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L Ehrenberg

Publications and source records attributed to L Ehrenberg.

At least 37 records · Page 2Linked to original sources
PubMed1994

Comparative two-stage cancer tests of ethylene oxide, N-(2-hydroxyethyl)-N-nitrosourea and X-rays.

Mutagenicity tests have shown that the potencies of ethylene oxide and other alkylating agents relative to that of low-LET ionising radiation are approximately the same in different biological systems. In the present study this relationship, the radiation-dose equivalence ("rad-equivalence") of doses of genotoxic chemicals, was tested for the induction of tumours in skin and lung of mice using different initiation-promotion protocols. The initiators used were X-rays, ethylene oxide and N-(2-hydroxyethyl)-N-nitrosourea (HOENU). This short-term treatment was followed by treatment with the "promoters" 12-O-tetradecanoylphorbol 13-acetate (TPA) and carbon tetrachloride. Unexpectedly, the animals treated with carbon tetrachloride did not show treatment-related liver tumours, but exhibited precocious death, mostly with lung tumours. According to estimates from in vitro tests the total in vivo dose from exposure to 400 ppm for 4 x 5 h corresponds to 700 rad-equivalents. Although still with great statistical uncertainty, this ratio is supported by the observed time-dependent frequencies of animals with papillomas (in the TPA series) and lung tumours (in the carbon tetrachloride series). Animals treated with HOENU exhibited high incidences of tumours of both these types in approximate agreement with the higher rad-equivalence of the treatments with this compound.

Animals↗
PubMed1994

On cancer risk estimation of urban air pollution.

The usefulness of data from various sources for a cancer risk estimation of urban air pollution is discussed. Considering the irreversibility of initiations, a multiplicative model is preferred for solid tumors. As has been concluded for exposure to ionizing radiation, the multiplicative model, in comparison with the additive model, predicts a relatively larger number of cases at high ages, with enhanced underestimation of risks by short follow-up times in disease-epidemiological studies. For related reasons, the extrapolation of risk from animal tests on the basis of daily absorbed dose per kilogram body weight or per square meter surface area without considering differences in life span may lead to an underestimation, and agreements with epidemiologically determined values may be fortuitous. Considering these possibilities, the most likely lifetime risks of cancer death at the average exposure levels in Sweden were estimated for certain pollution fractions or indicator compounds in urban air. The risks amount to approximately 50 deaths per 100,000 for inhaled particulate organic material (POM), with a contribution from ingested POM about three times larger, and alkenes, and butadiene cause 20 deaths, respectively, per 100,000 individuals. Also, benzene and formaldehyde are expected to be associated with considerable risk increments. Comparative potency methods were applied for POM and alkenes. Due to incompleteness of the list of compounds considered and the uncertainties of the above estimates, the total risk calculation from urban air has not been attempted here.

Air Pollution↗
PubMed1993

Genotoxic effects of ethylene oxide and propylene oxide in mouse bone marrow cells.

Ethylene oxide and propylene oxide are high-volume reactive alkylating agents used primarily as intermediates in the chemical industry. Studies were undertaken to investigate the ability of these alkylating agents to induce chromosomal aberrations, micronuclei and sister-chromatid exchanges in mouse bone marrow cells. The mice were exposed to these chemicals by intraperitoneal injection. The data show that both compounds are effective in inducing chromosomal alterations. Our studies confirm the findings reported by different investigators that ethylene oxide is more cytotoxic than propylene oxide. This difference is to a large extent due to a faster detoxification of propylene oxide than of ethylene oxide.

Animals↗
PubMed1992

Degree of alkylation of macromolecules in vivo from variable exposure.

Measurements of adducts formed with blood proteins, particularly haemoglobin, are increasingly being used to monitor human exposures to genotoxic chemicals. Information about the relationships between levels of genotoxic chemicals in the environment, e.g., concentration in the air, and levels of protein adducts in the blood is particularly important in setting safety standards and assessing risks. This paper describes the relationships between level of exposure to alkylating agents and level of haemoglobin adducts, considering the zero-order kinetics of the disappearance of these adducts. For comparison the corresponding relationship for adducts to macromolecules subjected to turnover, with first-order kinetics of disappearance, is described. For chemically stable and unstable adducts different exposure situations are considered: acute, chronic, intermittent and varying exposure levels. It is shown how an optimum solution of the problem of establishing the relationship between long-term exposure at varying levels (e.g., in work environments) and adduct level can be reached. Through mathematical derivations, which are given, expressions applicable to various exposure patterns are obtained and presented.

Alkylation↗
PubMed1992

On the bioactivation and genotoxic action of fluoranthene.

Fluoranthene (FA) was studied with respect to possible mechanisms of its high mutagenicity but low carcinogenicity, in comparison with the corresponding properties of benzo[a]pyrene (BaP), and with regard to the synergism of these two compounds shown by van Duuren and Goldschmidt (J Natl Cancer Inst 56, 1976, 1237). FA and BaP activated by S9 from Aroclor 1254 (PCB)-treated rats induce HPRT mutations in CHO cells with about equal effectiveness at the same exposure doses, which also lead to the same frequencies of repairable DNA adducts, enzyme-induced strand breaks being used as an indirect measure of adducts to DNA. FA was also shown to be an efficient inducer of SCE in human peripheral lymphocytes cocultivated with PCB-treated HepG2 cells or with liver cells from PCB-pretreated rats. For the induction of SCE, FA and BaP were shown to act additively. From metabolic studies with liver microsomes from C57Bl/6 mice it is concluded that, whereas BaP induces the metabolism of BaP to the mutagenic epoxide, neither BaP nor FA is able to induce the metabolism of FA. In mutation experiments with V79 cells (XEM2) constitutive for P450 IA1 activity, BaP 7,8-diol but not FA 2,3-diol provokes a high frequency of HPRT mutations. In cells constitutive for P450 IA2 enzymatic activity FA and BaP are but weakly mutagenic and practically nonmutagenic, respectively. Due to the additivity of the genotoxic effects of FA and BaP, induction of an error-prone condition by the latter compound seems to be excluded.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Pharmacokinetics of ethylene in man; body burden with ethylene oxide and hydroxyethylation of hemoglobin due to endogenous and environmental ethylene.

The inhalation pharmacokinetics and the endogenous production of ethylene has been determined in healthy volunteers with respect to the formation of the carcinogen ethylene oxide. Ethylene showed a low degree of accumulation in the body determined in six subjects, the thermodynamic partition coefficient "body/air" being 0.53 +/- 0.23 (mean +/- SD) and the accumulation factor "body/air" at steady-state being 0.33 +/- 0.13 (mean +/- SD). The rate of metabolism was directly proportional to the exposure concentration. Only 2% of ethylene inhaled was metabolized to ethylene oxide, whereas 98% of ethylene was exhaled unchanged. The rate of the endogenous production of ethylene was 32 +/- 12 nmol/h (mean +/- SD), as calculated from exhalation data from 14 subjects. The resulting body burden was 0.44 +/- 0.19 nmol/kg (mean +/- SD). By analyzing published data on ethylene oxide in man its half-life was estimated to be 42 min. Using the pharmacokinetic parameters of ethylene and ethylene oxide, the body burden of ethylene oxide due to the sum of the exposure to environmental ethylene of about 15 ppb and to endogenous ethylene exposure of 0.44 nmol/kg was predicted to be 0.25 nmol/kg. In the blood of five non-smokers and one smoker the hemoglobin adduct resulting from the reaction of ethylene oxide with the N-terminal valine, N-(2-hydroxyethyl)valine, was quantified by gas chromatography/mass spectrometry. The value of 20 +/- 5 pmol/g Hb (mean +/- SD) found in the non-smokers corroborated the steady-state level of 18 +/- 3 pmol/g Hb (mean +/- SD) calculated from the pharmacokinetic approach.

Adult↗
PubMed1992

Inhibition of recA induction by the radioprotector 2-mercaptoethylamine.

Our earlier finding that the radioprotective action of 2-mercaptoethylamine (MEA) is counteracted by ascorbate suggests a biochemical mechanism of action, which is supported by observations that MEA is not radioprotective in Rec- E. coli strains. In this study we show that MEA inhibits the induction of the recA gene by UV- or gamma-irradiation or by nalidixic acid in Escherichia coli strain GE94, which contains a recA-lacZ fusion. This effect, which may be counteracted by cysteine, indicates that in general MEA inhibits the induction of SOS functions.

Cysteamine↗
PubMed1992

Use of biomarkers in epidemiology: quantitative aspects.

Cancer initiators (mutagens) present, due to the absence of definable no effect threshold, a special problem in toxicology, requiring a high sensitivity of detection methods. Disease epidemiology aiming at identification of carcinogens and quantification of associated risks has a low resolving power, the detectable incidence or mortality increments being often orders of magnitude larger than those which are of public concern. Other drawbacks of disease epidemiology is the long latency times and the influence of confounders. The use of genetic endpoints as biomarkers suffers from low cause specificity, although this drawback seems to be overcome, partly at least, by emerging methods for determination of mutation spectra at the DNA level. Proximal cancer initiators/mutagens are electrophilic compounds or metabolites that can react with nucleophilic atoms in nucleic acids and proteins. These reactions lead to 'adducts' that can be identified and quantified, e.g. in lymphocytes and erythrocytes in blood samples. The shift from biological observations to chemical analysis permits sufficient sensitivity, and measurement can be done shortly after onset of exposure. The well-defined life span of the adducts to hemoglobin (Hb) offer possibilities of dose calculation and risk estimation. For these reasons the measurement of adducts to Hb and DNA constitutes a powerful epidemiological tool, applications of which has been initiated in work environments and the general environment and also in the search for a priori unknown carcinogens.

Animals↗
PubMed1992

Risk assessment of urban air pollution.

Urban air pollution, originating in western countries mainly from automotive engine exhausts, contains thousands of components, many of which are genotoxic, i.e. are putative cancer initiators. Other pollution components, such as NO2 and certain particles, may have cocarcinogenic/promotive effects, at least at higher exposure levels. Cancer risk assessment of this complex mixture has to combine data from the exposure history, from epidemiological studies as well as from animal carcinogenicity tests, and from in vitro studies of fractions and individual components. Data for metabolism and pharmaco-kinetics have also to be considered. A multiplicative linear model is assumed to be valid for cancer initiation at low levels. Attempts are being made to determine the target dose from ultimate carcinogens (reactive metabolites) via macromolecule adduct levels, and to base the risk assessment on the radiation-dose equivalent to the chemical dose. So far this has been possible only for simple alkenes, which are metabolized to epoxides, and indirectly, via benzo(a)pyrene (BaP), for particle-bound polycyclic aromatic hydrocarbons (PAH). The lifetime risk of cancer (all sites) from ethene is estimated accordingly to 1.4 x 10(-4) per microgram m-3, and from PAH to 12 x 10(-4) per ng m-3 BaP. For other components indicated to give risk contribution (NOx, volatile PAH, benzene, aldehydes, butadiene) essential data are lacking and only very rough estimates can be given at this time.

Air Pollutants↗
PubMed1991

Human health risk assessment and biological reactive intermediates: hemoglobin binding.

There is ample evidence to show that the demonstration of adducts to hemoglobin and other proteins of electrophilically reactive compounds or biological reactive intermediates (BRI) is a relevant indication of the formation of the corresponding DNA adducts, and also that the rates of formation of protein- and DNA adducts are proportional. Measurement of hemoglobin and DNA adducts are therefore complementary. The former has so far been used mainly in the monitoring of low-mol.wt alkylators and BRI whereas DNA adduct monitoring has been applicable mostly to bulky compounds. Since dose-response curves are presumably linear, demonstration of adducts should be taken as identification of genotoxic risk factors. The fast development of analytical methods renders quantification of associated risks increasingly important: For instance, using adduct analysis in the search for a priori unknown carcinogens/mutagens, analytical procedures should be developed towards a power permitting detection of unacceptable risks, at the same time as unnecessary banning of factors originating from beneficial procedures should be avoided.

Alkylating Agents↗
PubMed1991

Studies of biological and chemical monitoring of low-level exposure to ethylene oxide.

Ten sanitary workers exposed to concentrations of ethylene oxide below 1 ppm were studied to determine whether effects could be observed at low exposure levels. A significant increase in the number of sister chromatid exchanges in cultured lymphocytes was found only for five subjects with relatively high exposure in the sterilization area. However, it was not possible to separate clearly the effect of smoking from that of ethylene oxide exposure. No increase in the frequencies of micronuclei in lymphocytes and buccal cells was found. The level of 2-hydroxyethyl adducts to the N-terminal valines in hemoglobin responded in a reliable fashion to chronic ethylene oxide exposure and smoking. Furthermore, measurement of levels of 2-hydroxyethyl adducts to the N-terminal valines in hemoglobin made it possible to reconstruct the dynamics of a leakage of ethylene oxide which involved three workers.

Adult↗
PubMed1990

Epidemiological studies of geographic variations of cancer incidence in Sweden. Choice of variables and statistical units.

The Swedish Cancer-Environment Registry has been used for studies of the parts of cancer incidences and of their variations between subpopulations, which, in a statistical sense, can be 'explained' by environmental variables. In previous studies the dependence of age-standardized incidences in municipalities (279 in Sweden) on population density, socio-economic variables, smoking habits and a variable for 'diagnostic intensity', assumed to allow for variations in under-diagnosing and under-reporting, was studied in, i.a., multiple-regression analyses. Due to intrinsic variation in potentially etiologic factors and in size, municipalities are less suitable as geographic units. Therefore a system was developed to build up, from parishes (about 2,600), pseudo-municipalities standardized with respect to size and some environmental variable(s), in the present study population density. This paper shows, for a number of cancer diseases and for total cancer, the superiority of pseudo-municipalities to municipalities with respect to power of explaining variation and, preliminarily, also incidence.

Female↗
PubMed1990

Approaches to risk assessment of automotive engine exhausts.

Contributions of alkenes to cancer risk from urban air pollution were estimated on the basis of radiation dose equivalent of target dose. The latter was inferred from the incremental carboxyhaemoglobin (COHb) level in urban areas, the ratio of epoxide-haemoglobin adducts to COHb levels in smokers and the alkenes/CO level ratios in cigarette smoke and urban air. This model predicts some 200 and 5 cancer cases annually in Sweden from ethene and propene, respectively. This indicates that the risk from alkenes is of the same order of magnitude as that from the particulate fraction of the pollution.

Air Pollutants↗
PubMed1989

Unsaturated lipids and intestinal bacteria as sources of endogenous production of ethene and ethylene oxide.

Studies of adducts to hemoglobin (Hb) have revealed levels of hydroxyethylations of i.a. N-terminus (valines) in knowingly unexposed animals and persons (non-smokers). This paper describes some exploratory experiments with mice, carried out with the aim of tracing the origin of these background levels. It is shown that the hydroxyethylvaline content in Hb is higher in animals fed unsaturated lipids and lower in bacterium-free as compared to control animals. Lipid peroxidation and metabolism of intestinal bacteria, giving rise to ethene, precursor of ethylene oxide, are thus indicated to be sources of observed background hydroxyethylations.

Animals↗
PubMed1988

Hemoglobin adducts in animals exposed to gasoline and diesel exhausts. 1. Alkenes.

Blood samples from rats and hamsters exposed to automotive engine exhausts in the Committee of Common Market Automobile Constructors long-term inhalation study at Battelle-Geneva were analysed for the levels of 2-hydroxyethylvaline (HOEtVal) and 2-hydroxypropylvaline (HOPrVal) in hemoglobin (Hb). These adducts to the N-terminus of the Hb chains were determined by gas chromatography-mass spectrometry of derivatives obtained by a modified Edman degradation that specifically cleaves off alkylated N-terminal amino acids (valine in Hb). The adduct levels found correspond to the metabolic conversion of about 5-10% of inhaled ethene and propene to ethylene oxide and propylene oxide, respectively, in agreement with results from earlier studies on mice inhaling radio-labelled alkenes. It is concluded that the alkenes, via epoxides, are the main sources of the observed HOEtVal and HOPrVal. From calculated doses and estimates of genotoxic potency the contribution from ethene in urban air to human cancer risk is discussed.

Alkenes↗
PubMed1988

Methylations in human hemoglobin.

Levels of N-Methylvaline (MeVal) and N tau-methylhistidine (MeHis) were measured in male smokers and non-smokers in a program aimed at mapping background alkylations of hemoglobin (Hb) as potential indicators of doses of exogenous and endogenous genotoxic agents. MeVal was also determined in Hb from rats, Syrian golden hamsters, mice and chickens. MeVal was found to occur at levels around 0.5 nmole/g Hb, with relatively little variation between individuals and species. MeVal was not significantly affected by smoking. This result contrasts with elevated levels of N-hydroxyethylvaline (HOEtVal) measured in the same persons (Törnqvist et al., 1986b). Levels of S-methylcysteine (MeCys) (Bailey et al., 1981) and MeHis were much higher than those of MeVal. The high levels of MeCys and MeHis may be due partly to misincorporation during protein synthesis and to artifacts. S-Adenosylmethionine and formaldehyde are possible endogenous sources of MeVal. One individual (smoker) out of 21 selected for measurement of MeVal was an outlier, with raised levels of both MeVal and HOEtVal, as would be expected in case of a defective detoxification system.

Animals↗
PubMed1988

Note on ethene and other low-molecular weight hydrocarbons in environmental tobacco smoke.

Levels of ethene and propene, together with those of some other light hydrocarbons (propane, butane, isobutane and ethyne), have been measured under realistic conditions in environmental tobacco smoke (ETS) as a step towards the elucidation of the sources of 2-hydroxyethyl and 2-hydroxypropyl adducts of hemoglobin observed in non-smokers. These adducts may reflect in vivo doses of carcinogenic epoxides that are metabolites of the respective alkenes. The data show that 2.0 mg ethene, 1.4 mg propene, and 0.7 mg propane together with smaller amounts of butane, isobutane and ethyne are released per cigarette smoked (0.66 g tobacco) of a common Swedish brand. The alkenes in ETS should be considered as contributing factors to a risk of systemic cancer from passive smoking. With regard to alkene intake, even a relatively mild exposure to ETS (2 cigarettes per h for 5 h per day in a 33 m3 room with one air change per hour is estimated to correspond to the active smoking of about one cigarette per day.

Alkenes↗