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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 of a slogan with the aim to characterise any
reliably conducted laboratory work.
This volume contains the main papers presented at the 1997 EUROTOX
Congress, Arhus, 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.
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.
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.
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 of a slogan with the aim to characterise any
reliably conducted laboratory work.
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