Abstract There is increasing concern about the degrada- tion and metabolisation as well as the biochemical mech- anisms of action of organometallic compounds. They are known to be immunotoxic and/or neurotoxic. Because of their different toxic capacities, the development of a reli- able correlation between molecular parameters and bio- chemical effects, which could be helpful in risk assess- ment, was an aim of this study. The tested organolead and -tin compounds decrease the viability of human cells in culture in a time- and concentration-dependent manner. Parabolic QSAR 1 models yield an adequate correlation between toxicity expressed as LC 50 and structural parame- ters like ionic molecular weight (MW ion ) or total surface area (TSA). Two main chemical attributes of the organo- metals are probably responsible for such a parabolic rela- tionship: the hydrophobic side chain and the polar metal atom. Furthermore, all tested organometal compounds evoke a persistent increase of the cytosolic free calcium concentration [Ca 2+ ] i . This effect is mainly due to an influx from the extracellular space. Further results suggest that Ca 2+ enters the cell via opened calcium channels. Based on the essential role of Ca 2+ within cellular signalling, the perturbation of calcium homeostasis appears to be an im- portant event in final cell killing by organometals and it is most likely that other biochemical mechanisms, e.g. acti- vation of phospholipase A 2 , are possibly mediated by an increase of [Ca 2+ ] i . Introduction Organic heavy metal compounds are ubiquitously distrib- uted toxins. Because of their pronounced fungicidal, in- secticidal and bacteriostatic properties, triorganotin com- pounds have been released into the environment as ingre- dients of wood preservatives, antifouling paints, fabric disinfectants and in agricultural products [1, 2]. Addition- ally, organolead compounds are still used as antiknock ad- ditives in fuel. For this reason the environment is contam- inated by organometals and they progressively concen- trate within organisms along the food chain [3]. As a re- sult of the increased usage of these biocides, there is an increasing concern about the environmental fate, espe- cially the degradation and metabolisation but also about the biochemical mechanisms of action of these com- pounds. Thus, the development of a reliable correlation between molecular parameters and biochemical effects could be helpful in risk assessment. Investigations using QSAR techniques were performed by different groups [4–7]. Their studies revealed that the toxicity of organic metal compounds depends firstly on the number of side chains and secondly on their length. However it is still un- der discussion whether the relation between structure and toxicity follows a linear or more complex pattern. Organometals are especially known to be immunotoxic and/or neurotoxic [8–10] and a variety of mechanisms have been proposed which could account for these effects. Previous experiments in our laboratory have shown that organolead and -tin compounds induce the liberation of arachidonic acid from cellular phospholipids by stimula- tion of phospholipases [11]. The primary affected lipids are phosphatidylethanolamine and phosphatidylcholine [12], the preferred substrates of a cytosolic phospholipase A 2 (PLA 2 ) [for review: 13, 14]. Further experiments with PLA 2 inhibitors and Ca 2+ depletion by EGTA corroborate our hypothesis that organometals activate a calcium- T. Ade · F. Zaucke · H.F. Krug The structure of organometals determines cytotoxicity and alteration of calcium homeostasis in HL-60 cells Fresenius J Anal Chem (1996) 354 : 609–614 © Springer-Verlag 1996 Received: 10 June 1995 / Accepted: 21 August 1995 LECTURE T. Ade () · F. Zaucke · H. F. Krug Forschungszentrum Karlsruhe, Institut für Toxikologie, P.O.Box 3640, D-76021 Karlsruhe, Germany 1 The abbreviations used are: TMT, trimethyltin chloride; TET, tri- ethyltin bromide; TPT, tripropyltin chloride; TBT, tri-n-butyltin chloride; DBT, di-n-butyltin dichloride; TEL, triethyllead chloride; DEL, diethyllead dichloride; TML, trimethyllead chloride; TPhL, triphenyllead chloride; QSAR, quantitative structure-activity rela- tionships; TSA, total surface area; MW ion , ionic molecular weight; fMLP, N-formyl-L-methionyl-L-leucyl-L-phenylalanine; fluo-3, fluo-3 free acid; fluo-3 AM, fluo-3 acetoxymethyl ester; Me 2 SO, dimethyl sulfoxide; PLA 2 , phospholipase A 2 (EC 3.1.1.4); FCS, fetal calf serum; HEPES, 4-(2-hydroxy-ethyl)-1-piperazineethane- sulfonic acid; EGTA, [ethylene-bis(oxyethylenenitrilo)]tetraacetic acid; [Ca 2+ ] i , cytosolic free Ca 2+ concentration