Environmental risk assessment for the serotonin re-uptake inhibitor fluoxetine: Case study using the European risk assessment framework.

The serotonin re-uptake inhibitor fluoxetine was selected for an environmental risk assessment, using the most recent European guideline (EMEA 2006) within the European Union (EU)-funded Environmental Risk Assessment of Pharmaceuticals (ERAPharm) project due to its environmental persistence, acute toxicity to nontarget organisms, and unique pharmacokinetics associated with a readily ionizable compound. As a widely prescribed psychotropic drug, fluoxetine is frequently detected in surface waters adjacent to urban areas because municipal wastewater effluents are the primary route of entry to aquatic environments. In Phase I of the assessment, the initial predicted environmental concentration of fluoxetine in surface water (initial PEC(SW)) reached or exceeded the action limit of 10 ng/L, when using both a default market penetration factor and prescription data for Sweden, Germany, and the United Kingdom. Consequently, a Phase II risk assessment was conducted in which green algae were identified as the most sensitive species with a NOEC of <0.6 microg/L. From this value, a predicted no effect concentration for surface waters (PNEC(SW)) of 0.012 microg/L was derived. The PEC/PNEC ratio was above the trigger value of 1 in worst-case exposure scenarios indicating a potential risk to the aquatic compartment. Similarly, risks of fluoxetine for sediment-dwelling organisms could not be excluded. No risk assessment was conducted for the terrestrial compartment due to a lack of data on effects of fluoxetine on soil organisms. The need for a separate risk assessment for the main metabolite of fluoxetine, norfluoxetine, was not conducted because of a lack of fate and effect studies. Based on published data, fluoxetine and norfluoxetine appeared to have a low to moderate bioaccumulation potential, which should be confirmed in formal studies according to OECD guidelines. Exposure assessments for fluoxetine according to the current framework rely heavily on K(OC) and K(OW) values. This approach is problematic, because fluoxetine is predominantly a cationic substance at environmental pH values. Consequently, the fate of fluoxetine (and other ionic substances) cannot be predicted using partition coefficients established for nonionic compounds. Further, published estimates for partition coefficients of fluoxetine vary, resulting in considerable uncertainties in both the exposure and environmental risk assessments of fluoxetine.

Impacts of climate change on indirect human exposure to pathogens and chemicals from agriculture.

Climate change is likely to affect the nature of pathogens/ chemicals in the environment and their fate and transport. We assess the implications of climate change for changes in human exposures to pathogens/chemicals in agricultural systems in the UK and discuss the effects on health impacts, using expert input and literature on climate change; health effects from exposure to pathogens/chemicals arising from agriculture; inputs of chemicals/pathogens to agricultural systems; and human exposure pathways for pathogens/chemicals in agricultural systems. We established the evidence base for health effects of chemicals/pathogens in the agricultural environment; determined the potential implications of climate change on chemical/pathogen inputs in agricultural systems; and explored the effects of climate change on environmental transport and fate of various contaminants. We merged data to assess the implications of climate change in terms of indirect human exposure to pathogens/chemicals in agricultural systems, and defined recommendations on future research and policy changes to manage adverse increases in risks.

Impacts of climate change on indirect human exposure to pathogens and chemicals from agriculture: [review] / Impactos das mudanças climáticas sobre a exposição humana indireta a elementos patogênicos e químicos da agricultura: [revisão]

Climate change is likely to affect the nature of pathogens/ chemicals in the environment and their fate and transport. We assess the implications of climate change for changes in human exposures to pathogens/chemicals in agricultural systems in the UK and discuss the effects on health impacts, using expert input and literature on climate change; health effects from exposure to pathogens/chemicals arising from agriculture; inputs of chemicals/pathogens to agricultural systems; and human exposure pathways for pathogens/chemicals in agricultural systems. We established the evidence base for health effects of chemicals/pathogens in the agricultural environment; determined the potential implications of climate change on chemical/pathogen inputs in agricultural systems; and explored the effects of climate change on environmental transport and fate of various contaminants. We merged data to assess the implications of climate change in terms of indirect human exposure to pathogens/chemicals in agricultural systems, and defined recommendations on future research and policy changes to manage adverse increases in risks.

É provável que a mudança climática afete a natureza, destino e transporte de elementos patogênicos/químicos no ambiente . Avaliamos as implicações das mudanças climáticas em mudanças na exposição humana a elementos patogênicos/químicos nos sistemas agrícolas no Reino Unido e discutimos os efeitos sobre os impactos à saúde, usando a contribuição de especialistas e literatura; efeitos à saúde da exposição a elementos patogênicos/químicos provenientes da agricultura; introdução de elementos químicos/patogênicos e caminhos de exposição humana a elementos patogênicos/químicos nos sistemas agrícolas. Definimos a base de evidência para efeitos de saúde de elementos químicos/patogênicos no ambiente agrícola; determinamos as possíveis implicações da mudança climática na introdução de elementos químicos/patogênicos nos sistemas agrícolas; e exploramos os efeitos da mudança climática no transporte ambiental e destino de diversos contaminantes. Consolidamos dados para avaliar as implicações das mudanças climáticas em relação à exposição humana indireta a elementos patogênicos/químicos nos sistemas agrícolas e recomendamos futuras pesquisas e mudanças políticas para administrar aumentos adversos nos riscos.

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.

Impacts of climate change on indirect human exposure to pathogens and chemicals from agriculture.

OBJECTIVE: Climate change is likely to affect the nature of pathogens and chemicals in the environment and their fate and transport. Future risks of pathogens and chemicals could therefore be very different from those of today. In this review, we assess the implications of climate change for changes in human exposures to pathogens and chemicals in agricultural systems in the United Kingdom and discuss the subsequent effects on health impacts. DATA SOURCES: In this review, we used expert input and considered literature on climate change; health effects resulting from exposure to pathogens and chemicals arising from agriculture; inputs of chemicals and pathogens to agricultural systems; and human exposure pathways for pathogens and chemicals in agricultural systems. DATA SYNTHESIS: We established the current evidence base for health effects of chemicals and pathogens in the agricultural environment; determined the potential implications of climate change on chemical and pathogen inputs in agricultural systems; and explored the effects of climate change on environmental transport and fate of different contaminant types. We combined these data to assess the implications of climate change in terms of indirect human exposure to pathogens and chemicals in agricultural systems. We then developed recommendations on future research and policy changes to manage any adverse increases in risks. CONCLUSIONS: Overall, climate change is likely to increase human exposures to agricultural contaminants. The magnitude of the increases will be highly dependent on the contaminant type. Risks from many pathogens and particulate and particle-associated contaminants could increase significantly. These increases in exposure can, however, be managed for the most part through targeted research and policy changes.

Meeting report: risk assessment of tamiflu use under pandemic conditions.

On 3 October 2007, 40 participants with diverse expertise attended the workshop Tamiflu and the Environment: Implications of Use under Pandemic Conditions to assess the potential human health impact and environmental hazards associated with use of Tamiflu during an influenza pandemic. Based on the identification and risk-ranking of knowledge gaps, the consensus was that oseltamivir ethylester-phosphate (OE-P) and oseltamivir carboxylate (OC) were unlikely to pose an ecotoxicologic hazard to freshwater organisms. OC in river water might hasten the generation of OC-resistance in wildfowl, but this possibility seems less likely than the potential disruption that could be posed by OC and other pharmaceuticals to the operation of sewage treatment plants. The work-group members agreed on the following research priorities: a) available data on the ecotoxicology of OE-P and OC should be published; b) risk should be assessed for OC-contaminated river water generating OC-resistant viruses in wildfowl; c) sewage treatment plant functioning due to microbial inhibition by neuraminidase inhibitors and other antimicrobials used during a pandemic should be investigated; and d) realistic worst-case exposure scenarios should be developed. Additional modeling would be useful to identify localized areas within river catchments that might be prone to high pharmaceutical concentrations in sewage treatment plant effluent. Ongoing seasonal use of Tamiflu in Japan offers opportunities for researchers to assess how much OC enters and persists in the aquatic environment.

The impact of synthetic pyrethroid and organophosphate sheep dip formulations on microbial activity in soil.

Sheep dip formulations containing organophosphates (OPs) or synthetic pyrethroids (SPs) have been widely used in UK, and their spreading onto land has been identified as the most practical disposal method. In this study, the impact of two sheep dip formulations on the microbial activity of a soil was investigated over a 35-d incubation. Microbial utilisation of [1-(14)C] glucose, uptake of (14)C-activity into the microbial biomass and microbial numbers (CFUs g(-1) soil) were investigated. In control soils and soils amended with 0.01% sheep dip, after 7d a larger proportion of added glucose was allocated to microbial biomass rather than respired to CO(2). No clear temporal trends were found in soils amended with 0.1% and 1% sheep dips. Both sheep dip formulations at 0.1% and 1% concentrations resulted in a significant increase in CFUs g(-1) soil and [1-(14)C] glucose mineralisation rates, as well as a decline in microbial uptake of [1-(14)C] glucose, compared to control and 0.01% SP- or OP-amended soils. This study suggests that the growth, activity, physiological status and/or structure of soil microbial community may be affected by sheep dips.

Chronic aquatic environmental risks from exposure to human pharmaceuticals.

This paper reviews current information on the chronic aquatic toxicity of human pharmaceuticals and how it should be measured. Chronic toxicity tests with Cyanobacteria are likely to be sensitive surrogates for both algae and other unicellular organisms, although possibly not for higher plants. In contrast, there is little evidence of a general need to perform chronic aquatic invertebrate tests for all human pharmaceuticals, although further acute-to-chronic ratio data are required for the main therapeutic classes and modes of action of pharmaceuticals before this issue can be fully resolved. Chronic fish tests may be necessary for some substances, but it is likely that these can be focused more accurately through use of information in mammalian toxicity datasets. For some substances and modes of action, life-cycle or partial life-cycle fish tests may be more relevant than reliance on early life-stage (ELS) tests, because the ELS test is unlikely to respond adequately to all pharmaceutical modes of action. Biomarkers may be useful in focusing research and testing efforts by identifying active substances and receptors of interest in aquatic species, and they may also be useful in field surveys for helping to establish possible cause and effect relationships. QSARs have been used by several authors to predict acute toxic effects, but predictions of chronic effects are currently hampered by the paucity of available chronic data to build predictive models. There seems to be no obvious reason why mixtures of pharmaceuticals in the environment should be treated in a different way to mixtures of other potentially hazardous substances. If mixture toxicity is considered to be an important environmental issue then all substances should be considered within an appropriate risk assessment framework.

Influence of plants on the chemical extractability and biodegradability of 2,4-dichlorophenol in soil.

This study investigated the fate and behaviour of [UL-(14)C] 2,4-dichlorophenol (DCP) in planted (Lolium perenne L.) and unplanted soils over 57 days. Extractability of [UL-(14)C] 2,4-DCP associated activity was measured using calcium chloride (CaCl(2)), acetonitrile-water and dichloromethane (DCM) extractions. Biodegradability of [UL-(14)C] 2,4-DCP associated activity was assessed through measurement of (14)CO(2) production by a degrader inoculum (Burkholderia sp.). Although extractability and mineralisation of [UL-(14)C] 2,4-DCP associated activity decreased significantly in both planted and unplanted soils, plants appeared to enhance the sequestration process. After 57 days, in unplanted soil, 27% of the remaining [UL-(14)C] 2,4-DCP associated activity was mineralised by Burkholderia sp., and 13%, 48%, and 38% of (14)C-activity were extracted by CaCl(2), acetonitrile-water and DCM, respectively. However, after 57 days, in planted soils, only 10% of the [UL-(14)C] 2,4-DCP associated activity was available for mineralisation, whilst extractability was reduced to 2% by CaCl(2), 17% by acetonitrile-water and 11% by DCM. This may be due to the effect of plants on soil moisture conditions, which leads to modification of the soil structure and trapping of the compound. However, the influence of plants on soil biological and chemical properties may also play a role in the ageing process.

Effects of organophosphate and synthetic pyrethroid sheep dip formulations on protozoan survival and bacterial survival and growth.

Sheep dipping with organophosphate or synthetic pyrethroid-based formulations is still widely used by farmers in the UK to control ectoparasites and results in 175-220 million litres of spent sheep dip produced each year. Spent sheep dip may be diluted in animal slurry or water prior to disposal onto land. However, the effects of this practice on the microbial ecology of animal slurries, soil and aquatic systems are still relatively unknown. This paper investigated the effect of Bayticol (synthetic pyrethroid sheep dip) and Ectomort (organophosphate sheep dip) concentrations on (i) the survival of 15 protozoan species, (ii) the recovery of the four species of amoebae, and (iii) bacterial survival and growth. This investigation found that overall Bayticol was less toxic to protozoa than Ectomort, with minimum inhibitory concentrations ranging from 0.01 to 0.03% (v/v) and 0.005 to 0.06% (v/v), respectively. Amoebic cysts remained viable and emerged from dormancy, thereby pointing to the potential for recovery of protozoan communities in contaminated environments. The presence of sheep dips did not affect bacterial survival and growth on agar; however, the five test bacteria were not able to utilise the sheep dips as sole carbon sources. These findings have implications for the contamination of animal slurries, soil and aquatic systems, in that there is the potential for significant increases in microbial numbers, containing putative pathogens due to the diminution of bacteriophagous protozoan populations.