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D E Hathway

Publications and source records attributed to D E Hathway.

At least 19 recordsLinked to original sources
PubMed2000

Toxic action/toxicity.

Some six or so physiological systems, essential to normal mammalian life, are involved in poisoning; an intoxication that causes severe injury to any one of them could be life threatening. Reversible chemical reactions showing Scatchard-type binding are exemplified by CO, CN- and cyclodiene neurotoxin insecticide intoxications, and by antigen-antibody complex formation. Haemoglobin (Hb) molecular biology accounts for the allosteric co-operativity and other characteristics of CO poisoning, CN- acts as a powerful cytochrome oxidase inhibitor, and antigen binding in a deep antibody cleft between two domains equipped with epitopes for antigen-binding groups explains hapten-specific immune reactions. Covalent chemical reactions with second-order (SN2) kinetics characterize Hg and Cd poisonings, the reactions of organophosphates and phosphonates with acetylcholinesterase and neurotoxic esterase and the reaction sequence whereby Paraquat accepts electrons and generates superoxide under aerobic conditions. Indirect carcinogens require cytochrome P450 activation to form DNA adducts in target-organ DNA and cause cancer, but a battery of detoxifying enzymes clustered with the P450 system must be overcome. Thus, S-metabolism competes ineffectively with target DNA for reactive vinyl chloride (VC) metabolites, epoxide hydrolase is important to the metabolism and carcinogenicity of alfatoxins and polycyclic aromatic hydrocarbons (benzo[a]pyrene, etc.), and the non-toxic 2-naphthylhydroxylamine N-glucuronide acts as a transport form in 2-naphthylamine bladder cancer. VC liver-cancer pathogenesis is explicable in terms of the presence of the glutathione S-transferase detoxifying system in hepatocytes and its absence from the fibroblastic elements, and of the VC concentrations reaching the liver by different administrative routes. In VC carcinogenicity, chemical reactions give imidazo-cyclization products with nucleoside residues of target DNA, and in benzene leukaemia, Z,Z-muconaldehyde forms cyclic products containing a pyrrole residue linked to purine. Increased HbCO concentrations reduce the O2-carrying capacity of the blood, and the changed shape of the O2-Hb dissociation curve parallels disturbance in O2 unloading. CN- acts on electron transport and paralyses respiration. In telodrin poisoning, preconvulsive glutamine formation abstracts tricarboxylic acid intermediates incommensurately with normal cerebral respiration. Antigen-antibody complexing depletes the antibody titre, available against infection. At high doses of Cd, Cd-thionein filtered through the kidneys is reabsorbed and tubular lesions produced. Some organophosphate insecticides promote irreversible acetylcholinesterase phosphorylation and blockade nerve function, and others react with neurotoxic esterase to cause delayed neuropathy. The evidence for Paraquat pulmonary poisoning suggests a radical mechanism involving three interrelated cyclic reaction stages. The action of N- and O8 (O substituent in 6-position of the purine) demethylases explains deletion mechanisms for DNA-alkyl adducts. DNA-directed synthesis in the presence of ultimate carcinogens provides for an estimation of misincorporations, which implicate the same transversions as those found by direct mutagenicity testing. Chemical carcinogens recognize tissue-sensitive cells and modify their heritable genetic complement. Oncoproteins encoded by activated oncogenes signal the transformation of normal cells into cancer cells. The importance of the H-ras oncogene and p53 tumour-suppressor gene is stressed. Antidotal action is analysed; for example, parenteral glutamine administration to telodrin-intoxicated rats restores the depleted cerebral glutamate level and prevents seizures. Glutamate acts as anticonvulsant in petit mal epilepsy. In general, therefore, the reaction of the toxicant-related substance with the relevant target-tissue macromolecule accounts for the biochemical/biological events at a cellular level a

Animals↗
PubMed1981

The induction of errors during in vitro DNA synthesis following chloroacetaldehyde-treatment of poly(dA-dT) and poly(dC-dG) templates.

Chloroacetaldehyde, a rearranged metabolic product of the human carcinogen vinyl chloride, reacts with the DNA-like polymers poly(dA-dT) and poly(dC-dG) to form etheno-adducts of the adenine and cytosine bases. These treated polymers, when used as templates for E. coli DNA polymerase I in an in vitro assay, show a decreased ability to direct DNA synthesis. At the same time, increased relative levels of non-complementary nucleotides are incorporated. With the poly(dA-dT) templates 1 dGMP residue is incorporated for every approx 60 ethenoadenine residues present whilst no increased misincorporation of dCMP was detected. With the poly(dC-dG) templates 1 misincorporation of dAMP or dTMP occurred in the presence of approx 30 and 80 ethenocytosine residues respectively. A nearest neighbour analysis shows that with the modified poly(dC-dG) templates the majority of the errors were incorporated opposite cytosine (or modified cytosine) bases.

Acetaldehyde↗
PubMed1980

Consideration of the evidence for mechanisms of 1,1,2-trichloroethylene metabolism, including new identification of its dichloroacetic acid and trichloroacetic acid metabolites in mice.

Data derived from studies with vinylidene chloride (1,1-dichloroethylene)and 1,1,2-trichloroethylene suggest that similar mutagenic and tumorogenic properties in mice may be attributable to rearrangement of the 2 haloalkene-derived haloepoxides, respectively, into chloroacetyl chloride and dichloroacetyl chloride. On the other hand, the relative harmlessness of 1,1,2-trichloroethylene in rats and man is due to alternative rearrangement of 1,1,2-trichloroethylene oxide into chloral and the further products of its metabolism. The identification in mice of the new 1,1,2-trichloroethylene metabolite, dichloroacetic acid (in addition to trichloroacetic acid) strongly supports this supposition. The small proportion of dichloroacetic acid in relation to the large proportion of trichloroacetic acid in the urine of the treated mice is consistent with a spill-over model that is now tentatively proposed for 1,1,2-trichloroethylene metabolism in these animals.

Acetates↗
PubMed1978

The biological fate of vinylidene chloride in rats.

The main eliminative route for [14C] vinylidene chloride ([14C]DCE) after intragastric, i.v. or i.p. administration to rats is pulmonary; both unchanged DCE and DCE-related CO2 are excreted by that route and other DCE metabolites via the kidneys. Part of the urinary 14C is of biliary origin. After intragastric dosing, the plot of the pulmonary output of unchanged DCE against the logarithm of reciprocal doses in biphasic. Pulmonary elimination of DCE and CO2 and urinary excretion of DCE metabolites after an intragastric dose occupy 3 days. In comparison, 80% of a small i.v. dose is excreted unchanged within 1 h of injection; more than 60% within 5 min. Biotransformation of DCE affords thiodiglycollic acid, and an N-acetyl-S-cysteinyl-acetyl derivative as major urinary metabolites together with substantial amounts of chloroacetic acid, dithioglycollic acid and thioglycolic acid. It is probable that chloroacetic acid, which is a DCE metabolite per se, lies on a main metabolic pathway for DCE, since it affords several metabolites in common with DCE. Furthermore, electrolysis of one molecular proportion of the [14C]thiodiglycollate metabolite from [1(-14)C]DCE or [1(-14C]chloroacetic acid gives 1 equivalent of 14CO2, and this evidence is consistent with the transformation of DCE into chloroacetic acid by a mechanism involving the migration of one Cl atom and the loss of the other one. CO2 (and hence urea) may be produced through the action of epoxide hydratase on 1,1-dichloroethylene oxide or by a minor oxidative pathway for chloroacetic acid. The N-acetyl-S-cysteinyl-acetyl derivative is probably formed via the reaction of 1,1-dichloroethylene oxide and glutathione S-epoxide transferase.

Acetates↗
PubMed1978

Interactions of vinyl chloride with rat-liver DNA in vivo.

9beta-D-2'-Deoxyribofuranosyl-imidazo-[2,1-i]purine ("etheno-deoxyadenosine") and 1beta-D-2'-deoxyribofuranosyl-1,2-dihydro-2-oxo-imidazo-[1,2-c]pyrimidine ("etheno-deoxycytidine") are identified in the enzyme hydrolysates obtained (i) from calf-thymus DNA which had been modified by chemical reaction with chloroacetaldehyde and (ii) from liver DNA prepared from rats which had been exposed orally to vinyl chloride in their drinking water (250 ppm) for approx. 2 years. Thus, vinyl chloride-derived chloroethylene oxide and/or chloroacetaldehyde behaves as a bifunctional alkylating agent towards deoxyadenosine and deoxycytidine residues of DNA. The separation of deoxyribonucleosides and the two etheno-deoxyribosyl-nucleosides by liquid chromatography, and the mass spectra of etheno-deoxyadenosine and etheno-deoxycytidine and of their O-bis-(trimethylsilyl) derivatives are described. In the animal experiment (ii), the resulting proportion of etheno-deoxyadenosine is small compared with that of etheno-deoxycytidine. Imidazo-[2,1-i]purine (etheno-adenine) is identified: (a) in the supernatant after sedimentation of the modified DNA in the model experiment (i), and (b) in the product resulting from the reaction between chloroacetaldehyde and deoxyadenosine. The effect on the structure of DNA of the imidazo-cyclization of deoxyadenosine and deoxycytidine residues and of the depurination of etheno-deoxyadenosine residues is discussed in relation to vinyl chloride oncogenicity.

Acetaldehyde↗
PubMed1978

Tissue-mediated mutagenicity of vinylidene chloride in Salmonella typhimurium TA1535.

Vinylidene chloride is weakly positive in the Salmonella typhimurium TA1535 test, mediated by kidney and liver post-mitochondrial supernatant (S-9 mix) from normal mice, but strongly positive with the S-9 mix from the induced animals. In the case of mediation by rat tissue, only liver S-9 mix from induced animals affords a significant positive response. These findings agree with the greater availability in treated mice than in rats of reactive vinylidene chloride metabolites, 1,1-dichloroethylene oxide and chloroacetyl chloride [5], and with the vinylidene carcinogeneicity found in mice but not in rats [9]. Exploratory tissue-mediated testing of vinylidene chloride involving liver S-9 mix from marmosets and man suggests a trend in the generation of alkylating metabolites and their reactions with bacterial DNA for these primates which resembles rats more than mice.

Animals↗
PubMed1978

Differences in metabolism of vinylidene chloride between mice and rats.

The present finding that mice metabolize a greater proportion of an oral dose (50 mg/kg) of vinylidence chloride. (1,1 - dichloroethylene, DCE) than rats implies (a) that the efficiency of DCE metabolism follows the known activity of cytochrome P-450 in the organs of these animals, and (b) that, in accordance with the LD(50) values, the real exposure (expressed as the amount of DCE metabolized) is relatively higher for orally dosed mice than rats, and (c) that DCE carcinogenicity would appear to be more likely in mice than rats.Mice metabolize DCE simiarly to rats (Jones and Hathway, 1977) but there are some differences. Thus, qualitatively, treated mice (but not rats) excrete a small amount of N-acetyl-S-(2carboxymethyl)cysteine. Quantitatively, (i) the relative proportions of the N-acetyl-S-(2-cysteinyl acetyl derivative that are formed in mice and rats parallel the activity of liver glutathione-S-epoxide transferase in these rodents, and (ii) there are marked differences in the proportions of DCE metabolites belonging to the chloroacetic acid branch of the metabolic pathway. Furthermore, the previously assumed β-thionase hydrolysis of thiodiglycollic acid (Jones and Hathway, 1977) is now established in vivo, and the possible biogenesis of the N-acetyl-S-cysteinyl acetyl derivative is verified by another tracer study. The conclusion is drawn that the DCE metabolites, 1,1-dichloroethylene oxide and chloroacetyl chloride, may be important to murine DCE carcinogenicity.

Animals↗
PubMed1977

Electrochemical analysis of the carboxy-14C-labelled aliphatic carboxylic acid metabolites resulting from tracer studies.

14C02 output from carboxy-14C-labelled aliphatic carboxylic acids is measured in the micro-scale Kolbe reaction. Irrespective of whether rats were dosed with 1,1-dichloro[1-14C]ethylene or with chloro[1-14C]acetic acid, 1 mol.equiv. of the resulting thio[14C]diglycollic acid yields by electrolysis approx. 0.7 equiv. of 14CO2, which is interpreted in terms of the labelling of one of the carboxylic acid groups of thiodiglycollic acid. This observation provides important evidence concerning thiodiglycollic acid biosynthesis from 1.1-dichloroethylene.

Carbon Dioxide↗
PubMed1977

Fate of methyl methacrylate in rats.

Up to 88% of a single dose of methyl[14C]methacrylate in rats is expired as 14CO2 in 10 days (65% in 2 h), irrespective of the route of administration and of the specific labelling of the propylene residue of the molecule. The implications of this observation, and of the excretion of small amounts of [14C]methylmalonate, [14C]-succinate and probably of [14C]beta-hydroxyisobutyrate and 2-formylpropionate, and of the formation of [14C] normal, physiological metabolites that may be accounted for by anabolism both from 14CO2 and from [14C]acetate emergent from the citric acid cycle, are that the metabolic pathway concerned involves intermediary metabolism and relates to mitochondrial function. Present findings are discussed in relation to the imputations of a report of carcinogenic risk.

Acrylates↗
PubMed1977

Dephenylation of N-phenyl-2-naphthylamine in dogs and its possible oncogenic implications.

N-Dephenylation of N-phenyl-2-naphthylamine (PBNA) is strictly limited in dogs, and a 5 mg/kg dose gives 0-10 microng of urinary 2-naphthylamine (BNA), which does not appear to undergo further metabolism. Neither 2-naphthylhydroxylamine (BNHA) nor 2-amino-1-naphthylsulphate were detected in the urine of treated animals. Urinary output of BNA varies markedly between dogs, and at different times in the same animal. The extent of PBNA N-dephenylation is unaltered by chronic administration. Calculations based on Druckery and Küpfmüller's equation (1948) and present data indicate that, for dogs to form BNA tumours through exposure to a relatively high dose-level of PBNA, the period of daily dosing would occupy, or even exceed, the normal life-span. The carcinogenic risk of PBNA to human subjects is discussed.

2-Naphthylamine↗
PubMed1977

Comparative mammalian metabolism of vinyl chloride and vinylidene chloride in relation to oncogenic potential.

Elucidation of the role of vinyl chloride metabolites in the various reaction sequences which comprise the metabolic pathway, including the interaction of reactive metabolities with some purine and pyrimidine residues of target-organ DNA, provides some explanation for the (oncogenic) properties associated with the original substance. Comparative investigation of the biological fate of vinylidene chloride reveals an agent of low oncogenic potential which is likely to be damaging only under special circumstances, and species differences which suggest that the mouse is more susceptible than the rat towards vinylidene chloride oncogenicity.

Animals↗
PubMed1975

The biological fate in rats of vinyl chloride in relation to its oncogenicity.

The main eliminative route for [14C]vinyl chloride after oral, i.v. or i.p. administration to rats is pulmonary; both unchanged vinyl chloride and vinyl chloride-related CO2 are excreted by that route and the other [14C] metabolites via the kidneys. After intragastric administration, pulmonary output of unchanged vinyl chloride is proportional to the logarithm of reciprocal dose. Excretion patterns after i.v. and i.p. injections are predictable from the characteristics of excretion following oral administration. Pulmonary excretion of unchanged vinyl chloride after oral dosing is complete within 3-4 h, but pulmonary elimination of CO2 and renal excretion of metabolites occupies 3 days. In comparison, 99% of a small i.v. dose is excreted unchanged within 1 h of injection; 80% within 2 min. The rate of elimination of a single oral doses of [14C]vinyl chloride is uninfluenced by up to 60 days' chronic dosing with the unlabelled substance. The distribution volume of vinyl chloride as displayed by whole-animal autoradiography agrees with deductions from excretion data. Small localization of 14C in the para-auricular region of appropriate sections occurs in sectioned tubules, belonging possibly to the Zymbal glands. Biotransformation of vinyl chloride into S-(2-chloroethyl) cysteine and N-acetyl-S-(2-chloroethyl) cysteine occurs through addition of cysteine, and biotransformation into: (i) chloroacetic acid, thiodiglycollic acid and glutamic acid, and (ii) into formaldehyde (methionine, serine), CO2 and urea is explicable in terms of an associative reaction with molecular O2 involving a singlet oxygen bonded transition state in dynamic equilibrium with a cyclic peroxide ground state. There is no evidence for chloroethylene oxide formation. Thiodiglycollic acid is the major metabolite of chloroacetic acid in rats; more than 60% of the dose. The interaction of vinyl chloride and of its primary metabolites with the intermediates of mammalian metabolism is discussed in relation to the oncogenicity of that substance.

Acetates↗