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Correlations between skin sensitisation potential and chemical reactivity
A32 1-12
Toxicology 81 Correlations between skin sensitisation potential and chemical reactivity By D W Roberts*, D L Williams, K Jones (Unilever Research, Port Sunlight Laboratory) A W Johnson, B Goodwin and J C E Alderson (Unilever Research, Colworth Laboratory). Some biological activities of chemicals can be related to their structures and a better understanding of the relationships promises to be of value for the preliminary assessment of safety of new substances. A connection between ability to sensitise and ability to alkylate nucleophiles has been observed by Landsteiner for halonitrobenzenes and by Mitchell et al for sesquiterpene lactones. We have compared, for a series of p-nitrobenzyl compounds, rate of reaction with n-butylamine under standard conditions against sensitisation potential as measured in a guinea-pig test. The results show that for this series sensitisation potential increases with increasing reactivity, and enable us to determine the approximate position of a "reactivity threshold" below which a p-nitrobenzyl compound is too unreactive to sensitise in the test used. The applicability of the correlation obtained to compounds not belonging to the p-nitrobenzyl series is being investigated, and results obtained so far will be presented and discussed.
To present the paper.
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MECHANISMSOF ORGAN-DIRECTEDTOXICITY OF BENZENE
LEON BRAIER, M.D. Dept. Physiology & Pharmacology; Tel-Aviv Medical School. Ramat-Aviv, ISRAEL. There are s t i l l many relevant questions to be answered concenrning the pathogenesis of benzene myelotoxicity. Among the unanswered questions the following ones have been selected to be discussed here: (I) is benzene acting by i t s e l f or through an active metabolite? I f so, what is the chemical structure of such a metabolite?; (2) is the intermediate metabolite of benzene formed: (1) in the liver, and transported from there to be bone marrow, or (2) in the bone marrow where benzene accumulates and develops its damaging effects? A rabbit model system has been designed with the aim of answer these questions. An experiment was carried out by ligating the efferent veins from one leg of the animal immediately before and for 15 minutes, after the injection of pure benzene (O.4ml/kg) in the femoral artery: Such a procedure was designed with the purpose of: (I) concentrating the benzene injected in the femoral marrow, and (2) preventing benzene from entering the circulation thus reaching the liver. 24h after the local injection of benzene necrosis of the "injected" femoral marrow was found in all the animals tested, contrasting with the normal aspect exhibited by the marrow at the opposite leg, used as control. Results from these experiments and plans for the future will be discussed in our presentation.
Toxicology 81 Correlations between skin sensitisation potential and chemical reactivity By D W Roberts*, D L Williams, K Jones (Unilever Research, Port Sunlight Laboratory) A W Johnson, B Goodwin and J C E Alderson (Unilever Research, Colworth Laboratory). Some biological activities of chemicals can be related to their structures and a better understanding of the relationships promises to be of value for the preliminary assessment of safety of new substances. A connection between ability to sensitise and ability to alkylate nucleophiles has been observed by Landsteiner for halonitrobenzenes and by Mitchell et al for sesquiterpene lactones. We have compared, for a series of p-nitrobenzyl compounds, rate of reaction with n-butylamine under standard conditions against sensitisation potential as measured in a guinea-pig test. The results show that for this series sensitisation potential increases with increasing reactivity, and enable us to determine the approximate position of a "reactivity threshold" below which a p-nitrobenzyl compound is too unreactive to sensitise in the test used. The applicability of the correlation obtained to compounds not belonging to the p-nitrobenzyl series is being investigated, and results obtained so far will be presented and discussed.
To present the paper.
1-13
MECHANISMSOF ORGAN-DIRECTEDTOXICITY OF BENZENE
LEON BRAIER, M.D. Dept. Physiology & Pharmacology; Tel-Aviv Medical School. Ramat-Aviv, ISRAEL. There are s t i l l many relevant questions to be answered concenrning the pathogenesis of benzene myelotoxicity. Among the unanswered questions the following ones have been selected to be discussed here: (I) is benzene acting by i t s e l f or through an active metabolite? I f so, what is the chemical structure of such a metabolite?; (2) is the intermediate metabolite of benzene formed: (1) in the liver, and transported from there to be bone marrow, or (2) in the bone marrow where benzene accumulates and develops its damaging effects? A rabbit model system has been designed with the aim of answer these questions. An experiment was carried out by ligating the efferent veins from one leg of the animal immediately before and for 15 minutes, after the injection of pure benzene (O.4ml/kg) in the femoral artery: Such a procedure was designed with the purpose of: (I) concentrating the benzene injected in the femoral marrow, and (2) preventing benzene from entering the circulation thus reaching the liver. 24h after the local injection of benzene necrosis of the "injected" femoral marrow was found in all the animals tested, contrasting with the normal aspect exhibited by the marrow at the opposite leg, used as control. Results from these experiments and plans for the future will be discussed in our presentation.