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Biomedical subjects

E Dybing

Publications and source records attributed to E Dybing.

At least 19 recordsLinked to original sources
PubMed1998

Consumption of fatty fish from the Baltic Sea and PCB in whole venous blood, plasma and cord blood from delivering women in the Aland/Turku archipelago.

The present study aimed to assess the role of fish consumption for the body burden of polychlorinated biphenyls (PCBs) in mothers living in the Aland and Turku archipelago in Finland. The overall objective was to investigate whether there exists an appropriate population for a full-scale prospective study on PCB-related developmental effects in infants. Concentrations of the four major PCBs were determined in whole venous blood and cord blood from 30 delivering mothers, of which 20 subjects consumed fatty fish from the Baltic Sea (2.5-12.5 meals per month) and the remaining 10 mothers did not. The concentrations of CB-118, CB-138, CB-153, and CB-180 in cord blood were generally two- to threefold lower than in whole blood from the mothers, but strong correlations were observed between PCBs in the two matrices (r = .67-.80). Neither the venous blood nor cord blood concentrations of PCBs, however, were correlated with stated fish intake. Moreover, the concentration of CB-153 in plasma was only weakly associated with fish intake, and the level of organic mercury in erythrocytes was not correlated with fish intake at all. The present results of CB-153 concentrations in women's blood are lower than those reported in other recent investigations. A reasonable contributing explanation is the rapid decline during the last decades of PCB in Baltic Sea fish, which has resulted in less impact of fish intake on the body burdens of PCB in relatively young women (median 30 yr in the present study) as compared with older females. The relatively low PCB levels in blood taken together with the low number of yearly deliveries in the archipelago population makes it an inappropriate study base for a prospective study of PCB-related health effects in infants.

Adult↗
PubMed1998

Single-strand breaks, cell cycle arrest and apoptosis in HL-60 and LLCPK1 cells exposed to 1,2-dibromo-3-chloropropane.

We investigated 1,2-dibromo-3-chloropropane (DBCP)-induced DNA damage, cell cycle alterations and cell death in two cell lines, the human leukemia HL-60 and the pig kidney LLCPK1, both of which are derived from potential target sites for DBCP-induced toxicity. DBCP (30-300 micromol/L) caused a concentration-dependent increase in the levels of DNA single-strand breaks in both cell lines as well as in cultured human renal proximal tubular cells. After extended DBCP exposure in LLCPK1 cells (100 micromol/L, 30 h), the level of DNA breaks returned almost to control values. Incubation for 48 h showed a clear reduction of growth with DBCP concentrations as low as 10 micromol/L. Flow cytometric analysis showed that DBCP (1-10 micromol/L) exposure for 24 h caused an accumulation of LLCPK1 cells in the G2/M-phase. In HL-60 cells the accumulation in G2/M-phase was less marked, and at higher concentrations the cells accumulated in S-phase. Flow cytometric studies of HL-60 and LLCPK1 cells exposed to 100-500 micromol/L DBCP showed increased number of apoptotic cells/bodies with a lower DNA content than that of the G1 cells. Microscopic studies revealed that there were increased numbers of cells with nuclear condensation and fragmentation, indicating that apoptosis was the dominant mode of death in these cell lines, following exposure to DBCP. The characteristic ladder pattern of apoptotic cells was observed when DNA from DBCP-treated HL-60 cells and LLCPK1 cells was electrophoresed in agarose. The finding that DBCP can cause an accumulation of cells in G2/M-phase and induce apoptosis in vitro may be of importance for the development of DBCP-induced toxicity in vivo.

Animals↗
PubMed1997

DNA damage, gadd153 expression, and cytotoxicity in plateau-phase renal proximal tubular epithelial cells treated with a quinol thioether.

2-Bromo-bis-(glutathion-S-yl)hydroquinone [2-Br-bis-(GSyl)HQ] causes DNA single-strand breaks (SSB), causes growth arrest, induces the expression of gadd153 (a gene inducible by growth arrest and DNA damage), and decreases histone H2B mRNA in log-phase renal proximal tubular epithelial cells (LLC-PK1). Renal epithelial cells in vivo normally exhibit a low mitotic index, therefore experiments in both plateau- and log-phase cells are necessary for a comprehensive understanding of the stress response to 2-Br-bis-(GSyl)HQ. In the present article we demonstrate that not all features of the stress response in log-phase cells are reproduced in plateau-phase cells. Thus, although 2-Br-bis-(GSyl)HQ causes concentration and time-dependent increases in DNA SSB, and increases the expression of gadd153, histone H2B mRNA levels are unaltered in plateau-phase cells. The relationship between reactive oxygen species, DNA damage, gene expression, and cytotoxicity was also investigated. Our findings suggest that (i) 2-Br-bis-(GSyl)HQ-mediated DNA damage in LLC-PK1 cells is mediated by the generation of H2O2; (ii) DNA damage, either directly or indirectly, contributes to cell death; and (iii) DNA damage, either directly or indirectly, provides the initial signal for gadd153 expression. In addition, DNA repair is rapid in LLC-PK1 cells, and the DNA-repair inhibitors 1-beta-D-arabinofuranosylcytosine and hydroxyurea have no effect on the amount of DNA SSB. Although the addition of 3-aminobenzamide following 2-Br-bis-(GSyl)HQ exposure has no effect on the removal of DNA SSB, it causes a slight but significant increase in gadd153 expression and cell viability, indicating that activation of poly(ADP-ribose)polymerase may exacerbate toxicity. Finally, aurintricarboxylic acid did not prevent DNA SSB or cytotoxicity in 2-Br-bis-(GSyl) HQ-treated LLC-PK1 cells, implying that activation of endonucleases does not play a role in these processes.

Animals↗
PubMed1997

[Are environmental chemicals with hormone-like properties a health problem?].

Lately, a hypothesis linking higher frequency of testicular cancer, reduced semen quality and malformation of the male sexual organs with increased embryonic/foetal exposure to oestrogenic chemicals has received wide attention in the media. There are several examples where point-source chemical pollution has been convincingly associated with endocrine-related changes in wildlife. Such changes have also been reproduced in experimental studies. There is very little evidence, however, of such an association in humans. Nevertheless, the findings provide a clear challenge to toxicologists and epidemiologists in order to elucidate possible public health risks from environmental exposure to chemicals with hormone-like effects. Better test strategies and reproductive toxicity test guidelines are needed in order to assess any such risks, and to provide a basis for possible regulatory action.

Animals↗
PubMed1997

Potency grading in carcinogen classification.

In 1992 the United Nations Conference on Environment and Development decided to harmonize carcinogen classification systems. A proposal for a harmonized classification system is currently being considered by the Organization for Economic Cooperation and Development (OECD). In many countries, classification of a chemical as carcinogenic triggers labeling requirements. Implicit in the labeling requirements are often restrictions on the sale of consumer products and workplace regulations. Many of the current classification systems for carcinogens use a single concentration limit for the minimum concentration of a carcinogen in a preparation (mixture) that requires labeling. For high-potency carcinogens, one concentration limit may not adequately express the hazard, whereas for low-potency carcinogens, one limit may overestimate the hazard caused by the carcinogen in the preparation (mixture). The potency grading system discussed consists of three potency groups: high-, medium-, and low-potency carcinogens. It is envisioned that the different classes will trigger different labeling requirements. In the process of potency grading, a preliminary conclusion as to whether a substance shows high, medium, or low potency is initially based on a tumorigenic dose descriptor. The preliminary potency evaluation may then be modified after due consideration of a number of additional elements. These may include evaluation of the dose-response curve; site-, species-, strain-, and sex-specific activity; mechanisms including genotoxicity; mechanistic relevance to humans; toxicokinetics; and other factors. The potency grading system discussed is applicable to most carcinogen classification systems, including that currently being considered by the OECD.

Animals↗
PubMed1997

T25: a simplified carcinogenic potency index: description of the system and study of correlations between carcinogenic potency and species/site specificity and mutagenicity.

A simplified carcinogenic potency index, the T25, is proposed as a practical method for the inclusion of potency considerations in carcinogen classification systems. The T25 is the chronic daily dose in mg per kg bodyweight which will give 25% of the animals tumours at a specific tissue site, after correction for spontaneous incidence, within the standard life span of that species. Calculated T25 values of a set of 113 US National Cancer Institute/National Toxicology Program (NC/NTP) carcinogens showed excellent correlation (correlation coefficient 0.96, P < 0.0001) with the carcinogenic potency index TD50 of Peto et al. (1984). The mean of T25 values for 51 transspecies, multiple common site NCI/NTP carcinogens were 10-fold lower than those for 62 NCI/NTP single species, single site carcinogens. For these 113 carcinogens, the mean T25 values were approximately 3-fold lower for agents that were also mutagenic in Salmonella compared to the non-mutagenic agents.

Abdominal Neoplasms↗
PubMed1996

[Chemoprevention of cancer. Prevention of cancer in groups with increased risk].

The term chemoprevention is defined as the use of specific natural or synthetic chemical agents to reverse, suppress or prevent carcinogenic development to a tumour. Many potential chemopreventive substances are pharmacologic agents which may already be in use or are naturally occurring compounds. Short-term tests and animal models are available for identifying potential chemopreventive agents. There are several similarities between clinical chemopreventive trials and cancer prevention by dietary intervention. The cost and length of chemopreventive trials can be reduced by using validated biomarkers as endpoint instead of cancer. Experience from chemoprevention of cancer is limited, seen in relation to use of chemical agents to reduce cardiovascular disease. However, a number of international clinical trials are now going on to evaluate the use of pharmacological substances as potential chemopreventive agents.

Anticarcinogenic Agents↗
PubMed1996

[Health damages from passive smoking].

Environmental tobacco smoke is a complex mixture of many chemical substances. The term passive smoking is used when a person breathes in air contaminated by tobacco smoke. Active and passive smoking expose an individual to the same substances, but the relative concentrations of the various substances differ. Thus, under conditions where individuals are exposed to an amount of nicotine corresponding to their smoking 1/2 a cigarette, they will be exposed to an amount of nitrosodimethylamine corresponding to their smoking about five cigarettes. Exposure of children to environmental tobacco smoke is associated with increased risk of lower respiratory tract infections, middle ear infections and asthma. Accumulating evidence points to passive smoking as a risk factor for the sudden infant death syndrome. Long term exposure to environmental tobacco smoke increases risk of lung cancer and heart disease. It is estimated that in Norway, 50 non-smokers die of lung cancer and 300-500 of heart disease annually, as a result of long term exposure to environmental tobacco smoke.

Europe↗
PubMed1996

Carcinogen classification systems: similarities and differences.

An overview of regulatory classification systems on carcinogens in the Organization for Economic Cooperation and Development (OECD) countries is presented based on a questionnaire study. Most OECD countries have implemented legislation including classification systems and lists of carcinogens. Basically, there are two types of classifications systems. The major difference between the two is that in one system carcinogens are classified according to the weight of evidence for carcinogenic effects in humans, whereas in the other carcinogens are allocated to various groups according to potency. Even if the classification systems may differ, the substances classified as carcinogens are to a large extent the same. Classification of carcinogens will in many countries require hazard labeling. This labeling, i.e., the limit for labeling of substances and preparations, and risk phrases show considerable similarities, but differ in certain aspects. Several countries have restrictions on sale and/or use of carcinogens. There is a trend toward introducing more mechanistic considerations in the classification of carcinogens.

Carcinogens↗
PubMed1996

Organ-specific and transplacental DNA damage and its repair in rats treated with 1,2-dibromo-3-chloropropane.

An in vivo genotoxicity assay system based on alkaline elution has been used to study the formation and removal of DNA damage induced by 1,2-dibromo-3-chloropropane (DBCP). Cells/nuclei from different tissues and organs of Wistar rats were prepared by a rapid mincing/homogenization technique. Thirty-six samples of which up to 11 were from different organs of the same animal, were then assayed in parallel for DNA damage (DNA single-strand breaks plus alkali-labile sites = SSBs) with a semi-automated alkaline elution system. A single i.p. injection of DBCP gave dose-(5 and 10 mg/kg) and time-(20 min-4 h) dependent SSBs in kidney and liver DNA from male rats. At 10 mg/kg DBCP, SSBs were formed in all organs examined except the bone marrow and colon; however, an increased dose of 40 mg/kg produced SSBs also in the latter two organs. The relative susceptibilities to DBCP-induced DNA damage were: kidney approximately duodenum > liver > lung approximately brain approximately urinary bladder approximately glandular stomach > spleen approximately testis > bone marrow approximately colon. These relative levels correlate with previous data on tissue distribution and organ necrosis in liver, kidney and testis of rats given a single i.p. dose of DBCP. When female rats were injected i.p. with 5, 10 or 20 mg/kg (nonhepatotoxic doses) at day 20 of pregnancy, similar levels of SSBs were detected in the livers of the dam and the fetuses. In adult male rats, time-dependent changes in SSBs were followed in the liver and kidney after DBCP exposure. In both organs SSBs peaked around 4 h post-exposure, 50% had been removed by 12-24 h, whereas at day 2-3 SSB frequencies had returned to control levels. Pretreatment of rats with phenobarbital prior to DBCP exposure reduced the maximum level of DNA damage as well as its persistence. In cultured primary hepatocytes from male rats exposed in vitro to DBCP (2-20 microM. 1 h), 50% of the initial DNA damage had been repaired within approximately 100 min. In conclusion, the experiments indicate that the distribution characteristics of DBCP are of major importance for DNA damage and its persistence in various organs of rats. The data are also in accordance with glutathione-S-transferase, rather than P450, being the most important pathway for metabolic activation of DBCP in rat extrahepatic tissues including the fetal liver. It appears that alkaline elution of cells/nuclei prepared from exposed animals constitutes a sensitive, rapid and versatile technique to study organ- and cell-specific genotoxicity in vivo.

Animals↗
PubMed1996

Environmental chemicals relevant for respiratory hypersensitivity: the indoor environment.

The allergenic constituents of non-industrial indoor environments are predominantly found in the biologic fraction. Several reports have related biological particles such as mites and their excreta, dander from pets and other furred animals, fungi and bacteria to allergic manifestations including respiratory hypersensitivity among the occupants of buildings. Also, bacterial cell-wall components and the spores of toxin-producing moulds may contribute to the induction of hypersensitivity, but the relevance for human health is not yet determined. The knowledge regarding hypersensitivity and asthmatic reactions after exposure to chemical agents is primarily based on data from occupational settings with much higher exposure levels than usually found in non-industrial indoor environments. However, there is evidence that indoor exposure to tobacco smoke, some volatile organic compounds (VOC) and various combustion products (either by using unvented stoves or from outdoor sources) can be related to asthmatic symptoms. In some susceptible individuals, the development of respiratory hypersensitivity or elicitation of asthmatic symptoms may also be related to the indiscriminate use of different household products followed by exposure to compounds such as diisocyanates, organic acid anhydrides, formaldehyde, styrene and hydroquinone. At present, the contribution of the indoor environment both to the development of respiratory hypersensitivity and for triggering asthmatic symptoms is far from elucidated.

Air Pollution, Indoor↗
PubMed1995

Metabolism of 1,2-dibromo-3-chloropropane by glutathione S-transferases.

The metabolism of 1,2-dibromo-3-chloropropane (DBCP), measured as the formation of water soluble metabolites and metabolites covalently bound to macromolecules, was studied in isolated rat liver, kidney, and testicular cells, in subcellular fractions, and with purified rat and human glutathione S-transferases (GSTs). The rate of formation of water soluble metabolites in the cells were in the order liver > kidney > testis. The rate of covalent macromolecular binding of reactive DBCP metabolites in the different cell types was of the same relative order. Pretreatment of the cells with the GSH depleting agent diethyl maleate (DEM) markedly decreased the rate of covalent binding in all cell types. Both the overall metabolism and the formation of DBCP metabolites that covalently bound to macromolecules, were substantially higher in rat testicular cells compared to hamster testicular cells. Rat liver cytosol and microsomes, and various purified rat and human GSTs extensively metabolized DBCP to water soluble metabolites in the presence of GSH. When compared to isolated cells, substantially lower rates of binding per mg protein could be observed in subcellular fractions. Binding of DBCP was detected in the microsomal and cytosolic fractions in the absence of NADPH, though in microsomes fortified with a NADPH-regenerating system, the generation of reactive DBCP metabolites was approximately doubled. Studies with purified rat GST isozymes showed that the relative overall GSH conjugation activity with DBCP was in the following order: GST form 3-3 > 2-2 approximately 12-12 > 1-1 > 4-4 approximately 8-8 approximately 7-7. Furthermore, human GST forms also readily metabolized DBCP with activities of GST A1-2 > A2-2 approximately A1-1 > M1a-1a > M3-3 approximately P1-1.

Animals↗
PubMed1995

[Peroxisome proliferation and possible cancer hazard].

Approximately 80 chemicals, including hypolipidemic fibrates, have been shown to induce peroxisome proliferation in rodent liver. There is a strong concordance between this effect and development of liver cancer in rats and mice. There is evidence that the peroxisome proliferators induce cancer via a non-genotoxic, receptor-mediated mechanism. Both oxidative stress as a consequence of peroxisome proliferation and preferential growth of preneoplastic lesions following hepatocyte proliferation have been proposed as underlying processes in the neoplastic development. Peroxisome proliferation does not seem to occur in human liver to any significant extent. Therefore exposure to chemicals with such an effect apparently represents little, if any, human carcinogenic hazard.

Adult↗
PubMed1995

[Target dose markers. Exposure indicators for environmental epidemiological studies].

It is of major importance to have good characterization of individual exposures in environmental epidemiological studies. Quantification of the dose at the site of action (target dose, biologically effective dose) gives the best correlation with health outcome. Target dose markers are indicators which have recently been applied in environmental epidemiological studies. Especially, measurements of adducts to macromolecules (DNA, protein) have been much used. The authors give an overview over available exposure markers, focusing on studies were target dose markers have been employed. It is important to be aware of the limitations associated with the use of such markers.

Biomarkers↗
PubMed1995

Comparative toxicity of (+)-(R)- and (-)-(S)-1,2-dibromo-3-chloropropane.

The haloalkane 1,2-dibromo-3-chloropropane (DBCP), an environmental pollutant that was widely used as a soil fumigant, is a carcinogen and a mutagen and displays target-organ toxicity to the testes and the kidneys. Because little is known about effects of stereochemistry on the metabolism and toxicity of halogenated alkyl compounds and because DBCP, which has a chiral center at C-2, may show enantioselectivity in its metabolism and/or toxicities, the optically pure enantiomers of DBCP were tested in vivo in rats for organ toxicity as well as for bacterial mutagenicity. Organ toxicity studies showed that (S)-DBCP was slightly more renal toxic than (R)-DBCP but was not significantly more toxic than the racemate, and that no significant differences were observed in the extents of testicular necrosis and atrophy caused by either enantiomer or the racemate. In contrast, (R)-DBCP was more mutagenic than either (S)-DBCP or the racemate to Salmonella typhimurium (S. typhimurium) strains TA 100 and TA104. However, there was little or no enantioselectivity in glutathione S-transferase (GST)-catalyzed conjugation reactions of glutathione with DBCP based on the lack of selectivity in the rates of disappearance of the enantiomers of DBCP in the presence of glutathione (GSH) and GSTs as monitored by chiral gas chromatography (GC).

Animals↗