Models for Risk Assessment of Reactive Chemicals in Aquatic Toxicology Modellen voor de risico-evaluatie van reactieve stoffen in de aquatische toxicologie (met een samenvatting in het Nederlands) Proefschrift Ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van Rector Magnificus, Prof. Dr. H.O. Voorma involge het besluit van het College voor Promoties in het openbaar te verdedigen op 31 mei 2000 des namiddags om 14.30 uur door Andreas Peter Freidig geboren op 28 april 1969, te Thun, Zwitserland Promotor: Prof. Dr. W. Seinen Co-promotor: Dr. J.L.M. Hermens ISBN 90-393-2409-3 Trefw.: ecotoxicology / risk assessment / acrylates The research described in this thesis was carried out at the Research Institute of Toxicology (RITOX), Utrecht University, P.O. Box 80.176, NL-3508 TD Utrecht, The Netherlands. The Project was financially supported by the Swiss National Foundation (Schweizerischer National Fonds), grant no. 83EU-046316. Qui tractaverunt scientias aut empirici aut dogmatici fuerent. Empirici, formicae more congerunt tantum et utuntur: Rationales aranearum more, telas ex se conficiunt: Apies vero ratio media est, quae materiamex floribus horti et agri elicit; sed tamen eam propria facultate vertit et digerit. Francis Bacon (1620), Novum Organicum, Lib. 1, XCV Experimental scientists are like the ant: they collect and use; the theoretical scientists resemble spiders; who make cowebs out of their own substance. But the bee takes the mid- dle course, it gathers its material from the flowers of the garden and of the field but trans- forms and digests it by a power of its own. (engl. transl. given in: Yates, F.E. (1978), Am J Physiol 3:R159-R160.) Referents Dr. J.N.M. Commandeur Vrije Universiteit, Amsterdam, the Netherlands Dr. B.I. Escher Swiss Federal Institute of Environmental Science and Technology (EAWAG), D(cid:159)bendorf, Switzerland Prof. Dr. S.A.L.M. Kooijman Vrije Universiteit, Amsterdam, the Netherlands Prof. Dr. I.M.C.M. Rietjens Wageningen University and Research Center, Wageningen, the Netherlands Prof. Dr. W. Slob National Institute of Public Health and the Environment (RIVM), Bilthoven, the Netherlands CONTENTS 1 Introduction 7 2 Quantitative structure-property relationships for the 23 chemical reactivity of acrylates and methacrylates. Environmental Toxicology and Chemistry (1999) 18(6):1133-1139. 3 Comparing the potency of chemicals with multiple modes 39 of action in aquatic toxicology: acute toxicity due to nar- cosis versus reactive toxicity of acrylic compounds. Environmental Science and Technology (1999) 33(17):3038-3043. 4 Narcosis and chemical reactivity in acute fish toxicity 57 QSARs. 5 GSH depletion in rat hepatocytes: a mixture study with 71 a,b -unsaturated esters. 6 A preliminary physiologically based pharmacokinetic and 87 pharmacodynamic model for ethyl acrylate in the rain- bow trout. 7 An elementary pharmacodynamic model (EPD) for the 107 analysis of time dependent aquatic toxicity data of reac- tive chemicals: Habers law revisited. 8 Summary and general discussion 123 Nederlandse samenvatting 139 Publications 142 Curriculum vitae 143 Dankwoord 144 6 INTRODUCTION 1 CHAPTER 8 Chapter 1 Introduction INTRODUCTION With industrialization, a tremendous number of chemical substances has entered our daily life (1). The increasing awareness of potential chemical hazards calls for a thorough risk assessment of these chemicals, both for humans health and the environment. In spite of that, it must be concluded today, that available information for most chemicals is not suffi- cient to perform a comprehensive risk assessment (2). Therefore, agencies like the environ- mental protection agency (EPA) in the US or the European chemical bureau (ECB) are de- veloping methods to predict the risk of a substance from its chemical structure (3-7). Such models will help to fill data gaps in risk assessment. In this thesis, some toxicological mod- els for reactive chemicals in aquatic organisms will be presented. This introduction will discuss structural properties of reactive chemicals, the use of these chemicals, and give some examples of exposure situations and toxicological effects. Additionally, a short over- view of available toxicological models will be given. The introduction is concluded with an outline of the thesis. STRUCTURE OF REACTIVE CHEMICALS A large number of synthetic and natural substances fall in the class of organic chemicals. A close look at these organics reveals that most of them contain carbon (C) and a few other elements, namely hydrogen (H), oxygen (O), nitrogen (N), sulfur (S), phosphorus (P) and the halogens fluorine (F), chlorine (Cl), bromine (Br) and iodine (I) (8). Certain combina- tions of atoms within a molecule can be identified as functional groups. As the name al- ready indicates, these groups are linked to an observable function of the molecule, gener- ally a chemical reaction. Certain functional groups are known to react with each other. Re- active organic chemicals can thus be defined as organic chemicals with reactive functional groups. It should be noted that reactivity is a relative term as it always refers to a reaction with something else. Some organic chemicals are called electrophiles because they contain functional groups which tend to acquire electrons during a chemical reaction. Electrophiles react preferably with nucleophilic functional groups. This classification is important, be- cause many biological substances such as proteins, enzymes or the DNA contain nucle- ophilic functional groups. They can be altered by chemical bonding of electrophilic xenobiotics and thereby lose their biological function (9-11). It is not surprising, that electrophilic groups are often present in carcinogenic, irritating or allergenic chemicals. Sev- eral authors have presented overviews of electrophilic groups which are connected to such toxic effects (12-16). In table 1, the structure of four electrophilic organic chemicals is shown. 9 Table 1: Some structures of electrophilic organic chemicals. O (1) Ethyl acrylate O O Cl (2) Epichlorohydrin O (3) Acrylamide N O (4) Trimethylammonium- O + ethylmetacrylate N These chemicals are all used in large amounts for very diverse purposes. In this introduc- tion, they will serve as examples to illustrate the risk, which is involved in the use of electrophilic organic chemicals. In this chapter, (cid:212)reactive oraganic chemicals(cid:213) will be used as a synonym for (cid:212)electrophilic chemicals(cid:213). USE OF REACTIVE CHEMICALS Reactive (electrophilic) chemicals are often used as intermediates for products of the chemical industry. They are used in large amounts and many of them are included in the high production volume chemical (HPVC) list of the EU (5, 15) which means that their annual production exceeds 1(cid:213)000 tons. To get a better idea in which products these chemi- cals eventually end up we will have a more detailed look at the four chemicals from table 1. a,b Ethyl acrylate (1), a reactive -unsaturated ester is used for the manufacturing of poly- 10 Chapter 1 Introduction