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PubMed1970

Polynuclear aromatic hydrocarbons in the water environment.

Many polynuclear aromatic hydrocarbons (PAH) are known to be carcinogenic to animals and probably to man. This review is concerned with carcinogenic and non-carcinogenic PAH in the water environment, with emphasis on 3,4-benzpyrene (BP) because it is ubiquitous, is one of the most potent of the carcinogenic PAH and has been widely studied. Although PAH are formed in combustion and other high-temperature processes, there is also evidence for their endogenous formation in plants, which may explain their ubiquity therein. Although the solubility of these compounds in pure water is very low, they may be solubilized by such materials as detergents, or they may otherwise occur in aqueous solution associated with or adsorbed on to a variety of colloidal materials or biota, and thereby be transported through the water environment. A notable characteristic of PAH is their sensitivity to light.PAH have been found in industrial and municipal waste effluents, and occur in soils, ground waters and surface waters, and their sediments and biota. With the exception of filtration or sorption by activated carbon, conventional water treatment processes do not efficiently remove them, and they have been found in domestic water supplies. Because of the ubiquity of PAH in the environment, it is impossible to prevent completely man's exposure to them; nevertheless their surveillance should be continued and their concentrations in the environment should be reduced where practicable.

Air Pollution↗

PubMed1981

Platinum interactions with nucleic acids: insights from model compounds.

A systematic review of the molecular structures of a large number of platinum(II) complexes with purine and pyrimidine bases and their nucleosides and nucleotides is presented. From these studies it is evident that the endocyclic nitrogen donor atoms of the heterocyclic purine and pyrimidine bases are dominant metal binding sites for Pt(II). Secondary interactions involving the exocyclic functional groups of the bases and the phosphate moiety of nucleotides are also noted. For Pt(II) complexes containing two adjacent (cis) bases, it is further indicated that intracomplex and intercomplex base-base interactions are of particular importance, giving rise in some cases to discontinuous helical arrays of Pt(II) complexes. These helical arrays may provide some insights into platinized-DNA polymers. Attention is also given to polynuclear species which are models for the family of mixed-valent platinum-pyrimidine blues. Finally, an attempt is made to extend the results of small molecule studies to give insights into the general area of Pt(II)-DNA chemistry and, in particular, the mode of action of the active anti-neoplastic agent cisPt.

Binding Sites↗

PubMed1976

Chemical carcinogenesis and experimental models using human tissues.

The majority of human cancer is caused by environmental agents including chemical carcinogens. These chemical carcinogens are both naturally-occurring compounds and products of an industrialized society. Most of the environmental chemical carcinogens require enzymatic activation into electrophilic metabolites which readily react with cellular macromolecules leading, in some cases, to malignant transformation of target epithelial cells. Model systems for studying carcinogenesis in human target tissues are being developed to link investigations using experimental animals with human cancer. Metabolism of chemical carcinogens is being studied in human tissues maintained in these model systems. For example, a marked variation among individuals in their capacity to metabolize carcinogenic polynuclear aromatic hydrocarbons has been observed. This inter-individual variation may, in part, be due to genetic factors. Model systems using human tissues should be useful in several areas of cancer research including: 1) identifying environmental carcinogens, their metabolic pathways and host factors determining susceptibility; and 2) testing new methods of prophylatic intervention in populations at high risk of developing cancer.

Binding Sites↗

PubMed1975

Antimicrobial activities of 81.723 hfu, a new pleuromutilin derivative.

The new pleuromutilin derivative 81.723 hfu is extremely active against gram-positive organisms such as streptococci, staphylococci, and against mycoplasmas. A number of Shigella, Klebsiella, and Escherichia coli strains were also found to be quite susceptible to this new agent, whereas other gram-negative organisms like Pseudomonas aeruginosa, Proteus species, and Alcaligenes faecalis proved to be naturally resistant to 81.723 hfu. The new compound acts bacteriostatically. Bactericidal effects have been observed only at concentrations which are 100-fold higher than the minimal inhibitory concentrations. The new antibiotic is well tolerated in all animal species tested so far and has been successfully used in the treatment of experimental infections with gram-positive organisms and with mycoplasmas in mice and rats. Resistance against this new compound arose gradually in all microorganisms investigated. It is noteworthy that the rate at which resistance against 81.723 hfu emerged in mycoplasmas (Mycoplasma gallisepticum and Mycoplasma hyorhinis) was significantly slower than the corresponding rate at which resistance against tylosin tartrate appeared. Mycoplasma strains which became insensitive to 81.723 hfu were also resistant to tylosin tartrate, whereas mycoplasmas which developed resistance against tylosin tartrate, although less sensitive to 81.723 hfu than wild-type strains, were still eliminated by this drug. In a strain of Klebsiella pneumoniae, complete cross-resistance was observed between the pleuromutilin derivative on one hand and lincomycin and erythromycin on the other. Modest degrees of cross-resistance were also observed with chloramphenicol. However, it appears unlikely that the latter phenomenon is sufficiently pronounced to affect treatment with either antibiotic.

Agaricales↗

PubMed1991

Effects of oxygen radicals on the conformation of sulfhydryl groups on human polymorphonuclear leukocyte membranes.

The healthy intact polymorphonuclear leukocytes (PMNs) were labeled with 4-maleimide-TEMPO spin labeling compound (MAL) to study the effects of oxygen radicals produced by phorbol myristate acetate (PMA)-stimulated PMNs on the conformation of sulfhydryl (SH) groups of PMN membrane proteins. The lipid peroxidation induced by PMA-stimulated PMNs was detected by evaluating the formation of malonaldehyde (MDA) with the thiobarbituric acid (TBA) test. From the experiments of luminol-dependent chemiluminescence (CL) and fluorometry, it was found that Chinese herbs schizandrin B (Sin B) and quercetin (Q) possessed scavenging properties for oxygen radicals produced during the PMN respiratory burst. These two herbs can also inhibit the conformation changes in SH binding sites on the PMN membrane proteins caused by oxygen radicals produced by the PMNs themselves. They also decreased the amount of MDA, which was a final product formed during lipid peroxidation.

Cell Membrane↗

PubMed1984

Heterotopic tracheal transplants: techniques and applications.

Heterotopic tracheal transplants, placed subcutaneously in syngeneic rats have been extensively used in our laboratory. The objective of these experiments was to study the toxic and/or carcinogenic effect of several compounds on the respiratory tract mucosa. This was attained by exposing the transplants to an intraluminal pettet containing the toxicant or carcinogen mixed with an adequate matrix (gelatin, beeswax, stearyl alcohol, silastic, etc.). By varying the concentration of the test chemicals, it is possible to study dose-response relationships, and by changing the pellet matrix, the effects of release rate (dose rate) can be analyzed. Several end points can be studied, such as histological changes in the mucociliary epithelium, changes in mucus secretion, tumor induction and changes in the in vitro behavior of the epithelial cells after in vivo exposure. In addition, by de-epithelializing the tracheal transplants and reseeding them with another cell population, e.g., from previously treated cell cultures or from human specimens and transplanting them subcutaneously in nude mice, completely new vistas on the effect of chemicals can be opened.

Animals↗

PubMed1994

Apoptosis of vascular smooth muscle cells. Protein kinase C and oncoprotein Bcl-2 are involved in regulation of apoptosis in non-transformed rat vascular smooth muscle cells.

We examined the effect of several inhibitors/activators of various protein kinases on the proliferation and apoptosis of nontransformed rat coronary vascular smooth muscle cells (SMC). As expected, all the compounds (calphostin C, KT5720, KT5823, verapamil, W7, and dibutyryl-cAMP) inhibited SMC proliferation, as judged by [3H]thymidine incorporation. Three (calphostin C, verapamil and dibutyryl-cAMP) of the six compounds caused occurrence of the classical apoptotic morphology in SMC. The effect of calphostin C, an inhibitor of protein kinase C, was examined in more detail due to the known involvement of this kinase in regulation of apoptosis in a variety of cell types. In SMC cultures exposed for 1, 2, and 3 days to 0.1 mumol/L calphostin C, 7 +/- 1%, 32 +/- 3%, and 29 +/- 3% of cells underwent apoptosis, respectively, as assessed by cell morphology (control cultures had 1 to 3% of apoptotic cells). The effect of calphostin C was transient in that on day 6 following exposure to this compound the number of apoptotic cells declined to control values. Simultaneous with the induction of apoptotic morphology in SMC, a decline was seen (within 24 hours) in expression of the oncoprotein Bcl-2 in morphologically nonapoptotic SMC. An altered distribution of Bcl-2 was seen in the apoptotic cells. The calphostin C-induced generation of apoptotic cells in SMC cultures and the decline/alteration of Bcl-2 expression were not accompanied by degradation of DNA into nucleosomal fragments. In conclusion, normal, nontransformed rat coronary artery vascular SMC undergo apoptosis when exposed to an inhibitor of protein kinase C (calphostin C), to a calcium channel blocker (verapamil), and to a stimulator of cAMP-dependent protein kinase (dibutyryl-cAMP). The induction of apoptosis by the inhibitor of protein kinase C is accompanied by alterations in the Bcl-2 expression but not by DNA fragmentation.

Animals↗

PubMed2002

Toxic contaminants and their biological effects in coastal waters of Xiamen, China. I. Organic pollutants in mussel and fish tissues.

Organochlorines and organophosphates were measured in four fish species (Lateolabrax japonicus, Pagrasomus major, Miichthys miiuy and Epinephalus awoara) and the mussel Perna viridis collected from aquaculture cages in coastal waters of Xiamen, China. Polycyclic aromatic hydrocarbon (PAH) metabolites were also measured in fish bile. Sites in Xiamen coastal waters (the harbour, Maluan and Tongan) are compared with a "cleaner" reference site at Dongshan Island. DDT was found in livers of all fish sampled (May 1998, 1999 and December 1999) ranging from 0.15 to 2.2 microg/g WW, but levels in muscle tissue (<0.5 ng/g to 0.22 microg/g WW) were at least an order of magnitude lower in the harbour, and were not detectable (<0.5 ng/g) in Tongan samples. All other pesticides examined were not detected in fish or mussels, except for dieldrin in one liver sample (0.07 microg/g WW). Food of the caged fish, small fish and dried pellets, had very low (0.015-0.027 microg/g WW) or non-detectable levels of DDT, indicating significant bioaccumulation of contaminants in caged fish and/or other possible sources of uptake (water and sediments). DDT levels in fish varied with species. DDT contamination in fish livers and whole mussels varied significantly with location. Highest concentrations in fish occurred in the harbour, and less consistently so in Tongan. Dongshan and Maluan had comparatively low levels of DDT. Relatively low residues of DDT in both fish and mussels at Dongshan likely reflect lower levels of pesticide input at this reference site. However, the low levels of DDT contamination in fish tissues from Maluan were unexpected in view of the close proximity of the harbour and possibly reflect the removal of particulate-bound contaminants by the intensive bivalve culture there. Consistently high proportions of DDT in the form of the parent compound (p,p'-DDT: fish 30-45%; mussels 40-65%) from all sites suggest recent releases of this chemical to the environment. Levels of two main groups of PAH metabolites (naphthalene and phenanthrene) in fish bile suggest a different environmental distribution pattern than that of pesticides, in that Dongshan fish appear to be no less exposed to hydrocarbons than those from Xiamen coastal waters.

Animals↗

PubMed1990

Organic micropollutants in lakes: a sedimentological approach.

Many very persistent and lipophilic compounds, considered to be of concern for chronic toxicity and bioaccumulation, are generally present in surface waters at very low and variable concentrations. Sediments represent a concentrated pool for these compounds and consequently they are often analyzed instead of water. Some theoretical models have been proposed recently (Håkanson, 1980; Galassi and Migliavacca, 1986; Provini et al., 1987) in order to estimate the concentration of these pollutants in water and their potential risk for aquatic biota and human health. In this work sediments from three subalpine lakes located in Northern Italy, very close to each other but with different anthropogenic loads, were collected at several stations for determination of the classes of organic micropollutants of urban, industrial, and agricultural origin. Results show that urban and industrial pollution are predominant in this area. Two classes of micropollutants seem to be most related to anthropogenic activities: PAH and trichloroalkylphosphates. The first reaches lake sediments through atmospheric deposition and point sources; the second, present only in two lakes, is more likely to be due to industrial effluents. The advantages and limitations of the sedimentological approach for risk assessment in the aquatic environment are discussed.

Chromatography, Gas↗

PubMed1995

Metabolic requirements for induction of contact hypersensitivity to immunotoxic polyaromatic hydrocarbons.

Experiments were performed to define the metabolic requirements for induction of contact hypersensitivity to polyaromatic hydrocarbons (PAHs), environmental xenobiotics that are both immunotoxic and carcinogenic. Evidence that conversion of the parent compound to a reactive metabolite was necessary for the development of contact hypersensitivity included the fact 1) that contact hypersensitivity to the polyaromatic hydrocarbon dimethylbenz(a)anthracene (DMBA) only occurred in strains of mice that could metabolize the compound, 2) that among the PAHs, only those that could induce aryl hydrocarbon hydroxylase, the rate-limiting enzyme in the PAH metabolic pathway, were immunogenic, and 3) that inhibitors of PAH metabolism reduced DMBA contact hypersensitivity. Cells from the XS52 Langerhans cell-like dendritic cell line were able to metabolize the PAH benzo(a)pyrene to its diol, quinone, and phenol metabolites. GM-CSF augmented benzo(a)pyrene metabolism in XS52 cells. Finally, in vivo depletion of CD8+, but not CD4+, T cell populations inhibited contact hypersensitivity to DMBA. The implications of these experiments are that at least for some contact allergens, the metabolic status of the host is a key determinant of individual susceptibility to the development of allergic contact dermatitis, and the metabolic pathway of an individual hapten may have ramifications for the T cell subpopulation-CD4 or CD8-that is activated.

Animals↗

PubMed1999

Development of an on-line coupling of liquid-liquid extraction, normal-phase liquid chromatography and high-resolution gas chromatography producing an analytical marker for the prediction of mutagenicity and carcinogenicity of bitumen and bitumen fumes.

A fast and fully automated system for the determination of polycyclic aromatic compounds (PACs) is described. The system has been developed to produce an analytical 'marker', correlating chemical characteristics (including PAC analysis) with mutagenicity and carcinogenicity. The products of interest are bitumen fumes, bitumen and other (heavy or even residual) oil products, regardless of their boiling range. Dimethyl sulphoxide (DMSO) extractables obtained from a flow-injection analysis (FIA) system are introduced on-line in a normal-phase liquid chromatographic (NPLC) system. Here, the PACs are separated from the DMSO and possible co-extracted heavy residual species. The final step incorporates on-line gas chromatographic analysis of the three-to-six-ring PAC fraction, followed by flame-ionisation detection for quantification. It was demonstrated that data obtained from samples in the distillate lubrication-oil range correlate well with data obtained from the manual DMSO-extraction method standardised by the Institute of Petroleum as IP346.

Carcinogenicity Tests↗

PubMed1985

Mucosal biotransformation of toxins in the gut.

A major fraction of foreign compounds entering the body is absorbed through the gastrointestinal tract in ingested food and beverages as well as in the swallowed respiratory mucus carrying part of the chemical loading of inspired air. The large surface area provides conditions for efficient absorption. The mucosa, however, forms an active barrier. There are several enzymes capable of oxidizing, reducing and hydrolysing xenobiotics as well as many enzymes conjugating either the compounds themselves or their reaction products. In the rat, the monooxygenase and uridine diphosphate glucuronosyltransferase activities appear to be highest in the oral end of the gut and decrease aborally. Compared with the hepatic activities the mucosal monooxygenase levels are lower, but the UDP-glucuronosyltransferase activities may even be higher than in the liver. The mucosal biotransformation activity is inducible. Within the gut mucosa the highest activities are close to the villus tips. Thus functional maturation of the cells in biotransformation appears to occur when cells are moving up from the crypts. The microvilli of the cells appear to be inactive in mono-oxygenation and glucuronidation. The metabolic products generated within the mucosal cells are released either into the blood or to the gut lumen. The xenobiotics and their metabolites meet in the lumen a rich bacterial flora. Microbes have high metabolic capacity in hydrolysis and reduction. These transformation products are absorbed again loading the host.

Animals↗

PubMed1988

Health risk assessment of residents living on harbour sludge.

A modelled approach for the assessment of exposure and health risks in a case of soil pollution with an unknown but probably large number of potential contaminants is presented. In 1983 the Steendijkpolder, a housing estate of about 800 houses, an agglomeration of schools and a tennis hall was built directly on a 4-m-thick layer of harbour sludge. The sludge originated from around 20 harbour basins in Rotterdam and the industrial area around the Nieuwe Waterweg. In the soil organic solvents, PAH's, aldrin, dieldrin, isodrin, telodrin and several heavy metals were found to be present as contaminants. Not all contaminants, including a number of halogenated compounds, were identified. The investigation of the other relevant environmental compartments in this situation, e.g. drinking-water, indoor-air and home grown vegetables showed that soil ingestion was the predominant route of intake of contaminants. Therefore the exposure of infants (age: 2-3 years) was calculated. The calculated intake of PAH by soil ingestion was around half the average intake of PAH in the daily diet. The extra exposure to drins (a group of cyclodiene insecticides) due to soil ingestion and inhaled contaminated indoor air was calculated to exceed twice the Acceptable Daily Intake (ADI) of dieldrin. The calculated maximal intake of Pb by soil ingestion exceeded the average intake of Pb in the daily diet by around 1.4 times. The maximal intake by soil ingestion of the other identified contaminants was relatively low. It was concluded that with the present knowledge the calculated exposure would not result in observable health damage.

Adult↗

PubMed1988

Carcinogenicity of aromatic hydrocarbons directly applied to rat mammary gland.

To obtain some initial evidence on the mechanism(s) of activation of PAH in rat mammary gland, we studied the carcinogenicity of a series of PAH directly applied to this tissue. A series of PAH which are or are not expected to be activated by one-electron oxidation because of their low or high ionization potential (IP), respectively, were tested. The compounds were dispersed as fine powders on an exposed mammary gland of female Sprague-Dawley rats. 5-Methylchrysene, dibenz[a,h]anthracene and benz[a]anthracene, which have relatively high IP, were inactive. In contrast, three PAH with relatively low IP, 7,12-dimethylbenz[a]anthracene, benzo[a]pyrene (BP), and 3-methylcholanthrene (MC), were potent carcinogens, 6-MethylBP, with low IP, and 7-methyl-benz[a]anthracene, with borderline IP, elicited only mesenchymal tumors, whereas BP 7,8-dihydrodiol and cyclopenta[cd]pyrene were inactive. A series of MC derivatives substituted at C-1 or C-2 was tested. Substituents at C-1, the position of activation in the one-electron oxidation pathway, generally suppressed carcinogenic activity. Substitution at C-2 did not eliminate carcinogenic activity, with the exception of MC2-one. These results provide initial information suggesting that one-electron oxidation may be a mechanism of activation for PAH in the mammary gland.

Animals↗

PubMed1996

Organic compounds in sludge-amended soils and their potential for uptake by crop plants.

Numerous toxic organic chemicals (TOs), with a wide range of chemical properties, can occur in sewage sludges. The vast majority of sludge-borne TOs occur at low concentrations, and even lower TO concentrations are expected in sludge-amended soils. Further, most TOs are so strongly reactive in the soil-sludge matrix that their bioavailabilities to plants are expected to be low. A host of experimental techniques have been employed to measure TO plant uptake and to relate bioavailability to TO chemical and physical properties. The strengths and weaknesses of several experimental approaches are examined, and the resulting data are evaluated. Sound experimental data, especially field data and/or data from studies with endogenously sludge-borne TOs, indicate negligible contamination of crop plants with TOs in sludge-amended soils. Assessing the potential for plant uptake of sludge-borne TOs involves determining: (a) which TOs are most likely present in biosolids and what are their toxicities; (b) what quantities of TOs are likely to be added to the growth media via biosolids application; (c) what effects various dissipation/dispersion reactions have on the potential bioavailability of TOs; and (d) what are the various mechanisms for plant uptake/metabolism of TOs.

Biological Availability↗

PubMedDate not supplied

The formation and occurrence of polynuclear aromatic hydrocarbons associated with food.

Polynuclear aromatic hydrocarbons are common contaminants of processed food, usually at trace levels. These hydrocarbons are products of combustion and pyrolysis, and are present in petroleum and coal, and in products derived from them. Most polynuclear aromatic hydrocarbons are not carcinogenic, but some of them are, and a few are potent inducers of skin and lung tumors in mice. Their carcinogenic properties have not been fully explored, but they seem to be less potent by ingestion or inhalation, and they are known as a group to produce cancer in humans. The most effective carcinogens among them are those with 5 or 6 fused rings, and these tend to be less prevalent in mixtures than the 3- and 4-ring hydrocarbons, most of which are not carcinogenic. Sophisticated analytical methods, using solvent extraction and chromatography have been developed to detect and measure polynuclear aromatic hydrocarbons at levels of 1 in 10(9) (1 part per billion) or less, and these have been applied to the measurement of individual compounds in foods, as well as in products of combustion and pyrolysis. Wood smoke and smoked foods contain the carcinogenic benzo[a]pyrene at levels of 1 ppb, and other hydrocarbons; liquid smoke has lower levels. Crude vegetable oils have higher concentrations, but purified 'deodorized' oils have benzo[a]pyrene levels near 1 ppb. Sausages cooked over burning logs had as much as 200 ppb benzo[a]pyrene. Charcoal-broiled steaks and ground meat had benzo[a]pyrene concentrations up to 50 micrograms/kg, while less fatty pork and chicken had lower concentrations (up to 10 micrograms/kg). It was probable that the rendered fat dripped on to the hot charcoal and pyrolyzed to form quantities of polynuclear aromatic hydrocarbons, which rose with the smoke to deposit on the meat. Therefore, oven cooking or cooking with a heat source above the meat, or segregation of the meat from the smoke resulted in food containing negligible amounts of polynuclear aromatic hydrocarbons. Modifications of cookings practices accordingly would greatly reduce exposure to this group of carcinogens.

Animals↗

PubMed2004

Radiation damage in coronene, rubrene and p-terphenyl, measured for incident electrons of kinetic energy between 100 and 200 kev.

We have measured the sensitivity of three highly conjugated organic compounds to electron irradiation. Using a 200 keV TEM, loss of crystallinity was determined from quantitative electron-diffraction measurements. Degradation of the molecular ring structure was monitored from fading of the 6 eV pi-excitation peak in the energy-loss spectrum. Measurements at incident energies between 30 keV and 100 eV were made using a scanning electron microscope (SEM), by recording gradual decay of the cathodoluminescence (CL) signal. Expressed in Grays, the energy dose required for CL decay in coronene is a factor of 30 lower than for destruction of crystallinity and a factor of 300 lower than for destruction of the molecular structure. Below 1 keV, the CL-decay cross section shows no evidence of a threshold effect, indicating that the damage involved is caused by valence-electron (rather than K-shell) excitation. Therefore even relatively radiation-resistant organic materials may undergo some form of damage when examined in a low-energy electron microscope or a low-voltage SEM.

Dose-Response Relationship, Radiation↗

PubMed1988

Arteriosclerotic plaque development is 'promoted' by polynuclear aromatic hydrocarbons.

In previous work we found that weekly injections of the polynuclear aromatic hydrocarbon (PAH) carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) induced spontaneous aortic plaques in cockerels to grow to a larger size and at a faster rate than plaques in control animals. To determine whether plaque-stimulating ability is related to carcinogenic potency or mutagenicity we have now tested a variety of agents, including PAH carcinogens, non-PAH carcinogens and weakly carcinogenic PAHs. Cockerels were injected weekly (from 4-20 weeks of age) with one of the following compounds: benzo[a]pyrene (B[a]P), benzo[e]pyrene (B[e]P), dibenz[a,h]anthracene (AH), dibenz[a,c]anthracene (AC), 3-methylcholanthrene (MCA), acetylaminofluorene (AAF), N-methyl-N,N'-nitro-nitrosoguanidine (MNNG) or anthracene (ANT). Plaques were present in the abdominal aortas of all animals. Plaque volumes were 8-14 times greater in AC-, B[a]P-, B[e]P-, MCA- and AH-treated cockerels than in controls. Plaques were slightly larger in the AAF-treated group than in control animals, and in the ANT- and MNNG-treated groups were indistinguishable in size from plaques in control animals. The largest plaque volumes were in AH-treated cockerels and were comparable in size to those elicited by DMBA treatment. The accelerated development of plaques is consistent with a 'promotional' role for these agents. There was a poor correlation between mutagenicity or carcinogenicity and plaque 'promotion', which may reflect a role for different metabolites in these processes.

2-Acetylaminofluorene↗