Archives of Toxicology – serie

The first oral contraceptive became available in 1960 and since then these sub­ stances, which have been used by millions of women, have probably been the most widely studied group of drugs in medical history (Drill, 1966, 1977). Part of the evaluation oCoral contraceptives has involved their effect on the reproductive organs of women, with particular attention directed to evaluation of a possible carcinogenic effect of these steroids. To the extent that cancer of the reproductive organs is a common finding in women, the endogenous female sex hormones have been implicated in the occur­ rence of the cancer. The administration of estrogen has also been reported to in­ crease the incidence of cancer of the breast, cervix or endometrium in some strains or species of animals. Thus, because of the possible tumorigenic effect of estrogens there has been considerable interest in the relationship of oral contraceptives to cancer of the breast and genital tract.

N-nitroso-compounds form an important class of carcinogenic chemicals which may be of environmental importance (Druckrey et al. , 1967; Magee et al. , 1976; IARC, 1978). The mechanism by which these carcinogens initiate neoplastic growth is not well understood but there is substantial evidence favoring the hypothesis that the simple dialkylnitrosamines and alkylnitrosamides act by means of their conversion to al- kylating agents. Alkylating species are generated from the nitrosamines by metabolic activation and from the nitrosamides by chemical decomposition at physiological pH. It is widely believed that DNA is the critical alkylation target. Alkylation takes place at at least 12 sites within the DNA molecule (Lawley, 1976; Singer, 1976; Pegg, 1977a). Al- though alkylation at the 7-position of guanine is the most extensive reaction with the DNA bases and provides a reliable measurement of the degree of interaction with the carcinogen (Swann and Magee, 1968, 1971), recent experiments have suggested that alkylation of oxygen atoms may be the critical reaction (Goth and Rajewsky, 1974; Margison and Kleihues, 1975; Nicoll et aI. , 1975; Pegg, 1977a).These laboratories have observed a correlation between the production and persistence of 06-alkyl- guanine and the occurrence oftumors in a variety of organs of rodents exposed to N-ni- troso-carcinogens. It has, therefore, been suggested that the ability of tissues to catalyze the removal of 06-alkylguanine from DNA may provide a protective mechanism against carcinogenesis.

Nervous system is in the most cases a likely target for the untoward effects of chemicals. The harmful consequences affect primarily the individual but may also considerably strain the whole society. The consumption of ethanol is a glaring example (National Institute on Alcohol Abuse and Alcoholism 1978). As ethanol, many organic liquids have similar immediate effects on the nervous system. The rapidity of the response suggests the involvement of the neuronal communication. The nervous system is also vulnerable to the depletion of oxygen, another common cause for the rapid deterioration of the brain function. It is quite impossible to list all the effects produced by the very large number of the individual chemicals. It would be more fruitful to try to understand the characteristics of the nervous system and the biochemical toxic mechanisms in the evaluation of the neurotoxicity of chemicals. Transfer of Xenobiotics in the Brain The adult central nervous system displays a functional barrier toward the blood-borne chemicals so that water-soluble compounds with an approximate molecular weight above 100 are largely prevented from directly entering the brain (Bradbury 1979). The functional barrier has morphological features typical to it and has a very close association of adjacent capillary cells separated by clefts of 12 A wide (Jacobs 1978). The nervous system capillaries are enveloped by glial cell tongues, and these pericytes contain contractile elements (Le Beux and Willemot 1978a, b) so that the capillaries can be constricted.

Many chemotherapeutic agents introduced for use in humans are carcinogenic in laboratory animals (Conklin et al. 1965; Shimkin et al. 1966; Griswold et al. 1968; Harris 1976). However, initially their beneficial effect in disseminated cancer was of such short duration that the inevitable death of the patient from his primary disease precluded any clinical manifestation of the carcinogenic potential. During the last decade, chemotherapy has radically changed the outlook for many patients with cancer. Combinations of drugs, administered as the primary treatment, have resulted in high rates of cure in patients with disseminated malignancies, such as stage IV Hodgkin's disease or childhood acute lymphocytic leukemia. In other disseminated forms of neoplasia, induction of a remission, a substantial palliation and a prolongation of survival have been achieved. In many instances of localised disease, where surgery with or without radiotherapy are the primary form of treatment, anticancer drugs have been used with success as adjuvant therapy for distant microscopic disease. With these spectacular achievements, secondary malignancies, in particular acute non-lymphocytic leukemia (ANLL), has become of major concern. Incidence Acute leukemia is the most frequent form of secondary neoplasia in patients treated for cancer (Penn 1981). In one large series, 5. 9% of all ANLL could be attributed to previous chemotherapy (Kapadia et al. 1980).

Trichloroethylene (TRI), administered orally at high doses for 18 months has been shown to increase the incidence of hepatocellular carcinoma in B6C3F 1 mice but not Osborne-Mendel rats (NCI, 1976). The interpretation of these studies has been confounded due to the presence of epoxide stabilizers in the TRI. However more recent studies have demonstrated that pure TRI also causes hepatocellular carcinoma in B6C3F mice (NTP, 1983) and Aldedey Park (Swiss) mice (Elcombe 1 and Pratt, unpublished data). Furthermore, no increase in the incidence of hepatocellular carcinoma was observed in Fisher 344 rats administered pure TRI (NTP, 1983). TRI has been extensively examined for mutagenic potential, but many studies were bedeviled by the presence of mutagenic epoxide stabilizers. However, in general, TRI has been found to be only 'marginally' mutagenic or non-mutagenic (Greim et ai., 1975; Simmon et ai., 1977; Bronzetti et ai., 1978; Waskell, 1978; Bartsch et ai., 1979; Slacik-Erben et ai., 1980). Covalent binding of trichloroethylene or its metabolites to protein, RNA and DNA has been illustrated in vitro (Van Duuren and Banerjee, 1976; Bolt et ai.,1977; Bolt and Filser, 1977; Uehleke and Poplawski-Tabarelli, 1977; Banerjee and Van Dauren, 1978). However, in vivo, only extremely low (indistinguishable from protein binding) or zero binding of TRI metabolites to DNA has been reported (Parchman and Magee, 1982; Stott et ai., 1982).

This supplement presents the papers submitted at the 27th meeting of the European Society of Toxicology, which was organised by the British Toxicology Society and held in Harrogate, England. As evident from the title of this book, the overall theme of the meeting was an exploration of some of the mechanisms of toxicity, as well as some models used in the investigation of toxic action. The topics dealt with can be grouped under four headings. The first of these, on the mechanisms involved in cell injury, was a joint symposium of the European Society of Toxicology and the Society of Toxicology of the United States of America. In the second group, mechanisms in carcinogen risk assessment were discussed. Mechanisms and models of teratogenesis was the subject of the third group of invited papers. Finally, a workshop on safety evaluation of biotechnological products dealt with present and future problems which this new area of technology poses for toxicologists. Short communications on recent studies and developments in toxicological techniques which were presented at the meeting are also included in this volume.

This supplement contains the papers submitted at EUROTOX 88, the joint Congress of the European Society of Toxicology and the Federation of the European Societies of Toxicology. The theme was one of monitoring and examining the effects of toxic substances in the biological response at the subcellular level. Mechanisms of metal carcinogenicity are discussed as well as the biomonitoring of chemical exposure. Reports are provided on the role of individual differences in man and the effect of risk assessment. Papers appear dealing with the genetic control of drug metabolizing enzymes. The role of metabolism in organic specific toxicity is discussed. Information is included on the toxicological impact of chemicals interfering with the endocrine system as well as on the effects of toxicants on the immune system. Presentations deal with the current status of risk assessment in environmental toxicology.

This proceedings of the European Society of ToxicologyMeeting held in Leipzig, September 12 - 14, 1990 deals withthe following topics;- Neurotoxicology of different noxious compounds,- New aspects and methods intoxicopathology,- Cardiovascular toxicology,- Toxic effects on haemostasis,- Toxic effects on liver and kidney,- Miscellaneous toxic effects.

This volume contains the main papers presented at the 1997 EUROTOX Congress, Århus, Denmark, 24-28 June 1997. Diversification in toxicology is seen as the application of basic science to such diverse areas as man and his environment. The pressing issues which have been dealt with not only include reproductive effects of environmental chemicals ("xenoestrogens"), but also receptor-mediated toxic responses, new frontiers in human and ecological toxicology, chemoprevention of cancer and molecular approaches in toxicological research. The practical and ethical facets of toxicology, e.g. ecotoxicological risk assessment, biomarkers of exposure, complex chemical mixtures as well as animal welfare and the ethics of animal experimentation, are also treated.

Ultraviolet radiation, a component of sunlight, has been recognized by photobiologists, dermatologists, and oculists as a potential hazard for human health because of its genotoxic, carcinogenic and immunotoxic properties. Its effects on human health include the induction of skin cancers, ocular damage and impairment of immunity to certain infections. A few decennia ago it was demonstrated that UV photons can affect the activity of the immune system through interactions with the skin. This means that UV not only changes normal cells into cancer cells but also permits the outgrowth of the UV -transformed cells by depressing the immune system. An intriguing question is what interactions between UV radiation and the skin initiates alterations in immune function in the exposed skin and systemically, i. e. in other places than the exposed skin. During the last 20 years many studies have been performed in order to investigate the immunosuppressive activities of UVB in laboratory animals and in human volunteers. In particular effects of UVB radiation on resistance to tumours and skin associated infections have been examined. In addition, effects of UVB radiation on immune parameters such as contact hypersensitivity and delayed-type hypersensitivity (both type IV hypersensitivity reactions), mixed lymphocyte reactions, mixed skin lymphocyte reactions, antigen presentation and numbers and function of Langerhans cells have been studied intensively. The antigenicity of murine tumours which are caused by UVB radiation was one of the first items to be investigated (Kripke, 1974).

Renal transport and xenobiotic metabolism play an important role in the detoxication and excretion of potentially toxic xenobiotics. However, recent experimental evidence has demonstrated that renal xenobiotic metabolism and renal transport processes also play an important role in the nephrotoxicity of xenobiotics and xenobiotic metabolites. The high blood flow to the kidney combined with its ability to concentrate solutes may expose the kidney to high concentrations of xenobiotics and xenobiotics metabolites present in the systemic circulation. Recently, it has been demonstrated that xenobiotic metabolites formed in the liver and other organs may be targeted to the kidney by selective transport systems~ many xenobiotics require enzymatic transformation to proximate reactive metabolites to elicit their toxic and carcinogenic effects. The enzymatic formation of reactive metabolites is termed bioactivation. The bioactivation mechanisms for many nephrotoxicants have, at least in part, been elucidated in the past 15 years. Many ultimate toxicants formed in the kidney are electrophiles whose interaction with cellular macromolecules may cause a perturbation of normal cell function resulting in necrosis and/or cancer (Anders 1988). Electrophilic metabolites may bind to nucleophilic sites in cellular macromolecules~ the importance of covalent modification of protein and DNA in cell killing and in the induction of tumors is established (Miller and Miller 1981~ Nelson and Pearson 1990~ Hinson and Roberts 1992). The objective of this review is to summarize new information about renal transport, renal bioactivation and their relation to nephrotoxicity using two relevant example for the basic mechanisms outlined above.

The book contains reviews and posters of the 31st Congressof the EUROTOX (Maastricht 1991).- Forensic Toxicology- Drug Toxicology- Environmental Toxicology

M. Pliftski Institute of Oceanography, GdaJisk University 46 Pilsudskiego Av. 81-378 Gdynia, Poland 2 The Baltic Sea with 366,000 km is only 0. 1% of the world's oceans but nevertheless, unique in many ways. The Baltic Sea is the largest area of brackish water in the world. As a formation of nature, it is a sea that in many ways resembles a lake. This makes its flora and fauna interesting and well adapted to the brackish water environment. The recent stage of biocoenosis composition is influenced by several features. Historically, during the last glaciation, when the Baltic was sometimes a huge marine bay and sometimes a large, freshwater lake, several ecosystems developed and were successively replaced. The flora and fauna composition of those previous biocoenosis was discovered from the geological layers corresponding to the Yoldic Sea, the Ancylus Lake and the Littorina Sea periods. Recently the marine influence has come from the North Sea water inflow, which greatly affects the salinity of the deep water. The freshwater influence comes from the fluvial water which gives the surface layer a lower salinity value. Salinity in the Baltic regions varies greatly - Gulf of Bothnia 2-4%0, the central Baltic proper 7-13%0, the Kattegat 15-300/00 in the surface water and 32- 34%0 in the bottom water, the Skagerrak 20-300/00 in the surface and 32-35%0 in the bottom water.