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Biomedical subjects

R Kroes

Publications and source records attributed to R Kroes.

At least 37 records · Page 2Linked to original sources
PubMed1993

The no-effect level of sodium bromide in healthy volunteers.

1. A total of 0, 4 and 9 mg kg-1 body weight sodium bromide was administered orally to 45 healthy female volunteers. 2. The experiment lasted for six menstrual cycles: only during the first three cycles was bromide administered; 3. At the start, at the end of the administration period and at the end of the experiment a physical examination and haematological and routine clinical chemistry tests were performed. Except for nausea in relation to the intake of bromide, no adverse effects were observed. 4. The bromide concentration in plasma rose to 3.22 +/- 0.93 mmol kg-1 in the 4 mg kg-1 group and to 7.99 +/- 1.89 in the 9 mg kg-1 group by the end of the administration period. 5. Before and at the end of the experiment the thyroid hormones (T4, FT4, TBG, T3 and TSH) were analysed. No significant differences were observed between the groups. 6. Before, after three menstrual cycles and at the end of the experiment an EEG with a Visual Evoked Response was recorded. At the 4 and 9 mg kg-1 dose level in the alpha 1-band and the beta-bands significant changes were found (P < 0.1 and P < 0.05, respectively). The Visual Evoked Response showed no significant differences between the three groups. 7. From this experiment and previous experiments a no-effect level in humans for sodium bromide of 4 mg kg-1 body weight is proposed.

Adult↗
PubMed1992

Induction of proliferative lesions of ventral prostate, seminal vesicle, and other accessory sex glands in rats by N-methyl-N-nitrosourea: effect of castration, pretreatment with cyproterone acetate and testosterone propionate and rat strain.

Wistar (Cpb:WU), F344 or Sprague-Dawley rats were sequentially treated with cyproterone acetate (CA) for 21 days, testosterone propionate (TP) for 3 days, followed by a single i.v. injection of N-methyl-N-nitrosourea (MNU). One group of Wistar rats was castrated 4 weeks after MNU injection, and another group 58 weeks after MNU, when the first prostatic carcinoma was detected. Control groups received only CA + TP, CA, MNU, or they remained untreated. Early or late castration inhibited the development of atypical hyperplasia of the ventral prostate in Wistar rats. This lesion was induced by the CA + TP + MNU treatment in F344 rats, but not Sprague-Dawley rats; in Wistar rats, it was induced by CA + TP treatment, irrespective of whether MNU was given. Hypertrophic-hyperplastic lesions of the seminal vesicle were induced by MNU, irrespective of pretreatment, and their development was prevented by early castration and inhibited by late orchiectomy. Dorsolateral prostate carcinomas and preneoplasia occurred only in low incidence in Wistar and Sprague-Dawley rats. These lesions were absent in F344 rats that had received treatment with CA + TP + MNU. No dorsolateral prostate (pre)neoplasia was found in Wistar rats subjected to early orchiectomy, but rats castrated at 58 weeks had an incidence similar to that for the intact group treated with CA + TP + MNU. This finding supports the contention that androgens are required for the development of MNU-induced prostatic cancer in rats but that advanced carcinomas are androgen insensitive. Differences in incidence and localization of prostatic proliferative lesions between F344 and Wistar rats and between dorsolateral and ventral prostate could not be explained by differences in epithelial cell proliferative responses to CA + TP treatment at the time of MNU injection, since they were similar in ventral and dorsolateral prostate and were more prominent in F344 rats than in Wistar rats. DNA damage as estimated by MNU-induced unscheduled DNA synthesis also did not differ between dorsolateral and ventral prostate.

Androgens↗
PubMed1991

[Environment, chemicals and public health].

It is obvious that, to the general public, environmental pollution determines the state of public health to a considerable extent. Scientifically, however, this relationship is less readily detectable, particularly when the environment polluted by chemicals is the polluted human environment. It is more correct to define 'environment' to include both the 'external' and the 'local' environment. The external environment includes a part which is directly affected by man, for instance when man-made chemicals are involved as well as the natural environment. The local or personal environment particularly concerns matters which may be comprised in the term 'lifestyle'. The above forms of environment may all affect health, although effects may differ in quality and quantity. These relationships are discussed, with special reference to the occurrence of cancer.

Carcinogens↗
PubMed1988

Forestomach carcinogens: pathology and relevance to man.

Squamous cell carcinomas of the forestomach have been observed in many carcinogenicity studies in rodents, especially after oral or gavage exposure. The histopathological diagnosis of forestomach lesions and the relevance of the data for human risk estimation can be controversial. The pathological classification may be troublesome because of the low-grade malignancy and the pseudoepitheliomatous hyperplasia that may develop after ulceration and inflammation. For human risk estimation it is important to understand the mechanism of action; this is illustrated by examples using butylated hydroxyanisole, methyl bromide, and epichlorohydrin. Another feature that complicates risk estimation is the absence of a homologue for the forestomach in man. The potential risk from non-genotoxic forestomach carcinogens in man involves exposure of the mouth, pharynx, and esophagus at dose levels that exert irritating action. It is assumed that exposure to non-genotoxic chemicals at concentrations far below those having irritating potential is not hazardous to humans.

Animals↗
PubMed1987

Contribution of toxicology towards risk assessment of carcinogens.

In the last decade many tests have been designed to detect possible carcinogenicity of compounds. Presently, many more or less simple and convenient systems are available to detect mutations, effects on chromosomes, DNA binding and damage and malignant transformation. These systems, which have been extensively refined during the last years, often show reasonably good relevance to carcinogenicity. Although inconsistencies in the patterns of response do indicate that their role as predictive indicators of carcinogenicity remains still uncertain, the use of such short-term tests in carcinogen risk assessment does seem feasible. Factors other than these tests should also be taken into consideration, since other characteristics like chemical structure, biotransformation, toxicokinetics, qualitative and quantitative physiological and/or morphological effects, species, strains, organ specificity, dose-response relation and information on studies in man, if available, are of importance too. In conjunction with the results of adequately performed carcinogenicity tests in mammals, one may attempt to classify carcinogens. Current knowledge does not permit a rigid classification, but may warrant a subclassification into carcinogens acting via a genetic or a non-genetic mechanism. It is emphasized that on theoretical and practical grounds a different extrapolation system should be used for the different types of carcinogens in risk assessment procedures. Evaluations on individual compounds should be made to decide whether such genotoxic or non-genotoxic compounds should be permitted in the human environment.

Animals↗
PubMed1986

The long-term study in rodents for identifying carcinogens: some controversies and suggestions for improvements.

Despite increasing standardisation and international harmonization of the long-term carcinogenicity study in rodents there are still areas of controversy such as high-dose selection, duration of the test period, combining or not combining the chronic toxicity and the carcinogenicity study, the use of historical control data, conditions for redundancy of the study, and significance of studies of restricted design. It is discussed that the 'Maximum Tolerated Dose', or doses above and below the 'metabolic break-point' should be included. In general a test period of 24 months is adequate, but the protocol should be flexible enough to allow extension beyond 24 months. Major advantages of the combined chronic toxicity/carcinogenicity study are that the toxicity and carcinogenicity data are obtained with the same sample of the test compound using the same batch of animals kept on the same diet under the same environmental conditions. It is discussed that the use of historical control data will not lead to a final conclusion on carcinogenic or non-carcinogenic potential of a compound. A long-term carcinogenicity study is considered redundant when adequate (semi-chronic) toxicity studies including reproduction and mutagenicity tests and pre-screens for carcinogenicity, do not indicate mutagenic or carcinogenic activity, and when there is a wide margin (e.g. 1000) between the 'no-observed-adverse effect level' and the (presumed) exposure level in humans. Studies of restricted design and conduct may clearly demonstrate carcinogenicity but also may easily lead to inconclusive results.

Animals↗
PubMed1986

Nutritional factors in lung, colon, and prostate carcinogenesis in animal models.

Dietary factors are now considered to be among the most important environmental risk determinants for cancer. In addition to epidemiological studies, experimental animal studies are an important tool to investigate dietary modulation in carcinogenesis. Results of recent experimental studies on the effect of some nutrients indicate that vitamin A did show an inverse relation with the occurrence of preneoplastic respiratory lesions but not with respiratory tract tumors in benzo[a]pyrene-induced respiratory carcinogenesis. Dietary fat increases respiratory tract tumors and preneoplastic lesions. In colon carcinogenesis, a fat-fiber interrelation was noticed in 1,2-dimethyl-hydrazine- and N-methyl-N'-nitro-N-nitrosoguanidine-induced tumors. Preliminary results in prostate carcinogenesis indicate that dietary fat did not influence the incidence of prostate cancer in a recently developed rat model. Some possible mechanisms in colon and prostate carcinogenesis are discussed.

1,2-Dimethylhydrazine↗
PubMed1985

[The histological study: an important parameter in checking the use of anabolics. Past, present, future?].

The histological methods used in checking the administration of oestrogens to fattening calves, introduced in the Netherlands in 1967, are discussed. Because of the increased use of combined treatment with oestrogens and androgens (both synthetic and natural), the suitability of the above histological techniques has become doubtful. Moreover, exogenous natural steroid hormones were not found to constitute any hazard to public health and could be safely used in husbandry. If administration of such anabolics is permitted the reasons for histological examination would cease to exist.

Anabolic Agents↗
PubMed1984

General toxicity testing: sense and non-sense, science and policy.

The dramatic increase in the number and variety of industrial chemicals in addition to natural compounds, and the increased public concern about their health effects, has in the last few decades led to a remarkable development in number and types of toxicity tests employed to assess safety of chemicals. Not too many years ago, toxicity tests were relatively simple in design and conduct. They were sometimes inadequate in a number of aspects. Toxicity testing has now become an unbalanced mixture of sound science and policy. Many times companies wishing to market products internationally are faced with a plethora of different national regulatory requirements. In this presentation attention is given to requirements for toxicity data and the need for harmonization in guidelines while avoiding rigid protocols. The wisdom and necessity of conducting all currently required tests will be considered. The relevance of certain biochemical, hematological, and pathological parameters is discussed as is the relevance of Good Laboratory Regulation for toxicity testing. The importance of a scientific evaluation of all chemical biological data derived from modern sensibly designed toxicity tests with respect to extrapolation and safety assessment is emphasized. Future development in certain areas of toxicity research is stressed and examples are given.

Animals↗
PubMed1983

Adenocarcinomas of the prostate induced by N-nitroso-N-methylurea in rats pretreated with cyproterone acetate and testosterone.

Prostatic adenocarcinomas were induced in 5 out of 20 Wistar rats upon a single administration of 50 mg/kg N-nitroso-N-methylurea (NMU). The rats were pretreated with a daily dose of 50 mg/kg cyproterone acetate for 3 weeks followed by 3 daily injections of 100 mg/kg testosterone. All tumours developed in the dorsolateral prostate and were invasively growing. In 2 cases distant metastases were found. Three proliferative lesions classified as carcinomas in situ were also found in the dorsolateral prostate. A total of 7/20 animals (35%) carried an adenocarcinoma and/or a carcinoma in situ. In addition, 6 epithelial hyperplasias were observed in the dorsolateral and 1 in the ventral prostate of non-tumour-bearing rats. The method described may provide a good animal model for cancer of the prostate and lead to a better understanding of prostatic carcinogenesis.

Adenocarcinoma↗
PubMed1983

Short-term tests in the framework of carcinogen risk assessment to man.

Short-term tests designed to detect possible carcinogenicity have been extensively refined during the last years. Presently, many more or less simple and convenient systems are available to detect mutations, chromosome effects, DNA damage, and malignant transformation. Although their relevance to carcinogenicity is often reasonably good, inconsistencies in the pattern of response indicate that their role as predictive indicators of carcinogenicity is still uncertain. The use of short-term tests in carcinogen risk assessment does seem feasible. These tests, however, should not be the only characteristic taken into consideration in such a risk assessment. Other characteristics such as chemical structure, biotransformation, and pharmacokinetics, qualitative and quantitative physiological and/or morphological effects, species, strain, and organ specificity, dose-response relation, and information on human studies, if available, are of importance too. Current knowledge does not permit a rigid classification of carcinogens, but does warrant a subclassification into genotoxic and nongenotoxic compounds. Whereas for genotoxic compounds a real threshold cannot be expected on a theoretical basis, the existence of a threshold may well be expected for nongenotoxic compounds. In conjunction with other characteristics it may then be decided whether a genotoxic or nongenotoxic compound may be or may not be permitted in the human environment. In this evaluation process it is anticipated that for genotoxic compounds other extrapolation systems should be used, as compared to nongenotoxic compounds, where in fact a conventional food toxicology safety factor may be applied. Short-term tests are very important in the subclassification with respect to genotoxicity and seem to be of value for the detection of promoter activity as well.

Animals↗