Recommendations on the environmental risk assessment of pharmaceuticals: Effect characterization.

The effects testing of pharmaceuticals consists of a tiered investigation of ecotoxicological endpoints. However, effects testing has to be performed only when the predicted environmental concentrations (PECs) of pharmaceuticals are above certain action limits. To study the appropriateness of these action limits, a literature search was performed for pharmaceuticals with predicted no-effect concentrations (PNECs) close to or below the action limits. Some human pharmaceuticals showed effects at concentrations ≤100 ng/L, mostly in nonstandard fish or invertebrate tests. In addition, antibiotics and parasiticides sometimes had effects at concentrations <10 mg/kg soil. To help in identifying pharmaceuticals that should undergo effects testing although their PECs are below the action limits, "however clauses" are postulated for pharmaceuticals that are potentially persistent, bioaccumulative, carcinogenic, mutagenic, or reproductively toxic. Effects testing should also be performed for pharmaceuticals that 1) affect target structures that are conserved across species, 2) have a high potency or a small therapeutic margin, 3) are from a new therapeutic class, and 4) are structurally similar to compounds with known effects. Furthermore, suggestions for improving the effects testing of pharmaceuticals are made. These include inter alia chronic effects testing as a general approach, the use of invertebrate tests including sexual reproduction, the application of endpoints reflecting the mode of action of the drug or known side effects, and the simulation of more realistic exposure conditions in terrestrial laboratory tests.

Pharmaceutical management through environmental product labeling in Sweden.

There is an increased awareness that medicinal products for human use may cause negative effects in the environment. In Sweden a voluntary environmental classification system for drugs has been established in collaboration between producers, authorities and the public health care, and used for five years. The idea is to enhance the market demand for medicines with less environmental impact, which in turn will stimulate the producers to design future medicines to be more environmentally friendly. The system is open to the public and based on assessment of the active ingredient in the medicinal product into several classes of risk and hazard, respectively. It is closely related to the EMEA guidelines. Risk is expressed as the ratio between the predicted environmental concentration (PEC) of the active ingredient (AI) and its predicted no effect concentration (PNEC). The hazard is expressed in terms of the AI's persistence, potential to bioaccumulation, and eco-toxicity. Drug data for the classification are delivered by the respective producers. Hitherto more than 300 AI, representing more than 50% of the Swedish volume of drug use, have been classified. Data for risk assessment were missing in 47% of AI. Among drugs with data 7% had a PEC/PNEC ratio >1, and another 7% had a ratio between 0.1 and 1. The AIs with highest ratio (>10) were two estrogens. Data for hazard assessment were lacking in 16% of the AI. Among drugs with environmental data 92% were not ready biodegradable, 23% had potential to bioaccumulation, and 61% were toxic to aquatic organisms at a concentration below 1 mg/l. These data are utilized by regional pharmaceutical expert groups when selecting substances to be recommended in public health care in Sweden. They may also be used by prescribing doctors who want to identify the environmentally most favourable substance among several with equivalent medical effect. We conclude that environmental data on human medicinal products are often missing, or reveal unfavourable environmental properties. A proper judgement of the environmental impact of an AI requires a joint evaluation of its risk and hazard. We suggest that the pharmaceutical producers should highlight environmental precaution when designing new AIs, and that the environmental data should be transparent to the general public.

High and low response in relation to nitric oxide formation but not to lipid peroxidation in patients with sepsis.

OBJECTIVES: Nitric oxide overproduction in sepsis syndrome was suspected to be responsible for hemodynamic derangement and, by induction of lipid peroxidation, for tissue damage. Therefore, nitric oxide formation and lipid peroxidation were quantified in septic patients (SP) vs. patients with localized infection (IF) or without inflammation (C). Nitric oxide formation in sepsis was additionally compared with data for clinical status. DESIGN: Prospective study with consecutive sampling of patients. SETTING: A university hospital intensive care unit and research laboratories. PATIENTS: SP, 24 patients; IP, 7; and C, 13. INTERVENTIONS: Plasma measurement of nitrate, lipid peroxides (primary endpoints), and N-hydroxy-L-arginine (secondary end point) MEASUREMENTS AND MAIN RESULTS: For nitrate, there was a sequence of C < IP = SP. Among SP, one group with significantly higher nitrate (high-responders for nitric oxide; SP-HR) vs. IP and C and a second group (low-responders; SP-LR) with increased concentration only vs. C could be identified. For SP-HR vs. IP, a strong time kinetics in nitric oxide formation was obvious, indicated by significant nitrate increase already 1 day before sepsis started, tripling up to the peak concentration, and then a lowering but still increased value on the first day after sepsis. N-hydroxy-L-arginine was significantly increased in SP-HR vs. C. For lipid peroxides, the concentrations were comparable in SP and IP, but both significantly increased vs. C. Clustering and coincident kinetics of lipid peroxidation related to nitric oxide were not obvious. Furthermore, there was no strong correlation of clinical data and nitric oxide clustering in sepsis. CONCLUSIONS: High- and low-responders for nitric oxide were identified among septic patients. This finding was not associated with significant differences in lipid peroxidation or clinical data.