Changes in the classification of carcinogenic chemicals in the work area

Carcinogenic chemicals in the work area are currently classified into three categories in section III of the German List of MAK and BAT Values (list of values on maximum workplace concentrations and biological tolerance for occupational exposures). This classification is based on qualitative criteria and reflects essentially the weight of evidence available for judging the carcinogenic potential of the chemicals. It is proposed that these categories – IIIA1, IIIA2, IIIB – be retained as Categories 1, 2, and 3, to correspond with European Union regulations. On the basis of our advancing knowledge of reaction mechanisms and the potency of carcinogens, these three categories are supplemented with two additional categories. The essential feature of substances classified in the new categories is that exposure to these chemicals does not contribute significantly to risk of cancer to man, provided that an appropriate exposure limit (MAK value) is observed. Chemicals known to act typically by nongenotoxic mechanisms and for which information is available that allows evaluation of the effects of low-dose exposures, are classified in Category 4. Genotoxic chemicals for which low carcinogenic potency can be expected on the basis of dose-response relationships and toxicokinetics, and for which risk at low doses can be assessed are classified in Category 5. The basis for a better differentiation of carcinogens is discussed, the new categories are defined, and possible criteria for classification are described. Examples for Category 4 (1,4-dioxane) and Category 5 (styrene) are presented.     

Emphysema in the renal allograft

Two diabetic patients in whom emphysematous pyelonephritis developed after renal transplantation are described. Clinical recognition of this unusual and serious infection is masked by the effects of immunosuppression. Abdominal radiographic, ultrasound, and computed tomography findings are discussed. The clinical presentation includes urinary tract infection, sepsis, and acute tubular malfunction of the allograft in insulin-dependent diabetics.     

Metabolism and pharmacokinetics of vinyl acetate

The hydrolysis of vinyl acetate (formation of acetic acid) has been studied in vitro with rat liver and lung microsomes, rat and human plasma and purified esterases (such as acetylcholine esterase, butyrylcholine esterase, carboxyl esterase). Characterization of the kinetic parameters revealed that rat liver microsomes and purified carboxyl esterase (from porcine liver) displayed the highest activity.In order to establish the rate of metabolism of vinyl acetate in vivo, rats were exposed in closed desiccator jar chambers, and gas uptake kinetics were studied. The decay of vinyl acetate was dose-dependent, indicating possible saturation of metabolic pathway(s). The maximal clearance (at lower concentrations) of vinyl acetate from the system (30 000 ml/h per kg body weight) was similar to the maximal ventilation rate in this species. This indicated that under conditions when metabolic enzymes are not saturated the metabolic rate is mainly determined by pulmonary uptake.The exposure of rats to vinyl acetate resulted in a transient exhalation of significant amounts of acetaldehyde into the closed exposure system. This indicates the presence of this metabolic intermediate of vinyl acetate in the organism in vivo.     

The "Tuebingen desiccator" system, a tool to study oxidative stress in vivo and inhalation toxicokinetics

The "Tuebingen desiccator," a gas-tight all-glass closed chamber system (CCS), has been established in Herbert Remmer's Institute of Toxicology, University of Tuebingen, to investigate the mechanisms underlying the exhalation of endogenous volatile hydrocarbons in rats under oxidative stress. Remmer and associates confirmed the former view that ethane and n-pentane were derived from polyunsaturated fatty acids, and they demonstrated that propane, n-butane and isobutane were released from amino acids. Hydrocarbons exhaled following acute ethanol treatment of rats resulted predominantly from ethanol-dependent inhibition of their metabolism and partly from oxidation of proteins. Exhalation of alkanes in carbon tetrachloride exposed rats did not reflect liver damage, which was, however, directly linked to the amount of carbon tetrachloride metabolized. As has first been shown in Herbert Remmer's institute by investigating the fate of inhaled vinyl chloride in rats, the CSS proved to be also an excellent tool for studying toxicokinetics of inhaled gaseous xenobiotics by means of gas uptake experiments. Based on results gained by such studies, it was recently demonstrated that knowledge of compound-specific physicochemical and species-specific physiological parameters are often sufficient to predict important toxicokinetic properties of inhaled chemicals such as tissue burdens at steady state. By means of the CCS, not only kinetics of a parent gaseous substance but also of gaseous metabolites can be investigated in vivo, as exemplified for ethylene oxide and 1, 2-epoxy-3-butene, metabolites of ethylene and 1,3-butadiene, respectively. Gas uptake studies in closed chamber systems are now worldwide used for determining toxicokinetic parameters relevant for physiological toxicokinetic modeling.     

Biological effects of imidazolium ionic liquids with varying chain lengths in acute Vibrio fischeri and WST-1 cell viability assays

Detailed biological studies of methyl- and some ethylimidazolium ionic liquids in luminescent bacteria as well as in the IPC-81 (leukemia cells) and C6 (glioma cells) rat cell lines are presented. Effective concentrations in these test systems are generally some orders of magnitude lower than effective concentrations [corrected] of the conventional solvents acetone, acetonitrile, methanol, and methyl t-butyl ether. No general influence of the anionic compound in the ionic liquids on toxicity could be found, although they seem to modulate toxicity in some cases. The clear influence of the alkyl chain length on toxicity was quantified by linear regression analysis. Alkyl chain length of the longer alkyl chain was varied from 3 to 10 carbon atoms. Consequences for a design of sustainable alternative solvents are briefly sketched.     

Influence of caloric restriction on the development of atherosclerosis in nonhuman primates: progress to date

Caloric restriction (CR) has been observed to retard aging processes and extend the maximum life span in rodents. In an effort to evaluate the effect of this nutritional intervention on physiologic variables in higher species, several nonhuman primate trials are ongoing. In particular, a study evaluating the independent effect of CR on the extent of atherosclerosis was initiated in 1993 in 32 adult cynomolgus monkeys. Therefore, the trial was designed to achieve identical cholesterol intake after animals were randomized to a control group or a calorie-restricted group (30% reduction from baseline caloric intake). The animals were routinely evaluated for glycated proteins, plasma insulin and glucose levels, insulin sensitivity, and specific measures for abdominal fat distribution by CT scans over a 4-year interval. The results from 4 years of intervention demonstrate that CR improves cardiovascular risk factors (such as visceral fat accumulation) and improves insulin sensitivity. In contrast to other primate studies with normolipidemic animals, CR had no independent effects on plasma lipid levels and composition in the presence of equivalent amounts of dietary cholesterol intake. Preliminary analysis of atherosclerotic lesion extent in the abdominal aorta has failed to demonstrate differences between control animals and CR animals. Follow- up studies are being conducted to determine the effect of CR on atherosclerosis extent in coronary and carotid arteries.      

Toxicokinetics of inhaled propylene in mouse, rat, and human

A physiological toxicokinetic (PT) model was developed for inhaled propylene gas (PE) in mouse, rat, and human. Metabolism was simulated to occur in the liver (90%) and in the richly perfused tissue group (10%). The partition coefficients tissue:air were determined in vitro using tissues of mice, rats, and humans. Most of the tissues have partition coefficients of around 0.5. Only adipose tissue displays a 10 times higher value. The partition coefficient blood:air in human is 0.44, about half of that in rodents. PE can accumulate in the organism only barely. For male B6C3F1 mice and male Fischer 344/N rats, parameters of PE metabolism were obtained from gas uptake experiments. Maximum rates of metabolism (V(maxmo)) were 110 micromol/h/kg in mice and 50.4 micromol/h/kg in rats. V(maxmo)/2 was reached in mice at 270 ppm and in rats at 400 ppm of atmospheric PE. Pretreatment of the animals with sodium diethyldithiocarbamate resulted in an almost complete inhibition of PE metabolism in both species. Preliminary toxicokinetic data on PE metabolism in humans were obtained in one volunteer who was exposed up to 4.5 h to constant concentrations of 5 and 25 ppm PE. The PT model was used to calculate PE blood concentrations at steady state. At 25 ppm, the blood values were comparable across species, with 0.19, 0.32, and 0.34 micromol/L for mouse, rat, and human, respectively. However, the corresponding rates of PE metabolism differed dramatically, being 8.3, 2.1, and 0.29 micromol/h/kg in mouse, rat, and human. For a repeated human exposure to 25 ppm PE in air (8 h/day, 5 days/week), PE concentrations in venous blood were simulated. The prediction demonstrates that PE is eliminated so rapidly that it cannot accumulate in the organism. For low exposure concentrations, it became obvious that the rate of uptake into blood by inhalation is limited by the blood flow through the lung and the rate of metabolism is limited by the blood flow through the metabolizing organs.