Patients with myelodysplastic syndrome (MDS) receiving hypomethylating agents commonly develop thrombocytopenia. This double-blind study evaluated the efficacy and safety of romiplostim, a peptibody protein that increases platelets, in patients with MDS receiving decitabine. Patients received romiplostim 750 μg (n = 15) or placebo (n = 14) and decitabine. Median platelet counts at the beginning of each decitabine cycle trended lower in placebo-treated than in romiplostim-treated patients. Bleeding events occurred in 43% of placebo-treated and 27% of romiplostim-treated patients, and platelet transfusions were administered to 57% of placebo-treated and 47% of romiplostim-treated patients. Overall clinical therapeutic response was achieved by 21% of placebo-treated and 33% of romiplostim-treated patients. Treatment was generally well tolerated. Progression to acute myeloid leukemia (AML) occurred in one patient per group. Adding romiplostim to decitabine treatment is well tolerated and may be beneficial, as indicated by trends toward higher platelet counts at the beginning of each treatment cycle and lower platelet transfusion rates and percentages of patients with bleeding events.

Arsenic is a ubiquitous element in the environment and has been classified as a human carcinogen primarily based on epidemiological evidence. It has been estimated there are over 100 million people globally being exposed to elevated arsenic from both natural and anthropogenic sources. Surprisingly, positive carcinogenicity animal studies were lacking until recent years. We aim to validate inorganic arsenate carcinogenic effect in C57Bl/6J mice, and establish the dose-response relationship using environmental concentrations of arsenic similar to those found in typical endemic-areas. Mice were given 0, 100, 250 or 500 μg As/L in the form of sodium arsenate in drinking water ad libitum over 2 years. Tumours occurred after about 18 months of arsenic exposure otherwise the animals appeared to be normal in their appearance and behaviour. Incidences of all types of tumours and non-tumourous lesions in the treated groups were higher than those observed in the control group. The induction of tumours was in a dose-response manner for some tumour types. Enlargement of the mesenteric lymph node due to hyperplasia or neoplasia of lymphoid elements was commonly observed. Apart from abdominal cavity lymph nodes, tumours were frequently observed in the liver, spleen and intestinal wall, and to a lesser extent in the lung with various other tissues also occasionally affected. Of the non-tumourous lesions, haemorrhagic ovarian cysts occurred more frequently in the treated groups than in the control group. Our results suggest that the C57Bl/6J mouse model can be a useful adjunct for further mechanistic studies of arsenic carcinogenesis. This bioassay data may also be considered for the risk evaluation of chronic exposure to inorganic arsenic.

Abstract 1769 Poster Board I-795 Introduction MDS patients receiving hypomethylating agents commonly develop clinically significant thrombocytopenia, for which platelet transfusions are often the only treatment. Romiplostim is a peptibody protein that increases platelet production by a mechanism similar to thrombopoietin. This report describes a phase 2, multicenter, randomized, double-blind, placebo-controlled study of romiplostim in combination with hypomethylating agents in patients with MDS. Results from patients receiving azacitidine have previously been reported (Kantarjian et al, ASH 2008, #224); we report results from the combination of romiplostim with decitabine. Methods Eligible patients had low, intermediate-1, or intermediate-2 risk MDS per IPSS. Patients were randomized (1:1) to receive placebo or 750μg romiplostim by weekly subcutaneous injection and were stratified by baseline platelet count (≥ or Results Twenty-nine patients were randomized and treated. Nine of 14 (64%) placebo-treated and 10/15 (67%) romiplostim-treated patients completed 4 cycles of decitabine. Baseline characteristics were generally well balanced between the 2 groups, except that more patients in the placebo group had an IPSS score >1 (8/14, 57%) than those in the romiplostim group (5/15, 33%). The primary endpoint was reached in 11/14 (79%) placebo patients and 12/15 (80%) romiplostim patients: After the first cycle, median platelet counts at the beginning of each decitabine cycle were lower in placebo-treated than in romiplostim-treated patients (Table). Platelet transfusions were administered to 57% of placebo patients and 47% of romiplostim patients. The overall incidence of bleeding events was higher in the placebo group (43%) than the romiplostim group (27%). An MDS treatment response (complete or partial response) was achieved by 5/14 (36%) placebo patients and 7/15 (47%) romiplostim patients. All patients experienced at least 1 adverse event. Serious adverse events occurred in 57% of placebo- and 53% of romiplostim-treated patients. One patient in the romiplostim group experienced a treatment-related serious adverse event (pulmonary artery thrombosis leading to study withdrawal). Bone marrow blasts were increased in 2 patients, both from the placebo group. Disease progression to AML (23% bone marrow blasts and 21% peripheral blasts) occurred in one patient from each treatment group. Four patients died: 2 in the placebo group (neutropenic sepsis and intracranial hemorrhage) and 2 in the romiplostim group (sepsis and acute cholecystitis). None of the deaths were considered investigational product-related. Conclusions Romiplostim in combination with decitabine appeared to be well tolerated in lower-risk MDS patients. A clinical benefit of adding romiplostim to decitabine treatment was indicated by numerically increased platelet counts at the beginning of each treatment cycle, decreased platelet transfusion rates and decreased bleeding events in romiplostim-treated patients compared with the placebo group. Conclusions are limited by the small sample size of this exploratory phase 2 study, and further investigation of the safety and efficacy of romiplostim in treatment-related thrombocytopenia in MDS is warranted. Disclosures Greenberg:Novartis: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Amgen: Consultancy, Research Funding. Off Label Use: Use of romiplostim, a thrombopoietin mimetic, to treat Thrombocytopenia in MDS. Damon:Celgene: Speakers Bureau; Genentech: Equity Ownership; Eisai: Speakers Bureau. Wei:Amgen Inc.: Employment, Equity Ownership. Kantarjian:Amgen Inc.: Research Funding. Franklin:Amgen Inc.: Employment, Equity Ownership.

The effects of residues from municipal solid waste landfill, Khon Kaen Municipality, Thailand, on corn (Zea mays L.) yield and heavy metal content were studied. Field experiments with randomized complete block design with five treatments (0, 20, 40, 60 and 80% v/v of residues and soil) and four replications were carried out. Corn yield and heavy metal contents in corn grain were analyzed. Corn yield increased by 50, 72, 85 and 71% at 20, 40, 60 and 80% treatments as compared to the control, respectively. All heavy metals content, except cadmium, nickel and zinc, in corn grain were not significantly different from the control. Arsenic, cadmium and zinc in corn grain were strongly positively correlated with concentrations in soil. The heavy metal content in corn grain was within regulated limits for human consumption.

There is very little information on the overall level of estrogenic activity, or concentrations of specific hormonal compounds in wastewater treatment plant (WWTP) discharges in Australia, compared with Europe, Japan, and North America. To partly address this, in 2004, water samples were collected as "grab" or "spot" samples from 12 WWTP facilities across southern Victoria at the point at which effluent enters the environment, either as recycled water or direct discharge to the receiving water. The WWTPs were of a variety of treatment types and served a diverse range of rural and regional municipalities. For instance, of the 12 WWTPs, 3 served municipalities with populations greater than 100,000, 4 with populations between 20,000 and 100,000, and 5 with populations less than 5,000. The principal treatment process in six was an activated sludge system, and three were trickle-filter-based systems. The remaining plants fall into a "miscellaneous" category, each plant having a mixture of treatment processes within the overall systems. The estrogenic activity and 17beta-estradiol concentrations of the samples were assessed using a yeast-based, in vitro reporter gene assay and enzyme-linked immunosorbant assays, respectively. Most of the effluents showed estrogenic activity in the assays (hER, no response: 7.9 ng/L EEQ; mER, no response: 44.5 ng/L EEQ). There was no correlation between estrogenic response and the results of a concurrent toxicity assay, suggesting that a lack of bioassay response was related to lack of estrogenic compounds, rather than the direct toxic effect of the sample. Estradiol concentrations were for the most part in the range 2-5 ng/L, with one sample at 18 ng/L. Despite the assurance our results might provide (of minimal impact in most cases if there is significant dilution), there is still a need for further extensive on-ground reassurance research to provide data for higher-level risk assessment by industry and government agencies. In particular, more research is warranted to verify the estrogenic activity and to expand the range of specific hormone/metabolites reported in these studies. Moreover, studies are required to determine if the estrogenic activity reported in this and other recent Australian studies is sufficient to induce a physiological effect in exposed aquatic organisms, especially Australian native fish.

Wildlife deaths associated with cyanide-bearing tailings dams are a significant environmental issue that has affected the gold mining industries for many years and still characterized by little knowledge about how to measure, monitoring, reduce or eliminate those deaths. The purpose of this paper is statistically to determine: the potential for establishing causal relations between exposure to cyanide (in its most common species relevant to tailings) and response (measured by death counts), to develop a protocol of data analysis, the understanding of the significance of data gaps, and the effect of likely risk management interventions to achieve the goals of the International Cyanide Management Code (ICMC); [ICMC The International Cyanide Management Institute. International cyanide management code, the international cyanide management institute 2005, www.cyanidecode.org.]. However, operator's certification under the ICMC is difficult because of the limited data and potentially serious underestimation of the death counts. This is due to observational skill and monitoring frequency, the small size of the carcasses, large extent of tailings facilities, carcasses loss by; entombment in tailings, sink, or taken by scavenging wildlife. This (1st order or bounding) assessment results focus on bird-deaths, which appear to be most frequent at sites where elevated cyanide concentrations are found. Those results indicate that the empirical causal associations we generate support the hypotheses that:Cyanide intake and bird-deaths is not linear, and that relationship is characterized by a threshold at approximately 50 mg weak-acid-dissociable cyanide (WADCN) per litre of tailings waste (50 mg/L); andThe counts of either wildlife deaths or visitations on tailings dams decrease as the surface area of the supernatant decreases.This paper also develops the basis for a complete risk assessment study to be based on additional data gathering activities and detailed statistical analyses. These two activities, combined with a risk management plan also being developed, will provide a tool for compliance with the ICMC. (C) 2007 Elsevier Ltd. All rights reserved.

We assess the status of present and future water supply, demand, and quality. Our results, for several sectors of the US economy are based on integrated data developed at the water resources region, and state levels from 1985 to 2000. Although we find that water quality is improving and that the overall supply of water is good, water shortages will principally affect some of the western water resource regions. Some other regions, associated with fast-growing metropolitan areas, are also vulnerable to water shortages. Those may occur earlier and in more area of the US than previously expected. Our conclusions take into account changes in the U.S. economy during the mid-eighties as well as the nineties, but do not account for such factors as regional-scale climate changes, shifts in low flow requirements and other legal changes that can be introduced by new environmental or energy legislation and regulations, and other events such as structural economic changes.

Landfill soils reclaimed from municipal solid waste landfill were characterized for agronomic properties and heavy metals. The samples were collected from Khon Kaen Municipality engineered landfill, Khon Kaen, Thailand, approximately aged 10-15 years, and screened with a 6.3-mm sieve. Chemical properties analysis was undertaken by appropriate procedure, and heavy metals were analyzed by inductively coupled plasma optical emission spectrometry (ICP-OES) and inductively coupled plasma mass spectrometry (ICP-MS). The landfill soil characteristics measured include pH, electrical conductivity (EC), cation exchange capacity (CEC), organic matter (OM), total N, available P, K, Mg and Ca; results obtained were 8.1, 4.2 dS/m, 4.4 cmol/kg, 4.9%, 0.27%, 23.2 mg/kg, 1.24 g/kg, 10.5 g/kg and 0.43 g/kg, respectively. The heavy metal contents in landfill soil included 2.0 As, 3.25 Cd, 3.3 Co, 38.0 Cr, 166.0 Cu, 1533.0 Fe, 0.72 Hg, 412 Mn, 22.0 Ni, 157.0 Pb, 1.0 Se, 44.0 Sn and 662 Zn mg/kg, respectively. These heavy metal concentrations were within permissible limits for land application described by Thailand and US EPA. This result indicated that municipal solid waste landfill had potential for recovery soil, and its use for soil amendment.

Wildlife deaths associated with cyanide-bearing mine waste solutions have plagued the gold mining industries for many years, yet there is little published data showing the relationship between wildlife mortality and cyanide toxicity. A gap of knowledge exists in monitoring, understanding the causal relationships and managing risks to wildlife from cyanide-bearing waste solutions and tailings. There is a need for the gold industry to address this issue and to meet the International Cyanide Management Code (ICMC) guidelines. The perceived extent of the issue varies, with one study finding the issue inadequately monitored and wildlife deaths grossly underestimated. In Nevada, USA during 1990 and 1991, 9512 carcasses were reported of over 100 species, although there was underestimation due to reporting being voluntary. Of these, birds comprised 80-91% of vertebrate carcasses reported annually. At Northparkes, Australia in 1995, it was initially estimated that 100 bird carcasses were present by mine staff following a tailings incident; when a thorough count was conducted, 1583 bird carcasses were recorded. Eventually, 2700 bird deaths were documented over a four-month period. It is identified that avian deaths are usually undetected and significantly underestimated, leading to a perception that a risk does not exist. Few guidelines and information are available to manage the risks of cyanide to wildlife, although detoxification, habitat modification and denying wildlife access have been used effectively. Hazing techniques have proven ineffective. Apparently no literature exists that documents accurate wildlife monitoring protocols on potentially toxic cyanide-bearing mine waste solutions or any understanding on the analysis of any derived dataset. This places the onus on mining operations to document that no risk to wildlife exists. Cyanide-bearing tailings storage facilities are environmental control structures to contain tailings, a standard practice in the mining industry. Cyanide concentrations below 50 mg/L weak-acid-dissociable (WAD) are deemed safe to wildlife but are considered an interim benchmark for discharge into tailings storage facilities (TSFs). Cyanide is a fast acting poison, and its toxicity is related to the types of cyanide complexes that are present. Cyanide in biota binds to iron, copper and sulfur-containing enzymes and proteins required for oxygen transportation to cells. The accurate determination of cyanide concentrations in the field is difficult to achieve due to sampling techniques and analytical error associated with loss and interferences following collection. The main WAD cyanide complexes in gold mine tailings are stable in the TSF environment but can release cyanide ions under varying environmental conditions including ingestion and absorption by wildlife. Therefore distinction between free, WAD and total cyanide forms in tailings water for regulatory purposes is justified. From an environmental perspective, there is a distinction between ore bodies on the basis of their copper content. For example, wildlife deaths are more likely to occur at mines possessing copper-gold ores due to the formation of copper-cyanide complexes which is toxic to birds and bats. The formation of copper-cyanide complex occurs preferentially to gold cyanide complex indicating the relative importance of economic vs. environmental considerations in the tailings water. Management of cyanide to a perceived threshold has inherent risks since cyanide has a steep toxicity response curve; is difficult to accurately measure in the field; and is likely to vary due to variable copper content of ore bodies and ore blending. Consequently, wildlife interaction needs to be limited to further reduce the risks. A gap in knowledge exists to design or manage cyanide-bearing mine waste solutions to render such facilities unattractive to at-risk wildlife species. This gap may be overcome by understanding the wildlife behaviour and habitat usage of cyanide-bearing solutions.