document

A prospective cohort study on the relationship between onion and leek consumption, garlic supplement use and the risk of colorectal carcinoma in the Netherlands

Dorant, E. (author), van den Brandt, P.A. (author), Goldbohm, R.A. (author), Instituut CIVO-Toxicologie en Voeding TNO (author)

The association between onion and leek consumption, garlic supplement use and colon and rectum carcinoma among men and women was evaluated in the Netherlands Cohort Study, a large-scale prospective cohort study on diet and cancer. Onions, leeks, and garlic belong to the Allium genus and contain large amounts of potentially chemopreventive...

article 1996

document

Dose-dependent kinetics and metabolism of 1,2-dichlorobenzene in rat: Effect of pretreatment with phenobarbital

Hissink, A.M. (author), van Ommen, B. (author), van Bladeren, P.J. (author), Instituut CIVO-Toxicologie en Voeding TNO (author)

Toxicity of halobenzenes has been ascribed mainly to their epoxides, but recent studies with bromobenzene have shown that secondary quinone metabolites are also involved in the alkylation of hepatic proteins. However, the relative contribution of the quinones and the epoxides to the toxicity of halobenzenes is still unclear. In order to...

article 1996

document

N7-methylguanine and O6-methylguanine levels in DNA of white blood cells from cancer patients treated with dacarbazine

van Delft, J.H.M. (author), Luiten-Schuite, A. (author), Souliotis, V.L. (author), Kyrtopoulos, S.A. (author), Ouwerkerk, J. (author), Keizer, H.J. (author), Baan, R.A. (author), Instituut CIVO-Toxicologie en Voeding TNO (author)

Methyl-DNA adducts are induced by a number of lifestyle, environmental and occupational carcinogens, however knowledge about their kinetics is scarce. Here, N7-methylguanine (N7-MeGua) and O6-methylguanine (O6-MeGua) levels were determined in the DNA of white blood cells from eight cancer patients treated iv with the antitumour drug dacarbazine ...

article 1996

document

Lack of inhibitory effects of beta-carotene, vitamin C, vitamin E and selenium on development of ductular adenocarcinomas in exocrine pancreas of hamsters

Appel, M.J. (author), van Garderen-Hoetmer, A. (author), Woutersen, R.A. (author), Instituut CIVO-Toxicologie en Voeding TNO (author)

The effects of vitamins E and E, β-carotene and selenium on development of N-nitrosobis(2-oxopropyl)amine (BOP)-induced pancreatic tumours in hamsters were investigated. Dietary supplementation of vitamin C, alone as well as in combination with β-carotene resulted in consistently lower numbers of advanced ductular lesions. The differences with...

article 1996

document

Transport of the glutathione conjugate of ethacrynic acid by the human multidrug resistance protein MRP

Instituut CIVO-Toxicologie en Voeding TNO (author), Zaman, G.J.R. (author), Cnubben, N.H.P. (author), van Bladeren, P.J. (author), Evers, R. (author), Borst, P. (author)

The multidrug resistance protein MRP has been shown to mediate the transport of glutathione S-conjugates across membranes. In this study we demonstrate that the glutathione S-conjugate of the diuretic drug ethacrynic acid, which is an efficient inhibitor of glutathione S-transferases, is a high-affinity substrate and inhibitor of the glutathione...

article 1996

document

Dietary fish oil (MaxEPA) enhances pancreatic carcinogenesis in azaserine-treated rats

Instituut CIVO-Toxicologie en Voeding TNO (author), Appel, M.J. (author), Woutersen, R.A. (author)

In the present study the putative chemopreventive effect of dietary fish oil (MaxEPA) on azaserine-induced pancreatic carcinogenesis in rats was investigated. Groups of rats were maintained on a semipurified low-fat (LF; 5 wt%) diet or on semipurified high-fat (HF; 25 wt%) diets containing 5 wt% linoleic acid (LA) and including 0.0, 1.2, 2.4, 4...

article 1996

document

Glutathione conjugation of the cytostatic drug ifosfamide and the role of human glutathione S-transferases

Dirven, H.A.A.M. (author), Megens, L. (author), Oudshoorn, M.J. (author), Dingemanse, M.A. (author), van Ommen, B. (author), van Bladeren, P.J. (author), Instituut CIVO-Toxicologie en Voeding TNO (author)

Development of drug resistance against alkylating cytostatic drugs has been associated with higher intracellular concentrations of glutathione (GSH) and increased expression of glutathione S-transferase (GST) enzymes. Therefore, enhanced detoxification by the glutathione/glutathione S-transferase pathway has been proposed as a major factor in...

article 1995

document

Differential effects of chemical irritants in rabbit and human skin organ cultures

van de Sandt, J.J.M. (author), Rutten, A.A.J.J.L. (author), Instituut CIVO-Toxicologie en Voeding TNO (author)

The toxicity of well known irritants was investigated in rabbit and human skin organ cultures. Test chemicals were selected from various categories of irritants and included both water-soluble and water-insoluble compounds. Using a highly standardized protocol, test chemicals were applied topically at concentrations relevant to the in vivo...

article 1995

document

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

Wolterbeek, A.P.M. (author), Roggeband, R. (author), Baan, R.A. (author), Feron, V.J. (author), Rutten, A.A.J.J.L. (author), Instituut CIVO-Toxicologie en Voeding TNO (author)

Vitamin A and β-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...

article 1995

document

Effects of aminoglutethimide alone and in combination with surgical castration, on pancreatic carcinogenesis in rats and hamsters

Visser, C.J.T. (author), Meijers, M. (author), van Garderen-Hoetmer, A. (author), Klijn, J.G.M. (author), Foekens, J.A. (author), Woutersen, R.A. (author), Instituut CIVO-Toxicologie en Voeding TNO (author)

The present 12-month study was carried out to investigate the effects of the aromatase inhibitor aminoglutethimide, alone and in combination with orchiectomy, on pancreatic carcinogenesis in azaserine-treated rats and N-nitrosobis(2-oxopropyl)amine-treated hamsters. Treatment of the animals started 4 months after the last injection with the...

article 1995

document

Effects of dietary fish oil (MaxEPA) on N-nitrosobis(2-oxopropyl)amine (BOP)-induced pancreatic carcinogenesis in hamsters

Appel, M.J. (author), Woutersen, R.A. (author), Instituut CIVO-Toxicologie en Voeding TNO (author)

In the present study the chemopreventive potential of 25% fat (HF) diets containing 2 wt% linoleic acid (LA) and including 0.0, 1.2, 2.4, 4.7, 7.1 or 9.4 wt% dietary fish oil (MaxEPA) has been investigated using the N-nitrosobis(2-oxopropyl)amine (BOP)-hamster model for pancreatic cancer. The number of pancreatic borderline lesions (BLL) was...

article 1995

document

Polymorphism in the glutathione conjugation activity of human erythrocytes towards ethylene dibromide and 1,2-epoxy-3-(p-nitrophenoxy)-propane

Ploemen, J.H.T.M. (author), Wormhoudt, L.W. (author), van Ommen, B. (author), Commandeur, J.N.M. (author), Vermeulen, N.P.E. (author), van Bladeren, P.J. (author), Instituut CIVO-Toxicologie en Voeding TNO (author)

In this study a polymorphism in the conjugating activity of human erythrocyte cytosol towards the dihaloethane, ethylene dibromide (EDB; 1,2-dibromoethane) was found. Two out of 12 human erythrocyte cytosols did not catalyze the formation of glutathione (GSH) conjugates of [1,2-14C]EDB. Ten cytosols formed the S,S'-ethylenebis(GSH) conjugate at...

article 1995

document

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

Feron, V.J. (author), Woutersen, R.A. (author), Arts, J.H.E. (author), Cassee, F.R. (author), de Vrijer, F. (author), van Bladeren, P.J. (author), Instituut CIVO-Toxicologie en Voeding TNO (author)

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...

article 1995

document

Human cytochrome P450 enzyme selectivities in the oxidation of chlorinated benzenes

Bogaards, J.J.P. (author), van Ommen, B. (author), Wolf, C.R. (author), van Bladeren, P.J. (author), Instituut CIVO-Toxicologie en Voeding TNO (author)

1,2-Dichlorobenzene 1,4-dichlorobenzene, 1,2,4-trichlorobenzene, 1,2,3,5-tetrachlorobenzene, and pentachlorobenzene were incubated with microsomes derived from cell lines expressing human CYP1A1, CYP1A2, CYP3A4, CYP2E1, or CYP2D6. The formation of phenolic metabolites as determined by gas chromatographic analysis evealed that CYP2E1 possessed...

article 1995

document

Release of arachidonic and linoleic acid metabolites in skin organ cultures as characteristics of in vitro skin irritancy

van de Sandt, J.J.M. (author), Maas, W.J.M. (author), Doornink, P.C. (author), Rutten, A.A.J.J.L. (author), Instituut CIVO-Toxicologie en Voeding TNO (author)

In vitro techniques make a major contribution to the development of alternatives to the in vivo 'Draize' skin irritation test, and the development of sensitive and generally applicable in vitro endpoints of cutaneous toxicity is an area of intensive research. To investigate in vitro characteristics of cutaneous irritation, skin explants of...

article 1995

document

Computer-aided biokinetic modelling combined with in vitro data

van Ommen, B. (author), de Jongh, J. (author), van de Sandt, J. (author), Blaauboer, B. (author), Hissink, E. (author), Bogaards, J. (author), van Bladeren, P. (author), Instituut CIVO-Toxicologie en Voeding TNO (author)

Within the framework of in vitro alternatives for in vivo safety assessment, the kinetic behaviour of a compound can be described by biokinetic models. These models, with emphasis on the physiologically based pharmacokinetic models, need a variety of biological, physicochemical and biochemical parameters. This paper deals with the possibilities...

article 1995

document

The role of human glutathione S-transferase isoenzymes in the formation of glutathione conjugates of the alkylating cytostatic drug thiotepa

Dirven, H.A.A.M. (author), Dictus, E.L.J.T. (author), Broeders, N.L.H.L. (author), van Ommen, B. (author), van Bladeren, P.J. (author), Instituut CIVO-Toxicologie en Voeding TNO (author)

Nonenzymatic and glutathione S-transferase (GST) catalyzed glutathione (GSH) conjugation has been postulated as a mechanism by which alkylating cytostatic drugs can be inactivated intracellularly. In this study, we describe studies on the glutathione-dependent biotransformation of thiotepa (tris(1-aziridinyl)phosphine sulfide), a trifunctional...

article 1995

document

Germ cell mutagenesis in lambdalacZ transgenic mice treated with ethylnitrosourea: Comparison with specific-locus test

van Delft, J.H.M. (author), Baan, R.A. (author), Instituut CIVO-Toxicologie en Voeding TNO (author)

Germ cell mutagenesis was studied in male λlacZ transgenic mice in such a way that the data can be compared with literature data for germ cell mutagenesis obtained with the specific-locus test. This comparison is of interest for validation of the transgenic mouse model. We studied mutagenesis induced by ethylnitrosourea (ENU) in mature...

article 1995

document

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

Feron, V.J. (author), Groten, J.P. (author), van Zorge, J.A. (author), Cassee, F.R. (author), Jonker, D. (author), van Bladeren, P.J. (author), Instituut CIVO-Toxicologie en Voeding TNO (author)

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...

article 1995

document

Epidermal cell proliferation and terminal differentiation in skin organ culture after topical exposure to sodium dodecyl sulphate

van de Sandt, J.J.M. (author), Bos, T.A. (author), Rutten, A.A.J.J.L. (author), Instituut CIVO-Toxicologie en Voeding TNO (author)

Epidermal cell proliferation and differentiation were investigated in vitro after exposure to the anionic surfactant sodium dodecyl sulfate (SDS). Human skin organ cultures were exposed topically to various concentrations of SDS for 22 h, after which the irritant was removed. Cell proliferation was measured immunohistochemically by incorporation...

article 1995