A follow-up study on renal tubular dysfunction in women living in the cadmium-polluted Jinzu River basin in Toyama, Japan. Part 1. Changes in the level of exposure to cadmium after soil replacement of polluted paddy fields and the related effects on the prognosis of renal tubular dysfunction

A follow-up study on renal tubular dysfunction was carried out on 193 female inhabitants of the cadmium (Cd)-polluted Jinzu River basin and 40 reference subjects living in an adjacent area in 1994-95. They were 54 to 70 years old when the initial examination was conducted in 1983-84. In the Cd-polluted Jinzu River basin, extensive reclamation of polluted rice fields has been conducted since 1979; as a result, the average Cd concentrations in polished rice consumed by the subjects in the 1994-95 study (0.12 ppm in 1994, 0.14 ppm in 1995) were significantly lower than those in the 1983-84 study (0.26 ppm in 1983, 0.29 ppm in 1984). The average Cd levels in urine in the follow-up study (7.5 micrograms/g Cr. in 1994, 7.7 micrograms/g Cr. in 1995) were also significantly lower than those in the initial study (13.5 micrograms/g Cr. in 1983, 13.3 micrograms/g Cr. in 1984). However, the mean values for urinary excretion of beta 2-microglobulin (beta 2-m) (3.9 mg/g Cr. in 1994, 3.7 mg/g Cr. in 1995) and glucose (203 mg/g Cr. in 1994, 251 mg/g Cr. in 1995) in the follow-up study were significantly higher than those obtained at the initial examination (2.0 mg/g Cr. and 125 mg/g Cr. in 1983 and 1.1 mg/g Cr. and 78 mg/g Cr. in 1984 for beta 2-m and glucose excretion, respectively). The magnitude of increase in urinary excretion of beta 2-m and glucose in inhabitants of the Cd-polluted area was significantly higher than that of the inhabitants of the reference area. Moreover, an increase was observed in the prevalence of renal tubular dysfunction determined by urinary beta 2-m exceeding 10 mg/g creatinine and urinary glucose exceeding 150 mg/g creatinine only among inhabitants of the Cd-polluted area; it is noteworthy that 31 new cases of renal tubular dysfunction were observed in the follow-up study. These results indicate that renal tubular dysfunction among inhabitants of the Cd-polluted Jinzu River basin is irreversible and progressive, and many new cases of renal tubular dysfunction were also noted over a period of 11 years, despite the fact that Cd exposure had decreased over the past 11 years.     

Dose-response relationship between total cadmium intake and metallothioneinuria using logistic regression analysis

The dose-response relationship for environmental cadmium exposure was assessed using logistic regression analysis. The prevalence of metallothioneinuria was employed as a response variable, while age and total cadmium intake, calculated from the average cadmium concentration in rice and duration of residence in the cadmium-polluted area, were used as explanatory variables. The target population comprised of 1843 cadmium-exposed and 240 non-exposed inhabitants of Ishikawa, Japan. The individuals were divided into 96 subgroups by sex, age (4 categories), cadmium concentrations in rice (3 categories) and length of residence in the polluted area (4 categories). Only total cadmium intake had a significant association with the prevalence of metallothioneinuria. In the non-exposed subjects total cadmium intakes corresponding to 2.5% prevalence of metallothioneinuria were calculated. Based on metallothionein levels expressed as either microgram/l urine or microgram/g creatinine, the total intakes were: 2.221 or 2.207 g in men and 2.365 or 0.319 g in women, respectively. Most of these values were similar to those reported by us previously, employing simple regression analysis. It is concluded, therefore, that a maximum allowable intake of about 2 g cadmium is a reasonable estimate for preventing the cadmium-induced renal dysfunction.     

Biological monitoring of cadmium exposure and renal effects in a population group residing in a polluted area in China

In an area of China, not previously studied in detail concerning cadmium pollution and possible adverse effects on the kidney of exposed populations, concentrations of cadmium in urine as an indicator of renal accumulation of cadmium was studied and related to indicators of renal dysfunction in order to examine if a relationship could be documented. Cadmium concentrations in urine were analysed by graphite furnace atomic absorption spectrometry and urinary beta-2 microglobulin (UBM) and albumin (UALB) were measured as indicators of renal dysfunction, Rice samples and urine samples were obtained from three areas in Zhejiang province, China, representing a highly exposed area, a medium exposed area and a control area, respectively. Cadmium concentrations in rice were 3.70, 0.51 and 0.072 mg/kg for the heavily, medium polluted areas and the control area, respectively. Cadmium concentrations in urine (geometric means) were 10.7, 1.62 and 0.40 micrograms/l in the high, medium and control areas respectively. There was a clear increase in UBM and UALB in the heavily exposed group in comparison to the control group and a slight increase in the medium exposed group. There was a statistically significant dose-response relationship between cadmium in urine and beta 2-microglobulin excretion in urine, which is similar to what has previously been reported in other countries. The findings constitute the first report concerning a dose-response relationship in this population group in Zhejiang province in China.     

Association between blood pressure and dietary factors in the dietary and nutritional survey of British adults

During the last few decades, the industrial production and use of Cd resulted in the release of significant quantities of Cd into the environment. Concern about health risks of human exposure to this toxic metal, which may be contained in soil and other environmental compartments, has increased significantly in recent years. Soil ingestion is a potentially important pathway of exposure to soil-absorbed environmental contaminants, especially for young children exhibiting hand-to-mouth behavior. Health risk assessments are usually based on unchanged bioavailability of soil-absorbed pollutants, e.g., heavy metals, neglecting interactions of metals with the soil matrix, which may lead to relatively lower bioavailability. This study was conducted to determine the bioavailability of Cd absorbed to soil in rats. Eight-week-old male Lewis rats were given either a soil polluted with CdCl2 (150 micrograms Cd/rat) dissolved in 5% gun acacia or an equal amount of Cd as CdCl2 dissolved in saline. Control rats were gavaged with isotonic saline. Cd concentrations in liver, kidney, brain, heart, and blood, as well as Cd content of urine and feces were analyzed using graphite furnace atomic absorption spectrometry. Tissue Cd concentrations in soil-treated animals were significantly lower than the tissue concentrations in the Cd-saline group; in the liver and kidneys of the Cd-saline and Cd-soil groups, 4 and 2.7% respectively, of the original doses were recovered. Relative bioavailability, calculated on the basis of blood Cd levels for the Cd-soil group as compared to the Cd-saline group, appeared to be 43%. No differences in the excretion pattern of Cd into feces were observed between the Cd-saline and Cd-soil groups. After 6 days, over 91% of the original dose was recovered in the feces of both Cd-treated groups. Cd excretion via urine was very low, but in the Cd-soil group a significant increase in urinary Cd was observed as compared to the control group. However, the amount of Cd excreted into urine of the Cd-soil group during the experimental period corresponded to only 0.01% of the original dose. In the Cd-saline group, no additional Cd was excreted into urine as compared to the control group. These results indicate that the soil matrix significantly reduced the absorption of Cd in the gastrointestinal tract. Consequently, exposure assessment models, assuming an unaffected bioavailability of soil-absorbed Cd, overestimate the internal dose and thereby overestimate health risks associated with direct ingestion of soil particles.     

Proteinuria, other selected urinary abnormalities and hypertension among teenage secondary school students in Nairobi, Kenya

Four hundred and three teenage secondary school students (50.6% males) from two girls' and two boys' Nairobi City Schools, selected by stratified sampling, were screened to determine the prevalence of proteinuria, haematuria, nitrituria and hypertension. Nine students (2.2%) had significant proteinuria while 14 (3.5%) had microscopic haematuria. Two students had combined proteinuria and haematuria. There was no statistically significant difference in the prevalence of proteinuria and/or haematuria between the sexes. Other urinary abnormalities detected were leucocyturia in 14(3.5%) and nitrites in four (1%). Leucocyturia was commonner in females (p = 0.001). Cloudy urinary appearance was significantly associated with the presence of leucocyturia (p = 0.0028) and proteinuria (p = 0.0276). Neither personal history of recurrent sore throat and skin infections nor family history of hypertension, diabetes mellitus or kidney disease was significantly associated with proteinuria or haematuria. Blood pressure tended to increase with age. Mean systolic and diastolic blood pressures were significantly higher in boys than girls in the age group 15-18 years (P < 0.001). Of the 397 students whose blood pressures were measured, four (1%) were found to be hypertensive. Weight and body mass index were strong positive correlates of blood pressure. The prevalence of proteinuria, haematuria, other urinary abnormalities and hypertension ranges between 1% and 3.5% among teenage secondary school children. The majority are asymptomatic and have no significant associations. It is recommended that routine urinalysis and blood pressure measurements should be part of the school health service so as to identify asymptomatic students who require close monitoring and/or intervention.     

Urinary fibrin-fibrinogen degradation products in nephrotic syndrome

The urinary concentration of fibrin-fibrinogen degradation products (F.D.P.) was measured in 90 patients with proteinuria above 2 g/1 and correlated with proteinuria, differential protein clearances, serum urea and creatinine, and renal biopsy findings. There was a linear correlation (r equals 0-7; P less than 0-001) between the urinary F.D.P. excretion and the selectivity of the proteinuria such that patients with highly selective proteinuria excreted only small amounts of F.D.P. whereas those with non-selective proteinuria excreted much higher levels. There was a significant correlation between the urinary F.D.P. excretion and the urine:serum (U:S) ratio of IgG excretion but not with the U:S ratio or urinary excretion of albumin or transferrin. Sephadex G200 column chromatography of the concentrated urine in 26 cases showed that patients with highly selective proteinuria excreted predominantly F.D.P. of low molecular weight in the urine whereas those with non-selective proteinuria excreted mainly fibrinogen and products of high molecular weight. Hence the type and quantity of F.D.P. in the urine are determined primarily by the differential filtration of fibrinogen and the various degradation products from the plasma through the glomerular basement membrane, which in turn is determined by the "pore size" of the basement membrane. In clinical nephrology measurement of the urinary F.D.P. level provides a rapid and convenient means of estimating the differential protein clearance.     

Azithromycin and clarithromycin inhibition of 50S ribosomal subunit formation in Staphylococcus aureus cells

A mercapturic acid attached to the aromatic ring of toluene was for the first time detected in human urine as a metabolite of toluene. Since the metabolism of toluene is usually considered to take place at the side-chain, this gives, besides the biosynthesis of cresols, a further hint of a metabolic conversion of the aromatic system. We examined a group of 33 workers occupationally exposed to toluene, determining the concentrations of toluene in ambient air and in whole blood, o-cresol and hippuric acid in urine and p-toluylmercapturic acid (p-TMA) in urine. All blood and urine samples were collected post-shift. The renal excretion of S-p-toluylmercapturic acid showed highly significant correlations with established parameters of a biological monitoring of toluene. The median ambient air concentration was 63 ppm, ranging from 13 to 151 ppm, the median concentration of toluene in whole blood was 804 microg/l, corresponding to median urinary concentrations for o-cresol of 2.3 mg/l, hippuric acid of 2.3 g/l and p-TMA of 20.4 microg/l. p-TMA was not detectable in urine samples of a control group of 10 non-exposed persons. Both the German Biological Tolerance Values (BAT-values) for toluene in blood (1000 microg/l) and o-cresol in urine (3 mg/l) correspond to a mean p-TMA elimination of approximately 50 microg/l, and thus are in agreement with each other. According to our results p-TMA reflects internal toluene exposure diagnostically sensitive and specifical. With the developed analytical procedure we determined a median benzylmercapturic acid (BMA) concentration of 190 microg/l in the urine samples of the toluene exposed persons. We also determined a median BMA concentration of 30 microg/l in the control samples of non-exposed persons. However, these results are preliminary and require further confirmation as the reliability of the method was determined only for p-TMA.     

Relationship between the development of hepato-renal toxicity and cadmium accumulation in rats given minimum to large amounts of cadmium chloride in the long-term: preliminary study

We wished to clarify the relationship between the sensitivity to induce hepato-renal toxicity and the level of cadmium (Cd) in the organs of rats exposed to minimum to large amounts of cadmium chloride (CdCl2). For this purpose, groups of female Sprague-Dawley (SD) rats, each consisting of 24 animals, were fed diet containing CdCl2 at concentrations of 0, 8, 40, 200, and 600 ppm for 2, 4, and 8 months from 5 weeks of age. All surviving rats given 600 ppm Cd were killed at 4 months because of deterioration of their general condition. Animals of this group showed anemia and decreased hematopoiesis in the bone marrow, in addition to reduction of cancellous bone in their femurs. Hepatotoxicity was observed after 2 months in the groups treated with > or = 200 ppm. By 4 months, the rats in the 600 ppm group had developed periportal liver cell necrosis. Renal toxicity characterized by degeneration of proximal tubular epithelia was apparent in the groups treated with > or = 200 ppm from 2 months, becoming more prominent in the high-dose rats at 4 months. Hepatic accumulation of Cd increased linearly with the duration of treatment. In contrast, the concentration of Cd in the renal cortex of rats treated with 600 ppm reached a plateau level of approximately 250 microg/g within the first 2 months. The renal concentration of Cd in the 200 ppm group when renal toxic lesions were first detected at 2 months ranged from 104 to 244 microg/g. No renal lesions were observed in the 40 ppm group after 8 months, despite the presence of 91-183 microg/g of Cd in the kidneys. The results thus suggest that renal toxicity would not be induced by treatment with minimum amounts of CdCl2 for periods longer than 8 months, although accumulation of Cd might gradually progress. A further 2-year feeding study of CdCl2 and Cd-polluted rice is now in progress.     

Urinary alpha1-microglobulin, beta2-microglobulin, and retinol-binding protein levels in general populations in Japan with references to cadmium in urine, blood, and 24-hour food duplicates

Possible cadmium (Cd) exposure-associated changes in urinary levels of low-molecular-weight proteins were studied in nonsmoking and non-drinking female members of the general Japanese population (378 subjects with no known occupational heavy metal exposure) who lived at 19 study sites (all without any known environmental heavy metal pollution) in 13 prefectures throughout Japan. The external Cd dose was evaluated in terms of daily Cd intake via food (Cd-F), whereas Cd levels in blood (Cd-B) and urine (Cd-U) were taken as internal dose indicators. When the subjects were classified according to Cd-F into three groups with "low" (20.4 micrograms/day as a geometric mean of 97 women), "middle" (35.0 micrograms/day, 120 women) and "high" (67.0 micrograms/day, 66 women) exposure, both Cd-B and Cd-U increased in parallel with the changes in Cd-F. However, there were no dose-dependent changes in beta2-microglobulin or retinol-binding protein levels in urine, alpha1-microglobulin levels appeared to increase, but the distribution of the cases above the two cutoff levels of 9.6 and 15.8 micrograms/mg creatinine among the three Cd-F groups did not show any bias. Overall, it was concluded that there was no apparent Cd exposure-associated elevation in urinary low-molecular-weight protein levels in the study population.     

Tubulointerstitial nephritis induced by the leukotriene receptor antagonist pranlukast

A 7-year-old boy with asthma was receiving the leukotriene receptor antagonist pranlukast (Ultair; SmithKline Beecham; Pittsburgh) as part of an open-label clinical trial. The patient's asthma improved, and he remained asymptomatic; but routine study evaluations 9 to 12 months into therapy showed microhematuria, proteinuria, glucosuria, anemia, and renal insufficiency. Renal biopsy demonstrated changes classic for acute allergic tubulointerstitial nephritis (ATIN), with mixed interstitial inflammatory infiltrate including eosinophils. Within 6 months of pranlukast withdrawal, anemia resolved and urinary sediment and renal function normalized. The case demonstrates that hypersensitivity reaction to pranlukast and resultant ATIN is possible, and that periodic urine testing in patients receiving pranlukast should be considered.     

Concurrent validity of Spanish-language versions of the Mini-Mental State Examination, Mental Status Questionnaire, Information-Memory-Concentration test, and Orientation-Memory-Concentration test: Alzheimer''s disease patients and nondemented elderly comparison subjects

A total of 34,000 adults in Fukui City who had participated in annual health examinations at least once between 1986 and 1988, were followed for a period of 5 years. The results were as follows; (1) The mortality rate during a 5 year period was significantly lower for participants in health examinations than in nonparticipants of the same age group. (2) Mortality was significantly related to obesity, systolic and diastolic blood pressure, glucosuria, proteinuria, occult blood in urine, GOT and cholesterol in man, in women obesity, systolic and diastolic blood pressure, glucosuria, proteinuria, GOT, GPT and cholesterol were related to mortality. (3) An increase in hazard ratio with increasing degree of thinness was suggested particularly in males. (4) Hazard ratios increased with decreasing cholesterol in both men and women combined. (5) Except for hypertension which increased risk for circulatory disease, none of the above data appeared to be related to specific causes of death.     

Medical surveillance studies of workers exposed to low level benzene

The paper presents th results of an investigation of haematotoxicity in workers exposed to low benzene concentrations. Forty-seven female workers in the shoemaking industry, exposed to solvent mixture and twenty-seven non-exposed controls were examined. Benzene concentrations in the working atmosphere ranged from 1.9 to 14.8 ppm. Significant differences in the levels of benzene in blood and phenols in pre- and post-shift urine between the exposed and control groups confirmed benzene exposure. Haemoglobin level and mean corpuscular haemoglobin concentration were significantly lower, and mean corpuscular volume was higher in the shoemaking workers than in controls. In the subgroup of shoemaking workers exposed to benzene concentrations of 5 ppm or lower, no differences in haematological parameters were found. In conclusion, exposure to a benzene concentration lower than 5 ppm does not appear to produce an increased level of abnormal haematological outcomes detectable in routine medical surveillance. The results of the study corroborate the present maximum permissible concentrations (5 ppm) as a protective limit preventing the onset of haematotoxic non-leukemogenic effects of chronic benzene exposure.     

Measurement of kidney concentrating ability in children with nonrenal glycosuria]

In non-renal (diabetic) glucosuria we did not find any statistically real relations between the concentration of glucose in the urine and cryoscopically measured osmolality in children with healthy kidneys. The close negative correlation of the conductance of the urine to the concentration of glucose is not only to be explained by changes of the viscosity, but is an expression of an increased re-absorption of sodium as a result of a compensatory hyperaldosteronism. In renal insufficiency the electrolytic conductibility of the urine is lower than the borderline area of the normal, even when under influence of the glucose excretion the osmolality of the urine is still to be found normal. Thus also on the conditions of a considerable glucosuria we can further judge the concentrating ability of the kidney in diabetes mellitus with the help of the measurement of the conductance of the urine.     

The role of T cell receptor dimerization for T cell antagonism and T cell specificity

Endemic nephropathy is a chronic renal disease with a high prevalence in a geographically limited area of Croatia. It has also been recorded in some parts of Bosnia, Serbia, Bulgaria and Romania. Despite numerous studies conducted to date, the etiology of this disease has not been clarified. Pathological studies of the kidney in the early stage of endemic nephropathy have shown renal tubules to be the primary sites of the pathologic process with an interstitial tissue reaction, whereas glomerular alterations are of a secondary character. Tubulointerstitial lesions can thus account for the symptoms of the disease, i.e. tubular proteinuria and reduced urine concentration capacity and urine acidification. Also, an increased incidence of malignant tumours of the urinary tract was found in the same geographic area.     

The expression of the urinary forms of human luteinizing hormone beta fragment in various populations as assessed by a specific immunoradiometric assay

Human gonadotrophins undergo metabolic transformations which result in the presence of several smaller, structurally and immunologically related forms of gonadotrophins in the urine. For luteinizing hormone (LH), a beta core fragment (LHbeta cf) has been isolated from the pituitary and characterized. The corresponding urinary fragment is inferred from mass spectral and immunochemical analysis of chromatographically separated urinary forms. Physicochemical characteristics, primarily mass spectral and chromatographic, indicate that the pituitary and urinary forms of LHbeta cf have a different structure, probably in the carbohydrate moieties. This communication characterizes the expression of LHbeta cf in the urine of both reproductive and post-reproductive age women and in men, employing assays highly specific for the pituitary form of the fragment. It was found that LHbeta cf is the predominant LH associated molecular form in the urine during peri-ovulatory period, peaking 1-3 days later than intact LH and reaching a concentration of approximately 600 fmol/mg creatinine, 7-fold higher than either LH or LH free beta subunit. Corresponding concentrations of human chorionic gonadotrophin (HCG) beta cf were <1% that of LHbeta cf. LHbeta cf cross-reaction with some LH or LHbeta monoclonal antibodies may well interfere with the accurate estimation of the day of the LH surge when urinary tests are utilized.     

Septicemia due to Shigella. A case report and review of the literature

To develop a proper protocol for biological exposure monitoring of acetone, we evaluated whether exposure to acetone on the previous day affects the biological monitoring value at the end of a work day. One hundred and ten male workers exposed to acetone in three acetate fiber manufacturing plants were monitored using a liquid passive sampler on two consecutive working days after 2 days without exposure. Urine samples were collected at the start of the workshift and the end of the shift on both days for each subject. For ten exposed workers urine samples were collected approximately every 2 h during and after the first working day until the following morning. Acetone concentrations in urine (Cu) at the start of the first working day were 1.3 +/- 2.4 (range: ND-14.1) mg/l in nonexposed workers and 2.4 +/- 5.6 (range: ND-40.3) mg/l in exposed workers. The urinary acetone concentration at the beginning of the second working day indicated that urinary levels of acetone do not decline to background level by the following morning when exposure concentration exceeds 300 ppm. However, linear regression analysis demonstrated that the relationship between environmental exposure level and urine level was similar on the 1st day and the 2nd day. Thus, although urine acetone levels did not return completely to baseline after high exposures, under the present exposure levels the exposure on the previous day did not significantly affect urinary acetone at the end of the workshift of the next day.     

Metabolism and excretion of dimethoate following ingestion of overtolerance peas and a bolus dose

Data to guide an exposure assessment were obtained by giving sugar peas containing overtolerance dimethoate residues (17 ppm; 8% oxon) and a bolus dose of dimethoate to a healthy adult male. The dimethoate tolerance on peas was and remains 2 ppm. Serial total urine samples were collected and analysed for dimethoate and its oxon, dimethylphosphate, dimethylphosphorothioate (DMTP) and dimethylphosphorodithioate. The dose of dimethoate administered was approx. 0.1 mg/kg body weight and produced no symptoms of toxicity. Dimethylphosphates appeared in the urine within 2 hr. The major metabolite (about 60%) was DMTP. Only traces (< 0.5%) of dimethoate and oxon were recovered from urine. Acetylcholinesterase inhibition was not observed although urinary metabolites were prominent, indicating that they are better indicators of acute exposure than cholinesterase inhibition. The results obtained using a bolus dose were virtually identical to those from the trial with overtolerance peas, and indicated that dimethoate is readily absorbed and its urinary metabolites are readily eliminated following exposures to low doses (0.1 mg/kg body weight).     

Impact of air pollution by lead on the heme biosynthetic pathway in school-age children

Blood-lead level (Pb-B), erythrocyte delta-aminolevulinic acid dehydratase (ALAD) activity, free erythrocyte porphyrin (FEP) concentration, delta-aminolevulinic acid concentration in urine (ALAU), hematocrit value, and hemoglobin concentration were compared for groups of children 10-13 years old from areas differently polluted by lead (rural area and lead smelter area). The biological responses of the children were also compared with those observed in adults similarly exposed to lead (Pb-B: 10-40 mug/100 ml). Compared with the rural children, children living less than 1 km from the smelter exhibited a significant increase of Pb-B and FEP, a significant inhibition of ALAD, and a slight positive correlation of ALAU with Pb-B; however, they showed no biological signs of anemia. In children living approximately 1.5 km from the smelter, there was still a significant increase of Pb-B and a concomitant inhibition of ALAD, but no change in FEP concentration. Comparison of the dose-response curves between Pb-B and FEP in adult males, adult females, and children indicates that the sensitivity to lead is in the order of children larger than or equal to women greater than men. Based on the FEP response, it is proposed that 25 mug Pb/100 ml blood be regarded as the maximum biologically allowable concentration of lead in blood of school-age children.     

Influence of gender and acetone pretreatment on benzene metabolism in mice exposed by nose-only inhalation

Benzene (BZ) requires oxidative metabolism catalyzed by cytochrome P-450 2E1 (CYP 2E1) to exert its hematotoxic and genotoxic effects. We previously reported that male mice have a two-fold higher maximum rate of BZ oxidation compared with female mice; this correlates with the greater sensitivity of males to the genotoxic effects of BZ as measured by micronuclei induction and sister chromatid exchanges. The aim of this study was to quantitate levels of BZ metabolites in urine and tissues, and to determine whether the higher maximum rate of BZ oxidation in male mice would be reflected in higher levels of hydroxylated BZ metabolites in tissues and water-soluble metabolites in urine. Male and female B6C3F, mice were exposed to 100 or 600 ppm 14C-BZ by nose-only inhalation for 6 h. An additional group of male mice was pretreated with 1% acetone in drinking water for 8 d prior to exposure to 600 ppm BZ; this group was used to evaluate the effect of induction of CYP 2E1 on urine and tissue levels of BZ and its hydroxylated metabolites. BZ, phenol (PHE), and hydroquinone (HQ) were quantified in blood, liver, and bone marrow during exposure and postexposure, and water-soluble metabolites were analyzed in urine in the 48 h after exposure. Male mice exhibited a higher flux of BZ metabolism through the HQ pathway compared with females after exposure to either 100 ppm BZ (32.0 2.03 vs. 19.8 2.7%) or 600 ppm BZ (14.7 1.42 vs. 7.94 + 0.76%). Acetone pretreatment to induce CYP 2E1 resulted in a significant increase in both the percent and mass of urinary HQ glucuronide and muconic acid in male mice exposed to 600 ppm BZ. This increase was paralleled by three- to fourfold higher steady-state concentrations of PHE and HQ in blood and bone marrow of acetone-pretreated mice compared with untreated mice. These results indicate that the higher maximum rate of BZ metabolism in male mice is paralleled by a greater proportion of the total flux of BZ through the pathway for HQ formation, suggesting that the metabolites formed along this pathway may be responsible for the genotoxicity observed following BZ exposure.     

Founder effect at PGL1 in hereditary head and neck paraganglioma families from the Netherlands

After repeated exposure to inhaled anesthetics, the hepatic function and metabolism of anesthetics may change. The purpose of this study was to investigate inorganic fluoride (F-) kinetics and renal and hepatic function after repeated exposure to sevoflurane. Ten patients (aged 40-70 yr) who had received sevoflurane anesthesia with a gas flow of 6 L/min for neurosurgery twice in 30-90 days were studied. Serum and urine F- concentrations were measured up to 24 h after anesthesia. Blood urea nitrogen, serum creatinine, serum and urine beta2-microglobulin, urine N-acetyl-beta-D-glucosaminidase, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin concentrations were measured up to 7 days after anesthesia. The area under the curve (AUC) of serum and urine F- concentration and half-life of serum F concentration were calculated. Urine beta2-microglobulin, AST, and ALT increased to abnormal levels after both anesthesias, with no difference between anesthesias. No measured variables, AUC of serum and urine F- concentration, or half-life of serum F- concentration showed any differences between the first and second anesthesias. In conclusion, the second exposure to sevoflurane with a high gas flow of 6 L/min in 30-90 days did not change the hepatic and renal function or affect the metabolism of sevoflurane. Implications: We studied the changes of metabolism of sevoflurane and hepatic and renal function after repeated sevoflurane anesthesia in 30-90 days. There were changes indicative of mild liver and kidney injury after sevoflurane anesthesia, but repeated exposure to sevoflurane did not enhance these changes.