Ecological indicators for abandoned mines, Phase 1: Review of the literature

Mine waters have been identified as a significant issue in the majority of Environment Agency draft River Basin Management Plans. They are one of the largest drivers for chemical pollution in the draft Impact Assessment for the Water Framework Directive (WFD), with significant failures of environmental quality standards (EQS) for metals (particularly Cd, Pb, Zn, Cu, Fe) in many rivers linked to abandoned mines. Existing EQS may be overprotective of aquatic life which may have adapted over centuries of exposure. This study forms part of a larger project to investigate the ecological impact of metals in rivers, to develop water quality targets (alternative objectives for the WFD) for aquatic ecosystems impacted by long-term mining pollution. The report reviews literature on EQS failures, metal effects on aquatic biota and effects of water chemistry, and uses this information to consider further work. A preliminary assessment of water quality and biology data for 87 sites across Gwynedd and Ceredigion (Wales) shows that existing Environment Agency water quality and biology data could be used to establish statistical relations between chemical variables and metrics of ecological quality. Visual representation and preliminary statistical analyses show that invertebrate diversity declines with increasing zinc concentration. However, the situation is more complex because the effects of other metals are not readily apparent. Furthermore, pH and aluminium also affect streamwater invertebrates, making it difficult to tease out toxicity due to individual mine-derived metals. The most characteristic feature of the plant communities of metal-impacted systems is a reduction in diversity, compared to that found in comparable unimpacted streams. Some species thrive in the presence of heavy metals, presumably because they are able to develop metal tolerance, whilst others consistently disappear. Effects are, however, confounded by water chemistry, particularly pH. Tolerant species are spread across a number of divisions of photosynthetic organisms, though green algae, diatoms and blue-green algae are usually most abundant, often thriving in the absence of competition and/or grazing. Current UK monitoring techniques focus on community composition and, whilst these provide a sampling and analytical framework for studies of metal impacts, the metrics are not sensitive to these impacts. There is scope for developing new metrics, based on community-level analyses and for looking at morphological variations common in some taxa at elevated metal concentrations. On the whole, community-based metrics are recommended, as these are easier to relate to ecological status definitions. With respect to invertebrates and fish, metals affect individuals, population and communities but sensitivity varies among species, life stages, sexes, trophic groups and with body condition. Acclimation or adaptation may cause varying sensitivity even within species. Ecosystem-scale effects, for example on ecological function, are poorly understood. Effects vary between metals such as cadmium, copper, lead, chromium, zinc and nickel in order of decreasing toxicity. Aluminium is important in acidified headwaters. Biological effects depend on speciation, toxicity, availability, mixtures, complexation and exposure conditions, for example discharge (flow). Current water quality monitoring is unlikely to detect short-term episodic increases in metal concentrations or evaluate the bioavailability of elevated metal concentrations in sediments. These factors create uncertainty in detecting ecological impairment in metal-impacted ecosystems. Moreover, most widely used biological indicators for UK freshwaters were developed for other pressures and none distinguishes metal impacts from other causes of impairment. Key ecological needs for better regulation and management of metals in rivers include: i) models relating metal data to ecological data that better represent influences on metal toxicity; ii) biodiagnostic indices to reflect metal effects; iii) better methods to identify metal acclimation or adaptation among sensitive taxa; iv) better investigative procedures to isolate metal effects from other pressures. Laboratory data on the effects of water chemistry on cationic metal toxicity and bioaccumulation show that a number of chemical parameters, particularly pH, dissolved organic carbon (DOC) and major cations (Na, Mg, K, Ca) exert a major influence on the toxicity and/or bioaccumulation of cationic metals. The biotic ligand model (BLM) provides a conceptual framework for understanding these water chemistry effects as a combination of the influence of chemical speciation, and metal uptake by organisms in competition with H+ and other cations. In some cases where the BLM cannot describe effects, empirical bioavailable models have been successfully used. Laboratory data on the effects of metal mixtures across different water chemistries are sparse, with implications for transferring understanding to mining-impacted sites in the field where mixture effects are likely. The available field data, although relatively sparse, indicate that water chemistry influences metal effects on aquatic ecosystems. This occurs through complexation reactions, notably involving dissolved organic matter and metals such as Al, Cu and Pb. Secondly, because bioaccumulation and toxicity are partly governed by complexation reactions, competition effects among metals, and between metals and H+, give rise to dependences upon water chemistry. There is evidence that combinations of metals are active in the field; the main study conducted so far demonstrated the combined effects of Al and Zn, and suggested, less certainly, that Cu and H+ can also contribute. Chemical speciation is essential to interpret and predict observed effects in the field. Speciation results need to be combined with a model that relates free ion concentrations to toxic effect. Understanding the toxic effects of heavy metals derived from abandoned mines requires the simultaneous consideration of the acidity-related components Al and H+. There are a number of reasons why organisms in waters affected by abandoned mines may experience different levels of metal toxicity than in the laboratory. This could lead to discrepancies between actual field behaviour and that predicted by EQS derived from laboratory experiments, as would be applied within the WFD. The main factors to consider are adaptation/acclimation, water chemistry, and the effects of combinations of metals. Secondary effects are metals in food, metals supplied by sediments, and variability in stream flows. Two of the most prominent factors, namely adaptation/ acclimation and bioavailability, could justify changes in EQS or the adoption of an alternative measure of toxic effects in the field. Given that abandoned mines are widespread in England and Wales, and the high cost of their remediation to meet proposed WFD EQS criteria, further research into the question is clearly justified. Although ecological communities of mine-affected streamwaters might be over-protected by proposed WFD EQS, there are some conditions under which metals emanating from abandoned mines definitely exert toxic effects on biota. The main issue is therefore the reliable identification of chemical conditions that are unacceptable and comparison of those conditions with those predicted by WFD EQS. If significant differences can convincingly be demonstrated, the argument could be made for alternative standards for waters affected by abandoned mines. Therefore in our view, the immediate research priority is to improve the quantification of metal effects under field circumstances. Demonstration of dose-response relationships, based on metal mixtures and their chemical speciation, and the use of better biological tools to detect and diagnose community-level impairment, would provide the necessary scientific information

A phase II study of continuous-infusion 5-fluorouracil with cisplatin and epirubicin in inoperable pancreatic cancer.

Carcinomas of the exocrine pancreas respond poorly to most chemotherapy regimens. Recently continuous infusional 5-fluorouracil (200 mg m-(2)day-1) with 3 weekly cisplatin (60 mg m-2) and epirubicin (50 mg m-2) (the ECF regimen) has proven to be an active regimen in gastric and breast cancer and consequently worthy of further study in pancreatic cancer. Thirty-five patients were treated with the ECF regimen as above, of whom 29 were evaluable for response and 32 were evaluable for toxicity. The mean age was 59 years (range 37-75). Sixteen patients had locally advanced disease at presentation and 19 had metastases. Objective tumour responses were documented in five (17.3%) patients who achieved a partial response; in 18 (62%) patients there were no change and six (20.7%) patients progressed on therapy. Patients with either stable disease or partial response had a significantly improved overall survival (median = 253 days) compared with patients who progressed (median = 170 days; P = 0.01). Grade 3/4 (WHO) toxicity (all cycles) included alopecia in 18 (56%) patients, nausea/vomiting in eight (25%) stomatitis in three (9%) and diarrhoea in seven (22%) patients, with rhinorrhoea and excessive lacrimation in one patient each. Neutropenic sepsis occurred in 13 cycles in ten patients, and there was one toxic death due to sepsis. There were eight other episodes of non-neutropenic sepsis requiring hospital admission. Fourteen patients (40%) experienced complications with their Hickman lines, including thrombotic episodes (six patients) or their line falling out (five patients). ECF can prolong survival in patients with locally advanced or metastatic pancreatic cancer who demonstrate a response or stabilisation of their disease. However, this is associated with considerable toxicity

A phase II study of the vitamin D analogue Seocalcitol in patients with inoperable hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a common malignant tumour, which has a poor prognosis. Surgical resection can be curative but most patients are inoperable and most chemotherapy agents have minimal activity in this disease. Seocalcitol, a vitamin D analogue, induces differentiation and inhibits growth in cancer cell lines and in vivo. The vitamin D receptor is expressed in hepatocytes and more abundantly in HCC cells. In total, 56 patients with inoperable advanced HCC were included in an uncontrolled study of oral Seocalcitol treatment for up to 1 year ( with possible extension for responders). The dose was titrated according to serum calcium levels. The treatment effect was evaluated by regular CT scans. Out of 33 patients evaluable for tumour response, two had complete response (CR), 12 stable disease and 19 progressive disease. The CRs appeared after 6 and 24 months of treatment, and lasted for 29 and at least 36 months ( patient still in remission when data censored). Seocalcitol was well tolerated; the most frequent toxicity was hypercalcaemia and related symptoms. Most patients tolerated a daily dose of 10 mug of Seocalcitol. This is the first study showing activity, by reduction in tumour dimensions, of a differentiating agent in patients with an advanced bulky, solid tumour. Seocalcitol may have an effect in the treatment of HCC, especially in early disease when a prolonged treatment can be instituted. The survival benefit with or without tumour response should be determined in controlled studies

Twelve weeks of protracted venous infusion of fluorouracil (5-FU) is as effective as 6 months of bolus 5-FU and folinic acid as adjuvant treatment in colorectal cancer.

We performed a multicentre randomised trial to compare the efficacy and toxicity of 12 weeks of 5-fluorouracil (5-FU) delivered by protracted intravenous infusion (PVI 5-FU) against the standard bolus regimen of 5-FU and folinic acid (5-FU/FA) given for 6 months as adjuvant treatment in colorectal cancer. A total of 716 patients with curatively resected Dukes' B or C colorectal cancer were randomised to 5-FU/FA (5-FU 425 mg m(-2) i.v. and FA 20 mg m(-2) i.v. bolus days 1-5 every 28 days for 6 months) or to PVI 5-FU alone (300 mg m(-2) day for 12 weeks). With a median follow-up of 19.8 months, 133 relapses and 77 deaths have been observed. Overall survival did not differ significantly (log rank P=0.764) between patients receiving 5-FU/FA and PVI 5-FU (3-year survival 83.2 vs 87.9%, respectively). Patients in the 5-FU/FA group had significantly worse relapse-free survival (RFS, log rank P=0.023) compared to those receiving PVI 5-FU (3-year RFS, 68.6 vs 80%, respectively). Grades 3-4 neutropenia, diarrhoea, stomatitis and severe alopecia were significantly less (P<0.0001) and global quality of life scores significantly better (P&<0.001) for patients in the PVI 5-FU treatment arm. In conclusion, infused 5-FU given over 12 weeks resulted in similar survival to bolus 5-FU and FA over a 6 month period, but with significantly less toxicity

A prospective study of chemotherapy-induced febrile neutropenia in the South West London Cancer Network. Interpretation of study results in light of NCAG/NCEPOD findings

BACKGROUND: Chemotherapy-induced febrile neutropenia is a medical emergency complicating the treatment of many cancer patients. It is associated with considerable morbidity and mortality, as well as impacting on healthcare resources. METHODS: A prospective study of all cases of chemotherapy-induced febrile neutropenia in the South West London Cancer Network was conducted over a 4-month period. Factors including demographics, treatment history, management of febrile neutropenia and outcome were recorded. RESULTS AND CONCLUSION: Our results reflect those of the recent National Chemotherapy Advisory Group (NCEPOD, 2008)/National Confidential Enquiry into Patient Outcomes and Death reports (NCAG, 2009) and highlight the need for network-wide c inical care pathways to improve outcomes in this area, British Journal of Cancer (2011) 104, 407-412. doi:10.1038/sj.bjc.6606059 www.bjcancer.com Published online 21 December 2010 (C) 2011 Cancer Research U

A phase II trial of the vitamin D analogue Seocalcitol (EB1089) in patients with inoperable pancreatic cancer

Inoperable cancer of the exocrine pancreas responds poorly to most conventional anti-cancer agents, and new agents are required to palliate this disease. Seocalcitol (EB1089), a vitamin D analogue, can inhibit growth, induce differentiation and induce apoptosis of cancer cell lines in vitro and can also inhibit growth of pancreatic cancer xenografts in vivo. Thirty-six patients with advanced pancreatic cancer received once daily oral treatment with seocalcitol with dose escalation every 2 weeks until hypercalcaemia occurred, following which patients continued with maintenance therapy. The most frequent toxicity was the anticipated dose-dependent hypercalcaemia, with most patients tolerating a dose of 10–15 μg per day in chronic administration. Fourteen patients completed at least 8 weeks of treatment and were evaluable for efficacy, whereas 22 patients were withdrawn prior to completing 8 weeks' treatment and in 20 of these patients withdrawal was due to clinical deterioration as a result of disease progression. No objective responses were observed, with five of 14 patients having stable disease in whom the duration of stable disease was 82–532 days (median=168 days). The time to treatment failure (n=36) ranged from 22 to 847 days, and with a median survival of approximately 100 days. Seocalcitol is well tolerated in pancreatic cancer but has no objective anti-tumour activity in advanced disease. Further studies are necessary to determine if this agent has any cytostatic activity in this malignancy in minimal disease states

Comparative Toxicity of Nanoparticulate CuO and ZnO to Soil Bacterial Communities

The increasing industrial application of metal oxide Engineered Nano-Particles (ENPs) is likely to increase their environmental release to soils. While the potential of metal oxide ENPs as environmental toxicants has been shown, lack of suitable control treatments have compromised the power of many previous assessments. We evaluated the ecotoxicity of ENP (nano) forms of Zn and Cu oxides in two different soils by measuring their ability to inhibit bacterial growth. We could show a direct acute toxicity of nano-CuO acting on soil bacteria while the macroparticulate (bulk) form of CuO was not toxic. In comparison, CuSO4 was more toxic than either oxide form. Unlike Cu, all forms of Zn were toxic to soil bacteria, and the bulk-ZnO was more toxic than the nano-ZnO. The ZnSO4 addition was not consistently more toxic than the oxide forms. Consistently, we found a tight link between the dissolved concentration of metal in solution and the inhibition of bacterial growth. The inconsistent toxicological response between soils could be explained by different resulting concentrations of metals in soil solution. Our findings suggested that the principal mechanism of toxicity was dissolution of metal oxides and sulphates into a metal ion form known to be highly toxic to bacteria, and not a direct effect of nano-sized particles acting on bacteria. We propose that integrated efforts toward directly assessing bioavailable metal concentrations are more valuable than spending resources to reassess ecotoxicology of ENPs separately from general metal toxicity

A phase II study of mitomycin C, cisplatin and continuous infusion 5-fluorouracil (MCF) in the treatment of patients with carcinoma of unknown primary site

Carcinoma of unknown primary site remains a common clinical diagnosis, accounting for between 5 and 10% of all cancer patients. Numerous combination chemotherapy regimens have been used in the management of carcinoma of unknown primary site, resulting in response rates of 0–48%. We present the results of a single centre phase II study of the use of the combination of mitomycin C (7 mg m−2 on day 1 of cycles 1, 3 and 5) cisplatin (60 mg m−2 on day 1) and continuous infusion 5-fluorouracil (300 mg m−2 daily), MCF, delivered as a 21-day cycle, in patients with carcinoma of unknown primary site. Thirty-one patients with a diagnosis of carcinoma of unknown primary site were treated in Aberdeen Royal Infirmary between 1997 and 2001 with MCF. In total, 136 cycles of MCF were delivered (median of 5 cycles per patient). Toxicity was acceptable, with 19% grade 3 or 4 neutropenia, 16% grade 3 or 4 thrombocytopenia and 13% grade 3 or 4 nausea and vomiting. No cases of neutropenic sepsis were seen and there were no treatment-related deaths, however, six patients developed thrombotic complications. The overall response rate was 27% (CR 3%; PR 23%). Median time to progression was 3.4 months (95% CI 1.1–5.6 months) and median overall survival was 7.7 months (95% CI 5.7–9.8 months). Survival at 1 year was 28%, and at 2 years, 10%. MCF is a tolerable regimen with comparable toxicity, response rates and survival data to most platinum-based combination chemotherapy regimens in use for this devastating disease