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Relaxin was measured in serum and amniotic fluid of 136 pregnant women between the 12th and 38th gestational week by means of a new human relaxin-RIA. The pregnancies consisted of 111 pathology-free single fetuses, 10 with rhesus incompatibility, 7 with chromosomal aberration and 8 with sonographic diagnosed abnormalities. Relaxin could be detected in all samples tested the levels being ten times lower in amniotic fluid compared to serum. Serum relaxin levels showed a slight but not statistically significant decrease with increasing gestational age, in amniotic fluid relaxin values were consistent over the course of pregnancy. The ratio of amniotic fluid to serum relaxin displayed a statistically significant increase from the 12th to 23rd week of pregnancy. Individual courses of relaxin concentration in amniotic fluid revealed only low intra-individual variations but distinct inter-individual differences.

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In order to clarify the etiology of a dose-related increase in the incidence of tubular cell adenocarcinomas of the kidney in male rats, the nephrotoxicity of p-dichlorobenzene (p-DCB) was investigated in a subchronic study. Groups of ten male and ten female Fischer 344 rats were dosed by gavage with 0 (controls), 75, 150, 300 or 600 mg p-DCB/kg/day in corn oil. Half of the animals were sacrificed after 4 weeks and the remainder after 13 weeks. Increased urinary LDH and epithelial cell excretion and exacerbation of hyaline droplet accumulation in the cytoplasm of renal cortical cells were observed in male rats over the entire dose range investigated. Tubular single cell necrosis, dilated tubules with granular cast formation in the outer zone of the medulla, were evident in male rats after 4 and 13 weeks of treatment with doses of 150-600 mg/kg/day. In female rats there was no indication of a nephrotoxic action of p-DCB. The effects on the kidney, both in their morphological characteristics and the fact that they occur exclusively in male animals, correspond to the light hydrocarbon nephropathy observed as a result of short-term treatment with a number of aliphatic and cyclic hydrocarbons. The development of cortical renal tumors seems to be associated with this kind of kidney damage which is unique to male rats. The literature on this subject generally regards these renal effects as not predictive for man.

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Eleven two-year toxicity/carcinogenicity experiments in control Wistar TNO/W.70 rats were started between 1973 and 1976. Tumors occurring were compiled on the basis of histopathological reports. Of the 1,000 male and 1,000 female rats at the beginning of the studies, 962 males and 968 females were evaluated. The remaining animals were unavailable due to autolysis or early death (before day 400). The histopathologic diagnosis for the eleven reports were performed by five different pathologists or groups of pathologists. A total of 827 tumors (375 in males and 452 in females) was seen in 686 rats (303 males, 383 females). 183 tumors (67 in males, 116 in females) were classified as malignant. 719 (86.9%) of all tumors and 120 (65.6%) of all malignant tumors were located in endocrine organs (pituitary, thyroid, adrenal, pancreatic islets) or in genital organs (testes, epididymides, seminal vesicles, ovaries, uterus, mammary gland). Average incidences of primary tumors found in the following organs were: pituitary 20.0%, thyroid 9.6%, uterus 9.2%, adrenals 4.1%, mamma 3.2%, testes 2.9%, ovaries 1.8%, skin 1.4% and 17 other organs each with a tumor frequency below 1%. This wide spectrum of spontaneous tumors with a mostly low incidence makes the Wistar rat a preferred strain for carcinogenicity studies. Despite nearly identical husbandry conditions, a marked variability was observed among experiments regarding the general incidence of benign and/or malignant tumors, particular tumors, and number of tumor-bearing animals. Differences in mortality among experiments had no pronounced effect on the variability of tumor incidences. Different evaluation criteria used by different pathologists did not appear to be a major cause of the observed variability with the probable exception of lesions in endocrine organs. The major cause would seem to be the biological variability of the animal material. The observed marked variability of tumor incidences between experiments would indicate that a considerable natural variability may also occur between groups of one carcinogenicity study. Therefore, information on historical control tumor data from the same rat strain kept under similar conditions is needed to interpret the incidences of tumors in carcinogenicity experiments.

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When 1,3-butadiene is incubated with liver postmitochondrial fractions from mouse, rat, monkey or man and a NADPH-regenerating system the formation rate of butadiene monoxide is different in the four species. With the exception of rhesus monkey the amount of epoxide is proportional to the monooxygenase activity. The sequence of epoxide formation is B6C3F1-mouse, Sprague Dawley rat, man, rhesus monkey. The relation between mouse and monkey was about 7:1. When 1,3-butadiene is incubated with homogenates from lung tissue, only tissues from mouse and rat produces measurable butadiene monoxide concentrations. The monooxygenase activity in lung tissue of the mouse was only 1/30 that in mouse liver. By contrast, lung tissue formed the epoxide concentrations comparable to those formed by liver tissue, whereas monkey and human lung tissue did not produce any measurable levels of butadiene monoxide. The data might suggest that the results of recent rodent inhalation studies with 1,3-butadiene could not automatically be extrapolated to man.

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When 1,3-butadiene is incubated with liver postmitochondrial fractions from mouse, rat, monkey or man and a NADPH-regenerating system, the formation rate of butadiene monoxide is different in the four species. With the exception of the rhesus monkey, the amount of epoxide is proportional to the monooxygenase activity. The sequence of epoxide formation is B6C3F1 mouse, Sprague Dawley rat, man, rhesus monkey. The ratio between mouse and monkey was about 7:1. When 1,3-butadiene is incubated with homogenates from lung tissue, only tissues from mouse and rat produce measurable butadiene monoxide concentrations. The monooxygenase activity in lung tissue of the mouse was only 1/30 that in mouse liver. By contrast, lung tissue formed epoxide concentrations comparable to those formed by liver tissue, whereas monkey and human lung tissue did not produce any measurable levels of butadiene monoxide. The data might suggest that the results of recent rodent inhalation studies with 1,3-butadiene could not automatically be extrapolated to man.

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Results from recent long-term inhalation, mutagenicity, embryotoxicity and metabolism studies on p-dichlorobenzene (p-DCB) are reviewed. Groups of male and female rats and female mice were exposed for 5 hr/day on 5 days/wk to p-DCB at concentrations of 0, 75 or 500 ppm for a total period of c. 76 wk (rats) or 57 wk (female mice) followed by 36 wk (rats) or 19 wk (female mice) without p-DCB exposure. No overt signs of toxicity were apparent at any exposure level nor were there treatment-related effects on the biochemical determinations, urine analyses or haematological parameters. Slightly elevated urinary coproporphyrin excretion and increased liver and kidney weights were regarded as treatment-related effects in the 500-ppm exposure group of the rats. The non-tumour and tumour pathology did not indicate any treatment-related effect in any group of either species. An embryotoxicity and teratology study on rats exposed to 0, 75, 200 or 500 ppm p-DCB vapour in air during the period of organogenesis did not demonstrate any signs of embryo- or foetotoxicity or teratogenicity at any exposure level. In a series of mutagenicity tests including the Salmonella typhimurium, dominant lethal and cytogenetic assays, p-DCB did not produce a mutagenic response. Studies using oral or inhalation routes of exposure demonstrated rapid metabolic transformation of p-DCB and excretion of the products, even after long-term exposure.

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Groups of male and female rats and mice were exposed to 0.05 and 0.15 ppm of toluene-diisocyanate (TDI) by inhalation for 6 h/day, 5 days/week for approx. 2 years. Type and incidence of tumours and the number of tumour-bearing animals of either species did not indicate any carcinogenic effect. Haematology, biochemistry, urinalysis, and cytogenicity did not reveal any untoward effect. Increased mortality (females only), reduced weight gain and signs of irritation in the upper and lower respiratory tract resulted from exposure to TDI in the mouse study with the highest incidence in the 0.15 ppm exposure level. Male and female rats of the 0.15 ppm group gained less weight during the first 12 weeks of the study. Histopathological examination in the rat study has not been completed, but no effect in the respiratory tract or in any other tissue has yet been seen.

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The results of this study demonstrate that prochlorperazine, haloperidol and droperidol are all effective post-operative anti-emetic compounds when compared to saline but vary in onset of activity and duration of action. Haloperidol has the shortest onset of action, being effective within 30 minutes of intravenous administration. Prochlorperazine has an intermediate onset of action and droperidol is the slowest of the three compounds but the only one to provide significant anti-emesis 4-24 hours following administration. Our data suggest that a combination of haloperidol and droperidol may be more effective as an anti-emetic than any one of the compounds used alone.

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Histologic sections of dog tracheas were taken from 20 dogs anesthetized and intubated for 5 to 7 hours with high-pressure, low-volume Shiley or low-pressure, high-volume Lanz endo-tracheal tubes. Microscopic examination and measurement showed that while the high-pressure, low-volume cuff produced deeper average mucosal erosion, the large-volume, low-pressure cuff resulted in significantly greater lengths of tracheal mucosa-cuff erosion. Maximal depth of penetration throught the basement membrane was similar in both groups. Grooves in the mucosa were seen in 50% of the high-volume-cuff trachea sections but none of the low-volume-cuff tracheal sections. These findings demonstrate that low-pressure, high-volume endotracheal tube cuffs produce different but significant tracheal damage after short-term intubation when compared to high-pressure, low-volume cuffs.

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Inhalation of 60% nitrous oxide in oxygen by seven adult male volunteers for 60 min was found to increase significantly polymorphonuclear leuocyte (PMN) chemotaxis, but not to influence total white or PMN blood cell counts. Also, the addition or morphine 0.2 mg kg-1 i.v. during the breathing of nitrous oxide did not alter any variable. These results indicate that nitrous oxide and nitrous oxide incombination with morphine do not depress PMN chemotaxis.

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