. The presence of S-methylcysteine, S-methylcysteine S-oxide and methyl mercapturic acid as minor urinary metabolites indicated that glutathione alkyl transferase action was responsible for at least part of the dealkylation. Hydrolysis and dealkylation may be equally important in the detoxication of dichlorvos.

Metabolism of the epoxy resin component 2,2-bis[4-(2,3-epoxypropoxy)phenyl]propane, the diglycidyl ether of bisphenol a (DGEBPA) in the mouse.; Part II. Identification of metabolites in urine and faeces following a single oral dose of 14C-DGEBPA

1. The major metabolic transformation of orally ingested 14C-DGEBPA is by hydrolytic ring-opening of the two epoxide rings to form diols. This metabolite (the bis-diol of DGEBPA) is excreted in both free and conjugated forms and is further metabolized to various carboxylic acids, including two containing a methylsulphonyl moiety. 2. The product of oxidative dealkylation either of DGEBPA (with concomitant formation of glycidaldehyde) or of the bis-diol of DGEBPA (with concomitant formation of glyceraldehyde) is excreted in both free and conjugated forms in amounts representing 5% of the dose. 3. The high activity of epoxide hydratase towards DGEBPA suggests that glyceraldehyde and not glycidaldehyde is formed in vivo. 4. Hepatic epoxide hydratase activity towards DGEBPA measured in vitro decreased in the order rabbit greater than mouse greater than rat. 5. Two discrete epoxide hydratases are present in large amounts in the mouse. One is membrane-bound in the liver microsomal fraction and the other is a soluble" enzyme located in the liver cytosol. This cytosolic enzyme was present in only very small amounts in the rat.

The Metabolism of Isopropyl Oxitol in Rat and Dog

1. An intraperitoneal dose of [14C]isopropyl Oxitol is rapidly metabolized in the rat.2. The major routes of excretion of radioactivity are the urine (73% dose) and in the expired air as [14C]carbon dioxide (14%).3. The major urinary metabolites were characterized as isopropoxyacetic acid (30% of the urinary radioactivity), N-isopropoxyacetyl glycine (46%) and ethanediol (13%).4. The metabolism of the compound in the dog is similar to that in the rat.

Metabolism of the epoxy resin component 2,2-bis[4-(2,3-epoxypropoxy)phenyl]propane, the diglycidyl ether of bisphenol a (DGEBPA) in the mouse.; Part I. A comparison of the fate of a single dermal application and of a single oral dose of 14C-DGEBPA

1. 14C-DGEBPA dermally applied to mice was only slowly eliminated in the feces (20% dose) and urine (3%), as a mixture of metabolites, over three days. Most of the applied radioactivity (66% dose) was extracted from the application area and its covering foil. 2. When 14C-DGEBPA was given orally to mice it was rapidly excreted; 80% of the administered 14C was eliminated in the feces and 11% in the urine 0-3 days after a single oral dose. 3. The urinary faecal metabolite profiles derived from dermal application and oral dosing were essentially similar.