Observation of the Self-Modulation Instability via Time-Resolved Measurements.

Self-modulation of an electron beam in a plasma has been observed. The propagation of a long (several plasma wavelengths) electron bunch in an overdense plasma resulted in the production of multiple bunches via the self-modulation instability. Using a combination of a radio-frequency deflector and a dipole spectrometer, the time and energy structure of the self-modulated beam was measured. The longitudinal phase space measurement showed the modulation of a long electron bunch into three bunches with an approximately 200 keV/c amplitude momentum modulation. Demonstrating this effect is a breakthrough for proton-driven plasma accelerator schemes aiming to utilize the same physical effect.

Inhibitory effect of tetrachloro-p-hydroquinone and other metabolites of hexachlorobenzene on hepatic uroporphyrinogen decarboxylase activity with reference to the role of glutathione.

Exposure of rats to HCB caused a dose-dependent depletion of GSH. Chlorophenolic and sulfur-containing metabolites of HCB incubated with GSH-free rat liver cytosolic protein drastically diminished the UROD activity. In addition, HCB also exhibited inhibitory potency. The most effective compounds studied were TCH and its oxidation product, chloranil. Incubation of liver cytosolic protein and of GSH with HCB and its metabolites yielded results that suggested interaction between the compounds and cell constituents--an interaction that may cause inhibition of the hepatic UROD activity in the HCB-exposed organism.

Biotransformation and porphyringogenic action of hexachlorobenzene and its metabolites in a primary liver cell culture.

Hexachlorobenzene (HCB) is metabolized in a primary culture of chick embryo liver cells and causes porphyrin accumulation within 24 h after administration. The HCB-metabolites, pentachlorothiophenol (PCThP), pentachlorobenzene (PeCB) and pentachlorophenol (PCP) identified in liver cell culture are already known from long-term experiments with rats. The pattern of accumulated porphyrins is comparable with the pathological porphyrin pattern observed in oral feeding studies with warm blooded laboratory animals. Protein bound radioactivity was found in cell cultures treated with [14C] HCB. Addition of the monooxygenase-inhibitor piperonyl butoxide or ascorbic acid decreased the irreversible binding of 14C-metabolites. The results show that biotransformation of HCB fulfils an essential role in the onset of porphyria. Since none of the main HCB-metabolites could induce a pathological porphyrin pattern, a reactive intermediate capable of reacting with glutathione or thiol-groups of uroporphyrinogen decarboxylase (UROG-D) is believed to be responsible for the inhibition of UROG-D. The chick embryo liver cell system may be considered as a useful and sensitive system for studying the metabolism of xenobiotics in relation to their toxicity.

Metabolic fate of hexabromobenzene in rats.

To study the metabolic fate of hexabromobenzene (HBB) in female rats, the substance was administered in oral doses of 16.6 mg/kg body weight every other day for 2 weeks and the animals' excreta were examined for metabolites. Unchanged HBB, pentabromobenzene, oxygen- and sulphur-containing metabolites were detected in feces and urine. The sulphur-containing substances contained free mercapto groups except for the presence in feces of a methylmercapto derivative. The amount of sulphur-containing metabolites was estimated to be 15 times greater than that of oxygen-containing compounds. The relative proportions of the unchanged compound and its metabolites in the excreta were about 1:4.

Enteral absorption and biotransformation of the food additive octyl gallate in the rat.

Following oral administration of 14C-labelled octyl gallate in a single dose of 15 mg/kg to female rats, only 20-30% of the radioactivity administered was detected in the tissues, while 60-80% of the dose was found in the contents of the gastro-intestinal tract up to 12 hr after administration. Isotope dilution analysis demonstrated the presence of the unchanged ester in the tissues. In the liver, the highest concentration of the ester demonstrated was 1.6 micrograms/g. in a rat killed 10 min after treatment. In the 24 hr following ip administration of labelled octyl gallate, about 91% of the administered radioactivity was recovered. Most of this was in the form of metabolites, only 9% being accounted for as unchanged ester.

2,2',4,4',5,5'-hexabromobiphenyl: its toxicokinetics, biotransformation and porphyrinogenic action in rats.

The porphyrinogenic action of 2,2',4,4',5,5'-hexabromobiphenyl and its toxicokinetics were studied in female Wistar rats that were treated every other day for 6 wk with oral doses of 112 mg/kg body weight. Subsequently, the animals were kept for a further period of 22.5 months but without supply of the brominated biphenyl. 10.5 months after cessation of treatment the compound reached a maximum concentration in the adipose tissue followed by a gradual decline of its content. In the liver the concentration of the substance started to decrease 3 months after cessation of treatment. In the excreta, hexabromobiphenylol and two pentabromobiphenyls were detected as metabolites. The rate of biotransformation amounted to about 5%. At the end of the dosing period no alterations in the content and profile of the hepatic porphyrins were observed. Urinary porphyrins and their precursors delta-aminolaevulinic acid and porphobilinogen were slightly elevated. The urinary porphyrin pattern and faecal porphyrin content and pattern did not differ from those of the controls. 15 and 18 months after cessation of treatment (16.5 and 19.5 months after the start of treatment) two animals were found to have marked alterations in the content and profile of hepatic porphyrins with uro- and heptacarboxyporphyrin predominating. It was concluded that there is an extreme delayed individual porphyric response to 2,2',4,4',5,5'-hexabromobiphenyl in female rats.

Elimination of porphyrins and their precursors in rats pretreated with hexabromobenzene.

The elimination times of porphyrins and their precursors and of hexabromobenzene (HBB) itself were studied in female rats given 15 mg HBB by stomach tube every other day for 4 months. The concentrations of HBB in the blood, liver and adipose tissue were in the ratio 1:1.5:25, 24 hr after the last dose. Two weeks after the end of treatment, HBB was no longer detectable in the tissues. In animals given a single oral dose of 16.6 mg HBB/kg body weight, HBB was no longer detectable in adipose tissue 12 days after dosing. The half-life of HBB in adipose tissue was about 2.5 days in the animals given HBB for 4 months, and at the end of the treatment the concentrations of porphyrin in the liver, urine and faeces were increased to about 1000, 600-700 and 60-70 times the control values. The amounts of delta-aminolaevulinic acid and porphobilinogen in the urine of treated animals were 6-7 times those in controls. After the end of HBB treatment, it took almost 1.5 yr for delta-aminolaevulinic acid and porphobilinogen excretion to return to normal. Nearly 2 yr were needed for complete elimination of the accumulated liver porphyrins.

[The value of 2 distinct prognosis scores in patients with peritonitis. The Mannheim Peritonitis Index versus the Apache II score]. / Unterschiedliche Aussagekraft von zwei verschiedenen Prognose-Scores bei Patienten mit Peritonitis. Mannheimer Peritonitis-Index versus Apache II-Score.

Seventy patients suffering from purulent peritonitis entered this study, 31 of them were taken in prospectively, to contrast two different prognostic scores, the Mannheim Peritonitis Index (MPI) vs. the Apache II (APS II). The MPI is shown as a prognostic index for peritonitis with high accuracy in individual prognosis. The simultaneous use of both scores, the MPI as well as the APS II, leads to a negligible improvement of prognostic accuracy. Moreover, sensitivity and specificity with the MPI are of higher accuracy than calculated with the APS II.

[Evaluation and requirements of natural room ventilation]. / Beurteilung und Erfordernisse der natürlichen Raumlüftung.

The current application of the carbon dioxide standard ("Kohlensäuremassstab") of 0.1 vol.-% CO2 given by Pettenkofer 140 years ago is assessed in order to evaluate tolerable indoor air and sufficient indoor air ventilation. For this purpose, criteria by Pettenkofer were contrasted by currently valid criteria. It was found that an actual guidance value should be clearly higher than the one given by Pettenkofer. As confirmed by recent measurements this actual guidance value should be around 0.15 vol.-% CO2. By means of a few examples requirements for indoor aeration of living rooms and classrooms are made evident. The corresponding calculations are based on the indoor air guidance value (i.e. actualised value of Pettenkofer) of 0.15 vol.-% CO2 and are based on respiration rates compiled in "Standards of exposure assessment" by the health authorities of the German federal states. The calculated number of complete renewals of air achieved by circulation shows that recent values given by others concerning the permitted indoor self aeration were set too low and require correction. Applying the demonstrated requirements for indoor ventilation many of the well known problems of indoor air can be minimised or even solved.

Studies on the toxicology of hexachlorobenzene. I. Pharmacokinetics.

In female rats dosed orally with 14C-hexachlorobenzene the extent of intestinal absorption of carbon-14 has been found to be dependent on the form of application. When the substance was given as a solution in oil about 80% of the dose administered was absorbed, but when given as an aqueous suspension only 6%. In animals treated with 14C-hexachlorobenzene dissolved in oil, all tissues contained radioactivity. Highest levels were found in adipose tissue, lowest in blood and muscle. Peak values of radioactivity were reached between 2 to 5 days after application. Elimination was studied after intraperitoneal application of 4 mg/kg14C-hexachlorobenzene dissolved in oil. Two weeks after administration, 34% of the radioactivity administered was recovered in the feces and 5% in urine. About 80% of carbon-14 excreted in feces and about 4% in urine was contained in the unchanged drug. This indicates that biodegradation of hexachlorobenzene in the rat is not insignificant. No radioactivity was detected in the expired air.

Excretion of metabolites of hexachlorobenzene in the rat and in man.

From the urine of rats treated with hexachlorobenzene (HCB), 21 metabolites were separated by capillary gas chromatography. Sulfur-containing metabolites were present in larger numbers and greater amounts than phenolic compounds. In studies on the origin of pentachlorophenol in man, HCB was determined in adipose tissue and pentachlorophenol in urine, and in 48 out of 60 females, 80-90% of the daily urinary pentachlorophenol appeared to be formed from HCB.

[Aviation fuels and aircraft emissions. A risk characterization for airport neighbors using Hamburg Airport as an example]. / Flugzeugtreibstoffe und Flugzeugemissionen. Eine Risikocharakterisierung für Flughafenanwohner am Beispiel des Hamburger Flughafens.

Aviation fuels are well characterised regarding their physical and chemical properties. Health effects of fuel vapours and of liquid fuel are described after occupational exposure and in animal studies. Exposure of the general population (airport visitors and people living in the vicinity of airports) may occur during fuel supply particularly in warm summers (odour). Aircraft emissions vary with the engine type and the kind of fuel. Combustion of aviation fuel results in CO2, H2O, CO, C, NOx and a great number of organic compounds. Among the emitted polyaromatic hydrocarbons (PAH) no compound characteristic for jet engines (tracer) could be detected so far. Hardly any data exist on the toxicology of jet engine emissions. According to analyses of their chemical composition, however, they contain various toxicologically relevant compounds including carcinogenic substances. Measurements in ambient air around the Hamburg Airport show no elevated pollutant levels. However, no such data exist on aldehydes, black smoke or fine particles. Annoying odours have been stated in some areas around the airport, which were mainly attributed to the aircraft engine emissions rather than to fuel vapours.

Studies on the toxicology of hexachlorobenzene. IV. Sulphur-containing metabolites.

After administration of hexachlorobenzene rats excrete sulphur-containing conjugates from which pentachlorothiophenol can be split off. In the present study we describe the identification of pentachlorothiophenol and pentachlorothioanisol in the livers of animals treated with hexachlorobenzene. In order to clarify the further fate of these two substances, we administered them to rats, and isolated the conversion products excreted in the urine and feces. The metabolites of pentachlorothiophenol and pentachlorothioanisol are excreted in both conjugated and free form. From extracts of the excreta, we isolated tetra- and trichlorobenzene with two or three sulphur-containing substituents on the ring, analogous compounds in which thiol groups were converted into sulphoxide and sulphone groups, as well as analogous compounds with a phenolic oxygen in addition to sulphur, and sulphur-containing compounds in which clorine was replaced by hydrogen. Following administration of the sulphoxide and of the sulphone of pentachlorothioanisol under analogous conditions, pentachlorothiophenol and pentachlorothioanisol and their metabolites were detected in the excreta of the animals. No evidence was obtained that the parent compounds are excreted in the unchanged form.

Hexachlorobenzene porphyria in rats as a model for human chronic hepatic porphyrias.

1. Hexachlorobenzene porphyria in the rat provides a suitable experimental model of the stages of development of human chronic hepatic porphyria. Just as in chronic hepatic porphyria in man, the development of experimental HCB porphyria in the rat can be divided into several stages. 2. The findings in this study indicate that porphyrins increase in the urine, liver, kidney, and spleen, and to a lesser degree in the serum, with uroporphyrin and heptacarboxylic porphyrin predominating. 3. In contrast to the distribution of porphyrin accumulation in the various organs, clear evidence of a uroporphyrinogen decarboxylase defect was found only in the liver. Formation of uroporphyrin and heptacarboxylic porphyrin by homogenized HCB kidney tissue did not deviate significantly from that by control kidney. The defect could not be unequivocally evaluated in the spleen because the spleen, like the red cells, normally forms considerable amounts of uroporphyrin from porphobilinogen, which were increased only a few times over in synthesis by the HCB spleen. 4. Isomer studies provide no evidence for an additional uroporphyrinogen cosynthase defect.

Studies on the toxicology of hexachlorobenzene. II. Identification and determination of metabolites.

Female rats were dosed intraperitoneally with 14C-hexaxhlorobenzene. The drug was administered on 2 or 3 occasions. The total doses amounted to 260 and 390 mg/kg 14C-hexachlorobenzene, respectively. Urine and feces from the animals were collected over a period of 4 weeks after the first injection. Both excreta and some tissues of the animals were examined for their content of radioactivity and for hexachlorobenzene and its metabolites. Gas chromatography, isotope dilution analysis, and combined gas chromatography-mass spectrometry were used to identify the metabolites of hexachlorobenzene. In urine pentachlorophenol, tetrachlorohydroquinone, and pentachlorothiophenol were present as major metabolites. One of the isomers of tetrachlorothiophenol was present as a minor metabolite. In the feces pentachlorophenol and pentachlorothiophenol only were identified. At the end of the experiment, carbon-14 excreted with urine and feces amounted to 7% and 27%, respectively, of the radioactivity administered. More than 90% of carbon-14 excreted in urine was contained in the major metabolites. In the feces about 30% of the excreted radioactivity was bound to metabolites and about 70% was contained in the unchanged drug, while in the tissues of the animals only pentachlorophenol was detected in measurable amounts, accounting for 10% of label in blood and less than 0.1% of carbon-14 determined in body fat. Total radioactivity contained in the metabolites detected in the animal body and in the excreta at the end of the experiment accounted for about 16% of the administered radioactivity.

[Uncertainty analysis of quantitative risk assessment in temporally variable exposures: model observations based on biological and epidemiological risk models]. / Unsicherheitsanalyse für quantitative Risikoabschätzungen bei zeitlich variablen Expositionen: Modellbetrachtungen auf Grundlage biologischer und epidemiologischer Risikomodelle.

Unit risks used for quantitative cancer risk assessment are defined for constant lifetime exposures. The condition of temporal stability, however, usually is not fulfilled in environmental health applications. In practice, cancer risks for time-dependent exposures are often estimated by calculating lifetime average exposure, assuming a mean life expectancy of 70 years. In the present paper we discuss the question whether this is an appropriate procedure considering various variants of multi stage and epidemiological relative risk models. For this purpose, lifetime risks for time dependent exposures as calculated according to the respective model assumptions, were compared with lifetime risks estimated by the lifetime average exposure approach. As typical exposure histories in environmental health applications we studied exposures either limited to the first 5 years of life (children scenario) or limited to duration of employment (30th to 65th year of age; occupational scenario). The consideration of multistage models (Armitage-Doll- and Moolgavkar-Venzon-Knudson model) in general would not induce serious bias in risk estimation when exposures are limited to middle ages (occupational scenario). On the other hand, when exposures occur only in very young ages or only in very old ages the risk estimated by using lifetime average exposure is not comparable with the predictions of multistage models. Whereas the degree of possible underestimation is bounded by factors well below 10, the amount of possible overestimation is unbounded and may become arbitrarily high, when exposures concentrate in extreme ages. In a second part of the study we investigated different relative risk models, taking lung cancer as an example. The models differed with respect to assumptions on latent periods and moderating effects of age at exposure and age at risk. The simulations showed that the unit risk concept is appropriate for the occupational scenario. For the children scenario results strongly depend on the assumptions made. Whereas the degree of possible underestimation is acceptable, in some models the degree of possible overestimation may become arbitrarily high. Both parts of the study showed that bias induced by using lifetime average exposure is acceptable when exposures are limited to middle ages. On the other hand, the unit risk concept should not uncritically be applied to exposures limited to early childhood (e.g., in kindergartens or due to mouthing activities). Depending on the assumptions made, lifetime risk may either be moderately underestimated or grossly overestimated. Without additional knowledge on mechanisms or latency period risk estimations are of questionable value. With respect to exposures in childhood regulation should concentrate on initiating substances or substances known to have long latent periods, respectively. With respect to cancers which occur relatively frequent already in childhood specific considerations are recommended.

[Health effects of ozone as component of summer smog]. / Gesundheitliche Wirkungen des Ozons als Bestandteil des Sommersmogs.

During the sunny summers of 1989 and 1990 in Germany the outdoor ozone levels repeatedly exceeded the value of the air quality guidelines proposed by the World Health Organization. Both in multiple sites within industrial polluted and in supposedly clean outside areas the ozone concentrations exceeded the value of 180 micrograms/m3. The following paper is intended to contribute to an understanding of the health effects of ozone. It compiles data and views on the formation and analysis of ozone, on its distribution as ambient ground level pollutant, on respiratory and common symptoms in man and on the toxicokinetics, responses and pathogenesis in experimental animals. Studies on healthy exercising adult volunteers exposed to 240 micrograms/m3 ozone in purified lab air or in ambient air revealed a significant influence on connections between forced vital capacity, forced expiratory volume, flow rate and peak expiratory flow rate and the pollutant. Exposure to lower ozone levels induced the same effects, but they were of smaller magnitude. Children aged 8-15 years exercising under field conditions showed decrements in lung function even at ozone levels well below 200 micrograms/m3. Restitution of lung function needs periods of several days, although the induction of effects is a matter of hours. The relevance of the transient pulmonary responses is widely unclear. Among patients with chronic obstructive pulmonary disease or asthma, the functional responsiveness to ozone is not greater than among healthy subjects. Interindividual differences in responsiveness occur but are not predictable. Information on chronic effects is rather limited.(ABSTRACT TRUNCATED AT 250 WORDS)

Uroporphyrinogen decarboxylase deficiency in experimental chronic hepatic porphyria.

During hexachlorobenzene feeding of rats the following biochemical signs of a chronic hepatic porphyria developed: porphyrinuria with increase of uro- and hexacarboxyporphyrin, hepatic prophyrin accumulation of uro- and heptacarboxyporphyrin and a diminished activity of uroporphyrinogen decarboxylase in the liver, but nut in the red cells. During the 5.3 days of the intoxication the behaviour of metabolite constellation and enzyme activities was inverse. Hexachlorobenzene porphyria in rats is a pathobiochemical model of chronic hepatic prophyria, which in man becomes clinically manifest as porphyria cutanea tarda.