Skin sensitization and possible groupings for 'read across' for rosin based substances.

A series of chemically modified rosin resins have been tested for their potential to cause skin sensitization using the mouse LLNA. Where direct comparative evidence is available, the results of the mouse LLNA are consistent with previously obtained data using the GPMT. Reactions with sufficient fumaric acid or maleic anhydride lead to maleopimaric acid anhydride (an acid anhydride), and give a clear response of a strong sensitizer that definitely requires classification. This sensitization is probably immunologically distinct from that claimed for oxidized rosin. Esterification will deactivate acid anhydrides formed from reacting rosin with maleic anhydride or fumaric acid. However, with maleic anhydride, there remains material capable of inducing a marginal (but classifiable under current criteria) immune response after the rosin had been maleinated and esterified. If proposed potency criteria are used these substances would not be considered 'strong sensitizers'. This response may be a function of a greater solubility in vehicle of the esterified maleinated (or fumarated) rosin over directly esterified material. Solubility limitations in the case of gum rosin directly esterified with pentaerythritol mean that it is not classifiable. Decarboxylated rosin and the glycerol ester of tall oil rosin are adequately soluble, and are not classifiable according to EU criteria. Polymers formed from rosin are also not classifiable as sensitizers. These studies confirm the value of grouping substances for 'read across' and the groupings chosen under the US EPA High Production Volume (HPV) Challenge Program. They also confirm the difficulties involved in dealing scientifically when examining the problem of skin sensitization associated with rosin related substances whilst still meeting current EU regulatory criteria.

Effect of a new series of bicyclic compounds with potential thymoleptic properties on the reserpine-resistant uptake mechanism of central and peripheral monoamine neurones in vivo and in vitro.

1. Bicyclic compounds with potential thymoleptic properties (Lu-compounds) have recently become available, and their effects on the membrane pumps of the central and peripheral monoamine neurones have now been tested and compared with those of the tricyclic antidepressant drugs.2. Biochemical and histochemical in vivo studies have been performed. The possible blocking action of Lu-compounds on the noradrenaline (NA) and 5-hydroxytryptamine (5-HT) displacement caused by 4,alpha-dimethyl-metatyramine (H 77/77) and 4-methyl-alpha-ethyl-meta-tyramine (H 75/12), respectively, has been studied, and a positive result has been taken as evidence for membrane pump blocking activity. No certain effects were obtained on the 5-HT displacement induced by H 75/12, whereas a partial blockade of the NA displacement by H 77/77 in central NA neurones was obtained after most of the Lu-compounds (Lu-3-010, 3-049, 3-092, 4-012) and especially after the thiophthalane derivative Lu 5-003. The ED50 of the latter drug was around 8 mg/kg, that is, somewhere between protriptyline (ED50 4 mg/kg) and desipramine (ED50 15 mg/kg) in potency.3. Histochemical in vivo studies on the rat iris revealed that Lu 5-003 and especially the corresponding phthalane derivative Lu 3-010 were potent in blocking the uptake of alpha-methyl-NA in the adrenergic nerve terminals of the iris. The other Lu-compounds were less active. The releasing effects of the Lu-compounds on the extragranular accumulation of alpha-methyl-NA in the adrenergic terminals were weak compared with membrane blocking activity.4. In vitro studies on the central and peripheral catecholamine (CA) neurones have also been performed. In the same way as, for example, protriptyline the Lu-compounds only blocked accumulation of alpha-methyl-NA in the NA terminals but not in the dopamine (DA) nerve terminals. Lu 5-003 and Lu 3-010 were the most potent of the Lu-drugs when added in vitro. The Lu-drugs were also injected in vivo after which the effect on the alpha-methyl-NA accumulation was studied in vitro. In isotope experiments with labelled alpha-methyl-NA it was found that desipramine, Lu-3-010, Lu 3-092 and Lu 4-012 were equally potent in blocking uptake in the central nervous system.

An ultrastructural and histochemical study of the short-term effects of 6-hydroxydopamine on adrenergic nerves in the domestic fowl.

1. The effects of 6-hydroxydopamine (6-OHDA) on adrenergic nerves in the domestic fowl have been investigated with ultrastructural and fluorescence histochemical methods.2. 6-OHDA depletes the nerves of catecholamine, initially by displacing it from the storage vesicles. 6-OHDA enters large as well as small vesicles, indicating that large granular vesicles in adrenergic nerves are sites of amine storage.3. Doses of 6-OHDA, insufficient to cause degeneration, still cause loading of the vesicles.4. The effects of various drugs on the action of 6-OHDA indicate that this drug must be taken up by the nerves and reach a critical extragranular axoplasmic concentration before degeneration will occur; 6-OHDA bound in the vesicles plays no part in the degenerative process.

The mechanism of action of the anti-herpes virus compound 2,3-dimethyl-6(2-dimethylaminoethyl)-6H-indolo-(2,3-b)quinoxaline.

The compound 2,3-dimethyl-6(2-dimethylaminoethyl)6H-indolo-(2,3-b)quinoxaline (B-220) has been shown to exhibit potent antiviral activity against herpes simplex virus type 1 (HSV-1), varicella-zoster virus (VZV) and cytomegalovirus (CMV). The mechanism of antiviral action of B-220 against HSV-1 has been studied; from the results it appears that B-220 binds by intercalation into the DNA helix and then disturbs steps that are vital for viral uncoating.

Introduction--risk from a philosophy of science point of view.

In this paper it is argued that risk assessment (RA) should be based on principles of philosophy of science. However, in the field of toxicology and the associated RA this is generally not the case. The aim of this presentation is to demonstrate various principles of philosophy of science, applied to 'risk'. Particularly in the context of RA, ignoring basic semantics and methodological principles creates unnecessary difficulties and confusion. Better knowledge about, e.g. semantics and the role and structure of theories, could help to avoid misconceptions and disagreements. We suggest a general theory of risk, which makes an attempt to answer the unequivocal question: what is risk?

A three month inhalation toxicity study in the squirrel monkey (Saimiri sciureus) with terbutaline sulfate (Bricanyl).

A study of the subacute toxicity of inhaled terbutaline sulfate was performed in the Squirrel monkey (Saimiri sciureus). 3 groups of monkeys were exposed 1 h daily 7 days/week for 3 months to terbutaline sulfate aerosols at concentrations of 0.039, 0.185 and 0.799 mg terbutaline/litre of air respectively. A fourth group was a chamber control receiving air only. The following clinical parameters were evaluated: physical appearance and behavior, weight gain, ophthalmoscopic appearance, electrocardiograms, hemograms, blood biochemical profiles and urinalyses. At termination necropsies were conducted and organ weights determined. A variety of staining techniques was employed in the histopathological examination of tissues. Special attention was given to heart and lung. The distribution of goblet cells in sections from the main bronchi and trachea was also investigated. Occasionally a few animals in both the intermediate and high dose groups showed small amounts of exudate and frothing around the mouth during exposure to their respective terbutaline aerosols. No other changes that could be attributed to the exposure to terbutaline aerosols were seen in any parameter.

Adhatoda vasica: a critical review of ethnopharmacological and toxicological data.

Adhatoda vasica (L.) Nees is a well-known plant drug in Ayurvedic and Unani medicine. It has been used for the treatment of various diseases and disorders, particularly for the respiratory tract ailments. During the last 20 years, several scientific reports on oxytocic and abortifacient effects of vasicine and alkaloid derived from the plant have appeared. This leads to questions concerning the safety of A. vasica as a herbal medicine. In this article, the major data on traditional uses as well as ethnopharmacological and toxicological studies, both published and unpublished, are reviewed and commented upon. The data have been evaluated from the point of view of correctness, reliability, relevance and importance for the overall evaluation of the safety of A. vasica.

Evaluating chemical risks: results of a survey of the British Toxicology Society.

1. Members of the British Toxicology Society participated in a survey to determine their attitudes, beliefs, and perceptions regarding risks from chemicals. Similar surveys had previously been conducted with toxicologists and members of the general public in the United States and Canada. Data from 312 completed questionnaires were analyzed. 2. In general, the British toxicologists judged risks to be quite low for most hazards, with the exception of cigarette smoking and asbestos. They tended to have quite favorable attitudes toward the use of chemicals and were confident about the adequacy of chemical regulations. 3. As in previous studies of toxicologists, women expressed higher perceptions of risk than did men and had consistently stronger anti-chemical attitudes. 4. Toxicologists working in industry had more favorable attitudes towards chemicals and their use than did those working in academic settings. 5. When asked to evaluate chemical technical summaries of various animals studies there was considerable disagreement among the respondents about the toxicity of the chemicals involved. 6. In general, British toxicologists were equivocal about the reliability of animal studies in predicting human effects (particularly carcinogenicity) probably because of the belief that animal studies overestimate risk. However, they were rather confident that human health risks could be assessed reasonably accurately.