Toxicology Letters 127 (2002) 225 – 237 Integration of mechanistic data in the toxicological evaluation of endocrine modulators Gisela H. Degen a, *, Petra Janning a , Ju ¨ rgen Wittsiepe b , Andreas Upmeier a , Hermann M. Bolt a a Institute of Occupational Physiology (IfADo), Uniersity of Dortmund, Ardeystr. 67, D-44139, Dortmund, Germany b Abt. fu ¨r Hygienie, Sozial - und Umweltmedizin, Ruhr Uniersita ¨t Bochum, Bochum, Germany Abstract Controversy has arisen concerning the likelihood of adverse health effects due to exposure to hormonally active agents or endocrine modulators such as environmental estrogens. With the aim to improve the basis for their toxicological evaluation, several chemicals of anthropogenic (bisphenol A, octylphenol, o,p -DDT) and of natural origin (daidzein, genistein) were investigated with regard to their mode of hormonal action and potency as well as toxicokinetics. Experimental toxicodynamic and toxicokinetic data illustrate important points in a comparative assessment of environmental estrogens. A novel concept, the Hygiene-Based Margine of Safety (HBMOS), has been suggested to characterize the relative impact of these potential endocrine modulators on human health: It integrates exposure scenarios (i.a. those generated within the European Existing Chemicals Programme) and in vivo rodent potency data for xenoestrogens and for dietary phytoestrogens. On the basis of these informations, HBMOS values calculated for the alkylphenol and bisphenol A appear sufficiently high to ensure the absence of a practical risk to human health under the present exposure conditions. For slowly accumulating compounds (e.g. DDT) with much longer half-lifes than isoflavones, such comparison should be based on comparative blood levels rather than on scenarios of daily exposures. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Environmental estrogens; Exposure to environmental estrogens; Toxicokinetics www.elsevier.com/locate/toxlet 1. Introduction Hormonally active agents, also termed ‘en- docrine disrupting chemicals’ or ‘endocrine modu- lators’ have become a topic and widely debated issue in toxicology and related fields due to con- cerns that exposure, especially early in life, may result in developmental, reproductive and/or on- cological effects (European Commission, 1997; US EPA, 1997). This paper will focus on estro- genic compounds since numerous environmental chemicals exert this type of hormonal activity, for instance plant constitutents (phytoestrogens), my- cotoxins and their metabolites, as well as anthro- pogenic chemicals. * Corresponding author. Tel.: +49-231-1084-351; fax: + 49-231-1084-403. E-mail address: degen@ifado.de (G.H. Degen). 0378-4274/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII:S0378-4274(01)00504-5