For authorization of agrochemicals, biocides, veterinary drugs or industrial chemicals, an assessment on their potential risk to the environment has to be submitted in accordance with the relevant directives (91/414/EC, BPD 98/8, 93/67/EC, Commission Reg. No. 1488/94) and guidance documents (TGD, TNsGs). Depending on the nature and level of exposure to the environment and the intrinsic chemical and toxicological properties of the substance, more or less extensive environmental fate and ecotoxicity testing is required to assess the risk. Currently, such a substantiated assessment of the potential impact to the environment is not explicitly required for pharmaceutical products used in human health care. So far, the assessment of unwanted side effects of medicinal drugs is focused on the "immediate" impact on man as a result of direct exposure to the drug. Further evaluation of the fate of medicinal drugs and the potential risk to the environment, following its prescribed usage in patients, is the sole responsibility of the pharmaceutical industry and their liability for the product.
Legislation
Since 1993, the European Union (Directive 93/39/EEC) has been demanding an "indication of any potential risks represented by the medicinal product for the environment."
In response to that, the European Agency for the Evaluation of Medicinal Products (EMEA) has been working on guidance documents and discussion papers to assess the impact of "new" medicinal drugs on the environment. Finally, the Committee for Proprietary Medicinal Products (CPMP) of the EMEA issued a "note for guidance on environmental risk assessment of medicinal products for human use." This was a draft document open for comments until January 2004.
Principles of the Environmental Risk Assessment of Pharmaceuticals
The above-mentioned draft document of the European Union represents a tiered approach to assess the environmental risk of a medicinal product and is similar to an approach for animal health products. The focus is on the surface water, i.e. the aquatic compartment of the environment. The main route of entry of medicinal products into the surface water is via the sewage system. The terrestrial compartment may be exposed via spreading of contaminated sewage sludge on agricultural land.
During the course of one year, thousands of tons of synthesized, biologically highly active medicinal drugs are administered to humans. Depending on the country, about two-thirds of these drugs are prescribed, and the rest is taken as self-medication. These drugs pass through the human body, undergoing metabolism or not, and leave via the urine or faeces. The unchanged drug or its metabolites are then transported with the waste water to sewage treatment facilities. Studies have shown that many pharmacologically active substances may degrade only poorly during sewage treatment (Kümmerer, K. (2001), Chemosphere, 45, 957-969). Therefore, the residues may end up in the surface water or in the terrestrial environment via land spreading of sewage sludge.
The tiered approach to assess the environmental risk of human pharmaceuticals consists of two phases. The phased procedure may be terminated when sufficient information is available either to indicate that the product is unlikely to represent a risk to the environment or to identify and sufficiently characterize the potential risk.
In general, the substances to be included in the environmental risk assessment should be based on the excretion profile in man (i.e., metabolites have to be assessed, as well). However, in most cases it will be sufficient to consider just the active moiety (parent molecule and metabolites containing the "active principle"). Substances like vitamins, electrolytes or amino acids can be exempted from further testing as they are considered to be of low environmental risk.
Phase I (Environmental Exposure Assessment)
In phase I, the Predicted Environmental Concentration (PEC) in surface water is calculated based on conservative estimations of the daily dose, the overall "market Penetration," the amount of waste water per inhabitant and the final dilution of the substance in surface water. If the PECSURFACE WATER is below 0.01 µg/l and no other concerns are apparent, there will be no need for further testing. If this action limit is exceeded, Phase II should be entered.
The action limit may not be applicable for a decision to go or not to go for Phase II (tests) for substances with an unusual potential for adverse toxicological effects (e.g. endocrine disrupters, cytotoxic and mutagenic substances). For such compounds, an expert assessment is required as to whether lower PEC action limits have to be established or testing using a special set of tests.
Phase II (Environmental Fate and Effects Analysis)
In tier A of phase II, a base set of environmental fate studies and aquatic ecotoxicity studies conducted according to the OECD guidelines is required to assess the fate and effects of medicinal product in the aquatic environment and in sewage treatment plants.
The end points of the ecotoxicity tests are used to derive a PNEC (predicted no effect concentration), for comparison with the PECSURFACE WATER refined with an estimate for market penetration of the product in EU member states or regions. If the ratio of PECSURFACE WATER to PNEC is above 1, indicating a potential risk, further evaluation is necessary in tier B of phase II. This can either be done by further refinement of the PEC or the PNEC by providing data supporting such a refinement. Data from Toxicokinetic studies on the fraction excreted and the results of environmental fate tests done in tier A can be used for this purpose. Abiotic and biotic degradation processes such as hydrolysis, photolysis, and microbial degradation contribute to the "clearance" of "degradable" substances in sewage treatment plants and from surface water. The octanol/water partition co-efficient is used as an indicator as to whether further testing on bioconcentration is needed in tier B (bioconcentration in fish, OECD 305). Data from the adsorption/desorption test and from the water/sediment study indicate the affinity to bind to sewage sludge and sediment. Refinement of the PNEC is possible by testing on chronic aquatic toxicity which allows to reduce the assessment factor for deriving the PNEC.
Further tier B tests evaluating the fate and effects to the terrestrial compartment are listed in Table 2, helping to address potential risks from land-spreading of contaminated sewage sludge. All tests have to be performed under the GLP quality standard.
What can RCC offer?
Environmental risk assessment of agrochemicals, biocides, animal health products and chemicals has been one of RCC's core businesses for the past 25 years. Today we use this solid expertise to offer a full package consisting of strategic consulting, identification and performance of the required tests and a risk assessment. We guarantee professional service through our experienced scientific and technical staff and state-of-the-art equipment.
We would like to be of help should you have any requests or demands resulting from the new EU legislation on the environmental safety of human health products.
- The authors are with RCC Ltd.