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The threshold of toxicological concern (TTC) is a pragmatic risk assessment tool that is based on the principle of establishing a human exposure threshold value for all chemicals, below which there is a very low probability of an appreciable risk to human health. The concept that there are levels of exposure that do not cause adverse effects is inherent in setting acceptable daily intakes (ADIs) for chemicals with known toxicological profiles. The TTC principle extends this concept by proposing that a de minimis value can be identified for many chemicals, in the absence of a full toxicity database, based on their chemical structures and the known toxicity of chemicals which share similar structural characteristics. The establishment and application of widely accepted TTC values would benefit consumers, industry and regulators. By avoiding unnecessary toxicity testing and safety evaluations when human intakes are below such a threshold, application of the TTC approach would focus limited resources of time, cost, animal use and expertise on the testing and evaluation of substances with the greatest potential to pose risks to human health and thereby contribute to a reduction in the use of animals. An Expert Group of the European branch of the International Life Sciences Institute-ILSI Europe-has examined the TTC principle for its wider applicability in food safety evaluation. The Expert Group examined metabolism and accumulation, structural alerts, endocrine disrupting chemicals and specific endpoints, such as neurotoxicity, teratogenicity, developmental toxicity, allergenicity and immunotoxicity, and determined whether such properties or endpoints had to be taken into consideration specifically in a step-wise approach. The Expert Group concluded that the TTC principle can be applied for low concentrations in food of chemicals that lack toxicity data, provided that there is a sound intake estimate. The use of a decision tree to apply the TTC principle is proposed, and this paper describes the step-wise process in detail. Proteins, heavy metals and polyhalogenated-dibenzodioxins and related compounds were excluded from this approach. When assessing a chemical, a review of prior knowledge and context of use should always precede the use of the TTC decision tree. The initial step is the identification and evaluation of possible genotoxic and/or high potency carcinogens. Following this step, non-genotoxic substances are evaluated in a sequence of steps related to the concerns that would be associated with increasing intakes. For organophosphates a TTC of 18microg per person per day (0.3 microg/kg bw/day) is proposed, and when the compound is not an OP, the TTC values for the Cramer structural classes III, II and I, with their respective TTC levels (e.g. 1800, 540 and 90 microg per person per day; or 30, 9 and 1.5 microg/kg bw /day), would be applied sequentially. All other endpoints or properties were shown to have a distribution of no observed effect levels (NOELs) similar to the distribution of NOELs for general toxicity endpoints in Cramer classes I, II and III. The document was discussed with a wider audience during a workshop held in March 2003 (see list of workshop participants).

Hyperplastic and metaplastic lesions in the prostate gland of bulls are used as morphological evidence for the illegal administration of oestrogens or compounds with oestrogenic activity, like stilbenes. Exogenous and endogenous androgens can suppress the effects of these drugs, resulting in suspect or negative results. The detection of epithelial changes immunohistochemically with cytokeratin antibodies appeared to facilitate the diagnosis of hyperplasia and metaplasia in the prostate. A specific and sensitive method for detecting such lesions in formalin-fixed, paraffin-embedded prostate samples has been developed with the commercially available cytokeratin monoclonal antibody 34 beta E12, and applied to bulls treated with diethylstilbestrol-dipropionate. The highly reproducible staining pattern of 34 beta E12 can be used for the detection of hyperplasia and metaplasia in the prostate glands of animals treated illegally with oestrogens.

This paper presents an overview of the studies carried out in small laboratory fish species to investigate the usefulness of histopathology as a tool in aquatic toxicology. The studies were performed with medaka (Oryzias latipes) and guppy (Poecilia reticulata) that were exposed to a variety of environmental contaminants for one and three months. Besides the measurement of routine toxicological parameters, total body histopathology was carried out. The data are summarized and evaluated in view of their contribution to the knowledge of toxicology, the specific responsiveness of animals and tissues, and the application in ecotoxicology. It is concluded that histopathology of (small) fish exposed to environmental contaminants may provide useful information as to target organs and mechanism of action: moreover, this technique can be more sensitive than routine parameters.

Aberrant or defective immune responses are known to be the result of primary immunodeficiency diseases, e.g., in the DiGeorge syndrome (thymic hypoplasia) in man, or in homozygous mice with the mut...

In the 2:1 co-crystal of 5-(2-pyridyl)-1H-1,2,4-triazole (pyt) and 1,4-dihydroxybenzene (dhb), 2C 7 H 6 N 4 -C 6 H 6 O 2 , the pyt molecules form two independent N-H...N hydrogen-bonded chains. The dhb molecules act as hydrogen-bonding bridges between the two pyt chains via two O-H...N hydrogen bonds. The complex is further stabilized by a number of weaker interactions, including C-H...N, C-H...O and C-H...π interactions.

After immunization of Wistar rats with different concentrations of ovalbumin (OA) emulsified in complete H37Ra adjuvant, the optimal antigen dose for specific IgM, IgG and IgE production and for delayed-type hypersensitivity appeared to be the same. It is therefore concluded that in the rat these function tests can be combined, which decreases the number of experimental animals needed. For the determination of IgM, IgG and IgE antibodies to OA, the enzyme-linked immunosorbent assay (ELISA) was used, which proved to be a specific method. In addition, using a multi-channel photometer, it is shown that specific antibody concentrations can be readily quantified by micro-ELISA instead of using end-point titrations.

Die Cd-, Zn-, Co-, Ni-, Cu- und Ag- Salze von 1,2,4-Triazol und 3-Brom-1 ,2,4-triazol werden durch Reaktion der Liganden mit Metallsalzen in wasiiger Losung erhalten (keine Ausb.-Angabe) und durch chemische Analyse, Schwingungs- und Elektronenabsorptionsspektren charakterisiert.

We studied the early events in athymic immunoincompetent rats after implantation with cultured thymic fragments (CIF) under the kidney capsule, with special emphasis on the settlement of lymphocytes and non-lymphnid RTl class II elements. At 2 weeks after grafting, tissue under the kidney capsule comprises strands of keratin-positive epithelial cells from the graft, without immigrant cells. At 3 weeks, the CTF graft is populated with lymphoeytes and with non-lymphoid RTl class II-positive cells expressing the recipient haplotype (allogeneic combinations). Part of these cells bear determinants recognized by an anti-rat dendritic cell antibody. At 4 weeks the graft exhibits a completely restored thymic architecture. Al the periphery, the first indications of T-cell competence generated after CTF implantation are observed 6 weeks after implantation. At 18 weeks. the peripheral thymus-dependent immune system is almost completely developed. This includes in vitro alloreactivity, even to the donor RTl haplotype of the graft. But skin grafts of the allogeneic CTF donor haplotype are not rejected. Thus, a state of in vivo tolerance is induced under the influence of grafted epithelium, which is not due to a specific deletion of alloreactive cells. We conclude that CTF regain their original thymic architecture between 2 and 4 weeks after implantation in (allogeneic) athymic nude recipients, and that only after this restoration does peripheral thymus-dependent immune competence start to develop.

In wasrig-ammoniakalischer Losung reagieren Metallsalze mit den entsprechenden Pyrazolen zu den Komplexen (I).

We studied the thymus-dependent immune system in congenitally athymic (nude) rats of the WAG (RT-1a) strain, at the ages of 2, 3, 5, 9 and 17 months. This included the histology of spleen, lymph nodes, and Peyer's patches, immunohistochemistry on tissue sections, and immunocytology on cell suspensions using a panel of monoclonal antibodies to T-lymphocyte subpopulations. in vitro mitogen responsiveness, and in vivo responsiveness to ovalbumin immunization. The results were compared with those in euthymic immunocompetent litter-mates of the same age. The cell marker analysis, especially in nude animals, was hampered by the staining of non-T cells by some of the antibodies (staining of putative macrophages, natural killer cells, cells of H-lymphocyte lineage, and of myeloid lineage I. Despite this, with age an increase in cells with these markers was observed; for instance, in spleen suspensions, cells labelled by the pan-I reagent MRCOX-19 increased from 5% at 2 months to 19% at 17 months (value in euthymic animals 34%). In the other assays too a gradual increase of T-cell reactivity with age was observed, from almost absent in 2- and 3-month-old nude rats to values in 17-month-old animals of about hall the level round in euthymic rats. However, none of the nude animals responded to ovalbumin immunization. These results indicate that in nude animals processes occur which compensate for the absent intrathymic T-cell generation. This applies in particular to changes in T-cell phenotype and mitogen responsiveness, but not to antigen responsiveness.