Articulo sobre productos quimicos peligrosos provenientes de la industria farmaceutica

REGULATORY TOXICOLOGY AND PHARMACOLOGY ARTICLE NO.

25, 220–225 (1997)

RT971102

Environmental Hazard Assessment of Pharmaceuticals
K.-P. Henschel, A. Wenzel, M. Diedrich, and A. Fliedner*
¨ ¨ Fraunhofer-Institut fur Umweltchemie und Okotoxikologie, Abt. Biochemische Okotoxikologie, 14558 Bergholz-Rehbrucke, Germany; ¨ ¨ ¨ ¨ and *Fraunhofer-Institut fur Umweltchemie und Okotoxikologie,Abt. Angewandte Okologie, 57392 Schmallenberg, Germany ¨ Received January 15, 1997

The pharmaceuticals and pharmaceutical metabolites salicylic acid, paracetamol, clofibrinic acid, and methotrexate were examined with regard to their biological degradability and toxicity toward algae, Daphnia, fish embryos, luminescent bacteria, ciliates, and the fish cell line BF-2. The EC50 values calculated forthe most sensitive organismic test (all except cell cultures) in each case were for salicylic acid, 37 mg/L (fish embryos); for paracetamol, 50 mg/L (Daphnia); for clofibrinic acid, 86 mg/L (fish embryos); and for methotrexate, 45 mg/L (ciliates). However, in the case of paracetamol, clofibrinic acid, and methotrexate, the fish cell line BF-2 reacted even more sensitively with EC50 values of 19 mg/L(paracetamol), 14 mg/L (clofibrinic acid), and 3 mg/L (methotrexate). Salicylic acid and paracetamol proved to be easily degradable. The predicted exposure concentration calculated according to the procedure of the EU Draft Phase I for new pharmaceuticals (CEC III/5504/94, draft 4) was based on the total estimated quantity of these substances consumed and indicated that their entry into theenvironment is theoretically possible. These results show that (1) the four tested pharmaceuticals may be present in the environment, (2) the substances led to effects in at least one ecotoxicological test, and (3) the most sensitive reactions were observed for a nonstandard test which incorporates relevant end points for the respective pharmaceuticals. This demonstrates that a limitation to thestandard tests (algae, Daphnia, and fish) would have underestimated the toxicity of paracetamol, clofibrinic acid, and methotrexate. In addition to improved exposure estimates, the EU guideline should therefore contain a test strategy adapted to their modes of action, which permits the definite identification of pharmaceuticals with high ecotoxic potential, and consequently the appropriate provisions. 1997Academic Press

and pesticides and is carried out within the European Union in accordance with certain unified principles. A similar evaluation is currently being discussed with regard to the registration of pharmaceuticals, as these are also anthropogenic substances, some of which may enter the environment in considerable quantities (Heberer and Stan, 1995; Stan et al., 1994, Richardson andBowron, 1985; Matsumoto, 1982). The EU Guideline 92/18 EWG for veterinary pharmaceuticals has been law in Germany since March 30, 1995. This is the first guideline to require ecotoxicity testing as part of the registration procedure. Furthermore, a draft evaluation strategy for assessing potential hazards to the environment (EMEA, 1996) is currently under discussion at the EU level. However, theanticipated EU guideline, regarding pharmaceuticals used in human medicine, has not yet been passed. The draft stipulates that, from January 1, 1995, the company applying for registration for a new product must make a declaration with regard to the potential risk which the product may pose to the environment (CEC III/5944/94). The processes by which this evaluation should be carried out are stillbeing discussed at the EU level (CEC III/5504/94, draft 4). Within this context, the following main points still need to be defined with regard to exposure and assessment of the potential risk to the environment: 1. The quantities concerned and their paths of entry into the environment; 2. The effects on nontarget organisms, applicability of the results of toxicity tests with mammals to nontarget...