Biomedical subjects

V J Feron

Publications and source records attributed to V J Feron.

At least 55 records · Page 3Linked to original sources

PubMed1995

Safety evaluation of the mixture of chemicals at a specific workplace: theoretical considerations and a suggested two-step procedure.

Procedures for the selection of compounds with high health hazard potential are reviewed, and major aspects of the assessment of health risks associated with exposure to mixtures of chemicals are discussed. Examples are given of additivity and synergism of effects following exposure to mixtures. Using these data from the literature a two-step procedure for the safety evaluation of the mixture of chemicals occurring at a specific workplace is suggested. The first step consists of estimating the relative health risk associated with each chemical; the estimation is based on the ratio between exposure level and degree of toxicity. Those chemicals representing a high risk are then selected for further consideration. The second step comprises the risk assessment, focusing on prediction of the risk associated with exposure to the mixture of selected chemicals. To allow such prediction the (presumable) mode of action of the selected compounds should be considered. A practical way to find out whether exposure to chemicals at a specific workplace is of serious health concern, could be the conduct of both a 4-week toxicity study in rats and 2 different types of genotoxicity studies with the mixture of selected chemicals, using exposure concentrations related to those occurring in practice.

Animals↗

PubMed1995

Toxicity studies in rats of simple mixtures of chemicals with the same or different target organs.

Mixtures of chemicals with different target organs or the same target organ but different target sites or different modes of action did not appear to be distinctly more hazardous than the individual chemicals, provided the dose level of each chemical in the mixture did not exceed its own 'No-Observed-Adverse-Effect Level'. Clearly, for such mixtures and exposure conditions the additivity assumption did not hold. However, the additivity rule appeared to be applicable to mixtures of chemicals with the same target organ and the same mechanism of action or receptor. Fractional 2-factorial study designs were found to be promising tools for examining possible combined actions or interactions of chemicals in a mixture.

Animals↗

PubMed1995

Relation between benzo[a]pyrene-DNA adducts, cell proliferation and p53 expression in tracheal epithelium of hamsters fed a high beta-carotene diet.

Vitamin A and beta-carotene protect against respiratory tract cancer by inhibiting the formation of DNA damage and controlling cellular proliferation and differentiation. Recently, it has been shown that the p53 tumor-suppressor gene plays a crucial role in the etiology of respiratory tract cancer. In the present study, we investigated the relationship between benzo[a]pyrene (B[a]P)-DNA adducts, cell proliferation and p53 expression and the possible effect of beta-carotene on such a relationship in tracheal epithelium of hamsters given intratracheal instillations of B[a]P-Fe2O3 particles suspended in saline. DNA-adducts were quantified by the 32P-postlabeling assay, cell proliferation was quantified by immunocytochemical detection of incorporated BrdU during S-phase, and p53 protein was detected by immunohistochemistry with an antibody that recognized both the wild-type and the mutated protein (BioGenex, Clone BP53-12-1). A clear relationship appeared to exist between the extent of B[a]P-DNA adduct formation, the induction of cell proliferation and the expression of p53 protein in hamster tracheal epithelium. These results suggest that B[a]P induces cell proliferation in hamster tracheal epithelial cells most likely by the induction of mutations in the p53 gene. Furthermore, beta-carotene was not found to influence the formation of B[a]P-DNA adducts, which is probably due to the high B[a]P dose. Moreover, beta-carotene did not statistically significantly affect cell proliferation and p53-protein expression in hamster tracheal epithelial cells.

Animals↗

PubMed1995

Benzo[a]pyrene-induced respiratory tract cancer in hamsters fed a diet rich in beta-carotene. A histomorphological study.

The effect of a high dietary level of beta-carotene on the formation of preneoplastic and neoplastic respiratory tract lesions was studied in hamsters intratracheally treated with benzo[a]pyrene (B[a]P) attached to ferric oxide (Fe2O3) and suspended in saline. In addition to conventional histopathological examinations, the expression of cytokeratins and the glutathione S-transferase isoenzyme Pi (GST-Pi) was determined in tracheal epithelium using immunocytochemical techniques. B[a]P treatment increased the expression of cytokeratins in tracheal mucous and ciliated epithelial cells as detected by antibody RCK102 (cytokeratins 5 and 8), which normally recognizes basal cells only. The expression of cytokeratins in mucous and ciliated cells as detected by antibody RGE53 (cytokeratin 18) was decreased by B[a]P treatment. Furthermore, the expression of the cytokeratin detected by antibody RKSE60 (cytokeratin 10), characteristic of metaplastic squamous cells, and the expression of the GST-Pi, characteristic of metaplastic changes, was increased in trachael epithelium of hamsters treated with B[a]P. There was no evidence for dietary beta-carotene affecting the expression of cytokeratins or GST-Pi. The incidence of preneoplastic changes and tumors of the respiratory tract was not reduced by dietary beta-carotene. On the contrary, the tumor response of the respiratory epithelium was almost twice as high in hamsters fed the high beta-carotene diet than in hamsters on the low beta-carotene diet. However, this difference was not statistically significant (P = 0.15); hence, the present study did not produce evidence for a clear effect of beta-carotene on B[a]P-induced respiratory tract cancer in hamsters.

Animals↗

PubMed1994

Nitrate, nitrite and N-nitroso compounds.

A risk assessment has been made on nitrate, nitrite and N-nitroso compounds encountered in the human diet. Vegetables constitute a major source of nitrate providing over 85% of the average daily human dietary intake. Nitrite and N-nitroso compounds present in the diet contribute relatively small amounts to the body burden and the major source of these biologically reactive compounds is derived from the bacterial and mammalian metabolism of ingested nitrate. Additionally, endogenous synthesis provides an important source contributing to the body burden of nitrate. Data from animal toxicological studies, human effects and epidemiological surveys have been reviewed and evaluated. It is concluded that there is no firm scientific evidence at present to recommend drastic reductions beyond the average levels of nitrate encountered in vegetables grown in keeping with good agricultural practice. Recommendations have also been made for further animal and human studies to be carried out to elucidate the potential risks to man from ingested nitrate.

Animals↗

PubMed1994

Acute, subacute, and subchronic inhalation toxicity studies of respirable polymeric methylene diphenyl diisocyanate (polymeric MDI) aerosol in rats.

Short-term inhalation toxicity studies with respirable polymeric methylene diphenyl diisocyanate (polymeric MDI) aerosol were performed in rats. The 4-hr LC50 was found to be 490 mg polymeric MDI/m3 (95.5% < 4.3 microns). Exposure of (4-week-old) rats to 0, 2.2, 4.9, or 13.6 mg polymeric MDI/m3 (95% < 5 microns) for 2 weeks resulted in mortality, severe growth retardation, and elevated lung weights at 13.6 mg/m3; at 4.9 mg/m3 slight growth retardation and slightly elevated lung weights were observed. A 13-week study with 6-week-old rats exposed to 0.35, 1.4, or 7.2 mg polymeric MDI/m3 (95% < 5 microns) revealed transient growth retardation and a slightly increased number of pulmonary alveolar macrophages occasionally accompanied by increased numbers of mononuclear cells and fibroblasts in alveolar septa only at 7.2 mg/m3. In a second 2-week study with 4- or 6-week-old rats exposed to 14.1 mg polymeric MDI/m3 (95% < 5 microns), 4-week-old rats died earlier and in greater numbers than 6-week-old rats. In a second 13-week study with 6-week-old rats, using exposure concentrations of 0, 4.1, 8.4, and 12.3 mg polymeric MDI/m3 (95% < 5 microns) and including a 4-week recovery period, 12.3 mg/m3 induced mortality, growth retardation, severe respiratory distress, increased lung weights, degeneration and hyperplasia of the nasal epithelium, accumulations of macrophages in the lungs and mediastinal lymph nodes, and focal inflammatory changes in the lungs.(ABSTRACT TRUNCATED AT 250 WORDS)

Aerosols↗

PubMed1994

Chronic inhalation toxicity and carcinogenicity study of respirable polymeric methylene diphenyl diisocyanate (polymeric MDI) aerosol in rats.

Four groups of 60 Wistar rats of each sex were exposed by inhalation to 0, 0.2, 1.0, or 6.0 mg/m3 respirable polymeric methylene diphenyl diisocyanate (polymeric MDI) aerosol (93.5% < 4.2 microns) for 6 hr a day, 5 days a week for up to 24 months. In addition, satellite groups of 10 rats/sex/group received the same treatment for 12 months. There was no adverse effect on general health, survival, body weight, or hematological or clinical chemistry parameters. Lung weights were increased in both males and females exposed to 6.0 mg polymeric MDI/m3 for 12 or 24 months. Gross examination at autopsy of males exposed to 6.0 mg polymeric MDI/m3 for 24 months revealed an increased incidence of spotted and discolored lungs. Increased incidences of degeneration and basal cell hyperplasia of the nasal olfactory epithelium, often accompanied by hyperplasia of Bowman's glands, were found in the 1.0 and 6.0 mg/m3 groups. Light and electron microscopic studies of the lungs revealed accumulations of alveolar macrophages containing polymeric MDI-associated refractile yellowish material at the level of the alveolar duct in all exposed groups. Alveolar duct epithelialization as well as fibrosis of tissues surrounding the macrophage accumulations occurred at the 1.0 and 6.0 mg/m3 exposure levels. In addition, increased incidences of calcareous deposits and localized alveolar bronchiolization were seen in the 6.0 mg/m3 group. Moreover, eight pulmonary adenomas (six in males and two in females) and one pulmonary adenocarcinoma (in a male) were observed in the 6.0 mg/m3 exposure group. The time sequence of the spectrum of pulmonary changes indicates that recurrent alveolar wall damage by polymeric MDI and/or polymeric MDI-containing alveolar macrophages leads to alveolar bronchiolization and ultimately to bronchioloalveolar tumors. No lung tumors were found in the lower concentration groups and in the control group. The incidence and distribution of other types of tumors were not influenced by polymeric MDI. It was concluded that in the present study, the "no-observed-adverse-effect level" of polymeric MDI was 0.2 mg/m3, and that chronic exposure to polymeric MDI at a level of 6.0 mg/m3 was related to the occurrence of pulmonary tumors. It was also concluded that exposure to polymeric MDI at concentrations not leading to recurrent lung tissue damage will not produce pulmonary tumors.

Adenocarcinoma↗

PubMed1994

Chronic toxicity and oncogenicity inhalation study with vinyl acetate in the rat and mouse.

Vinyl acetate was evaluated for chronic toxicity and oncogenicity in male and female rats and mice in a 104-week study. Target concentrations were 0, 50, 200, and 600 ppm. The study included interim terminations at approximately 53 and 83 weeks and a group whose exposure was terminated at 70 weeks and allowed a 15-week recovery period. Over the course of the exposures, body weight gain was consistently depressed in all 600 ppm groups and in the 200 ppm mice. Except for female rats of the 600 ppm exposure group, recovery animals showed significant improvements in weight gain relative to controls. There were no changes in hematological parameters of either species that could be unequivocally related to treatment. The only effect noted on clinical chemical parameters during the study were decreases in blood glucose in the 600 ppm females. There were no adverse effects on survival in either species. Increases in lung weight were noted in rats and mice primarily in the 600 ppm groups. These changes were associated with bronchial exfoliation, macrophage accumulation, and fibrous plaques and buds extending into the airway lumen, and bronchial/bronchiolar epithelial disorganization. The most significant histopathological changes were noted in the nasal cavity. In the olfactory epithelium of both rats and mice, the main nonneoplastic changes included epithelial atrophy, regenerative effects (squamous metaplasia and respiratory metaplasia of olfactory epithelium), basal cell hyperplasia, and epithelial nest-like infolds. No nonneoplastic changes were observed in the respiratory epithelium of rats, while squamous metaplasia at the naso/maxilloturbinate region was prevalent in mice. Nonneoplastic changes were similar in the recovery groups. Oncogenic responses to vinyl acetate exposure were mainly confined to the nasal cavity in rats and included endo- and exophytic papillomas, squamous cell carcinoma, carcinoma in situ in olfactory regions, and endophytic papilloma in respiratory regions. Squamous cell carcinomas were also found either in areas normally covered by cuboidal epithelium or areas of unknown origin. One squamous cell carcinoma was found in the larynx of a rat of the 600 ppm groups. One squamous cell carcinoma was found in the lung of a mouse of the 600 ppm group.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Inhalation↗

PubMed1994

Biochemical and histopathological changes in nasal epithelium of rats after 3-day intermittent exposure to formaldehyde and ozone alone or in combination.

To get a better insight into the pathophysiology of the nasal changes induced by formaldehyde-ozone mixtures, a 3-day inhalation study was carried out in rats, using intermittent exposure to formaldehyde (3.6 ppm) and ozone (0.4 ppm) alone or in combination and focusing on biochemical and histopathological changes in rat nasal respiratory epithelium. Formaldehyde dehydrogenase, glutathione S-transferase, glutathione reductase, and glucose-6-phosphate dehydrogenase activities in this epithelium were not affected by the individual compounds. However, combined exposure to formaldehyde and ozone resulted in slightly decreased activities of these enzymes. Formaldehyde was found to induce rhinitis, degeneration, frank necrosis, hyperplasia and squamous metaplasia of the ciliated and non-ciliated nasal respiratory epithelium, while ozone induced disarrangement, flattening and slight basal cell hyperplasia of the non-ciliated cuboidal epithelium accompanied by influx of neutrophils. Proliferating cell nuclear antigen (PCNA) expression was elevated not only in nasal areas showing ozone-induced histopathological changes but also in the otherwise normal-appearing epithelium of the nasal septum. No interactive effects were found with respect to proliferative response of the nasal respiratory epithelium after exposure to the formaldehyde-ozone mixture. The present study did not provide evidence of a major role of glutathione and glutathione-dependent enzymes in the pathogenesis of nasal lesions induced by formaldehyde and/or ozone, demonstrated the potential of ozone to affect the mucociliary epithelium lining the nasal septum, and suggested that PCNA expression is a sensitive tool for detection of early effects of respiratory irritants.

Administration, Inhalation↗

PubMed1994

High survival rate of hamsters given intratracheal instillations of benzo[a]pyrene and ferric oxide and kept on a high beta-carotene diet.

The study described in this paper was primarily conducted to identify the cell types involved in the formation, progression and regression of metaplastic changes in the respiratory tract epithelium of hamsters after intratracheal intubations with benzo[a]pyrene. Furthermore, the role of vitamin A and beta-carotene in these processes was studied. In the course of the study a remarkable effect of dietary beta-carotene on survival of hamsters became a subject of investigation. Hamsters were fed diets with various levels of vitamin A or beta-carotene and were treated intratracheally with a suspension of benzo[a]pyrene with ferric oxide in saline. The tumour response of the respiratory tract was very low (2.8%) and hyper- and metaplasia of respiratory epithelium were virtually absent. However, an interesting observation was an exceptionally low mortality of only 2% after 69 weeks in the group of hamsters fed a high beta-carotene diet (1% w/w), whereas in the other groups mortality after 69 weeks amounted to 25%. Although the exact cause of death of most of the hamsters could not be established, a 40% reduction of lipid peroxidation in the livers was found in the high beta-carotene group. Moreover, in this group the degree and incidence of nephrosis and of focal mineralization of kidneys and heart were lower than in the other groups. These favourable effects of the high beta-carotene diet may have contributed to the unusually high survival rate in hamsters fed this diet. Further studies are planned to verify and study this observation.

Animals↗

PubMed1994

DNA adduct formation and repair in hamster and rat tracheas exposed to benzo[a]pyrene in organ culture.

Syrian golden hamsters are much more susceptible than Wistar rats to the induction of tracheal tumors by benzo[a]pyrene (B[a]P). To investigate whether this difference is reflected in the pattern of DNA adduct induction and removal, tracheas from either species were isolated and exposed to B[a]P (5 micrograms/ml) in organ culture. At various time-points B[a]P-DNA adducts were quantified by 32P-postlabeling; unscheduled DNA synthesis (UDS) and cell proliferation were determined by [3H]thymidine incorporation during the 18 h before sampling. In an induction-repair experiment tracheas were exposed to B[a]P for 2 days, and cultured for another 4 days without B[a]P. After 2 days of exposure total B[a]P-DNA adduct levels were 10 times higher in hamster compared to rat tracheas. In hamster tracheas one major adduct was formed (95%), namely the adduct between (+)-anti-benzo[a]pyrene diolepoxide and deoxyguanosine (BPDE-N2dG). In rat tracheas BPDE-N2dG comprised approximately 60% of the total B[a]P-DNA adduct level. The other major adduct found in rat tracheas is probably derived from interaction of syn-BPDE and deoxyadenosine. During exposure to B[a]P in hamsters the adduct level increased to 36 +/- 19 adducts/10(6) nucleotides (add/10(6)n) on day 2. Two days after removal of B[a]P the B[a]P-DNA adduct level had decreased to 60% of that on day 2; there was no further decrease in the B[a]P-DNA adduct level, despite considerable cell proliferation at the end of the 6 day culture period. UDS increased during exposure to B[a]P and decreased after removal of B[a]P. In rats removal of B[a]P did not lead to a decrease in the B[a]P-DNA adduct level, which agreed with the observed absence of UDS. In a second experiment tracheas were exposed to B[a]P continuously for 15 days. In hamster tracheas the total B[a]P-DNA adduct level increased from 11 +/- 0.7 add/10(6)n after 1 day of exposure to 105 +/- 2 add/10(6)n after 15 days; also UDS increased with increasing exposure until day 11. Cell proliferation was low at the end of the culture period. In rat tracheas no progressive increase in the B[a]P-DNA adduct level was seen, UDS was not increased and cell proliferation had increased significantly at the end of the exposure period. The extent of adduct induction in the trachea of the two species corresponded with the different susceptibilities to B[a]P-induced tumor formation.

Animals↗

PubMed1994

Immunocytochemical identification of DNA adducts, O6-methylguanine and 7-methylguanine, in respiratory and other tissues of rat, mouse and Syrian hamster exposed to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

The present paper reports about an immunocytochemical inventory of the cell types involved in the metabolic activation of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to a DNA methylating metabolite. The formation and distribution of the methylated DNA bases O6-methylguanine (O6-meGua) and 7-methylguanine (7-MeGua) were studied in respiratory tissues, oesophagus, liver, kidneys, pancreas, small intestine, colon and prostate of rat, mouse and hamster 6 h after treatment with a single dose of 30 mg NNK/kg. The tissue- and cell-specific distribution of O6-meGua- and 7-meGua-specific nuclear staining showed the same patterns and were remarkably similar in rat, mouse and hamster in spite of the diverging spectra of NNK-induced tumours in these species. In nasal tissue, a target for NNK-induced tumourigenesis in rat and hamster, but not in mouse, adduct-specific nuclear staining was observed in all three species in sustentacular cells, Bowman glands, respiratory epithelial cells and serous glands. Both methylated DNA bases were also observed in basal cells of the olfactory epithelium of rat and (occasionally) hamster, but not in those of the mouse. In the trachea, a target for NNK-induced tumourigenesis in hamster only, substantial adduct-specific nuclear staining was found in basal epithelial and glandular cells of the hamster; in the same cells of rat and mouse only a weak nuclear staining was found. In the lung, a common target for NNK-induced tumourigenesis, the formation of O6-meGua and 7-meGua was restricted predominantly to bronchial and proximal bronchiolar epithelium. Nuclear staining in the rat was occasionally found in alveolar cells and was also observed in hepatocytes. In the three species investigated, O6-meGua- and 7-MeGua-specific nuclear staining was found in target and non-target tissues. Apparently, and in analogy with results obtained in other studies, the species-specific organotropy for tumour formation of NNK is not exclusively determined by DNA methylation. Expanding methylation data with literature data on factors considered to be involved in tumour formation, namely proliferation, toxicity and DNA repair among others, still did not lead to a satisfactory explanation for the species-specific organotropy observed. Additional factors (yet to be identified), need to be taken into account in order to explain (and predict) tumourigenic effects induced by monofunctional methylating agents.

Animals↗

PubMed1994

Spontaneous squamous cell carcinoma of nasal and paranasal structures in the Cpb:WU (Wistar random) rat: nasolachrymal duct as major site of origin.

Spontaneous nasal tumors in ageing rats are very rare. Chronic irritation and disruption of nasal, paranasal, buccal, and dental tissues have been associated with the occurrence of tumors of the nasal and paranasal structures in rats. To find out whether there is a relationship between malocclusion (MO) and nasal squamous cell carcinoma (SCC) in Cpb:WU (Wistar random) rats, a total of 899 untreated control rats (548 males and 351 females) from eight long-term toxicity/carcinogenicity studies was screened for nasal tumors and MO. All relevant data and the histopathology of the nasal and paranasal structures of a sample of these rats (189 males and 197 females from three of the studies) and all rats bearing a nasal tumor were subjected to a detailed analysis. Of the 899 rats, 84 males (15%) and 78 females (22%) suffered from MO. Microscopic examination revealed an unexpectedly high incidence of lesions in the nasolachrymal duct (NLD): 64 out of 189 males (34%) and 68 out of 197 females (34.5%) showed inflammatory changes, with or without squamous metaplasia and/or hyperplasia of the lining epithelium of the NLD. The incidence of NLD lesions was much higher in the animals with than without MO, suggesting an interaction of both phenomena. Eight of the 899 untreated control rats had a nasal tumor; all were SCCs and all occurred in males. The origin of the tumors was as follows: 2 NLD, 2 most probably NLD, 2 presumably NLD, 1 of unknown origin but possibly NLD, and 1 probably a cutaneous epidermoid cyst. On the basis of these findings, it was concluded that nasal SCC in Cpb:WU (Wistar random) rats prevails in males and is primarily associated with chronic inflammation of the NLD rather than with MO, although MO probably is an (indirectly) contributing factor.

Animals↗

PubMed1993

Subacute (4-wk) oral toxicity of a combination of four nephrotoxins in rats: comparison with the toxicity of the individual compounds.

In a 4-wk study, 10-wk-old Wistar rats were fed the nephrotoxins hexachloro-1,3-butadiene (HCBD), mercuric chloride, d-limonene and lysinoalanine either alone or in combination. These nephrotoxins damage epithelial cells of the proximal tubules, but by different mechanisms. Each chemical was given alone at a Minimum-Nephrotoxic-Effect Level (MNEL), and at a No-Nephrotoxic-Effect Level (NNEL). The combination was given at the MNEL, the NNEL and one-quarter of the NNEL of the individual chemicals. The individual nephrotoxins caused slight growth depression in males at the MNEL, but not at the NNEL, whereas the combination depressed growth slightly at the NNEL and severely at the MNEL. In females at the MNEL, only HCBD retarded growth; in contrast to the effect in males this was not aggravated by combined treatment. Nephrotoxicity was more severe in males fed the combination than in males given the nephrotoxins alone. The former showed decreased renal concentrating ability and moderate histopathological changes in the kidneys at the MNEL, and a dose-dependent increase in kidney weight and number of epithelial cells in the urine at the NNEL and the MNEL. The males treated with a single agent showed slightly increased kidney weights, and/or slight histopathological changes in the kidneys at the MNEL, and (with d-limonene only) epithelial cells in the urine at the NNEL and MNEL. In females, renal changes induced by the combination were not more severe than those observed with individual compounds. No adverse changes attributable to treatment were observed in rats fed the combination at one-quarter of the NNEL. In the present study, combined exposure to four nephrotoxins at their individual NNEL did not constitute an obviously increased hazard, indicating absence of synergistic interaction, whereas at the MNEL clearly enhanced (renal) toxicity occurred in males, although not in females.

Animals↗

PubMed1993

Acute (24 hr) toxicity of a combination of four nephrotoxicants in rats compared with the toxicity of the individual compounds.

To identify possible hazards of combined exposure to chemicals with the same target organ, a 24-hr single dose experiment was carried out in which the renal toxicity of mercuric chloride, potassium dichromate, d-limonene and hexachloro-1:3-butadiene administered simultaneously was compared with the nephrotoxicity of the individual compounds, using a total of 11 groups each consisting of five 12-wk-old male Wistar rats. The dose levels used were based on the results of a range-finding study with the individual compounds in the same strain of rats kept under similar experimental conditions, and comprised the 'Minimum-Nephrotoxic-Effect Level' (MNEL) and the 'No-Nephrotoxic-Effect Level' (NNEL) of each of the four compounds alone and in combination. A group of vehicle-treated rats served as controls. At the MNEL of the combination, antagonism of effects was encountered, seen for example as less severely increased activity of gamma-glutamyl transferase in the urine. Synergism of effects was also observed, for example increased severity of renal tubular necrosis, and more markedly increased activity of urinary lysozyme, lactate dehydrogenase, alkaline phosphatase and N-acetyl-beta-glucosaminidase. More importantly, however, at the NNEL of the combination no signs of impaired renal function or renal damage were observed, suggesting absence of both dose additivity and potentiating interaction at the tested subeffective levels of the individual nephrotoxicants.

Acetylglucosaminidase↗

PubMed1992

Multi-compartment model to study the effect of air-blood and blood-tissue partition coefficients on concentration-time-effect relationships.

The influence of the air-blood (lambda) and blood-tissue partition coefficients of substances on the concentration-time-effect relationship E = [aCnT]b was studied by model simulation of uptake and distribution of gases. The model consisted of a lung compartment and four tissue compartments. Rat and human model parameters were obtained from physiological data, and substance-dependent variables. The observable effect E (righting reflex, mortality, etc.) for directly acting systemic agents was supposed to be related to the (arbitrarily chosen) concentration of the substance in the arterial blood or in the liver compartment. We conclude that for a directly acting systemic agent n greater than or equal to 1. If n less than 1 other mechanisms such as metabolism must be incorporated in the model which, however, should not be excluded when n greater than or equal to 1. If the observable effect is related to arterial concentration of the substance, n increases with decreasing lambda. If the liver concentration is related to the observable effect, man and rat may behave quite differently. This has major consequences for the extrapolation of animal results to the human situation in risk assessment.

Air↗

PubMed1992

Rat pituitary changes observed with magnetic resonance imaging following removal of estrogen stimulus: correlation with histopathology and immunohistology.

The effect of estrogen withdrawal on pituitary glands of rats treated with estradiol-17 beta for various lengths of time was monitored by magnetic resonance imaging (MRI) and histological examination. Estrogen pellets were removed at seven different time points ranging from 4 to 206 days after pellet implantation. High-resolution mid-sagittal MR images of the rat head were made 1 day before pellet implantation, immediately following pellet withdrawal, and 14 and 28 days after pellet withdrawal. Twenty-eight days after pellet withdrawal pituitary glands were fixed and processed for histological examination. Enlarged pituitaries were detected by MRI from 16 days after implantation and onwards. Twenty-eight days after estrogen withdrawal the typical triangular shape of the normal pituitary had returned and pituitary morphology was indistinguishable from that of normal pituitaries in all rats that had been treated with estrogen for up to 114 days. Pituitaries of rats that had received estrogen for 186 days had a normal MR image 28 days after estrogen withdrawal, but microscopic examination revealed multifocal hyperplasias of prolactin-positive cells throughout the pars distalis. MRI of rats treated for 206 days showed tumorously enlarged pituitaries. There was no evidence of tumor regression in these rats 28 days after pellet removal. It was concluded that hypertrophic pituitaries regained a normal size, shape and morphology after estrogen withdrawal, except for a remarkable type of hyperplasia following estrogen treatment for 186 days and a recovery period of 28 days. In tumorous pituitaries no regression of lesions was noticed.

Animals↗

PubMed1992

Adenomatoid odontogenic tumorlike lesion in a male Wistar rat.

An odontogenic tumor in the maxilla of a male Wistar rat is described. The tumor consisted of large epithelial areas with peripheral palissading and with juxtaepithelial material resembling dentin. The neoplastic odontogenic epithelium seems capable of inducing peridental mesenchyme to form a kind of dental hard tissue normally not present at that site.

Animals↗