Biomedical subjects

D Jonker

Publications and source records attributed to D Jonker.

17 recordsLinked to original sources

PubMed2001

The benchmark approach applied to a 28-day toxicity study with Rhodorsil Silane in rats. the impact of increasing the number of dose groups.

The OECD study design, aimed at obtaining a no-observed-adverse-effect level (NOAEL), may be suboptimal for deriving a benchmark dose. Therefore the present subacute (28-day) study was carried out to evaluate a multiple dose study design and to compare the results with the common OECD design. Seven groups of 10 female rats each were intragastrically administered corn oil without (controls) or with 50, 150, 300, 450, 600 or 750 mg Rhodorsil Silane/kg body weight/day, once daily (7 days/week) for 4 weeks. From the complete dataset, two subsets were selected, one representing a study design with seven dose groups of five animals (7 x 5 design), the other representing a study design with four dose groups of 10 animals (4 x 10 design). Under the conditions of the present study, the NOAEL for Rhodorsil Silane 198 was assessed at 50 mg/kg body weight/day, based on the data of the 4 x 10 design. The benchmark approach resulted in a benchmark dose of 19 mg/kg body weight/day, based on the data of the 7 x 5 design. Comparison of the results demonstrated that the multiple dose (7 x 5) design led to a more reliable result than the OECD (4 x 10) design, despite the smaller total number of animals. The dose-response analysis showed that at "the NOAEL" the effect on relative spleen weight was larger than 10%, illustrating that at the NOAEL, adverse effects may occur.

Alanine Transaminase↗

PubMed2001

Absence of adverse effects of sodium metabisulphite in manufactured biscuits: results of subacute (28-days) and subchronic (85-days) feeding studies in rats.

Sulphites are extensively used in the food and drinks industry. Their toxicity has been previously evaluated by addition to the diet or drinking water of laboratory animals. Because interactions between sulphites and food constituents occur, the present work was conducted to determine the subacute and subchronic toxicity of sulphite-bound compounds in a finished product: manufactured biscuits. The studies were performed on Sprague Dawley, rats for 28 and 85 days of dietary exposure. Diets were prepared from sulphited or untreated (controls) biscuits with the addition of sugar, protein, vitamins and minerals according to the nutritional requirements of the animals. Groups of 10 male and 10 female rats were administered diets containing sulphited biscuits at levels of 0, 10, 35 and 75%, corresponding to 10-15, 35-45, 150-170 and 310-340 mg SO2/kg diet. In both studies, no death or clinical abnormalities were reported. Growth rate, food consumption and food conversion efficiency were not affected by treatment. No dose-related changes were observed for haematology, clinical chemistry, ocular examination, renal-function, urinalysis, organ weights or gross and microscopic examinations. The liver concentrations of vitamins A, B1, C and E were not significantly changed except for an increase in vitamin E in high-dose males after 28 days' exposure. Based on these data, the no-observed-adverse-effect level (NOAEL) of sulphites in baked biscuits was judged to be 310 mg SO2/kg diet or 25 mg/kg body weight/day.

Animal Nutritional Physiological Phenomena↗

PubMed1999

Short-term tests of estrogenic potential of plant stanols and plant stanol esters.

To test for potential estrogenic activity of plant stanols and plant stanol esters, two short-term tests were performed. These were the E-screen test, which measures a substance's ability to induce proliferation of estrogen-responsive human breast adenocarcinoma (MCF-7) cells in culture, and an in vivo test, which measures uterotrophic activity in immature female rats fed the test substance. Four samples of vegetable oil-derived stanols (containing 88-99% stanols) were tested in the E-screen test, and one sample of wood-derived and one of vegetable oil-derived stanol fatty acid esters were tested in the in vivo test. In the E-screen test, the positive control substance, 17beta-estradiol, at 100 pM, produced a statistically significant, 11.6-fold increase in cell proliferation, as measured by sulforhodamine B staining. None of the stanol preparations produced any increase in cell proliferation when tested at 1, 10, and 100 microM. The highest dose of each stanol sample was associated with microscopic evidence of cytotoxicity and crystalline precipitation in the culture dishes. In the in vivo test, the positive control compound, diethylstilbestrol, produced a significant, dose-related increase in absolute and relative uterus weight in young female rats (17 days old at the start of treatment) fed the compound at 5, 10, and 20 ppb in the diet for 4 days. Neither of the two stanol ester preparations caused any significant change in absolute or relative uterus weight when fed at a concentration of 8.3% in the diet for 4 days. Thus, under the conditions of testing used, neither the free stanols nor the stanol fatty acid ester preparations showed evidence of estrogenic or uterotrophic activity.

Analysis of Variance↗

PubMed1999

13-week oral toxicity study with stanol esters in rats.

Plant sterols and their saturated derivatives, known as stanols, reduce serum cholesterol when consumed in amounts of approximately 2 g per day. Stanol fatty acid esters have been developed as a highly fat-soluble form that may lower cholesterol more effectively than stanols. Stanol esters occur naturally in human diets, but at levels far below those known to lower cholesterol. The present study was conducted to assess the safety of stanol esters upon subchronic ingestion at levels comparable to or exceeding those recommended for lowering cholesterol. Two stanol fatty acid ester preparations, wood-derived stanol esters and vegetable oil-derived stanol esters, were fed to groups of 20 male and 20 female Wistar rats for 13 weeks, at dietary concentrations of 0, 0.2, 1, and 5% total stanols (equivalent to 0, 0.34, 1.68, and 8.39% wood-derived stanol esters and 0, 0.36, 1.78, and 8.91% vegetable oil-derived stanol esters). Both preparations were well tolerated as evidenced by the absence of clinical changes or major abnormalities in growth, food and water consumption, ophthalmoscopic findings, routine hematological and clinical chemistry values, renal concentrating ability, composition of the urine, appearance of the feces, estrus cycle length, organ weights, gross necropsy findings, and histopathological findings. Plasma cholesterol and phospholipids were slightly decreased in males fed the stanol esters. In both sexes, plasma levels of plant sterols were decreased whereas those of stanols tended to increase. Fecal excretion of sterols, including cholesterol, and stanols was markedly increased in the stanol ester groups. Compared to controls, male rats fed stanol esters showed somewhat lower liver weights and more pronounced glycogen depletion. These hepatic changes were considered to reflect an altered nutritional condition and not a pathological condition. Plasma levels of vitamin E, vitamin K1, and, to a lesser extent, vitamin D were decreased in males and females fed the high-dose diets. Hepatic levels of vitamins E and D showed similar changes (vitamin K1 in the liver was not determined). For both preparations, the mid-dose level (1% total stanols in the diet) was a no-observed-adverse-effect level. This dietary level provided approximately 0.5 g total stanols/kg body wt/day.

Animals↗

PubMed1999

Characterization of the decrease of extracellular striatal dopamine induced by intrastriatal morphine administration.

The effect of intrastriatally-administered morphine on striatal dopamine (DA) release was studied in freely moving rats. Morphine (1, 10 or 100 microM) was given into the striatum by reversed microdialysis, and concentrations of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were simultaneously measured from the striatal dialysates. Intrastriatally-administered morphine significantly and dose-dependently decreased the extracellular concentration of DA, the concentrations of the acidic DA metabolites were only slightly decreased. The effect of morphine was antagonized by naltrexone (2.25 mg kg(-1), s.c.). Pretreatment with a preferential kappa-opioid receptor antagonist, MR2266 [(-)-5,9 alpha-diethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphane; 1 mg kg(-1), s.c.], had no effect on the decrease of extracellular DA evoked by intrastriatal morphine (100 microM). Intrastriatal administration of the selective micro-opioid receptor agonist [D-Ala2,MePhe4,Gly-ol5] enkephalin (DAMGO; 1 microM), significantly decreased the extracellular concentration of DA in the striatum. When the rats were given morphine repeatedly in increasing doses (10-25 mg kg(-1), s.c.) twice daily for 7 days and withdrawn for 48 h, the decrease of extracellular DA induced by morphine (100 microM) was significantly less than that seen in saline-treated controls. Our results show that besides the well-known stimulatory effect there is a local inhibitory component in the action of morphine on striatal DA release in the terminal regions of nigrostriatal DA neurones. Tolerance develops to this inhibitory effect during repeated morphine treatment. Furthermore, our results suggest that the effect of intrastriatally-administered morphine is mediated by the micro-opioid receptors.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1999

Neoadjuvant chemotherapy before surgery for resectable carcinoma of the lower esophagus.

Neoadjuvant chemotherapy before surgery has been proposed to improve the outcome in patients with early lower esophageal cancer. To evaluate its effectiveness, we performed a systematic retrospective analysis of consecutive patients treated at the Ottawa Regional Cancer Center with prospective inclusion criteria. Between 1988 and 1992 patients were treated with surgery alone. From 1992 until 1997, patients were uniformly treated with neoadjuvant chemotherapy consisting of cisplatin and 5-fluorouracil. Surgical resection was then performed. Nineteen patients received neoadjuvant chemotherapy and 15 received surgery alone. Although the two arms of the study were balanced for age and sex, there were more patients in the neoadjuvant arm with squamous histology, weight loss and regional nodes at diagnosis. In the neoadjuvant arm, two patients did not have surgery because of progression or toxicity. However, complete resection rates were similar. There was no difference in overall survival or disease-free survival between the two arms (p > 0.4). Multivariate analysis revealed that only the nodal status at diagnosis was predictive of outcome. Neoadjuvant chemotherapy with this regimen does not result in improved survival over surgery alone.

Adenocarcinoma↗

PubMed1995

Toxicology of chemical mixtures: challenges for today and the future.

A major challenge for the toxicologist involved in safety evaluation of chemical mixtures is to test the hypothesis that as a rule exposure to mixtures of chemicals at (low) non-toxic doses of the individual chemicals is of no health concern. A series of repeated dose studies in rats with defined mixtures of chemicals with the same or different target organs revealed that exposure to a combination of chemicals compared with exposure to the individual compounds did not constitute an evidently increased hazard, provided each chemical was administered at a level similar to, or slightly lower than, its own 'No-Observed-Adverse-Effect-Level'. The results of subacute oral toxicity studies in rats with defined mixtures of nephrotoxicants with similar mode of action underlined the applicability of the additivity assumption for a mixture of chemicals with simple similar action. Safety evaluation of complex chemical mixtures is a challenge that can be tackled as follows: first, identify the (e.g. ten) most risky chemicals in the mixture, and, second, assess the hazard and the potential health risk of the mixture of the most risky chemicals, using procedures developed for defined mixtures. To identify interactions between individual compounds, a most promising testing strategy appeared to be a statistical approach using a fractional two-level factorial design. A challenge for today and the future is to gradually substitute mixture-oriented (real life-oriented) standard setting for (unrealistic) single chemical-oriented standard setting.

Administration, Inhalation↗

PubMed1995

Human diets cooked by microwave or conventionally: comparative sub-chronic (13-wk) toxicity study in rats.

To compare the possible effects of microwave and conventional cooking on a range of common dietary components, mixed human diets containing beef, potatoes and vegetables were fed to groups of 10 male and 10 female Wistar rats for 13 wk. The diet ingredients were cooked by either of the methods in a normal and an abused manner, the latter consisting of the normal treatment followed by two cycles of reheating to approximately 85 degrees C and cooling. The cooked ingredients were freeze-dried, ground and mixed with supplements of vitamins and minerals to meet the rat requirements. An additional control group was fed a cereal-based rodent diet. Criteria to assess toxicity included clinical observations, ophthalmoscopy, growth, food and water intake, haematology, clinical chemistry, urinalysis, organ weights, micronucleated erythrocytes in bone marrow, gross examination at autopsy and microscopic examination of a wide range of organs. The results indicate no adverse effects of the diets cooked by microwave compared with those cooked conventionally.

Analysis of Variance↗

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↗

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↗

PubMed1993

The relationship between sexual abuse and female suicidal behavior.

This study investigated the relationship between suicide attempts and a history of sexual abuse. In a sample of 158 female suicide attempters aged 20 years or older, 50% of the subjects reported having been sexually abused at some time. Sexually abused suicide attempters had shown more suicidal behavior in the past than their non-sexually abused counterparts (even though they were significantly younger), and were characterized by a more severe problem history. In the past, as well as shortly after the index attempt, they had experienced more serious problems in their relationships with significant others, with sexuality, and with self-fulfillment. At follow-up 1 year later, significantly more sexually abused women had attempted suicide during the intervening period than the women without a history of sexual abuse, and they also had more serious sexual problems. It is concluded that within a group of female suicide attempters, those with a history of sexual abuse are disproportionately vulnerable to repeated suicidal behavior.

Adolescent↗

PubMed1992

21-day intravenous toxicity study with feline interferon in rats.

The toxicity of recombinant feline interferon, a prospective antiviral drug for cats, was examined in a subacute study. Groups of five male and five female Wistar rats were given iv feline interferon in 20 mM-NaCl at doses of 0, 5, 15 and 50 MU/kg body weight/day for 21 consecutive days. Criteria to assess toxicity included clinical observations, ophthalmoscopy, growth, food and water intake, haematology, clinical chemistry, urinalysis, organ weights, gross examination at autopsy and microscopic examination of the liver, kidneys, spleen, adrenals, heart, mesenteric lymph nodes and thymus. No treatment-related were observed even at the highest dose level. The no-observed-adverse-effect level for feline interferon in this study was therefore 50 MU/kg body weight/day.

Animals↗

PubMed1990

4-week oral toxicity study of a combination of eight chemicals in rats: comparison with the toxicity of the individual compounds.

In a 4-wk oral toxicity study, 4-wk-old male and female Wistar rats were exposed to a combination of arbitrarily chosen chemicals comprising sodium metabisulphite, Mirex, Loperamide, metaldehyde, di-n-octyltin dichloride, stannous chloride, lysinoalanine and potassium nitrite. The dose levels used were based on the "no-observed-adverse-effect level" (NOAEL) and the "minimum-observed-adverse-effect level" (MOAEL) of the individual compounds obtained in similar studies with Wistar rats previously performed at TNO-CIVO, and comprised 0 (controls), 1/10 and 1/3 of the NOAEL, the NOAEL and the MOAEL. In comparison with the adverse effects of the individual compounds, both more severe and less severe adverse effects were observed at the MOAEL of the combined compounds, indicating interaction of effects at this exposure level. Slightly decreased haemoglobin content and slightly increased relative kidney weight were the only treatment-related adverse effects seen in the NOAEL group. In the 1/10 and 1/3 NOAEL groups no untoward effects were found that could be related to treatment. The present study clearly demonstrates absence of a simple additive effect, and provides some, but no convincing, evidence for an increased risk from exposure to a combination of chemicals when each chemical is administered at its own individual NOAEL. At lower dose levels no increased risk appears to exist. These generalizations may not be fully justifiable from a purely scientific point of view but are the most important practical lesson learnt from the present study.

Administration, Oral↗

PubMed1988

Comparison of the effects of ascorbyl palmitate and L-ascorbic acid on paracetamol-induced hepatotoxicity in the mouse.

The effects of ascorbyl palmitate (ASCP) and free L-ascorbic acid (LAA) on the hepatotoxicity of paracetamol (acetaminophen) and the in vivo covalent binding of reactive paracetamol metabolites to hepatic proteins has been studied in male MF1 mice. The oral administration of [3H(G)]paracetamol (600 mg/kg) resulted in covalent binding to hepatic proteins, a depletion of hepatic non-protein sulphydryl (NPS) groups after 2 h, and a marked elevation of plasma alanine aminotransferase (ALAT) activity after 24 h. The co-administration of paracetamol and ASCP (1412 mg/kg, equivalent to 600 mg/kg free LAA), but not paracetamol and LAA (600 mg/kg), significantly reduced covalent binding of paracetamol metabolites at 2 and 4 h after treatment. In addition ASCP, but not LAA, significantly reduced the depletion of NPS groups and the elevation of plasma ALAT activity. ASCP also completely prevented the 35% mortality observed at 24 h in paracetamol treated mice. These results demonstrate that ASCP, but not LAA, when co-administered orally with the analgesic is an effective inhibitor of paracetamol-induced hepatotoxicity in the mouse. The mechanism by which ASCP prevents liver injury appears to involve destruction of reactive paracetamol metabolites which is associated with a sparing action on hepatic reduced glutathione levels.

Acetaminophen↗

PubMedDate not supplied

Toxicity of mixtures of nephrotoxicants with similar or dissimilar mode of action.

The toxicity of mixtures of chemicals with the same target organ was examined in rats using nephrotoxicants with similar or dissimilar modes of action. In a 4-wk feeding study, lysinoalanine, mercuric chloride, hexachloro-1,3-butadiene and d-limonene, each affecting renal proximal tubular cells but through different modes of action, were administered simultaneously at their individual lowest-observed-nephrotoxic-effect level (LONEL), no-observed-nephrotoxic-effect level (NONEL) and NONEL/4. Combined exposure at the LONEL resulted in increased growth depression and increased renal toxicity in male but not in female rats. Co-exposure at the NONEL produced only weak signs of toxicity (slightly retarded growth and increased renal weight), and rats co-exposed at the NONEL/4 did not show any treatment-related changes. The absence of an obviously increased hazard on combined exposure at the NONEL suggested absence of synergism and probably also of additivity. In a subsequent study the additivity assumption (dose addition) was tested, using the similarly acting nephrotoxicants tetrachloroethylene, trichloroethylene, hexachloro-1,3-butadiene and 1,1,2-trichloro-3,3,3-trifluoropropene. The compounds were given to female rats by daily oral gavage for 32 days either alone, at the LONEL and NONEL (= LONEL/4), or in combinations of four (at the NONEL and LONEL/2) or three (at the LONEL/3). Relative kidney weight was increased on exposure to the individual compounds at their LONEL and, to about the same extent, on combined exposure at the NONEL or the LONEL/3. As assessed by this endpoint, the renal toxicity of the mixtures corresponded to the effect expected on the basis of the additivity assumption. The other endpoints were not (or hardly) affected on combined exposure.

Administration, Oral↗

PubMedDate not supplied

Experimental designs and risk assessment in combination toxicology: panel discussion.

Advancing our knowledge on the toxicology of combined exposures to chemicals and implementation of this knowledge in guidelines for health risk assessment of such combined exposures are necessities dictated by the simple fact that humans are continuously exposed to a multitude of chemicals. A prerequisite for successful research and fruitful discussions on the toxicology of combined exposures (mixtures of chemicals) is the use of defined terminology implemented by an authoritative international body such as, for example, the International Union of Pure and Applied Chemistry (IUPAC) Toxicology Committee. The extreme complexity of mixture toxicology calls for new research methodologies to study interactive effects, taking into account limited resources. Of these methodologies, statistical designs and mathematical modelling of toxicokinetics and toxicodynamics seem to be most promising. Emphasis should be placed on low-dose modelling and experimental validation. The scientifically sound so-called bottom-up approach should be supplemented with more pragmatic approaches, focusing on selection of the most hazardous chemicals in a mixture and careful consideration of the mode of action and possible interactive effects of these chemicals. Pragmatic approaches may be of particular importance to study and evaluate complex mixtures; after identification of the 'top ten' (most risky) chemicals in the mixture they can be examined and evaluated as a defined (simple) chemical mixture. In setting exposure limits for individual chemicals, the use of an additional safety factor to compensate for potential increased risk due to simultaneous exposure to other chemicals, has no clear scientific justification. The use of such an additional factor is a political rather than a scientific choice.

Hazardous Substances↗