2-Phenoxyethanol: a neurotoxicant?
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Animals↗
Biomedical subjects
E Bomhard
Publications and source records attributed to E Bomhard.
Acarbose and acetaminophen: a dangerous combination?
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Acarbose↗
Short- and intermediate-term carcinogenicity testing--a review. Part 1: the prototypes mouse skin tumour assay and rat liver focus assay.
Carcinogenicity testing is by far the most expensive and time-consuming study type of toxicology. For many years, the lifetime exposure with the maximum tolerated dose in two rodent species has been the gold standard of carcinogenicity testing of pharmaceuticals. Major change was introduced by the Fourth International Conference on Harmonization in July 1997; a chronic rodent bioassay in one species and a short-term carcinogenicity assay are regarded as sufficient for registration. Such requirements provide the opportunity to redirect the vast resources previously spent on the lifetime study in the second species. Numerous experimental protocols for short- and intermediate-term carcinogenicity testing in many target tissues have been available for years. The first part of this review describes the basic principles of short- and intermediate-term carcinogenicity testing using the examples of the widely used mouse skin tumour assay and the rat liver foci assay. In the context of these experimental models, the discrimination and quantification of initiating and promoting activity and the use of preneoplastic lesions as endpoints in carcinogenicity testing are described. The review includes the limitations of the models with regard to the extrapolation from effects observed in animal experiments to a potential exposure of humans.
Age Factors↗
Short- and intermediate-term carcinogenicity testing--a review. Part 2: available experimental models.
Numerous experimental protocols for short- and intermediate-term carcinogenicity assays have been available for many years. This paper surveys various of these test systems in rodents, fish species, non-vertebrates and avian embryos in ovo. The mouse skin tumour assay and the rat liver foci assay were used to introduce the basic concepts of short- and intermediate-term carcinogenicity testing in the previous part of the review. The focus of this second part of the review is on rodent assays for carcinogenicity testing in the lung, kidney, urinary bladder, pancreas, stomach, oral cavity, small intestine, colon, and on the possibility to combine several target organs in multi-organ models. The potential use of various fish species, non-vertebrates and hatching eggs for carcinogenicity testing is outlined and the advantages and limitations are discussed. This review also presents the problem of validation of any carcinogenicity test system and proposes a strategy for contemporary safety assessment of chemicals with regard to the detection and evaluation of carcinogenicity.
Animals↗
Subacute oral toxicity of tetraethylene glycol and ethylene glycol administered to Wistar rats.
A subacute toxicity study with administration of tetraethylene glycol in dosages of 0-220-660-2000 mg/kg body weight to male and female Wistar rats via gavage was conducted in order to characterize a possible toxic action of this compound. The structurally related compound ethylene glycol is known to cause kidney toxicity. Therefore, special attention was paid to investigating possible toxic effects of tetraethylene glycol on this organ. In order to compare possible treatment-related effects of tetraethylene glycol with those known from ethylene glycol, a group of male and female rats was treated with 2000 mg ethylene glycol/kg body weight. Daily oral application of tetraethylene glycol over 4 weeks was tolerated without toxic effects up to and including 2000 mg/kg body weight. Daily oral application of ethylene glycol over 4 weeks resulted in treatment-related effects on the kidneys. A slight decrease in the urinary excretion of potassium, calcium and phosphate (males), a diminished pH-value of the urine, and a slight increase in osmolality (females) were observed. In both sexes excretion of oxalate was significantly increased and microscopic examination of urinary sediment revealed calcium oxalate crystals. Kidney weights of males and females were slightly elevated. Histopathology revealed crystals in renal tubuli, renal pelvis, and urinary bladder; tubulopathy and epithelial hyperplasia within the renal pelvis were also observed. Therefore, the study confirmed the kidney as target for ethylene glycol toxicity and gave no indications of tetraethylene glycol-induced toxic effects.
Administration, Oral↗
Calcium channel blockers and the risk of cancer: a preclinical assessment.
The preclinical evidence for a potential influence of calcium channel blockers (CCBs) on carcinogenesis is discussed in the light of a broad database from rodent carcinogenicity studies as well as literature data. In all bioassays performed in rats and mice on the dihydropyridine CCBs--nifedipine, nimodipine, nisoldipine, and nitrendipine--no evidence was found for a carcinogenic potential of these compounds. Calcium is an essential intracellular signal for cell proliferation and apoptosis. The crucial role of increased cell proliferation in all stages of carcinogenesis is well documented. Some indirect experimental evidence also points to a role of defective apoptosis in tumor promotion. CCBs uniformly inhibit cell proliferation, whereas the influence of CCBs on apoptosis is inconsistent, resulting in an inhibition or increase in apoptosis dependent on cell type. Accordingly, antitumorigenic effects of CCBs have been reported based on their antiproliferative action. A tumor-promoting effect of CCBs based on inhibition of apoptosis, however, remains purely speculative and, in fact, can be denied based on the results of in vivo bioassays. It is therefore concluded that there is no preclinical evidence that should give rise to concern over the carcinogenic potential of dihydropyridine-type CCBs.
Animals↗
D-glucose combined chronic toxicity and carcinogenicity studies in Sprague-Dawley rats and Syrian golden hamsters.
After an initial period of 16 weeks with increasing concentrations, D-glucose was administered at 30% in the diet to 50 male and 50 female Sprague-Dawley rats from the 17th to the 112th study week. Additional 10 male and 10 female animals were treated for 14 months and then sacrificed for interim examination. Groups of 60 male and 60 female Syrian golden hamsters received D-glucose in the form of 20% solution in tap water for a period of 80 weeks. In each case, groups consisting of an equal number of untreated animals served as controls. General behavior and mortality were not affected by the treatment. The rats and hamsters treated with glucose showed significantly higher body weights of up to a maximum of 16% in male and 26% in female rats, or 15% in male and female hamsters. In rats, the increase was evident by week 14, and in the hamsters by week 10. Glucose-dosed rats displayed a slightly increased feed intake and a reduced water intake. Both parameters, however, were not influenced in hamsters. Hematological and histopathological examination showed no pertinent changes in hematopoetic tissue. Sharply increased blood glucose and renal glucose excretion values were present in rats beginning with 18 months and were indicative of the development of non-insulin-dependent diabetes mellitus (NIDDM). The insulin concentrations in peripheral blood were not appreciably affected, although there was a trend to higher values in males at all evaluation times and in females only at 3 months. Pathological evaluation did not show any compound related non-neoplastic lesions. The incidences of islet cell adenomas in the pancreas of male rats were significantly increased and the cortical adenomas in the adrenals of females were decreased. In addition, the mammary gland adenomas (in females) and the Leydig cell tumors of the testes were decreased. In hamsters, the incidence of adrenocortical adenomas were increased in the females. No other pertinent neoplastic changes were observed. In conclusion, the increases and decreases in benign neoplasms of hormone-sensitive tissues, appear to be the result of nutritionally/metabolism-induced modulation of the homeostasis in these 4 tissues in both species, and not the result of chronic glucose administration.
Adrenal Cortex Neoplasms↗
Quantitation of alpha(2)-microglobulin after administration of structurally divergent chemical compounds.
alpha(2)-Microglobulin-induced nephropathy is a phenomenon which is exclusively found in adult male rats. Various chemicals are able to bind to alpha(2)-microglobulin thus inhibiting its proteolytic degradation in lysosomes of the P2 segment of the rat nephron. The accumulation of this protein in 'protein droplets' or 'hyaline droplets' leads to necrosis, followed by regeneration which possibly later results in the formation of tumours. Here we report the development of a monoclonal antibody which is specific for alpha(2)-microglobulin. It was utilized to measure alpha(2)-microglobulin concentrations in plasma and tissues, and to stain alpha(2)-microglobulin in fixed tissue slides. In two studies we administered to adult male Wistar rats two groups of compounds: (1) one group of structurally diverse compounds, which give an overview of chemical entities capable of inducing the accumulation of alpha(2)-microglobulin; and (2) another group of structurally closely related compounds (i.e. substituted benzene derivatives) for the purpose of elucidating possible structure-activity relationships. The degree of alpha(2)-microglobulin-induced nephropathy was determined by immunohistochemical staining of kidney sections. In addition, liver and kidney tissue and plasma concentrations of alpha(2)-microglobulin were not found to be elevated whereas kidney tissue concentrations were higher than the controls. The increase over control values ranged from 154% (1,4-dichloromethyl-benzene) to 321% [alpha-methyl-4-(1-methylethyl)-cyclohexanemethanol]. Comparing structurally related benzene derivatives, the hyaline droplet accumulating (HDA) potential was found to depend both on the type of substituent and its position at the aromatic ring. In general HDA activity increased in the order benzene approximately equal to phenol approximately equal to alkylated phenols < halogenated phenols < halogenated benzenes. Further QSAR studies are needed to provide a theoretical base for these observations.
Alpha-Globulins↗
Calcium channel blockers and cancer: is there preclinical evidence for an association?
The preclinical evidence for a potential influence of calcium channel blockers (CCB) on carcinogenesis is discussed in the light of rodent carcinogenicity studies as well as mechanistic data. In the bioassays performed in rats and mice on the dihydropyridine CCB nifedipine, nimodipine, nisoldipine and nitrendipine, no evidence was found for a carcinogenic potential of these compounds. Moreover, the mechanistic knowledge on the influence of CCB on the fundamental processes of cell proliferation and apoptosis is not in favor of a tumor-promoting activity of these compounds. It is, therefore, concluded that there is no preclinical evidence that the therapeutic use of CCB of the dihydropyridine class is associated with an increased risk of cancer.
Animals↗
Urinary antigens as markers of papillary toxicity. I. Identification and characterization of rat kidney papillary antigens with monoclonal antibodies.
Monoclonal antibodies were prepared in an attempt to develop diagnostic tools for the identification of toxic damage to the rat renal papilla. One IgG and five IgM monoclonal antibodies, reacting with antigens localized in the papilla were obtained. Three of the IgM class and the IgG class monoclonal antibodies were found to be specific for antigens localized in collecting ducts, two of them staining papillary collecting ducts more intensely than cortical collecting ducts. The IgG class antibody, termed Pap X 5C10, recognizes an antigen located at high density on the luminal side of papillary collecting duct epithelial cells and at lower density in cortical collecting duct cells. One of the IgM class monoclonal antibodies reacts with an antigen localized in epithelial cells as ascending and descending loops of Henle and of connecting tubules. Another of the IgM class monoclonal antibodies reacts with an antigen localized in the interstices of the inner medulla. All these monoclonal antibodies react with their antigens in native frozen as well as in Bouin-fixed and paraffin-embedded tissue slices. Molecular properties of the Pap X 5C10 antigen have been investigated by gel permeation chromatography, SDS-PAGE, Western blotting, and isoelectric focusing. The results indicate that the antigen in both its tissue-derived and urinary form is of large (150-200 kDa) molecular size and can be separated into two molecular species with isoelectric points of pH 7.2 and 7.3 respectively. In the urine the antigens recognized by the monoclonal antibodies form large complexes with Tamm-Horsfall protein. The antigen-containing complexes can be extracted from urine by adsorption to diatomaceous earth and elution with SDS-containing buffer. Using sandwich ELISA-type assays it is possible to determine the concentration of the antigens. In preliminary experiments we were able to show that at least three of the antigens are detected in the urine following toxic insults to the kidney. The monoclonal antibodies prepared and the tests developed thus may provide direct diagnostic access to the renal papilla and allow, for the first time, early detection of papillary damage.
Animals↗
Frequency of spontaneous tumours in Wistar rats in 2-year studies.
Tumours occurring in 1270 male and 1270 female control rats of the strain Wistar (BOR:WISW (SPF Cpb), breeder: Winkelmann, Borchen), which had been employed in 22 different 2-year studies, were compiled on the basis of histopathology reports. 1261 male and 1259 female rats were evaluated. The remaining animals were unavailable due to autolysis. A total of 1485 tumours (722 in males, 763 in females) were seen in 1165 rats (570 males, 595 females), of which 333 were classified als malignant (119 in males, 214 in females). About 70% of all primary tumours were located in the pituitary, thyroid gland, adrenal glands and uterus. Average frequencies of primary tumours: pituitary 19.8% (18.0% in males, 21.5% in females), uterus (excluding polyps) 11.8%, thyroid gland 9.0% (9.3% in males, 8.7% in females), adrenal glands 8.1% (12.7% in males, 3.5% in females), testes 7.2%, ovaries 3.5%, mammary glands 3.1% (0.1% in males, 6.1% in females) and various other organs having tumour frequencies of less than 3%. Male rats exhibited strikingly more tumours of the adrenal glands, brain, skin, parathyroid glands, endocrine and exocrine pancreas, heart, spleen and lung, while tumours of the pituitary, vascular tissue and thymus were predominant in females. A comparison of these data with those from preceding 2-year studies in Wistar rats shows a certain increase in primary tumours of the mammary glands, parathyroid glands, exocrine pancreas, endocard, brain and vascular tissue.
Animals↗
Frequency of spontaneous tumours in NMRI mice in 21-month studies.
Tumours occurring in 900 male and 900 female mice of the strain NMRI (BOR: NMRI (SPF Han), breeder: Winkelmann, Borchen) employed as control groups in 18 different studies lasting for 21 months on average (study No. 8 for 20 months, study No. 5 for 24 months) were compiled on the basis of histopathology reports. 883 male and 874 female mice were evaluated. The remaining animals were unavailable due to autolysis. A total of 1522 tumours (689 in males, 833 in females) were seen in 1061 mice (493 males, 568 females), 830 of which were classified as malignant (318 in males, 512 in females). About 70% of all primary tumours were located in the haemolymophoreticular tissue, lungs, ovaries, adrenals and uterus. Average incidences of primary tumours found in the following organs were: haemolymphoreticular tissue 22.9%, lungs 21.6%, ovaries 12.1%, adrenals 6.9%, uterus 6.6%, liver 4.4%, Harderian gland 4.4%, pituitary 3.5%, mamma 3.3% and various other organs with a tumour frequency below 3%. Male mice exhibited markedly more tumours of the lungs, adrenals, liver and Harderian glands, while tumours of the haemolymphoreticular tissue and pituitary were predominant in females. A comparison of these data with those from preceding two-year or life-span studies using NMRI mice from other breeders revealed a certain increase in primary tumours of the adrenals, Harderian glands as well as pituitary. This result could be due to more frequent examinations.
Animals↗
Frequency of spontaneous tumors in Wistar rats in 30-months studies.
Tumors occurring in 450 male and 450 female control rats of the strain Wistar (BOR:WISW (SPF Cpb), breeder: Winkelmann, Borchen) employed in 9 control groups from 7 different 30-month studies were compiled on the basis of histopathology reports. 445 male and 448 female rats were evaluated. The remaining animals were unavailable due to autolysis. A total of 1211 tumors (565 in males, 646 in females) were seen in 716 rats (333 males, 383 females), 251 of which were classified as malignant (100 in males, 151 in females). About 44% of all primary tumors were located in the pituitary and adrenals alone. Average frequencies of primary tumors: pituitary 35.4%, uterus 34.0%, adrenals 26.5%, testes 15.8%, thyroid gland 11.8%, mammary glands 11.4% and 22.5% in females respectively, skin/subcutis 6.3%, ovaries 2.9%, endocrine pancreas 2.5%, hemolymphoreticular system 2.3%, liver 1.9%, heart 1.7% and various other organs showing tumor frequencies of less than 1.5%. Male animals exhibited strikingly more tumors of the adrenals, skin, endocrine pancreas, heart and brain, while pituitary tumors were predominant in females. A comparison of these data with those from 24-month studies in Wistar rats from the same breeder shows a considerable increase above all in the number of primary tumors, the number of tumor bearers as well as the number of tumors in the pituitary, adrenals, testes, mammary glands and heart. An extension of carcinogenicity studies to 30 months probably makes it harder to recognise tumorigenic effects of test substances, at least in some organs, than in two-year studies because of the high and variable spontaneous tumor rates.
Adrenal Gland Neoplasms↗
Excretion of urinary enzymes in female Sprague-Dawley rats in relation to cellular compartment, creatinine excretion and diuresis.
One hundred and one young-adult female Sprague-Dawley rats were acclimatized to metabolic cages for 2 days. After that time 24-hour urine was collected at a constant cooling temperature of 0-4 degrees C. After gel filtration the enzyme activities were determined, and the resulting values were used to calculate 24-hour excretions. The following reference ranges (2.5 and 97.5 percentiles) were determined (in mU/24 h): lactate dehydrogenase 43-181; phosphohexoseisomerase 45-1445; glutathione-S-transferase 1-299; alkaline phosphatase 27-1239; leucine arylamidase 72-377; gamma-glutamyltransferase 1334-9188; arylsulphatase A 59-309; beta-galactosidase 76-305; beta-glucuronidase 20-2756; beta-N-acetyl-D-glucosaminidase 66-491; glutamate dehydrogenase 7-711. There was a significant (though not very high) correlation with diuresis for the lysosomal enzymes beta-N-acetyl-D-glucosaminidase, arylsulphatase A and beta-galactosidase, and for glutamate dehydrogenase, lactate dehydrogenase, phosphohexoseisomerase and alkaline phosphatase. The relation to creatinine excretion was markedly close for the lysosomal enzymes beta-N-acetyl-D-glucosaminidase, arylsulphatase A and beta-galactosidase (r = 0.71-0.83), as well as for alkaline phosphatase, leucine arylamidase and gamma-glutamyltransferase. There was a relatively high correlation between the excretion of beta-N-acetyl-D-glucosaminidase, arylsulphatase A and beta-galactosidase among themselves (r = 0.63-0.81) as well as between leucine arylamidase and gamma-glutamyltransferase (r = 0.75).
Animals↗
Relationships between structure and induction of hyaline droplet accumulation in the renal cortex of male rats by aliphatic and alicyclic hydrocarbons.
A rapidly growing list of hydrocarbons has been reported to induce morphological changes in the kidney of adult male rats, beginning with hyaline droplet accumulation (HDA) followed by the development of granular casts, later on chronic nephrosis as sequela, and finally renal adenomas and carcinomas. The present study focuses on identifying structure-based properties common to HDA-inducing aliphatics and cycloaliphatics. On the basis of rank-ordered activities reported in the literature, a calculated n-octanol-water partition coefficient above 3.5 and the presence of an isopentyl structural moiety appear to be associated with HDA-inducing activity in aliphatics. A binding site model for highly active aliphatics has been derived by superimposing their minimum energy conformations along the common isopentyl substructure and calculating the union volume of their respective van der Waal (VDW) volumes. Generalization of this model to include cycloaliphatics has been achieved by maximizing the steric overlap of the VDW volumes of the compounds with their binding site union volume. HDA-inducing cycloaliphatics are correctly identified on the basis of their negligible excess volume. This approach has been used to predict the HDA-inducing activity of previously untested compounds. Eighteen aliphatic/cycloaliphatic hydrocarbons were screened in a study on adult male Wistar rats treated with 250 mg/kg per day for 5 days. Azan-stained kidney sections were semiquantitatively evaluated for the presence of HDA. The predicted and observed HDA activities were in very good agreement.
Alpha-Globulins↗
Determination of urinary glutathione S-transferase and lactate dehydrogenase for differentiation between proximal and distal nephron damage.
Cytosolic glutathione S-transferase (GST) activity is confined to the proximal convoluted and straight tubules. Damage to these parts of the nephron should result in leakage of GST into the urinary space. Lactate dehydrogenase (LDH), in contrast, is more generally distributed along the nephron. Measurement of both enzyme activities could therefore be expected to discriminate between different localizations of nephrotoxicity. To test this hypothesis, we determined both enzyme activities in 24 h urine samples from 10-12 female Sprague-Dawley rats, each treated with single i.p. injections of puromycin aminonucleoside (PAN, 130 mg/kg), Na2 CrO4 10, 20, 30 mg/kg), mercuric chloride (HgCl2, 0.5, 0.75, 1.0 mg/kg), folic acid (125, 350, 375 mg/kg), ethyleneimine (0.5, 2.0, 5.0 microliters/kg). Bovine serum albumin (BSA) was injected by the same method, twice daily on 3 consecutive days (2.5, 7.14 g/kg). The results obtained indicate a characteristic dose- and time-dependent pattern of excreted enzyme activities for each of the tested compounds. In both models with primarily glomerular damage, proximal tubular parts were also affected, as could be demonstrated by increased urinary GST and histopathological changes. Damage, mainly to the S1/S2 segment by 20 or 30 mg Na2 CrO4/kg, resulted in moderate to marked increases in LDH excretion, while GST was only moderately elevated at 30 mg/kg. Extreme increases in GST and LDH output were measured after predominant S3 segment damage after 0.75 and 1.0 mg HgCl2/kg. The distally active compounds, folic acid and ethyleneimine, did not increase GST excretion at lower doses. At the high doses, a small rise in GST excretion indicated some, probably secondary, proximal tubular involvement, which correlated with the histopathological findings in these groups.
Animals↗
Differences in liver sensitivity to methyl carbamate between Wistar and Fischer 344 rats.
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Alanine Transaminase↗
Spontaneous tumors in NMRI mice from carcinogenicity studies.
Twelve carcinogenicity experiments in NMRI mice from two different breeders were started at three different locations between 1974 and 1979. Tumors occurring in untreated control mice were compiled on the basis of histopathological reports. Of the 629 male and 627 female mice at the beginning of the studies, 614 males and 591 females were evaluated. The remaining animals were unavailable due to autolysis. The histopathologic diagnoses were performed by a team of 5 pathologists. A total of 1,220 tumors was seen (585 in males and 635 in females), of which 527 were classified as malignant (218 in males and 309 in females). About 56% of all tumors were located in the lungs and lymphoreticular system (LRS). Average frequencies of primary tumors: lungs 28.7%, LRS 28.2%, ovaries 21.3%, uterus 4.6%, vascular tissue 4.5%, mammary glands 3.9%, liver 3.2%, Harderian glands 3.2%, testes 3.1%, adrenals 3.1%, stomach 2.9%, pituitary 2.2%, endocrine pancreas 1.2%, thyroid 1.0%, Cowper's glands 1.0% and various other organs having tumor frequencies of less than 1%. This wide spectrum of spontaneous tumors with comparatively low frequencies renders NMRI mice a suitable strain for carcinogenicity studies. Male animals exhibited strikingly more tumors of the lungs, liver, Harderian glands, adrenals, endocrine pancreas and intestine, while LRS and pituitary tumors were predominant in females. Some tumor frequencies seem to be influenced by different husbandry conditions and different stocks. However, even under nearly identical husbandry conditions, the general frequency of benign and/or malignant tumors and of particular tumors varied markedly from one study to the next. Differences in mortality among studies had no pronounced effect on the range of tumor frequencies. Due to this biological variability in animal material, an interpretation of tumor frequencies in carcinogenicity studies necessitates an in-depth knowledge of the variability of tumor data for this mouse strain under similar husbandry conditions.
Animals↗