Evaluation and assessment of the efficacy of an abatement strategy in a former lead smelter community, Boolaroo, Australia.

This study examines the recent soil Lead Abatement Strategy (LAS) in Boolaroo, New South Wales, Australia, that was designed to "achieve a reduction in human exposure to lead dust contamination in surface soils". The abatement programme addressed legacy contamination of residential areas following closure of lead smelting operations in 2003 at the Pasminco Cockle Creek Smelter (PCCS). The principal objective of the LAS was to "cap and cover" lead-contaminated soils within the urban environment surrounding the PCCS. Soil lead concentrations of 2500-5000 mg/kg were scheduled for removal and replacement, while concentrations between 1500 and 2500 mg/kg were replaced only under limited circumstances. To date, there has been no industry, government or independent assessment of the clean-up programme that involved >2000 homes in the township of Boolaroo. Thus, by measuring post-abatement soil lead concentrations in Boolaroo, this study addresses this knowledge gap and evaluates the effectiveness of the LAS for reducing the potential for lead exposure. Soil lead concentrations above the Australian residential soil health investigation level value for residential soils (300 mg/kg) were identified at all but one of the residential properties examined (n = 19). Vacuum dust samples (n = 17) from the same homes had a mean lead concentration of 495 mg/kg (median 380 mg/kg). Bio-accessibility testing revealed that lead in household vacuum dust was readily accessible (% bio-accessible) (mean = 92 %, median = 90 %), demonstrating that the risk of exposure via this pathway remains. Assessment of a limited number of properties (n = 8) where pre-abatement soil lead levels were available for comparison showed they were not statistically different to post-abatement. Although the LAS did not include treatment of non-residential properties, sampling of community areas including public sports fields, playgrounds and schools (n = 32) was undertaken to determine the contamination legacy in these areas. Elevated mean soil lead concentrations were found across public lands: sports fields = 5130 mg/kg (median = 1275 mg/kg), playgrounds and schools = 812 mg/kg (median = 920 mg/kg) and open space = 778 mg/kg (median = 620 mg/kg). Overall, the study results show that the LAS programme that was dominated by a "cap and cover" approach to address widespread lead contamination was inadequate for mitigating current and future risk of lead exposures.

Geochemical sources, forms and phases of soil contamination in an industrial city.

This study examines current soil contamination in an Australian industrial city, Newcastle. Public (roadside verges and parks) and private (homes) surface soils (n=170) contained metal(loid)s elevated above their respective Australian Health Investigation Levels (HIL). Lead (Pb), the most common contaminant in the city, exceeds the HIL for residential soils (HIL-A, 300mg/kg) in 88% of private soils (median: 1140mg/kg). In-vitro Pb bio-accessibility analysis of selected soils (n=11) using simulated gastric fluid showed a high affinity for Pb solubilisation (maximum Pb concentration: 5190mg/kg, equating to 45% Pb bio-accessibility). Highly soluble Pb-laden Fe- and Mn-oxides likely contribute to the bio-accessibility of the Pb. Public and private space surface soils contain substantially less radiogenic Pb (range: 208Pb/207Pb: 2.345-2.411, 206Pb/207Pb: 1.068-1.312) than local background soil (208Pb/207Pb: 2.489, 206Pb/207Pb: 1.198), indicating anthropogenic contamination from the less radiogenic Broken Hill type Pb ores (208Pb/207Pb: 2.319, 206Pb/207Pb: 1.044). Source apportionment using Pb isotopic ratio quantification and soil mineralogy indicate the city's historic copper and steel industries contributed the majority of the soil contaminants through atmospheric deposition and use of slag waste as fill material. High-temperature silicates and oxides combined with rounded particles in the soil are characteristic of smelter dust emissions. Additionally, a preliminary investigation of polycyclic aromatic hydrocarbons in soils, sometimes associated with ferrous metal smelting, coal processing or burning of fossil fuels, shows that these too pose a health exposure risk (calculated in comparison to benzo(a)pyrene: n=12, max: 13.5mg/kg, HIL: 3mg/kg).

Experimental antitumour activity of S 16020-2 in a panel of human tumours.

The antitumour activity of S 16020-2, a new topoisomerase II inhibitor, was evaluated in comparison with doxorubicin against 13 human tumours, including colon (HT-29, Colo320DM), breast (MCF7, MDAMB-231), ovary (SK-OV-3, A2780, NIH:OVCAR-3), non-small cell lung (NCI-H460, A549, Calu-6, NCI-H125) and small-cell lung (NCI-H69, SCLC6) cancers. S 16020-2 was administered weekly intravenous within a dose range of 20-90 mg/kg for 3 weeks. Antitumour responses were obtained in all the tumour types tested except in the two colon cancers. S 16020-2 produced significant growth delays in nine tumour models and induced regressions of all A549 lung tumours. The antitumour activity of S 16020-2 was superior to that of doxorubicin against the NCI-H460, A549, NCI-H69, SCLC6 and NIH:OVCAR-3 xenografts. These results demonstrate the broad spectrum of antitumour activity of S 16020-2 in a large panel of in vivo experimental models and confirm its interest as a potential agent in the treatment of malignant disease.

In vivo antitumor activity of S 16020-2, a new olivacine derivative.

The antitumor activity of S 16020-2, a new olivacine derivative, was investigated in vivo and compared with that of Adriamycin and elliptinium acetate in a panel of murine (P388 leukemia, M5076 sarcoma, Lewis lung carcinoma, and B16 melanoma) and human (NCI-H460 non-small-cell lung and MCF7 breast carcinomas) tumor models. S 16020-2 given i.v. was active against P388 leukemia implanted i.p., s.c., or intracerebrally. The therapeutic effect of an intermittent schedule (administration on days 1, 5, 9) was superior to that of single-dose treatment, allowing the i.v. administration of high total doses of S 16020-2 and resulting in the cure of 60% of mice in the i.p. P388 model. In this model, S 16020-2 was more active than elliptinium acetate and showed a better therapeutic index than Adriamycin: > or = 8 versus 2. A good therapeutic effect of S 16020-2 was also observed in three P388 leukemia sublines displaying the classic multidrug-resistance phenotype, namely, P388/VCR, P388/VCR-20, and P388/MDRC.04, the latter being totally insensitive to vincristine and Adriamycin. However, S 16020-2 was not active against the P388/ADR leukemia, a model highly resistant to adriamycin in vivo. S 16020-2 was both more active than Adriamycin and curative in the M5076 sarcoma and Lewis lung carcinoma implanted s.c. In the B16 melanoma implanted i.p. or s.c., S 16020-2 was less active than Adriamycin. Against the NCI-H460 human tumor xenograft, S 16020-2 demonstrated activity superior to that of Adriamycin (T/C = 20% versus 43% on day 21). Against the MCF7 breast cancer xenograft, S 16020-2 was active, but less so than Adriamycin (T/C = 23% versus 9% on day 21), whereas elliptinium acetate was marginally active (T/C = 49% on day 24). The hematological toxicity of S 16020-2 given to B6D2F1 mice at pharmacological dose appeared to be less severe than that of Adriamycin, particularly in bone-marrow stem cells. These results demonstrate that S 16020-2 is a highly active antitumor drug in various experimental tumor models and is markedly more efficient than elliptinium acetate. Because of its pharmacological profile, which is globally different from that of Adriamycin, S 16020-2 is considered an interesting candidate for clinical trials.

Studies of the potency of protein kinase inhibitors on ATPase activities.

Tyrosine as well as serine/threonine protein kinase inhibitors have potentially two sites of interaction with their targets: the protein-substrate binding site and the ATP binding site. The latter could be modelized by measuring the capacity of protein kinase inhibitors to inhibit ATPase activities. In order to do so, we assess a novel, highly sensitive HPLC method based on hydrophilic separation of [gamma-32P]ATP and [32P]Pi. The novel assay is presented. Furthermore, the potency of 13 protein kinase inhibitors was tested on two types of ATPase, namely: apyrase and partially purified liver mitochondria F1-ATPase. The method described for the assay of ATPase can be used with almost any type of enzyme catalyzing this activity. Only cibacron blue and suramin show interesting capacities in inhibiting these ATPase activities pointing out that several widely used protein kinase inhibitors are at least somewhat specific in that they do not inhibit these two ATPases.

Antitumor activity of S 16020-2 in two orthotopic models of lung cancer.

S 16020-2, a new olivacine derivative selected on the basis of its cytotoxicity in vitro and antitumor activity in vivo, was evaluated against the human A549 and the murine Lewis lung tumor models implanted s.c. and i.v. Against Lewis lung carcinoma implanted s.c., S 16020-2 was found to be curative, with an activity and therapeutic index (Ti = 4) similar to that of cyclophosphamide. S 16020-2 administered weekly demonstrated a high therapeutic efficacy against A549 non-small cell lung carcinoma implanted s.c. in nude mice and induced tumor regression at 80 mg/kg. When A549 tumor cells were injected i.v. in SCID mice, experimental metastases rapidly developed and the progressive invasion of the lung tissue by tumor preceded the death of animals. In this model, S 16020-2 administered at 40 mg/kg i.v. following an early (days 8, 18 and 28) or delayed (days 20, 30 and 40) treatment schedule prolonged the survival of tumor-bearing mice with T/C values of 150 and 145%, respectively. Against the i.v. Lewis lung carcinoma, S 16020-2 was also highly active since when administered at 60 mg/kg on days 5, 9 and 13 it totally inhibited tumor growth and cured up to 89% of mice. When administered on days 11, 15 and 19 to animals with established tumors, S 16020-2 was still active but not curative. In the presented studies, S 16020-2 antitumor activity was superior to that of adriamycin and comparable or superior to cyclophosphamide (used as reference compounds). Our results demonstrate the efficacy of S 16020-2 against these highly aggressive and chemoresistant tumor models.