Biomedical subjects
Publications and source records attributed to M Døssing.
Antipyrine clearance was estimated by a one-sample technique in 14 patients with acute fever and clinical pneumonia. Antipyrine clearance during the acute illness was 31.4 +/- 7.6 ml/min (X +/- SD). Fourteen and 28 days later during convalescence, clearance values were higher (47.8 +/- 18.9 and 49.2 +/- 15.0 ml/min, respectively). We conclude that microsomal hepatic drug metabolism in adults is impaired during pneumonia.
Thirty-two fit patients scheduled for explorative arthrotomy of the knee were allocated randomly to either halothane/oxygen anesthesia or spinal anesthesia with bupivacaine 0.25 mg X kg-1. The day before and 1, 10, and 21 days after surgery, the aminopyrine breath test (ABT) was performed. The day before and 5, 10, and 21 days after surgery, the antipyrine clearance (APcl) was measured by the single sample saliva technique. The ABT as well as the APcl were increased significantly postoperatively (P less than 0.01). The day after surgery the ABT was increased by 13 +/- 21% in the spinal anesthesia group only, whereas a late increase by 14 +/- 31% was found in the halothane group. Five days after surgery, the APcl was increased by 36 +/- 45% in the spinal anesthesia group and by 21 +/- 28% in the halothane group. Both tests returned to base line values within 3 weeks postoperatively. In five volunteers following the same sampling scheme but receiving bupivacaine 0.25 mg X kg-1 im without surgery, no change in the ABT or the APcl was observed. The authors conclude that surgery may cause microsomal enzyme induction regardless of the anesthetic agent or technique used. The mechanism of this induction remains to be elucidated.
The saliva clearance of antipyrine was measured in 18 children from four samples taken about 9, 13, 22 and 25 h after ingestion of 20 mg kg-1. Antipyrine clearance determined from each of the samples using a volume of distribution estimated from age (A) and body weight (BW) and height (BH) (V = 1.535 X A + 0.339 X BW + 0.300 X BH - 35.63 (1] correlated closely with clearance determined from the total elimination curve (r greater than 0.94). Random variation and systematic deviation were minimal when the 22 h sample was used for clearance determination (r = 0.98, P less than 0.001, regression curve slope = 1.00, intercept = 0.58 and residual variance = 4.02). The one-sample method for determination of antipyrine saliva clearance is non-invasive, easy to perform and acceptable to children.
Acute pancreatic injury has been attributed to occupational exposure to chemical agents in workers, but there have been no previous reports of occupationally induced chronic pancreatitis. Severe chronic exocrine pancreatic insufficiency was found in a 29-year-old house painter, where other known causes of chronic pancreatitis could be ruled out. The patient had previously experienced abdominal pain and diarrhoea associated with exposure to spray paints followed by remission of the symptoms during vacations. Although the association between exposure and pancreatic insufficiency may be a random one, a possible causal relation should be further evaluated.
The impact of occupational exposure to jet fuel on antipyrine elimination was studied in 91 fuel-filing attendants. The mean antipyrine clearance was enhanced to 68.4 (SD 19.5) ml/min during exposure to jet fuel compared to 57.9 (SD 18.1) ml/min after an exposure-free period of two to four weeks. The corresponding values for 47 office workers (referents) were 62.7 (SD 22.2) ml/min and 56.4 (SD 22.3) ml/min. The median jet fuel concentration in the breathing zone of the fuel-filling attendants was 31 (range 1-1 020) mg/m3. No known inducing factor could be identified in the work environment of the office workers. No difference in the concentration of aspartate aminotransferase and alkaline phosphatase in serum was found either within or between the groups. Our study indicates that jet fuel, which is a mixture of aliphatic and aromatic organic solvents resembling gasoline and white spirit, is an inducer of hepatic drug metabolism in man.
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In a climatic exposure chamber four healthy volunteers were exposed to 100ppm toluene, 100ppm toluene + ethanol, 100ppm toluene + cimetidine, and 100ppm toluene + propranolol for 7h each at random over four consecutive days. A control experiment and 3.5h of exposure to 200ppm toluene were also performed. Ethanol inhibited toluene metabolism by 0.5 as expressed by the urinary excretion of two of the metabolites of toluene, namely o-cresol and hippuric acid. In agreement with this, the mean alveolar concentration of toluene was greater by 1.7 during ethanol exposure; 45 min after discontinuation of exposure the increase was by 3.3. Neither cimetidine nor propranolol changed toluene metabolism significantly. The results indicate that ethanol may prolong the time interval in which toluene is retained in the human body in persons simultaneously exposed to ethanol and toluene. When using o-cresol or hippuric acid in biological monitoring of persons occupationally exposed to toluene, the consumption of ethanol should be considered.
The activity of the hepatic microsomal enzyme system, which may be of great importance for metabolic activation and deactivation of hepatotoxic agents and carcinogens, is changed by exposure to commonly used industrial chemicals. The antipyrine test is the most widely used method for assessing microsomal enzyme activity in man. The clearance of antipyrine can be accurately calculated from one sample of saliva obtained about 24 h after an oral dose of the drug. By measuring antipyrine metabolism during exposure to industrial chemicals and at the end of 3-4 weeks free from exposure, the impact of industrial chemicals on antipyrine metabolism can be estimated, provided the chemicals are eliminated within 3-4 weeks. This test can be performed by skilled and unskilled workers using written instructions. This has broadened the application of the test. Other noninvasive indices of microsomal enzyme activity include the aminopyrine and caffeine breath tests and the urinary excretion of 6-beta-hydroxycortisol and D-glucaric acid. These tests probably reflect the activity of different but overlapping parts of the microsomal enzyme system and may be of value in research in occupational medicine. Previous studies indicate that chlorinated hydrocarbon insecticides, phenoxyacids, chlorophenols, polychlorinated biphenyles, some organic solvents and high concentrations of inhalation anaesthetics may stimulate microsomal enzyme activity, while styrene, toluene and inhalation anaesthetics in concentrations at about the allowed safety limit values have no effect. Lead, chemicals used by spray painters, and carbon disulphide probably inhibit the activity. While the short-term consequences of these changes include altered metabolism of hormones, vitamins, drugs, and other microsomally metabolized compounds, the possible impact on health on a long-term scale is unknown. It is now possible to study this with the use of the available noninvasive simple indices of microsomal enzyme activity. The potentially useful applications include biological monitoring of environmental carcinogenesis and hepatotoxicity.
Physical fitness, as expressed by maximal oxygen uptake (Vo2max), was measured in 14 subjects before and during physical education consisting of 4 to 8 hr of daily physical training. Mean pulse rate during training was 115 bpm. After 3 mo of physical training, Vo2max increased a mean 6% (range -5% to +23%). Corresponding mean increases in hepatic drug metabolism, as expressed by the metabolism of the model drugs antipyrine and aminopyrine, were 12% (range -12% to +59%) and 13% (range -21% to +47%). Changes in the two groups were still present 6 mo after physical education. There was only a moderately close but nonetheless significant correlation (r = 0.7) between the extent of change in Vo2max and the corresponding relative change in antipyrine metabolism during the 3-mo period of this investigation. The correlation between oxygen uptake and aminopyrine metabolism (r = 0.6) was slightly less and was not significant. Improved physical fitness associated with enhanced drug metabolism may lead to changes in drug efficacy and drug toxicity that may be clinically important in the case of drugs with low therapeutic indices.
During a period of 18 months three workers were admitted to hospital with jaundice that had developed two to four months after beginning work at a chemical plant. Liver biopsies showed severe centrilobular, haemorrhagic liver cell necrosis. The pathological changes resolved within six to 18 months. No damage to other organs was observed. The only worker who resumed work at the plant developed clinical and biochemical evidence of relapse of liver damage. Exposure to carbon disulphide, isopropanol, toluene, and acrylonitrile among others was shown, but liver damage may have been caused by a synergistic, hepatotoxic reaction mediated through the hepatic microsomal enzyme system. It was not possible to decide which chemical was responsible.
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Four healthy subjects were investigated weekly for 14 weeks by the antipyrine one sample saliva test, the 48-h urinary excretion of major antipyrine metabolites and the 2-h aminopyrine breath test before, during and after stimulation and inhibition of drug metabolism with phenobarbital and cimetidine, respectively. The phenobarbital-induced enhancement of antipyrine clearance (1.33-2.03 times) and of the aminopyrine breath test (0.94-1.19 times) occurred one week after beginning drug administration and persisted for 10 days after its cessation. The cimetidine-related inhibition of antipyrine clearance (0.62-0.85 times) and of the aminopyrine breath test (0.52-0.93 times) was observed 24 h after beginning cimetidine administration and subsided within two days after the last dose. During enhancement and inhibition the clearance of antipyrine to 3-hydroxymethyl-, 4-hydroxy- and norantipyrine varied as the total antipyrine clearance. The intraindividual variation in antipyrine clearance was 6-8%, and the corresponding variation in urinary excretion of antipyrine metabolites was 10-20%. It is concluded that the influence of phenobarbital and cimetidine on hepatic microsomal enzyme activity can be monitored simply by measurement of the blood concentration of the drug. Whether this simple relationship applies to other microsomally mediated drug interactions requires further evaluation.
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1 Clearance of a substance that follows first order kinetics can be determined from multiple plasma concentrations (the standard method) or from only one plasma concentration and an assumed volume of distribution (the simplified method). 2 On the basis of statistical considerations it is shown that the variance of the clearance determined by the standard method has a minimum when the mean sampling time is equal to the reciprocal elimination constant. For the simplified method the variance of the clearance is minimal when the sampling time is equal to the reciprocal elimination constant multiplied by one plus the ratio between the squared coefficients of variation of the concentration and the volume of distribution. 3 The sampling times determined in this way are optimal in the sense that the variance of the clearance estimate will be larger for any alternative choice of the same number of sampling times. In practice, the optimal sampling times can only be determined approximately because the elimination constant is not known exactly. The loss in precision of the clearance estimation arising herefrom will be less if the elimination constant is underestimated than if it is overestimated to the same relative extent. 4 In theory, the simplified method with optimal sampling time will give a more precise clearance determination than the standard method, if the number of optimally spaced sampling times is less than one plus the ratio between the squared coefficients of variation of the concentration and volume of distribution. In studies where each subject serves as his own control and the coefficient of variation of the volume of distribution is relatively small the simplified method will be of higher precision unless the number of samples with the standard method is unusually large.
Among 156 patients admitted to hospital because of suspected solvent intoxication or dementia following long-term occupational exposure to organic solvents, twenty-three had elevated aminotransferases in serum. In thirteen of these no particular cause of this elevation could be found and the chronic exposure to aliphatic and aromatic organic solvents is therefore likely to have played a pathogenetic role and a liver biopsy was performed. Liver histology revealed significant steatosis in eleven patients and in six of these focal necroses were also observed. Moreover, six of the biopsies showed enlarged portal tracts with fibrosis. Necrosis was only observed in liver specimens from patients who recently had been exposed to solvents. A causal relation between occupational exposure to aliphatic and aromatic organic solvents such as white spirit, xylene, toluene and styrene, and toxic liver injury is suggested by this descriptive study but needs confirmation.
Exposure to toluene vapour enhances hepatic microsomal enzyme function in animals as assessed by the metabolism of the test drug antipyrine. Thirty six printing trade workers with long term occupational exposure to a mixture of organic solvents and 39 matched controls were randomly allocated into four groups. Eighteen printers and 21 controls were exposed to 100 ppm of toluene during 6.5 hours in an exposure chamber. The remaining 18 printers and 18 controls were exposed to 0 ppm of toluene under similar conditions. The salivary clearance of antipyrine was measured immediately after the stay in the exposure chamber to investigate a possible acute change in liver function and was repeated two weeks later, shortly before the summer vacation. Antipyrine clearance was measured again at the end of the summer vacation-four weeks after exposure. To study a possible effect of chronic exposure on antipyrine clearance 12 printing trade workers with 17 years (median) of occupational exposure to toluene vapour at concentrations of about 100 ppm were investigated before and four weeks after cessation of exposure. No difference in antipyrine clearance was found either within the groups or between the groups at any of the measurements.
It is not known whether urinary excretion of hippuric acid (HA) or orthocresol (O-Cr) is to be preferred for the biological monitoring of workers with occupational exposure to toluene. To study this, 42 printing trade workers with more than 10 years' exposure to a mixture of organic solvents including toluene (0-20 ppm) and 43 control subjects matched by age, smoking habits, and living accommodation were investigated. Each matched pair was randomised to an experimental exposure of either 100 ppm or 0 ppm toluene for 6.5 hours under controlled conditions in an exposure chamber. Urinary excretion of HA and O-Cr was determined by high pressure liquid chromatography from samples obtained before exposure, during the first three hours, and during the last 3.5 hours of exposure. No difference in HA and O-Cr excretion was found between printing trade workers and controls. The median O-Cr excretion increased 29 times during exposure, whereas the HA excretion increased only five times. Thus only 3% of the O-Cr excretion originated from other sources than toluene whereas the corresponding value for HA was 19%. Standardisation of the concentrations of HA and O-Cr in relation to urinary creatinine reduced the relative variation by 29% and 56% respectively. This was not reduced further by expressing the excretions as average excretion rates based on total volume of urine collected. Background urinary O-Cr excretion was three to four times higher among smokers than non-smokers, probably due to the content of O-Cr in cigarettes. The O-Cr excretion in unexposed smokers was, however, 10 times lower that that of the non-smokers during the end of the experimental exposure to 100 ppm toluene.