Antero Aitio

Urinary and blood manganese in occupationally nonexposed populations and in manual metal are welders of mild steel

SummaryTo obtain reference values for blood and serum manganese levels, blood specimens were collected from 29 men and 36 women. Mn in blood showed a normal distribution; its upper 97.5% limit in blood was 0.38 μmol/l. Mn in serum showed a skewed distribution, which did not differ from the normal one after logarithmic transformation. The respective reference limit was 19 nmol/l. In both specimens, the levels of Mn were significantly lower in men than in women. To obtain reference values for Mn in urine, midday urine specimens were collected from 58 men and 96 women. Mn in urine also showed a skewed distribution, and the upper 97.5% limit was 38 nmol/l. The levels of Mn in blood and urine were statistically significantly higher in manual metal arc (MMA) welders of mild steel (MS) than in the reference populations. Five MMA/MS welders were subjected to a further study in which the ambient intramask Mn levels and urinary Mn excretion were monitored throughout a full working week. For two welders the correlation of Mn in urine specimens voided in the afternoon was good with the before noon Mn concentrations in the hygienic measurements; for the rest the correlation was minimal. Mn in diurnal urine specimens collected in six portions showed fluctuation if specific gravity or creatinine in urine was used to standardize for the urinary flow, but it was less evident for urinary Mn excretion rate. Our results seem to indicate that the measurement of Mn in urine or blood may be used for monitoring Mn exposure in MMA/MS welders only at the group level.

Occupational exposure to lead and neuropsychological dysfunction

OBJECTIVE: To evaluate the neuropsychological effects of current low level and previous higher levels of exposure to lead and evaluate the relation between effects of lead and bone lead. METHODS: A neuropsychological test battery was given to 54 storage battery workers with well documented long term exposure to lead. The effect was studied in two subgroups: those whose blood lead had never exceeded 2.4 mmol/l (the low BPbmax group, n = 26), and those with higher exposure about 10 years earlier (the high BPbmax group, n = 28). In both groups, the recent exposure had been low. Correlations between the test scores and the indices of both long term and recent exposure--including the content of lead in the tibial and calcaneal bone--and covariance analyses were used to assess the exposure-effect relation. Age, sex, and education were controlled in these analyses. RESULTS: Analyses within the low BPbmax group showed a decrement in visuospatial and visuomotor function (block design, memory for design, Santa Ana dexterity), attention (digit symbol, digit span), and verbal comprehension (similarities) associated with exposure to lead and also an increased reporting of subjective symptoms. The performance of the high BPbmax group was worse than that of the low BPbmax group for digit symbol, memory for design, and embedded figures, but there was no reporting of symptoms related to exposure, probably due to selection in this group. No relation was found between the output variables and the tibial lead concentration. The calcaneal lead concentrations were related to the symptoms in the low BPbmax group. CONCLUSIONS: Neuropsychological decrements found in subjects with high past and low present exposure indicate that blood lead concentrations rising to 2.5-4.9 mmol/l cause a risk of long lasting or even permanent impairment of central nervous system function. Milder and narrower effects are associated with lower exposures; their reversibility and time course remain to be investigated. History of blood lead gives a more accurate prediction of the neuropsychological effects of lead than do measurements of bone lead.

Organ specific induction of drug metabolizing enzymes by 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat

Abstract The effect of 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) was studied on the activities of arylhydrocarbon hydroxylase, ethoxycoumarin deethylase, cytochrome c reductase, epoxide hydratase, UDP glucuronosyltransferase, and glutathione S -transferase in the liver, kidney, lung, small intestinal mucosa, and testis of male Wistar rats. There was a severalfold increase in the activity of monooxygenase in the liver, kidney, and lung, whereas virtually no effect could be detected in the intestine or testes. The proportion of 3- and 9-hydroxylation of the total hydroxylation of benzo( a )pyrene decreased in the liver, but increased in the kidney. TCDD had no significant effect on epoxide hydratase or glutathione S -transferase activities in any tissues. UDP glucuronosyltransferase exhibited a sevenfold increase in the liver, less than twofold in the kidney, and none in other tissues. Treatment of the microsomes with digitonin, trypsin, or phospholipase A did not reveal additional induction UDP glucurnosyltransferase, although all were able to increase measurable enzymatic activity in control and TCDD-treated animals. TCDD seems to be different from phenobarbital and polycyclic hydrocarbons as an effector of not only monooxygenase but also epoxide hydratase, UDP glucuronosyltransferase, and glutathione S -transferase.

Glucuronide Synthesis in the Rat and Guinea Pig Lung

Abstract1. Rat and guinea pig lungs were shown to possess uridinediphosphate glucuronyltransferase activity which occurs in the microsomal fraction of lung homogenates. The O-glucuronides formed were identified by using radioactive isotopes and chromatographic techniques, and by hydrolysis by β-glucuronidase.2. UDP-glucuronyltransferase activity in the lung was 1/3–2/3 of that in the liver when calc. per mg microsomal protein, but less than 10% per unit wet weight. The activity of guinea pig lung was twice that of rat lung.3. Digitonin enhanced the activity of the UDP-glucuronyltransferase of the lung 2–3-fold, compared with 4–5-fold in the liver of the guinea pig and 8–9-fold in liver of the rat. Digitonin increased the apparent Km value for 4-methyl-umbelliferone 5-fold both in the pulmonary and hepatic microsomes.

Enhancement of drug oxidation and conjugation by carcinogens in different rat tissues

The administration of carcinogenic polycyclic hydrocarbons has been shown to enhance hepatic drug oxidation [ 1, 21. An increase takes place also in the skin [3-61, lungs and gastrointestin~ tract [7-91, kidneys [S] and placenta [ 1 O] . The oxidation step in detoxi~cation is followed in viva by conjugation. In separate studies an e~ancement of ~ucuronide synthesis has been reported in the liver [ 1 1 1 S] and skin [ 161. The time courses of the responses have not, however, received much attention. The present study was performed to clarify the responses of arylhydrocarbon hydroxylase (EC 1.14.1.1) and UDP glucuro]~yItransferase (EC 2.4.1.17) in the intestinal mucosa, liver and kidneys after an administration of 3,4-benzpyrene and 3-methylcholanthrene to rats. These two enzymes have a close functional and topochemical relationship which suggests that their synthesis might have a common control mechanism. The rise of the UDP glucuronyhransferase activity was preceded with a much more pronounced rise of the arylhydrocarbon hydroxylase activity in all tissues studied. The induction of the hepatic hydroxylase was significantly higher when the intraperitoneal administration route was used instead of the intragastric one.

UDF glucuronyltransferase activity in various rat tissues

Abstract 1. 1. A low UDP glucuronyltransferase (4-methylumbelliferone) activity was detected in the brain, heart, retroperitoneal fat and diaphragm of the rat. No activity could be observed in the blood. An intermediate activity resided in the thymus, spleen and lung. The highest activity per unit weight was in the liver, duodenal mucosa, adrenal gland and kidney. 2. 2. The placenta from rat, rabbit and guinea pig exhibited a microsomal UDP glucuronyltransferase activity towards 4-methylumbelliferone. The activity was highest in the placenta from guinea pig, where it was about 10% of the level in the fetal liver. 3. 3. Alveolar macrophages from rat and guinea pig had low whereas those from rabbit had no UDP glucuronyltransferase activity. The alveolar macrophages evidently are not the only cells in the lungs capable of glucuronide synthesis. 4. 4. To obtain true values for the UDP glucuronyltransferase activity in the 12,000 g supernatant fractions from the spleen, thymus and lung, it was necessary to block the action of the β-glucuronidase in the incubation with d -glucaro-1,4-lactone. 5. 5. Although the activity of the UDP glucuronyltransferase is widely distributed in the different organs and tissues, the liver, gastrointestinal mucous membrane and kidney evidently are most important quantitatively, and the liver has by far the highest capacity for glucuronidation due to its size and high activity.

Gastrointestinal Distribution of Glucuronide Synthesis and the Relevant Enzymes in the Rat

The rate of o-aminophenol glucuronide synthesis in the small intestine of the rat was found to decrease when going from the oral to the aboral end, where it was 15 per cent of the duodenal level. In the glandular stomach, caecum, and colon, the activity was 34, 15 and 30 per cent, respectively, of the duodenal value. The decrease in UDP glucuronyltransferase (p-nitrophenol) activity in the mucosal extracts was almost linear and amounted to 66 per cent from the oral to the aboral end of the small intestine. In the glandular stomach, caecum, and colon, the activities were 63, 32, and 83 per cent respectively, of the duodenal value. The β-glucuronidase activity increased linearly by 41 per cent when going from the oral to the aboral end of the small intestine. In the glandular stomach, caecum, and colon, activities of 82, 221, and 162 per cent respectively of the duodenal ones were observed.These results indicate that the distribution pattern of glucuronide synthesis, observed in tissue slices, and the UDP g...

Inhibition of drug metabolizing enzymes by heavy metals in vitro

Abstract Cadmium iodide was a potent inhibitor of benzo(a)pyrene hydroxylation, ethoxycoumarin deethylation, epoxide hydration, and glutathione conjugation, but had no effect on cytochrome c reduction. Mercuric acetate inhibited cytochrome c reduction, benzo(a)pyrene hydroxylation, ethoxycoumarin deethylation, and glutathione conjugation, but was without effect on epoxide hydration. Nickel, cobalt, chromium and zinc salts had no effect on epoxide hydration or glutathione conjugation. Lead salts did not affect either monooxygenation, cytochrome c reduction, epoxide hydration, or glutathione conjugation.

Enhanced glucuronide formation in different tissues following drug administration

Abstract A study was made of the o -aminophenol glucuronide synthesis in the slices of the liver, kidney and gastrointestinal tract after the administration of 3,4-benzpyrene, cinchophen, 3-methylcholanthrene, phenobarbital and salicylic acid to elucidate whether the responses of the different tissues are similar to these drugs known to enhance drug metabolism. A 1.6-fold increase of o -aminophenol glucuronide synthesis was found in liver slices 5 days after a single intraperitoneal injection of 3-methylcholanthrene whereas there was no increase in the slices from the kidney or from the various parts of the gastrointestinal tract. The i.p. administration of 3,4-benzpyrene had a similar effect. The intragastric administration of cinchophen for 3 days resulted in a two-fold increase of the synthesis in the slices from the liver, glandular stomach, caecum and colon, and a 3-fold increase was found in the kidney. In the duodenum only a slight increase of activity was observed when the analysis was carried out 24 hr after the last dose, but a 1.6-fold increase was found after 48 hr. The i.p. administration of phenobarbital for 3 days resulted in a 1.4-fold increase of the synthesis in the liver, but no change of activity was found in the kidney or in the various parts of the gastrointestinal tract. The intragastric administration of salicylic acid for 3 days resulted in a 1.9-fold increase in the kidney but only insignificant changes were found in the various parts of the gastrointestinal tract or in the liver when analysed 24 hr after the last dose. The enhancement of the glucuronide biosynthesis caused by the administration of the various drugs thus reveals marked organ specificity.

Urinary excretion of chlorinated phenols in saw-mill workers.

SummaryThe excretion and conjugation of chlorophenols were studied in workers exposed to 2,4,6-tri-, 2,3,4,6-tetra-, and pentachlorophenolates, the main components of the chlorophenolate product manufactured by direct chlorination of phenol. The workers were exposed in two different saw mills in which sodium chlorophenolate was used for treatment of lumber during the warm season. Urine specimens were collected at the end of the treatment season as well as at the start of a new treatment period in the spring. Serum specimens were collected towards the end of the treatment period. Total and unconjugated chlorophenols were analyzed with a gas chromatographic method. The maximal concentrations of urinary 2,4,6-tri-, 2,3,4,6-tetra- and pentachlorophenol at the end of the lumber-treatment period were 1–11.8, 3.4–17.3, and 0.2–0.9 μmol/l, respectively, and the average apparent half-times calculated using a one-compartment model were 18 h, 4.3 days and 16 days, respectively. For 2,3,4,6-tetrachlorophenol, the data of some subjects showed a better fit with a two-compartment model; the corresponding half-times were 5.3 and 26 days. During the continuous-exposure period the average serum levels of tetra- and pentachlorophenol were rather similar before and after the working day: 2.79 ±1.78 μmol/l for tetrachlorophenol and 0.85 ± 0.4 μmol/l for pentachlorophenol. Renal clearance values for tetra-and pentachlorophenol were related to urine flow and indicated tubular reabsorption. At low concentrations, sulfate conjugation was dominant. With increasing chlorophenol concentrations the proportion of glucuronide conjugation was increased, especially for pentachlorophenol.