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Biomedical subjects

A S Wright

Publications and source records attributed to A S Wright.

At least 37 records · Page 2Linked to original sources
PubMed1988

Prospective detection and assessment of genotoxic hazards: a critical appreciation of the contribution of L. Ehrenberg.

Advances in our understanding of the mechanisms of chemical carcinogenesis are now being applied to improve the quality of prospective risk assessment. The contribution of Ehrenberg and his colleagues (at the University of Stockholm) probably represents the most comprehensive application of mechanistic knowledge to this field during the past 20 years. The strategic approach developed by the Swedish group was based on the identification of differences between man and experimental risk models in factors that determine the relationships between exposure and biological response and the development of methods to compensate for these differences. Many of the critical stages in chemical carcinogenesis and the cellular determinants of these stages have now been identified. As a first step in seeking to improve risk assessment, Ehrenberg introduced the target dose concept, in which the doses of carcinogens penetrating to the cellular target (DNA) are determined. This approach provides an improved basis for determining exposures to carcinogenic agents and also for compensating for species differences in factors such as metabolism that determine the relationships between exposure dose and the dose at the critical target. The target dose concept is now widely accepted and has led to the development of new biomedical monitoring techniques, based, for example, on the measurement of haemoglobin adducts, which are now being applied to detect and identify genotoxic hazards. The introduction of the target dose concept has led to significant improvements in the quality of prospective risk assessment. Further improvements necessitate procedures to compensate for differences between man and prospective risk models in factors that determine subsequent stages of the carcinogenic process. Ehrenberg has proposed that the rad-equivalence approach may be of value in this respect. Its application has accurately predicted the incidence of leukaemias in occupational cohorts which had exposures to ethylene oxide in common. The possible general applicability of this approach is discussed.

Carcinogenicity Tests↗
PubMed1988

An immunoassay for monitoring human exposure to ethylene oxide.

A novel immunochemical approach has been developed to monitor human exposures to ethylene oxide (EO). The method exploits the interaction of EO with the amino function of the N-terminal valine residue of the alpha-chain of human haemoglobin (Hb). Antibodies were raised against the adducted valine in the form of the N-terminal tryptic heptapeptide and have been used to develop a sensitive radioimmunoassay (RIA) for the adducted heptapeptide. This method has been fully validated against a gas chromatography-mass spectrometry (GC-MS) method and has been applied to the monitoring of EO exposure in a group of sterilization workers.

Environmental Monitoring↗
PubMed1988

Human organ culture techniques for the detection and evaluation of genotoxic agents.

In order to obtain information on the genotoxic metabolism of carcinogens in human skin in vivo, model in-vitro systems have been developed to mimic in-vivo metabolism qualitatively. Direct labelling (3H and 14C) and 32P-postlabelling analyses of benzo[alpha]pyrene (BP)-DNA adducts in human skin explants, CD1 mouse explants and CD1 mouse skin in vivo have thus allowed comparisons of the genotoxic metabolism of BP in mouse and human skin.

Animals↗
PubMed1987

Microbial mutagenicity studies with (Z)-1,3-dichloropropene.

This study has confirmed that the direct mutagenicity previously observed when S. typhimurium TA100 was treated with (Z)-1,3-dichloropropene (DCP) was in fact due to trace impurities. These impurities result from autoxidation of (Z)-1,3-DCP and have now been identified. Both (Z)- and (E)-2-chloro-3-(chloromethyl)oxiranes (DCP oxides) were identified as significant products during this autoxidation. The mutagenic impurities formed by autoxidation were completely removed by adsorption chromatography on silicic acid. (Z)-1,3-DCP purified in this way had no direct-acting mutagenicity towards S. typhimurium TA100. However, (Z)-1,3-DCP undergoes mono-oxygenase-catalysed conversion into bacterial mutagens in the presence of S9 fraction or washed microsomes from rat liver. The glutathione-linked conjugation systems of mammalian tissues provided efficient protection against this indirect mutagenic action. However, the low concentration of glutathione in standard bacterial mutagenicity assays limits the glutathione S-alkyl transferase-catalysed detoxification of (Z)-1,3-DCP and its primary bioactivation product(s). When the concentration of glutathione was adjusted to the normal physiological concentration, the mono-oxygenase-dependent mutagenic action of (Z)-1,3-DCP was virtually eliminated. These results therefore are consistent with the view that bacterial mutation assays are only qualitative indicators of potential mammalian genotoxicity.

Allyl Compounds↗
PubMed1986

Comparison of hydrocarbon-DNA adducts formed in mouse skin in vivo and in organ culture in vitro following treatment with benzo[a]pyrene.

Species differences in the metabolism of toxic chemicals can confound the extrapolation of experimentally determined risk data to man. However, it is often difficult to obtain reliable information on human metabolism, particularly of genotoxic agents. In this study, comparisons of chromatographic profiles of DNA adducts formed in vivo and in vitro have been applied to develop and validate in vitro systems as models for the bioactivation of precursor genotoxic agents in vivo. Reversed phase h.p.l.c. analysis showed that the DNA adducts obtained from the skin (epidermal and dermal) of mice (CD1, CF1 and athymic nude mice) treated topically with [3H] or [14C]benzo[a]pyrene (BP) were qualitatively very similar to those formed in mouse (CD1) skin explant cultures. In each case the principal product was the N2-deoxyguanosine adduct, (+)-N2-(7R,8S,9R-trihydroxy-7,8,9,10-tetrahydrobenzo[a]-pyrene-10S- yl)-2'-deoxyguanosine, derived from (+)-7R,8S-dihydroxy-9R,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene. The use of [14C]BP has provided an accurate reference profile of BP-DNA adducts formed in mouse skin in vivo. These findings show that mouse skin explants maintained in organ culture effectively mimic the bioactivation of BP and the binding of the products to the DNA of mouse skin in vivo. Such culture techniques are readily transferable to human skin thus permitting the indirect determination of bioactivation pathways in human skin in vivo for comparison with those of mouse skin and other models used to determine the human hazard. In principle, this approach to validate in vitro bioactivation systems may be applied to all human tissues.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1985

Genotoxicity studies with mineral oils; effects of oils on the microbial mutagenicity of precursor mutagens and genotoxic metabolites.

In vitro genotoxicity assays are extensively used to predict carcinogenic activity in vivo. The standard microbial mutagenicity assays however often fail to yield positive results with mineral oils which are carcinogenic to mice in long-term skin-cancer studies. A comprehensive programme of studies has therefore investigated the basis of this apparently anomalous behaviour. This investigation has addressed the possible effects of oils on the bioactivation of precursor mutagens and the disposition of mutagenic metabolites by studying the microbial mutagenicity of selected precursor mutagens (benzo[a]pyrene, benzo[a]anthracene, 2-aminoanthracene and 2-naphthylamine) and intrinsically reactive mutagens [+/- )-benzo[a]pyrene-4,5-oxide and (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene) in the presence and absence of mineral oils. Notably the mutagenicity associated with the deliberate additions of these mutagens or precursor mutagens to oils was readily detected by the microbial assays. The mutagenicity of only one of the precursor mutagens, benzo[a]pyrene, was significantly reduced by the oils, and then only in the standard plate-incorporation assay. Interestingly the degree of suppression appeared to be related to the polycyclic aromatic hydrocarbon content of the oils. In the case of 2-aminoanthracene large enhancements in its mutagenicity were observed in the presence of oils. These latter findings appear to be due to effects of oils on the bioactivation of precursor mutagens rather than on the disposition of their bioactivation products. The mutagenicity of intrinsically reactive mutagens, of a type generated by bioactivation of polycyclic aromatic hydrocarbons, was not significantly reduced in the presence of mineral oils. This indicates that it is unlikely that components in oils trap or facilitate the deactivation of ultimate mutagens whether these pre-exist in the oil or are formed from precursors by bioactivation in the in vitro test system. Viewed overall these results suggest that mineral oils judged to be carcinogenic on the basis of in vivo studies in mouse skin may possess only very weak genotoxic potential. While this potential is likely to be a prerequisite for carcinogenic action, the current results cause attention to be focussed on other factors, e.g. promotion, as potentially important determinants of the carcinogenic potencies of mineral oils in mouse skin.

2-Naphthylamine↗
PubMed1985

Cytogenetic, immunological, and haematological effects in workers in an ethylene oxide manufacturing plant.

Samples of blood were collected from a group of plant workers engaged in the manufacture of ethylene oxide (EO) for periods of up to 14 years and also from a group of control personnel matched by age and smoking habits. Peripheral blood lymphocytes were cultured for cytogenetic analysis. Selected immune and haematological parameters were also investigated. The results of these studies showed no statistically significant difference between the group of plant workers and the control group in respect of any of the biological parameters investigated in this study. Nevertheless, duration of employment in EO manufacturing was positively correlated (p less than 0.05) with the frequency of chromosome breaks and with the percentage of neutrophils in a differential white blood cell count and negatively correlated (p less than 0.05) with the percentage of lymphocytes. As the values of these parameters remained within the normal limits of control populations, the correlations were considered to have no significance for health. Atmospheric concentrations of EO were determined using personnel air samplers and were generally below the detection limit (less than 0.05 ppm) during stable plant operations, although transient concentrations of up to 8 ppm were occasionally recorded. The amount of alkylation (2-hydroxyethyl groups) of the Nt atom of histidinyl residues in haemoglobin was also measured in an attempt to gauge recent individual exposures to EO. Variable but, in most instances, readily measurable amounts of Nt-(2'-hydroxyethyl)-L-histidine (Nt represents the N3 atom of histidine) were found in the haemoglobin of plant workers and in the control group who had not knowingly been exposed to an exogenous source of EO. There was no statistically significant difference between the results obtained in the control group and in the group of plant workers.

Adult↗
PubMed1984

The protective action of glutathione on the microbial mutagenicity of the Z- and E-isomers of 1,3-dichloropropene.

The Z(cis)- and E(trans)-isomers of 1,3-dichloropropene (DCP), in confirmation of previous reports, caused dose-dependent increases in the numbers of reverse mutations in Salmonella typhimurium TA100 in the presence and absence of a 9000 X g supernatant fraction (S9) from the livers of Aroclor-treated rats. The relevance of these findings to mammals is uncertain, not least because of major differences in the metabolism of the DCPs in the microbial assay systems and in vivo. For example, (Z)-DCP is efficiently detoxified in mammals by the operation of a glutathione (GSH)-dependent S-alkyl transferase. It is possible that such detoxification could proceed only very slowly in the microbial assays because the concentrations of GSH could be severely rate-limiting even in those assays fortified by the addition of S9. The results obtained in the current study demonstrate a dramatic reduction in the microbial mutagenicity of both (Z)- and (E)-DCP when the concentration of GSH in the microbial assays was adjusted to a normal physiological concentration (5 mM). However, this protective action of GSH was at least as effective in the absence of S9 as in its presence, suggesting that it was not mediated by mammalian GSH transferase. There appears to be little or no GSH alkyl or aryl transferase in the cytosol of S. typhimurium TA100, but intracellular GSH is present at a concentration similar to that found in mammalian cells. Since the uncatalysed reaction between the DCPs and glutathione is relatively slow, the effect is not due simply to their destruction by GSH. It is possible that a physiological concentration of extracellular GSH maintains the intracellular GSH in a reduced form in which its nucleophilic thiol group competes effectively with the nucleophilic centres in the bacterial DNA for the haloalkenes. The current results highlight the efficiency of GSH-linked systems in affording protection against the genotoxic action of the DCPs. It may be presumed that their operation would exert a major limiting effect on the genotoxicity of (Z)- and (E)-DCP in mammals.

Allyl Compounds↗
PubMed1984

Molecular phenotyping of non-transformed and chemically transformed C3H10T1/2 mouse fibroblasts.

A systematic molecular phenotyping approach based on two-dimensional gel electrophoresis is being applied in an attempt to identify protein changes associated with malignant transformation. Using the C3H10T1/2 mouse cell line, two-dimensional polypeptide maps of the non-transformed cell line, several chemically transformed lines and a tumour cell line were compared. Although there is a large degree of similarity between the protein profiles of all cell lines, clear differences are evident. Initial results are consistent with the view that many of the protein changes are incidental to malignant transformation. Changes induced by 3-methylcholanthrene are retained after transplantation of the cells into nude mice.

Animals↗
PubMed1981

Effects of dieldrin, diet, and bedding on enzyme function and tumor incidence in livers of male CF-1 mice.

The effects of naturally occurring microsomal enzyme inducers on hepatocellular drug-metabolizing enzyme systems and also upon the incidence of "spontaneous" liver tumors in CF-1 mice were investigated, using animals maintained on semisynthetic diet and filter-paper bedding as controls. The administration of dieldrin, a potent microsomal enzyme inducer with tumorigenic properties in livers of CF-1 mice, to some of the experimental treatment groups served as a positive control. Conventional diet and sawdust bedding caused induction of the liver monooxygenase system, although this effect was far less pronounced than that produced by dieldrin. The incidence of liver tumors in mice exposed to conventional diet and sawdust bedding was similar to that seen in the control group. The incidence of liver tumors was significantly increased in dieldrin-treated mice, including those maintained on semisynthetic diet and filter-paper bedding. Both benign and malignant tumors were found in dieldrin-treated mice, the latter type of lesion showing evidence of lung metastasis. These results, together with evidence that dieldrin and its mammalian metabolites possess neither genotoxic activity nor potential, are consistent with the concept that dieldrin exacerbates or facilitates the expression of a preexisting oncogenic factor which is genetically linked and possibly viral in origin.

Animals↗
PubMed1981

Alkylation of DNA by organophosphorus pesticides.

Methods for the detection of in vivo alkylation of nucleic acids are discussed. Alkylation of mammalian DNA at N-7 of guanine provides the most sensitive and least equivocal evidence of methylation by an exogenous chemical or its metabolite. No 7-methylguanine was detected in the combined DNA from the lungs, livers, hearts, brains, kidneys, testes and spleens from 20 rats exposed to 0.064 micrograms l-1 of [Me-14C]-dichlorvos at a specific radioactivity of 113 Ci mol-1 for 12 hrs.

Alkylating Agents↗
PubMed1980

The effect of hepatic microsomal monooxygenase induction on the metabolism and toxicity of the organophosphorus insecticide chlorfenvinphos.

The induction of rat liver microsomal monooxygenase by pretreatment of rats with dieldrin affords a 10-fold protection against the acute toxic effects of the organophosphorus insecticide, chlorfenvinphos. Metabolism studies were carried out to confirm that the protection was due to an enhanced rate of detoxification (via oxidative deethylation). At low doses of chlorfenvinphos (2.5 mg . kg-1), dieldrin pretreatment caused minimal changes in the metabolic profiles. However, at a higher dose (13.2 mg . kg-1), giving clinical signs of intoxication in the control animals, the dieldrin pretreated rats produced 5 times more deethylchlorofenvinphos than did the control animals. The results support the conclusion that the effect of enzyme induction on the metabolism of substrates of that enzyme are dose-dependent. Alterations in metabolism, therefore, are not an automatic consequence of enzyme induction.

Animals↗