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Active pharmaceutical ingredient (API) residues have been found to be widespread in the aquatic environment, albeit in most cases at trace levels, with the route to the environment predominantly being via therapeutic use and subsequent excretion to sewer. Although manufacturing discharges may be a low overall contributor to environmental concentrations, they need to be managed effectively so that they do not adversely affect the local receiving environment. In order to achieve this, a risk-based approach is proposed that identifies the long-term and short-term concentrations, referred to as environmental reference concentrations (ERCs) and maximum tolerable concentrations (MTCs), respectively, of an API which should not be exceeded in the aquatic environment receiving effluent from pharmaceutical manufacturing sites. The ERC approach is based on established environmental quality standard concepts currently used in much national and international legislation. Building on these concepts, the approach takes into account indirect exposure of potential consumers such as fish-eating mammals and humans, as well as primary producers (e.g., algae) and primary and secondary consumers (e.g., invertebrates and fish). Although chronic toxicity data are preferred for ERC derivation, acute data, with appropriate considerations of uncertainty, may be used when chronic data are not available. This approach takes all available information into account, particularly for older established medicines that may predate current regulatory requirements for environmental data, and consequently helps prioritize resources for environmental testing. The ERC approach has been applied to 30 of AstraZeneca's APIs. Merits of the approach are discussed together with opportunities for potential future refinement.

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Female Sprague-Dawley rats were given a single oral dose of 10 micrograms TCDD/kg body wt after delivery. Pups were killed on postnatal day (PND) 0, 2, 4, 8, or 16. Dams and remaining weanlings were killed on PND 22 and 32, respectively. Thymus weight was lower in dams exposed to TCDD than in controls, whereas no differences in body weight or relative liver weight were found. The total amount and the concentration of vitamin A were lower in the liver but higher in the kidneys and in serum of TCDD-treated dams than in controls. TCDD-exposed weanlings showed lower weight gain, liver enlargement and thymus atrophy compared to controls. Growth reduction became more pronounced with time, liver enlargement was at its peak on PND 8 and thymus atrophy was most pronounced on PND 16, although all three effects persisted throughout the study. The total amount of vitamin A increased at a similar rate in control and TCDD-exposed weanlings throughout lactation. When the young started to eat pelleted diet there was a pronounced increase in hepatic vitamin A content. Between PND 16 and 32 controls increased their hepatic vitamin A content 21-fold, compared to 12-fold in TCDD-exposed offspring. The hepatic stores of TCDD-treated animals reached 45% of the stores of control pups on PND 32. From PND 8 renal vitamin A was significantly higher in the TCDD-exposed young than in the controls. At PND 32 TCDD-exposed weanlings had six times more renal vitamin A than controls.

The polychlorinated dibenzo-p-dioxins/dibenzofurans 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) were studied for liver tumour promoting activity in a medium-term altered foci assay in nitrosamine-initiated female Sprague-Dawley rats. The congeners under study were administered by weekly subcutaneous injections at three dose levels for 20 weeks. Evaluation of gamma-glutamyltranspeptidase (GGT+), altered hepatic foci development, showed that all congeners studied acted as potent promoters of hepatocarcinogenesis. TCDD and PeCDD were virtually equipotent as enhancers of foci development while PeCDF displayed approximately ten per cent of the activity of the dioxins. Analysis of the dioxin- and furan-congeners by gas chromatography/mass spectroscopy (GC/MS) technique showed that the retention of PeCDD and PeCDF in liver tissue was approximately 7 and 20 times, respectively, as high as the retention of TCDD. Based on the concentration of the respective congener in liver tissue, PeCDD and PeCDF were 0.14 and 0.007 times as active as TCDD as promoters of foci development. The dose related enhancement of GGT+ foci development induced by the PCDD/PCDF congeners was accompanied by an increased incidence of histological changes in the liver.