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Biomedical subjects

G Würtzen

Publications and source records attributed to G Würtzen.

At least 19 recordsLinked to original sources
PubMed2006

Risk assessment of substances that are both genotoxic and carcinogenic report of an International Conference organized by EFSA and WHO with support of ILSI Europe.

The European Food Safety Authority (EFSA) and the World Health Organization (WHO), with the support of the International Life Sciences Institute, European Branch (ILSI Europe), organized an international conference on 16-18 November 2005 to discuss how regulatory and advisory bodies evaluate the potential risks of the presence in food of substances that are both genotoxic and carcinogenic. The objectives of the conference were to discuss the possible approaches for risk assessment of such substances, how the approaches may be interpreted and whether they meet the needs of risk managers. ALARA (as low as reasonably achievable) provides advice based solely on hazard identification and does not take into account either potency or human exposure. The use of quantitative low-dose extrapolation of dose-response data from an animal bioassay raises numerous scientific uncertainties related to the selection of mathematical models and extrapolation down to levels of human exposure. There was consensus that the margin of exposure (MOE) was the preferred approach because it is based on the available animal dose-response data, without extrapolation, and on human exposures. The MOE can be used for prioritisation of risk management actions but the conference recognised that it is difficult to interpret it in terms of health risk.

Animals↗
PubMed2004

Structure-based thresholds of toxicological concern (TTC): guidance for application to substances present at low levels in the diet.

The threshold of toxicological concern (TTC) is a pragmatic risk assessment tool that is based on the principle of establishing a human exposure threshold value for all chemicals, below which there is a very low probability of an appreciable risk to human health. The concept that there are levels of exposure that do not cause adverse effects is inherent in setting acceptable daily intakes (ADIs) for chemicals with known toxicological profiles. The TTC principle extends this concept by proposing that a de minimis value can be identified for many chemicals, in the absence of a full toxicity database, based on their chemical structures and the known toxicity of chemicals which share similar structural characteristics. The establishment and application of widely accepted TTC values would benefit consumers, industry and regulators. By avoiding unnecessary toxicity testing and safety evaluations when human intakes are below such a threshold, application of the TTC approach would focus limited resources of time, cost, animal use and expertise on the testing and evaluation of substances with the greatest potential to pose risks to human health and thereby contribute to a reduction in the use of animals. An Expert Group of the European branch of the International Life Sciences Institute-ILSI Europe-has examined the TTC principle for its wider applicability in food safety evaluation. The Expert Group examined metabolism and accumulation, structural alerts, endocrine disrupting chemicals and specific endpoints, such as neurotoxicity, teratogenicity, developmental toxicity, allergenicity and immunotoxicity, and determined whether such properties or endpoints had to be taken into consideration specifically in a step-wise approach. The Expert Group concluded that the TTC principle can be applied for low concentrations in food of chemicals that lack toxicity data, provided that there is a sound intake estimate. The use of a decision tree to apply the TTC principle is proposed, and this paper describes the step-wise process in detail. Proteins, heavy metals and polyhalogenated-dibenzodioxins and related compounds were excluded from this approach. When assessing a chemical, a review of prior knowledge and context of use should always precede the use of the TTC decision tree. The initial step is the identification and evaluation of possible genotoxic and/or high potency carcinogens. Following this step, non-genotoxic substances are evaluated in a sequence of steps related to the concerns that would be associated with increasing intakes. For organophosphates a TTC of 18microg per person per day (0.3 microg/kg bw/day) is proposed, and when the compound is not an OP, the TTC values for the Cramer structural classes III, II and I, with their respective TTC levels (e.g. 1800, 540 and 90 microg per person per day; or 30, 9 and 1.5 microg/kg bw /day), would be applied sequentially. All other endpoints or properties were shown to have a distribution of no observed effect levels (NOELs) similar to the distribution of NOELs for general toxicity endpoints in Cramer classes I, II and III. The document was discussed with a wider audience during a workshop held in March 2003 (see list of workshop participants).

Animals↗
PubMed1994

The intake of chemicals related to age in long-term toxicity studies--considerations for risk assessment.

The estimation of acceptable daily intake (ADI) is generally based on results from long-term toxicity studies. Long-term exposure of rodent and nonrodent species is extrapolated to lifetime exposure in humans, using uncertainty factors to compensate inter- and intraspecies differences. Special consideration can be given to groups of humans at increased risk, such as children, due to higher susceptibility or higher predicted intake. A retrospective study of long-term carcinogenesis studies was performed at the National Toxicology Program of the National Institute of Environmental Health Sciences to gain insight into the relationship between age and intake of test compounds. In these long-term studies, average intake of feed and drinking water, and consequently chemicals dosed in these, was approximately two times higher on a body weight basis in young animals (postweaning) than in adults. Thus, estimating an ADI from the NOEL of this type of studies already includes a higher dose for the young. When maximum levels for food additives are being set using the already established ADI, it may not be necessary to add an additional uncertainty factor for different ages, unless there are other specific reasons to do so, such as unduly high exposure and toxicity at a certain age. Compared to intake per kilogram of body weight at the end of the study, the ADI already includes an extra uncertainty factor of approximately 2 for young individuals.

Aging↗
PubMed1994

Four-week toxicity study of 4-methoxytoluene in rats.

4-Methoxytoluene was given by gavage to 4 groups of 20 rats at dosage levels of 0, 40, 120 or 240 mg kg-1 body weight/day for 4 weeks. There was a statistically significant decrease in serum creatinine and urea in the intermediate and high dose group for both sexes. Among males, a statistically significant decrease in the packed cell volume was observed in the high and intermediate dose group. A no-observed-effect level of 40 mg kg-1 body weight/day was determined.

Administration, Oral↗
PubMed1989

Effects of dietary protein and butylated hydroxytoluene on the kidneys of rats.

Semipurified diet using Na-caseinate or lactalbumin as the only protein source was given to female rats to study the influence of nephrocalcinosis on butylated hydroxytoluene (BHT) induced kidney damage. The study showed, that BHT induces nephropathy in female rats irrespective of the diet used. Pronounced nephrocalcinosis was only found in rats fed the Na-caseinate diet. Thus, this study does not indicate a connection between the development of the BHT-nephropathy and nephrocalcinosis. The results from this study once more stress the influence of the diet on reaction of the animal to experimental procedures.

Animals↗
PubMed1989

Short term toxicity study in rats dosed with isoeugenol benzyl ether.

Isoeugenol benzyl ether was given to rats by gavage for 28 days at 0, 60, 120, and 240 mg/kg body weight/day. For both sexes at the highest dose and females at the intermediate dose statistically significantly decreased values were found for body weight, blood glucose (also for males at intermediate dose), blood urea and relative liver weights. No dose-related histopathological changes were seen in any organs. The no effect level was 60 mg/kg body weight/day.

Animals↗
PubMed1986

Carcinogenicity study on butylated hydroxytoluene (BHT) in Wistar rats exposed in utero.

Groups of 60, 40, 40 and 60 F0 Wistar rats of each sex were fed a semi-synthetic diet containing butylated hydroxytoluene (BHT) in concentrations to provide intakes of 0, 25, 100 or 500 mg/kg body weight/day, respectively. The F0 rats were mated and groups of 100, 80, 80 or 100 F1 rats of each sex were formed from 40, 29, 30 and 44 litters, respectively. After weaning, the highest dose (500 mg BHT/kg/day) was lowered to 250 mg/kg/day for the F1 rats. The numbers of litters of ten or more pups at birth decreased with increasing BHT dose. At weaning, treated F1 rats had lower body weights than the controls, the extent of the reduction being dose related; the effect, which persisted throughout the study, was most pronounced in the males. The survival of BHT-treated F1 rats of both sexes was significantly better than that of the controls. No significant changes attributable to BHT treatment were found in the haematological parameters. F1 females on the highest dose showed an increase in serum cholesterol and phospholipids, and serum triglycerides were reduced in this group in both sexes. Dose-related increases in the numbers of hepatocellular adenomas and carcinomas were statistically significant (at P less than 0.05 or lower) in male F1 rats when all groups together were tested for heterogeneity or analysis for trend. The increase in hepatocellular adenomas and carcinomas in treated female F1 rats was only statistically significant for adenomas (at P less than 0.05) in the analysis for trend. All hepatocellular tumours were detected when the F1 rats were more than 2 yr old. Tumours were found in many other organs of some of the treated rats, but their incidence was not significantly different from that in controls. The role of BHT in the development of hepatocellular tumours requires further elucidation.

Animals↗
PubMed1985

Subchronic oral toxicity of turmeric oleoresin in pigs.

Turmeric oleoresin was fed for 102-109 days to groups of eight pigs (males and females) at dietary levels providing intakes of 60, 296 and 1551 mg/kg body weight/day. Twelve pigs served as controls. The highest dose group showed a reduction in weight gain and in food-conversion efficiency. Statistically significant dose-related increases in the weight of the liver and the thyroid were recorded at all dose levels. Pericholangitis, hyperplasia of the thyroid and epithelial changes in the kidney and urinary bladder were observed in the two higher dose groups. It is questionable whether a no-adverse-effect level can be established on the basis of the observations in this experiment. Further studies should be initiated to elucidate the mechanism of action of turmeric.

Administration, Oral↗
PubMed1984

Toxicological studies on malachite green: a triphenylmethane dye.

The oral LD50 for malachite green oxalate was found to be 275 mg/kg in rats while the approximate lethal dose for NMRI mice was 50 mg/kg. No systemic effects were seen after dermal application of 2,000 mg/kg. Repeated administration in the diet for 28 days to rats produced only minor changes in serum urea and aspartate aminotransferase levels. The rats at the highest dose level showed decreased weight gain and appeared clinically to have elevated motor activity. No sex differences were observed in either acute or prolonged experiments. In accord with human experience malachite green was irritating to mucous membranes, but no effects were seen on intact skin nor was it shown to be sensitizing. It was found to be a mutagen in the Salmonella/microsome test after metabolic activation but without clastogenic activity when tested at maximally tolerated levels in mice in the micronucleus test.

Animals↗
PubMed1983

Short term toxicity study in rats dosed with pulegone and menthol.

Pulegone and menthol, components of peppermint oil, were investigated in rats. The substances were administered by gavage for 28 days at 0, 20, 80, 160 mg pulegone and 0, 200, 400, 800 mg menthol/kg body wt./day, respectively. At the two highest doses, pulegone induced atonia, decreased blood creatinine content, lowered terminal body weight and caused histopathological changes in the liver and in the white matter of cerebellum. For menthol at all dose levels a significant increase in absolute and relative liver weights and vacuolisation of hepatocytes was found. No sign of encephalopathy was observed in rats given menthol. The no effect level for pulegone was 20 mg/kg body wt./day and for menthol less than 200 mg/kg body wt./day.

Animals↗
PubMed1983

Short term toxicity study in rats dosed with peppermint oil.

Peppermint oil was given p.o. to groups of 10 male and 10 female rats at dosage levels of 0, 10, 40 and 100 mg/kg bw/day respectively for 28 days. Histopathological changes in the white matter of the cerebellum especially were seen at dose levels of 40 and 100 mg/kg bw/day and consisted of cyst-like spaces scattered in the white matter. There were no obvious signs of clinical symptoms due to the encephalopathy.

Animals↗
PubMed1980

Magnesium stearate given perorally to rats. A short term study.

Magnesium stearate was fed to groups of 20 male and 20 female rats at levels of 0, 5, 10 and 20% in a semisynthetic diet for 3 months. Decreased weight gain was found in males in the 20% group. Urolithiasis was found in 8 males and in 7 females in the same group. Reduced relative liver weight was seen in males in the 10% and in the 20% groups, and an increased amount of iron was found in the livers of the 20% group. Nephrocalcinosis was reduced in females in the 20% group. In this experiment the no-effect-level is estimated to be 5% magnesium stearate in the diet, corresponding to 2500 mg/kg body wt/day.

Animals↗
PubMed1978

Hemiglobin formation in vitro induced by azo dyes and their metabolites.

Azo dyes which after reduction by the intestinal flora yield aniline are known as inducers of Heinz bodies after oral intake (J.J.-P. Drake, 1975). The effect of aniline is thought to depend on its metabolic conversion to the known hemiglobin inducers, phenylhydroxylamine and o- and p-aminophenol (A. de Bruin, 1976). The azo dyes used for colouring of foods are reduced in vivo forming sulphonated primary aromatic amines, many of which are of aminonaphthol structure. Such compounds could be potential hemiglobin inducers. This possibility was investigated in vitro by incubating the following azo dyes and their metabolites, with red cells in Krebs-Ringer phosphate solution: Chrysoin S, Scharlach GN, Azorubine, Sunset Yellow FCF, Food Red 17, Orange GGN, Ponceau 4R, Amaranth, Ponceau 6R and Fast Yellow AB. The concentration in the incubate was 0.5 mmol/l and the hemiglobin formation was measured after 1 h. The effect on red cells from pigs was compared with the effect on human red cells. Only the metabolites containing amino and naphthol groups together were active. The activity depended on the number and position of the sulfonic acid groups.

Animals↗
PubMed1978

A short term peroral study of the food colour, Ponceau 6R in pigs.

Ponceau 6R (the tetrasodium salt of 1-(4-sulpho-1-naphthyl-azo)-2-naphthol-3,6,8-trisulphonic acid) was fed to pigs at dietary levels of 0 (control), 100, 500 and 1500 mg/kg body wt./day for 102--105 days. In the 1500-mg group a decrease in weight gain and food utilization was seen, and 1 pig died with a hemolytic anaemia. Dose dependent discolouration was seen of the connective tissue in the groups given 1500 and 500 mg/kg body wt. For this effect the no-effect-level was 100 mg Ponceau 6R/kg body wt. per day.

Anemia, Hemolytic↗