Jürg P. Seiler – författare

After more than twenty years of use Good Laboratory Practice, or GLP, has attained a secure place in the world of testing chemicals and other “test items” with regard to their safety for humans and the environment. Gone are the days when the GLP regulations were hotly debated amongst scientists in academia and industry and were accused of stifling flexibility in, imaginative approaches to, and science-based conduct of, all kinds of studies concerned with toxic effects and other parameters important for the evaluation and assessment of products submitted for registration and permission to market. The GLP regulations have developed from rules on how to exactly document the planning, conduct and reporting of toxicity studies to a quality system for the management of a multitude of study types, from the simple determination of a physical/chemical parameter to the most complex field studies or ecotoxicology studies. At the same time the term “Good Laboratory Practice” has become somewhat ofa slogan with the aim to characterise any reliably conducted laboratory work.

After more than twenty years of use Good Laboratory Practice, or GLP, has attained a secure place in the world of testing chemicals and other “test items” with regard to their safety for humans and the environment. Gone are the days when the GLP regulations were hotly debated amongst scientists in academia and industry and were accused of stifling flexibility in, imaginative approaches to, and science-based conduct of, all kinds of studies concerned with toxic effects and other parameters important for the evaluation and assessment of products submitted for registration and permission to market. The GLP regulations have developed from rules on how to exactly document the planning, conduct and reporting of toxicity studies to a quality system for the management of a multitude of study types, from the simple determination of a physical/chemical parameter to the most complex field studies or ecotoxicology studies. At the same time the term “Good Laboratory Practice” has become somewhat ofa slogan with the aim to characterise any reliably conducted laboratory work.

After more than twenty years of use Good Laboratory Practice, or GLP, has attained a secure place in the world of testing chemicals and other “test items” with regard to their safety for humans and the environment. Gone are the days when the GLP regulations were hotly debated amongst scientists in academia and industry and were accused of stifling flexibility in, imaginative approaches to, and science-based conduct of, all kinds of studies concerned with toxic effects and other parameters important for the evaluation and assessment of products submitted for registration and permission to market. The GLP regulations have developed from rules on how to exactly document the planning, conduct and reporting of toxicity studies to a quality system for the management of a multitude of study types, from the simple determination of a physical/chemical parameter to the most complex field studies or ecotoxicology studies. At the same time the term “Good Laboratory Practice” has become somewhat ofa slogan with the aim to characterise any reliably conducted laboratory work.

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.

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.

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 volume contains the main papers presented at the 1994 EUROTOX Congress, Basel, Switzerland, August 21-24, 1994. Toxicology has become a less descriptive science because more importance has been placed on the mechanisms underlying toxic effects. This is reflected in symposia and workshops devoted to species differences in organ toxicity, receptor-mediated toxicity and stereochemical effects of xenobiotics. Recent progress in the fields of immunotoxicology, ecotoxicology, and neurotoxicology is highlighted and documented together with the present discussion on harmonized regulatory guidelines.

The volume contains the main papers presented at the 1994 EUROTOX Congress, Basel, Switzerland, August 21-24, 1994. Toxicology has become a less descriptive science because more importance has been placed on the mechanisms underlying toxic effects. This is reflected in symposia and workshops devoted to species differences in organ toxicity, receptor-mediated toxicity and stereochemical effects of xenobiotics. Recent progress in the fields of immunotoxicology, ecotoxicology, and neurotoxicology is highlighted and documented together with the present discussion on harmonized regulatory guidelines.